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malformations. They require vascular imaging tests (eg, CTA, MRA, and/or conventional angiography). SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 24/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Classification Cerebrovascular disease is caused by one of several pathophysiologic processes ( table 1 and table 2) involving the blood vessels of the brain. (See 'Classification' above.) Initial evaluation Sudden loss of focal brain function is the core feature of the onset of ischemic stroke. However, patients with conditions other than stroke can present in a similar fashion ( table 3). The initial evaluation requires a rapid but broad assessment to stabilize vital signs, determine if intracranial hemorrhage is present, and decide if reperfusion therapy with intravenous thrombolysis ( table 4) or mechanical thrombectomy is warranted for patients with ischemic stroke. (See 'Initial general assessment' above and 'Is the patient a candidate for reperfusion?' above.) https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 25/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Determining the type of stroke After completing the initial assessment, the goal of the subsequent evaluation is to determine the underlying pathophysiology of the stroke based upon the history, physical examination, and initial neuroimaging findings ( table 1). Certain constellations of symptoms and signs can suggest a specific ischemic process ( table 5). (See 'Determining a presumptive diagnosis of stroke subtype' above.) Confirming the diagnosis Confirming the precise pathophysiologic process is aided by more directed diagnostic testing, including cardiac studies and neurovascular imaging. (See 'Confirming the diagnosis' above.) Cardiac monitoring Cardiac monitoring for at least the first 24 hours after the onset of ischemic stroke is useful to look for arrhythmias. For patients with a cryptogenic ischemic stroke or transient ischemic attack (TIA) and no evidence of atrial fibrillation on electrocardiogram (ECG) and 24-hour cardiac monitoring, we suggest ambulatory cardiac monitoring for several weeks. All patients with suspected embolic stroke should have an echocardiogram. (See 'Cardiac evaluation' above and 'Echocardiography' above.) Blood tests A number of blood tests are indicated in patients with brain ischemia, including a complete blood count, platelet count, prothrombin time and partial thromboplastin time, and serum lipids. However, indications to test for hypercoagulable disorders are limited. Furthermore, it remains unclear if the inherited thrombophilias directly predispose to arterial stroke as they do to venous thrombosis. (See 'Blood tests' above.) Evaluation for a bleeding disorder in patients with hemorrhagic stroke In this setting, all patients require platelet count, prothrombin time, activated partial thromboplastin time, and thrombin time and/or ecarin clotting time if the patient is known or suspected to be taking a direct thrombin inhibitor or a direct factor Xa inhibitor. (See 'Evaluation of patients with intracerebral hemorrhage' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Caplan LR. Terms describing brain ischemia by tempo are no longer useful: a polemic (with apologies to Shakespeare). Surg Neurol 1993; 40:91. 2. Caplan LR. TIAs: we need to return to the question, 'What is wrong with Mr. Jones?'. Neurology 1988; 38:791. https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 26/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate 3. Gorelick PB, Hier DB, Caplan LR, Langenberg P. Headache in acute cerebrovascular disease. Neurology 1986; 36:1445. 4. Ginsberg MD, Busto R. Combating hyperthermia in acute stroke: a significant clinical concern. Stroke 1998; 29:529. 5. Caplan LR. Imaging and laboratory diagnosis. In: Caplan's Stroke: A Clinical Approach, 4th, S aunders, Philadelphia 2009. p.87. 6. Moncayo J, Devuyst G, Van Melle G, Bogousslavsky J. Coexisting causes of ischemic stroke. Arch Neurol 2000; 57:1139. 7. Barnett HJ, Gunton RW, Eliasziw M, et al. Causes and severity of ischemic stroke in patients with internal carotid artery stenosis. JAMA 2000; 283:1429. 8. Caplan LR. Diagnosis and the clinical encounter. In: Caplan's Stroke: A Clinical Approach, 4th, Saunders, Philadelphia 2009. p.64. 9. Caplan LR, Gorelick PB, Hier DB. Race, sex and occlusive cerebrovascular disease: a review. Stroke 1986; 17:648. 10. Petty GW, Brown RD Jr, Whisnant JP, et al. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke 1999; 30:2513. 11. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335:765. 12. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903. 13. Kawachi I, Colditz GA, Stampfer MJ, et al. Smoking cessation and decreased risk of stroke in women. JAMA 1993; 269:232. 14. Kase CS, Caplan LR. Intracerebral Hemorrhage, Butterworth-Heinemann, Boston 1996. 15. Labovitz DL, Hauser WA, Sacco RL. Prevalence and predictors of early seizure and status epilepticus after first stroke. Neurology 2001; 57:200. 16. Caplan LR. Brain embolism. In: Practical Clinical Neurocardiology, Caplan LR, Chimowitz M, Hurst JW (Eds), Marcel Dekker, New York 1999. 17. Glass TA, Hennessey PM, Pazdera L, et al. Outcome at 30 days in the New England Medical Center Posterior Circulation Registry. Arch Neurol 2002; 59:369. 18. Sarkar S, Ghosh S, Ghosh SK, Collier A. Role of transcranial Doppler ultrasonography in stroke. Postgrad Med J 2007; 83:683. https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 27/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate 19. Mart nez-S nchez P, Serena J, Alexandrov AV, et al. Update on ultrasound techniques for the diagnosis of cerebral ischemia. Cerebrovasc Dis 2009; 27 Suppl 1:9. 20. Saito K, Kimura K, Nagatsuka K, et al. Vertebral artery occlusion in duplex color-coded ultrasonography. Stroke 2004; 35:1068. 21. Caplan LR. Posterior Circulation Disease: Clinical Findings, Diagnosos, and Management, Bla ckwell Science, Boston 1996. 22. Dittrich R, Ritter MA, Droste DW. Microembolus detection by transcranial doppler sonography. Eur J Ultrasound 2002; 16:21. 23. Wilterdink JL, Furie KL, Easton JD. Cardiac evaluation of stroke patients. Neurology 1998; 51:S23. 24. Adams RJ, Chimowitz MI, Alpert JS, et al. Coronary risk evaluation in patients with transient ischemic attack and ischemic stroke: a scientific statement for healthcare professionals from the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke Association. Stroke 2003; 34:2310. 25. Touz E, Varenne O, Chatellier G, et al. Risk of myocardial infarction and vascular death after transient ischemic attack and ischemic stroke: a systematic review and meta-analysis. Stroke 2005; 36:2748. 26. Calvet D, Touz E, Varenne O, et al. Prevalence of asymptomatic coronary artery disease in ischemic stroke patients: the PRECORIS study. Circulation 2010; 121:1623. 27. Amarenco P, Lavall e PC, Labreuche J, et al. Prevalence of coronary atherosclerosis in patients with cerebral infarction. Stroke 2011; 42:22. 28. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. 29. Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014; 370:2478. 30. Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014; 370:2467. 31. Albers GW, Bernstein RA, Brachmann J, et al. Heart Rhythm Monitoring Strategies for Cryptogenic Stroke: 2015 Diagnostics and Monitoring Stroke Focus Group Report. J Am Heart Assoc 2016; 5:e002944. 32. Steinberg JS, Varma N, Cygankiewicz I, et al. 2017 ISHNE-HRS expert consensus statement on ambulatory ECG and external cardiac monitoring/telemetry. Heart Rhythm 2017; 14:e55. https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 28/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate 33. Buck BH, Hill MD, Quinn FR, et al. Effect of Implantable vs Prolonged External Electrocardiographic Monitoring on Atrial Fibrillation Detection in Patients With Ischemic Stroke: The PER DIEM Randomized Clinical Trial. JAMA 2021; 325:2160. 34. Bernstein RA, Kamel H, Granger CB, et al. Effect of Long-term Continuous Cardiac Monitoring vs Usual Care on Detection of Atrial Fibrillation in Patients With Stroke Attributed to Large- or Small-Vessel Disease: The STROKE-AF Randomized Clinical Trial. JAMA 2021; 325:2169. 35. Kishore A, Vail A, Majid A, et al. Detection of atrial fibrillation after ischemic stroke or transient ischemic attack: a systematic review and meta-analysis. Stroke 2014; 45:520. 36. Dussault C, Toeg H, Nathan M, et al. Electrocardiographic monitoring for detecting atrial fibrillation after ischemic stroke or transient ischemic attack: systematic review and meta- analysis. Circ Arrhythm Electrophysiol 2015; 8:263. 37. Afzal MR, Gunda S, Waheed S, et al. Role of Outpatient Cardiac Rhythm Monitoring in Cryptogenic Stroke: A Systematic Review and Meta-Analysis. Pacing Clin Electrophysiol 2015; 38:1236. 38. Wachter R, Gr schel K, Gelbrich G, et al. Holter-electrocardiogram-monitoring in patients with acute ischaemic stroke (Find-AFRANDOMISED): an open-label randomised controlled trial. Lancet Neurol 2017; 16:282. 39. Israel C, Kitsiou A, Kalyani M, et al. Detection of atrial fibrillation in patients with embolic stroke of undetermined source by prolonged monitoring with implantable loop recorders. Thromb Haemost 2017; 117:1962. 40. Tsivgoulis G, Katsanos AH, Grory BM, et al. Prolonged Cardiac Rhythm Monitoring and Secondary Stroke Prevention in Patients With Cryptogenic Cerebral Ischemia. Stroke 2019; 50:2175. 41. Tirschwell D, Akoum N. Detection of Subclinical Atrial Fibrillation After Stroke: Is There Enough Evidence to Treat? JAMA 2021; 325:2157. 42. Shimizu T, Takada T, Shimode A, et al. Association between paroxysmal atrial fibrillation and the left atrial appendage ejection fraction during sinus rhythm in the acute stage of stroke: a transesophageal echocardiographic study. J Stroke Cerebrovasc Dis 2013; 22:1370. 43. Warraich HJ, Gandhavadi M, Manning WJ. Mechanical discordance of the left atrium and appendage: a novel mechanism of stroke in paroxysmal atrial fibrillation. Stroke 2014; 45:1481. 44. Horowitz DR, Tuhrim S, Weinberger JM, et al. Transesophageal echocardiography: diagnostic and clinical applications in the evaluation of the stroke patient. J Stroke Cerebrovasc Dis 1997; 6:332. https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 29/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate 45. Harloff A, Handke M, Reinhard M, et al. Therapeutic strategies after examination by transesophageal echocardiography in 503 patients with ischemic stroke. Stroke 2006; 37:859. 46. Markus HS, Hambley H. Neurology and the blood: haematological abnormalities in ischaemic stroke. J Neurol Neurosurg Psychiatry 1998; 64:150. 47. de Lau LM, Leebeek FW, de Maat MP, et al. Screening for coagulation disorders in patients with ischemic stroke. Expert Rev Neurother 2010; 10:1321. 48. Hankey GJ, Eikelboom JW, van Bockxmeer FM, et al. Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke 2001; 32:1793. 49. Bushnell CD, Goldstein LB. Diagnostic testing for coagulopathies in patients with ischemic stroke. Stroke 2000; 31:3067. 50. Levine SR, Brey RL, Tilley BC, et al. Antiphospholipid antibodies and subsequent thrombo- occlusive events in patients with ischemic stroke. JAMA 2004; 291:576. 51. Janardhan V, Wolf PA, Kase CS, et al. Anticardiolipin antibodies and risk of ischemic stroke and transient ischemic attack: the Framingham cohort and offspring study. Stroke 2004; 35:736. 52. Nojima J, Kuratsune H, Suehisa E, et al. Strong correlation between the prevalence of cerebral infarction and the presence of anti-cardiolipin/beta2-glycoprotein I and anti- phosphatidylserine/prothrombin antibodies Co-existence of these antibodies enhances ADP-induced platelet activation in vitro. Thromb Haemost 2004; 91:967. 53. Rothwell PM, Howard SC, Power DA, et al. Fibrinogen concentration and risk of ischemic stroke and acute coronary events in 5113 patients with transient ischemic attack and minor ischemic stroke. Stroke 2004; 35:2300. 54. Fibrinogen Studies Collaboration, Danesh J, Lewington S, et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 2005; 294:1799. 55. Macellari F, Paciaroni M, Agnelli G, Caso V. Neuroimaging in intracerebral hemorrhage. Stroke 2014; 45:903. 56. Cucchiara B, Messe S, Sansing L, et al. Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke 2008; 39:2993. 57. Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology 2008; 71:1084. Topic 1083 Version 45.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 30/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate GRAPHICS Characteristics of stroke subtypes Stroke type Clinical course Risk factors Other clues Intracerebral Gradual onset and Hypertension, trauma, bleeding May be hemorrhage progression during diatheses, illicit drugs (eg, precipitated by minutes or hours in most patients, but may amphetamines, cocaine), vascular malformations. More common in sex or other physical activity. present abruptly with maximal deficit at onset. Black people and Asian people than in White people. Patient may have reduced alertness. Subarachnoid hemorrhage Abrupt onset of sudden, severe headache. Focal Smoking, hypertension, moderate to heavy alcohol use, genetic May be precipitated by brain dysfunction less susceptibility (eg, polycystic kidney sex or other common than with other types. disease, family history of subarachnoid hemorrhage) and physical activity. Patient may have sympathomimetic drugs (eg, cocaine) reduced alertness. Ischemic Stuttering progression Atherosclerotic risk factors (age, May have neck (thrombotic) with periods of improvement. Lacunes smoking, diabetes mellitus, etc). Males affected more commonly than bruit. develop over hours or at females. May have history of TIA. most a few days; large artery ischemia may evolve over longer periods. Ischemic Sudden onset with Atherosclerotic risk factors as listed Can be (embolic) deficit maximal at onset. Clinical findings may above. Males affected more commonly than females. History of precipitated by getting up at improve quickly. heart disease (valvular, atrial night to urinate fibrillation, endocarditis). or sudden coughing or sneezing. Graphic 69907 Version 5.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 31/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Headache and vomiting in stroke subtypes The frequency of sentinel headache, onset headache, and vomiting in three subtypes of stroke: subarachnoid hemorrhage, intraparenchymal (intracerebral) hemorrhage, and ischemic stroke. Onset headache was present in virtually all patients with SAH and about one-half of those with IPH; all of these symptoms were infrequent in patients with IS. SAH: subarachnoid hemorrhage; IPH: intraparenchymal (intracerebral) hemorrhage; IS: ischemic stroke. Data from: Gorelick PB, Hier DB, Caplan LR, Langenberg P. Headache in acute cerebrovascular disease. Neurology 1986; 36:1445. Graphic 60831 Version 4.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 32/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Pathophysiologic ischemic stroke classification Large vessel atherothrombotic stroke More common Bifurcation of the common carotid artery Siphon portion of the common carotid artery Middle cerebral artery stem Intracranial vertebral arteries proximal to middle basilar artery Origin of the vertebral arteries Less common Origin of the common carotid artery Posterior cerebral artery stem Origin of the major branches of the basilar-vertebral arteries Origin of the branches of the anterior, middle, and posterior cerebral arteries Small vessel (lacunar) stroke Mechanism Lipohyalinotic occlusion Less frequently proximal atherothrombotic occlusion Least likely embolic occlusion Most common locations Penetrating branches of the anterior, middle, and posterior cerebral and basilar arteries Cardioaortic embolic stroke Cardiac sources definite - antithrombotic therapy generally used Left atrial thrombus Left ventricular thrombus Atrial fibrillation and paroxysmal atrial fibrillation Sustained atrial flutter Recent myocardial infarction (within one month) Rheumatic mitral or aortic valve disease Bioprosthetic and mechanical heart valve Chronic myocardial infarction with ejection fraction <28 percent https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 33/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Symptomatic heart failure with ejection fraction <30 percent Dilated cardiomyopathy Cardiac sources definite - anticoagulation hazardous Bacterial endocarditis (exception nonbacterial) Atrial myxoma Cardiac sources possible Mitral annular calcification Patent foramen ovale Atrial septal aneurysm Atrial septal aneurysm with patent foramen ovale Left ventricular aneurysm without thrombus Isolated left atrial spontaneous echo contrast ("smoke") without mitral stenosis or atrial fibrillation Mitral valve strands Ascending aortic atheromatous disease (>4 mm) True unknown source embolic stroke Other Dissection Moyamoya Binswanger's disease Primary thrombosis Cerebral mass Graphic 55099 Version 4.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 34/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Acute stroke differential diagnosis Migraine aura Seizure with postictal paresis (Todd paralysis), aphasia, or neglect Central nervous system tumor or abscess Cerebral venous thrombosis Functional deficit (conversion reaction) Hypertensive encephalopathy Head trauma Mitochondrial disorder (eg, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes or MELAS) Multiple sclerosis Posterior reversible encephalopathy syndrome (PRES) Reversible cerebral vasoconstriction syndromes (RCVS) Spinal cord disorder (eg, compressive myelopathy, spinal dural arteriovenous fistula) Subdural hematoma Syncope Systemic infection Toxic-metabolic disturbance (eg, hypoglycemia, exogenous drug intoxication) Transient global amnesia Viral encephalitis (eg, herpes simplex encephalitis) Wernicke encephalopathy Graphic 69869 Version 7.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 35/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 36/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 37/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 38/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Time course of embolic stroke Embolic stroke occurs suddenly, with symptoms maximal at onset. This patient had multiple embolic events with different clinical symptoms (initially weakness, followed by paresthesias). Graphic 73261 Version 1.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 39/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Stuttering time course of thrombotic stroke The course of weakness of the right limb in a patient with a thrombotic stroke reveals fluctuating symptoms, varying between normal and abnormal, progressing in a stepwise or stuttering fashion with some periods of improvement. Graphic 64107 Version 2.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 40/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Time course of lacunar infarction Penetrating artery occlusions usually cause symptoms that develop over a short period of time, hours or at most a few days, compared to large artery-related brain ischemia which can evolve over a longer period. A stuttering course may ensue, as with large artery thrombosis. This patient had a pure motor hemiparesis. Graphic 52246 Version 1.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 41/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Time course of neurologic changes in intracerebral hemorrhage Schematic representation of rapid downhill course in terms of unusual behavior (solid line), hemimotor function (dotted line), and consciousness (dash-dotted line) in a patient with intracerebral (intraparenchymal) hemorrhage. Graphic 61491 Version 3.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 42/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Stroke mortality related to blood pressure and age Stroke mortality rate, pictured on a log scale with 95% CI, in each decade of age in relation to the estimated usual systolic and diastolic blood pressure at the start of that decade. Stroke mortality increases with both higher pressures and older ages. For diastolic pressure, each age-specific regression line ignores the left-hand point (ie, at slightly less than 75 mmHg) for which the risk lies significantly above the fitted regression line (as indicated by the broken line below 75 mmHg). CI: confidence interval. Data from Prospective Studies Collaboration, Lancet 2002; 360:1903. Graphic 66793 Version 5.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 43/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Major cerebral vascular territories Representation of the territories of the major cerebral vessels shown in a coronal section of the brain. Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases. Harrison's Principles of Internal Medicine, 13th ed, McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 65199 Version 2.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 44/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Anterior cerebral artery distribution and signs and symptoms of occlusion Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 60945 Version 3.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 45/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Middle cerebral artery distribution and signs and symptoms of occlusion Reproduced with permission from Kistler JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 81813 Version 2.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 46/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Posterior cerebral artery distribution and signs and symptoms of occlusion Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 60416 Version 2.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 47/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Inferior pontine syndrome Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 71587 Version 1.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 48/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Medullary syndrome Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 73073 Version 1.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 49/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Midpontine syndrome Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 68785 Version 1.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 50/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Acute ischemic stroke syndromes according to vascular territory Artery involved Syndrome Anterior cerebral artery Motor and/or sensory deficit (leg > face, arm) Grasp, sucking reflexes Abulia, paratonic rigidity, gait apraxia Middle cerebral artery Dominant hemisphere: aphasia, motor and sensory deficit (face, arm > leg > foot), may be complete hemiplegia if internal capsule involved, homonymous hemianopia Non-dominant hemisphere: neglect, anosognosia, motor and sensory deficit (face, arm > leg > foot), homonymous hemianopia Posterior cerebral artery Homonymous hemianopia; alexia without agraphia (dominant hemisphere); visual hallucinations, visual perseverations (calcarine cortex); sensory loss, choreoathetosis, spontaneous pain (thalamus); III nerve palsy, paresis of vertical eye movement, motor deficit (cerebral peduncle, midbrain) Penetrating vessels Pure motor hemiparesis (classic lacunar syndromes) Pure sensory deficit Pure sensory-motor deficit Hemiparesis, homolateral ataxia Dysarthria/clumsy hand Vertebrobasilar Cranial nerve palsies Crossed sensory deficits Diplopia, dizziness, nausea, vomiting, dysarthria, dysphagia, hiccup Limb and gait ataxia Motor deficit Coma Bilateral signs suggest basilar artery disease Internal carotid artery Progressive or stuttering onset of MCA syndrome, occasionally ACA syndrome as well if insufficient collateral flow Graphic 75487 Version 7.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 51/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Occlusion of middle and anterior cerebral arteries Reproduced with permission from: Netter, FH, Caplan, LR. Cerebrovascular Disease, Section III, Plate 8. In: The Netter Collection of Medical Illustrations, Vol 1, Nervous System, Part II, Neurologic and Neuromuscular Disorders, Netter, FH, Jones, HR, Dingle, RV (Eds), MediMedia USA, Inc 1986. Copyright 1986 Elsevier. Graphic 69630 Version 1.0 https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 52/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Contributor Disclosures Louis R Caplan, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 53/53
7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Use and utility of stroke scales and grading systems : Larry B Goldstein, MD, FAAN, FANA, FAHA : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 09, 2023. INTRODUCTION This topic will review stroke scales and grading systems that are used for ischemic and hemorrhagic stroke. Grading systems used to classify patients with subarachnoid hemorrhage are reviewed separately. (See "Subarachnoid hemorrhage grading scales".) Categorization systems used in the classification and etiology of stroke are also discussed elsewhere. (See "Stroke: Etiology, classification, and epidemiology", section on 'TOAST classification' and "Stroke: Etiology, classification, and epidemiology", section on 'SSS-TOAST and CCS classification'.) ROLE OF SCALES IN STROKE ASSESSMENT In addition to their importance for assessing the impact of therapeutic interventions in clinical trials, stroke scales are useful in the routine clinical setting as aids to improve diagnostic accuracy, help determine the appropriateness of specific treatments, monitor a patient's neurologic deficits through the continuum of care, and predict and gauge outcomes. Not only are different types of scales needed for these different purposes, but no single scale is suitable for capturing all of the effects of stroke. A plethora of stroke scales have been developed for each of these purposes as discussed in the sections that follow. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 1/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Dimensions of disease The International Classification of Functioning, Disability and Health, developed by the World Health Organization, categorizes the impact of disease into three dimensions [1]: Body Dimension, referring to the structure and function of body systems Activities Dimension, referring to the complete range of activities performed by an individual Participation Dimension, classifying areas of life in which an individual is involved, has access, has societal opportunities or barriers These three general dimensions correspond to what clinicians might describe as neurologic impairments (ie, deficits such as a hemianopsia, aphasia, limb paresis, gait imbalance, or sensory loss), disabilities (ie, loss of the ability to perform daily tasks, such as eating, dressing, and bathing, resulting from physiological deficits), and handicaps (ie, the impact of deficits and disabilities on social participation such as employment) [2]. Additionally, it is becoming increasingly important to assess the effects of disease and treatment on quality of life. Measuring the impact of stroke Although the impact of stroke as reflected by these different dimensions (body, activity, participation) is generally consistent, it is important to measure each dimension, as focusing on any one alone could be misleading. As an example, consider a patient with a paralyzed hand. This deficit would be measured in the Body Dimension as a motor impairment. With compensatory strategies such as the use of the unimpaired hand or prosthetics, that same patient might have no disability (ie, able to eat, dress, bathe). If the patient was a truck driver, they might be able to return to work by driving a modified vehicle (no handicap), whereas if they were a watchmaker, they might be unable to return to their previous employment (ie, a social handicap). Thus, the impact of a neurologic impairment on quality of life can be quite different depending on individual circumstances. In addition, a stroke considered to be mild based upon a measure of one dimension may be severe when measured on a different dimension [3]. A homonymous inferior quadrantanopia might represent a minimal impairment and result in no disability, but could be an important handicap and have a large impact on quality of life because driving a motor vehicle is precluded. Therefore, when choosing a stroke scale, one must first consider why it is being used and what it is measuring. STROKE DIAGNOSIS https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 2/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Because of poor recognition and the nonspecific nature of many stroke symptoms, stroke scales and grading systems have been developed both to aid the general public, emergency responders, and emergency physicians in the identification of persons with acute stroke, and to hasten transport of stroke victims to appropriate medical facilities. These tools must be simple and rapidly applicable. Selected diagnostic scales The best-studied scales for general stroke recognition and diagnosis are the Face Arm Speech Test (FAST), the Cincinnati Prehospital Stroke Scale (CPSS), the Los Angeles Prehospital Stroke Screen (LAPSS), and the Recognition of Stroke in the Emergency Room (ROSIER). FAST and CPSS are simple and easy to use, which makes them most appropriate for the general public and nonmedical first responders [4]. Each evaluates the presence or absence of facial weakness, arm weakness, and speech difficulty. The main difference between the two is that FAST incorporates assessment of language function during normal conversation, whereas CPSS tests language by asking the patient to repeat a short sentence. Both the American Stroke Association and the United States Centers for Disease Control and Prevention promote FAST as a tool to increase public awareness of stroke signs and symptoms [5,6]. LAPSS and ROSIER are more complex and may be more appropriate for use by trained emergency responders and emergency physicians [4]. The LAPSS and ROSIER scales incorporate additional items to help exclude stroke mimics and to increase specificity with a potential disadvantage of reduced sensitivity [7]. FAST The Face Arm Speech Test (FAST; the "T" is a reminder of the importance of time and the need to reach a hospital immediately) evaluates patients with suspected stroke by assessing them for the presence of facial weakness, arm weakness, and speech impairment ( figure 1) [8]. FAST is considered positive if at least one item is abnormal. A prospective study found good agreement for the detection of the acute stroke signs between emergency medical responders using the FAST system and stroke physicians [9]. The scale is insensitive to isolated stroke-related visual or sensory impairments, vertigo, and gait disturbances. BE-FAST The BE-FAST test is a modification of FAST that accounts for imbalance or leg weakness (B for balance) and visual symptoms (E for eyes), as these potentially debilitating symptoms are not otherwise captured by either screening tool [10]. The BE-FAST test may reduce the likelihood of a stroke diagnosis missed using the FAST test but requires field validation in a prospective study. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 3/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate CPSS The CPSS focuses on the assessment facial paresis, arm drift, and abnormal speech ( table 1) [11]. In a prospective report evaluating the CPSS, the diagnostic accuracy for emergency department physicians compared with non-physician emergency medical personnel was similar with high correlation for total score between these groups [12]. The presence of an abnormality on any one of the three stroke scale items was associated with a marked increase in the likelihood of stroke [13]. It has the same limitations as FAST for certain stroke-related deficits that can occur in isolation. LAPSS The LAPSS assesses for unilateral arm drift, handgrip weakness, and facial paresis ( form 1) [14]. The criteria for an "in-the-field" stroke diagnosis are met when the patient age is >45 years, seizure/epilepsy history is absent, symptom duration is <24 hours, the patient is not a full-time wheelchair user or bedridden at baseline, the blood glucose is between 60 and 400 mg/dL, and a unilateral deficit is present in one of the three items (arm, handgrip, or face). The LAPSS was evaluated in an observer-blind prospective study of all non-comatose, non-trauma patients with neurologic complaints compatible with stroke who were transported by emergency medical technicians to a single hospital [14]. Compared with the final diagnosis, a prehospital stroke diagnosis made by paramedics with LAPSS had a sensitivity of 91 percent (95% CI 76-98 percent) and specificity of 97 percent (95% CI 93-99 percent). ROSIER The ROSIER scale was developed to facilitate rapid stroke patient identification and triage by emergency department clinicians [15]. The ROSIER scale incorporates the Glasgow Coma Scale ( table 2) and measurement of blood pressure and blood glucose along with assessment of a seven-item stroke-recognition scale. The first two items inquire about clinical history to exclude stroke mimics [15]: Loss of consciousness or syncope (yes = -1; no = 0) Seizure activity (yes = -1; no = 0) The next five items inquire about specific neurologic deficits of new acute onset (or present since awakening from sleep): Asymmetric facial weakness (yes = +1; no = 0) Asymmetric arm weakness (yes = +1; no = 0) Asymmetric leg weakness (yes = +1; no = 0) Speech disturbance (yes = +1; no = 0) Visual field defect (yes = +1; no = 0) https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 4/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate The total score range is -2 to +5. Stroke is unlikely, but not completely excluded, if total score is 0 [15]. When prospectively validated at a cut-off score of >0 in the original publication, the scale had a sensitivity of 93 percent (95% CI 89-97 percent) and specificity of 83 percent (95% CI 77-89 percent) [15]. A 2020 systematic review and meta-analysis identified 15 datasets that evaluated the ROSIER scale and found that the combined sensitivity and specificity were 88 and 66 percent, respectively [16]. Utility of stroke diagnostic scales In a 2019 systematic review of studies evaluating the accuracy of stroke recognition scales used in the prehospital setting or emergency department, the CPSS had the highest sensitivity in prehospital settings, while the ROSIER had the highest sensitivity in emergency department settings [4]. LARGE VESSEL OCCLUSION TRIAGE Selected triage scales The advent of proven therapies for the treatment of patients with large-vessel distribution ischemic stroke requires the triage of patients to centers capable of rapid endovascular clot retrieval [17]. Scales that have been evaluated as stroke triage aids to detect patients with large vessel occlusion include the Rapid Arterial oCclusion Evaluation (RACE) scale ( table 3), the Los Angeles Motor Scale (LAMS) ( table 4), the Cincinnati Stroke Triage Assessment Tool (C-STAT) ( table 5), and the Field Assessment Stroke Triage for Emergency Destination (FAST-ED) scale ( table 6). As reviewed below, none of the available scales predict stroke due to large vessel occlusion with both high sensitivity and specificity. With this limitation in mind, our EMS providers generally use RACE. (See 'Utility of stroke triage scales' below.) RACE The RACE scale is based on the items of National Institutes of Health Stroke Scale (NIHSS) that had the highest predictive value for large artery occlusion, as determined in a retrospective study of 654 patients with acute ischemic stroke of the anterior circulation [18]. The RACE scale assesses facial palsy, limb motor function, head and gaze deviation, and aphasia or agnosia, as shown in the table ( table 3). The RACE score ranges from a normal of 0 to a maximum of 9 points. For detecting large vessel occlusion, a RACE scale score 5 had sensitivity and specificity of 85 and 68 percent, respectively [18]. LAMS The LAMS ( table 4) employs a three-item motor score derived from the LAPSS and assesses facial droop, arm drift, and grip strength, with the total score ranging from 0 to 5 points [19]. In a retrospective study of 119 patients with anterior circulation ischemic stroke evaluated within 12 hours of time last known well, a LAMS score of 4 predicted a large vessel occlusion with a sensitivity and specificity of 81 and 89 percent, respectively [20]. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 5/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate C-STAT The C-STAT ( table 5) is a three-item score that assigns two points for conjugate gaze deviation, one point if the patient answers incorrectly on one of two level of consciousness questions and does not follow one of two commands from the NIHSS, and one point for arm weakness; the total score ranges from 0 to 4 points [21,22]. In a prospective study of prehospital evaluation with complete data for 58 patients who had a positive FAST score among 158 screened for suspicion for stroke or TIA, a C-STAT score 2 had a sensitivity of 71 percent (95% CI 29-96) and specificity of 70 percent (95% CI 55-83) for the diagnosis of large vessel stroke [22]. FAST-ED The FAST-ED scale ( table 6) assigns points for facial palsy, arm weakness, speech changes, eye deviation, and denial or neglect; the total score ranges from 0 to 9 [23]. In a retrospective study of 727 patients suspected of having acute stroke within 24 hours of symptom onset, large vessel occlusion was detected in 240. For prediction of large vessel occlusion, a FAST-ED score 4 had a sensitivity of 61 percent and a specificity of 89 percent [23]. Utility of stroke triage scales Although detection of ischemic stroke caused by a large artery occlusion is important to help identify patients who may benefit from mechanical thrombectomy, none of the available scales predicts this type of stroke with optimal accuracy. Triage decisions based on the use of these scales will miss some patients with large vessel occlusion who have milder stroke impairments [24]. This limitation needs to be understood if these scales are used to help triage patients for mechanical thrombectomy. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Mechanical thrombectomy for acute ischemic stroke".) In a 2018 systematic review of prediction scales for large vessel occlusion, the sensitivities of these scales ranged from 47 to 73 percent, and the specificities ranged from 78 to 90 percent; no single scale could predict a large vessel occlusion with high sensitivity and specificity [24]. A prospective cohort study of 2007 patients conducted in the Netherlands comparing seven stroke prediction scales found that sensitivities for large vessel occlusion ranged from 38 to 62 percent and specificities ranged from 80 to 93 percent, with LAMS and RACE having the highest accuracy [25]. Another prospective cohort study from the Netherlands of over 1000 patients with suspected stroke found that the RACE was the best performing scale for detecting large vessel occlusion [26]. Another cohort study found similar calibrations for RACE, LAMS C-STAT, and FAST- ED [27]. None had an AUC (area under the receiver operating curve) >0.8, a threshold generally considered for clinical usefulness. STROKE IMPAIRMENT AND SEVERITY https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 6/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate The main stroke impairment scales are the National Institutes of Health Stroke Scale (NIHSS), the Pediatric National Institutes of Health Stroke Scale (pedNIHSS), the European Stroke Scale, and the Canadian Neurologic Scale (CNS). The Scandinavian Stroke Scale has also been used in clinical trials. Although these scales are useful to assess the severity of neurologic impairment due to stroke, they are not useful for making the diagnosis of stroke. Stroke severity and prognosis Stroke severity is assessed with an impairment-level scale, such as the NIHSS. Stroke prognosis is largely determined by the severity of the patient's initial impairments. The association of neurologic impairment, stroke severity, and outcome after ischemic stroke is reviewed separately. (See "Overview of ischemic stroke prognosis in adults", section on 'Neurologic severity'.) NIHSS The NIHSS is both reliable and valid, and has become a standard stroke impairment scale for use in both clinical trials and as part of clinical care in the United States in many other countries [28-32]. As examples, the NIHSS score is part of the assessment that helps determine whether a patient is a candidate for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy (see "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke"). In addition, the baseline NIHSS score is predictive of long-term outcome after acute stroke, as noted above. The NIHSS can also be assessed remotely and may be useful in telemedicine programs [33]. The NIHSS measures neurologic impairment using a 15 item scale ( table 7) [28]. A printable version of the NIHSS is available online at https://www.stroke.nih.gov/documents/NIH_Stroke_Scale_508C.pdf. An NIHSS calculator (calculator 1) is best used by a certified NIHSS examiner in conjunction with a copy of the full NIHSS. Both physician and nurse stroke providers can be trained to use the scale with similar levels of accuracy [34]. Reliability can be further improved through the use of standardized video training [35,36]. However, the value of routine retraining is uncertain [37]. The NIHSS has been validated for retrospective use based upon information available in the patient's medical record over a range of severities [38-41]. An important limitation of the NIHSS is that it does not capture all stroke-related impairments, particularly with infarction involving the vertebrobasilar circulation [42,43]. This is also true for modified, shortened versions of the scale [44,45]. Modified NIHSS The modified NIHSS (mNIHSS) is a shortened version of the NIHSS that omits level of consciousness (item 1a), facial weakness (item 4), limb ataxia (item 7), and dysarthria (item 10) from the original NIHSS and condenses the sensory test (item 8) choices from three to two responses ( table 8) [46]. In the original derivation study and subsequent prospective https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 7/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate validation, the validity and reliability of the mNIHSS was nearly identical to the original NIHSS [44,46]. The use of the "Cookie Theft" picture for language assessment as part of the NIHSS may be culturally biased [47]. An alternative has not yet been adopted. Pediatric NIHSS The Pediatric National Institutes of Health Stroke Scale (PedNIHSS) was developed by modifying the adult NIHSS so that examination items and testing materials are age-appropriate ( table 9 and figure 2 and figure 3 and figure 4) [48]. In a multicenter, prospective cohort study of children with acute arterial ischemic stroke, the PedNIHSS showed good interrater reliability when employed by trained pediatric neurologists. Other impairment scales European Stroke Scale The European Stroke Scale was designed to evaluate patients with stroke involving the territory of the middle cerebral artery. It is similar to the NIHSS and is also reliable and partially validated [49]. Canadian Neurological Scale The Canadian Neurological Scale (CNS) is simpler and more rapidly performed than the NIHSS, but does not capture many stroke-related impairments ( table 10) [50,51]. Like the NIHSS, the CNS has been validated for use retrospectively based on information available in the patient's medical record over a range of severities [40,52]. Scandinavian Stroke Scale The Scandinavian Stroke Scale assesses consciousness, gaze palsy, arm and leg weakness, dysphasia, orientation, facial palsy, and gait [53]. The scale has good to excellent reliability. It can be reliably scored based on data routinely recorded in the medical record and has been validated for retrospective use [54]. Specific neurologic deficits Scales to measure specific types of deficits have been developed and validated in patients with stroke: Motor impairments (eg, Fugl-Meyer Assessment [55,56], Motor Assessment Scale [57], and Motricity Index [58,59]) Balance (eg, Berg Balance Scale [60]) Arm/hand function (eg, Research Action Arm Test [61-64]) Mobility (eg, Rivermead Mobility Index [65]) Aphasia (eg, Frenchay Aphasia Screening Test [66,67] and Porch Index of Communicative Ability [68]) Cognition (eg, Montreal Cognitive Assessment [MoCA] [69,70]) https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 8/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate These scales are most useful for research studies targeting specific types of deficits. One exception is the MoCA, which is a widely used clinical screening test for cognitive impairment. The MoCA includes assessments of executive functions that are commonly affected by stroke. (See "Mental status scales to evaluate cognition", section on 'Montreal Cognitive Assessment (MoCA)'.) In addition, depression commonly complicates the recovery of stroke patients, and several instruments are available to aid in its diagnosis and measurement, including the following: Beck Depression Inventory (BDI) [71] Center for Epidemiological Studies of Depression (CES-D) [72] Hamilton Depression Scale [73] Personal Health Questionnaire (PHQ-9) [74] Of these, aphasic patients and older adults may have difficulty with the BDI, CES-D, and the PHQ- 9. The Hamilton Depression Scale is observer- rather than patient-rated, but its inter-observer reliability may be limited. These depression rating scales have been used primarily in research settings. The PHQ-9 has been validated for use as a depression screening tool in general practice settings. A simple two-question screen for depression has been used in primary care settings, but its use in stroke populations has not been assessed [75]. DISABILITY The two most frequently used stroke disability scales are the Barthel Index (BI) and the Functional Independence Measure (FIM). Both were similarly responsive to change in disability in one study [76], whereas another report found that the FIM was more sensitive to change [77]. Instrumental activities of daily living (IADL) scales attempt to bridge the gap between disability and handicap. Combining basic scales such as the BI or FIM with IADL assessments may provide more comprehensive information than can be gleaned from either type of scale alone and can be a useful strategy for both clinical and research applications in stroke patients [78]. Barthel Index The BI measures 10 basic aspects of self-care and physical dependency ( table 11) [79-81]. A normal score is 100, and lower scores indicate increasing disability; a BI >60 corresponds to assisted independence, and a BI <40 corresponds to severe dependency [80]. A systematic review and meta-analysis concluded that the interrater reliability of the BI is excellent [82]. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 9/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Although not specifically designed as a stroke scale, the BI correlates moderately well with radiologic infarct size [83-86]. In addition, the BI is frequently used as an outcome measure for stroke trials [81], and limited evidence suggests that the BI can predict outcome after stroke [83,87,88]. However, the predictive capacity of the BI for outcome is reduced in the setting of acute stroke, particularly within the first 72 hours [42,89]. In addition, the BI has significant limitations related to floor and ceiling effects, meaning that the BI is relatively insensitive to change in function at the extreme ends of the scale [3,77,81]. FIM The FIM is a proprietary instrument that assesses patient disability in 13 aspects of motor function and five aspects of cognitive function [90-92]. The FIM is widely used for monitoring functional improvement through the course of rehabilitation therapy [93,94]. It can be assessed by telephone as well as in person [95]. A systematic review concluded that the FIM may have some utility for predicting outcome after stroke, though high-quality evidence was limited [91]. IADL As noted above, IADL scales attempt to bridge the gap between disability and handicap [96]. They are intended to capture the patient's ability to live independently in the home and assess a variety of activities (cooking, home management, recreation, etc). Several IADL scales are available, but the Frenchay Activities Index was specifically developed for use with stroke patients and is reliable [97-99]. HANDICAP The main stroke handicap scales are the Rankin Scale and its derivatives, the modified Rankin Scale (mRS), the Rankin Focused Assessment, and the Oxford Handicap Scale [100-104]. Of these, the mRS is the most widely used. The Craig Handicap Assessment and Reporting Technique (CHART) was specifically designed to assess handicap [105,106], but has not been used as extensively as the mRS in the assessment of patients with stroke. Modified Rankin Scale The mRS measures functional independence on a seven grade scale ( table 12) [100,101]. The mRS has been used as a measure of stroke-related handicap in many interventional trials and is frequently used as a global measure of the functional impact of stroke [31,107,108]. In addition, the mRS score at 90 days after intravenous thrombolysis or endovascular interventions for acute ischemic stroke is a proposed "core metric" of comprehensive stroke centers in the United States [31]. A systematic review published in 2007 concluded that interrater reliability of the mRS was moderate and was improved with structured interview [109], although a subsequent study found no significant difference between standard and structured mRS [110]. A systematic review https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 10/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate published in 2009 found that the overall interrater reliability of the mRS was moderate but varied widely among included studies; the effect of structured interview was inconsistent [111]. The mRS score shows moderate correlation with the volume of cerebral infarction [85,86,112]. The mRS ( table 12) places particular emphasis on the patient's ability to walk. Because it is weighted towards physical function [107], the results of the mRS correlate closely with scores on the Barthel Index [113-115] and therefore do not fully reflect the impact of stroke on social participation. There has been some debate regarding cutoffs and the analysis of mRS data in the setting of clinical trials. Different trials have used dichotomous cutoff scores of 1, 2, or 3 to identify those with favorable compared with unfavorable outcomes. Another approach is using a so- called "shift" analysis, in which the entire range of possible scores is considered rather than dichotomous outcomes [116]. Some trials that were negative using prespecified dichotomous cutoffs might have been positive if a shift analysis had been used [117]. QUALITY OF LIFE Health-related quality of life (HRQOL) reflects the physical, emotional, and social aspects of life that can be affected by acute or chronic disease [118]. These types of assessments are generally used for research and not clinical purposes. Generic scales Several generic scales have been used for the assessment of HRQOL in patients with stroke, including the following: Sickness Impact Profile [119,120] Short Form 36 [121] Health Utilities Index [122-125] EuroQol [126-128] The use of these HRQOL scales in patients with stroke is particularly challenging because the scales are generally lengthy, and because the disease itself can affect the patient's ability to respond, often necessitating obtaining responses from proxies [129]. The physical subscore of the Sickness Impact Profile correlates with stroke-related impairments as measured with the National Institutes of Health Stroke Scale (NIHSS) and Canadian Neurologic Scale (CNS) [114]. Disability scores measured with the Barthel Index and handicap scores measured with the Rankin Scale explain only 33 percent of the variance in Sickness Impact Profile scores [130]. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 11/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Stroke-specific scales One response to the difficulty of assessing quality of life in stroke patients with generic scales has been the development of stroke-specific HRQOL instruments, such as the following: Stroke Impact Scale (SIS) [131] Stroke-Specific Quality of Life Scale [132,133] Stroke-adapted version of the Sickness Impact Profile [134] The SIS was designed to measure changes in hand function, activities of daily living, mobility, emotion, communication, memory, thinking, and participation after stroke [131]. The SIS is reliable, valid, and sensitive to change [131,135]. A briefer version focused on physical functioning has also been developed [136]. In addition, the SIS has been evaluated for postal administration [137]. As with other HRQOL scales, a major limitation of the SIS is that assessment is made by self-report of the patient, posing an obstacle to its use in patients with aphasia or other cognitive impairments [42]. This limitation can be partially addressed by use of a proxy [138]. ADDITIONAL STROKE SCALES A number of stroke scales specific to transient ischemic attack (TIA), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage are discussed in separate topic reviews. These include: 2 TIA The ABCD score ( table 13) is intended to estimate the risk of ischemic stroke in the first days after a TIA. Intracerebral hemorrhage The ICH score is intended to predict mortality after intracerebral hemorrhage. Subarachnoid hemorrhage Grading systems used to classify patients with subarachnoid hemorrhage include the Glasgow Coma Scale, the Hunt and Hess grading system, the World Federation of Neurological Surgeons scale, the Fisher scale, the modified Fisher scale, and the Ogilvy and Carter grading system. (See "Subarachnoid hemorrhage grading scales".) SUMMARY AND RECOMMENDATIONS Stroke scales are useful for clinical and research purposes as aids to improve diagnostic accuracy, determine the suitability of specific treatments, monitor change in neurologic https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 12/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate impairments, and measure outcome. No single stroke scale is available or appropriate for all purposes, and each available scale has its own inherent limitations. (See 'Role of scales in stroke assessment' above.) The Cincinnati Prehospital Stroke Scale (CPSS) or the Face Arm Speech Test (FAST) have been suggested for use by prehospital personnel because they are easy to learn and rapidly administered. BE-FAST offers the advantage of also capturing vertebrobasilar symptoms and is being used more widely, but it has not been fully validated in the prehospital setting. (See 'Stroke diagnosis' above.) Scales to detect ischemic stroke caused by large artery occlusion, such as the Rapid Arterial oCclusion Evaluation (RACE) scale, have limited utility; none of the available scales has both high sensitivity and specificity. (See 'Large vessel occlusion triage' above.) The National Institutes of Health Stroke Scale (NIHSS) is a measure of general stroke impairment and is useful for both clinical and research purposes. (See 'NIHSS' above.) Despite their shortcomings, the Barthel Index and Rankin Scales are the most widely used measures of stroke-related disability and handicap, respectively. (See 'Barthel Index' above and 'Modified Rankin Scale' above.) Health-Related Quality of Life (HRQOL) in patients with stroke may be best measured with a stroke-specific instrument such as the Stroke Impact Scale (SIS). Use of UpToDate is subject to the Terms of Use. REFERENCES 1. World Health Organization. International Classification of Functioning, Disability and Health (ICF). http://www.who.int/classifications/icf/en/ (Accessed on April 21, 2011). 2. Orgogozo JM. The concepts of impairment, disability, and handicap. Cerebrovasc Dis 1994; 4 (Suppl 2):2. 3. Duncan PW, Samsa GP, Weinberger M, et al. Health status of individuals with mild stroke. Stroke 1997; 28:740. 4. Zhelev Z, Walker G, Henschke N, et al. Prehospital stroke scales as screening tools for early identification of stroke and transient ischemic attack. Cochrane Database Syst Rev 2019; 4:CD011427. 5. American Stroke Association. Stroke symptoms. Available at: https://www.stroke.org/en/abo ut-stroke/stroke-symptoms (Accessed on March 05, 2021). https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 13/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate 6. Centers for Disease Control and Prevention. Stroke signs and symptoms. Available at: http s://www.cdc.gov/stroke/signs_symptoms.htm (Accessed on March 05, 2021). 7. Rudd M, Buck D, Ford GA, Price CI. A systematic review of stroke recognition instruments in hospital and prehospital settings. Emerg Med J 2016; 33:818. 8. Harbison J, Hossain O, Jenkinson D, et al. Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance staff using the face arm speech test. Stroke 2003; 34:71. 9. Nor AM, McAllister C, Louw SJ, et al. Agreement between ambulance paramedic- and physician-recorded neurological signs with Face Arm Speech Test (FAST) in acute stroke patients. Stroke 2004; 35:1355. 10. Aroor S, Singh R, Goldstein LB. BE-FAST (Balance, Eyes, Face, Arm, Speech, Time): Reducing the Proportion of Strokes Missed Using the FAST Mnemonic. Stroke 2017; 48:479. 11. Kothari R, Hall K, Brott T, Broderick J. Early stroke recognition: developing an out-of-hospital NIH Stroke Scale. Acad Emerg Med 1997; 4:986. 12. Kothari RU, Pancioli A, Liu T, et al. Cincinnati Prehospital Stroke Scale: reproducibility and validity. Ann Emerg Med 1999; 33:373. 13. Goldstein LB, Simel DL. Is this patient having a stroke? JAMA 2005; 293:2391. 14. Kidwell CS, Starkman S, Eckstein M, et al. Identifying stroke in the field. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke 2000; 31:71. 15. Nor AM, Davis J, Sen B, et al. The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. Lancet Neurol 2005; 4:727. 16. Han F, Zuo C, Zheng G. A systematic review and meta-analysis to evaluate the diagnostic accuracy of recognition of stroke in the emergency department (ROSIER) scale. BMC Neurol 2020; 20:304. 17. Schlemm L, Ebinger M, Nolte CH, Endres M. Impact of Prehospital Triage Scales to Detect Large Vessel Occlusion on Resource Utilization and Time to Treatment. Stroke 2018; 49:439. 18. P rez de la Ossa N, Carrera D, Gorchs M, et al. Design and validation of a prehospital stroke scale to predict large arterial occlusion: the rapid arterial occlusion evaluation scale. Stroke 2014; 45:87. 19. Llanes JN, Kidwell CS, Starkman S, et al. The Los Angeles Motor Scale (LAMS): a new measure to characterize stroke severity in the field. Prehosp Emerg Care 2004; 8:46. 20. Nazliel B, Starkman S, Liebeskind DS, et al. A brief prehospital stroke severity scale identifies ischemic stroke patients harboring persisting large arterial occlusions. Stroke 2008; https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 14/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate 39:2264. 21. Katz BS, McMullan JT, Sucharew H, et al. Design and validation of a prehospital scale to predict stroke severity: Cincinnati Prehospital Stroke Severity Scale. Stroke 2015; 46:1508. 22. McMullan JT, Katz B, Broderick J, et al. Prospective Prehospital Evaluation of the Cincinnati Stroke Triage Assessment Tool. Prehosp Emerg Care 2017; 21:481. 23. Lima FO, Silva GS, Furie KL, et al. Field Assessment Stroke Triage for Emergency Destination: A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes. Stroke 2016; 47:1997. 24. Smith EE, Kent DM, Bulsara KR, et al. Accuracy of Prediction Instruments for Diagnosing Large Vessel Occlusion in Individuals With Suspected Stroke: A Systematic Review for the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke. Stroke 2018; 49:e111. 25. Nguyen TTM, van den Wijngaard IR, Bosch J, et al. Comparison of Prehospital Scales for Predicting Large Anterior Vessel Occlusion in the Ambulance Setting. JAMA Neurol 2021; 78:157. 26. Duvekot MHC, Venema E, Rozeman AD, et al. Comparison of eight prehospital stroke scales to detect intracranial large-vessel occlusion in suspected stroke (PRESTO): a prospective observational study. Lancet Neurol 2021; 20:213. 27. Grewal P, Lahoti S, Aroor S, et al. Effect of Known Atrial Fibrillation and Anticoagulation Status on the Prehospital Identification of Large Vessel Occlusion. J Stroke Cerebrovasc Dis 2019; 28:104404. 28. Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989; 20:864. 29. Goldstein LB, Bertels C, Davis JN. Interrater reliability of the NIH stroke scale. Arch Neurol 1989; 46:660. 30. Wityk RJ, Pessin MS, Kaplan RF, Caplan LR. Serial assessment of acute stroke using the NIH Stroke Scale. Stroke 1994; 25:362. 31. Leifer D, Bravata DM, Connors JJ 3rd, et al. Metrics for measuring quality of care in comprehensive stroke centers: detailed follow-up to Brain Attack Coalition comprehensive stroke center recommendations: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42:849. 32. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 15/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344.
impairments, and measure outcome. No single stroke scale is available or appropriate for all purposes, and each available scale has its own inherent limitations. (See 'Role of scales in stroke assessment' above.) The Cincinnati Prehospital Stroke Scale (CPSS) or the Face Arm Speech Test (FAST) have been suggested for use by prehospital personnel because they are easy to learn and rapidly administered. BE-FAST offers the advantage of also capturing vertebrobasilar symptoms and is being used more widely, but it has not been fully validated in the prehospital setting. (See 'Stroke diagnosis' above.) Scales to detect ischemic stroke caused by large artery occlusion, such as the Rapid Arterial oCclusion Evaluation (RACE) scale, have limited utility; none of the available scales has both high sensitivity and specificity. (See 'Large vessel occlusion triage' above.) The National Institutes of Health Stroke Scale (NIHSS) is a measure of general stroke impairment and is useful for both clinical and research purposes. (See 'NIHSS' above.) Despite their shortcomings, the Barthel Index and Rankin Scales are the most widely used measures of stroke-related disability and handicap, respectively. (See 'Barthel Index' above and 'Modified Rankin Scale' above.) Health-Related Quality of Life (HRQOL) in patients with stroke may be best measured with a stroke-specific instrument such as the Stroke Impact Scale (SIS). Use of UpToDate is subject to the Terms of Use. REFERENCES 1. World Health Organization. International Classification of Functioning, Disability and Health (ICF). http://www.who.int/classifications/icf/en/ (Accessed on April 21, 2011). 2. Orgogozo JM. The concepts of impairment, disability, and handicap. Cerebrovasc Dis 1994; 4 (Suppl 2):2. 3. Duncan PW, Samsa GP, Weinberger M, et al. Health status of individuals with mild stroke. Stroke 1997; 28:740. 4. Zhelev Z, Walker G, Henschke N, et al. Prehospital stroke scales as screening tools for early identification of stroke and transient ischemic attack. Cochrane Database Syst Rev 2019; 4:CD011427. 5. American Stroke Association. Stroke symptoms. Available at: https://www.stroke.org/en/abo ut-stroke/stroke-symptoms (Accessed on March 05, 2021). https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 13/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate 6. Centers for Disease Control and Prevention. Stroke signs and symptoms. Available at: http s://www.cdc.gov/stroke/signs_symptoms.htm (Accessed on March 05, 2021). 7. Rudd M, Buck D, Ford GA, Price CI. A systematic review of stroke recognition instruments in hospital and prehospital settings. Emerg Med J 2016; 33:818. 8. Harbison J, Hossain O, Jenkinson D, et al. Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance staff using the face arm speech test. Stroke 2003; 34:71. 9. Nor AM, McAllister C, Louw SJ, et al. Agreement between ambulance paramedic- and physician-recorded neurological signs with Face Arm Speech Test (FAST) in acute stroke patients. Stroke 2004; 35:1355. 10. Aroor S, Singh R, Goldstein LB. BE-FAST (Balance, Eyes, Face, Arm, Speech, Time): Reducing the Proportion of Strokes Missed Using the FAST Mnemonic. Stroke 2017; 48:479. 11. Kothari R, Hall K, Brott T, Broderick J. Early stroke recognition: developing an out-of-hospital NIH Stroke Scale. Acad Emerg Med 1997; 4:986. 12. Kothari RU, Pancioli A, Liu T, et al. Cincinnati Prehospital Stroke Scale: reproducibility and validity. Ann Emerg Med 1999; 33:373. 13. Goldstein LB, Simel DL. Is this patient having a stroke? JAMA 2005; 293:2391. 14. Kidwell CS, Starkman S, Eckstein M, et al. Identifying stroke in the field. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke 2000; 31:71. 15. Nor AM, Davis J, Sen B, et al. The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. Lancet Neurol 2005; 4:727. 16. Han F, Zuo C, Zheng G. A systematic review and meta-analysis to evaluate the diagnostic accuracy of recognition of stroke in the emergency department (ROSIER) scale. BMC Neurol 2020; 20:304. 17. Schlemm L, Ebinger M, Nolte CH, Endres M. Impact of Prehospital Triage Scales to Detect Large Vessel Occlusion on Resource Utilization and Time to Treatment. Stroke 2018; 49:439. 18. P rez de la Ossa N, Carrera D, Gorchs M, et al. Design and validation of a prehospital stroke scale to predict large arterial occlusion: the rapid arterial occlusion evaluation scale. Stroke 2014; 45:87. 19. Llanes JN, Kidwell CS, Starkman S, et al. The Los Angeles Motor Scale (LAMS): a new measure to characterize stroke severity in the field. Prehosp Emerg Care 2004; 8:46. 20. Nazliel B, Starkman S, Liebeskind DS, et al. A brief prehospital stroke severity scale identifies ischemic stroke patients harboring persisting large arterial occlusions. Stroke 2008; https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 14/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate 39:2264. 21. Katz BS, McMullan JT, Sucharew H, et al. Design and validation of a prehospital scale to predict stroke severity: Cincinnati Prehospital Stroke Severity Scale. Stroke 2015; 46:1508. 22. McMullan JT, Katz B, Broderick J, et al. Prospective Prehospital Evaluation of the Cincinnati Stroke Triage Assessment Tool. Prehosp Emerg Care 2017; 21:481. 23. Lima FO, Silva GS, Furie KL, et al. Field Assessment Stroke Triage for Emergency Destination: A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes. Stroke 2016; 47:1997. 24. Smith EE, Kent DM, Bulsara KR, et al. Accuracy of Prediction Instruments for Diagnosing Large Vessel Occlusion in Individuals With Suspected Stroke: A Systematic Review for the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke. Stroke 2018; 49:e111. 25. Nguyen TTM, van den Wijngaard IR, Bosch J, et al. Comparison of Prehospital Scales for Predicting Large Anterior Vessel Occlusion in the Ambulance Setting. JAMA Neurol 2021; 78:157. 26. Duvekot MHC, Venema E, Rozeman AD, et al. Comparison of eight prehospital stroke scales to detect intracranial large-vessel occlusion in suspected stroke (PRESTO): a prospective observational study. Lancet Neurol 2021; 20:213. 27. Grewal P, Lahoti S, Aroor S, et al. Effect of Known Atrial Fibrillation and Anticoagulation Status on the Prehospital Identification of Large Vessel Occlusion. J Stroke Cerebrovasc Dis 2019; 28:104404. 28. Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989; 20:864. 29. Goldstein LB, Bertels C, Davis JN. Interrater reliability of the NIH stroke scale. Arch Neurol 1989; 46:660. 30. Wityk RJ, Pessin MS, Kaplan RF, Caplan LR. Serial assessment of acute stroke using the NIH Stroke Scale. Stroke 1994; 25:362. 31. Leifer D, Bravata DM, Connors JJ 3rd, et al. Metrics for measuring quality of care in comprehensive stroke centers: detailed follow-up to Brain Attack Coalition comprehensive stroke center recommendations: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42:849. 32. Powers WJ, Rabinstein AA, Ackerson T, et al. 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Intermodal agreement of follow-up telephone functional assessment using the Functional Independence Measure in patients with stroke. Arch Phys Med Rehabil 1996; 77:431. 96. Chong DK. Measurement of instrumental activities of daily living in stroke. Stroke 1995; 26:1119. 97. Schuling J, de Haan R, Limburg M, Groenier KH. The Frenchay Activities Index. Assessment of functional status in stroke patients. Stroke 1993; 24:1173. 98. Tooth LR, McKenna KT, Smith M, O'Rourke P. Further evidence for the agreement between patients with stroke and their proxies on the Frenchay Activities Index. Clin Rehabil 2003; 17:656. 99. Post MW, de Witte LP. Good inter-rater reliability of the Frenchay Activities Index in stroke patients. Clin Rehabil 2003; 17:548. 100. RANKIN J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J 1957; 2:200. 101. van Swieten JC, Koudstaal PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. 102. Bamford JM, Sandercock PA, Warlow CP, Slattery J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1989; 20:828. 103. New PW, Buchbinder R. Critical appraisal and review of the Rankin scale and its derivatives. Neuroepidemiology 2006; 26:4. 104. Saver JL, Filip B, Hamilton S, et al. Improving the reliability of stroke disability grading in clinical trials and clinical practice: the Rankin Focused Assessment (RFA). Stroke 2010; 41:992. 105. Whiteneck GG, Charlifue SW, Gerhart KA, et al. Quantifying handicap: a new measure of long-term rehabilitation outcomes. Arch Phys Med Rehabil 1992; 73:519. 106. Segal ME, Schall RR. Assessing handicap of stroke survivors. A validation study of the Craig Handicap Assessment and Reporting Technique. Am J Phys Med Rehabil 1995; 74:276. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 20/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate 107. de Haan R, Limburg M, Bossuyt P, et al. The clinical meaning of Rankin 'handicap' grades after stroke. Stroke 1995; 26:2027. 108. Kuklina E, Callaghan W. Chronic heart disease and severe obstetric morbidity among hospitalisations for pregnancy in the USA: 1995-2006. BJOG 2011; 118:345. 109. Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke 2007; 38:1091. 110. Quinn TJ, Dawson J, Walters MR, Lees KR. Exploring the reliability of the modified rankin scale. Stroke 2009; 40:762. 111. Quinn TJ, Dawson J, Walters MR, Lees KR. Reliability of the modified Rankin Scale: a systematic review. Stroke 2009; 40:3393. 112. Lev MH, Segal AZ, Farkas J, et al. Utility of perfusion-weighted CT imaging in acute middle cerebral artery stroke treated with intra-arterial thrombolysis: prediction of final infarct volume and clinical outcome. Stroke 2001; 32:2021. 113. Wolfe CD, Taub NA, Woodrow EJ, Burney PG. Assessment of scales of disability and handicap for stroke patients. Stroke 1991; 22:1242. 114. De Haan R, Horn J, Limburg M, et al. A comparison of five stroke scales with measures of disability, handicap, and quality of life. Stroke 1993; 24:1178. 115. Burn JP. Reliability of the modified Rankin Scale. Stroke 1992; 23:438. 116. Saver JL. Number needed to treat estimates incorporating effects over the entire range of clinical outcomes: novel derivation method and application to thrombolytic therapy for acute stroke. Arch Neurol 2004; 61:1066. 117. Savitz SI, Lew R, Bluhmki E, et al. Shift analysis versus dichotomization of the modified Rankin scale outcome scores in the NINDS and ECASS-II trials. Stroke 2007; 38:3205. 118. Williams LS. Health-related quality of life outcomes in stroke. Neuroepidemiology 1998; 17:116. 119. Bergner M, Bobbitt RA, Carter WB, Gilson BS. The Sickness Impact Profile: development and final revision of a health status measure. Med Care 1981; 19:787. 120. Rothman ML, Hedrick S, Inui T. The Sickness Impact Profile as a measure of the health status of noncognitively impaired nursing home residents. Med Care 1989; 27:S157. 121. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30:473. 122. Mathias SD, Bates MM, Pasta DJ, et al. Use of the Health Utilities Index with stroke patients and their caregivers. Stroke 1997; 28:1888. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 21/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate 123. Grootendorst P, Feeny D, Furlong W. Health Utilities Index Mark 3: evidence of construct validity for stroke and arthritis in a population health survey. Med Care 2000; 38:290. 124. Rothman ML, Williams KHR. Validity of the Health Utilities Index in evaluating therapies for acute stroke [abstract]. Qual Life Res 1997; 6:710. 125. Goldstein LB, Lyden P, Mathias SD, et al. Telephone assessment of functioning and well- being following stroke: is it feasible? J Stroke Cerebrovasc Dis 2002; 11:80. 126. EuroQol Group. EuroQol a new facility for the measurement of health-related quality of life. Health Policy 1990; 16:199. 127. Dorman PJ, Waddell F, Slattery J, et al. Is the EuroQol a valid measure of health-related quality of life after stroke? Stroke 1997; 28:1876. 128. Dorman P, Slattery J, Farrell B, et al. Qualitative comparison of the reliability of health status assessments with the EuroQol and SF-36 questionnaires after stroke. United Kingdom Collaborators in the International Stroke Trial. Stroke 1998; 29:63. 129. Sneeuw KC, Aaronson NK, de Haan RJ, Limburg M. Assessing quality of life after stroke. The value and limitations of proxy ratings. Stroke 1997; 28:1541. 130. de Haan R, Limburg M. The relationship between impairment and functional health scales in the outcome of stroke. Cerebrovasc Dis 1994; 4 (Suppl 2):19. 131. Duncan PW, Wallace D, Lai SM, et al. The stroke impact scale version 2.0. Evaluation of reliability, validity, and sensitivity to change. Stroke 1999; 30:2131. 132. Williams LS, Weinberger M, Harris LE, et al. Development of a stroke-specific quality of life scale. Stroke 1999; 30:1362. 133. Post MW, Boosman H, van Zandvoort MM, et al. Development and validation of a short version of the Stroke Specific Quality of Life Scale. J Neurol Neurosurg Psychiatry 2011; 82:283. 134. van Straten A, de Haan RJ, Limburg M, et al. A stroke-adapted 30-item version of the Sickness Impact Profile to assess quality of life (SA-SIP30). Stroke 1997; 28:2155. 135. Lin KC, Fu T, Wu CY, et al. Psychometric comparisons of the Stroke Impact Scale 3.0 and Stroke-Specific Quality of Life Scale. Qual Life Res 2010; 19:435. 136. Duncan PW, Lai SM, Bode RK, et al. Stroke Impact Scale-16: A brief assessment of physical function. Neurology 2003; 60:291. 137. Duncan PW, Reker DM, Horner RD, et al. Performance of a mail-administered version of a stroke-specific outcome measure, the Stroke Impact Scale. Clin Rehabil 2002; 16:493. 138. Duncan PW, Lai SM, Tyler D, et al. Evaluation of proxy responses to the Stroke Impact Scale. Stroke 2002; 33:2593. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 22/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Topic 14084 Version 16.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 23/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate GRAPHICS Face Arm Speech Test Reproduced with permission from: Harbison J, Hossain O, Jenkinson D, et al. Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance sta using the face arm speech test. Stroke 2003; 34:71. Copyright 2003 Lippincott Williams & Wilkins. Graphic 54134 Version 7.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 24/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Cincinnati Prehospital Stroke Scale (CPSS) The CPSS evaluates for facial palsy, arm weakness, and speech abnormalities. Items are scored as either normal or abnormal. Facial droop The patient shows teeth or smiles Normal: Both sides of face move equally. Abnormal: One side of face does not move as well as the other. Arm drift The patient closes their eyes and extends both arms straight out for 10 seconds Normal: Both arms move the same, or both arms do not move at all. Abnormal: One arm either does not move, or one arm drifts down compared to the other. Speech The patient repeats "The sky is blue in Cincinnati" Normal: The patient says correct words with no slurring of words. Abnormal: The patient slurs words, says the wrong words, or is unable to speak. Reproduced from: Kothari RU, Pancioli A, Liu T, et al. Cincinnati Prehospital Stroke Scale: reproducibility and validity. Ann Emerg Med 1999; 33:373. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 62856 Version 3.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 25/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Los Angeles Prehospital Stroke Screen Reproduced with permission from: Kidwell CS, Starkman S, Eckstein M, et al. Identifying stroke in the eld. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke 2000; 31:71. Copyright 2000 Lippincott Williams & Wilkins. Graphic 78128 Version 10.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 26/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Glasgow Coma Scale (GCS) Score Eye opening Spontaneous 4 Response to verbal command 3 Response to pain 2 No eye opening 1 Best verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible sounds 2 No verbal response 1 Best motor response Obeys commands 6 Localizing response to pain 5 Withdrawal response to pain 4 Flexion to pain 3 Extension to pain 2 No motor response 1 Total The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. Graphic 81854 Version 9.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 27/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Rapid Arterial oCclusion Evaluation (RACE) scale RACE NIHSS score Item score equivalence Facial palsy Absent 0 0 Mild 1 1 Moderate to severe 2 2 to 3 Arm motor function Normal to mild 0 0 to 1 Moderate 1 2 Severe 2 3 to 4 Leg motor function Normal to mild 0 0 to 1 Moderate 1 2 Severe 2 3 to 4 Head and gaze deviation Absent 0 0 Present 1 1 to 2 Aphasia* (if right hemiparesis) Performs both tasks correctly 0 0 Performs 1 task correctly 1 1 Performs neither tasks 2 2 Agnosia (if left hemiparesis) Patient recognizes their arm and the impairment 0 0 Does not recognize their arm or the impairment 1 1 Does not recognize their arm nor the impairment 2 2 Score total 0 to 9 Aphasia: Ask the patient to (1) "close your eyes"; (2) "make a fist" and evaluate if the patient obeys. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 28/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Agnosia: Ask the patient: (1) while showing their the paretic arm: "Whose arm is this" and evaluate if the patient recognizes their own arm. (2) "Can you lift both arms and clap" and evaluate if the patient recognizes their functional impairment. From: P rez de la Ossa N, Carrera D, Gorchs M, et al. Design and validation of a prehospital stroke scale to predict large arterial occlusion: the rapid arterial occlusion evaluation scale. Stroke 2014; 45:87. DOI: 10.1161/STROKEAHA.113.003071. Copyright American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130953 Version 2.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 29/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate The Los Angeles Motor Scale (LAMS) Facial droop Absent 0 Present 1 Arm drift Absent 0 Drifts down 1 Falls rapidly 2 Grip strength Normal 0 Weak grip 1 No grip 2 From: Nazliel B, Starkman S, Liebeskind DS, et al. A brief prehospital stroke severity scale identi es ischemic stroke patients harboring persisting large arterial occlusions. Stroke 2008; 39:2264. DOI: 10.1161/STROKEAHA.107.508127. Copyright 2008 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130951 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 30/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Cincinnati Stroke Triage Assessment Tool (C-STAT) Score Symptom NIHSS equivalent 1 on NIHSS item for Gaze 2 points Conjugate gaze deviation 1 on NIHSS item for Level of consciousness 1b and 1c 1 point Incorrectly answers at least one of two level of consciousness questions on NIHSS (age or current month) and does not follow at least one of two commands (close eyes, open and close hand) 2 on the NIHSS item for Motor arm 1 point Cannot hold arm (either right, left, or both) up to 10 seconds before arm(s) falls to bed NIHSS: National Institutes of Health Stroke Scale. From: Katz BS, McMullan JT, Sucharew H, et al. Design and validation of a prehospital scale to predict stroke severity: Cincinnati Prehospital Stroke Severity Scale. Stroke 2015; 46:1508. DOI: 10.1161/STROKEAHA.115.008804. Copyright American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130949 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 31/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate The FAST-ED scale and its correspondence to the NIHSS NIHSS FAST-ED Item score source score Facial palsy Normal or minor paralysis 0 0 to 1 Partial or complete paralysis 1 2 to 3 Arm weakness No drift 0 0 Drift or some effort against gravity 1 1 to 2 No effort against gravity or no movement 2 3 to 4 Speech changes Absent 0 0 Mild to moderate 1 1 Severe, global aphasia, or mute 2 2 to 3 Eye deviation Absent 0 0 Partial 1 1 Forced deviation 2 2 Denial/neglect Absent 0 0 Extinction to bilateral simultaneous stimulation in only 1 sensory modality 1 1 Does not recognize own hand or orients only to one side of the 2 2 body FAST-ED: Field Assessment Stroke Triage for Emergency Destination; NIHSS: National Institutes of Health Stroke Scale. From: Lima FO, Silva GS, Furie KL, et al. Field Assessment Stroke Triage for Emergency Destination: A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes. Stroke 2016; 47:1997. DOI: 10.1161/STROKEAHA.116.013301. Copyright 2016 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 32/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Graphic 130950 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 33/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The investigator must choose a response if a full 0 = Alert; keenly responsive. 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. evaluation is prevented by such obstacles as an endotracheal tube, language barrier, 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored to attend, or is obtunded and requires only if the patient makes no movement (other than reflexive posturing) in response _____ strong or painful stimulation to make movements (not stereotyped). to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no 1 = Answers one question correctly. 2 = Answers neither question correctly. partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The patient is asked to open and close the eyes 0 = Performs both tasks correctly. _____ 1 = Performs one task correctly. and then to grip and release the non-paretic hand. Substitute another one step 2 = Performs neither task correctly. command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 34/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If the patient has a conjugate deviation of the total gaze paresis is not present. 2 = Forced deviation, or total gaze paresis eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a not overcome by the oculocephalic maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, 0 = No visual loss. 1 = Partial hemianopia. using finger counting or visual threat, as appropriate. Patients may be encouraged, 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as 3 = Bilateral hemianopia (blind including cortical blindness). normal. If there is unilateral blindness or
29/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate The Los Angeles Motor Scale (LAMS) Facial droop Absent 0 Present 1 Arm drift Absent 0 Drifts down 1 Falls rapidly 2 Grip strength Normal 0 Weak grip 1 No grip 2 From: Nazliel B, Starkman S, Liebeskind DS, et al. A brief prehospital stroke severity scale identi es ischemic stroke patients harboring persisting large arterial occlusions. Stroke 2008; 39:2264. DOI: 10.1161/STROKEAHA.107.508127. Copyright 2008 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130951 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 30/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Cincinnati Stroke Triage Assessment Tool (C-STAT) Score Symptom NIHSS equivalent 1 on NIHSS item for Gaze 2 points Conjugate gaze deviation 1 on NIHSS item for Level of consciousness 1b and 1c 1 point Incorrectly answers at least one of two level of consciousness questions on NIHSS (age or current month) and does not follow at least one of two commands (close eyes, open and close hand) 2 on the NIHSS item for Motor arm 1 point Cannot hold arm (either right, left, or both) up to 10 seconds before arm(s) falls to bed NIHSS: National Institutes of Health Stroke Scale. From: Katz BS, McMullan JT, Sucharew H, et al. Design and validation of a prehospital scale to predict stroke severity: Cincinnati Prehospital Stroke Severity Scale. Stroke 2015; 46:1508. DOI: 10.1161/STROKEAHA.115.008804. Copyright American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130949 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 31/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate The FAST-ED scale and its correspondence to the NIHSS NIHSS FAST-ED Item score source score Facial palsy Normal or minor paralysis 0 0 to 1 Partial or complete paralysis 1 2 to 3 Arm weakness No drift 0 0 Drift or some effort against gravity 1 1 to 2 No effort against gravity or no movement 2 3 to 4 Speech changes Absent 0 0 Mild to moderate 1 1 Severe, global aphasia, or mute 2 2 to 3 Eye deviation Absent 0 0 Partial 1 1 Forced deviation 2 2 Denial/neglect Absent 0 0 Extinction to bilateral simultaneous stimulation in only 1 sensory modality 1 1 Does not recognize own hand or orients only to one side of the 2 2 body FAST-ED: Field Assessment Stroke Triage for Emergency Destination; NIHSS: National Institutes of Health Stroke Scale. From: Lima FO, Silva GS, Furie KL, et al. Field Assessment Stroke Triage for Emergency Destination: A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes. Stroke 2016; 47:1997. DOI: 10.1161/STROKEAHA.116.013301. Copyright 2016 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 32/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Graphic 130950 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 33/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The investigator must choose a response if a full 0 = Alert; keenly responsive. 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. evaluation is prevented by such obstacles as an endotracheal tube, language barrier, 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored to attend, or is obtunded and requires only if the patient makes no movement (other than reflexive posturing) in response _____ strong or painful stimulation to make movements (not stereotyped). to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no 1 = Answers one question correctly. 2 = Answers neither question correctly. partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The patient is asked to open and close the eyes 0 = Performs both tasks correctly. _____ 1 = Performs one task correctly. and then to grip and release the non-paretic hand. Substitute another one step 2 = Performs neither task correctly. command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 34/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If the patient has a conjugate deviation of the total gaze paresis is not present. 2 = Forced deviation, or total gaze paresis eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a not overcome by the oculocephalic maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, 0 = No visual loss. 1 = Partial hemianopia. using finger counting or visual threat, as appropriate. Patients may be encouraged, 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as 3 = Bilateral hemianopia (blind including cortical blindness). normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial fold, asymmetry on smiling). raise eyebrows and close eyes. Score symmetry of grimace in response to noxious 2 = Partial paralysis (total or near-total stimuli in the poorly responsive or non- paralysis of lower face). comprehending patient. If facial trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 35/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate other physical barriers obscure the face, these should be removed to the extent 3 = Complete paralysis of one or both sides (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the 0 = No drift; limb holds 90 (or 45) degrees appropriate position: extend the arms (palms down) 90 degrees (if sitting) or 45 for full 10 seconds. 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not degrees (if supine). Drift is scored if the arm falls before 10 seconds. The aphasic patient hit bed or other support. is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) stimulation. Each limb is tested in turn, degrees, drifts down to bed, but has some effort against gravity. beginning with the non-paretic arm. Only in the case of amputation or joint fusion at the _____ shoulder, the examiner should record the score as untestable (UN), and clearly write 3 = No effort against gravity; limb falls. 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the 0 = No drift; leg holds 30-degree position appropriate position: hold the leg at 30 degrees (always tested supine). Drift is for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. scored if the leg falls before 5 seconds. The aphasic patient is encouraged using urgency in the voice and pantomime, but not 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. against gravity. _____ Only in the case of amputation or joint fusion at the hip, the examiner should 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and 4 = No movement. clearly write the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. 0 = Absent. _____ 1 = Present in one limb. Test with eyes open. In case of visual defect, 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, are performed on both sides, and ataxia is scored only if present out of proportion to explain:________________ weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 36/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick when tested, or withdrawal from noxious 0 = Normal; no sensory loss. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the stimulus in the obtunded or aphasic patient. Only sensory loss attributed to stroke is affected side; or there is a loss of superficial pain with pinprick, but patient is aware of scored as abnormal and the examiner should test as many body areas (arms [not being touched. hands], legs, trunk, face) as needed to 2 = Severe to total sensory loss; patient is accurately check for hemisensory loss. A score of 2, "severe or total sensory loss," not aware of being touched in the face, arm, and leg. should only be given when a severe or total loss of sensation can be clearly _____ demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of information about comprehension will be 0 = No aphasia; normal. _____ 1 = Mild-to-moderate aphasia; some obtained during the preceding sections of obvious loss of fluency or facility of comprehension, without significant the examination. For this scale item, the patient is asked to describe what is limitation on ideas expressed or form of expression. Reduction of speech and/or happening in the attached picture, to name the items on the attached naming sheet and comprehension, however, makes conversation about provided materials to read from the attached list of sentences. Comprehension is judged from responses here, as well as to all of the commands in difficult or impossible. For example, in conversation about provided materials, examiner can identify picture or naming the preceding general neurological exam. If visual loss interferes with the tests, ask the card content from patient's response. patient to identify objects placed in the hand, repeat, and produce speech. The 2 = Severe aphasia; all communication is through fragmentary expression; great need intubated patient should be asked to write. for inference, questioning, and guessing by The patient in a coma (item 1a=3) will automatically score 3 on this item. The the listener. Range of information that can be exchanged is limited; listener carries examiner must choose a score for the patient with stupor or limited cooperation, burden of communication. Examiner cannot but a score of 3 should be used only if the https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 37/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal, an adequate sample of speech must 0 = Normal. 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can be obtained by asking patient to read or repeat words from the attached list. If the be understood with some difficulty. patient has severe aphasia, the clarity of articulation of spontaneous speech can be 2 = Severe dysarthria; patient's speech is so slurred as to be unintelligible in the absence _____ rated. Only if the patient is intubated or has of or out of proportion to any dysphasia, or other physical barriers to producing speech, the examiner should record the score as is mute/anarthric. untestable (UN), and clearly write an explanation for this choice. Do not tell the UN = Intubated or other physical barrier, explain:________________ patient why he or she is being tested. 11. Extinction and inattention (formerly neglect): Sufficient information to identify 0 = No abnormality. 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous bilateral simultaneous stimulation in one of the sensory modalities. stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient 2 = Profound hemi-inattention or extinction to more than one modality; _____ has aphasia but does appear to attend to both sides, the score is normal. The does not recognize own hand or orients to only one side of space. presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 38/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate The Modified National Institutes of Health Stroke Scale (mNIHSS) scoring sheet Patient score Item number Item name Scoring guide 1b LOC questions 0 = Answers both correctly 1 = Answers one correctly _____ 2 = Answers neither correctly 1c LOC commands 0 = Performs both tasks correctly 1 = Performs one task _____ correctly 2 = Performs neither task 2 Gaze 0 = Normal 1 = Partial gaze palsy _____ 2 = Total gaze palsy 3 Visual fields 0 = No visual loss 1 = Partial hemianopsia _____ 2 = Complete hemianopsia 3 = Bilateral hemianopsia 5a Left arm motor 0 = No drift 1 = Drift before 10 seconds 2 = Falls before 10 seconds _____ 3 = No effort against gravity 4 = No movement https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 39/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate 5b Right arm motor 0 = No drift 1 = Drift before 10 seconds 2 = Falls before 10 seconds _____ 3 = No effort against gravity 4 = No movement 6a Left leg motor 0 = No drift 1 = Drift before 5 seconds 2 = Falls before 5 seconds _____ 3 = No effort against gravity 4 = No movement 6b Right leg motor 0 = No drift 1 = Drift before 5 seconds 2 = Falls before 5 seconds _____ 3 = No effort against gravity 4 = No movement 8 Sensory 0 = Normal _____ 1 = Abnormal 9 Language 0 = Normal 1 = Mild aphasia _____ 2 = Severe aphasia 3 = Mute or global aphasia 11 Neglect 0 = Normal 1 = Mild _____ 2 = Severe Score (out of 31): _____ The item numbers correspond to the NIHSS scale. The scale is shorter, having only 11 total items (versus 15 items on the NIHSS). LOC: level of consciousness. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 40/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate From: Meyer BC, Hemmen TM, Jackson CM, Lyden PD. Modi ed National Institutes of Health Stroke Scale for use in stroke clinical trials: prospective reliability and validity. Stroke 2002; 33:1261. DOI: 10.1161/01.str.0000015625.87603.a7. Copyright 2002 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130998 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 41/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Pediatric National Institutes of Health Stroke Scale (PedNIHSS) PedNIHSS INSTRUCTIONS: Administer stroke scale items in the order listed. Follow directions provided for each exam item. Scores should reflect what the patient does, not what the clinician thinks the patient can do. MODIFICATIONS FOR CHILDREN: Modi cations to testing instructions from the adult version for use in children are shown in bold italic with each item where appropriate. Items with no modi cations should be administered and scored with children in the same manner as for adults. Scale definition and Item# and instructions scoring guide 1a. Level of consciousness: The investigator must choose a response, even if a full evaluation 0 = Alert; keenly responsive. is prevented by such obstacles as an endotracheal tube, language barrier, orotracheal trauma/bandages. A 3 is scored only if the 1 = Not alert, but arousable by minor stimulation to obey, answer, or respond. patient makes no movement (other than reflexive posturing) in response to noxious stimulation. 2 = Not alert, requires repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, areflexic. 1b. LOC questions: The patient is asked the month and his/her age. The answer must 0 = Answers both questions be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will correctly. 1 = Answers one question correctly. score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from any cause, 2 = Answers neither question language barrier or any other problem not secondary to aphasia correctly. are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non- verbal cues. Modi ed for children, age 2 years and up. A familiar Family Member must be present for this item: Ask the child "how old are you?" Or "How many years old are you?" for question number one. Give credit if the child states the correct age, or shows the correct number of ngers for his/her age. For the second question, ask the child "where is XX?", XX referring to the name of the parent or other familiar family member present. Use the name for that person which the child typically uses, eg, https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 42/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate "mommy". Give credit if the child correctly points to or gazes purposefully in the direction of the family member. 1c. LOC commands: The patient is asked to open and close the eyes and then to grip 0 = Performs both tasks and release the non-paretic hand. For children one may substitute the command to grip the hand with the command "show me your correctly. 1 = Performs one task correctly. nose" or "touch your nose". Substitute another one step command if the hands cannot be used. Credit is given if an 2 = Performs neither task unequivocal attempt is made but not completed due to weakness. correctly. If the patient does not respond to command, the task should be demonstrated to them (pantomime) and score the result (ie, follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or reflexive (oculocephalic) eye movements will be scored but caloric 0 = Normal. 1 = Partial gaze palsy. This score is given when gaze is testing is not done. If the patient has a conjugate deviation of the eyes that can be overcome by voluntary or reflexive activity, the abnormal in one or both eyes, but where forced deviation or score will be 1. If a patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI) score a 1. Gaze is testable in all aphasic total gaze paresis are not present. patients. Patients with ocular trauma, bandages, pre-existing blindness or other disorder of visual acuity or fields should be tested with reflexive movements and a choice made by the 2 = Forced deviation, or total gaze paresis not overcome by investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a the oculocephalic maneuver. partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting (for children >6 years) or 0 = No visual loss. 1 = Partial hemianopia. visual threat (for children age 2 to 6 years) as appropriate. Patient must be encouraged, but if they look at the side of the moving 2 = Complete hemianopia. fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining 3 = Bilateral hemianopia (blind including cortical blindness). eye are scored. Score 1 only if a clear-cut asymmetry, including quadrantanopia is found. If patient is blind from any cause score 3. Double simultaneous stimulation is performed at this point. If there is extinction patient receives a 1 and the results are used to answer question 11. 4. Facial palsy: Ask, or use pantomime to encourage the patient to show teeth or 0 = Normal symmetrical raise eyebrows and close eyes. Score symmetry of grimace in movement. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 43/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate response to noxious stimuli in the poorly responsive or non- 1 = Minor paralysis (flattened comprehending patient. If facial trauma/bandages, orotracheal tube, tape or other physical barrier obscures the face, these nasolabial fold, asymmetry on smiling). should be removed to the extent possible. 2 = Partial paralysis (total or near total paralysis of lower face). 3 = Complete paralysis of one or both sides (absence of facial movement in the upper and lower face). 5 & 6. Motor arm and leg: https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 44/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate The limb is placed in the appropriate position: extend the arms 5a. Left arm (palms down) 90 degrees (if sitting) or 45 degrees (if supine) and the leg 30 degrees (always tested supine). Drift is scored if the arm 5b. Right arm 0 = No drift, limb holds 90 (or 45) degrees for full 10 falls before 10 seconds or the leg before 5 seconds. For children too immature to follow precise directions or uncooperative for seconds. any reason, power in each limb should be graded by observation of spontaneous or elicited movement according to the same 1 = Drift, limb holds 90 (or 45) degrees, but drifts down grading scheme, excluding the time limits. The aphasic patient is before full 10 seconds; does encouraged using urgency in the voice and pantomime but not noxious stimulation. Each limb is tested in turn, beginning with not hit bed or other support. the non-paretic arm. Only in the case of amputation or joint fusion at the shoulder or hip, or immobilization by an IV board, may the 2 = Some effort against gravity, limb cannot get to or score be "9" and the examiner must clearly write the explanation maintain (if cued) 90 (or 45) degrees, drifts down to bed, for scoring as a "9". Score each limb separately. but has some effort against gravity. 3 = No effort against gravity, limb falls. 4 = No movement. 9 = Amputation, joint fusion explain. 6a. Left leg 6b. Right leg 0 = No drift, leg holds 30 degrees position for full 5 seconds. 1 = Drift, leg falls by the end of the 5 second period but does not hit bed. 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. 3 = No effort against gravity, leg falls to bed immediately. 4 = No movement. 9 = Amputation, joint fusion explain. 7. Limb ataxia: https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 45/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate This item is aimed at finding evidence of a unilateral cerebellar 0 = Absent. lesion. Test with eyes open. In case of visual defect, insure testing 1 = Present in one limb. is done in intact visual field. The finger-nose-finger and heel-shin 2 = Present in two limbs. tests are performed on both sides, and ataxia is scored only if present out of proportion to weakness. In children, substitute this task with reaching for a toy for the upper extremity, and kicking a toy or the examiner's hand, in children too young (<5 years) or otherwise uncooperative for the standard exam item. Ataxia is absent in the patient who cannot understand or is paralyzed. Only in the case of amputation or joint fusion may the item be scored "9", and the examiner must clearly write the explanation for not scoring. In case of blindness test by touching nose from extended arm position. 8. Sensory: Sensation or grimace to pin prick when tested, or withdrawal from 0 = Normal; no sensory loss. noxious stimulus in the obtunded or aphasic patient. For children 1 = Mild to moderate sensory too young or otherwise uncooperative for reporting gradations of loss; patient feels pinprick is sensory loss, observe for any behavioral response to pin prick, less sharp or is dull on the affected side; or there is a loss and score it according to the same scoring scheme as a "normal" response, "mildly diminished" or "severely diminished" response. of superficial pain with Only sensory loss attributed to stroke is scored as abnormal and pinprick but patient is aware the examiner should test as many body areas [arms (not hands), he/she is being touched. legs, trunk, face] as needed to accurately check for hemisensory 2 = Severe to total sensory loss. A score of 2, "severe or total," should only be given when a severe or total loss of sensation can be clearly demonstrated. loss; patient is not aware of being touched in the face, Stuporous and aphasic patients will therefore probably score 1 or arm, and leg. 0. 9. Best language: A great deal of information about comprehension will be obtained 0 = No aphasia, normal. during the preceding sections of the examination. For children age 6 years and up with normal language development before 1 = Mild to moderate aphasia; some obvious loss of fluency onset of stroke: The patient is asked to describe what is or facility of comprehension, happening in the attached picture, to name the items on the without significant limitation on ideas expressed or form of attached naming sheet, to repeat words from the attached list, and to read from the attached list of sentences (see Table expression. Reduction of S1 "Language testing items" below, and see separate gures speech and/or for Cookie theft picture, Picture naming for PedNIHSS, and comprehension, however, Reading for PedNIHSS). Comprehension is judged from responses makes conversation about provided material difficult or here as well as to all of the commands in the preceding general neurological exam. If visual loss interferes with the tests, ask the impossible. For example in patient to identify objects placed in the hand, repeat, and produce conversation about provided speech. The intubated patient should be asked to write. The materials examiner can patient in coma (question 1a = 3) will arbitrarily score 3 on this identify picture or naming card from patient's response. item. The examiner must choose a score in the patient with stupor https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 46/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate or limited cooperation but a score of 3 should be used only if the 2 = Severe aphasia; all patient is mute and follows no one step commands. For children communication is through age 2 years to 6 years (or older children with premorbid language skills <6 year level), score this item based on observations of fragmentary expression; great need for inference, language comprehension and speech during the examination. questioning, and guessing by The patient with brain stem stroke who has bilateral loss of the listener. Range of sensation is scored 2. If the patient does not respond and is quadriplegic score 2. Patients in coma (item 1a = 3) are arbitrarily information that can be exchanged is limited; listener given a 2 on this item. carries burden of communication. Examiner cannot identify materials provided from patient response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal an adequate sample of speech 0 = Normal. must be obtained by asking patient to read or repeat words from 1 = Mild to moderate; patient the attached list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be rated. Only if the slurs at least some words and, at worst, can be understood patient is intubated or has other physical barrier to producing with some difficulty. speech, may the item be scored "9", and the examiner must 2 = Severe; patient's speech is clearly write an explanation for not scoring. Do not tell the patient why he/she is being tested. so slurred as to be unintelligible in the absence of or out of proportion to any dysphasia, or is mute/anarthric. 9 = Intubated or other physical barrier, explain. 11. Extinction and inattention (formerly neglect): Sufficient information to identify neglect may be obtained during 0 = No abnormality. the prior testing. If the patient has a severe visual loss preventing 1 = Visual, tactile, auditory, visual double simultaneous stimulation, and the cutaneous stimuli spatial, or personal inattention or extinction to are normal, the score is normal. If the patient has aphasia but does appear to attend to both sides, the score is normal. The bilateral simultaneous presence of visual spatial neglect or anosognosia may also be stimulation in one of the taken as evidence of abnormality. Since the abnormality is scored sensory modalities. only if present, the item is never untestable. 2 = Profound hemi-inattention or hemi-inattention to more than one modality. Does not https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 47/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate recognize own hand or orients to only one side of space. Table S1. Language testing items for PedNIHSS: Repetition Each of 4 word-repetition tasks is presented: a. Stop b. Stop and go c. If it rains we play inside d. The President lives in Washington Reading Each of 3 items is presented for the child to read (see separate "Reading items figure for PedNIHSS"). Adjust expectations according to child's age/school level. Name Pictures are presented of a clock, pencil, skateboard, shirt, baseball, and bicycle (see separate "Picture naming figure for PedNIHSS"). Fluency and word finding The Cookie theft picture is presented and the child is asked to describe what he/she sees (see separate "Cookie theft picture for NIHSS and PedNIHSS"). NIHSS: National Institutes of Health Stroke Scale; PedNIHSS: Pediatric National Institutes of Health Stroke Scale. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 76120 Version 2.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 48/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Reading items figure for PedNIHSS Words to test reading for Item 9 (Best language) of PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83404 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 49/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Picture naming figure for PedNIHSS Pictures to test naming for Item 9 (Best language) of PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83405 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 50/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Cookie theft picture for NIHSS and PedNIHSS Cookie theft picture to test story-telling for Item 9 Best language of NIHSS and PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83406 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 51/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Canadian Neurological Scale Patient Name: Rater Name: Date: Time: Mentation Score Level consciousness Alert 3.0 Drowsy 1.5 Orientation Oriented 1.0 Disoriented/NA 0.0 Speech Normal 1.0 Expressive deficit 0.5 Receptive deficit 0.0 TOTAL: Motor functions (no comprehension deficit) Weakness Score Face None 0.5 Present 0.0 Arm: proximal None 1.5 Mild 1.0 Significant 0.5 Total 0 Arm: distal None 1.5 Mild 1.0 Significant 0.5 Total 0 Leg None 1.5 Mild 1.0 Significant 0.5 Total 0 TOTAL: Motor response (comprehension deficit) Score https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 52/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Face Symmetrical .5 Asymmetrical 0 Arms Equal 1.5 Unequal 0 Legs Equal 1.5 Unequal 0 TOTAL: Reproduced with permission from: C t R, Hachinski VC, Shurvell BL, et al. The Canadian Neurological Scale: a preliminary study in acute stroke. Stroke 1986; 17:731. Copyright 1986 Lippincott Williams & Wilkins. Graphic 55644 Version 9.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 53/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Barthel Index Activity Score Feeding 0 = Unable 5 = Needs help cutting, spreading butter, etc, or requires modified diet 10 = Independent Bathing 0 = Dependent 5 = Independent (or in shower) Grooming 0 = Needs to help with personal care 5 = Independent face/hair/teeth/shaving (implements provided) Dressing 0 = Dependent 5 = Needs help but can do about half unaided 10 = Independent (including buttons, zips, laces, etc) Bowels 0 = Incontinent (or needs to be given enemas) 5 = Occasional accident 10 = Continent Bladder 0 = Incontinent, or catheterized and unable to manage alone 5 = Occasional accident 10 = Continent Toilet use 0 = Dependent 5 = Needs some help, but can do something alone 10 = Independent (on and off, dressing, wiping) Transfers (bed to chair and back)
or limited cooperation but a score of 3 should be used only if the 2 = Severe aphasia; all patient is mute and follows no one step commands. For children communication is through age 2 years to 6 years (or older children with premorbid language skills <6 year level), score this item based on observations of fragmentary expression; great need for inference, language comprehension and speech during the examination. questioning, and guessing by The patient with brain stem stroke who has bilateral loss of the listener. Range of sensation is scored 2. If the patient does not respond and is quadriplegic score 2. Patients in coma (item 1a = 3) are arbitrarily information that can be exchanged is limited; listener given a 2 on this item. carries burden of communication. Examiner cannot identify materials provided from patient response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal an adequate sample of speech 0 = Normal. must be obtained by asking patient to read or repeat words from 1 = Mild to moderate; patient the attached list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be rated. Only if the slurs at least some words and, at worst, can be understood patient is intubated or has other physical barrier to producing with some difficulty. speech, may the item be scored "9", and the examiner must 2 = Severe; patient's speech is clearly write an explanation for not scoring. Do not tell the patient why he/she is being tested. so slurred as to be unintelligible in the absence of or out of proportion to any dysphasia, or is mute/anarthric. 9 = Intubated or other physical barrier, explain. 11. Extinction and inattention (formerly neglect): Sufficient information to identify neglect may be obtained during 0 = No abnormality. the prior testing. If the patient has a severe visual loss preventing 1 = Visual, tactile, auditory, visual double simultaneous stimulation, and the cutaneous stimuli spatial, or personal inattention or extinction to are normal, the score is normal. If the patient has aphasia but does appear to attend to both sides, the score is normal. The bilateral simultaneous presence of visual spatial neglect or anosognosia may also be stimulation in one of the taken as evidence of abnormality. Since the abnormality is scored sensory modalities. only if present, the item is never untestable. 2 = Profound hemi-inattention or hemi-inattention to more than one modality. Does not https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 47/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate recognize own hand or orients to only one side of space. Table S1. Language testing items for PedNIHSS: Repetition Each of 4 word-repetition tasks is presented: a. Stop b. Stop and go c. If it rains we play inside d. The President lives in Washington Reading Each of 3 items is presented for the child to read (see separate "Reading items figure for PedNIHSS"). Adjust expectations according to child's age/school level. Name Pictures are presented of a clock, pencil, skateboard, shirt, baseball, and bicycle (see separate "Picture naming figure for PedNIHSS"). Fluency and word finding The Cookie theft picture is presented and the child is asked to describe what he/she sees (see separate "Cookie theft picture for NIHSS and PedNIHSS"). NIHSS: National Institutes of Health Stroke Scale; PedNIHSS: Pediatric National Institutes of Health Stroke Scale. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 76120 Version 2.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 48/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Reading items figure for PedNIHSS Words to test reading for Item 9 (Best language) of PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83404 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 49/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Picture naming figure for PedNIHSS Pictures to test naming for Item 9 (Best language) of PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83405 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 50/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Cookie theft picture for NIHSS and PedNIHSS Cookie theft picture to test story-telling for Item 9 Best language of NIHSS and PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83406 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 51/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Canadian Neurological Scale Patient Name: Rater Name: Date: Time: Mentation Score Level consciousness Alert 3.0 Drowsy 1.5 Orientation Oriented 1.0 Disoriented/NA 0.0 Speech Normal 1.0 Expressive deficit 0.5 Receptive deficit 0.0 TOTAL: Motor functions (no comprehension deficit) Weakness Score Face None 0.5 Present 0.0 Arm: proximal None 1.5 Mild 1.0 Significant 0.5 Total 0 Arm: distal None 1.5 Mild 1.0 Significant 0.5 Total 0 Leg None 1.5 Mild 1.0 Significant 0.5 Total 0 TOTAL: Motor response (comprehension deficit) Score https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 52/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Face Symmetrical .5 Asymmetrical 0 Arms Equal 1.5 Unequal 0 Legs Equal 1.5 Unequal 0 TOTAL: Reproduced with permission from: C t R, Hachinski VC, Shurvell BL, et al. The Canadian Neurological Scale: a preliminary study in acute stroke. Stroke 1986; 17:731. Copyright 1986 Lippincott Williams & Wilkins. Graphic 55644 Version 9.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 53/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Barthel Index Activity Score Feeding 0 = Unable 5 = Needs help cutting, spreading butter, etc, or requires modified diet 10 = Independent Bathing 0 = Dependent 5 = Independent (or in shower) Grooming 0 = Needs to help with personal care 5 = Independent face/hair/teeth/shaving (implements provided) Dressing 0 = Dependent 5 = Needs help but can do about half unaided 10 = Independent (including buttons, zips, laces, etc) Bowels 0 = Incontinent (or needs to be given enemas) 5 = Occasional accident 10 = Continent Bladder 0 = Incontinent, or catheterized and unable to manage alone 5 = Occasional accident 10 = Continent Toilet use 0 = Dependent 5 = Needs some help, but can do something alone 10 = Independent (on and off, dressing, wiping) Transfers (bed to chair and back) https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 54/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate 0 = Unable, no sitting balance 5 = Major help (one or two people, physical), can sit 10 = Minor help (verbal or physical) 15 = Independent Mobility (on level surfaces) 0 = Immobile or <50 yards 5 = Wheelchair independent, including corners, >50 yards 10 = Walks with help of one person (verbal or physical) >50 yards 15 = Independent (but may use any aid; for example, stick) >50 yards Stairs 0 = Unable 5 = Needs help (verbal, physical, carrying aid) 10 = Independent Total (0-100): The Barthel ADL Index: Guidelines The index should be used as a record of what a patient does, not as a record of what a patient could do The main aim is to establish degree of independence from any help, physical or verbal, however minor and for whatever reason The need for supervision renders the patient not independent Patient performance should be established using the best available evidence provided by the patient, family, friends and caregivers; direct observation and common sense are also important, but direct testing is not needed Usually the patient's performance over the preceding 24 to 48 hours is important, but occasionally longer periods will be relevant Middle categories imply that the patient supplies over 50 percent of the effort Use of aids to be independent is allowed ADL: activities of daily living. References: 1. Mahoney FI, Barthel D. Functional evaluation: The Barthel Index. Maryland State Medical Journal 1965; 14:56. Used with permission. 2. Loewen SC, Anderson BA. Predictors of stroke outcome using objective measurement scales. Stroke 1990; 21:78. 3. Gresham GE, Phillips TF, Labi ML. ADL status in stroke: Relative merits of three standard indexes. Arch Phys Med Rehabil 1980; 61:355. 4. Collin C, Wade DT, Davies S, Horne V. The Barthel ADL Index: A reliability study. Int Disability Study 1988; 10:61. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 55/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Graphic 77371 Version 3.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 56/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 57/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate 2 ABCD score 2 The ABCD score can be used to estimate the risk of ischemic stroke in the first two days after TIA. The score is tallied as follows: Age: 60 years 1 point <60 years 0 points Blood pressure elevation when first assessed after TIA: Systolic 140 mmHg or diastolic 90 mmHg 1 point Systolic <140 mmHg and diastolic <90 mmHg 0 points Clinical features: Unilateral weakness 2 points Isolated speech disturbance 1 point Other 0 points Duration of TIA symptoms: 60 minutes 2 points 10 to 59 minutes 1 point <10 minutes 0 points Diabetes: Present 1 point Absent 0 points Data from: Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and re nement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:283. Graphic 62381 Version 3.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 58/59 7/5/23, 12:14 PM Use and utility of stroke scales and grading systems - UpToDate Contributor Disclosures Larry B Goldstein, MD, FAAN, FANA, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 59/59
7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Brain arteriovenous malformations : Robert J Singer, MD, Christopher S Ogilvy, MD, Guy Rordorf, MD : Jos Biller, MD, FACP, FAAN, FAHA : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 22, 2023. INTRODUCTION Arteriovenous malformations (AVMs) are the most dangerous of the cerebrovascular malformations with the potential to cause intracranial hemorrhage and epilepsy in many cases. They have become the focus of scientific study leading to technological advances that have permitted these high-flow lesions to be treated, often with a multidisciplinary approach utilizing surgical, radiosurgical, and endovascular techniques. This topic review will discuss brain AVMs. Three other general subtypes of congenital vascular malformations have been described: developmental venous anomalies, capillary telangiectasias, and cavernous malformations. These are discussed separately. (See "Vascular malformations of the central nervous system".) PATHOGENESIS AND PATHOLOGY The pathogenesis of brain AVMs is not well understood. Traditionally, brain AVMs were considered sporadic congenital developmental vascular lesions, but this notion has been disputed by many well-documented reports of de novo brain AVM formation [1-3]. The size of brain AVMs varies widely, and some undergo growth, remodeling, or regression over time [4,5]. Rare cases of familial brain AVMs have been reported but it is unclear if these are coincidental or indicate true familial occurrence [6]. However, genetic variation may influence brain AVM development and clinical course [7-9]. Somatic variants in the mitogen-activated protein kinase signaling pathway have been identified in several patients with sporadic brain AVMs [10,11]. https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 1/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate The most common genetic cause of brain AVMs is hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu syndrome), an autosomal dominant condition. Patients with HHT may have cerebral or spinal cord involvement with telangiectasias, brain AVMs, aneurysms, or cavernous malformations. The presence of more than one brain AVM, otherwise uncommon, is highly predictive of HHT [12]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".) The angioarchitecture of brain AVMs is direct arterial to venous connections without an intervening capillary network. Both the arterial supply as well as the venous drainage may be by single or multiple vessels. Gliotic brain is usually admixed with the vascular tangle, and calcification may be seen in the vascular nidus and surrounding brain. The high-flow arteriovenous communication potentiates a variety of flow-related phenomena such as the development of afferent and efferent pedicle aneurysms, which occur in 20 to 25 percent of patients, and arterialization of the venous limb. Aneurysms can be a source of bleeding in patients with brain AVMs and are thought to worsen their prognosis [13]. Abnormal flow and a vascular steal phenomenon have been suggested to underlie some clinical symptoms associated with brain AVMs [14]. Histopathologic studies demonstrate areas of chronic ischemia and gliosis in the region of the malformation. EPIDEMIOLOGY Brain AVMs are uncommon, occurring in approximately 0.1 percent of the population, one-tenth the incidence of intracranial aneurysms [4]. Supratentorial lesions account for 90 percent of brain AVMs; the remainder are in the posterior fossa. They usually occur as single lesions, but as many as 9 percent are multiple [15]. Brain AVMs underlie an estimated 1 to 2 percent of all strokes, 3 percent of strokes in young adults, and 9 percent of subarachnoid hemorrhages [16,17]. CLINICAL PRESENTATION Brain AVMs usually present between the ages of 10 and 40 years. There are two peaks in age at presentation, one in childhood and then again at age 30 to 50. The presentation depends on symptoms produced (seizure, hemorrhage, or incidental). The patient's age, as well as the size, location, and vascular features of the AVM, influence the clinical presentation, which typically falls into one of five categories [2,4,18,19]: https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 2/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate Intracranial hemorrhage (40 to 60 percent) Hemorrhages are usually intraparenchymal, but isolated or concurrent intraventricular or subarachnoid hemorrhage may also occur, depending upon the location of the brain AVM [19]. Bleeding into the subarachnoid space is common for superficial AVMs. The clinical presentation of these events is described separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Retrospective data suggest that initial presentation with hemorrhage may be more likely for children compared with adults (56 versus 43 percent in one study [20]). Seizure (10 to 30 percent) Seizures are typically focal, either simple or partial complex, but often have secondary generalization. Patients with cortically-located, large, multiple, and superficial-draining AVMs are more likely to present with seizures [18,21]. The location of the AVM influences the seizure type and semiology. (See "Focal epilepsy: Causes and clinical features".) Focal neurologic deficit This presentation is fairly unusual for cerebral AVM. While a vascular steal syndrome has been hypothesized to cause this presentation, in most cases a focal neurologic deficit is caused by mass effect due to hemorrhage, or is a postictal effect of seizure [4]. Headache There are no specific headache features that associate with AVM, which may be incidental to the headaches [4]. In one study, 0.2 percent of patients with headache and normal neurologic examinations were found to have an AVM [22]. Incidental finding (10 to 20 percent) A number of asymptomatic brain AVMs are discovered on imaging with brain magnetic resonance imaging (MRI) or computed tomography (CT) scan obtained for other reasons [2]. NATURAL HISTORY An understanding of the natural history of brain AVMs, particularly in terms of hemorrhage rates, is critical to making decisions about management options. Hemorrhage risk A meta-analysis summarized the natural history of cerebral AVMs as reported in nine studies including 3923 patients and 18,423 patient-years of follow-up and reported an overall annual hemorrhage rate of 3 percent [23]. Similarly, in an individual patient level meta-analysis of four cohorts with 2525 patients and over 6000 years of follow-up, the https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 3/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate overall annual rate of intracranial hemorrhage was 2.3 percent (95% CI 2.0-2.7 percent) [24], and in the observation arm of the ARUBA trial, the annual rate of ICH was approximately 2 percent [25]. Potential risk factors have been identified that appear to impact hemorrhage rates: Hemorrhage as the initial clinical presentation is the strongest predictor for subsequent hemorrhage in patients with untreated brain AVMs [23,24]. In the systemic review, the annual rate of hemorrhage was 2.2 percent (95% CI 1.7-2.7) for unruptured AVMs and 4.5 percent (95% CI 3.7-5.5) for ruptured AVMS [23]. In the individual patient level meta- analysis, the annual rate for unruptured and ruptured brain AVMs was 1.3 and 4.8 percent, respectively [24]. In one database, children were not at higher risk of subsequent ICH after initial hemorrhage when compared with adults [20]. In another series, clinically silent hemorrhage seen on neuroimaging was also a risk factor for subsequent hemorrhage [26]. Increasing age at diagnosis was the only other risk factor identified in an individual patient level meta-analysis (n = 2525), with the risk increasing by approximately 30 percent per decade (hazard ratio [HR] 1.34, 95% CI 1.17-1.53) [24]. Anatomic and vascular features of the AVM also appear to be risk factors for subsequent hemorrhage, as shown by the systematic review [23]. These include: Exclusive deep venous drainage (HR 2.4, 95% CI 1.1-3.8) Deep brain location (HR 2.4, 95% CI 1.4-3.4) Associated aneurysms (HR 1.8, 95% CI 1.6-2.0) In contrast, size of the brain AVM was not associated with hemorrhage risk in the systematic review or the patient level meta-analysis [23,24]. Pregnancy is not a risk factor for hemorrhage from a brain AVM according to most of the available studies, but the issue is controversial, and the data are not definitive [27-30]. In a retrospective analysis of 393 pregnant patients 18 to 40 years of age with brain AVMs, the risk of hemorrhage during the pregnancy and puerperium was not increased compared with the control period (odds ratio 0.71, 95% CI 0.61-0.82) [28]. Combinations of risk factors may identify patients at particularly low or high risk, as found in a study from the Columbia databank [31]. Using three risk factors (hemorrhage at initial AVM presentation, deep venous drainage, and deep brain location), the approximate average annual hemorrhage rates were as follows: No risk factor, 1 percent annually One risk factor, 5 percent annually https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 4/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate Two risk factors, 10 to 15 percent annually Three risk factors, >30 percent annually Seizure and epilepsy risk Seizures and epilepsy may develop subsequent to presentation. In one population-based series, the five-year risk of a first-ever seizure risk for AVMs that were discovered incidentally was 8 percent [32]. In contrast, for patients who presented with ICH or focal neurologic deficits, the five-year risk of a first seizure was 23 percent. Additional factors associated with increased seizure risk were younger age, temporal location, cortical involvement, and nidus diameter >3 cm [21]. In patients lacking a history of intracranial hemorrhage or focal neurologic deficit, the five-year risk of developing epilepsy after a first seizure was 58 percent. DIAGNOSIS The diagnosis of brain AVMs is typically made noninvasively on imaging with brain computed tomography (CT) or magnetic resonance imaging (MRI) and/or angiography with computed tomography angiography (CTA) or magnetic resonance angiography (MRA) during the evaluation of patients who present with intracranial hemorrhage or unexplained seizures, acute neurologic deficits, or altered mental status. All patients with these presentations require neuroimaging, ideally with brain MRI. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Hemorrhagic stroke in children" and "Evaluation and management of the first seizure in adults" and "Seizures and epilepsy in children: Clinical and laboratory diagnosis".) In addition, a substantial proportion of brain AVMs are diagnosed incidentally when neuroimaging is obtained for another indication. (See 'Clinical presentation' above.) Conventional contrast angiography (ie, digital subtraction angiography [DSA]) may be necessary in some cases to make or confirm the diagnosis. DSA is typically required to plan interventional treatment, sometimes in combination with MRI. There is no role for routine screening of the general population for brain AVMs or for screening family members of patients with brain AVMs [6,33]. Unlike aneurysms, brain AVMs are not hereditary, with the exception of individuals with hereditary hemorrhagic telangiectasia (HHT). The role of screening for patients with HHT or suspected HHT is discussed separately. The diagnosis of HHT should be suspected in patients with spontaneous and recurrent epistaxis, multiple mucocutaneous telangiectasia at characteristic sites, gastrointestinal telangiectasia, pulmonary or hepatic arteriovenous malformation, or a first-degree relative with HHT. (See https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 5/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber- Rendu syndrome)" and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) NEUROIMAGING Computed tomography In the absence of acute hemorrhage, noncontrast computed tomography (CT) has a lower sensitivity for detecting brain AVMs and vascular anomalies than magnetic resonance imaging (MRI) [19]. In patients who present with hemorrhage, CT characteristically demonstrates intraparenchymal hemorrhage without significant edema. However, compression of the nidus by the hematoma often precludes CT diagnosis of brain AVM in the setting of acute intracerebral hemorrhage; more sensitive techniques such as MRI or angiography are required in such cases ( image 1). The ability of CT to identify brain AVMs in the acute setting may be improved by computed tomography angiography (CTA), which has a high sensitivity and specificity (95 and 99 percent, respectively) for the diagnosis of an underlying intracranial vascular malformation [34]. Magnetic resonance imaging MRI is sensitive for delineating the location of the brain AVM nidus and often an associated draining vein. It also has unique sensitivity in demonstrating remote bleeding related to these lesions [2,19]. Dark flow voids are appreciated on T1- and T2- weighted studies ( image 2). Similar to CTA, magnetic resonance angiography (MRA) a high sensitivity and specificity (98 and 99 percent, respectively) for the diagnosis of an underlying intracranial vascular malformation [34]. Angiography Catheter contrast angiography (ie, digital subtraction angiography [DSA]) is essential for treatment planning and post-treatment follow-up of brain AVMs ( image 3 and image 4) [19]. It has the highest spatial and temporal resolution of all the neuroimaging methods used to evaluate and diagnose brain AVMs. Anatomic and physiologic information such as the nidus configuration, its relationship to surrounding vessels, and localization of the draining or efferent portion of the brain AVM are readily obtained with this technique. DSA is required to evaluate for the presence of an early draining vein without a visible nidus, which is a risk factor for subsequent hemorrhage and cannot be detected using CTA or MRA [19]. Contrast transit times provide additional useful information regarding the flow state of the lesion; this can help in identifying venous outflow obstruction, which can influence endovascular treatment planning. The presence of associated aneurysm suggests a lesion at higher risk for subsequent hemorrhage. https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 6/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate Angiography is associated with a low risk of immediate neurologic complications, mainly ischemic stroke [19]. In addition, the high frame rates, magnified views, and multiple injections required for some diagnostic and interventional procedures may lead to high doses of radiation exposure with potential for long-term adverse effects [35]. ACUTE MANAGEMENT ISSUES Acute intracranial hemorrhage Brain AVM rupture typically causes intracerebral hemorrhage (ICH); isolated or concurrent intraventricular or subarachnoid hemorrhage may also occur, depending upon the AVM location. When an ICH is large and causing severe deficits, urgent clot evacuation surgically (with or without AVM treatment) is appropriate. If the ICH is smaller with minimal deficits or if the AVM is in an area with high risk for worsening deficits, conservative observation can be instituted with consideration for later treatment of the AVM, depending on the lesion and patient specific factors. The acute management of acute ICH, intraventricular hemorrhage, and subarachnoid hemorrhage are reviewed in detail elsewhere. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Intraventricular hemorrhage" and "Nonaneurysmal subarachnoid hemorrhage" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Acute seizures Individuals with AVMs may present with or develop seizures (see 'Clinical presentation' above and 'Hemorrhage risk' above). Prophylactic antiseizure medication therapy to prevent a first seizure occurrence is generally not recommended. If a seizure occurs, appropriate antiseizure medication treatment should be administered to prevent recurrent seizures. The choice of the initial antiseizure medication depends upon individual circumstances and contraindications. The treatment of seizures and epilepsy is discussed in detail separately. (See "Initial treatment of epilepsy in adults" and "Overview of the management of epilepsy in adults".) Although antiseizure medication therapy is generally successful in preventing recurrent seizures [32], drug-resistant epilepsy (also known as intractable or medically refractory epilepsy) develops in a significant minority of patients with brain AVMs and seizures, 18 percent in one series [36]. The treatment of seizures and epilepsy is discussed in detail separately. (See "Initial treatment of epilepsy in adults" and "Overview of the management of epilepsy in adults" and "Evaluation and management of drug-resistant epilepsy".) https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 7/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate MANAGEMENT OF THE AVM Treatment goals and options The major goals of interventional treatment are to reduce the risk of AVM-related hemorrhage, seizures, and other neurologic impairments. However, the efficacy of interventional methods for improving outcomes remains unproven and high-quality evidence is lacking. The main options for brain AVM treatment are conservative medical management versus microsurgical excision or stereotactic radiosurgery; endovascular embolization is typically used as an adjunctive intervention to surgery, or less often for stereotactic radiosurgery. The exact technique chosen for treatment is contingent on a number of patient- and lesion-specific variables. (See 'Choice of treatment' below.) Management decisions are most appropriately made by a multidisciplinary team of experienced clinicians who consider AVM features in the context of individual patient values and preferences [37]. Who should be treated? The management of AVMs in any given patient is individualized based on factors such as patient age and medical comorbidities as well as the anatomic and vascular features of the AVM. Many experts believe that interventional treatment is reasonable for most patients with ruptured brain AVMs (see 'Ruptured AVMs' below) and for selected patients with unruptured AVMs (see 'Unruptured AVMs' below) [38]. In all cases, however, the natural history of brain AVMs must be weighed against the risks and benefits of any intervention [2,19,37,38]. Interventions for brain AVMs are associated with considerable risks, including permanent neurologic complications or death in approximately 5 to 7.5 percent. (See 'Risk of interventions' below.) In determining whether a patient should undergo medical management or interventional AVM treatment, several factors are considered. Besides a history of previous rupture, other important factors influencing management include patient age, AVM size, AVM location, venous drainage pattern, and associated aneurysms. (See 'Other factors influencing treatment' below.) Several of these parameters are incorporated into the Spetzler-Martin grading scale ( table 1), which can be used to estimate surgical risk. Conservative medical management is usually preferred for Spetzler-Martin grade 4 or 5 lesions, which are considered to be at high risk of surgical morbidity. (See 'Spetzler-Martin grading scale' below.) Ruptured AVMs For most patients with ruptured AVM, we suggest intervention. Patients with a prior history of AVM rupture are at higher risk of subsequent hemorrhage than those https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 8/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate without this history (see 'Hemorrhage risk' above). Thus, interventional AVM treatment is indicated for most patients who present with acute intracranial hemorrhage or have remote intracranial hemorrhage demonstrated on imaging, particularly those with other risk factors that favor treatment, such as deep location or exclusively deep venous drainage. Conservative medical management may be reasonable for older patients without additional risk factors or patients with an unacceptable risk of surgery. However, some experts recommend intervention for any ruptured AVM when technically feasible. (See 'Other factors influencing treatment' below and 'Spetzler-Martin grading scale' below.) AVMs with angiographic features suggesting an increased risk of recurrent hemorrhage, such as an associated aneurysm, are treated acutely. Other AVMs are generally treated four to six weeks after the hemorrhage; absorption of the hematoma and resolution of any surrounding edema improve access to the AVM [37]. In patients undergoing radiosurgery, hematoma resolution may improve accuracy of the targeting of the radiation. Unruptured AVMs For patients with unruptured AVM who are not at high risk of rupture, we suggest conservative management. Interventional treatment of unruptured AVMs may be performed in select patients if the treatment-related risks are thought to be lower than the natural history risk of hemorrhage. Patients with symptoms (eg, seizures) refractory to medical treatment or with AVM features posing high risk for rupture should also be considered for treatment. The treatment must be considered on a patient by patient basis, taking into account the various factors that influence the natural history of the lesion and the estimate of treatment-related risks. Typically, a multi-modality team evaluation is performed, and the risks and benefits of each treatment modality (surgical excision, radiosurgery, embolization) are considered alone or in combination. The angiographic and anatomic details of each AVM are carefully evaluated to estimate the potential for post-treatment morbidity. Intervention is often favored for young individuals at low risk of treatment-related adverse outcomes. Conservative medical therapy is a reasonable option for patients with unruptured brain AVMs who have no additional risk factors for hemorrhage such as deep location or exclusively deep venous drainage (see 'Hemorrhage risk' above), whereas microsurgical excision is reasonable for patients with additional risk factors for recurrent hemorrhage and Spetzler-Martin grade 1 or grade 2 lesions ( table 1), suggesting low surgical risk. (See 'Spetzler-Martin grading scale' below.) Data from a single randomized controlled trial (the ARUBA trial) suggest that interventions for unruptured brain AVMs are not beneficial and may be harmful compared with medical management, but the results are somewhat controversial. In the ARUBA trial, patients with unruptured AVMs were assigned to medical versus interventional (surgery, radiotherapy, and/or https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 9/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate endovascular therapy) treatment [25]. The trial was halted early with outcome data on 223 patients followed for a mean of 33 months. By intention-to-treat analysis, the composite rate of symptomatic stroke (ischemic and hemorrhagic) and death was lower in the medical treatment group compared with the interventional group (10 versus 31 percent; hazard ratio 0.27, 95% CI 0.14-0.54). The rate of neurologic disability was also lower in medically treated patients (15 versus 46 percent). In an extended follow-up (median 50.4 months), the superiority of medical therapy appeared durable; the incidence of death or symptomatic stoke was lower for patients assigned to medical management than for those assigned to interventional therapy (3.4 versus 12.3 per 100 patient-years; HR 0.31, 95% CI 0.17-0.56) [39]. Two patients died in the medically treated group and four assigned to interventional therapy. Criticism of the ARUBA trial includes small patient numbers, early stopping, and the nonstandardized and variable treatment approaches used in the interventional arm [40]. Other factors influencing treatment The patient's age, presentation, anatomic and vascular features of the AVM, presence of associated seizures, and Spetzler-Martin grading scale score ( table 1) are considered when making treatment decisions; each of these factors influences the choice between interventional treatments versus conservative medical management. Age Patient age is an important factor in the decision to treat brain AVMs; those with a longer life expectancy will accrue a higher lifetime risk of hemorrhage [41]. Thus, therapy is more likely to be recommended for children and young adults, while older individuals with shorter life expectancies may be managed more conservatively. However, long-term outcomes to guide treatment are lacking [42]. (See 'Hemorrhage risk' above.) The cumulative hemorrhage risk can be estimated by the formula: N Lifetime risk of hemorrhage = 1 - (1 - P) where P is the annual probability of hemorrhage and N is the expected years of life remaining [43]. As an example, a 60-year-old female with a newly diagnosed unruptured brain AVM and no other contributing comorbid conditions would expect to live approximately 20 years. If the annual risk of AVM hemorrhage is 3 percent, the formula gives a cumulative risk of hemorrhage over her expected life span of 46 percent. This compares with an overall risk of treatment morbidity and mortality of approximately 5 percent, with much or most of the treatment risk involving the periprocedural period. AVM characteristics https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 10/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate AVM location AVMs located in eloquent brain or brainstem regions (ie, areas that control language, motor, sensory, or visual functions) present a challenge for risk assessment; significant clinical morbidity is likely to result if a surgical complication occurs or if the AVM ruptures. Such patients may be more likely to be considered for radiosurgery. Deep venous drainage Similarly, deep venous drainage is a risk factor for both surgical complications and for AVM rupture. AVM size Large brain AVMS are not clearly at higher risk of bleeding than smaller lesions, but are more difficult to treat; larger size is associated with higher risk by surgical and radiosurgical techniques. Obliteration rates fall with radiosurgery when larger lesions are treated with safe dosages of radiation. Lesions greater than 6 cm are likely to be managed conservatively. In some patients with large lesions, endovascular treatments may be useful to decrease the size of the aneurysm if the vascular anatomy is determined to be amenable to this approach. Associated aneurysm Treatment of aneurysms associated with AVMs varies depending on aneurysm location and diameter [17]. When believed to be the source of hemorrhage, aneurysms are generally treated with surgery or endovascular therapy, depending on their location and size, according to the expertise of the available experienced clinicians. Aneurysms associated with unruptured AVMs do not necessarily require treatment, depending on their size the other anatomic features. Seizures Available data, largely observational, suggest that interventional management of brain AVMs does not reduce the risk of subsequent seizures or epilepsy, but definitive conclusions cannot be made. A 2016 systematic review and meta-analysis identified only two controlled observational studies that compared interventional AVM treatments with antiseizure medication management alone for patients with brain AVMs and epilepsy [44]. In the pooled data from these two studies, rates of seizure freedom were similar between treatment groups (risk ratio 0.99, 95% CI 0.69-1.43); the overall proportion of patients who achieved seizure freedom with medical management in the two studies was 57 percent [45] and 46 percent [46] respectively. In the ARUBA trial, the rate of seizures per patient year was similar for the interventional group compared with medical management, but confidence in this finding is limited; among other issues, seizures were not the focus of the trial, and follow-up was only 33 months [25]. Risk of interventions Interventions for brain AVMs are associated with considerable risks. In a 2011 systematic review and meta-analysis of observational studies, findings included permanent neurologic complications or death in approximately 5 to 7.5 percent, and incomplete https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 11/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate obliteration of the AVM in 13 to 96 percent [47]. By intervention, persistent neurologic deficits or death after microsurgery occurred in a median 7.4 percent of patients, after embolization in a median 6.6 percent, and after stereotactic radiosurgery in a median 5.1 percent. In the ARUBA trial, which enrolled 223 patients with unruptured brain AVMs, subjects assigned to interventional therapy had a higher number of strokes (45 versus 12) and neurologic deficits unrelated to stroke (14 versus 1) compared with those assigned to medical management [25]. Spetzler-Martin grading scale The Spetzler Martin grading scale classifies the risk of surgical AVM removal according to AVM size, location in eloquent or noneloquent brain areas, and whether deep venous drainage is present or absent ( table 1) [48]. AVM size is determined by the largest dimension of the nidus in centimeters on imaging with computed tomography (CT), magnetic resonance imaging (MRI), or digital subtraction angiography (DSA). Eloquent brain areas include regions of cortex devoted to sensorimotor, visual, and language functions, and certain deeper structures: the internal capsules, basal ganglia, thalamus, hypothalamus, brain stem, cerebellar peduncles, and deep cerebellar nuclei [48,49]. Deep venous drainage is considered present if any or all of the outflow occurs via deep veins such as internal cerebral veins, basal veins, and precentral cerebellar vein [19]. A higher Spetzler-Martin grading scale score correlates with increased risk of surgical morbidity and neurologic deficits. A modification of the Spetzler-Martin grading scale that supplements the neuroimaging information with clinical features (age, sex, baseline disability), may perform better in predicting surgical risk, but requires independent validation [50]. Other grading scales are also being evaluated for this purpose [51]. Choice of treatment For patients selected for intervention, microsurgical excision is often preferred for patients with brain AVMs associated with a low risk of poor treatment outcomes, correlating with Spetzler-Martin ( table 1) grade 1 or grade 2 lesions [38], with radiosurgery as an alternative for small lesions based upon location or other vascular or anatomic features. Stereotactic radiosurgery is also preferred for small grade 3 lesions. Large grade 3 lesions that involve eloquent cortex have a high surgical morbidity and available evidence suggests that treatment is no better than observational medical management. Conservative medical management is usually preferred for grade 4 or 5 lesions, although some may benefit from partial obliteration with endovascular treatment for high-risk features such as associated aneurysms located within the nidus or on feeding arteries. Microsurgical resection appears to have the highest success rate for seizure control among treatment options for brain AVMs. When analyzed by type of intervention in systematic reviews https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 12/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate and meta-analyses, the median rate of seizure freedom was highest for resective surgery (73 to 78 percent), followed stereotactic radiosurgery (52 to 63 percent) and embolization (49 to 54 percent) [44,52]. However, as previously noted, observational data suggest that interventional management of brain AVMs may not reduce the risk of subsequent seizures or epilepsy. (See 'Other factors influencing treatment' above.) Particular advantages and disadvantages of the interventional modalities for brain AVMs are discussed in the sections that follow. Microsurgical excision Open microsurgical excision has the longest history of use for the definitive treatment of selected patients with AVMs and offers the best chance immediate cure in patients considered to be at high risk of hemorrhage [37]. The surgery is complicated and often requires detailed planning with review of imaging studies. The main advantages of microsurgical excision compared with other interventions (radiosurgery and endovascular embolization) include a high success rate of complete nidus obliteration, the immediate elimination of hemorrhage risk, and long-term durability [19]. Disadvantages include the invasive nature of the treatment with a risk of neurologic impairments related to dissection of normal adjacent brain parenchyma and neurovascular structures needed to reach the AVM, and a longer recovery period. Postoperative complications include arterial or venous infarction or hemorrhage from the resection cavity. Typically, an arteriogram is performed after the surgery to document complete resection of the lesion. There have been isolated cases of hemorrhage into a resection bed despite obliteration on angiography. The mechanism of such bleeding is uncertain, but may be venous in nature. In addition to cortical injury, deep fiber tract injury can cause transient or permanent morbidity. Pre-operative assessment utilizing functional MRI studies with tractography may help minimize such complications. An important factor in recommending therapy is an assessment of surgical risk. Multiple or large lesions, those in eloquent brain areas, and those with deep venous drainage are more difficult to safely resect. Many surgeons use the Spetzler-Martin grading scale ( table 1) to assess the surgical risk [19]. Several studies have correlated surgical risk with higher Spetzler-Martin grading scale score [53,54]. Female sex may also increase surgical risk [55]. Stereotactic radiosurgery Stereotactic radiosurgery is most successful when used to treat small brain AVMs eg, <3 cm in diameter [2]. Latency period Stereotactically focused high energy beams of photons or protons to a defined volume containing the brain AVM nidus induces progressive thrombosis of properly selected lesions via fibrointimal hyperplasia and subsequent luminal obliteration. The time course of these changes is usually one to three years, sometimes longer, and the https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 13/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate time between treatment and obliteration is referred to as the latency period. During this latency period, the patient remains at risk for hemorrhage [2]. (See "Stereotactic cranial radiosurgery".) The magnitude of brain AVM hemorrhage risk during the latency period between treatment and obliteration is uncertain; however, the best evidence suggests that it gradually declines during this interval [56]. This is an important consideration, particularly for lesions at higher bleeding risk. Existing studies are generally limited by retrospective and observational design. Earlier studies reported conflicting results, including increased [57-59], decreased [60,61], and unchanged [62,63] bleeding rates during the latency period. One of the largest studies including 500 patients found that the risk of hemorrhage declined by 54 percent during the latency period and by 88 percent after obliteration. The risk reduction was greater among patients who presented with hemorrhage than those who presented without hemorrhage. Another study including 657 patients had similar findings [64]. An untreated cerebral aneurysm was found to be a risk factor for hemorrhage in the latency period in another consecutive case series; the hemorrhage rate was 6.4 percent per year for untreated aneurysms versus 0.8 percent per year for clipped or embolized aneurysms [65]. Once the lesion is completely obliterated, the hemorrhage risk from the brain AVM is very low [66-68], but not totally eliminated [67,69-71]. Incomplete lesion obliteration, hypertension, and prior hemorrhage are risk factors for late bleeding [71]. Success rate Successful brain AVM obliteration with radiosurgery depends upon lesion size and dose of radiation [70]. Complete cure is considerably higher with smaller lesions; an overall 80 percent obliteration rate by three years occurs with lesions that are 3 cm or smaller [59,72-75]. Larger lesions have reported obliteration rates of 30 to 70 percent at three years [72,74,76]. Brain AVMs with a diffuse nidus or associated neovascularity were less likely to achieve a radiographic cure in one clinical series of 248 patients [77]. Despite the lower initial success rates for angiographic obliteration seen with larger brain AVMs (>3 cm), some amount of lesion volume reduction (mean 66 percent) typically occurs [78,79]. The success rate of radiographic brain AVM obliteration also varies with the amount of radiation delivered to the margin of the lesion. Doses of 16, 18, and 20 Gray (Gy) are associated with obliteration rates of about 70, 80, and 90 percent, respectively [79-81]. In one series, brainstem lesions were associated with lower obliteration rates, perhaps because of more conservative radiation dosing [82]. Radiation dose is generally selected according to a protocol which takes in account the size and location of the lesion. https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 14/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate Retreatment with radiosurgery is effective for complete obliteration in about 60 to 80 percent of patients with residual brain AVMs, depending on the size and other factors [78,83]. Complications Complications after radiosurgery include radiation necrosis, which can produce new neurologic deficits and seizures. In a multinational study that included 1255 patients undergoing radiosurgery for cerebral AVMs, therapy-related complications developed in 102 (8 percent) and included radiographic parenchymal lesions, cranial nerve deficits, seizures, headaches, and cyst formation [84]. Symptoms were disabling in 21, fatal
preferred for patients with brain AVMs associated with a low risk of poor treatment outcomes, correlating with Spetzler-Martin ( table 1) grade 1 or grade 2 lesions [38], with radiosurgery as an alternative for small lesions based upon location or other vascular or anatomic features. Stereotactic radiosurgery is also preferred for small grade 3 lesions. Large grade 3 lesions that involve eloquent cortex have a high surgical morbidity and available evidence suggests that treatment is no better than observational medical management. Conservative medical management is usually preferred for grade 4 or 5 lesions, although some may benefit from partial obliteration with endovascular treatment for high-risk features such as associated aneurysms located within the nidus or on feeding arteries. Microsurgical resection appears to have the highest success rate for seizure control among treatment options for brain AVMs. When analyzed by type of intervention in systematic reviews https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 12/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate and meta-analyses, the median rate of seizure freedom was highest for resective surgery (73 to 78 percent), followed stereotactic radiosurgery (52 to 63 percent) and embolization (49 to 54 percent) [44,52]. However, as previously noted, observational data suggest that interventional management of brain AVMs may not reduce the risk of subsequent seizures or epilepsy. (See 'Other factors influencing treatment' above.) Particular advantages and disadvantages of the interventional modalities for brain AVMs are discussed in the sections that follow. Microsurgical excision Open microsurgical excision has the longest history of use for the definitive treatment of selected patients with AVMs and offers the best chance immediate cure in patients considered to be at high risk of hemorrhage [37]. The surgery is complicated and often requires detailed planning with review of imaging studies. The main advantages of microsurgical excision compared with other interventions (radiosurgery and endovascular embolization) include a high success rate of complete nidus obliteration, the immediate elimination of hemorrhage risk, and long-term durability [19]. Disadvantages include the invasive nature of the treatment with a risk of neurologic impairments related to dissection of normal adjacent brain parenchyma and neurovascular structures needed to reach the AVM, and a longer recovery period. Postoperative complications include arterial or venous infarction or hemorrhage from the resection cavity. Typically, an arteriogram is performed after the surgery to document complete resection of the lesion. There have been isolated cases of hemorrhage into a resection bed despite obliteration on angiography. The mechanism of such bleeding is uncertain, but may be venous in nature. In addition to cortical injury, deep fiber tract injury can cause transient or permanent morbidity. Pre-operative assessment utilizing functional MRI studies with tractography may help minimize such complications. An important factor in recommending therapy is an assessment of surgical risk. Multiple or large lesions, those in eloquent brain areas, and those with deep venous drainage are more difficult to safely resect. Many surgeons use the Spetzler-Martin grading scale ( table 1) to assess the surgical risk [19]. Several studies have correlated surgical risk with higher Spetzler-Martin grading scale score [53,54]. Female sex may also increase surgical risk [55]. Stereotactic radiosurgery Stereotactic radiosurgery is most successful when used to treat small brain AVMs eg, <3 cm in diameter [2]. Latency period Stereotactically focused high energy beams of photons or protons to a defined volume containing the brain AVM nidus induces progressive thrombosis of properly selected lesions via fibrointimal hyperplasia and subsequent luminal obliteration. The time course of these changes is usually one to three years, sometimes longer, and the https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 13/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate time between treatment and obliteration is referred to as the latency period. During this latency period, the patient remains at risk for hemorrhage [2]. (See "Stereotactic cranial radiosurgery".) The magnitude of brain AVM hemorrhage risk during the latency period between treatment and obliteration is uncertain; however, the best evidence suggests that it gradually declines during this interval [56]. This is an important consideration, particularly for lesions at higher bleeding risk. Existing studies are generally limited by retrospective and observational design. Earlier studies reported conflicting results, including increased [57-59], decreased [60,61], and unchanged [62,63] bleeding rates during the latency period. One of the largest studies including 500 patients found that the risk of hemorrhage declined by 54 percent during the latency period and by 88 percent after obliteration. The risk reduction was greater among patients who presented with hemorrhage than those who presented without hemorrhage. Another study including 657 patients had similar findings [64]. An untreated cerebral aneurysm was found to be a risk factor for hemorrhage in the latency period in another consecutive case series; the hemorrhage rate was 6.4 percent per year for untreated aneurysms versus 0.8 percent per year for clipped or embolized aneurysms [65]. Once the lesion is completely obliterated, the hemorrhage risk from the brain AVM is very low [66-68], but not totally eliminated [67,69-71]. Incomplete lesion obliteration, hypertension, and prior hemorrhage are risk factors for late bleeding [71]. Success rate Successful brain AVM obliteration with radiosurgery depends upon lesion size and dose of radiation [70]. Complete cure is considerably higher with smaller lesions; an overall 80 percent obliteration rate by three years occurs with lesions that are 3 cm or smaller [59,72-75]. Larger lesions have reported obliteration rates of 30 to 70 percent at three years [72,74,76]. Brain AVMs with a diffuse nidus or associated neovascularity were less likely to achieve a radiographic cure in one clinical series of 248 patients [77]. Despite the lower initial success rates for angiographic obliteration seen with larger brain AVMs (>3 cm), some amount of lesion volume reduction (mean 66 percent) typically occurs [78,79]. The success rate of radiographic brain AVM obliteration also varies with the amount of radiation delivered to the margin of the lesion. Doses of 16, 18, and 20 Gray (Gy) are associated with obliteration rates of about 70, 80, and 90 percent, respectively [79-81]. In one series, brainstem lesions were associated with lower obliteration rates, perhaps because of more conservative radiation dosing [82]. Radiation dose is generally selected according to a protocol which takes in account the size and location of the lesion. https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 14/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate Retreatment with radiosurgery is effective for complete obliteration in about 60 to 80 percent of patients with residual brain AVMs, depending on the size and other factors [78,83]. Complications Complications after radiosurgery include radiation necrosis, which can produce new neurologic deficits and seizures. In a multinational study that included 1255 patients undergoing radiosurgery for cerebral AVMs, therapy-related complications developed in 102 (8 percent) and included radiographic parenchymal lesions, cranial nerve deficits, seizures, headaches, and cyst formation [84]. Symptoms were disabling in 21, fatal in two, and resolved completely in 42 (41 percent). The risk of radiation necrosis with permanent neurologic deficit is 1 to 3 percent in most reports [72,74,79,85]. In another case series, 10 of 75 patients who had not had seizures and were not on antiseizure medications before radiosurgery had provoked seizures after radiosurgery [86]. The risk of hemorrhage following angiographically confirmed AVM obliteration appears low. In a retrospective cohort of 1607 patients treated with radiosurgery, hemorrhage occurred in 16 patients (1 percent) [87]. Only two of these 16 patients had developed a recurrent AVM, suggesting that hemorrhagic recurrence may also be due to other factors such as dysregulated neovascular proliferation following treatment. The incidence of complications are related to the brain AVM location and the volume treated [75,88]. Thalamic, basal ganglionic, and brainstem locations are particularly prone to development of deficits after radiosurgery [82,88,89]. The risk of complications is also related to the radiation dose directed to the surrounding tissue. The risk of complications is also increased in large brain AVMs that require larger treatment volumes. In a series of 73 patients, in whom one-half of the brain AVMs were >3 cm in diameter, the incidence of post-treatment imaging abnormalities and clinical complications rose with increasing treatment volume [90]. In patients whose treatment volumes were >14 mL and who received a dose 16 Gy, the incidence of post-treatment MRI abnormalities was 72 percent, and 22 percent required resection for radiation necrosis. The rate of post- treatment hemorrhage was also higher for treatment volumes 14 mL (7.5 versus 2.7 percent per person-year). Repeated radiosurgery is also associated with increased complications; but the rate is not clearly prohibitive [83,91]. In one series of 15 patients who underwent two radiosurgeries with a mean dose per session of 18 Gy and 21 Gy, three (20 percent) had permanent radiation-induced complications [91]. No rebleeding occurred over 137 patient-years of follow-up. https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 15/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate In contrast to standard fractionation cranial irradiation, radiosurgery does not appear to impact cognitive function. One study of 10 patients found no effect of radiosurgical treatment of brain AVMs upon neuropsychological performance 11 months after treatment [92]. Endovascular embolization Despite initial optimism that embolic agents such as microparticles and cyanoacrylates could cure brain AVMs, less than 25 percent of lesions are cured by this approach alone [93]. Typically, AVMs successfully treated with endovascular embolization are small and have a single draining vein [2]. Some experts suggest that embolization can be an effective adjunct to surgery and radiosurgery [94]. Embolization prior to surgery is employed to reduce blood loss and to occlude vessels that may be difficult to control during surgery [95]. Embolization prior to radiosurgery is 3 controversial; it has been used to reduce the nidus size of large brain AVMs to less than 10 cm , as these large AVMs have a lower cure rate with radiosurgery alone. Embolization may also reduce overall flow to the AVM. However, there is some evidence suggesting that embolization may reduce the obliteration rate and the rate of favorable outcomes after radiosurgery [96-100]; this drawback may be caused be embolic material in the AVM that can make it difficult to accurately target the nidus and can shield the AVM from the effects of radiation [19,38]. Endovascular therapy may also be used as primary treatment for intranidal aneurysms. (See "Treatment of cerebral aneurysms", section on 'Endovascular therapy'.) A meticulous analysis of angiographic information (size, eloquent location, deep versus superficial venous drainage, vascular anatomy/number of feeders) determines the suitability for embolization [94,101]. Generally, only afferent pedicles to the nidus are embolized in an attempt to avoid occlusion of branches irrigating normal brain. The risk of new neurologic deficits following endovascular treatment ranges from 8 to 20 percent [93,101,102]. Disabling treatment complications appear to be uncommon [101,102]. The most feared complications are ischemic stroke from embolic material occluding vessels to healthy cerebral adjacent tissue, and periprocedural hemorrhage. Hemorrhage with AVM embolization is usually the result of venous occlusion from the embolic material. Follow-up Long-term follow-up is recommended after AVM treatment with brain MRI, magnetic resonance angiography (MRA), and in some cases with DSA [103]. For adult patients treated with embolization and microsurgical excision, DSA is obtained immediately after the procedures to document complete obliteration of the AVM. https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 16/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate For adult patients treated with radiosurgery, interval MRI and MRA studies can be obtained at six months and one year. The regression of the AVM nidal volume can be accurately measured and followed with MRI, and the patient can be monitored for white matter change consistent with small vessel occlusion, post-therapy edema, or radiation necrosis [104]. Once an AVM is no longer visualized on an MRI and MRA, DSA can be performed to confirm complete obliteration. For adult patients treated with microsurgical excision, radiosurgery, and/or embolization, no further studies are needed if complete obliteration is documented, unless new symptoms occur. For children treated with microsurgical excision, radiosurgery, and/or embolization, DSA is obtained after both treatment and in a delayed fashion, typically at six months and at five years [103]. For patients who are managed conservatively, we defer follow-up imaging unless new symptoms develop. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 17/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Arteriovenous malformations in the brain (The Basics)") SUMMARY AND RECOMMENDATIONS Definition and epidemiology Brain arteriovenous malformations (AVMs) are cerebrovascular malformations characterized by direct arterial to venous connections without an intervening capillary network. They occur in about 0.1 percent of the population but may be the cause of an estimated 1 to 2 percent of all strokes, 3 percent of strokes in young adults, and 9 percent of subarachnoid hemorrhages. (See 'Pathogenesis and pathology' above and 'Epidemiology' above.) Clinical presentation Brain AVMs usually present between the ages of 10 and 40 years with intracranial hemorrhage, seizure, focal neurologic deficit, or headache; a substantial number are asymptomatic and are found incidentally. Hemorrhage is the most common presentation, particularly in children. (See 'Clinical presentation' above.) Risk of hemorrhage Overall, annual hemorrhage rates from brain AVMs are between 2 and 3 percent. After an initial hemorrhage, annual hemorrhage rates are approximately 5 percent. Combinations of risk factors (eg, hemorrhage at initial AVM presentation, deep venous drainage, and deep brain location) may identify patients at particularly low or high risk. Patients with none of these risk factors have an estimated annual hemorrhage rate of approximately 1 percent, while those with all three risk factors may have an annual hemorrhage rate of >30 percent. (See 'Hemorrhage risk' above.) Imaging diagnosis Brain AVMs can be detected on computed tomography, magnetic resonance imaging, and/or noninvasive angiography with computed tomography angiography or magnetic resonance angiography. Digital subtraction angiography is essential for treatment planning and follow-up after treatment of brain AVMs. (See 'Neuroimaging' above.) Management The management of AVMs in any given patient is individualized based on risk factors such as patient age, medical comorbidities, and the anatomic and vascular features of the AVM ( table 1) as well as the risks of morbidity with intervention (see 'Natural history' above and 'Who should be treated?' above): https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 18/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate For most patients with a ruptured AVM, we suggest intervention (Grade 2C). In some cases, intervention may not be technically feasible or safe or desired by the patient. (See 'Ruptured AVMs' above.) For patients with an unruptured AVM who are not at high risk of rupture, we suggest conservative management (Grade 2C). However, interventional treatment of unruptured AVMs may be performed in select patients at low treatment-related risks, with symptoms (eg, seizures) refractory to medical treatment, or with AVM features posing high risk for rupture. (See 'Unruptured AVMs' above.) For patients selected for intervention, microsurgical excision is often preferred for patients with brain AVMs associated with a low risk of poor treatment outcomes, with radiosurgery as an alternative. Conservative medical management is usually preferred for patients with brain AVMs associated with a high risk of poor treatment outcomes, although some may benefit from partial obliteration with endovascular treatment. (See 'Choice of treatment' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Dalton A, Dobson G, Prasad M, Mukerji N. De novo intracerebral arteriovenous malformations and a review of the theories of their formation. Br J Neurosurg 2018; 32:305. 2. Flemming KD, Lanzino G. Management of Unruptured Intracranial Aneurysms and Cerebrovascular Malformations. Continuum (Minneap Minn) 2017; 23:181. 3. Pabaney AH, Rammo RA, Tahir RA, Seyfried D. Development of De Novo Arteriovenous Malformation Following Ischemic Stroke: Case Report and Review of Current Literature. World Neurosurg 2016; 96:608.e5. 4. Mohr JP, Kejda-Scharler J, Pile-Spellman J. Diagnosis and treatment of arteriovenous malformations. Curr Neurol Neurosci Rep 2013; 13:324. 5. Moftakhar P, Hauptman JS, Malkasian D, Martin NA. Cerebral arteriovenous malformations. Part 1: cellular and molecular biology. Neurosurg Focus 2009; 26:E10. 6. van Beijnum J, van der Worp HB, Schippers HM, et al. Familial occurrence of brain arteriovenous malformations: a systematic review. J Neurol Neurosurg Psychiatry 2007; 78:1213. 7. Scimone C, Donato L, Marino S, et al. Vis- -vis: a focus on genetic features of cerebral cavernous malformations and brain arteriovenous malformations pathogenesis. 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Assessment of cerebral arteriovenous malformations with high temporal and spatial resolution contrast-enhanced magnetic resonance https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 26/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate angiography: a review from protocol to clinical application. Top Magn Reson Imaging 2008; 19:251. Topic 1087 Version 37.0 https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 27/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate GRAPHICS Cerebellar hematoma due to ruptured AVM (A) Noncontrast head CT showing acute right cerebellar ICH with smaller adjacent focus of hemorrhage (black arrow). (B) Subsequent FLAIR sequence on brain MRI after decompressive craniectomy showing flow void (white arrow) adjacent to ICH (white dashed arrow). (C) Digital subtraction angiogram subsequently identified an AVM with a nidus (white arrowhead), feeding artery (white thick arrow), and draining vein (white short arrow). CT: computed tomography; ICH: intracerebral hemorrhage; FLAIR: fluid-attenuated inversion recovery; MRI: magnetic resonance imaging; AVM: arteriovenous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 132273 Version 1.0 https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 28/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate MRI of brain arteriovenous malformation T2-weighted MRI of the brain demonstrates multiple flow voids in the right hemisphere, suggestive of a large arteriovenous malformation. MRI: magnetic resonance imaging. From: Flemming KD, Lanzino G. Management of Unruptured Intracranial Aneurysms
malformations of the brain: influencing factors and evolution with time. Stroke 2012; 43:1247. 72. Lunsford LD, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for arteriovenous malformations of the brain. J Neurosurg 1991; 75:512. 73. Ogilvy CS. Radiation therapy for arteriovenous malformations: a review. Neurosurgery 1990; 26:725. 74. Fabrikant JI, Levy RP, Steinberg GK, et al. Stereotactic charged-particle radiosurgery: clinical results of treatment of 1200 patients with intracranial arteriovenous malformations and pituitary disorders. Clin Neurosurg 1992; 38:472. 75. Skj th-Rasmussen J, Roed H, Ohlhues L, et al. Complications following linear accelerator based stereotactic radiation for cerebral arteriovenous malformations. Int J Radiat Oncol Biol Phys 2010; 77:542. 76. Friedman WA, Bova FJ, Bollampally S, Bradshaw P. Analysis of factors predictive of success or complications in arteriovenous malformation radiosurgery. Neurosurgery 2003; 52:296. 77. Zipfel GJ, Bradshaw P, Bova FJ, Friedman WA. Do the morphological characteristics of arteriovenous malformations affect the results of radiosurgery? J Neurosurg 2004; 101:393. https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 24/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate 78. Foote KD, Friedman WA, Ellis TL, et al. Salvage retreatment after failure of radiosurgery in patients with arteriovenous malformations. J Neurosurg 2003; 98:337. 79. Pollock BE, Meyer FB. Radiosurgery for arteriovenous malformations. J Neurosurg 2004; 101:390. 80. Flickinger JC, Pollock BE, Kondziolka D, Lunsford LD. A dose-response analysis of arteriovenous malformation obliteration after radiosurgery. Int J Radiat Oncol Biol Phys 1996; 36:873. 81. Karlsson B, Lindquist C, Steiner L. Prediction of obliteration after gamma knife surgery for cerebral arteriovenous malformations. Neurosurgery 1997; 40:425. 82. Maruyama K, Koga T, Niranjan A, et al. Radiosurgery for brainstem arteriovenous malformation. Prog Neurol Surg 2013; 27:67. 83. Hauswald H, Milker-Zabel S, Sterzing F, et al. Repeated linac-based radiosurgery in high- grade cerebral arteriovenous-malformations (AVM) Spetzler-Martin grade III to IV previously treated with radiosurgery. Radiother Oncol 2011; 98:217. 84. Flickinger JC, Kondziolka D, Lunsford LD, et al. A multi-institutional analysis of complication outcomes after arteriovenous malformation radiosurgery. Int J Radiat Oncol Biol Phys 1999; 44:67. 85. Ding D, Yen CP, Xu Z, et al. Radiosurgery for patients with unruptured intracranial arteriovenous malformations. J Neurosurg 2013; 118:958. 86. Yang SY, Kim DG, Chung HT, Paek SH. Radiosurgery for unruptured cerebral arteriovenous malformations: long-term seizure outcome. Neurology 2012; 78:1292. 87. Chen CJ, Ding D, Kumar JS, et al. Hemorrhage and Recurrence of Obliterated Brain Arteriovenous Malformations Treated With Stereotactic Radiosurgery. Stroke 2022; 53:e363. 88. Flickinger JC, Kondziolka D, Lunsford LD, et al. Development of a model to predict permanent symptomatic postradiosurgery injury for arteriovenous malformation patients. Arteriovenous Malformation Radiosurgery Study Group. Int J Radiat Oncol Biol Phys 2000; 46:1143. 89. Pollock BE, Gorman DA, Brown PD. Radiosurgery for arteriovenous malformations of the basal ganglia, thalamus, and brainstem. J Neurosurg 2004; 100:210. 90. Miyawaki L, Dowd C, Wara W, et al. Five year results of LINAC radiosurgery for arteriovenous malformations: outcome for large AVMS. Int J Radiat Oncol Biol Phys 1999; 44:1089. 91. Buis DR, Meijer OW, van den Berg R, et al. Clinical outcome after repeated radiosurgery for brain arteriovenous malformations. Radiother Oncol 2010; 95:250. https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 25/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate 92. Blonder LX, Hodes JE, Ranseen JD, Schmitt FA. Short-term neuropsychological outcome following Gamma Knife radiosurgery for arteriovenous malformations: a preliminary report. Appl Neuropsychol 1999; 6:181. 93. Raymond J, Gentric JC, Magro E, et al. Endovascular treatment of brain arteriovenous malformations: clinical outcomes of patients included in the registry of a pragmatic randomized trial. J Neurosurg 2023; 138:1393. 94. Krings T, Hans FJ, Geibprasert S, Terbrugge K. Partial "targeted" embolisation of brain arteriovenous malformations. Eur Radiol 2010; 20:2723. 95. Brown RD Jr, Flemming KD, Meyer FB, et al. Natural history, evaluation, and management of intracranial vascular malformations. Mayo Clin Proc 2005; 80:269. 96. Kano H, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for arteriovenous malformations after embolization: a case-control study. J Neurosurg 2012; 117:265. 97. Schwyzer L, Yen CP, Evans A, et al. Long-term results of gamma knife surgery for partially embolized arteriovenous malformations. Neurosurgery 2012; 71:1139. 98. Starke RM, Kano H, Ding D, et al. Stereotactic radiosurgery for cerebral arteriovenous malformations: evaluation of long-term outcomes in a multicenter cohort. J Neurosurg 2017; 126:36. 99. Ding D, Starke RM, Kano H, et al. Stereotactic radiosurgery for Spetzler-Martin Grade III arteriovenous malformations: an international multicenter study. J Neurosurg 2017; 126:859. 100. Cohen-Inbar O, Lee CC, Xu Z, et al. A quantitative analysis of adverse radiation effects following Gamma Knife radiosurgery for arteriovenous malformations. J Neurosurg 2015; 123:945. 101. Starke RM, Komotar RJ, Otten ML, et al. Adjuvant embolization with N-butyl cyanoacrylate in the treatment of cerebral arteriovenous malformations: outcomes, complications, and predictors of neurologic deficits. Stroke 2009; 40:2783. 102. Hartmann A, Pile-Spellman J, Stapf C, et al. Risk of endovascular treatment of brain arteriovenous malformations. Stroke 2002; 33:1816. 103. Copelan A, Drocton G, Caton MT, et al. Brain Arteriovenous Malformation Recurrence After Apparent Microsurgical Cure: Increased Risk in Children Who Present With Arteriovenous Malformation Rupture. Stroke 2020; 51:2990. 104. Saleh RS, Singhal A, Lohan D, et al. Assessment of cerebral arteriovenous malformations with high temporal and spatial resolution contrast-enhanced magnetic resonance https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 26/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate angiography: a review from protocol to clinical application. Top Magn Reson Imaging 2008; 19:251. Topic 1087 Version 37.0 https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 27/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate GRAPHICS Cerebellar hematoma due to ruptured AVM (A) Noncontrast head CT showing acute right cerebellar ICH with smaller adjacent focus of hemorrhage (black arrow). (B) Subsequent FLAIR sequence on brain MRI after decompressive craniectomy showing flow void (white arrow) adjacent to ICH (white dashed arrow). (C) Digital subtraction angiogram subsequently identified an AVM with a nidus (white arrowhead), feeding artery (white thick arrow), and draining vein (white short arrow). CT: computed tomography; ICH: intracerebral hemorrhage; FLAIR: fluid-attenuated inversion recovery; MRI: magnetic resonance imaging; AVM: arteriovenous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 132273 Version 1.0 https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 28/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate MRI of brain arteriovenous malformation T2-weighted MRI of the brain demonstrates multiple flow voids in the right hemisphere, suggestive of a large arteriovenous malformation. MRI: magnetic resonance imaging. From: Flemming KD, Lanzino G. Management of Unruptured Intracranial Aneurysms and Cerebrovascular Malformations. Continuum (Minneap Minn) 2017; 23:181. DOI: 10.1212/CON.0000000000000418. Copyright 2017 American Academy of Neurology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 53992 Version 6.0 https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 29/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate Brain arteriovenous malformation pretreatment angiography Characteristic angiographic appearance of a brain arteriovenous malformation (AVM) before therapy. Courtesy of Guy Rordorf, MD. Graphic 75190 Version 2.0 https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 30/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate Brain arteriovenous malformation posttreatment angiography Angiogram obtained after the brain arteriovenous malformation (AVM) seen in the prior radiograph was treated. Courtesy of Guy Rordorf, MD. Graphic 62349 Version 2.0 https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 31/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate Spetzler-Martin grading scale for intracranial arteriovenous malformations Score Size 0 to 3 cm 1 3.1 to 6.0 cm 2 >6 cm 3 Location Noneloquent brain area 0 Eloquent brain area* 1 Deep venous drainage Absent 0 Present 1 Score = sum of all categories, with lesions graded 1 to 5 based upon total sum (eg, 1 point = grade 1). Associated with significant neurologic impairment (eg, language area, motor cortex, others). Reference: 1. Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg 1986; 65:476. Graphic 71261 Version 4.0 https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 32/33 7/5/23, 12:18 PM Brain arteriovenous malformations - UpToDate Contributor Disclosures Robert J Singer, MD No relevant financial relationship(s) with ineligible companies to disclose. Christopher S Ogilvy, MD Consultant/Advisory Boards: Cerevasc [Hydrocephalus]; Contour [Aneurysms]; Medtronic [Chronic subdural hematoma]. All of the relevant financial relationships listed have been mitigated. Guy Rordorf, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/brain-arteriovenous-malformations/print 33/33
7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cerebral amyloid angiopathy : Steven M Greenberg, MD, PhD : Scott E Kasner, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 08, 2023. INTRODUCTION Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta-peptide deposits within small- to medium-sized blood vessels of the brain and leptomeninges. CAA is an important cause of lobar intracerebral hemorrhage in older adults [1,2]. In addition to intracerebral hemorrhage, CAA may present with transient neurological symptoms, an inflammatory encephalopathy, as a contributor to cognitive impairment, or with incidental microbleeds or hemosiderosis on magnetic resonance imaging (MRI). The clinical features, diagnosis, and management of CAA is discussed here. Alzheimer disease, which is also characterized by abnormal amyloid beta-peptide deposits in the brain, is discussed separately. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease" and "Clinical features and diagnosis of Alzheimer disease".) Other causes of intracerebral hemorrhage are discussed in detail separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Superficial siderosis".) EPIDEMIOLOGY The incidence of CAA is strongly age dependent. By autopsy, CAA can be identified by the replacement of at least some cerebral blood vessel walls with amyloid beta-peptide. In one series of 784 autopsy cases, the prevalence of CAA ranged from 2.3 percent for patients between the ages of 65 and 74, 8.0 percent for those age 75 to 84, and 12.1 percent in patients over the https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 1/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate age of 85 [3]. In an autopsy study of 1079 patients whose mean age at death was 89.7 years, the prevalence of moderate-to-severe CAA was 36 percent [4]. CAA-related symptoms are uncommon at ages younger than 60 years but can occur in middle-aged or younger individuals either sporadically or due to rare genetic or iatrogenic causes [5-7]. The prevalence of CAA among older patients with dementia is higher than those without dementia. In a systematic review of population-based studies, nearly 60 percent of patients with dementia showed CAA pathology compared with less than 40 percent among those without dementia [8]. Among patients with Alzheimer disease, more than 80 percent had pathologic evidence of CAA [9]. PATHOPHYSIOLOGY Pathogenesis The pathology of CAA involves deposition of amyloid beta-peptide within the cerebral vasculature. Vascular amyloid deposits in CAA are biochemically similar to the material comprising senile plaques in Alzheimer disease [1]. The primary constituent of each is amyloid beta-peptide, a 39 to 43 amino acid fragment of the amyloid precursor protein (APP). Development of CAA The factors other than aging that initiate and promote amyloid beta-peptide deposition leading to CAA are not well understood. Genetic factors can cause CAA in an autosomal dominant manner and can increase the risk for sporadic CAA (see 'Genetic susceptibilities' below). Rarely, deposition of amyloid beta-peptide may occur with a neurosurgical procedure and/or exposure to cadaveric central nervous system tissue, and clinical manifestations of iatrogenic CAA may subsequently develop decades later [7,10-12]. Development of hemorrhage Vascular rupture and bleeding in CAA appear to be a multistep process involving the deposition of amyloid beta-peptide in the vascular wall and subsequent vascular changes such as concentric splitting of the vascular wall. The relationship between CAA and hypertension is debated. Although many patients with CAA- related hemorrhage are normotensive [13-15], elevated blood pressure nonetheless appears to contribute to the risk of hemorrhage recurrence [16]. Despite shared pathologic features, the pathophysiology of CAA and Alzheimer disease appear distinct [17]. There is no clinical overlap between amyloid beta CAA and the non-central nervous system systemic amyloidoses, such as primary (amyloid AL) and secondary (amyloid AA) amyloidosis. Genetic susceptibilities CAA is sporadic in most patients. A small minority of patients have an identified monogenic cause [18,19]. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 2/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Amyloid precursor protein variant Variant forms of the gene that encodes the APP are responsible for some cases of early-onset CAA that are inherited in an autosomal dominant pattern. While most of these variants are also associated with at least some of the neuropathologic features of Alzheimer disease, at least two APP variants (Glu693Gln and Leu705Val) have been reported to cause autosomal-dominant CAA with minimal parenchymal amyloid plaques or neurofibrillary tangles [18-20]. The Dutch-type Glu693Gln APP pathologic variant is associated with cerebral amyloid deposition with a more aggressive course than patients with sporadic CAA [21]. The causative amino acid substitutions in these hereditary forms of CAA may increase the toxic effects of amyloid beta-peptide on the vessel wall [22,23], decrease the peptide's susceptibility to proteolysis [24], or impair its clearance from the central nervous system [25]. Apolipoprotein E Patients carrying the apolipoprotein E (APOE) epsilon 2 (e2) or epsilon 4 (e4) alleles appear to be at greater risk for CAA-related hemorrhage than those with only the common APOE epsilon 3 (e3) allele [26-30]. One systematic review found evidence for a dose-dependent association between APOE e4 and sporadic CAA [31]. APOE e4 also promotes deposition of amyloid beta-peptide in Alzheimer disease [32] and following severe head injury [33]. APOE e2 or e4 alleles are present in approximately two-thirds of patients with CAA compared with only about one-quarter of older adult controls without evidence of CAA. These alleles are associated with an increased likelihood of having a CAA-related hemorrhage [26,27], earlier age of disease onset (mean age of first hemorrhage 75 versus 82 years in patients who are not carriers of APOE e2 or e4), and a greater risk of hemorrhage recurrence (two-year cumulative recurrence rate of 28 percent in carriers of e2 or e4 versus 10 percent for the APOE e3/e3 genotype) [34]. The APOE e2 and e4 alleles act via separate mechanisms. APOE e4 increases amyloid beta- peptide deposition [32]. APOE e2 causes amyloid-laden vessels to undergo changes such as concentric wall splitting and necrosis that predispose to rupture [27,35,36]. Patients with CAA who have both APOE e2 and e4 alleles appear to have a particularly early onset of disease and a high risk of early recurrence [27,34]. Carriers of the APOE e2 allele also have larger intracerebral hemorrhage (ICH) volumes, increased mortality, and worse functional outcomes compared with noncarriers, while these associations are not seen for carriers of the APOE e4 allele [37]. Data from a population-based, case-control study suggest that the risk of lobar ICH associated with APOE alleles may be modified by variation elsewhere in the APOE gene [38]. Notably, overall APOE haplotype (combination of multiple alleles on one chromosome) was https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 3/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate also independently associated with lobar ICH, suggesting the presence of regulatory variants that could influence the effect of APOE e2 or e4 on the risk of lobar ICH [39]. CR1 gene variant A case-control genetic association study that included a prospective followup of 178 ICH survivors found that a variant within the CR1 gene (rs6656401) influences the risk and recurrence of CAA-related ICH [40]. In the same report, this genetic variant was also associated with the severity of vascular amyloid deposition on pathologic examination of 544 autopsy studies from two community-based clinical-pathological studies of aging. ACUTE INTRACEREBRAL HEMORRHAGE The most common clinical manifestation of CAA is acute lobar intracerebral hemorrhage (ICH) ( image 1) [41]. The term "lobar" refers to location in the cortex and subcortical white matter of a hemispheric lobe of the brain; this contrasts with the deep locations, such as putamen, thalamus, and pons, which are characteristic of hypertensive hemorrhage. The lobar location of the hemorrhages reflects the underlying distribution of the vascular amyloid deposits, which favor cortical vessels and largely spare white matter, deep gray matter, and the brainstem. Involvement of the blood vessels in the cerebellum and leptomeninges can also give rise to the less common clinical presentations of cerebellar or subarachnoid/subdural hemorrhage. Clinical features The clinical presentation of CAA-related hemorrhage varies with the lesion size and brain region impacted. Lobar hemorrhages can cause hemiparesis from involvement of pyramidal motor neurons and tracts. A large lobar hemorrhage may cause depressed consciousness from direct involvement or secondary mass effect on reticular activating system networks. In comparison, smaller lobar or cerebellar hemorrhages may cause more limited focal deficits related to the underlying brain structure impacted. The clinical presentation of intracerebral hemorrhage is described in more detail separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Clinical presentation'.) In rare cases, small cortical hemorrhages may irritate meningeal nociceptors to cause isolated headache. They may also infrequently be asymptomatic, found on imaging pursued for other indications [42,43]. (See 'Microbleeds' below.) Imaging features Imaging findings in acute hemorrhage can vary in size and location, but specific imaging patterns and associated findings are common in CAA-related hemorrhage. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 4/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Lobar regions CAA-related lobar hemorrhages preferentially arise in posterior lobar brain regions. Analysis of the spatial distribution of 321 intracerebral hemorrhages in 59 patients with CAA revealed that hemorrhages were significantly more likely to occur in the temporal and occipital than the frontal and parietal lobes (ratio of actual to expected hemorrhages 1.37, 1.43, 0.58, and 1.0, respectively) [44]. The explanation for the posterior brain clustering of CAA hemorrhages is undetermined, but it may be related to as-yet unknown characteristics of posterior circulation vessels that influence amyloid beta- peptide elimination or to increased vulnerability of these brain regions to minor trauma [44,45]. CAA-related lobar hemorrhages often extend beyond the brain tissue into the subarachnoid and subdural spaces and, less frequently, may rupture into ventricles [46,47]. Extension of the hemorrhage into the subarachnoid space and the presence of elongated "finger-like" projections appear to be characteristic features of CAA-related lobar hemorrhages that may assist in diagnosis [48]. Cerebellum The cerebellum may contain variable amounts of vascular amyloid in individuals with CAA. The cerebellum is also a site of CAA-related hemorrhage, with predilection for the cerebellar cortex and vermis rather than the cerebellar nuclei and deep white matter [49-51]. Convexity subarachnoid hemorrhage Subarachnoid hemorrhage can also occur within the convexity of the cerebral hemispheres (cSAH) in patients with CAA due to amyloid deposition at the cortical surface. cSAH may occur along with acute ICH, located either adjacent to or remote from the ICH. In addition, patients may present with isolated cSAH and seizures or other focal symptoms due to dysfunction of underlying cortex. (See 'Transient focal neurologic episodes' below.) Associated chronic hemorrhagic findings T2-weighted gradient-echo or susceptibility- weighted brain MRI sequences obtained in patients with an acute lobar hemorrhage may also show chronic cerebral microbleeds (CMBs) and/or cortical superficial siderosis (cSS). CMBs are typically asymptomatic lesions and are found in the juxtacortical and cortical lobar regions with a predilection for temporal and occipital lobes. cSS represents cSAH in the chronic phase. The presence of cSS likely reflects severe CAA in the leptomeningeal vessels [52]. (See 'Incidental chronic imaging features' below.) Differential diagnosis Differentiation of nontraumatic lobar ICH related to CAA from other causes depends upon the clinical and radiographic appearance. Other causes include: Lobar extension of a hypertensive hemorrhage (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis") https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 5/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Hemorrhagic transformation of an ischemic stroke (see "Neuroimaging of acute stroke") Hemorrhagic venous infarction from cerebral venous thrombosis (see "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis") Hemorrhage of arteriovenous malformation (AVM) (see "Vascular malformations of the central nervous system") Hemorrhagic tumor (see "Overview of the clinical features and diagnosis of brain tumors in adults") Clinical features that favor diagnoses other than CAA include younger age (many hemorrhages attributed to AVM occur before age 35 to 40 [53]), prodromal symptoms (progressive headache may suggest cerebral venous thrombosis), or patient-level risk factors (eg, active metastatic cancer may suggest hemorrhagic tumor, high thromboembolic risk in a patient with atrial fibrillation not treated with anticoagulation may suggest hemorrhagic transformation of ischemic infarct). Imaging features may also help identify diagnoses other than CAA in patients with lobar hemorrhage ( table 1). Brain MRI can help identify evidence of acute ischemia or enhancement associated with tumors. Corresponding computed tomographic (CT) angiography or MR angiographic studies can help identify the presence of an associated arterial or venous occlusion or AVM. This differential diagnosis and the evaluation to determine etiology is discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Subsequent imaging'.) Diagnostic approach The presence of CAA should be suspected clinically in patients age 50 years or older with or without a clinical manifestation of CAA who have characteristic acute or chronic hemorrhagic findings and/or white matter features on brain MRI in the absence of an alternative cause. Definite CAA is only diagnosed postmortem. A full pathologic examination of the brain showing amyloid deposition with vasculopathy, evidence of brain hemorrhage, and absence of other diagnostic lesions confirms CAA [54]. During life, the diagnosis of probable CAA can be made with clinical evaluation and MRI of the brain. Examination of a sample of brain tissue obtained by brain biopsy further supports the diagnosis but is infrequently performed. For all patients, we use hemorrhagic imaging features on T2-weighted MRI sequences and additional white matter markers to support the diagnosis of probable CAA. (See 'Imaging-based diagnosis' below.) For select patients in whom imaging features are equivocal or the cause of a clinical manifestation is uncertain, we use additional adjunctive testing. (See 'Adjunctive diagnostic https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 6/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate testing for some patients' below.) Imaging-based diagnosis All patients with suspected CAA should undergo brain MRI, including T2-weighted sequences, which accentuate the signal dropout caused by iron- containing deposits left by old hemorrhages ( image 2) [55]. Chronic lobar hemorrhages, cSS, and CMBs appear dark on such sequences. Inclusion of white matter features, including enlarged perivascular spaces in the centrum semiovale and multispot pattern subcortical hyperintensities on T2-weighted sequences in the MRI criteria for probable CAA, increased the diagnostic sensitivity in version 2.0 of the Boston criteria [56]. (See 'The Boston criteria for CAA' below.) To support the diagnosis of probable CAA with MRI, we look for the presence of either of the following findings not attributable to another cause [56] (see 'Differential diagnosis' above): Two or more hemorrhagic lesions (ICH, CMB, cSAH, or cSS foci in any combination) in the lobar brain regions, entirely sparing regions typical of hypertensive hemorrhage (basal ganglia, thalamus, or pons) ( image 3 and image 4 and image 5 and image 6) [57-59] One lobar hemorrhagic lesion and one white matter lesion, defined as either severe (ie, >20 per hemisphere) dilated perivascular spaces in the centrum semiovale or multiple (ie, >10) ovoid-shaped white matter hyperintensities on T2-weighted imaging in bilateral subcortical regions A single hemorrhagic lesion (eg, lobar hemorrhage, cSAH, cSS focus, or lobar CMB) or isolated white matter features create less diagnostic certainty but can be suggestive of the diagnosis (classified as "possible CAA"). The Boston criteria for CAA The Boston criteria provide a framework for various levels of diagnostic certainty in patients with intracerebral hemorrhage with or without pathologic tissue analysis ( table 2). Initial versions of the criteria included clinical, radiologic, and pathologic data to support the diagnosis of CAA [54,58]. The Boston criteria version 2.0 for sporadic CAA update the modified Boston criteria to include expanded imaging findings (hemorrhagic and white matter features) with validation data across multiple time epochs, medical centers, and both hemorrhagic and nonhemorrhagic clinical presentations ( table 2). (See 'Transient focal neurologic episodes' below and 'Cerebral amyloid angiopathy-related inflammation' below and 'Cognitive impairment' below and 'Incidental chronic imaging features' below.) https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 7/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate In a retrospective, multicenter review of 341 patients who presented with clinical features consistent with CAA and had both MRI and brain tissue available for analysis, the inclusion of additional imaging findings to the Boston criteria version 2.0 produced a higher diagnostic accuracy for probable CAA than the previous modified Boston criteria (84.8 versus 79.8 percent) [56]. The specificity was 95 percent for both sets of criteria. Adjunctive diagnostic testing for some patients While not commonly performed for evaluation and diagnosis of most patients with typical symptoms and imaging findings, additional testing to support the diagnosis of probable CAA may be performed in circumstances when the above criteria are not met. Follow up brain MRI Follow-up imaging, typically three to six months after the acute event, may show resolution of the acute hemorrhage and help exclude underlying alternative causes. Interval development of subclinical neuroimaging findings, namely strictly lobar CMB or cSS, may provide further support for the diagnosis of CAA. (See 'Microbleeds' below and 'Cortical superficial siderosis' below.) Brain biopsy Brain biopsies are done rarely for the diagnosis of CAA. However, brain tissue may be obtained during surgical evacuation of select acute lobar hemorrhages. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Subsequent imaging'.) Evacuated hematoma specimens and accompanying leptomeningeal or parenchymal tissue from older adult patients should routinely be examined with Congo red stain or beta-amyloid immunostain for CAA. Based upon data from a postmortem model, nearly all blocks of tissue from brains with CAA-related hemorrhage demonstrate some degree of CAA [3], often with evidence of advanced disease such as complete amyloid replacement of the smooth muscle layer or the appearance of vessel breakdown [60-62]. Signs of advanced disease are rare in single-tissue specimens from asymptomatic older adult brains; thus, their presence points toward a degree of CAA severe enough to cause hemorrhage. Cerebrospinal fluid analysis Up to a 50 percent reduction in levels of cerebrospinal fluid (CSF) amyloid beta 42 and beta 40 protein have been found in patients with CAA [63]. In combination with the finding of mildly increased total tau levels, CSF analysis distinguished patients with CAA from normal controls with a high degree of accuracy. Similar results were obtained in an independent study [64]. We obtain CSF when the imaging diagnosis is uncertain and when confirming the diagnosis may affect clinical decisions, such as whether to give or withhold antithrombotic treatment. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 8/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Positron emission tomography Positron emission tomography (PET) using 11C- Pittsburgh compound B (PIB), a ligand that binds to beta-amyloid, demonstrates increased uptake in patients with CAA-related hemorrhage compared with normal controls [65,66]. Another PET study of the amyloid ligand florbetapir showed elevated retention in patients with CAA but not hypertension-related intracerebral hemorrhages [67]. Compared with patients with Alzheimer disease, median binding of PIB is lower in CAA and may differ in its distribution. Current and future hemorrhagic lesions in patients with CAA appear to occur preferentially in local regions of concentrated amyloid detected by PIB [68,69]. PET imaging is typically used in research settings. Genetic testing There is no clearly defined clinical role for genetic testing in sporadic CAA. In particular, apolipoprotein E (APOE) genotype is neither sensitive nor specific for the diagnosis of CAA, as the epsilon 2 (e2) and epsilon 4 (e4) alleles are present in only a subset of patients [26,27]. Acute management Acute CAA-related hemorrhage is treated like other acute nontraumatic intracerebral hemorrhages. Of note, surgical biopsy or hematoma resection appears to carry little or no additional risk in CAA compared with other types of ICH and can be performed when indicated [70]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Evaluation and management of elevated intracranial pressure in adults".) Prevention of recurrent hemorrhage Survivors of lobar hemorrhage and patients with other clinical manifestations of CAA are at risk for future hemorrhagic complications (see 'Prognosis' below). This risk should be factored into decision-making when assessing the risks and benefits of other medications for patients with CAA. Managing anticoagulant and antiplatelet medications Because of the risk of spontaneous lobar hemorrhage in patients with CAA, we weigh the risks and benefits of using of anticoagulant and antiplatelet agents at an individual-level, in agreement with guidelines from the American Heart Association [71]. The major determinants of ICH risk in CAA patients are: History of prior ICH Presence of particular CAA-associated imaging features such as disseminated cSS (see 'Incidental chronic imaging features' below) Class of agent used (highest ICH risk with warfarin, then the direct oral anticoagulants [DOACs; also called non-vitamin K antagonist oral anticoagulants, or NOACs], then antiplatelet agents, and lowest with no agent) https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 9/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Duration of treatment Warfarin in particular increases both the frequency (approximately 7- to 10-fold) and severity (approximately 60 percent mortality) of cerebral hemorrhage [72-74]. The benefit of anticoagulants or antiplatelets is determined by the strength of the clinical indication and the availability of alternative treatments. In select patients with compelling indications for anticoagulation due to high risk of thromboembolism and absence of alternatives, anticoagulation may be used after discussion with the patient regarding risks and benefits. We reserve anticoagulation in CAA patients for those at high-risk for thromboembolic complications related to specific indications. These may include: Cancer-related thrombophilia with high risk of or prior venous thromboembolism (see "Risk and prevention of venous thromboembolism in adults with cancer") Hypercoagulable (acquired and inherited) conditions (see "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors") Mechanical prosthetic heart valve replacement (see "Antithrombotic therapy for mechanical heart valves") Other temporary high-risk indications for anticoagulation (see "Atrial fibrillation: Left atrial appendage occlusion", section on 'Postprocedure management' and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement") Because ICH risk is a function of antithrombotic treatment duration as well as type, we recommend in these situations the shortest and least intense treatment course that is still compatible with effective thrombosis prevention. In other patients, we pursue alternatives to anticoagulation, based on indication. Atherosclerotic disease We reserve aspirin for selected patients with CAA who have clear indications for antiplatelet therapy. Aspirin appears to increase the risk of hemorrhage but to a lesser extent than anticoagulants [75]. However, some data in patients with established atherosclerotic risk factors suggest antiplatelet use may not increase the risk of ICH recurrence. In an open-label trial of 537 patients with a history of occlusive vascular disease who developed ICH, patients were assigned to restart or avoid antiplatelet therapy at a median of 76 days following ICH [76]. At a median two-year follow- https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 10/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate up, there was a trend toward less ICH recurrence in those assigned to restart antiplatelet therapy (4 versus 9 percent; hazard ratio 0.51, 95% CI 0.25-1.03). Atrial fibrillation The management of atrial fibrillation in patients with CAA-related ICH is uncertain. Left atrial appendage closure is a reasonable treatment option for individuals with CAA who are at high risk for atrial fibrillation-related cardioembolic stroke [77]. (See "Atrial fibrillation: Left atrial appendage occlusion" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Of note, some retrospective studies have reported good outcomes for patients with atrial fibrillation who were restarted on anticoagulation with warfarin after recovery from an anticoagulant-related intracerebral hemorrhage [78]. Conclusions from these retrospective analyses are limited by the likelihood of indication bias regarding which patients were or were not re-anticoagulated, but they offer a rationale for randomized trials to address this question [79]. The DOACs appear at least as effective as warfarin for prevention of ischemic strokes in patients with atrial fibrillation and confer lower risks for ICH. While they have not been studied for this indication, some experts use these agents (dabigatran, apixaban, edoxaban, rivaroxaban) for patients with atrial fibrillation and CAA who are at high risk for both ischemic and hemorrhagic stroke. Other potential alternatives to anticoagulation in high-risk patients with atrial fibrillation are discussed separately. Some nonsteroidal anti-inflammatory medications have weak antithrombotic properties. We prefer the nonacetylated salicylates (eg, magnesium salicylate) drugs over other nonsteroidal anti-inflammatory drugs as they do not appear to affect platelet function. Thrombolytic therapy We do not routinely offer thrombolytic therapy for indications such as acute ischemic stroke, myocardial infarction, or pulmonary embolism in patients with a history of CAA-related ICH. Intravenous thrombolysis for ischemic stroke is contraindicated in patients with a history of ICH [80]. Endovascular mechanical thrombectomy may be an option for patients with a history of lobar ICH. Because patients with CAA are at risk of hemorrhagic complications from thrombolytic therapy, the risks and benefits of acute therapies should be discussed with patients or their proxies whenever possible. A large trial evaluating the use of tissue-type plasminogen activator for acute myocardial infarction identified severe CAA at postmortem examination in two of five patients with intracerebral hemorrhagic complications [81]. Additionally, in one analysis of acute ischemic https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 11/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate stroke, patients reported an association between number of cortical microbleeds and an elevated risk of hemorrhagic complications after systemic thrombolysis [82]. However, the specific treatment benefits of thrombolytic therapy in such patients were not assessed. Blood pressure control Although the vascular pathology in CAA does not appear primarily driven by hypertension, control of blood pressure within normal limits is nonetheless advisable. We use intensive blood pressure goals, as tolerated ( table 3). (See "Antihypertensive therapy for secondary stroke prevention", section on 'Patients with intracerebral hemorrhage'.) Support for lowering of blood pressure in patients diagnosed with CAA came from a secondary analysis of data from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial [15]. At a median follow up of 3.9 years, those assigned to active treatment (perindopril plus indapamide) had a 77 percent reduction (3 versus 13 events) of probable CAA-related ICH. These results are consistent with observational data showing reduced risk of ICH recurrence among ICH survivors with lower ambulatory blood pressures [16]. Managing statin use We do not withhold statin agents for most CAA patients when otherwise indicated. While a number of studies have found an inverse relationship between total and low-density lipoprotein cholesterol and the risk of ICH [83,84], treatment with statins does not appear to increase the risk of primary ICH or to negatively impact prognosis according to a number of studies and meta-analyses [85-88]. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Management of statins'.) Prognosis Lobar hemorrhage in general is associated with features that are both favorable (their superficial location and tendency to spare the ventricles) and unfavorable to outcome (older age and somewhat larger hematoma size) [89-91]. Mortality Overall mortality in acute lobar hemorrhage due to CAA is in the range of 10 to 30 percent [90,91], with the best prognosis for patients with smaller hematomas (<50 mL) and higher level of consciousness on admission (Glasgow coma scale 8). Recurrence CAA carries a substantially higher risk of hemorrhage recurrence than for hypertensive hemorrhage. In two case series of ICH survivors, recurrence rates were 21 percent at 2 years and 24 percent at a median 2.6 years, respectively [34,92]. Another report of 104 survivors of primary lobar ICH found that patients with history of ICH prior to the index event were at approximately six times the risk as those without a previous history. The risk for recurrent ICH was even higher in those who had more than one prior ICH [75]. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 12/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Recurrent hemorrhages have a tendency to arise in areas of prior hemorrhage [44]. Areas of high amyloid deposition on amyloid imaging appear to predict sites for future hemorrhage [68]. Recurrent ICH is more likely with increasing number of CMBs and disseminated cSS (see 'Incidental chronic imaging features' below). In a study of 94 consecutive survivors of primary lobar hemorrhage, the three-year cumulative risk of recurrent hemorrhage for patients with one, two, three to five, and six or greater CMBs on the baseline gradient-echo MRI was 14, 17, 38, and 51 percent, respectively (hazard ratio 1.7, 95% CI 1.2-2.4 for each increase in category) [93]. In a study of 118 patients diagnosed with CAA (104 with a symptomatic lobar ICH), the cumulative risk of new ICH at four years was 74 percent for the 27 individuals with disseminated cSS (defined as involving more than three cortical sulci) versus only 25 percent for the 77 without siderosis at baseline [94]. Similarly, the presence of cSAH in patients with CAA is associated with an increased risk of recurrent ICH [95]. Carriers of the e2 or e4 APOE alleles are also at increased risk compared with the more common APOE e3/e3 genotype [34]. (See 'Genetic susceptibilities' above.) Incident dementia The association of subsequent dementia in patients with lobar ICH may reflect an elevated rate of ICH recurrence and/or the relationship of CAA with cognitive impairment. In a study of 255 patients with lobar and nonlobar ICH followed for five years, patients with lobar ICH had higher rates of dementia (36 versus 21 percent) and higher rates of disability (60 versus 31 percent) compared with those with nonlobar ICH [96]. This finding is consistent with a prior study of 218 ICH survivors with one-year incidence of new- onset dementia of 23.4 percent for lobar ICH versus 9.2 percent for nonlobar ICH [97]. In another cohort of 97 patients with lobar ICH, the rate of dementia after median 2.5-year follow-up was 26 percent [98]. (See 'Cognitive impairment' below.) INCIDENTAL CHRONIC IMAGING FEATURES Patients with CAA are frequently asymptomatic unless they develop a specific clinical episode. Evidence suggestive of CAA may be identified in asymptomatic patients who undergo brain MRI for unrelated symptoms (eg, chronic headaches). Microbleeds Chronic evidence of tiny asymptomatic bleeding within the brain can be detected on brain MRI and may reflect CAA. These microbleeds (or microhemorrhages) appear as 2 to 10 mm focal areas of hemosiderin deposition on gradient echo or other T2-weighted https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 13/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate sequences ( image 7). In population-based studies, cerebral microbleeds are detected in 5 to 23 percent of older individuals [99-102]. Microbleeds can arise from small-vessel disease (CAA or hypertensive vasculopathy) and may represent a milder and somewhat distinct manifestation from overt (macro-)hemorrhage. Analysis of CAA patients in a neuroimaging study who underwent autopsy showed those with a large number of microbleeds had thicker-walled vessels due to beta-amyloid deposition compared with patients with a lower proportion or absence of microbleeds [103]. Microbleeds are also more prevalent among those using antiplatelet agents than nonusers [104,105]. Evaluation and differential diagnosis Focal areas of hemosiderin deposition on MRI should be reviewed with some care since lesions and structures other than hemorrhage can produce signal dropout. These include mineralization (particularly of the basal ganglia), flow-void from a cortical vessel, or adjacent air in the nasal sinuses. When establishing the presence of at least two hemorrhages, lesions that do not clearly represent independent hemorrhagic foci (for example, small blood deposits close to a larger hematoma) should not be counted. Cerebral microbleeds are not specific for CAA as they can be seen in multiple conditions. Such conditions may include: Hypertension [106,107] Cerebral cavernous malformations [108] Coagulopathy [109,110] Thrombocytopenia [111,112] Anticoagulant medications [113] Central nervous system vasculitis [114] Infective endocarditis [115] End-stage kidney failure [116] Traumatic brain injury [117] Prior cardiac surgery [118] While microbleeds in general are not specific to CAA, cortical microbleeds (CMBs; (ie, those restricted to the cerebral cortex or superficial cerebellar regions [cerebellar cortex and vermis]), suggest CAA [106,107]. In contrast, microbleeds that involve the basal ganglia, thalamus, or pons are believed to result from hypertensive microangiopathy. The association between lobar microbleeds and APOE e4 in the Rotterdam and other studies support the hypothesis that these more superficial lesions often originate from CAA [30,101,102,119,120]. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 14/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Management and prognosis For patients with acute ischemic stroke and a known history of CAA with CMBs only (ie, without a history of lobar hemorrhage or cortical superficial siderosis), we do not withhold systemic intravenous thrombolytic therapy if they otherwise meet eligibility criteria ( table 4), in agreement with guideline statements from the American Heart Association [80]. Over the long-term, the risk of incident hemorrhage in patients with multiple CMBs is nonetheless substantial [121]. Thus, other measures for primary prevention are similar as for patients with an ICH presentation. (See 'Prevention of recurrent hemorrhage' above.) CMBs are associated with an elevated risk of death. One study found that an incidental finding of multiple CMBs in an older adult was associated with a sevenfold risk of stroke- related death compared to individuals without CMBs [122]. Cortical superficial siderosis Evidence of chronic bleeding at the surface of the brain seen on imaging as foci of cSS may be seen in patients with CAA. They likely reflect the chronic form of acute convexity subarachnoid hemorrhage ( image 6) [54,123,124]. cSS is typical at the convexities of the cerebral hemispheres in patients with CAA but may also be found along the cerebellar folia [51]. cSS is frequently found in CAA patients with microbleeds and appears to signal higher risk for future ICH, particularly disseminated cSS. (See 'Microbleeds' above and 'Prognosis' above.) cSS typically is an asymptomatic imaging finding but is also detected in many CAA patients who present with transient neurologic symptoms [124,125]. (See 'Transient focal neurologic episodes' below.) Evaluation and differential diagnosis cSS is common in patients with CAA (40 to 60 percent) but is unusual in patients with ICH of other cause (0 to 4 percent) [54,125].
(older age and somewhat larger hematoma size) [89-91]. Mortality Overall mortality in acute lobar hemorrhage due to CAA is in the range of 10 to 30 percent [90,91], with the best prognosis for patients with smaller hematomas (<50 mL) and higher level of consciousness on admission (Glasgow coma scale 8). Recurrence CAA carries a substantially higher risk of hemorrhage recurrence than for hypertensive hemorrhage. In two case series of ICH survivors, recurrence rates were 21 percent at 2 years and 24 percent at a median 2.6 years, respectively [34,92]. Another report of 104 survivors of primary lobar ICH found that patients with history of ICH prior to the index event were at approximately six times the risk as those without a previous history. The risk for recurrent ICH was even higher in those who had more than one prior ICH [75]. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 12/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Recurrent hemorrhages have a tendency to arise in areas of prior hemorrhage [44]. Areas of high amyloid deposition on amyloid imaging appear to predict sites for future hemorrhage [68]. Recurrent ICH is more likely with increasing number of CMBs and disseminated cSS (see 'Incidental chronic imaging features' below). In a study of 94 consecutive survivors of primary lobar hemorrhage, the three-year cumulative risk of recurrent hemorrhage for patients with one, two, three to five, and six or greater CMBs on the baseline gradient-echo MRI was 14, 17, 38, and 51 percent, respectively (hazard ratio 1.7, 95% CI 1.2-2.4 for each increase in category) [93]. In a study of 118 patients diagnosed with CAA (104 with a symptomatic lobar ICH), the cumulative risk of new ICH at four years was 74 percent for the 27 individuals with disseminated cSS (defined as involving more than three cortical sulci) versus only 25 percent for the 77 without siderosis at baseline [94]. Similarly, the presence of cSAH in patients with CAA is associated with an increased risk of recurrent ICH [95]. Carriers of the e2 or e4 APOE alleles are also at increased risk compared with the more common APOE e3/e3 genotype [34]. (See 'Genetic susceptibilities' above.) Incident dementia The association of subsequent dementia in patients with lobar ICH may reflect an elevated rate of ICH recurrence and/or the relationship of CAA with cognitive impairment. In a study of 255 patients with lobar and nonlobar ICH followed for five years, patients with lobar ICH had higher rates of dementia (36 versus 21 percent) and higher rates of disability (60 versus 31 percent) compared with those with nonlobar ICH [96]. This finding is consistent with a prior study of 218 ICH survivors with one-year incidence of new- onset dementia of 23.4 percent for lobar ICH versus 9.2 percent for nonlobar ICH [97]. In another cohort of 97 patients with lobar ICH, the rate of dementia after median 2.5-year follow-up was 26 percent [98]. (See 'Cognitive impairment' below.) INCIDENTAL CHRONIC IMAGING FEATURES Patients with CAA are frequently asymptomatic unless they develop a specific clinical episode. Evidence suggestive of CAA may be identified in asymptomatic patients who undergo brain MRI for unrelated symptoms (eg, chronic headaches). Microbleeds Chronic evidence of tiny asymptomatic bleeding within the brain can be detected on brain MRI and may reflect CAA. These microbleeds (or microhemorrhages) appear as 2 to 10 mm focal areas of hemosiderin deposition on gradient echo or other T2-weighted https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 13/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate sequences ( image 7). In population-based studies, cerebral microbleeds are detected in 5 to 23 percent of older individuals [99-102]. Microbleeds can arise from small-vessel disease (CAA or hypertensive vasculopathy) and may represent a milder and somewhat distinct manifestation from overt (macro-)hemorrhage. Analysis of CAA patients in a neuroimaging study who underwent autopsy showed those with a large number of microbleeds had thicker-walled vessels due to beta-amyloid deposition compared with patients with a lower proportion or absence of microbleeds [103]. Microbleeds are also more prevalent among those using antiplatelet agents than nonusers [104,105]. Evaluation and differential diagnosis Focal areas of hemosiderin deposition on MRI should be reviewed with some care since lesions and structures other than hemorrhage can produce signal dropout. These include mineralization (particularly of the basal ganglia), flow-void from a cortical vessel, or adjacent air in the nasal sinuses. When establishing the presence of at least two hemorrhages, lesions that do not clearly represent independent hemorrhagic foci (for example, small blood deposits close to a larger hematoma) should not be counted. Cerebral microbleeds are not specific for CAA as they can be seen in multiple conditions. Such conditions may include: Hypertension [106,107] Cerebral cavernous malformations [108] Coagulopathy [109,110] Thrombocytopenia [111,112] Anticoagulant medications [113] Central nervous system vasculitis [114] Infective endocarditis [115] End-stage kidney failure [116] Traumatic brain injury [117] Prior cardiac surgery [118] While microbleeds in general are not specific to CAA, cortical microbleeds (CMBs; (ie, those restricted to the cerebral cortex or superficial cerebellar regions [cerebellar cortex and vermis]), suggest CAA [106,107]. In contrast, microbleeds that involve the basal ganglia, thalamus, or pons are believed to result from hypertensive microangiopathy. The association between lobar microbleeds and APOE e4 in the Rotterdam and other studies support the hypothesis that these more superficial lesions often originate from CAA [30,101,102,119,120]. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 14/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Management and prognosis For patients with acute ischemic stroke and a known history of CAA with CMBs only (ie, without a history of lobar hemorrhage or cortical superficial siderosis), we do not withhold systemic intravenous thrombolytic therapy if they otherwise meet eligibility criteria ( table 4), in agreement with guideline statements from the American Heart Association [80]. Over the long-term, the risk of incident hemorrhage in patients with multiple CMBs is nonetheless substantial [121]. Thus, other measures for primary prevention are similar as for patients with an ICH presentation. (See 'Prevention of recurrent hemorrhage' above.) CMBs are associated with an elevated risk of death. One study found that an incidental finding of multiple CMBs in an older adult was associated with a sevenfold risk of stroke- related death compared to individuals without CMBs [122]. Cortical superficial siderosis Evidence of chronic bleeding at the surface of the brain seen on imaging as foci of cSS may be seen in patients with CAA. They likely reflect the chronic form of acute convexity subarachnoid hemorrhage ( image 6) [54,123,124]. cSS is typical at the convexities of the cerebral hemispheres in patients with CAA but may also be found along the cerebellar folia [51]. cSS is frequently found in CAA patients with microbleeds and appears to signal higher risk for future ICH, particularly disseminated cSS. (See 'Microbleeds' above and 'Prognosis' above.) cSS typically is an asymptomatic imaging finding but is also detected in many CAA patients who present with transient neurologic symptoms [124,125]. (See 'Transient focal neurologic episodes' below.) Evaluation and differential diagnosis cSS is common in patients with CAA (40 to 60 percent) but is unusual in patients with ICH of other cause (0 to 4 percent) [54,125]. However, cSS and superficial siderosis involving the cerebellum or brainstem can also arise from several other unrelated causes. These are discussed separately. (See "Superficial siderosis", section on 'Etiology'.) Patients with isolated hemorrhagic imaging findings such as a single CMB or equivocal focus of cSS may develop progressive subclinical findings to further support the diagnosis of CAA. As an example, in one cohort of 118 patients with probable CAA who underwent follow-up imaging at a mean interval of 2.2 years, progression of cSS was found in 28 percent and new CMBs were found in 18 percent [126]. Management and prognosis For patients with acute ischemic stroke and a known history of CAA with cSS, we do not routinely offer systemic thrombolytic therapy. cSS https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 15/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate represents an imaging marker of prior ICH, a contraindication for intravenous thrombolysis ( table 4). Endovascular mechanical thrombectomy may be an option for such patients when treatment benefits are felt to outweigh the hemorrhagic risks. For patients with cSS and a history of ischemic stroke, we individualize the use of antithrombotic therapy based on overall risks and benefits. Retrospective data on such patients who resume antiplatelets or anticoagulants have shown a higher subsequent risk of recurrent ischemic stroke than hemorrhage, suggesting that use of antithrombotics may be considered [127]. The approach to primary stroke prevention in patients with cSS is similar as that for patients with a prior ICH presentation. (See 'Prevention of recurrent hemorrhage' above.) cSS is associated with poor functional outcome in CAA [128]. Disseminated cSS in CAA appears to be an independent predictor of recurrent ICH [94,129], and radiologic progression of cSS on serial imaging has been associated with an increased risk of subsequent ICH [126]. cSS has also associated with an elevated risk of epilepsy in patients with CAA [130]. Nonhemorrhagic imaging findings Nonhemorrhagic findings on brain MRI may also be found in patients with CAA [56]. Acute ischemic micro-infarcts Asymptomatic punctate hyperintense lesions on diffusion-weighted image (DWI) sequencing are occasionally found in patients with CAA [131]. In one retrospective review of brain MRIs from 78 patients with probable CAA, subacute infarcts were identified on DWI in 15 percent [132]. Brain atrophy Cerebral atrophy of white matter is associated with CAA. In one study, white matter volume was lower in patients with CAA than age-matched patients with Alzheimer disease and healthy controls [133]. In CAA patients, atrophy was most pronounced in occipital regions and was more severe in those with higher cortical microbleeds. White matter hyperintensities Chronic white matter hyperintensities on T2-weighted sequences of brain MRI frequently represent small-vessel disease related to multiple conditions. Imaging patterns suggestive of CAA include the "multispot" pattern of multiple (ie, >10), typically bilateral lesions with a round or ovoid appearance [134]. In more advanced cases, white matter hyperintensities may be confluent. Such prominent findings may be seen preferentially in the subcortical parietal and occipital lobes of patients with advanced CAA [135]. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 16/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Centrum semiovale perivascular spaces Dilated perivascular spaces are identified typically on brain MRI as hyperintense lesions on T2-weighted sequences. They have been associated with vascular disease and aging, but the presence of multiple (>20) dilated perivascular spaces in the subcortical centrum semiovale regions has been associated with CAA with and without ICH [56,129,136-138]. TRANSIENT FOCAL NEUROLOGIC EPISODES A less common clinical manifestation of CAA is transient focal neurologic episodes (TFNE) [139- 141]. These have also been called "amyloid spells." Pathogenesis and clinical features Patients report recurrent, brief, and often stereotyped spells of weakness, numbness, paresthesias, or other cortical symptoms that can spread smoothly over contiguous body parts over several minutes. In one cohort, transient neurologic symptoms occurred in 14 percent of patients with CAA, and positive symptoms (positive visual aura, limb jerking) were as common as negative symptoms (vision loss, limb weakness, dysphasia) [142]. These episodes may reflect abnormal activity (ie, cortical spreading depression) of the surrounding cortex typically in response to the small hemorrhages [143]. In one study, CAA patients with cortical superficial siderosis (cSS) or convexity subarachnoid hemorrhage (cSAH) were more likely to have transient neurologic symptoms compared with CAA patients without these symptoms (50 versus 19 percent) [142]. Evaluation and diagnosis The description of TFNEs can be similar to other transient neurologic attacks such as transient ischemic attacks (TIAs), seizures, and migraine auras. Clinical features more suggestive of TFNE over other diagnoses include the smooth spread of the symptoms over minutes and the stereotypic recurrence of symptoms over time. Symptoms of TFNE tend to localize to the site of a cSAH, prior lobar hemorrhage, or focus of cSS [144]. (See 'Incidental chronic imaging features' above.) Additionally, diagnostic evaluation at the time of acute symptoms can support the diagnosis of TFNE and exclude alternative causes. This may include: Brain MRI with gradient echo or other T2-weighted sequences to identify cSAH, cSS, or cortical microbleeds (CMBs) in the region of cortex corresponding to TFNE symptoms Vascular imaging to exclude hemodynamically significant stenosis in the relevant vascular supply https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 17/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Electroencephalogram showing no epileptiform activity or seizure in the brain region corresponding to TFNE symptoms Additional testing may be performed to exclude TIA or ischemic stroke if indicated by clinical features or patient risk profile. (See "Differential diagnosis of transient ischemic attack and acute stroke" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) Features that support an alternative diagnosis include: TIAs may present in a patient with vascular risk factors as sudden loss of focal neurologic function attributable to a specific cerebrovascular arterial territory. Seizures may occur in a patient with a history of epilepsy or seizures as focal or diffuse symptoms. They may be associated with temporary postictal weakness or other loss of function. Migraines typically occur in younger patients with a prior history of migraines. Neurologic symptoms typifying the aura may wax over minutes prior to the onset of a headache. The differential diagnosis and evaluation of patients with transient neurologic episodes is discussed in greater detail separately. (See "Differential diagnosis of transient ischemic attack and acute stroke", section on 'Transient neurologic events' and "Differential diagnosis of transient ischemic attack and acute stroke", section on 'Distinguishing transient attacks'.) Management Avoiding misdiagnosis is critical since the administration of antithrombotics for TFNE symptoms presumed to be a TIA may increase the risk of hemorrhagic stroke from CAA [144]. In one series, transient neurologic symptoms in a patient with CAA appeared to predict a high early risk of symptomatic intracerebral hemorrhage, which occurred in 50 percent of patients over a median follow-up period of 14 months [142]. TFNE are typically brief and self-limited but may recur. Patients should be reassured that TFNE that recur typically resolve within weeks [143]. Medications used for seizures or migraine such as topiramate or levetiracetam have been used for those with recurrent or bothersome attacks [143,145]. Other general measures, applicable to patients with hemorrhagic features of CAA, are discussed separately. (See 'Prevention of recurrent hemorrhage' above.) CEREBRAL AMYLOID ANGIOPATHY-RELATED INFLAMMATION https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 18/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Cerebral amyloid angiopathy-related inflammation (CAA-ri) appears to represent a distinct manifestation of CAA characterized by an inflammatory response to amyloid deposition in the brain with subacute and often progressive neurologic symptoms [146,147]. CAA-ri may be a milder form of a condition called Abeta-related angiitis. CAA-ri is characterized by perivascular inflammation, while Abeta-related angiitis is a true vasculitis with inflammation throughout the vessel wall [148-150]. These two inflammatory syndromes share similar clinical presentations, imaging properties, and response to treatment, except that Abeta-related angiitis typically requires more aggressive immunosuppressive treatment. (See 'Management' below.) Clinical and diagnostic features The clinical presentation of a CAA-ri syndrome is that of acute or subacute cognitive decline rather than hemorrhage [151,152]. Patients or family members may report memory impairment, personality changes, confusion, or alterations in level of consciousness. Seizures, new and persistent headaches, and focal and progressive neurologic signs are common. Patients with CAA-ri are younger than those with other manifestations of CAA. In a systematic review of 21 studies that included 378 patients with CAA-ri, the mean age at diagnosis was 66 years [153]. Cognitive decline was reported in 70 percent, encephalopathy in 54 percent, focal neurologic symptoms in 55 percent, headaches in 31 percent, and seizures in 37 percent. The differential diagnosis includes primary, viral, and autoimmune encephalitides as well as cerebral neoplasm and other causes of rapidly progressive dementia [154-156]. (See "Primary angiitis of the central nervous system in adults", section on 'Diagnostic approach'.) Diagnostic studies in this setting typically include brain MRI with contrast, serologic, and cerebrospinal fluid (CSF) analysis. Brain biopsy may be performed both to make a positive diagnosis of CAA-related inflammation as well to exclude other conditions. Findings that support the diagnosis of CAA-ri include: Brain MRI typically shows a (potentially reversible) leukoencephalopathy consisting of patchy or confluent white matter hyperintensities on T2-weighted sequences, characteristically in subcortical white matter, often asymmetric; multiple microbleeds and/or cortical superficial siderosis are seen on gradient echo sequences ( image 8). Gadolinium enhancement may be found in up to half of cases [153,157]. Angiography or magnetic resonance angiography does not show evidence of large- or medium-vessel vasculitis. Neuropathology shows perivascular inflammation with multinucleated giant cells that is associated with amyloid-laden vessels. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 19/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Erythrocyte sedimentation rate and C-reactive protein are normal [152]. CSF analysis may be normal but often shows a pleocytosis and/or mildly elevated protein. Anti-amyloid autoantibodies have been detected in the CSF during the acute phase of inflammation and return to control levels during remission [158-160]. CSF assay for anti- amyloid antibodies is not yet commercially available but may eventually emerge as a diagnostic test. Clinical and radiographic improvement may occur with immunosuppressive treatment [146,147,152,161]. (See 'Management' below.) The diagnosis of CAA-ri is made in symptomatic patients with diagnostic imaging evidence of inflammation and hemorrhagic features of CAA who have undergone evaluation to exclude other sources ( table 5). A validation study of proposed criteria for the diagnosis of probable CAA-related inflammation showed high sensitivity (82 percent) and specificity (97 percent) [157]. Management We typically treat patients with suspected CAA-related inflammation with a course of high-dose glucocorticoids followed by a gradual oral taper. Our treatment protocol is usually methylprednisolone 1000 mg per day for three to five days, followed by an oral glucocorticoid taper over approximately 6 to 12 weeks. A repeat brain MRI scan approximately four to six weeks after treatment onset use clinical symptoms and changes in the subcortical white matter hyperintensities as evidence for treatment response. Although glucocorticoid therapy is most often used in this setting [160,162-164], other immunosuppressive treatments, such as cyclophosphamide, methotrexate, and mycophenolate mofetil, have also been used with a favorable response in isolated cases [152,165,166]. While data are limited, available evidence from observational studies supports treating inflammatory forms of CAA with immunosuppressive therapy [147,162-167]. In one series of 48 patients with CAA-related inflammation, those who were treated with immunosuppression (mostly glucocorticoids) were more likely to improve clinically (94 versus 50 percent) and radiographically (86 versus 29 percent) [167]. Treated patients were also less likely to have recurrent symptoms during a median of 2.7 years of follow-up (26 versus 71 percent). The response to therapy may be seen within the first few months and may be more durable when glucocorticoids are tapered slowly. In an observational study of 113 patients with CAA- related inflammation of whom 88 percent received immunosuppressive therapy, clinical recovery was reported by three months in 70 percent and resolution of inflammatory features on neuroimaging occurred in 45 percent [162]. By 12 months, the rates of clinical and radiologic recovery were 84 and 77 percent, respectively. Symptomatic recurrence was likelier in patients treated with high-dose pulse of intravenous glucocorticoids alone than those treated with pulse https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 20/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate intravenous glucocorticoids followed by a gradual oral glucocorticoid taper (hazard ratio 4.68, 95% CI 1.57 13.93). Additional measures to mitigate the associated risks of future bleeding associated with CAA should be based on the risks associated with hemorrhagic features. (See 'Prevention of recurrent hemorrhage' above.) COGNITIVE IMPAIRMENT Advanced CAA is associated with cognitive impairment. The majority of patients diagnosed with CAA appear to have cognitive impairment in at least one domain on neuropsychological testing [17]. An autopsy series found that moderate to severe CAA (present in one-third of the study population) was associated with faster rates of decline in global cognition, perceptual speed, episodic memory, and semantic memory, independently of age, sex, education, Alzheimer disease pathology, and other potential covariates [168]. Pathogenesis The pathogenesis of cognitive impairment in CAA may be multifactorial, with contributions from both vascular injury and Alzheimer disease pathology. Relationship to Alzheimer disease CAA is common in conjunction with Alzheimer disease, appearing in moderate to severe form in 30 of 117 (26 percent) Alzheimer disease brains in an autopsy series; CAA with hemorrhage occurred in six (5.1 percent) [5,169]. Another autopsy study found that patients with both CAA and Alzheimer disease had more severe cognitive impairment than patients with Alzheimer disease alone [170]. Similarly, an MRI study in Alzheimer disease patients found that the presence of multiple microbleeds was associated with worse cognitive performance [171]. However, only about 25 percent of CAA patients appear to have clinical histories of dementia prior to their first hemorrhage [89]. (See "Clinical features and diagnosis of Alzheimer disease".) Relationship to vascular dementia Cerebrovascular disease may contribute to cognitive impairment in patients with CAA. Studies in population- and hospital-based subjects have correlated the number and presence of microbleeds with cognitive impairment and dementia, raising the possibility that these lesions are contributors to neurologic dysfunction, as well as markers of small-vessel disease [172,173]. In one study of patients who underwent MRI because of transient ischemic attack or stroke, a finding of lobar microhemorrhage but not deep microhemorrhage was associated with cognitive impairment [174]. Additionally, clinically silent acute or subacute cerebral infarcts on diffusion-weighted imaging have been detected in 15 to 23 percent of patients with CAA [132,175], and cerebral https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 21/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate microinfarcts on T1 and fluid-attenuated inversion recovery (FLAIR) imaging have been found in 35 to 39 percent [176,177]. These data are consistent with autopsy and imaging studies showing an association between CAA severity and volume of white matter hyperintensity and/or microinfarct burden [139,178-182]. Cognitive impairment in CAA is also associated with ultrastructural white matter abnormalities measured by diffusion-tensor imaging-based methods [183,184]. Vascular dementia is discussed in more detail separately. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia".) Evaluation and management The evaluation and management of patients with cognitive impairment in the setting of CAA does not differ from other settings. Supportive care is the mainstay for patients with cognitive impairment related to CAA, like that of patients with other forms of cognitive impairment and dementia. This is discussed in greater detail separately. (See "Management of the patient with dementia".) Other general measures, applicable to all patients with CAA, are discussed separately. (See 'Prevention of recurrent hemorrhage' above.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Definition Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta-peptide deposits within small- to medium-sized blood vessels of the brain and leptomeninges. CAA is an important cause of lobar intracerebral hemorrhage in older adults. (See 'Introduction' above.) Diagnosis The diagnosis of probable CAA can be made with clinical evaluation and magnetic resonance imaging (MRI) of the brain ( table 2). Follow-up MRI examinations may be helpful if the initial study is equivocal. (See 'Diagnostic approach' above.) Acute intracerebral hemorrhage The most common clinical manifestation of CAA is acute lobar intracerebral hemorrhage (ICH) ( image 1). CAA-related lobar hemorrhages most commonly arise in posterior lobar brain regions. Because of their superficial location, CAA-related hemorrhages often extend beyond the brain tissue into the subarachnoid and https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 22/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate subdural spaces and less frequently rupture into ventricles. (See 'Acute intracerebral hemorrhage' above.) Because of the risk of spontaneous lobar hemorrhage in patients with CAA, we weigh the risks and benefits of using of anticoagulant and antiplatelet agents at an individual level. We reserve anticoagulation in CAA patients for those at high risk for thromboembolic complications related to specific indications. (See 'Managing anticoagulant and antiplatelet medications' above.) Incidental imaging features Chronic evidence of asymptomatic bleeding and other imaging findings can be detected on brain MRI in CAA patients with or without lobar hemorrhage. (See 'Incidental chronic imaging features' above.) Microbleeds (or microhemorrhages) appear as 2 to 10 mm focal areas of hemosiderin deposition on gradient echo or other T2*-weighted sequences ( image 7) and have an anatomic distribution similar to that of intracerebral hemorrhage, with a predilection for the cerebral cortex. Cortical superficial siderosis (cSS) can represent a focus of remote bleeding related to CAA ( image 6) and is thought to be the chronic form of acute convexity subarachnoid hemorrhage. Nonhemorrhagic imaging findings such as ischemic microinfarcts, cerebral atrophy, white matter hyperintensities, and multiple dilated perivascular spaces may also be found in patients with CAA. Transient focal neurologic episodes Patients with CAA may present with transient focal neurologic episodes (TFNE) described as recurrent, brief, and often stereotyped spells of weakness, numbness, paresthesias, or other cortical symptoms. Symptoms spread smoothly over contiguous body parts over several minutes and tend to localize to the site of a prior lobar hemorrhage or focus of cSS. (See 'Transient focal neurologic episodes' above.) Cerebral amyloid angiopathy-related inflammation Cerebral amyloid angiopathy- related inflammation (CAA-ri) is a distinct manifestation of CAA. Patients present with acute or subacute cognitive decline, seizures, new persistent headaches, or other progressive neurologic signs ( table 5); imaging demonstrates a patchy or confluent immediately subcortical leukoencephalopathy along with lobar microhemorrhages ( image 8). For patients with suspected CAA-ri, we suggest treatment with a course of immunosuppressive therapy, most often with glucocorticoids (Grade 2C). (See 'Cerebral https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 23/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate amyloid angiopathy-related inflammation' above.) 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Topic 1128 Version 45.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 37/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate GRAPHICS Lobar hemorrhage in cerebral amyloid angiopathy Acute superficial lobar hemorrhage in the left frontal lobe seen on computed tomography scan in a patient with cerebral amyloid angiopathy (A). Flair magnetic resonance image performed one week later shows the high signal intensity of subacute hemorrhage with surrounding edema extending into the subcortical white matter (B). Hemorrhage (now low signal intensity consistent with hemosiderin) and edema are mostly resolved on a three-month follow-up study (C). Courtesy of Eric D Schwartz, MD. Graphic 50480 Version 4.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 38/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Characteristic features and initial diagnostic imaging for common underlying causes of spontaneous isolated convexity subarachnoid hemorrhage Suspected Choice of initial diagnostic Characteristic feature(s) etiology imaging test(s) Age >60 years CAA MRI brain with T2-weighted SWI or GRE sequences Baseline cognitive impairment Recurrent thunderclap headache (>2 RCVS CTA or MRA of head within 1 week) MRI brain Exposure to vasoactive substance Risk factor for venous thrombosis CVT CTV or MRV of head Head CT features suggestive of venous thrombosis (eg, hyperdense venous sinus; venous infarction) MRI brain New heart murmur Mycotic aneurysm MRI brain with contrast or cerebral DSA Systemic/cutaneous evidence of embolism Clinical history of active cancer Brain tumor MRI brain with contrast Clinical history of new persistent headaches Head CT features suggestive of tumor (eg, vasogenic edema) Headache prior to neurologic deficits Intracranial dissection CTA of head or cerebral DSA Clinical history of connective tissue disorder Head CT features suggestive of AVM AVM Cerebral DSA (calcification or hypodense flow voids adjacent to SAH) History of minor/occult trauma may be Occult trauma MRI brain elicited Evidence of extracranial bleeding or systemic injuries Clinical history of new persistent headaches Vasculitis MRI brain with contrast Cerebral DSA Progressive cognitive or other neurologic impairments Brain and meningeal biopsy https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 39/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Patients with spontaneous isolated convexity SAH present with bleeding restricted to the surface of the cerebral hemispheres. The suspected underlying cause of convexity SAH may be identified by initial diagnostic imaging test. Additional imaging and/or other testing may be warranted if initial imaging is nondiagnostic. Refer to specific UpToDate topics for additional information on the diagnostic evaluation of conditions that may present with convexity SAH. SAH: subarachnoid hemorrhage; CAA: cerebral amyloid angiopathy; MRI: magnetic resonance imaging; SWI: susceptibility-weighted imaging; GRE: gradient recall echo imaging; RCVS: reversible cerebral vasoconstriction syndrome; CTA: computed tomographic angiography; MRA: magnetic resonance angiography; CT: computed tomography; CVT: cerebral venous thrombosis; CTV: computed tomography venography; MRV: magnetic resonance venography; DSA: digital subtraction angiography; AVM: arteriovenous malformation. Refer to UpToDate topic on the causes of venous thrombosis. Graphic 140108 Version 2.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 40/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Old hemorrhages on gradient echo MRI Comparison of CT scan (A), T2- weighted MRI (B), and gradient echo MRI (C) demonstrates the utility of the last for detecting old hemorrhages consistent with cerebral amyloid angiopathy. In addition to the the left frontoparietal hemorrhage seen on all studies (arrowheads), the gradient- echo sequence demonstrates multiple areas of decreased signal in gray- white regions (arrows) consistent with chronic hemorrhage. CT: computed tomography; MRI: magnetic resonance imaging. Reproduced with permission from Greenberg SM, Finklestein SP, Schaefer PW. Petechial hemorrhages accompanying lobar hemorrhage: detection by gradient-echo MRI. Neurology 1996; 46:1751. Graphic 81579 Version 12.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 41/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Acute and subacute lobar hemorrhage Noncontrast head CT shows acute right parietal ICH (A). T2* susceptibility-weighted sequence on MRI performed one day later shows an acute ICH in the right frontal and parietal hemisphere (B) as well as a subacute hemorrhage in the left occipital lobe (thick arrow) and chronic ICH in right inferior parietal lobule (C; arrow). In addition, multiple microbleeds at cerebral corticomedullary junctions (B, C) are consistent with cerebral amyloid angiopathy. CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132283 Version 1.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 42/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Distinctive distribution of cerebral microbleeds (A-C) CMBs on T2-weighted gradient echo MRI sequences suggestive of deep penetrating (hypertensive) vasculopathy. CMBs predominate in bilateral thalami (A), brainstem (B), and dentate nucleus of cerebellum (C). (D-F) CMBs on T2-weighted gradient echo MRI sequences suggestive of cerebral amyloid angiopathy. CMBs predominate in cerebral hemispheres (D, E). Associated findings include lobar hemorrhage (D; arrow and thick arrow) and superficial siderosis (F; circles). CMB: cerebral microbleeds; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 43/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Graphic 132282 Version 1.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 44/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Various radiologic patterns of subarachnoid hemorrhage on noncontrast compu tomography (CT) of the head (A) Obvious large SAH: hyperdense blood in all the basal cisterns, with some dilatation of the temporal horn the lateral ventricles, suggesting early hydrocephalus. (B) More subtle, smaller SAH: small hyperdense collection of blood in the basal cistern adjacent to the left p and suprasellar cistern (short solid arrow). (C) Perimesencephalic SAH: the long solid arrows indicate a perimesencephalic (sometimes called a pretrun SAH. These hemorrhages represent approximately 10% of nontraumatic SAHs. They are thought to be caused venous bleeding, will have a negative CTA result, and usually have an excellent outcome. However, the radiographic pattern is also observed with posterior circulation aneurysms, so all of these patients require neurosurgical consultation and vascular imaging. (D) Convexal SAH: the arrowheads indicate a high convexal SAH. This pattern is observed in two groups of
with leukoaraiosis: a positron emission tomography/magnetic resonance imaging study. Ann Neurol 2013; 73:529. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 36/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate 183. McCreary CR, Beaudin AE, Subotic A, et al. Cross-sectional and longitudinal differences in peak skeletonized white matter mean diffusivity in cerebral amyloid angiopathy. Neuroimage Clin 2020; 27:102280. 184. Raposo N, Zanon Zotin MC, Schoemaker D, et al. Peak Width of Skeletonized Mean Diffusivity as Neuroimaging Biomarker in Cerebral Amyloid Angiopathy. AJNR Am J Neuroradiol 2021; 42:875. Topic 1128 Version 45.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 37/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate GRAPHICS Lobar hemorrhage in cerebral amyloid angiopathy Acute superficial lobar hemorrhage in the left frontal lobe seen on computed tomography scan in a patient with cerebral amyloid angiopathy (A). Flair magnetic resonance image performed one week later shows the high signal intensity of subacute hemorrhage with surrounding edema extending into the subcortical white matter (B). Hemorrhage (now low signal intensity consistent with hemosiderin) and edema are mostly resolved on a three-month follow-up study (C). Courtesy of Eric D Schwartz, MD. Graphic 50480 Version 4.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 38/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Characteristic features and initial diagnostic imaging for common underlying causes of spontaneous isolated convexity subarachnoid hemorrhage Suspected Choice of initial diagnostic Characteristic feature(s) etiology imaging test(s) Age >60 years CAA MRI brain with T2-weighted SWI or GRE sequences Baseline cognitive impairment Recurrent thunderclap headache (>2 RCVS CTA or MRA of head within 1 week) MRI brain Exposure to vasoactive substance Risk factor for venous thrombosis CVT CTV or MRV of head Head CT features suggestive of venous thrombosis (eg, hyperdense venous sinus; venous infarction) MRI brain New heart murmur Mycotic aneurysm MRI brain with contrast or cerebral DSA Systemic/cutaneous evidence of embolism Clinical history of active cancer Brain tumor MRI brain with contrast Clinical history of new persistent headaches Head CT features suggestive of tumor (eg, vasogenic edema) Headache prior to neurologic deficits Intracranial dissection CTA of head or cerebral DSA Clinical history of connective tissue disorder Head CT features suggestive of AVM AVM Cerebral DSA (calcification or hypodense flow voids adjacent to SAH) History of minor/occult trauma may be Occult trauma MRI brain elicited Evidence of extracranial bleeding or systemic injuries Clinical history of new persistent headaches Vasculitis MRI brain with contrast Cerebral DSA Progressive cognitive or other neurologic impairments Brain and meningeal biopsy https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 39/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Patients with spontaneous isolated convexity SAH present with bleeding restricted to the surface of the cerebral hemispheres. The suspected underlying cause of convexity SAH may be identified by initial diagnostic imaging test. Additional imaging and/or other testing may be warranted if initial imaging is nondiagnostic. Refer to specific UpToDate topics for additional information on the diagnostic evaluation of conditions that may present with convexity SAH. SAH: subarachnoid hemorrhage; CAA: cerebral amyloid angiopathy; MRI: magnetic resonance imaging; SWI: susceptibility-weighted imaging; GRE: gradient recall echo imaging; RCVS: reversible cerebral vasoconstriction syndrome; CTA: computed tomographic angiography; MRA: magnetic resonance angiography; CT: computed tomography; CVT: cerebral venous thrombosis; CTV: computed tomography venography; MRV: magnetic resonance venography; DSA: digital subtraction angiography; AVM: arteriovenous malformation. Refer to UpToDate topic on the causes of venous thrombosis. Graphic 140108 Version 2.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 40/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Old hemorrhages on gradient echo MRI Comparison of CT scan (A), T2- weighted MRI (B), and gradient echo MRI (C) demonstrates the utility of the last for detecting old hemorrhages consistent with cerebral amyloid angiopathy. In addition to the the left frontoparietal hemorrhage seen on all studies (arrowheads), the gradient- echo sequence demonstrates multiple areas of decreased signal in gray- white regions (arrows) consistent with chronic hemorrhage. CT: computed tomography; MRI: magnetic resonance imaging. Reproduced with permission from Greenberg SM, Finklestein SP, Schaefer PW. Petechial hemorrhages accompanying lobar hemorrhage: detection by gradient-echo MRI. Neurology 1996; 46:1751. Graphic 81579 Version 12.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 41/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Acute and subacute lobar hemorrhage Noncontrast head CT shows acute right parietal ICH (A). T2* susceptibility-weighted sequence on MRI performed one day later shows an acute ICH in the right frontal and parietal hemisphere (B) as well as a subacute hemorrhage in the left occipital lobe (thick arrow) and chronic ICH in right inferior parietal lobule (C; arrow). In addition, multiple microbleeds at cerebral corticomedullary junctions (B, C) are consistent with cerebral amyloid angiopathy. CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132283 Version 1.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 42/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Distinctive distribution of cerebral microbleeds (A-C) CMBs on T2-weighted gradient echo MRI sequences suggestive of deep penetrating (hypertensive) vasculopathy. CMBs predominate in bilateral thalami (A), brainstem (B), and dentate nucleus of cerebellum (C). (D-F) CMBs on T2-weighted gradient echo MRI sequences suggestive of cerebral amyloid angiopathy. CMBs predominate in cerebral hemispheres (D, E). Associated findings include lobar hemorrhage (D; arrow and thick arrow) and superficial siderosis (F; circles). CMB: cerebral microbleeds; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 43/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Graphic 132282 Version 1.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 44/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Various radiologic patterns of subarachnoid hemorrhage on noncontrast compu tomography (CT) of the head (A) Obvious large SAH: hyperdense blood in all the basal cisterns, with some dilatation of the temporal horn the lateral ventricles, suggesting early hydrocephalus. (B) More subtle, smaller SAH: small hyperdense collection of blood in the basal cistern adjacent to the left p and suprasellar cistern (short solid arrow). (C) Perimesencephalic SAH: the long solid arrows indicate a perimesencephalic (sometimes called a pretrun SAH. These hemorrhages represent approximately 10% of nontraumatic SAHs. They are thought to be caused venous bleeding, will have a negative CTA result, and usually have an excellent outcome. However, the radiographic pattern is also observed with posterior circulation aneurysms, so all of these patients require neurosurgical consultation and vascular imaging. (D) Convexal SAH: the arrowheads indicate a high convexal SAH. This pattern is observed in two groups of patients. In younger patients, it is usually due to RCVS, but in older ones, it often indicates amyloid angiopath a patient presenting with a severe rapid-onset headache, RCVS would be the likely diagnosis. (E) Traumatic SAH: the history usually suggests a traumatic SAH (the most common cause). However, if this pattern (dashed arrows indicate small amounts of SAH abutting bone, often in the anterior frontal and temp bones) is observed in a patient without a clear history of trauma, the likely cause is a traumatic SAH. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 45/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate SAH: subarachnoid hemorrhage; CTA: computed tomography angiography; RCVS: reversible cerebral vasoconstriction syndrome. Reproduced from: Edlow JA. Managing Patients With Nontraumatic, Severe, Rapid-Onset Headache. Ann Emerg Med 2018; 71:400. Illus used with the permission of Elsevier Inc. All rights reserved. Graphic 121315 Version 1.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 46/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Brain MRI findings in cortical superficial siderosis Axial susceptibility-weighted images from a patient with cortical superficial siderosis showing bilateral frontoparietal superficial cortical hypointensity due to hemosiderin deposition (A, B) and sparing of the infratentorial region (C). MRI: magnetic resonance imaging. Courtesy of Neeraj Kumar, MD. Graphic 130369 Version 1.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 47/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Boston Criteria for cerebral amyloid angiopathy Boston criteria for Modified Boston criteria [3] sporadic CAA version 2.0, Boston criteria, 2001 [2] version 1.5, 2010 [1] 2022 Definite CAA Full postmortem examination Full postmortem examination demonstrating: Full postmortem examination demonstrating: demonstrating: Lobar, cortical, or cortico- Lobar, cortical, or cortico- Spontaneous ICH, TFNE, subcortical hemorrhage subcortical hemorrhage cSAH, cognitive impairment Severe CAA with Severe CAA with vasculopathy vasculopathy Severe CAA with Absence of other diagnostic lesion Absence of other diagnostic lesion vasculopathy Absence of other diagnostic lesion Probable CAA with supporting pathology Clinical data and pathologic tissue Clinical data and pathologic tissue (evacuated hematoma Clinical data and pathologic tissue (evacuated hematoma (evacuated hematoma or cortical biopsy): or cortical biopsy): or cortical biopsy): Lobar, cortical, or cortico- subcortical hemorrhage Lobar, cortical, or cortico- subcortical hemorrhage Presentation with spontaneous ICH, TFNE, cSAH, or cognitive impairment Some degree of CAA in specimen Some degree of CAA in specimen Absence of other diagnostic lesion Absence of other diagnostic lesion Some degree of CAA in specimen Absence of other diagnostic lesion Probable CAA Clinical data and MRI demonstrating: Clinical data and MRI demonstrating: Clinical data and MRI demonstrating: Age 50 years Age 55 years Age 55 years Plus either: Plus either: Multiple hemorrhages restricted to lobar, cortical, Presentation with spontaneous ICH, Multiple hemorrhages restricted to lobar, or cortico-subcortical regions (cerebellar TFNE, or cognitive impairment cortical, or cortico- subcortical regions hemorrhage allowed) (cerebellar Absence of other cause of Two or more lobar hemorrhagic lesions hemorrhage allowed) hemorrhage https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 48/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate on T2-weighted or imaging (eg, ICH, Single lobar, cortical, or CMB, cSS, cSAH) cortico-subcortical hemorrhage and focal Absence of other cause of or disseminated superficial siderosis hemorrhage or Absence of other cause of hemorrhage or superficial One lobar hemorrhagic lesion on T2-weighted siderosis imaging (eg, ICH, CMB, cSS, cSAH) One white matter feature (eg, >20 perivascular spaces in centrum semiovale or WMH in a multispot pattern) Absence of any deep hemorrhagic lesions on T2- weighted imaging (eg, ICH, CMB) Absence of other cause of hemorrhagic lesions Possible CAA Clinical data and MRI Clinical data and MRI Clinical data and MRI demonstrating: demonstrating: demonstrating: Age 50 years Age 55 years Age 55 years Plus either: Plus either: Single lobar, cortical, or cortico-subcortical Presentation with spontaneous ICH, Single lobar, cortical, or cortico-subcortical hemorrhage TFNE, cSAH, or cognitive hemorrhage Absence of other cause of hemorrhage or impairment Focal or One lobar disseminated superficial siderosis hemorrhagic lesion on T2-weighted Absence of other cause of imaging (eg, ICH, CMB, cSS, cSAH) hemorrhage or superficial siderosis https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 49/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Absence of other cause of hemorrhage or One white matter feature (eg, >20 perivascular spaces in centrum semiovale or WMH in a multispot pattern) Absence of any deep hemorrhagic lesions on T2- weighted imaging (eg, ICH, CMB) Absence of other cause of hemorrhagic lesions The Boston criteria incorporate clinical, radiologic, and pathologic data to provide diagnostic certainty for patients with suspected CAA. Successive iterations of these criteria reflect the evolving understanding of these diagnostic features. Refer to UpToDate topics for additional information on the diagnosis and evaluation of patients with suspected CAA. CAA: cerebral amyloid angiopathy; ICH: intracerebral hemorrhage; TFNE: transient focal neurologic event; cSAH: convexity subarachnoid hemorrhage; MRI: magnetic resonance imaging; cSS: cortical superficial siderosis; WMH: white matter hyperintensity. Hemorrhagic lesion in the cerebellum is not counted as either lobar or deep hemorrhagic lesion. Other causes of hemorrhagic lesion: antecedent head trauma, hemorrhagic transformation of an ischemic stroke, arteriovenous malformation, hemorrhagic tumor, and vasculitis. Other causes of cortical superficial siderosis and acute convexity subarachnoid hemorrhage should also be excluded. Other causes of intracerebral hemorrhage: excessive warfarin (INR >3.0); antecedent head trauma or ischemic stroke; central nervous system tumor, vascular malformation, or vasculitis; and blood dyscrasia or coagulopathy. (INR >3.0 or other nonspecific laboratory abnormalities permitted for diagnosis of possible CAA.) Siderosis restricted to 3 or fewer sulci. Siderosis affecting at least 4 sulci. References: 1. Charidimou A, Boulouis G, Frosch MP, et al. The Boston criteria version 2.0 for cerebral amyloid angiopathy: A multicentre, retrospective, MRI-neuropathology diagnostic accuracy study. Lancet Neurol 2022; 21:714. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 50/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate 2. Linn J, Halpin A, Demaerel P, et al. Prevalence of super cial siderosis in patients with cerebral amyloid angiopathy. Neurology 2010; 74:1346. 3. Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston criteria. Neurology 2001; 56:537. Graphic 139328 Version 1.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 51/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Goal blood pressure according to baseline risk for cardiovascular disease and method of measuring blood pressure Routine/conventional office blood pressure Unattended AOBPM, (manual measurement daytime ABPM, or home with stethoscope or blood pressure oscillometric device) Higher-risk population 125 to 130/<80 120 to 125/<80 Known ASCVD Heart failure Diabetes mellitus Chronic kidney disease Age 65 years Calculated 10-year risk of ASCVD event 10% Lower-risk 130 to 139/<90 125 to 135/<90 None of the above risk factors All target ranges presented above are in mmHg. On average, blood pressure readings are 5 to 10 mmHg lower with digital, unattended, or out-of- office methods of measurement (ie, AOBPM, daytime ABPM, home blood pressure) than with routine/standard methods of office measurement (ie, manual auscultatory or oscillometric measurement), presumably due to the "white coat effect." However, it is critical to realize that this average difference in blood pressures according to the methodology of measurement applies to the population and not the individual. Some patients do not experience a white coat effect, and, therefore, there is some uncertainty in setting goals that are specific to the method of measurement. When treating to these goals, a patient may (inadvertently) attain a blood pressure below the given target. Provided the patient does not develop symptoms, side effects, or adverse events as a result of the treatment regimen, then reducing or withdrawing antihypertensive medications is unnecessary. Less aggressive goals than those presented in the table may be appropriate for specific groups of patients, including those with postural hypotension, the frail older adult patient, and those with side effects to multiple antihypertensive medications. AOBPM: automated oscillometric blood pressure monitoring; ABPM: ambulatory blood pressure monitoring; ASCVD: atherosclerotic cardiovascular disease; ACC/AHA: American College of Cardiology/American Heart Association. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 52/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Office blood pressure must be performed adequately in order to use such measurements to manage patients. Critical to an adequate office assessment of blood pressure are proper patient positioning (eg, seated in a chair, feet flat on the floor, arm supported, remove clothing covering the location of cuff placement) and proper technique (eg, calibrated device, proper-sized cuff). The average of multiple measurements should be used for management. Refer to UpToDate topics on measurement of blood pressure. Office readings should not be used to manage blood pressure unless it is performed adequately. Home blood pressure, like office blood pressure, must be performed adequately in order for the measurements to be used to manage patients. First, the accuracy of the home blood pressure device must be verified in the clinician's office. Second, the clinician should verify that the cuff and bladder that the patient will use are the appropriate size. Third, patients should measure their pressure after several minutes of rest and while seated in a chair (back supported and feet flat on the floor) with their arm supported (eg, resting on a table). Fourth, the blood pressure should be measured at different times per day and over multiple days. The average value of these multiple measurements is used for management. Home blood pressure readings should not be used to manage blood pressure unless it is performed adequately and in conjunction with office blood pressure or ambulatory blood pressure. The level of evidence supporting the lower goal in higher-risk individuals is stronger for some risk groups (eg, patients with known coronary heart disease, patients with a calculated 10-year risk 15%, chronic kidney disease) than for other risk groups (eg, patients with diabetes, patients with a prior stroke). Refer to UpToDate topics on goal blood pressure for a discussion of the evidence. Prior history of coronary heart disease (acute coronary syndrome or stable angina), prior stroke or transient ischemic attack, prior history of peripheral artery disease. In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized (eg, reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers, rather than targeting one of the blood pressure goals in the table. The 2013 ACC/AHA cardiovascular risk assessment calculator should be used to estimate 10-year cardiovascular disease risk. In the large subgroup of patients who have an initial (pretreatment) blood pressure 140/ 90 mmHg, but who do not have any of the other listed cardiovascular risk factors, some experts would set a more aggressive blood pressure goal of <130/<80 mmHg rather than those presented in the table. This more aggressive goal would likely reduce the chance of developing severe hypertension and ultimately lower the relative risk of cardiovascular events in these lower-risk patients over the long term. However, the absolute benefit of more aggressive blood pressure lowering in these patients is comparatively small, and a lower goal would require more intensive pharmacologic therapy and corresponding side effects. Graphic 117101 Version 3.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 53/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Lobar versus nonlobar hemorrhage and microbleeds Axial SWI magnetic resonance imaging from two different patients. In panel A, there are multiple lobar hemorrhages including a left parietal lobar hematoma (arrowhead) and many lobar microbleeds (arrows), without microbleeds in the basal ganglia or brainstem (not shown), meeting criteria for probable cerebral amyloid angiopathy. In panel B, there is a left thalamic hematoma (arrowhead) with microbleeds in the basal ganglia (arrows). This pattern of nonlobar hemorrhages is not consistent with cerebral amyloid angiopathy, and instead is probably caused by hypertension. SWI: susceptibility-weighted imaging. Courtesy of Eric Smith, MD. Graphic 119376 Version 1.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 54/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 55/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 56/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 57/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate CAA-related perivascular inflammation (A) T2 weighted axial MR image shows periventricular white matter hyperintensity in a patient who presented with memory difficulties. (B) Gradient echo MR image from the same patient shows multiple low intensity foci (arrows) consistent with microhemorrhages, which are not seen on the T2 weighted image (A). The microhemorrhages are located peripherally, as opposed to hypertensive related hemorrhages that may occur centrally. (C) FLAIR MR image demonstrates patchy and confluent periventricular white matter hyperintensity. CAA: cerebral amyloid angiopathy; MR: magnetic resonance; FLAIR: fluid- attenuated inversion recovery. https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 58/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Courtesy of Eric D Schwartz, MD. Graphic 55227 Version 3.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 59/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Criteria for the diagnosis of cerebral amyloid angiopathy-related inflammation (CAA-ri) Diagnosis Criteria Probable CAA-ri 1. Age 40 years 2. Presence of one or more of the following clinical features: headache, decrease in consciousness, behavioral change, or focal neurological signs and seizures; the presentation is not directly attributable to an acute ICH 3. MRI shows unifocal or multifocal WMH lesions (corticosubcortical or deep) that are asymmetric and extend to the immediately subcortical white matter; the asymmetry is not due to past ICH 4. Presence of one or more of the following corticosubcortical hemorrhagic lesions: cerebral macrobleed, cerebral microbleed, or cortical superficial siderosis [1] 5. Absence of neoplastic, infectious, or other cause Possible CAA-ri 1. Age 40 years 2. Presence of one or more of the following clinical features: headache, decrease in consciousness, behavioral change, or focal neurological signs and seizures; the presentation is not directly attributable to an acute ICH 3. MRI shows WMH lesions that extend to the immediately subcortical white matter 4. Presence of one or more of the following corticosubcortical hemorrhagic lesions: cerebral macrobleed, cerebral microbleed, or cortical superficial siderosis [1] 5. Absence of neoplastic, infectious, or other cause CAA-ri: cerebral amyloid angiopathy-related inflammation; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging; WMH: white matter hyperintensity. Reference: 1. Charidimou A, Linn J, Vernooij MW, et al. Cortical super cial siderosis: detection and clinical signi cance in cerebral amyloid angiopathy and related conditions. Brain 2015; 138:2126. Reproduced with permission from: Auriel E, Charidimou A, Gurol ME, et al. Validation of clinicoradiological criteria for the diagnosis of cerebral amyloid angiopathy-related in ammation. JAMA Neurol 2016; 73(2):197-202. Copyright 2016 American Medical Association. All rights reserved. Graphic 118977 Version 10.0 https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 60/61 7/5/23, 12:19 PM Cerebral amyloid angiopathy - UpToDate Contributor Disclosures Steven M Greenberg, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cerebral-amyloid-angiopathy/print 61/61
7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) : Claire L Shovlin, PhD, FRCP : Lawrence LK Leung, MD : Jennifer S Tirnauer, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 25, 2023. INTRODUCTION Hereditary hemorrhagic telangiectasia (HHT; also called Osler-Weber-Rendu syndrome) is a vascular disorder inherited as an autosomal dominant trait, with a variety of clinical manifestations that vary between relatives who have the same HHT pathogenic gene variant. The most common problems are epistaxis, gastrointestinal bleeding, and iron deficiency anemia, along with characteristic mucocutaneous telangiectasia. In addition, arteriovenous malformations (AVMs) frequently affect the pulmonary, hepatic, and/or cerebral circulations, demanding knowledge of the risks and benefits of screening and treatment of patients with these complications. The pathophysiology, epidemiology, and diagnosis of HHT will be reviewed here. The management of HHT is discussed in detail separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs" and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) Additional discussions of pulmonary AVMs, which affect over one-half of individuals with HHT, are also discussed separately. (See "Pulmonary arteriovenous malformations: Epidemiology, etiology, and pathology in adults" and "Pulmonary arteriovenous malformations: Clinical https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 1/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate features and diagnostic evaluation in adults" and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".) EPIDEMIOLOGY Epidemiologic studies suggest clinical prevalence rates between 1:5000 and 1:8000, with approximately 85,000 individuals affected in Europe [1-6]. Much higher rates are described in certain geographically isolated populations (eg, 1:1330 in Afro-Caribbean residents of Curacao and Bonaire [5]). The rate of diagnosis is lower in lower socioeconomic groups [7]. The majority of patients are unaware of their diagnosis of HHT and have not been diagnosed at the time of hospital admission [8]. As a result, HHT has been subject to under-reporting [7]. PATHOPHYSIOLOGY Genetics HHT is inherited as an autosomal dominant trait with varying penetrance and expression. Pathogenic variants in multiple genes can cause HHT, with three major disease-associated genes [9,10]. As of 2022, 611 different HHT-causal variants are reported on the HHT mutation database hosted by the University of Utah [11]. Of these, pathogenic variants are distributed as follows [11]: ENG (HHT1) 333 of 611 (55 percent). These pathogenic variants cause loss-of-function in ENG (protein product: endoglin, OMIM #187300). ACVRL1 (HHT2) 263 (43 percent). These pathogenic variants cause loss-of-function in ACVRL1 (protein product: activin receptor-like kinase 1, ALK1, OMIM #600376). SMAD4 (JPHT) 15 (3 percent). JPHT is a juvenile polyposis-HHT overlap syndrome in which pathogenic variants cause loss-of-function in SMAD4 (OMIM #175050) [12]. Many additional pathogenic variants in these three HHT genes have been described, with none particularly common in different HHT families across the globe [13]. More recently, homozygosity or heterozygosity for pathogenic variants in GDF2 have been described as a rare cause of HHT [14-16]. GDF2 encodes the ALK1/endoglin ligand bone morphogenetic protein (BMP)-9. It was previously recognized to cause HHT-like features [17,18]. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 2/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate These four genes all encode proteins involved in the BMP/transforming growth factor beta (TGF- beta) signaling pathway discussed further below. (See 'Cellular changes' below.) HHT is distinguished clinically and functionally from other vascular malformation syndromes resulting from pathogenic variants in mitogen-associated protein (MAP) kinase pathways. Heritable pathogenic variants in RASA1 and EPHB4 cause separate capillary malformation- arteriovenous malformation (CM-AVM) syndromes CM-AVM1 and CM-AVM2, respectively [19-22]. Somatic variants leading to endothelial overactivation of MAP kinase pathways lead to a number of vascular malformation syndromes discussed separately. (See "Venous malformations".) Genotype-phenotype correlations and variable penetrance All classical features of HHT (nosebleeds; diagnostic mucocutaneous and gastrointestinal telangiectasia; pulmonary, hepatic, cerebral, and rare arteriovenous malformations [AVMs]) (see 'Overview of clinical features' below) can be seen in patients with HHT1, HHT2, and JPHT. (See 'Genetics' above.) Classical features of HHT are strongly predictive of a variant in ENG or ACVRL1 [23]. Nevertheless, for this monogenic condition, there is marked individual variability, with advances in genetic understanding exposing the scale of reduced penetrance, and some of the contributors to phenotypic variability: In keeping with other monogenic diseases, null alleles that define HHT do not imply that individual will necessarily develop particular clinical features of HHT [24]. In a 2022 study of 152 unrelated adults in the United Kingdom with genetically confirmed HHT due to pathogenic variants in ACVRL1, ENG, or SMAD4, only 104 (68 percent) met a clinical diagnosis of HHT [25]. This group included 83 unrelated probands with one or more pulmonary AVMs and genetically-confirmed HHT; of these 83, 20 (24 percent) had few if any features of HHT [25]. It has been recognized for more than two decades that pulmonary and cerebral AVMs are more common in HHT1 patients, while hepatic AVMs, hepatic AVM-associated pulmonary hypertension, and pulmonary arterial hypertension (PAH) are more common in children and adults with HHT2 [26-31]. Variants in genes that increase the likelihood of developing pulmonary AVMs (in HHT1) and hepatic AVMs (in HHT2) are recognized [32-34]. These include hypomorphic variants in the remaining disease allele from the unaffected parent [33]. Variants in other genes have been implicated, potentially inherited from either parent, particularly protein tyrosine phosphatase non-receptor type 14 PTPN14 and a disintegrin and metalloprotease 17 (ADAM17) for pulmonary AVMs in HHT1 [32,35]. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 3/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate There have been no clear data that HHT bleeding differs between molecular HHT subtypes. Instead, new data suggest that HHT bleeding is more severe if there is chance coinheritance of a deleterious DNA variant in one of 35 coagulation and platelet genes that cause bleeding disorders in the general population [36]. These variants affecting hemostasis are very common in the general population. In 104 patients with HHT undergoing whole genome sequencing, predicted loss of function variants in platelet genes were found in 10 percent of patients (1 in 10), and loss of function variants in coagulation genes were found in 12.5 percent (1 in 8) [36]. Further, in blinded analyses, HHT patients with more severe hemorrhage were more likely to have a deleterious variant in a platelet gene or coagulation gene [36]. When the individual is the first affected ("founder") member of the family, mosaicism may be present [37-39]. This can pose challenges for molecular testing [37-41]. It is believed that most, if not all, cases of HHT result from haploinsufficiency (lack of sufficient protein for normal function) for endoglin (encoded by ENG) or ALK1 (encoded by ACVRL1); the most consistent mechanism is via generation of a premature termination codon resulting in nonsense-mediated decay of the abnormal messenger RNA (mRNA) transcript [42]. There is ongoing debate regarding whether vascular malformations result from local loss of endoglin/ALK1 expression, with newer evidence pointing to somatic loss of the second allele in lesions [43]. The University of Utah hosts the HHT mutation database [11]. Cellular changes The HHT genes (ENG, ACVRL1, SMAD4 and GDF2) all encode proteins involved in the bone morphogenetic protein (BMP) signaling pathway, which is required for the development and maintenance of arteriovenous identity. Disruption of their function perturbs vascular remodeling and disrupts blood vessel wall integrity. Endoglin, ALK1 and Smad4 proteins modulate signaling by the BMP/transforming growth factor beta (TGF ) superfamily, ligands for which include BMP2, TGF-betas, activins, and inhibins. Endoglin and ALK1 are transmembrane glycoproteins expressed abundantly on vascular endothelial cells. ALK1 is a type I receptor for the superfamily; endoglin associates with different superfamily receptor complexes (and with ALK1, a receptor complex for BMP9 [44]). Smad4 acts downstream of these receptors in signal transduction cascades. In most cell types, TGF-beta 1 signaling via the type II receptor (TbetaRII) is propagated through ALK5 (TbetaRI), although in endothelial cells, TbetaRII signaling can also be propagated through ALK1 [45]. Endoglin can modify TGF-beta-1 signaling, but with the discovery of specific ligands https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 4/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate for ALK1, attention has also focused on BMP ligands BMP9 and BMP10 [46]. BMP9 is of particular interest, where the endoglin-BMP9 interaction has been defined and clinical evidence has emerged [14,17,44]. The pure pulmonary artery hypertension (PAH) phenotype seen in patients with HHT is indistinguishable from primary PAH in the general population, caused by pathogenic DNA sequence variants in BMPR2, which encodes the BMPRII protein that also associates with ALK1, and where GDF2 (encoding BMP9) has also been identified as disease causal. (See 'Genotype- phenotype correlations and variable penetrance' above and "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Genetic mutations'.) Vascular lesions Individuals with HHT can have vascular lesions in a variety of vascular beds, and the lesions can include arteriovenous shunts (eg, AVMs/arteriovenous fistulae [AVFs]) and telangiectasia. Arteriovenous shunts An arteriovenous shunt is a direct communication between arteries and veins. In anatomic shunts, abnormal vessels replace the normal capillary bed. These may be sacs (eg, for pulmonary AVMs), small collections of intervening vessels (nidal AVMs), or direct high-flow connection between the arterial and venous side (AVFs). Telangiectasia A telangiectasia is a small, dilated blood vessel (arteriole, venule, or capillary) that is apparent near the surface of skin or mucous membranes. These lesions can also be seen in other disorders besides HHT, or in otherwise healthy individuals, as part of a syndrome or in isolation. Additional vascular lesions are increasingly recognized, some seen more commonly in patients with HHT, and others, such as aneurysms, present at rates similar to the general population [47]. Differing disease patterns in members of the same family, as well as in mouse models, suggest that other genetic and environmental influences modify the HHT phenotype, and modifier genes are now described as above [32-34,36]. (See 'Genotype-phenotype correlations and variable penetrance' above.) Why AVMs develop in particular vascular beds and not others remains unclear and is the subject of ongoing research. One possibility that has supporting evidence in some examined lesions suggests that somatic loss of the second allele occurs in some lesions, noting that in the limited AVM data, there is evidence of persistent expression of the second allele [43,48]. Several animal models of HHT have been described. Null mice for ENG and ACVRL1 die between embryonic day 10.5 to 11.5 because of gross vascular and cardiac defects [49]. Heterozygous mice develop variable but more HHT-specific features including nosebleeds, telangiectasia, https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 5/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate dilated vessels, and AVMs [50,51]. Conditional LoxP knockout alleles for all three HHT genes and for ALK1 have been created; in animal models, they cause HHT-like vascular malformations to occur in a consistent and predictable manner [52]. There is substantial interest in roles of vascular endothelial growth factor (VEGF) in HHT. Increased plasma levels of VEGF and TGF-beta-1 have been seen in HHT patients [53,54]. Furthermore, treatment with angiogenesis inhibitors has some efficacy in treating HHT. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Bevacizumab and other systemic antiangiogenic therapies'.) It is unclear whether VEGF is involved directly in the pathogenesis of what has been recognized as a BMP/TGF-beta superfamily disease, or whether these observations reflect the role of angiogenesis as a "second hit" phenomenon in HHT [33,55]. CLINICAL FEATURES Overview of clinical features The combination of epistaxis, gastrointestinal bleeding, and iron deficiency anemia associated with characteristic telangiectasia on the lips, oral mucosa, and fingertips ( picture 1) has become firmly established as a medical entity. All three areas were addressed within the Second International Guidelines [56]; they are prominent in new tools to evaluate quality of life in HHT [57,58]. The classical constellation of findings underestimates potentially life-threatening aspects of HHT. In major series to date, at least one-half of HHT patients have pulmonary arteriovenous malformations (PAVMs), placing them at risk of early onset, preventable strokes; cerebral abscess; and other complications [59-61]. Similarly hepatic AVMs affect approximately one-half of HHT patients and there is increasing concern about their implications, leading to a focus for the Second International Guidelines [56]. Approximately 10 percent have cerebral involvement [59,62,63] with varying vascular abnormalities [47]. Separate sets of considerations apply in pregnancy and pediatrics; these areas are also addressed. Individuals with HHT present to a wide range of clinicians spanning medical, surgical, general practice disciplines, and emergency departments, most of whom lack appreciation of the full range of consequences of the diagnosis of HHT for patients and their families [64]. Separate Consensus Frameworks have been generated by the European Reference Network, VASCERN, to assist general clinicians as they encounter people with HHT during a standard consultation, and separately, HHT specialists [65]. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 6/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Most patients with HHT experience only epistaxis, mucocutaneous telangiectasia, and a tendency to develop iron deficiency anemia secondary to blood loss [6,13,66,67]. However, some patients can have substantial symptoms, particularly attributable to severe recurrent nosebleeds and/or gastrointestinal bleeding, resulting in transfusion dependence, augmented when visceral arteriovenous malformations (AVMs) are present with resultant higher cardiac outputs. Visceral AVMs are usually silent, but they can cause major pathology (see 'Sites of large arteriovenous malformations' below): PAVMs allow systemic venous blood to bypass the normal pulmonary circulation, resulting in paradoxical embolic stroke, brain abscess, migraines, and other complications; hemorrhage is rare except in pregnancy when it occurs at a rate of approximately 1 percent ( image 1 and table 1) (see 'Pulmonary AVMs' below). Although PAVMs differ in size and complexity of vascular supply, all present the risk of continuous right-to-left shunting, determined by the proportion of the cardiac output flowing through the AVMs. Cerebral vascular malformations in HHT are more diverse and span a range of vascular abnormalities with varying risks of hemorrhage, from minimal risk (eg, benign developmental venous anomalies, capillary malformations [sometimes inappropriately referred to as micro-AVMs], and cavernous malformations), to greater risk of hemorrhage (nidal AVMs) and significant risk of hemorrhage (AV fistulae [AVFs]) [47]. (See 'Cerebral vascular abnormalities' below.) Hepatic AVMs can result in high-output cardiac failure or other pathologies, and are increasingly recognized as causing significant morbidity, requiring careful management and timely interventions. (See 'Hepatic involvement' below.) The majority of children in HHT families are troubled only by epistaxis, but there are children who become symptomatic due to AVMs, and issues are discussed further within the Second International Guidelines and European consensus statement [47,68]. As noted above, most, if not all, AVMs may be present in childhood. In a series of 44 children screened in a multidisciplinary HHT center, 52 percent had hepatic AVMs, 45 percent had PAVMs, and 16 percent had cerebral AVMs [69]. (See 'Onset of disease manifestations' below.) Despite the evident morbidity and mortality associated with HHT, life expectancy is surprisingly good, particularly in older individuals and in more recent series. Possible explanations are provided by relative protection from certain cancers, as might be predicted from the anticancer efficacy of antibodies that mimic the molecular basis of HHT (see 'Cancer frequency' below) and reduced rates of myocardial infarction [70]. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 7/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Onset of disease manifestations HHT telangiectasia are not generally present at birth; they develop with increasing age. Screening programs that use imaging rather than clinical assessment identify AVMs earlier than the classical age-related prevalence studies, which were based on clinical signs; in the imaging-based studies, approximately 70 percent of individuals developed some clinical sign of HHT by the age of 16 years, rising to over 90 percent by the age of 40 years. The following describe the findings from these more intensive screening programs: Epistaxis is usually the earliest sign of disease, often occurring in childhood. Mucocutaneous and gastrointestinal telangiectasia develop progressively with age [67,71]. PAVMs generally become apparent after puberty, although they may be present during childhood, and a computed tomography (CT)-based screening program indicated similar incidences in 74 children and 476 adults with HHT [72]. Age of development of cerebral vascular malformations appears to depend on type, with most thought to have developed during childhood [73]. There are specific circumstances in which HHT pathologies become more hazardous, the most important of which is pregnancy, which results in a 1 percent risk of maternal death per pregnancy (due to PAVM hemorrhage, cerebral hemorrhage, and thrombotic complications), with all published maternal deaths occurring in women previously considered well. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Pregnancy'.) There is also significant morbidity and mortality in younger patients, predominantly attributed to the consequences of visceral AVMs, especially pulmonary, cerebral, and hepatic AVMs; pulmonary hypertension; and venous thromboembolism (VTE). (See 'Pulmonary hypertension' below and 'Venous thromboembolism' below.) Many of these risks were quantified by a prospective 30-year follow-up series in Denmark [3] and a retrospective study of the parents of 74 Italian patients with HHT [74]. Even in these long retrospective series, for patients who did not present spontaneously to a clinician before the age of 60 years, there was no excess mortality [3]. A subsequent 20-year follow-up series from Denmark indicated that life expectancy can be normalized for patients whose epistaxis, anemia, and PAVMs are expertly managed [75]. This finding was confirmed by a second study in Europe [76]. Epistaxis The most common clinical manifestation of HHT is spontaneous, recurrent epistaxis from telangiectasia of the nasal mucosa. Some patients experience no or minimal occasional episodes, but for the majority, recurrent and frequent epistaxis is a feature, with many patients https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 8/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate experiencing daily bleeds. In an online survey of 666 patients with HHT, 649 (97 percent) reported nosebleeds, and 326 (49 percent) reported the use of specialist invasive treatments for epistaxis, most requiring multiple different modalities [77]. In another study of 220 patients with HHT, nearly one-half reported nosebleeds occurring daily, and three-quarters reported nosebleeds at least once a week [78]. A summary of additional studies is provided within the Second HHT International Guidelines [56]. Epistaxis may be provoked by a variety of factors, such as changes in external temperature, humidity, activity, and posture. Additional data also highlight the possibility of dietary aggravation of nosebleeds in patients with HHT (eg, from alcohol, spices, high-salicylate dietary items, and migraine-precipitating foods) [77,78]. Patients can present with hemodynamic disturbance secondary to acute blood loss, particularly for patients describing arterial bleeds (ie, gushing nosebleeds in the epistaxis severity score) [79,80]. Management and prevention of epistaxis can range from mild interventions, such as nasal humidification, to tranexamic acid (which is effective but carries potential side effects), to more aggressive measures, depending on the severity of bleeding. Ablative therapies are recommended before considering systemic antiangiogenic therapy, with septodermoplasty and Young's procedure to close the nostrils also recommended for the most severe cases, as discussed in the Second HHT International Guidelines [56]. Iron supplementation is commonly needed, and blood transfusions may be required. These subjects are discussed in detail separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Epistaxis' and "Approach to the adult with epistaxis" and "Management of epistaxis in children".) Gastrointestinal bleeding Recurrent gastrointestinal bleeding occurs in up to one-third of patients with HHT, often presenting as iron deficiency anemia or an acute gastrointestinal bleeding episode, most commonly in patients over the age of 40 years [71,81]. Gastrointestinal bleeding probably contributes less frequently to iron deficiency than under-recognized epistaxis. In many patients, improvement in nasal hemorrhage is able to significantly reduce iron and transfusion requirements. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Iron status'.) Telangiectasia can occur throughout the gastrointestinal tract and are more common in the stomach or duodenum than in the colon ( picture 2A-B). They are visualized by endoscopy, are similar in size and appearance to mucocutaneous telangiectasia, and may be surrounded by an anemic halo. Less commonly, AVMs and aneurysms occur; these lesions may be visualized on https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 9/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate angiographic studies of the gastrointestinal tract ( image 2). (See "Angiodysplasia of the gastrointestinal tract".) Recommendations for management from the HHT International Guidelines are presented separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Therapy for specific vascular lesions and iron deficiency'.) Mucocutaneous telangiectasia Telangiectasia of the skin and buccal mucosa are present in most individuals in later life but may be absent or subtle when younger [71]. They mostly occur on the lips, tongue, buccal mucosa, and fingertips, but can occur elsewhere, where they are less HHT specific and therefore not used for diagnostic purposes ( picture 1 and picture 3) [82]. Bleeding can occur but is rarely clinically important. Sites of large arteriovenous malformations Clinically important AVMs can occur in a number of organs, such as the lung, brain, and liver. While single AVMs can occur sporadically in the normal population as well as in patients with HHT, the presence of multiple AVMs in an organ such as the lung or brain make a sporadic etiology less likely [8,83]. However, single AVMs are still strongly associated with HHT in both organs. Additionally, CT-based research screening programs of asymptomatic individuals have identified pancreatic AVMs at surprisingly high frequency [84]. Pulmonary AVMs Pulmonary arteriovenous malformations (PAVMs) are abnormal vessels that replace normal capillaries between the pulmonary arterial and venous circulations, often resulting in bulbous sac-like structures ( image 3 and image 4). They provide a direct capillary-free communication between the pulmonary and systemic circulations. Patients with PAVMs are at risk for complications, most commonly neurologic sequelae due to paradoxical embolism, with embolic material evading the filtering function of the pulmonary capillaries and reaching the central nervous system. The clinical features, diagnosis, and epidemiology of PAVMs are discussed in detail separately. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults" and "Pulmonary arteriovenous malformations: Epidemiology, etiology, and pathology in adults".) Management of PAVMs is also presented in detail separately, including screening, embolization, and the use of prophylactic antibiotics to reduce the role of brain abscess. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Pulmonary AVMs' and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 10/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Hypoxia and respiratory symptoms Pulmonary arterial blood passing through these right-to-left shunts cannot be oxygenated, leading to hypoxemia. Hypoxemia results in an erythrocytotic stimulus, which can lead to clinically significant levels of secondary polycythemia. However, the majority of patients with PAVMs have no respiratory symptoms, and most are unaware that they have HHT or PAVMs [8,85]. In one review, fewer than one-third of affected individuals exhibited physical signs indicating a substantial right-to-left shunt, such as cyanosis, clubbing, and/or polycythemia ( table 2) [86]. These proportions are likely to fall still further as more patients are diagnosed with more sensitive screening programs. When symptoms such as reduced exercise capacity occur, this generally reflects low hemoglobin and/or airflow limitation rather than hypoxemia [87,88]. Cerebral embolic events (ischemic stroke and brain abscess) and bleeding Catastrophic embolic cerebral events (embolic stroke, transient ischemic attack, and brain abscess) occur in patients with clinically silent PAVMs and carry significant morbidity and mortality, indicating the need for early diagnosis and intervention, including embolization of PAVMs and antibiotic prophylaxis for interventional procedures, especially dental [8,89]. Ischemic stroke The burden of ischemic stroke due to paradoxical embolism is summarized in a 2022 review [90]. A study of 497 consecutive patients with CT-proven PAVMs found that 61 (12 percent) had acute, noniatrogenic ischemic stroke at a median age of 52 years [91]. Additionally, the first nationwide analysis of 4,271,010 patients with ischemic stroke found that 822 had a PAVM diagnosis, with strokes occurring a decade earlier than stroke in patients without PAVMs [92]. Other studies have documented that ischemic stroke precedes the diagnosis of HHT [8]. As recently reviewed, the burden of silent cerebral infarction in patients with PAVMs is considerably higher than that of clinical stroke, with evidence of silent cerebral infarction by magnetic resonance imaging (MRI) in nearly 50 percent of individuals with PAVMs by 50 years of age [63,90,93]. Brain abscess In a 2017 study of 445 consecutive adults with HHT and CT-confirmed PAVMs, 37 (8.3 percent) had brain abscesses [94]. By multivariate logistic regression, brain abscess was associated with low oxygen saturation (indicated greater right-to-left shunt), higher transferrin saturation, intravenous use of iron for anemia, male sex, and venous thromboemboli. There were no relationships between the anatomic attributes of PAVMs and the likelihood of brain abscess. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Natural history' and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Pulmonary AVMs'.) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 11/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Very occasionally, PAVMs may bleed; this event is rare unless PAVMs have developed a systemic arterial supply (spontaneously or posttreatment), the individual is pregnant, or the individual has pulmonary hypertension. PAVM hemorrhage may lead to hemoptysis or hemothorax. Hemorrhage may occur from the fragile PAVM vessels into a bronchus or the pleural cavity, causing hemoptysis or hemothorax, respectively. However, this is rare outside of pregnancy [8,95]. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Pregnancy'.) Patients with PAVMs have an increased prevalence of migraine [96]; migraine may be precipitated by intravenous injections for CT imaging [97]. Migraine symptoms may be reduced after embolization of PAVMs [98]. (See 'Migraines' below.) Cerebral vascular abnormalities Patients with HHT may have cerebral or spinal cord involvement. Cerebrovascular malformations range from benign developmental venous anomalies, through capillary malformations (sometimes inappropriately referred to as micro- AVMs) and cavernous malformations, all with a low hemorrhagic risk, to classical nidal AVMs and high-flow cerebral arteriovenous fistulae (CAVFs; generally found in children) [47]. As detailed in a position statement from the European Reference Network for Rare Vascular Diseases (VASCERN), the clinical presentations and prognosis depend on the type and location of the lesion [47]. Other vascular and nonvascular pathology can occur as in the general population, and these appear to include aneurysms at no greater frequency than in the general population ( image 5) [73,99]. Cerebral vascular malformations affect approximately 10 percent of HHT patients, are often multiple, and are usually silent [59,62,83,100]. They can affect children, when the risks are considerably higher due to the higher prevalence of CAVFs [47]. While full screening across large populations of children in HHT families has not been undertaken, in one cohort of 52 children with HHT referred to neurologic services, neuroimaging at a median age of 5.2 years revealed cerebrovascular malformations in 14 (27 percent), with three developing new lesions over time. Unusually for the broader groups of HHT children, this cohort was highly symptomatic: three had an intracerebral hemorrhage (age of presentation, four to eight years) and another three had ischemic stroke or transient ischemic attack. The most dangerous lesions in HHT are cerebral AVFs, which predominantly affect children. High-flow shunts through AVFs in young infants can present with systemic circulatory overload or hydrovenous dysfunction (eg, macrocephaly, hydrocephalus). Other presentations include seizures, ischemia of the surrounding tissue due to a steal effect, or hemorrhage. Hemorrhage may be less frequent than that seen in non-HHT cerebral AVMs, in part due to the lower https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 12/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate frequency of associated aneurysms. (See "Vascular malformations of the central nervous system", section on 'Capillary telangiectasias'.) Cerebral hemorrhage often has devastating effects. Thus, patients with symptoms suggestive of cerebral AVMs (eg, unexplained headache or neurologic symptoms) deserve further assessment as in the non-HHT population, including noninvasive imaging and ultimately assessment by experienced neurointerventional centers. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Cerebral lesions'.) For patients without symptoms, the situation is more nuanced and carefully expressed in a recent statement led by European Neurointerventionalists [47]. In the expert European centers, screening discussions are conducted with all families in an informed and personalized way to help all make the appropriate choice [47]. This is important because it is not clear that invasive interventions for incidentally discovered cerebral AVMs are appropriate. Since the 2014 publication of the ARUBA trial, which demonstrated an increased risk of bleeding with treatment of asymptomatic cerebral AVMs, many more countries restrict screening to symptomatic patients or only perform screens after pretest counseling of patients [101]. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Cerebral lesions' and "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Cerebral AVM screening'.) Brain MRI is the most sensitive noninvasive test ( image 6). Safety data have demonstrated that individuals with PAVMs that were embolized using metal-containing materials previously designated MRI-incompatible can actually undergo MRI [93]. Hepatic involvement Hepatic involvement occurs in up to two-thirds of patients with HHT [102-105]. As emphasized in guidance from a 2016 document, this is usually silent [106]; however, symptoms can occur and can be improved by appropriate treatments. The potential varying symptoms relate to development of high-output heart failure, portal hypertension, or biliary disease, reflecting different patterns of vascular involvement [107-109]. Large AVMs between the hepatic artery and hepatic vein can cause a significant left-to-right shunt with increased cardiac output that, particularly when combined with anemia, places patients at risk of angina and heart failure [107,110]. (See "Hepatic hemangioma".) Portal hypertension and hepatic encephalopathy, particularly after episodes of gastrointestinal bleeding, may result both from shunts between the hepatic artery and portal vein, and from increased sinusoidal blood flow, leading to enhanced deposition of fibrous tissue and pseudocirrhosis of the liver [107,111]. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 13/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate In our experience, hepatic AVMs affect approximately 50 percent of HHT patients; they are usually silent and not associated with abnormal liver function tests, hepatomegaly or liver bruit. The diagnosis can be established noninvasively by Doppler ultrasonography, CT, or MRI. [112]. Liver biopsy is not recommended as it is not useful in the diagnosis of HHT and may be complicated by bleeding [108]. The natural history of hepatic AVMs was studied in 154 patients with HHT and hepatic vascular malformations who were followed over a median period of 44 months (range: 12 to 181 months) [113]. Eight (5.2 percent) died from vascular malformation-related complications and 39 (25.3 percent) experienced nonfatal complications. The average incidence rates of death and complications were 1.1 and 3.6 per 100 person-years, respectively, while the rate of complete response to therapy was 63 percent. The Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia (2020) provided new recommendations for the management of hepatic AVMs [56]. Diagnostic testing is recommended in patients with symptoms or signs suggestive of complicated liver AVMs (including heart failure, pulmonary hypertension, abnormal cardiac biomarkers, abnormal liver function tests, abdominal pain, portal
11/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Very occasionally, PAVMs may bleed; this event is rare unless PAVMs have developed a systemic arterial supply (spontaneously or posttreatment), the individual is pregnant, or the individual has pulmonary hypertension. PAVM hemorrhage may lead to hemoptysis or hemothorax. Hemorrhage may occur from the fragile PAVM vessels into a bronchus or the pleural cavity, causing hemoptysis or hemothorax, respectively. However, this is rare outside of pregnancy [8,95]. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Pregnancy'.) Patients with PAVMs have an increased prevalence of migraine [96]; migraine may be precipitated by intravenous injections for CT imaging [97]. Migraine symptoms may be reduced after embolization of PAVMs [98]. (See 'Migraines' below.) Cerebral vascular abnormalities Patients with HHT may have cerebral or spinal cord involvement. Cerebrovascular malformations range from benign developmental venous anomalies, through capillary malformations (sometimes inappropriately referred to as micro- AVMs) and cavernous malformations, all with a low hemorrhagic risk, to classical nidal AVMs and high-flow cerebral arteriovenous fistulae (CAVFs; generally found in children) [47]. As detailed in a position statement from the European Reference Network for Rare Vascular Diseases (VASCERN), the clinical presentations and prognosis depend on the type and location of the lesion [47]. Other vascular and nonvascular pathology can occur as in the general population, and these appear to include aneurysms at no greater frequency than in the general population ( image 5) [73,99]. Cerebral vascular malformations affect approximately 10 percent of HHT patients, are often multiple, and are usually silent [59,62,83,100]. They can affect children, when the risks are considerably higher due to the higher prevalence of CAVFs [47]. While full screening across large populations of children in HHT families has not been undertaken, in one cohort of 52 children with HHT referred to neurologic services, neuroimaging at a median age of 5.2 years revealed cerebrovascular malformations in 14 (27 percent), with three developing new lesions over time. Unusually for the broader groups of HHT children, this cohort was highly symptomatic: three had an intracerebral hemorrhage (age of presentation, four to eight years) and another three had ischemic stroke or transient ischemic attack. The most dangerous lesions in HHT are cerebral AVFs, which predominantly affect children. High-flow shunts through AVFs in young infants can present with systemic circulatory overload or hydrovenous dysfunction (eg, macrocephaly, hydrocephalus). Other presentations include seizures, ischemia of the surrounding tissue due to a steal effect, or hemorrhage. Hemorrhage may be less frequent than that seen in non-HHT cerebral AVMs, in part due to the lower https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 12/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate frequency of associated aneurysms. (See "Vascular malformations of the central nervous system", section on 'Capillary telangiectasias'.) Cerebral hemorrhage often has devastating effects. Thus, patients with symptoms suggestive of cerebral AVMs (eg, unexplained headache or neurologic symptoms) deserve further assessment as in the non-HHT population, including noninvasive imaging and ultimately assessment by experienced neurointerventional centers. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Cerebral lesions'.) For patients without symptoms, the situation is more nuanced and carefully expressed in a recent statement led by European Neurointerventionalists [47]. In the expert European centers, screening discussions are conducted with all families in an informed and personalized way to help all make the appropriate choice [47]. This is important because it is not clear that invasive interventions for incidentally discovered cerebral AVMs are appropriate. Since the 2014 publication of the ARUBA trial, which demonstrated an increased risk of bleeding with treatment of asymptomatic cerebral AVMs, many more countries restrict screening to symptomatic patients or only perform screens after pretest counseling of patients [101]. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Cerebral lesions' and "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Cerebral AVM screening'.) Brain MRI is the most sensitive noninvasive test ( image 6). Safety data have demonstrated that individuals with PAVMs that were embolized using metal-containing materials previously designated MRI-incompatible can actually undergo MRI [93]. Hepatic involvement Hepatic involvement occurs in up to two-thirds of patients with HHT [102-105]. As emphasized in guidance from a 2016 document, this is usually silent [106]; however, symptoms can occur and can be improved by appropriate treatments. The potential varying symptoms relate to development of high-output heart failure, portal hypertension, or biliary disease, reflecting different patterns of vascular involvement [107-109]. Large AVMs between the hepatic artery and hepatic vein can cause a significant left-to-right shunt with increased cardiac output that, particularly when combined with anemia, places patients at risk of angina and heart failure [107,110]. (See "Hepatic hemangioma".) Portal hypertension and hepatic encephalopathy, particularly after episodes of gastrointestinal bleeding, may result both from shunts between the hepatic artery and portal vein, and from increased sinusoidal blood flow, leading to enhanced deposition of fibrous tissue and pseudocirrhosis of the liver [107,111]. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 13/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate In our experience, hepatic AVMs affect approximately 50 percent of HHT patients; they are usually silent and not associated with abnormal liver function tests, hepatomegaly or liver bruit. The diagnosis can be established noninvasively by Doppler ultrasonography, CT, or MRI. [112]. Liver biopsy is not recommended as it is not useful in the diagnosis of HHT and may be complicated by bleeding [108]. The natural history of hepatic AVMs was studied in 154 patients with HHT and hepatic vascular malformations who were followed over a median period of 44 months (range: 12 to 181 months) [113]. Eight (5.2 percent) died from vascular malformation-related complications and 39 (25.3 percent) experienced nonfatal complications. The average incidence rates of death and complications were 1.1 and 3.6 per 100 person-years, respectively, while the rate of complete response to therapy was 63 percent. The Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia (2020) provided new recommendations for the management of hepatic AVMs [56]. Diagnostic testing is recommended in patients with symptoms or signs suggestive of complicated liver AVMs (including heart failure, pulmonary hypertension, abnormal cardiac biomarkers, abnormal liver function tests, abdominal pain, portal hypertension, or encephalopathy), with high agreement among experts. There was lower agreement (84 percent) for a recommendation to screen all asymptomatic patients, and expert involvement is recommended in these cases [56]. Additionally, estimation of patients prognoses using predictors for liver AVMs is recommended to identify those in need of closer monitoring; management is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Hepatic AVMs'.) Iron deficiency Epistaxis commonly causes iron deficiency and sequelae due to generation of hemorrhage-adjusted iron requirements (HAIR) that cannot be met through diet alone [114]. A much smaller proportion of individuals develop iron deficiency anemia due to gastrointestinal bleeding. Screening and management was reviewed in detail in the Second International Guidelines for the Diagnosis and Management of HHT [56]. The approach to managing anemia in this HHT, which is characterized by severe continuing blood losses, differs from the management of anemia in many other settings. It was recommended that all adults with HHT and any children with recurrent bleeding or symptoms of anemia should be tested for anemia and iron deficiency; that initial treatment of iron deficiency and anemia should be with oral iron (which has been shown to increase https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 14/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate hemoglobin in HHT patients, even at modest doses [115]); and that intravenous iron is recommended where oral iron is not effective, not absorbed/tolerated, or where patients are presenting with severe anemia [56]. Management of iron deficiency is presented separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Iron deficiency and iron deficiency anemia'.) It is important to emphasize that anemia in HHT may be enhanced by other conditions, with the most common exacerbators in our experience being: Menorrhagia [114] Intercurrent infection and/or inflammation preventing iron absorption, along with iron- poor diets [116] Low grade hemolysis [36,117]. Pulmonary hypertension Pulmonary hypertension is not a single disease entity; as in the general population, it can result from multiple causes in people who also have HHT. That said, pulmonary hypertension in HHT is usually due to increased pulmonary flow due to systemic AVMs and/or anemia [118,119]. However, it may be due to a pure pulmonary arterial hypertension (PAH) phenotype indistinguishable from PAH in the general population [119]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".) Venous thromboembolism Patients with HHT are at increased risk of VTE, the management of which can be compounded by other aspects of their HHT, as clinicians often consider (incorrectly) that treatment or prophylaxis with anticoagulants is contraindicated in HHT [56,120,121]. The Second HHT International Guidelines recommended with high agreement among experts that HHT patients receive anticoagulation (prophylactic or therapeutic) or antiplatelet therapy where there is an indication, with consideration of their individualized risks, and that bleeding in HHT is not an absolute contraindication for these therapies [56]. Data from the European Reference Network suggest that heparin and warfarin remain the agents of choice [122]. In a study of 609 patients with HHT recruited prospectively in two separate series at a single center, low serum iron levels, attributed to inadequate replacement of hemorrhagic iron losses, were associated with elevated plasma levels of coagulation factor VIII and an increased VTE risk [123]. Management of VTE in individuals with HHT is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Individuals who require anticoagulation (VTE and AF)'.) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 15/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate In each series, there was an inverse association between factor VIII levels and serum iron that persisted after adjustment for age, inflammation, and/or von Willebrand factor. Low serum iron levels were also associated with VTE: the age-adjusted odds ratio (OR) of 0.91 (95% CI 0.86-0.97) per 1 micromol/L increase in serum iron implied a 2.5-fold increase in VTE risk for a serum iron of 6 micromol/L compared with the mid-normal range (17 micromol/L). The association appeared to depend upon factor VIII levels, as once adjusted for factor VIII levels, the association between VTE and iron was no longer evident. Arterial thromboses and platelets Iron deficiency is also emerging as a strong risk factor for ischemic stroke in HHT patients with PAVMs. In a series of 497 consecutive patients with HHT and CT-proven PAVMs, the risk of stroke decreased as serum iron increased (adjusted OR 0.96 per mg/mL increase in serum iron; 95% CI 0.92-1.00) [91]. The actual platelet count did not differ in patients with and without strokes. This finding means that for the same PAVMs, the stroke risk would approximately double with serum iron 6 micromol/L compared with mid-normal range (eg, 7 to 27 micromol/L) [91]. This study in HHT patients confirmed data from the 1970s in non- HHT patients that iron deficiency is also associated with enhanced platelet aggregation in response to 5-hydroxytryptamine (5HT) [124]. Importantly, the Second International Guidelines for HHT recommend avoiding the use of dual antiplatelet therapy and anticoagulation where possible in HHT [56]. Migraines Migraines are more common in HHT patients than in patients without HHT [125- 127]. Migraine features and precipitants appear indistinguishable from migraines in the general population [78]. Multiple studies demonstrate that the risk of migraine in HHT patients is approximately doubled by the presence of PAVMs, and there is evidence that migraines improve following PAVM treatment [78,96,98,127-129]. (See 'Pulmonary AVMs' above.) Cancer frequency The frequency of various cancer types in patients with HHT versus controls has been studied. A survey of cancer frequency in patients with HHT over 60 years and age- matched controls showed that despite the predisposition to gastrointestinal cancers conferred by SMAD4 mutation in some patients, age-adjusted rates of cancer were similar in individuals with HHT versus controls (OR 1.04, 95% CI 0.90-1.21) [130]. Evaluation of common cancer types revealed a lower incidence of lung cancer (OR 0.48, 95% CI 0.30-0.70); an increase in early-onset but fewer late-onset colorectal cancers; no difference in prostate cancer; and a higher incidence of breast cancer (OR 1.52, 95% CI 1.07-2.14). The increase in breast cancer was speculatively attributed to thoracic radiation exposure. A subsequent study of 246 PAVM patients demonstrated that protocols for diagnosis, treatment, and follow-up result in levels of radiation exposure that would be classified as harmful, particularly in patients with underlying HHT; the https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 16/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate mean cumulative effective dose (CED) of radiation over an 11-year period was 51.7mSv, and in 26 patients, CED exceeded 100mSv [131]. CT scans accounted for 46 percent of the CED, and interventional procedures accounted for 51 percent. Laboratory findings Routine coagulation and platelet counts are usually normal in HHT. Iron deficiency is the most common finding, especially in those with insufficient iron supplementation. Iron deficiency may be found in people with or without anemia, depending on whether there is a concurrent polycythemic drive due to PAVM-induced hypoxemia. A comparison of red cell indices in HHT patients compared with controls (healthy blood donors) noted a dramatic increase in anemia in the HHT patients [9]. In people with HHT, iron deficiency is associated with marginal increases in platelet counts, as seen in the general population, though the platelet count exceeded 400,000/microL in only 35 of 465 individuals (7.5 percent) and exceeded 500,000/microL in only 7 individuals (1.5 percent), and there was no association with ischemic stroke. Iron deficiency is also associated with elevated factor VIII levels and a shortened activated partial thromboplastin time (aPTT) [91,132]; these findings are associated with an increased prevalence of VTE [123]. DIAGNOSIS HHT may be diagnosed clinically (using three or more Cura ao Criteria (see 'Consensus criteria' below)), or by documentation of a pathogenic or likely pathogenic variant in an HHT gene. (See 'Genetic testing' below.) The Second International Guidelines on HHT recommend making (or excluding) the diagnosis using the Cura ao criteria and/or identifying pathogenic variant in one of the HHT genes [56]. HHT can be diagnosed clinically with confidence, particularly if there is a first-degree relative with HHT, even when an HHT gene variant has not been identified in the family. (See 'Clinical features' above.) HHT can be excluded with relative confidence if a known familial pathogenic variant is not present in the individual, taking into account the exact variant subtype. Absence of HHT clinical features does not preclude a diagnosis of HHT as shown by genetic studies [25]. Absence of an HHT causal variant does not preclude a diagnosis of HHT unless the causal gene in that family has already been identified in a preceding generation. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 17/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate When the individual is the first affected ("founder") member of the family, mosaicism may be present [37-39]; this can pose challenges for molecular testing [40,41]. A child of a parent with HHT should be considered to have possible HHT unless the disorder is excluded by genetic testing for the known familial variant. Consensus criteria International consensus diagnostic criteria (the Cura ao diagnostic criteria) are based upon the following four findings [133,134]: Spontaneous and recurrent epistaxis Multiple mucocutaneous telangiectasia at characteristic sites Visceral involvement (eg, gastrointestinal telangiectasia; pulmonary, cerebral, or hepatic arteriovenous malformations [AVMs]) A first-degree relative with HHT These criteria define "definite" (three or four criteria), "suspected" (two criteria), and "unlikely" (zero or one criterion). These have been validated by molecular studies; in probands who met the strictly applied criteria in an HHT Center of Excellence, 137 of 141 (97.2 percent) were found to have a pathogenic variant in either ENG (66 of 141 [46.8 percent]), ACVRL1 (69 of 141 [48.9 percent]), or SMAD4 (2 of 141 [2.8 percent]) [135]. Genetic testing The diagnosis may be established or confirmed by identification of a pathogenic sequence variant in ENG, ACVRL1, SMAD4, or GDF2. Although this is not required to make a diagnosis of HHT, the Second International Guidelines suggest genetic testing for all individuals with HHT, as it may facilitate family testing and additional evaluations (eg, screening colonoscopies for individuals with pathogenic variants in the SMAD4 gene) [56]. Genetic testing can also be used to establish the diagnosis in individuals with suspected HHT who do not meet clinical criteria. (See 'Consensus criteria' above.) Genetic testing does not detect all variants that might be present, and care is required not to over-interpret sequence variants that are not disease-causing. Detailed discussions for HHT are provided within the context of the American College of Medical Genetics and Genomics (ACMG) guidance and current databases [9]. Multiple centers for genetic testing are available in different countries. Previously reported variants (including pathogenic, likely pathogenic, benign, likely benign, and variants of unknown significance [VUSs]/pending classification) are registered on the HHT mutation database, available at http://arup.utah.edu/database/HHT/ [136] and on ClinVar [137]. A more general discussion of variant classification and determination of significance is presented separately. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 18/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate (See "Secondary findings from genetic testing", section on 'Definitions and classification of variants'.) RESOURCES Educational materials for patients with HHT and the location of specialized centers for diagnosing and managing HHT and pulmonary arteriovenous malformations (PAVMs) are available from Cure HHT, VASCERN HHT, and other patient groups. Additional information is available online: Introduction to HHT from VASCERN HHT https://www.youtube.com/watch? v=0YjWf7Agn40&feature=youtu.be Overview of HHT https://www.youtube.com/watch?v=z2gALD8xSNE&feature=youtu.be SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".) SUMMARY AND RECOMMENDATIONS Prevalence Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder with a clinical prevalence of 1:5000 to 1:8000. The true prevalence is likely to be higher in view of the paucity of clinical symptoms present in genetically-confirmed individuals diagnosed based on other presentations. Many individuals with HHT are unaware of their disease. (See 'Epidemiology' above.) Pathophysiology All HHT genes encode proteins involved in bone morphogenetic protein (BMP) signalling, most commonly ENG (encodes endoglin) and ACVRL1 (encodes ALK1). Rarer causes are SMAD4, which is important to identify because haploinsufficiency also results in juvenile polyposis syndrome requiring additional screening, and GDF2, which is rare and has an increased association with pulmonary hypertension. Pathogenic variants in these genes perturb vascular remodeling and disrupt blood vessel wall integrity. (See 'Pathophysiology' above.) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 19/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Clinical features Patients with HHT may be asymptomatic or have a wide spectrum of clinical manifestations. Overall life expectancy is normal with appropriate management, but there can be life-limiting complications, and these subgroups are the ones most familiar to hospital clinicians. As summarized in the Consensus Orphanet statement from the European Reference Network, the most common signs include epistaxis, cutaneous or mucosal telangiectasia, anemia, and complications of visceral arteriovenous malformations (AVMs). The age of onset of AVM complications varies from childhood to older adulthood. (See 'Clinical features' above.) Pulmonary Pulmonary AVMs (PAVMs) may manifest with brain abscess, stroke, transient ischemic attack, chronic hypoxemia, or rarely, hemorrhagic rupture. CNS Central nervous system (CNS) AVMs can bleed, or rarely cause symptoms of compression. Hepatic Hepatic AVMs can remain latent; in a limited number of individuals, they can lead to high output cardiac failure, portal hypertension, pulmonary hypertension, or ischemic cholangitis. Gastrointestinal Gastrointestinal telangiectasia increase with age and can worsen anemia due to chronic blood loss. Diagnosis HHT may be diagnosed clinically (using three or more Cura ao Criteria) or by genetic testing showing a pathogenic or likely pathogenic variant in an HHT gene. (See 'Genetic testing' above.) The following four international consensus criteria define "definite HHT" (three to four criteria present), "suspected HHT" (two criteria), and "unlikely HHT" (zero or one criterion). (see 'Consensus criteria' above): Spontaneous and recurrent nosebleeds Multiple mucocutaneous telangiectasia at characteristic sites Visceral involvement (gastrointestinal, pulmonary, cerebral, or hepatic AVMs) A first-degree relative with HHT Management Management of HHT is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs" and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 20/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Vijeya Ganesan, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. 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Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. Nat Commun 2012; 3:616. 33. Letteboer TG, Benzinou M, Merrick CB, et al. Genetic variation in the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia 1 (HHT1) and may influence expression of PTPN14. Front Genet 2015; 6:67. 34. Pawlikowska L, Nelson J, Guo DE, et al. The ACVRL1 c.314-35A>G polymorphism is associated with organ vascular malformations in hereditary hemorrhagic telangiectasia patients with ENG mutations, but not in patients with ACVRL1 mutations. Am J Med Genet A 2015; 167:1262. 35. Kawasaki K, Freimuth J, Meyer DS, et al. Genetic variants of Adam17 differentially regulate TGF signaling to modify vascular pathology in mice and humans. 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Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1. Cell Rep 2017; 19:1917. 45. Bertolino P, Deckers M, Lebrin F, ten Dijke P. Transforming growth factor-beta signal transduction in angiogenesis and vascular disorders. Chest 2005; 128:585S. 46. Bailly S. HHT is not a TGF-beta disease. Blood 2008; 111:478. 47. Eker OF, Boccardi E, Sure U, et al. European Reference Network for Rare Vascular Diseases (VASCERN) position statement on cerebral screening in adults and children with hereditary haemorrhagic telangiectasia (HHT). Orphanet J Rare Dis 2020; 15:165. 48. Bourdeau A, Cymerman U, Paquet ME, et al. Endoglin expression is reduced in normal vessels but still detectable in arteriovenous malformations of patients with hereditary hemorrhagic telangiectasia type 1. Am J Pathol 2000; 156:911. 49. Bourdeau A, Dumont DJ, Letarte M. A murine model of hereditary hemorrhagic telangiectasia. 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Sadick H, Riedel F, Naim R, et al. Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-beta1 as well as high ALK1 tissue expression. Haematologica 2005; 90:818. 55. Gkatzis K, Thalgott J, Dos-Santos-Luis D, et al. Interaction Between ALK1 Signaling and Connexin40 in the Development of Arteriovenous Malformations. Arterioscler Thromb Vasc Biol 2016; 36:707. 56. Faughnan ME, Mager JJ, Hetts SW, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med 2020; 173:989. 57. Le TTT, Martinent G, Dupuis-Girod S, et al. Development and validation of a quality of life measurement scale specific to hereditary hemorrhagic telangiectasia: the QoL-HHT. Orphanet J Rare Dis 2022; 17:281. 58. Kasthuri RS, Chaturvedi S, Thomas S, et al. Development and performance of a hereditary hemorrhagic telangiectasia-specific quality-of-life instrument. Blood Adv 2022; 6:4301. 59. Haitjema T, Disch F, Overtoom TT, et al. Screening family members of patients with hereditary hemorrhagic telangiectasia. Am J Med 1995; 99:519. 60. Cottin V, Plauchu H, Bayle JY, et al. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia. Am J Respir Crit Care Med 2004; 169:994. 61. van Gent MW, Post MC, Snijder RJ, et al. Real prevalence of pulmonary right-to-left shunt according to genotype in patients with hereditary hemorrhagic telangiectasia: a transthoracic contrast echocardiography study. Chest 2010; 138:833. 62. Fulbright RK, Chaloupka JC, Putman CM, et al. MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations. AJNR Am J Neuroradiol 1998; 19:477. 63. Brinjikji W, Iyer VN, Yamaki V, et al. 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features in ENG and ALK1 mutation carriers. J Thromb Haemost 2007; 5:1149. 29. Lesca G, Olivieri C, Burnichon N, et al. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network. Genet Med 2007; 9:14. 30. Bossler AD, Richards J, George C, et al. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat 2006; 27:667. 31. Kilian A, Latino GA, White AJ, et al. Genotype-Phenotype Correlations in Children with HHT. J Clin Med 2020; 9. 32. Benzinou M, Clermont FF, Letteboer TG, et al. Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. Nat Commun 2012; 3:616. 33. Letteboer TG, Benzinou M, Merrick CB, et al. Genetic variation in the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia 1 (HHT1) and may influence expression of PTPN14. Front Genet 2015; 6:67. 34. Pawlikowska L, Nelson J, Guo DE, et al. The ACVRL1 c.314-35A>G polymorphism is associated with organ vascular malformations in hereditary hemorrhagic telangiectasia patients with ENG mutations, but not in patients with ACVRL1 mutations. Am J Med Genet A 2015; 167:1262. 35. Kawasaki K, Freimuth J, Meyer DS, et al. Genetic variants of Adam17 differentially regulate TGF signaling to modify vascular pathology in mice and humans. Proc Natl Acad Sci U S A 2014; 111:7723. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 23/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate 36. Joyce KE, Onabanjo E, Brownlow S, et al. Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variation. Blood Adv 2022; 6:3956. 37. Best DH, Vaughn C, McDonald J, et al. Mosaic ACVRL1 and ENG mutations in hereditary haemorrhagic telangiectasia patients. J Med Genet 2011; 48:358. 38. Lee NP, Matevski D, Dumitru D, et al. Identification of clinically relevant mosaicism in type I hereditary haemorrhagic telangiectasia. J Med Genet 2011; 48:353. 39. T rring PM, Kjeldsen AD, Ousager LB, Brusgaard K. ENG mutational mosaicism in a family with hereditary hemorrhagic telangiectasia. Mol Genet Genomic Med 2018; 6:121. 40. McDonald J, Wooderchak-Donahue WL, Henderson K, et al. Tissue-specific mosaicism in hereditary hemorrhagic telangiectasia: Implications for genetic testing in families. Am J Med Genet A 2018; 176:1618. 41. Clarke JM, Alikian M, Xiao S, et al. Low grade mosaicism in hereditary haemorrhagic telangiectasia identified by bidirectional whole genome sequencing reads through the 100,000 Genomes Project clinical diagnostic pipeline. J Med Genet 2020; 57:859. 42. Govani FS, Giess A, Mollet IG, et al. Directional next-generation RNA sequencing and examination of premature termination codon mutations in endoglin/hereditary haemorrhagic telangiectasia. Mol Syndromol 2013; 4:184. 43. Snellings DA, Gallione CJ, Clark DS, et al. Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Bi-allelic Loss of ENG or ACVRL1. Am J Hum Genet 2019; 105:894. 44. Saito T, Bokhove M, Croci R, et al. Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1. Cell Rep 2017; 19:1917. 45. Bertolino P, Deckers M, Lebrin F, ten Dijke P. Transforming growth factor-beta signal transduction in angiogenesis and vascular disorders. Chest 2005; 128:585S. 46. Bailly S. HHT is not a TGF-beta disease. Blood 2008; 111:478. 47. Eker OF, Boccardi E, Sure U, et al. European Reference Network for Rare Vascular Diseases (VASCERN) position statement on cerebral screening in adults and children with hereditary haemorrhagic telangiectasia (HHT). Orphanet J Rare Dis 2020; 15:165. 48. Bourdeau A, Cymerman U, Paquet ME, et al. Endoglin expression is reduced in normal vessels but still detectable in arteriovenous malformations of patients with hereditary hemorrhagic telangiectasia type 1. Am J Pathol 2000; 156:911. 49. Bourdeau A, Dumont DJ, Letarte M. A murine model of hereditary hemorrhagic telangiectasia. J Clin Invest 1999; 104:1343. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 24/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate 50. Gu Y, Jin P, Zhang L, et al. Functional analysis of mutations in the kinase domain of the TGF- beta receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia. Blood 2006; 107:1951. 51. Urness LD, Sorensen LK, Li DY. Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet 2000; 26:328. 52. Park SO, Lee YJ, Seki T, et al. ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood 2008; 111:633. 53. Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 1997; 390:465. 54. 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Electronic address: easloffice@easloffice.eu. EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatol 2016; 64:179. 107. Garcia-Tsao G, Korzenik JR, Young L, et al. Liver disease in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2000; 343:931. 108. DeLeve LD, Valla DC, Garcia-Tsao G, American Association for the Study Liver Diseases. Vascular disorders of the liver. Hepatology 2009; 49:1729. 109. Buscarini E, Plauchu H, Garcia Tsao G, et al. Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations. Liver Int 2006; 26:1040. 110. Caselitz M, Wagner S, Chavan A, et al. Clinical outcome of transfemoral embolisation in patients with arteriovenous malformations of the liver in hereditary haemorrhagic telangiectasia (Weber-Rendu-Osler disease). Gut 1998; 42:123. 111. Fogerty RL, Greenwald JL, McDermott S, et al. Case 7-2017. A 73-Year-Old Man with Confusion and Recurrent Epistaxis. N Engl J Med 2017; 376:972. 112. Buscarini E, Buscarini L, Civardi G, et al. Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: imaging findings. AJR Am J Roentgenol 1994; 163:1105. 113. Buscarini E, Leandro G, Conte D, et al. Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia. Dig Dis Sci 2011; 56:2166. 114. Finnamore H, Le Couteur J, Hickson M, et al. Hemorrhage-adjusted iron requirements, hematinics and hepcidin define hereditary hemorrhagic telangiectasia as a model of hemorrhagic iron deficiency. PLoS One 2013; 8:e76516. 115. Rizvi A, Macedo P, Babawale L, et al. Hemoglobin Is a Vital Determinant of Arterial Oxygen Content in Hypoxemic Patients with Pulmonary Arteriovenous Malformations. Ann Am Thorac Soc 2017; 14:903. 116. Finnamore HE, Whelan K, Hickson M, Shovlin CL. Top dietary iron sources in the UK. Br J Gen Pract 2014; 64:172. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 29/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate 117. Thielemans L, Layton DM, Shovlin CL. Low serum haptoglobin and blood films suggest intravascular hemolysis contributes to severe anemia in hereditary hemorrhagic telangiectasia. Haematologica 2019; 104:e127. 118. Vorselaars VM, Velthuis S, Snijder RJ, et al. Pulmonary hypertension in hereditary haemorrhagic telangiectasia. World J Cardiol 2015; 7:230. 119. Girerd B, Montani D, Coulet F, et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 2010; 181:851. 120. Gaetani E, Agostini F, Porfidia A, et al. Safety of antithrombotic therapy in subjects with hereditary hemorrhagic telangiectasia: prospective data from a multidisciplinary working group. Orphanet J Rare Dis 2019; 14:298. 121. Devlin HL, Hosman AE, Shovlin CL. Antiplatelet and anticoagulant agents in hereditary hemorrhagic telangiectasia. N Engl J Med 2013; 368:876. 122. Shovlin CL, Millar CM, Droege F, et al. Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis 2019; 14:210. 123. Livesey JA, Manning RA, Meek JH, et al. Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia. Thorax 2012; 67:328. 124. Woods HF, Youdim MB, Boulllin D, Callender S. Monoamine metabolism and platelet functio n in iron-deficiency anaemia. In: Iron metabolism. In CIBA Foundation Symposium 51 (new s eries), Elsevier, Amsterdam 1977. p.227. 125. HODGSON CH, BURCHELL HB, GOOD CA, CLAGETT OT. Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous fistula: survey of a large family. N Engl J Med 1959; 261:625. 126. Steele JG, Nath PU, Burn J, Porteous ME. An association between migrainous aura and hereditary haemorrhagic telangiectasia. Headache 1993; 33:145. 127. Marziniak M, Jung A, Guralnik V, et al. An association of migraine with hereditary haemorrhagic telangiectasia independently of pulmonary right-to-left shunts. Cephalalgia 2009; 29:76. 128. Thenganatt J, Schneiderman J, Hyland RH, et al. Migraines linked to intrapulmonary right-to- left shunt. Headache 2006; 46:439. 129. Post MC, van Gent MW, Plokker HW, et al. Pulmonary arteriovenous malformations associated with migraine with aura. Eur Respir J 2009; 34:882. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 30/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate 130. Hosman AE, Devlin HL, Silva BM, Shovlin CL. Specific cancer rates may differ in patients with hereditary haemorrhagic telangiectasia compared to controls. Orphanet J Rare Dis 2013; 8:195. 131. Hanneman K, Faughnan ME, Prabhudesai V. Cumulative radiation dose in patients with hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations. Can Assoc Radiol J 2014; 65:135. 132. Shovlin CL, Sulaiman NL, Govani FS, et al. Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism. Thromb Haemost 2007; 98:1031. 133. Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 2000; 91:66. 134. Faughnan ME, Palda VA, Garcia-Tsao G, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet 2011; 48:73. 135. Mcdonald J, Bayrak-Toydemir P, Whitehead A. Curacao Criteria highly predictive of a mutatio n in ACVRL1 or ENG. Proceedings of the 11th International HHT Scientific Conference, June 1 1-14, 2015; p.33. 136. http://arup.utah.edu/database/HHT/ (Accessed on August 29, 2012). 137. https://www.ncbi.nlm.nih.gov/clinvar/ (Accessed on September 18, 2020). Topic 1345 Version 43.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 31/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate GRAPHICS Mucosal telangiectasias in hereditary hemorrhagic telangectasia (Osler Weber Rendu syndrome) Superficial telangectasias are seen on the lips of a man with hereditary hemorrhagic telangectasia syndrome who had a solitary pulmonary arteriovenous malformation. Reproduced with permission from Gossage JR, Kanj G, Am J Respir Crit Care Med 1998; 158:643 Graphic 77416 Version 4.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 32/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate MRI showing pulmonary AVM-induced cerebral abscess Contrast-enhanced magnetic resonance image (MRI) from a patient with HHT and pulmonary AVM. Note enhancing vascular capsule and central area of necrosis in the temporoparietal abscess. PAVM: Pulmonary arteriovenous malformation. Reproduced by permission from: Macmillan Publishers Ltd: Shovlin C, Bamford K, Wray D. Post-NICE 2008: Antibiotic prophylaxis prior to dental procedures for patients with pulmonary arteriovenous malformations (PAVMs) and hereditary haemorrhagic telangiectasia. Br J Dent 2008; 205:531. Copyright 2008. Graphic 63662 Version 7.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 33/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Overview of the incidence, presenting findings, evaluation, and management of the major clinical features of hereditary hemorrhagic telangiectasia (HHT) Presentation Site Incidence Evaluation Treatment patterns Nasal >90% Nose bleeds are History, Routine therapy includes telangiectasia usually the first inspection nasal lubrication and treatment of iron manifestation of HHT, frequently deficiency when needed. commencing in childhood. Laser treatment is generally preferred over cauterization. Surgery in expert hands offers good results for selected patients. Medical (systemic) treatments are an alternative and may be highly beneficial, but carry risks of prothrombotic side effects. Emergency treatments such as packing may be required. Mucocutaneous 50 to 80% Increase in size Inspection (oral, Generally not indicated, telangiectasia and number with age. Main mucosa, conjunctivae, but laser therapy can be used. concerns are face, trunk, cosmetic. May hemorrhage. extremities, nail beds) Gastrointestinal 11 to 40% Onset generally Flexible Iron supplementation and transfusion are the telangiectasia over 30 years: Iron deficiency endoscopy, endoscopy mainstays of treatment. anemia, occasionally angiogram, capsule Medical (systemic) treatments are available and may be highly acute gastrointestinal endoscopy beneficial, but they carry hemorrhage. risks of prothrombotic side effects. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 34/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Pulmonary >50% Usually silent. Chest Therapeutic AVMs Cyanosis, clubbing, bruit, radiography, blood gas embolization. Antibiotic prophylaxis for dyspnea, measurement, dental and surgical procedures. paradoxical embolism, helical CT, angiography, Surgical resection may be indicated in highly cerebral abscess. chest echocardiography selected cases. Cerebral AVMs 10 to 15% Usually silent. CT, MRI, Doppler Most do not require Headache, sonography, treatment. epilepsy, ischemia, angiography Therapeutic embolization, neurovascular surgery, or intracerebral hemorrhage. stereotactic radiosurgery in highly selected cases. Hepatic AVMs 30 to 70% Usually silent. Doppler Most do not require Hepatic artery- hepatic vein sonography, CT, MRI treatment. For the small proportion AVMs: of patients who develop symptoms, standard Hyperdynamic circulation. hepatic medical care is often sufficient to resolve Portasystemic shunts: Ascites symptoms. and Liver transplantation in encephalopathy. selected cases. Embolization is a higher- risk procedure; some centers do not perform embolization unless the patient is accepted into a liver transplantation program. Less-common clinical manifestations include AVMs in other sites, high cardiac output states, and pulmonary hypertension. Refer to UpToDate for additional details of our approach. AVM: arteriovenous malformation; CT: computed tomography; MRI: magnetic resonance imaging. Adapted and updated from the original table in: Shovlin CL, Letarte M. Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms. Thorax 1999; 54:714. Graphic 74593 Version 3.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 35/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Endoscopic image of colonic angiodysplasia Angiodysplasia appears endoscopically as peripherally expanding dilated capillaries with a central origin measuring between 0.1 to 1.0 cm in diameter. Courtesy of Rome Jutabha, MD. Graphic 50137 Version 4.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 36/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Endoscopic image of colonic angiodysplasia Courtesy of T Edward Bynum, MD. Graphic 73541 Version 2.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 37/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Angiography of colonic angiodysplasia A superior mesenteric arteriogram demonstrates puddling of contrast material in tortuous distended vessels in the cecal wall (arrows). Courtesy of Jonathan Kruskal, MD. Graphic 52754 Version 4.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 38/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Oral telangiectasia in hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) Osler-Weber-Rendu syndrome (also known as hereditary hemorrhagic telangiectasia). Note the multiple 1 to 2 mm, discrete, red macular and papular telangiectases on the lower lip and tongue. Reproduced with permission from: Fitzpatrick TB, Johnson RA, Wol K, Suurmond D. Color Atlas & Synopsis of Clinical Dermatology, 4th ed, McGraw Hill Medical Publishing, New York 2001. Copyright 2001 McGraw-Hill. Graphic 52483 Version 6.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 39/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate CT of a pulmonary arteriovenous malformation (AVM) Pulmonary arteriovenous malformation presenting as a solitary pulmonary nodule. Chest CT shows a nodule in the periphery of the right middle lobe (arrow) with a proximal tail-like extension corresponding to the supplying artery and the draining vein. CT: computed tomography; AVM: arteriovenous malformation. Courtesy of Paul Stark, MD. Graphic 56072 Version 5.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 40/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Angiogram showing pulmonary arteriovenous malformation (AVM) Magnified view of the left lower lung field from a digital subtraction angiogram in a patient with PAVM and HHT. The angiography catheter (c) is seen entering the feeding artery at the upper left corner. The angiogram shows a single feeding artery (a), which bifurcates to supply the two sacs of the bilobed PAVM. The draining vein (v) is seen as a faint vessel inferior to the feeding artery. PAVM: pulmonary arteriovenous malformation; HHT: hereditary hemorrhagic telangiectasia. Courtesy of James R Gossage, MD. Graphic 54651 Version 4.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 41/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Complications of pulmonary AVMs in all published series 1948-1999 Mean, percent Range, percent Respiratory Asymptomatic 50 25 to 58 Dyspnea 48 27 to 71 Chest pain 14 6 to 18 Haemoptysis 11 4 to 18 Haemothorax <1 0 to 2 Cyanosis 30 9 to 73 Clubbing 32 6 to 68 Bruit 49 25 to 58 Embolic phenomenon Cerebral abscess 10 0 to 25 CVA or TIA 27 11 to 55 Shovlin CL, Letarte M. Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms. Thorax 1999; 54:714. Graphic 54074 Version 2.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 42/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Brain arteriovenous malformation pretreatment angiography Characteristic angiographic appearance of a brain arteriovenous malformation (AVM) before therapy. Courtesy of Guy Rordorf, MD. Graphic 75190 Version 2.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 43/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate MRI of brain arteriovenous malformation T2-weighted MRI of the brain demonstrates multiple flow voids in the right hemisphere, suggestive of a large arteriovenous malformation. MRI: magnetic resonance imaging. From: Flemming KD, Lanzino G. Management of Unruptured Intracranial Aneurysms and Cerebrovascular Malformations. Continuum (Minneap Minn) 2017; 23:181. DOI: 10.1212/CON.0000000000000418. Copyright 2017 American Academy of Neurology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 53992 Version 6.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 44/45 7/5/23, 12:20 PM Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) - UpToDate Contributor Disclosures Claire L Shovlin, PhD, FRCP Patent Holder: Imperial College London [The use of trametinib for treatment of HHT bleeding is the subject of a patent application by my employer]. Grant/Research/Clinical Trial Support: National Institute for Health Research [Imaging angiogenesis by PET CT - A pilot study in patients with arteriovenous malformations and hereditary haemorrhagic telangiectasia]. Consultant/Advisory Boards: European Reference Network for Rare Multisystemic Vascular Diseases [HHT]; Genomics England Respiratory GeCIP [Genomic medicine]; International Guidelines Committee [Cure HHT]; NHS Genomic Medicine Service Alliance [Genomic medicine]; NIH ClinGen Expert Panel for hereditary haemorrhagic telangiectasia GRAMB [HHT]. All of the relevant financial relationships listed have been mitigated. Lawrence LK Leung, MD No relevant financial relationship(s) with ineligible companies to disclose. Jennifer S Tirnauer, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-hereditary-hemorrhagic-telangiectasia-osler-weber-rendu-syndrome/print 45/45
7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Hemorrhagic stroke in children : Evelyn K Shih, MD, PhD, Lauren A Beslow, MD, MSCE : Scott E Kasner, MD, Douglas R Nordli, Jr, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 17, 2022. INTRODUCTION Although less common than in adults, hemorrhagic stroke can affect children, resulting in significant morbidity and mortality. An overview of hemorrhagic stroke in children beyond the newborn period is provided here. Other clinical aspects of stroke in neonates and children are reviewed elsewhere: (See "Stroke in the newborn: Classification, manifestations, and diagnosis".) (See "Stroke in the newborn: Management and prognosis".) (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors".) (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis".) (See "Ischemic stroke in children: Management and prognosis".) (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease".) (See "Prevention of stroke (initial or recurrent) in sickle cell disease".) (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) CLASSIFICATION https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 1/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate Hemorrhagic stroke encompasses spontaneous intracerebral hemorrhage (ICH), isolated intraventricular hemorrhage, and nontraumatic subarachnoid hemorrhage [1]. ICH is defined by intraparenchymal hemorrhage or a combination of intraparenchymal and intraventricular hemorrhage ( image 1). Despite its common usage, the term hemorrhagic stroke remains confusing. It has also been used to denote hemorrhagic transformation of arterial ischemic stroke or of cerebral venous sinus thrombosis, but it does not encompass those entities, strictly speaking. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Subsequent imaging'.) EPIDEMIOLOGY Although stroke in children is relatively rare compared with adults, it is a significant cause of childhood death and lifelong disability. A stroke suffered within the first decade may cause functional sequelae for multiple decades to follow. Hemorrhagic stroke is a notable contributor to childhood morbidity and mortality, as it accounts for about half of all childhood strokes, compared with <20 percent of adult strokes [2,3]. The estimated incidence of all types of stroke (ischemic and hemorrhagic) in children ranges 2 to 13 per 100,000 children per year in the developed world [4,5]. A study of a California-wide hospital discharge database for first stroke admission for children ages 1 month through 19 years found an annual incidence rate of 1.1 per 100,000 children for hemorrhagic stroke and 1.2 per 100,000 children for ischemic stroke [4]. Similarly, a retrospective cohort study of 2.3 million children (age <20 years) followed for more than a decade revealed an average annual incidence rate of 1.4 per 100,000 children for hemorrhagic stroke [6]. Among hemorrhagic stroke subtypes, the estimated annual incidence of intracerebral hemorrhage in developed countries ranges from 1.1 to 5.2 per 100,000 children [4,5], while the estimated annual incidence of subarachnoid hemorrhage is 0.4 per 100,000 children [4]. ETIOLOGY AND RISK FACTORS Ruptured vascular malformations are the most common cause of intracerebral hemorrhage (ICH) in children. In contrast, hypertension and amyloid angiopathy are the most frequent causes of ICH in adults. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 2/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate Aneurysms are the most common cause of nontraumatic subarachnoid hemorrhage in both adults and children. (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis".) The etiology and risk factors of perinatal hemorrhagic stroke are reviewed separately. (See "Stroke in the newborn: Classification, manifestations, and diagnosis", section on 'Hemorrhagic stroke'.) Vascular malformations Depending on the series, vascular malformations are responsible for 18 to 90 percent of childhood ICH cases [3,7-9], with arteriovenous malformations (AVMs) being the most common type and cavernous malformations and aneurysms found less frequently ( image 2) [10]. AVMs consist of abnormal direct connections between arteries and veins without intervening capillaries that give rise to high-flow lesions extremely prone to rupture (see "Brain arteriovenous malformations"). The incidence of cerebral AVMs in adults has been estimated to be 1 per 100,000 person-years [11]. Many AVM lesions are thought to be congenital, so this estimate may reflect the incidence in children as well; however, only a small percentage of AVMs (estimated 8 to 20 percent) become symptomatic under the age of 15 years [12,13]. The risk of hemorrhage from a cerebral AVM in children has been estimated at 2 percent per year [14]. AVMs account for 14 to 46 percent of ICH in children and nearly 50 percent of intraparenchymal hemorrhage [15-17]. Although most AVMs are isolated developmental lesions, there are genetic causes that predispose to multiple AVMs. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder of vascular dysplasia associated with mucocutaneous telangiectasias and AVMs. AVMs in patients with HHT most often occur in the pulmonary, hepatic, and cerebral circulations [18,19]. Multiplicity of brain AVMs is highly predictive of the diagnosis of HHT [20]. Incidence of HHT is reported to be 1 in 5000 to 8000 individuals per year [21], although this is likely to be an underestimate due to the variability in clinical manifestations. Approximately 20 percent of adults with HHT have cerebrovascular malformations [22]. The prevalence of cerebrovascular malformations in children with HHT is unknown but believed to approximate that of adult [23]. In one of the largest case series of pediatric patients with confirmed HHT, 11 of 115 children had cerebral AVMs and >50 percent developed symptomatic ICH [19]. Arteriovenous fistulas differ from AVMs because there is an absence of a discrete nidus between the arterial feeder and draining vein. Arteriovenous fistulas are worth noting as these also carry a significant risk of hemorrhage of 1.5 percent per year. However, arteriovenous fistulas are much rarer, comprising only 4 percent of pediatric cerebral vascular malformations [24,25]. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 3/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate Cavernous malformations (cavernomas or cavernous angiomas) have an estimated annual incidence of 0.56 per 100,000 people, which is approximately one-half that of AVMs [26]. Cavernous malformations consist of dilated sinusoidal vessels lined by endothelium without intervening neural parenchyma. "Leaking" of blood into surrounding tissue can occur due to dysfunctional endothelial cell connections. These are considered to be low-flow lesions. Cavernous malformations have been found to have a prevalence of 0.5 percent in autopsy studies [27,28] and are estimated to account for 20 to 25 percent of pediatric intraparenchymal hemorrhage [3,16,29]. While symptoms may manifest in all age groups, affected children tend to cluster in two age groups: infants and toddlers under the age of 3 years and children in early puberty, ages 12 to 16 years [30,31] While aneurysms are one of the most common vascular anomalies of the central nervous system, they are far less common in children than in adults, with a reported prevalence ranging from 0.5 to 5 percent of the total prevalence of intracranial aneurysms in the general population [32-39]. Aneurysms in children are felt to be different from those in adults in the following respects [33,39-41]: Pediatric aneurysms tend to be larger in size There is a higher incidence of giant aneurysms in children There tends to be a male predominance in children The most common cause of nontraumatic subarachnoid hemorrhage in children and adolescents is rupture of a cerebral aneurysm [6]. Ruptured aneurysms can also cause intraparenchymal hemorrhage or can present with nonhemorrhagic symptoms like headaches or seizures. Hematologic In reports from developed countries, hematologic abnormalities (including thrombocytopenia or platelet dysfunction, hemophilia and other congenital or acquired coagulopathies, and sickle cell disease) were the major risk factor for pediatric hemorrhagic stroke, found in 10 to 30 percent of cases [42]. In resource-limited countries, ICH secondary to underlying hematologic disorders occurs more frequently than hemorrhage due to vascular malformations. A retrospective study of 50 children with ICH at a single institution in Pakistan demonstrated that 52 percent had bleeding disorders compared with 14 percent with vascular malformations [43]. Similarly, a retrospective analysis of 94 children with hemorrhagic stroke in China found that 88 percent of patients had a bleeding diathesis compared with 14 percent with AVM [44]. Special populations with hematologic abnormalities include children with immune thrombocytopenia (ITP), hemophilia, and sickle cell disease: https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 4/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate With ITP, intracranial hemorrhage is estimated to occur in up to 1 percent. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Intracranial hemorrhage'.) With hemophilia, the reported ICH prevalence in children is 3 to 12 percent [45-47]. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Intracranial bleeding'.) With sickle cell disease (SCD), affected individuals are at risk for ischemic and hemorrhagic stroke. One report suggested that children with SCD had a >200-fold higher risk of hemorrhagic stroke compared with children without SCD [48]. In other reports, specific factors associated with hemorrhage in children with SCD included premorbid hypertension, transfusion within the last 14 days, treatment with glucocorticoids, low steady-state hemoglobin concentration, high steady-state leukocyte count, and late effects of moyamoya-type vasculopathy [49-51]. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease" and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) Cancer A smaller proportion of hemorrhagic stroke in children is attributable to cancer. In one case series of 69 children with intraparenchymal hemorrhage, brain tumors accounted for 13 percent cases [7]. In another case series from a tertiary cancer center, ICH occurred in 3 percent of over 1000 children with brain tumors and in 1 percent of nearly 1600 children with acute leukemia [52]. [53,54] Other Although much less common than in the adult population, hypertension has also been associated with ICH in children. In one small retrospective cohort study, 45 percent of children th with ICH had elevated blood pressure above the 90 percentile at presentation; however, only 14 percent continued to have persistently elevated blood pressure on follow-up, and none required antihypertensive treatment [55]. Another cause of hemorrhagic stroke in childhood is moyamoya disease. Ischemic cerebrovascular events, either transient ischemic attack or infarction, are more prevalent than hemorrhagic events in children with moyamoya, while hemorrhagic stroke is more common in adults. However, moyamoya can cause either ICH or subarachnoid hemorrhage in children. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Clinical presentations'.) Drugs of abuse, coagulopathies secondary to liver dysfunction, and porphyria are rare causes of hemorrhagic stroke in children. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 5/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate Cohort studies have shown that 9 to 23 percent of childhood ICH remains cryptogenic without a definitive risk factor identified despite extensive evaluation [8,56,57]. However, some proportion of these cryptogenic cases may be due to vascular malformations that have self-obliterated at the time of the incident hemorrhage [58]. CLINICAL FEATURES AND PRESENTATION Among all children who present outside the perinatal period, headache is the most common symptom of hemorrhagic stroke, affecting 46 to 80 percent [7,8,10,17]. Other common presenting symptoms in children include: Nausea and emesis in nearly 60 percent [8] Seizures (either generalized or focal) in 20 to 40 percent [7,8,59] Focal neurologic deficits such as hemiparesis or aphasia, which range in frequency from 13 to 50 percent [8,17,55,58] Neck pain Altered level of consciousness in 50 percent or more [7,8,56,58] The clinical presentation of hemorrhagic stroke can vary based upon the age of the child; younger children are most likely to present with only nonspecific features (eg, altered mentation, seizures, vomiting) while older children are more likely to present with headache, mental status change, and focal neurologic deficits. There is overlap between symptoms in pediatric hemorrhagic stroke, pediatric arterial ischemic stroke, and pediatric cerebral sinovenous thrombosis. All can present with headache, altered mental status, focal neurologic deficits, and seizures. Therefore, neuroimaging is required to differentiate among these entities. However, severe sudden headache with rapid alteration in level of consciousness may be more indicative of a hemorrhage. In a retrospective review of 85 children with nontraumatic intracerebral hemorrhage (ICH) at a tertiary pediatric hospital, the most common clinical signs in young children (<6 years of age) were mental status change, seizures, or vomiting [55]. In contrast, older children ( 6 years of age) often presented with headache and focal neurologic deficits in addition to symptoms of mental status change and nausea/vomiting, allowing clinicians to quickly narrow the differential diagnosis. Another cohort study found that children younger than three years of age at time of hemorrhage onset (n = 9) presented with vague symptoms of general deterioration, increased crying and sleepiness, irritability, feeding difficulty, vomiting, and sepsis-like symptoms with cold extremities [17]. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 6/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate The onset of clinical symptoms due to hemorrhagic stroke is variable and ranges from rapid occurrence over minutes to insidious progression over several hours to days. In a cohort study of 22 children with ICH, the median time to hospital presentation was 70 minutes, but 23 percent of children presented after 24 hours [8]. A prospective study of 53 children with ICH found that acute symptomatic seizures, defined as those occurring from presentation to seven days after onset, occurred in 36 percent [59]. Thus, acute symptomatic seizures with ICH may be more common in children than in adults, where the corresponding rate is estimated to range from 5 to 30 percent (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Clinical presentation'). Further, children with ICH may present with seizures more commonly than children with arterial ischemic stroke, in whom seizures at stroke onset have been reported in 22 percent [60]. Cortical involvement of ICH, which is an important predictor of acute symptomatic seizures in adults [61,62], was not related to acute symptomatic seizures in the pediatric ICH cohort [59]. The pace of symptom onset may be related to the underlying etiology, with aneurysm rupture expected to correlate with sudden onset, while other mechanisms may allow for subacute onset, at least in some cases. However, data are sparse. In a small cohort study of children with spontaneous ICH, approximately half had acute onset of symptoms while the other half had a subacute course [17]. Among children with a known onset, there were four with aneurysms, and the presentation was acute in three; among 16 children with arteriovenous malformation and known onset, an acute presentation occurred in 10 cases (63 percent). Other factors that could affect the rapidity of symptom development are size and location of hemorrhage, intraventricular extension, and presence of hydrocephalus. INITIAL EVALUATION AND DIAGNOSIS The diagnosis of hemorrhagic stroke requires confirmation by brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) [63]. Therefore, clinical suspicion for hemorrhage in the setting of a compatible presentation (eg, headache, mental status changes, seizure, vomiting, or focal neurologic deficits) as described above should prompt urgent imaging. (See 'Clinical features and presentation' above.) For children of school age or older, the acute onset of headache, particularly when severe, (eg, sometimes reported as the "worst headache of life") should prompt evaluation for intracerebral or subarachnoid hemorrhage. However, the diagnosis of hemorrhagic stroke in children can be difficult because the presentation is often nonspecific and subacute. In one small study, most cases with delayed diagnosis (7 of 11) had subacute onset [17]. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 7/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate The initial evaluation should center on rapid diagnosis of the hemorrhage, assessment for presence of elevated intracranial pressure, and identification of easily correctible risk factors such as thrombocytopenia or coagulopathy. Children with hemorrhagic stroke are also at increased risk of subsequent ischemic stroke due to compression of blood vessels from mass effect from the intracerebral hemorrhage, vasospasm after subarachnoid hemorrhage, or underlying vasculopathy (such as moyamoya or cocaine-induced vasculopathy) [64]. Urgent neuroimaging Neuroimaging with CT or MRI as the initial study is necessary to determine the cause, to distinguish hemorrhagic stroke from ischemic stroke, and to distinguish stroke from stroke mimics. In a stable patient, MRI is preferred because of the lack of radiation and the better resolution of the parenchyma. MRI with gradient echo and/or susceptibility- weighted sequences is equally sensitive for acute hemorrhage and more sensitive for chronic hemorrhage than CT [65]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Brain MRI'.) However, MRI is not universally available and may require sedation [65]. Noncontrast head CT should be performed if a patient with suspected hemorrhage is unstable or if obtaining an MRI might delay diagnosis. CT is quick, widely available, does not require sedation in most cases, and is highly sensitive for acute hemorrhage. Noncontrast head CT reveals the diagnosis of subarachnoid hemorrhage in more than 90 percent of cases if performed within 24 hours of bleeding onset; the sensitivity of modern head CT for detecting SAH is highest in the first six hours after subarachnoid hemorrhage (nearly 100 percent when interpreted by expert reviewers). Limited data suggest that proton density and fluid-attenuated inversion recovery (FLAIR) sequences on brain MRI may be as sensitive as head CT for the detection of acute subarachnoid hemorrhage. If neuroimaging is negative for blood and there is high clinical concern for subarachnoid hemorrhage, lumbar puncture should be performed to detect red blood cells or xanthochromia if there are no contraindications (eg, large hemorrhage with significant edema causing impending herniation). (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.) Laboratory studies First-line laboratory studies should include electrolytes, blood urea nitrogen and creatinine, glucose, complete blood count with platelets, coagulation studies (prothrombin time, international normalized ratio, and activated partial thromboplastin time) [63]. Type and screen should be sent for any child who will undergo surgery. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 8/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate DIFFERENTIAL DIAGNOSIS Hemorrhagic stroke must first be differentiated from other types of acute intracerebral vascular events, such as arterial ischemic stroke and cerebral sinovenous thrombosis, both of which may have concomitant hemorrhagic transformation [66]. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) The differential diagnosis for hemorrhagic stroke ( table 1) also includes a broad list of diagnoses that can mimic stroke syndromes. The most common childhood stroke mimics are: Migraine syndromes (see "Types of migraine and related syndromes in children" and "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Forms of migraine with aura') Postictal (Todd) paralysis (see "Differential diagnosis of transient ischemic attack and acute stroke", section on 'Transient neurologic events') Other conditions that may mimic stroke include the following: Brain tumors (see "Clinical manifestations and diagnosis of central nervous system tumors in children") Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (see "Reversible posterior leukoencephalopathy syndrome") Intracranial infections including abscess, encephalitis, and meningitis White matter diseases ( algorithm 1) including multiple sclerosis, acute disseminated encephalomyelitis, and leukodystrophies (see "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis" and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis" and "Differential diagnosis of acute central nervous system demyelination in children") Metabolic derangements such as hypoglycemia (see "Approach to hypoglycemia in infants and children") Organic or amino acidurias (see "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features") https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 9/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate Mitochondrial diseases such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (see "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS') Methotrexate and other chemotherapeutic agent neurotoxicity (see "Overview of neurologic complications of conventional non-platinum cancer chemotherapy" and "Overview of neurologic complications of platinum-based chemotherapy") Bell's palsy (see "Facial nerve palsy in children") Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (see "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)") Conversion disorders Musculoskeletal conditions Neuroimaging is required to diagnose hemorrhagic stroke and to distinguish stroke from mimics. (See 'Initial evaluation and diagnosis' above.) MANAGEMENT Once diagnosis of hemorrhagic stroke is confirmed (see 'Initial evaluation and diagnosis' above), the focus should shift to stabilization of the patient, treatment of elevated intracranial pressure (if present), and close monitoring for brain herniation. There are currently no established evidence-based diagnostic or management guidelines for children with hemorrhagic stroke. The American Heart Association (AHA) scientific statement for the management of stroke in infants and children includes recommendations for children with hemorrhagic stroke [67], which are mostly extrapolated from adult guidelines or are based on expert opinion derived from small retrospective pediatric studies. Immediate consultations Immediate consultations should be obtained from neurosurgery and neurology; hematology should also be consulted if hematologic abnormalities are present on laboratory studies (eg, activated partial thromboplastin time [aPTT], prothrombin time [PT], international normalized ratio [INR], complete blood count [CBC]) or are suspected. Platelet transfusion may be required if there is thrombocytopenia or concern for platelet dysfunction. Coagulopathy may require intravenous vitamin K and/or fresh frozen plasma, and children with factor VIII or IX deficiency typically require urgent factor replacement. Any child on an anticoagulant medication who presents with hemorrhage should receive blood products, https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 10/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate protamine, or vitamin K as warranted. (See "Reversal of anticoagulation in intracranial hemorrhage".) Potential need for decompressive hemicraniectomy and hematoma evacuation should be discussed with neurosurgery. (See 'Surgical management' below.) Supportive measures Subsequent supportive medical management of children with hemorrhagic stroke centers on preventing the progression of brain injury, with primary goals of reducing metabolic demand on brain tissue and avoiding hematoma expansion [63]. Isotonic fluids without glucose should be immediately started to maintain euvolemia, and normothermia should be maintained with acetaminophen and cooling blankets, as temperature elevation >37.5 C increased the likelihood of poor outcome in adult intraparenchymal hemorrhage [68]. Children who present with seizures should be treated with appropriate antiseizure medication (see "Seizures and epilepsy in children: Initial treatment and monitoring"). Prophylactic antiseizure medication treatment is unproven, though there are no high-quality studies of prophylactic antiseizure medication administration in pediatric hemorrhagic stroke. The AHA pediatric stroke guidelines make no recommendations regarding prophylactic antiseizure medication treatment in intracerebral hemorrhage (ICH) [67]. We agree with the AHA guidelines for management of ICH, which recommend against prophylactic antiseizure medications [69]. While treatment of hypertension is a mainstay of hemorrhagic stroke management in adults [63], no clear evidence for managing hypertension after ICH exists in children. It may be a th reasonable goal to lower a child's blood pressure to the 95 percentile for age and sex if elevated after hemorrhage to help prevent hematoma expansion. However, this is not evidence based and may cause a reduction in cerebral perfusion, thereby exacerbating secondary brain injury, particularly if there is elevated intracranial pressure. Any use of antihypertensive medication should be used cautiously. Intracranial pressure Medical management General measures for children with increased intracranial pressure include: Rapid treatment of hypoxia, hypercarbia, and hypotension Elevation of the head of the bed to at least 30 degrees Maintenance of the head and neck midline to facilitate venous drainage Aggressive treatment of fever with antipyretics and cooling blankets Control of shivering in intubated patients with muscle relaxants (eg, vecuronium, rocuronium) https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 11/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate Maintenance of adequate analgesia to blunt the response to noxious stimuli Intracranial pressure (ICP) may become precipitously elevated in hemorrhagic stroke due to mass effect from the hemorrhage or from obstructive or communicating hydrocephalus from intraventricular hemorrhage. This contrasts with acute ischemic stroke, in which increased ICP typically develops several days after the incident event as infarcted brain tissue become edematous. To help reduce or prevent elevated ICP, the head of the bed should be elevated to at least 30 degrees, and the neck should be maintained in a midline position to promote venous drainage. Signs and symptoms of elevated ICP should be frequently reassessed, including presence of positional headache, vomiting, irritability or combativeness, declining mental status, sixth nerve palsies, and papilledema. While Cushing's triad (ie, hypertension, bradycardia, and respiratory depression) is highly suggestive of elevated ICP, this is typically a late finding. For any neurologic deterioration, a head computed tomography (CT) should be obtained promptly to assess for worsening hemorrhage, hydrocephalus, edema, or herniation. Direct ongoing measurement of ICP may require placement of an intraventricular catheter, which can also aid in ICP reduction via direct cerebrospinal fluid drainage, or a subdural bolt if an intraventricular catheter is not technically feasible due to small size of a child's ventricles or other reasons. Nonsurgical interventions for management of increased ICP include hyperventilation to PCO of 2 25 to 30 mmHg (if the child is intubated) and hyperosmolar therapy with intravenous mannitol (bolus 1 g/kg, given as an intravenous infusion through an in-line filter over 20 to 30 minutes, followed by infusions of 0.25 to 0.5 g/kg as needed, generally every six to eight hours) or hypertonic saline to promote osmotic diuresis (see "Elevated intracranial pressure (ICP) in children: Management", section on 'Hyperosmolar therapy'). If hyperosmolar therapy is administered, close monitoring of plasma osmoles and electrolytes is required to avoid hypovolemia, hypotension, and renal failure. Glucocorticoids should be avoided because they did not improve outcomes in randomized controlled trials of adults with ICH [70,71], and the resultant hyperglycemia may lead to worse outcomes [72,73]. Surgical management Ultimately, medical interventions for elevated ICP are only temporizing measures, and surgical evacuation of a parenchymal hematoma or decompressive craniectomy may be necessary to control refractory elevations in ICP and/or mass effect. Surgical hemorrhage evacuation for supratentorial ICH is controversial, and no high-quality studies in children have evaluated early surgical hematoma evacuation or hemicraniectomy. In adults, randomized trials have not conclusively demonstrated benefit. (See "Spontaneous https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 12/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate intracerebral hemorrhage: Acute treatment and prognosis", section on 'Surgical approaches for selected patients'.) As children typically lack the baseline cerebral atrophy found in older adults that permits expansion of the hematoma without consequent compression of the surrounding parenchyma, it is biologically plausible that children may benefit from hematoma evacuation to reduce ICP. If a child is undergoing resection of an underlying vascular malformation that is at high risk for acute rebleeding, it may be optimal to concurrently evacuate the hematoma. Surgical evaluation also might be warranted if a child is comatose, has elevated intracranial pressure that is refractory to medical management, or a worsening neurological examination. As in adults, cerebellar hemorrhages >3 cm in diameter in a child who is deteriorating or in whom brainstem compression and/or hydrocephalus is developing due to compression on the ventricular system should also be considered for surgical evacuation. If a cerebellar hemorrhage is evacuated, suboccipital craniectomy is typically performed at the same time. While hemicraniectomy has not been studied in the setting of pediatric hemorrhagic stroke, there are some series in which hemicraniectomy was associated with improved function and survival in pediatric arterial ischemic stroke [74,75]. In a child who undergoes surgical hematoma evacuation due to a supratentorial hemorrhage causing elevated intracranial pressure that is refractory to medical management, the surgeon may elect to perform a concomitant hemicraniectomy, particularly if the intracranial pressure remains elevated after hematoma evacuation or if there is herniation out of the craniotomy defect. Identifying the etiology Obtaining dedicated cerebrovascular imaging in the acute setting is critical to guide appropriate interventions given the high rate of vascular malformations underlying hemorrhagic stroke in children. Cerebral angiography is a minimally invasive modality that may be used for diagnosis and treatment of vascular causes of ICH [76]. While conventional cerebral angiography remains the gold standard, many institutions opt to first use noninvasive modalities. One retrospective study found that a combination of magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and magnetic resonance venography (MRV) images accurately identified the cause of ICH in 66 percent of subjects, which was statistically equivalent to the diagnostic yield of conventional cerebral angiography alone (61 percent) [77]. However, another retrospective case series of children with nontraumatic ICH reported identification of the cause of bleeding in 97 percent of children who underwent conventional cerebral angiography compared with 80 percent of children who did not have angiography [7]. Another alternative is CT angiography (CTA), which can be rapidly obtained without the need for sedation in some children, is more widely available than MRA, and may offer superior https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 13/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate angioarchitectural visualization compared with MRA [78]. CTA also has a higher sensitivity for detecting aneurysms up to 2 mm in size. However, CTA exposes the child to both ionizing radiation and an iodinated contrast agent, requires a large bore intravenous line, and may be nondiagnostic if the child moves during the study. For children with hemorrhagic stroke and no identified cause despite a thorough evaluation, including appropriate noninvasive vascular imaging, we suggest conventional cerebral angiography. As an acute hemorrhage with large hematoma and significant cerebral edema can obscure visualization of an underlying vascular malformation, vascular studies that are initially nondiagnostic should be repeated weeks to months later once the clot has been reabsorbed if no other cause for the hemorrhage (eg, tumor, coagulopathy) is found [76]. The yield of an extensive evaluation for a bleeding diathesis in children with hemorrhagic stroke is not well-studied. A rational approach is to obtain the screening laboratory studies suggested above (see 'Laboratory studies' above) (ie, a complete blood count with platelets, coagulation studies, prothrombin time, international normalized ratio, and activated partial thromboplastin time) and to pursue additional testing if the screening studies are abnormal or if an underlying vascular lesion or tumor is not found. Higher-level studies may include factor VIII, IX, and XIII levels and von Willebrand disease studies and should be ordered in consultation with a hematologist. (See "Approach to the child with bleeding symptoms" and "Approach to the child with unexplained thrombocytopenia" and "Clinical manifestations and diagnosis of hemophilia" and "Clinical presentation and diagnosis of von Willebrand disease".) Treatment of vascular lesions Endovascular and/or surgical management of vascular malformations may be required in the acute setting depending on the location and vascular anatomy of the lesion in conjunction with the clinical status of the child. Multidisciplinary consultation with neurosurgery, interventional radiology, and neurology is advised to choose the optimal approach to treatment of these lesions [67]. Vascular malformations other than aneurysm typically have a low risk of acute rebleeding (although they may rebleed at later times) [79-81]. Therefore, many centers will await hematoma resolution prior to definitive treatment so that the full extent of the vascular malformation can be elucidated. However, if hematoma evacuation is needed, a vascular malformation may be addressed at the same time. Some arteriovenous malformations that cannot be treated with endovascular or surgical techniques may be amenable to gamma knife or proton beam therapy once the hematoma has retracted. Aneurysms have a higher rate of acute rebleeding [82]. Therefore, aneurysm repair typically occurs in the acute setting. AVMs with an aneurysmal component that may cause acute https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 14/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate rebleeding also may require earlier intervention. Follow-up imaging Due to the high risk of recurrence, we suggest follow-up imaging for most children with hemorrhagic stroke due to a vascular malformation. In addition, we suggest follow-up imaging in cases where a vascular cause is not found but is suspected. Even when complete resection of an arteriovenous malformation is achieved, there is a substantial risk of recurrence. In one retrospective report of 28 children who underwent surgical resection of arteriovenous malformations, 4 had recurrence leading to repeat resections [83]. Of note, two of the children in this cohort had arteriovenous malformations that were not detected until 17.7 and 25 months after the incident hemorrhage. While the frequency and modality of follow-up imaging is center-dependent, our suggested protocol is to obtain brain MRI with MRA at three to six months after the first hemorrhage, and/or a conventional angiogram between three and six months. Additional follow-up imaging at later points is typically necessary. In children with an unresected cavernous malformation, periodic imaging with MRI is suggested if the child is having frequent symptoms such as headaches or seizures. Genetic screening Genetic screening may be reasonable if multiple vascular malformations are found on imaging or if there is a suggestive family history [67]. The most common genetic cause of brain AVMs is hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant condition. Patients with HHT may have cerebral or spinal cord involvement with telangiectasias, brain AVMs, aneurysms, or cavernous malformations. (See
intracerebral hemorrhage: Acute treatment and prognosis", section on 'Surgical approaches for selected patients'.) As children typically lack the baseline cerebral atrophy found in older adults that permits expansion of the hematoma without consequent compression of the surrounding parenchyma, it is biologically plausible that children may benefit from hematoma evacuation to reduce ICP. If a child is undergoing resection of an underlying vascular malformation that is at high risk for acute rebleeding, it may be optimal to concurrently evacuate the hematoma. Surgical evaluation also might be warranted if a child is comatose, has elevated intracranial pressure that is refractory to medical management, or a worsening neurological examination. As in adults, cerebellar hemorrhages >3 cm in diameter in a child who is deteriorating or in whom brainstem compression and/or hydrocephalus is developing due to compression on the ventricular system should also be considered for surgical evacuation. If a cerebellar hemorrhage is evacuated, suboccipital craniectomy is typically performed at the same time. While hemicraniectomy has not been studied in the setting of pediatric hemorrhagic stroke, there are some series in which hemicraniectomy was associated with improved function and survival in pediatric arterial ischemic stroke [74,75]. In a child who undergoes surgical hematoma evacuation due to a supratentorial hemorrhage causing elevated intracranial pressure that is refractory to medical management, the surgeon may elect to perform a concomitant hemicraniectomy, particularly if the intracranial pressure remains elevated after hematoma evacuation or if there is herniation out of the craniotomy defect. Identifying the etiology Obtaining dedicated cerebrovascular imaging in the acute setting is critical to guide appropriate interventions given the high rate of vascular malformations underlying hemorrhagic stroke in children. Cerebral angiography is a minimally invasive modality that may be used for diagnosis and treatment of vascular causes of ICH [76]. While conventional cerebral angiography remains the gold standard, many institutions opt to first use noninvasive modalities. One retrospective study found that a combination of magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and magnetic resonance venography (MRV) images accurately identified the cause of ICH in 66 percent of subjects, which was statistically equivalent to the diagnostic yield of conventional cerebral angiography alone (61 percent) [77]. However, another retrospective case series of children with nontraumatic ICH reported identification of the cause of bleeding in 97 percent of children who underwent conventional cerebral angiography compared with 80 percent of children who did not have angiography [7]. Another alternative is CT angiography (CTA), which can be rapidly obtained without the need for sedation in some children, is more widely available than MRA, and may offer superior https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 13/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate angioarchitectural visualization compared with MRA [78]. CTA also has a higher sensitivity for detecting aneurysms up to 2 mm in size. However, CTA exposes the child to both ionizing radiation and an iodinated contrast agent, requires a large bore intravenous line, and may be nondiagnostic if the child moves during the study. For children with hemorrhagic stroke and no identified cause despite a thorough evaluation, including appropriate noninvasive vascular imaging, we suggest conventional cerebral angiography. As an acute hemorrhage with large hematoma and significant cerebral edema can obscure visualization of an underlying vascular malformation, vascular studies that are initially nondiagnostic should be repeated weeks to months later once the clot has been reabsorbed if no other cause for the hemorrhage (eg, tumor, coagulopathy) is found [76]. The yield of an extensive evaluation for a bleeding diathesis in children with hemorrhagic stroke is not well-studied. A rational approach is to obtain the screening laboratory studies suggested above (see 'Laboratory studies' above) (ie, a complete blood count with platelets, coagulation studies, prothrombin time, international normalized ratio, and activated partial thromboplastin time) and to pursue additional testing if the screening studies are abnormal or if an underlying vascular lesion or tumor is not found. Higher-level studies may include factor VIII, IX, and XIII levels and von Willebrand disease studies and should be ordered in consultation with a hematologist. (See "Approach to the child with bleeding symptoms" and "Approach to the child with unexplained thrombocytopenia" and "Clinical manifestations and diagnosis of hemophilia" and "Clinical presentation and diagnosis of von Willebrand disease".) Treatment of vascular lesions Endovascular and/or surgical management of vascular malformations may be required in the acute setting depending on the location and vascular anatomy of the lesion in conjunction with the clinical status of the child. Multidisciplinary consultation with neurosurgery, interventional radiology, and neurology is advised to choose the optimal approach to treatment of these lesions [67]. Vascular malformations other than aneurysm typically have a low risk of acute rebleeding (although they may rebleed at later times) [79-81]. Therefore, many centers will await hematoma resolution prior to definitive treatment so that the full extent of the vascular malformation can be elucidated. However, if hematoma evacuation is needed, a vascular malformation may be addressed at the same time. Some arteriovenous malformations that cannot be treated with endovascular or surgical techniques may be amenable to gamma knife or proton beam therapy once the hematoma has retracted. Aneurysms have a higher rate of acute rebleeding [82]. Therefore, aneurysm repair typically occurs in the acute setting. AVMs with an aneurysmal component that may cause acute https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 14/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate rebleeding also may require earlier intervention. Follow-up imaging Due to the high risk of recurrence, we suggest follow-up imaging for most children with hemorrhagic stroke due to a vascular malformation. In addition, we suggest follow-up imaging in cases where a vascular cause is not found but is suspected. Even when complete resection of an arteriovenous malformation is achieved, there is a substantial risk of recurrence. In one retrospective report of 28 children who underwent surgical resection of arteriovenous malformations, 4 had recurrence leading to repeat resections [83]. Of note, two of the children in this cohort had arteriovenous malformations that were not detected until 17.7 and 25 months after the incident hemorrhage. While the frequency and modality of follow-up imaging is center-dependent, our suggested protocol is to obtain brain MRI with MRA at three to six months after the first hemorrhage, and/or a conventional angiogram between three and six months. Additional follow-up imaging at later points is typically necessary. In children with an unresected cavernous malformation, periodic imaging with MRI is suggested if the child is having frequent symptoms such as headaches or seizures. Genetic screening Genetic screening may be reasonable if multiple vascular malformations are found on imaging or if there is a suggestive family history [67]. The most common genetic cause of brain AVMs is hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant condition. Patients with HHT may have cerebral or spinal cord involvement with telangiectasias, brain AVMs, aneurysms, or cavernous malformations. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber- Rendu syndrome)", section on 'Genetic testing'.) Familial cases of cavernous malformation are associated with genetic variants of CCM1, CCM2, and CCM3. (See "Vascular malformations of the central nervous system", section on 'Cavernous malformations'.) PROGNOSIS The estimated mortality rate for children with hemorrhagic stroke ranges from 5 to 33 percent, and many studies (largely retrospective) report that neurologic outcomes are poor in approximately 25 to 57 percent of children, as discussed in the sections that follow. Mortality Older studies show that hemorrhagic stroke has a significantly higher mortality than arterial ischemic stroke in children [3,29,84,85] but lower mortality compared with that in https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 15/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate the adult population [86]. In a 2005 report, pooled data from multiple heterogeneous studies suggested an average mortality rate of 25 percent in children with hemorrhagic stroke [87]; later studies reported mortality rates ranging from 5 to 33 percent [8,88-90]. Neurologic outcome Neurologic outcome after hemorrhagic stroke has not been well studied in children. Most data are derived from small retrospective cohort studies or case series. Some data suggest neurologic deficits may persist in up to approximately 75 percent, and disability may be present in more than half of survivors [8,90-92]. As an example, a prospective cohort study of pediatric intracerebral hemorrhage (ICH) included 22 children from a single tertiary care center [8]. At follow-up (median 3.5 months), clinically significant disability (defined as moderate disability or worse, with patients unable to function normally and requiring additional care) was present in 57 percent, and neurologic deficits were present in 71 percent. Scholastic performance is frequently impaired in survivors of ICH [8]. In one cohort including 30 survivors of ICH (age 6 to 17 years), most returned to school within a year of onset, but less than one half were attending age-appropriate classes and the remainder required additional educational support [93]. In a retrospective study of 128 children with childhood stroke, of whom 82 had hemorrhagic stroke, 36 percent required special educational services at long-term follow up (median 43 months) [92]. Epilepsy at two years occurred in 13 percent of children in a prospective study of 53 children with ICH [59]. Elevated intracranial pressure that required urgent intervention during the acute hospitalization was a risk factor for a first remote symptomatic seizure and for developing epilepsy. Children with a diagnosis of epilepsy following stroke have worse parent-reported scores of health status than those without this diagnosis [94]. Outcome predictors In adult ICH, initial hematoma volume is the strongest predictor of mortality and functional outcome, and the level of consciousness at presentation is also an important prognostic factor. The 30-day mortality is approximately 90 percent if the size of the 3 hemorrhage exceeds 60 cm and the Glasgow coma scale (GCS) is <9 at presentation. This 3 compares with an estimated 19 percent mortality when the hemorrhage volume is <30 cm and the GCS is 9 [95]. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Risk factors for poor outcomes'.) Similarly, clinical and imaging features of the acute ICH associated with poor functional outcome in children include [8,90]: ICH volume Altered mental status Length of stay in an intensive care unit https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 16/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate Hemorrhage volume must be taken in the context of percentage of total brain volume (TBV) to account for the markedly varying brain sizes of children of different ages. In a retrospective report of 30 consecutive children, the strongest association with outcome was the intraparenchymal component of ICH expressed as a percentage of TBV; intraparenchymal hemorrhage 4 percent of TBV was independently associated with poor outcome, defined as severe disability or death (odds ratio [OR] 22.5, 95% CI 1.4-354) [56]. The odds of poor outcome 3 at 30 days increased significantly for every 10 cm of additional hemorrhage volume. Other predictors of poor outcome from retrospective studies include initial GCS 8, coagulopathy, and older age (11 to 18 years) [9,96]. Studies in adults suggest that posterior fossa hemorrhage and presence of intraventricular hemorrhage are predictors of poor outcome (see "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Risk factors for poor outcomes'). However, data from small pediatric cohort studies have not confirmed that these factors predict poor outcome in children [8,56,89,97]. Prediction scores Pediatric ICH score The adult ICH score [98] is the most commonly used clinical grading scale for predicting mortality and functional outcome following adult ICH (see "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Clinical prediction scores'). A similar pediatric ICH score was developed to assist with risk stratification in children following ICH. While the pediatric ICH score mirrors its adult counterpart, several components required alterations. Hemorrhage volume was expressed as a percent of TBV to account for the varying brain sizes of children of different ages. Due to the lack of availability of GCS scores in most children, the presence of herniation was used. Isolated intraventricular hemorrhage had not been predictive of outcome in previous studies and was present in about 40 percent of children, so this variable was replaced with hydrocephalus [99]. Thus, the pediatric ICH score is comprised of the following components: Intraparenchymal hemorrhage volume as percentage of TBV - - <2 percent = 0 points 2 to 3.99 percent = 1 point 4 percent = 2 points Hydrocephalus? - No = 0 points Yes = 1 point https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 17/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate Herniation? - No = 0 points Yes = 1 point Infratentorial location? - No = 0 points Yes = 1 point Therefore, the total pediatric ICH score ranges from 0 to 5 points. In one prospective cohort of 60 children with ICH, a pediatric ICH score 2 was sensitive for predicting severe disability or death and a score 1 was sensitive for predicting moderate disability or worse [99]. However, the pediatric ICH score has not been established as generally valid in independent populations. Modified pediatric ICH score The modified pediatric ICH (mPICH) score incorporated early altered mental status, a reported predictor of worse outcome following ICH [8], and intraventricular hemorrhage into the pediatric ICH score to improve prediction sensitivity for moderate or severe disability [100]. The modified pediatric ICH (mPICH) score (range, 0 to 13) is assigns points for presence of six variables as follows: Forebrain herniation, 4 points Altered mental status at initial presentation, 3 points Hydrocephalus, 2 points Infratentorial ICH, 2 points Intraventricular hemorrhage, 1 point ICH volume >2 percent of TBV, 1 point Using a retrospectively selected validation cohort of 43 children, an mPICH score of >4 was sensitive for predicting moderate disability or worse, a score >5 was sensitive for predicting severe disability or worse, and a score >6 was sensitive for predicting vegetative state or death [100]. Hemorrhagic stroke recurrence Data from pooled studies suggest that recurrence risk after hemorrhagic stroke in childhood is approximately 10 percent [87], but the length of follow-up in these studies was highly variable. Limited data suggest that the risk of recurrence depends mainly on etiology; children with untreated or incompletely treated vascular malformations and those with hematologic disorders appear to have the highest risk of recurrence [29,101]. In a population-based retrospective cohort study of 116 children with nontraumatic hemorrhagic stroke in northern California who were followed for a mean of 4.2 years, a recurrent https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 18/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate hemorrhagic stroke affected 11 children at a median of approximately three months (range 7 days to 5.7 years) [64]. The highest risk period was the first six months. The estimated five-year cumulative recurrence rate was 10 percent (95% CI 5-18 percent). Among the 11 recurrent hemorrhagic strokes, there were 5 due to cavernous malformations, 2 caused by to arteriovenous malformation, 2 attributed to tumor, 1 with hypertension, and 1 with idiopathic thrombocytopenia. Among the 9 children with a second hemorrhage and a structural cause (vascular malformation or tumor), the lesion was untreated in 6 and partially treated in 2 (partially resected tumor and second cavernous malformation which was not the cause of first hemorrhage). There were no recurrences among 29 children with idiopathic hemorrhagic stroke. Another study monitored adults and children with brain arteriovenous malformations (AVMs) for a total of 3620 person-years in the adult group and 996 person-years in the childhood group, starting from initial presentation [14]. The unadjusted rates of subsequent ICH were similar for children and adults (2.0 and 2.2 percent, respectively) However, compared with adults, children with AVMs were more likely to present with hemorrhage, and after adjusting for the higher proportion of hemorrhagic presentation in children, the risk of a subsequent ICH was lower for children (hazard ratio 0.1, 95% CI 0.01-0.86). These results suggest that cerebral AVMs in children do not need to be treated more aggressively than those in adults. However, although their annualized risk of hemorrhage is similar to adults, their cumulative risk is greater given their greater number of years left to live. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Classification Hemorrhagic stroke encompasses spontaneous intracerebral hemorrhage (ICH), isolated intraventricular hemorrhage, and nontraumatic subarachnoid hemorrhage. ICH is defined by intraparenchymal hemorrhage with or without associated intraventricular hemorrhage. (See 'Classification' above.) Epidemiology Hemorrhagic stroke accounts for approximately one-half of all childhood strokes. The annual incidence rate is approximately 1 per 100,000 children. (See 'Epidemiology' above.) https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 19/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate Etiologies Hemorrhagic stroke in children living in developed countries is most commonly due to ruptured vascular malformations. Hematologic abnormalities, cancer, and hypertension are less common causes. Aneurysms are the most common cause of nontraumatic subarachnoid hemorrhage. (See 'Etiology and risk factors' above.) Clinical features The most common presenting symptom of hemorrhagic stroke in children is headache. Other common presenting symptoms include nausea and emesis, seizures, neck pain, focal neurologic deficits, and altered level of consciousness. (See 'Clinical features and presentation' above.) Diagnosis The diagnosis of hemorrhagic stroke requires confirmation by brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI). (See 'Urgent neuroimaging' above.) Differential diagnosis and evaluation The differential diagnosis for hemorrhagic stroke includes a broad list of diagnoses that can mimic stroke syndromes ( table 1), with the most common being migraine syndromes and postictal (Todd) paralysis. (See 'Differential diagnosis' above.) Testing to identify underlying causes includes dedicated cerebrovascular imaging and screening laboratory studies. (See 'Identifying the etiology' above.) Management The goals of acute hemorrhagic stroke management include stabilization of the patient, treatment of elevated intracranial pressure (if present), and close monitoring for brain herniation. (See 'Management' above.) We suggest multidisciplinary consultation to choose the optimal endovascular and/or surgical approach of vascular malformations. (See 'Treatment of vascular lesions' above.) Follow-up imaging is warranted in cases where a vascular lesion is suspected but not found during the acute evaluation as well as for most children with hemorrhagic stroke due to a vascular malformation due to the risk of recurrence. (See 'Follow-up imaging' above.) Prognosis The estimated mortality rate for children with hemorrhagic stroke ranges from 5 to 33 percent. Neurologic deficits may persist in up to approximately 75 percent, and disability may be present in more than half of ICH survivors. (See 'Prognosis' above.) Use of UpToDate is subject to the Terms of Use. 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Radiology 2018; 286:651. 101. Nelson MD Jr, Maeder MA, Usner D, et al. Prevalence and incidence of intracranial haemorrhage in a population of children with haemophilia. The Hemophilia Growth and Development Study. Haemophilia 1999; 5:306. Topic 107995 Version 14.0 https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 27/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate GRAPHICS Hemorrhagic stroke subtypes Hemorrhagic stroke subtypes. (A) Axial head CT demonstrating large left temporal acute IPH (arrows) with surrounding edema and mass ef ventricle (arrowhead) with left to right midline shift. The underlying cause of hemorrhage in this patient was (B) Axial T2/FLAIR MRI sequence showing non-traumatic SAH visible as hyperintense signal within the cerebra right frontal lobe (arrows).
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High critical care usage due to pediatric stroke: results of a population-based study. Neurology 2012; 79:420. 89. Lo WD, Hajek C, Pappa C, et al. Outcomes in children with hemorrhagic stroke. JAMA Neurol 2013; 70:66. 90. Porcari GS, Beslow LA, Ichord RN, et al. Neurologic Outcome Predictors in Pediatric Intracerebral Hemorrhage: A Prospective Study. Stroke 2018; 49:1755. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 26/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate 91. Greenham M, Gordon A, Anderson V, Mackay MT. Outcome in Childhood Stroke. Stroke 2016; 47:1159. 92. Yvon E, Lamotte D, Tiberghien A, et al. Long-term motor, functional, and academic outcome following childhood ischemic and hemorrhagic stroke: A large rehabilitation center-based retrospective study. Dev Neurorehabil 2018; 21:83. 93. Hawks C, Jordan LC, Gindville M, et al. Educational Placement After Pediatric Intracerebral Hemorrhage. Pediatr Neurol 2016; 61:46. 94. Smith SE, Vargas G, Cucchiara AJ, et al. Hemiparesis and epilepsy are associated with worse reported health status following unilateral stroke in children. Pediatr Neurol 2015; 52:428. 95. Broderick JP, Brott TG, Duldner JE, et al. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke 1993; 24:987. 96. Huang X, Cheng Z, Xu Y, et al. Associations of Clinical Characteristics and Etiology With Death in Hospitalized Chinese Children After Spontaneous Intracerebral Hemorrhage: A Single-Center, Retrospective Cohort Study. Front Pediatr 2020; 8:576077. 97. Kleinman JT, Beslow LA, Engelmann K, et al. Evaluation of intraventricular hemorrhage in pediatric intracerebral hemorrhage. J Child Neurol 2012; 27:526. 98. Hemphill JC 3rd, Bonovich DC, Besmertis L, et al. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001; 32:891. 99. Beslow LA, Ichord RN, Gindville MC, et al. Pediatric intracerebral hemorrhage score: a simple grading scale for intracerebral hemorrhage in children. Stroke 2014; 45:66. 100. Gu don A, Blauwblomme T, Boulouis G, et al. Predictors of Outcome in Patients with Pediatric Intracerebral Hemorrhage: Development and Validation of a Modified Score. Radiology 2018; 286:651. 101. Nelson MD Jr, Maeder MA, Usner D, et al. Prevalence and incidence of intracranial haemorrhage in a population of children with haemophilia. The Hemophilia Growth and Development Study. Haemophilia 1999; 5:306. Topic 107995 Version 14.0 https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 27/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate GRAPHICS Hemorrhagic stroke subtypes Hemorrhagic stroke subtypes. (A) Axial head CT demonstrating large left temporal acute IPH (arrows) with surrounding edema and mass ef ventricle (arrowhead) with left to right midline shift. The underlying cause of hemorrhage in this patient was (B) Axial T2/FLAIR MRI sequence showing non-traumatic SAH visible as hyperintense signal within the cerebra right frontal lobe (arrows). (C) Axial head CT with isolated IVH in the third (C, left panel) and fourth (C, right panel) ventricles (arrows) ass hydrocephalus. (D) Axial (D, left panel) and sagittal (D, right panel) T1-weighted MRI sequence demonstrating a large right fro (arrows) with intraventricular extension into the entire right lateral ventricle (arrowheads). CT: computed tomography; IPH: intraparenchymal hemorrhage; FLAIR: fluid-attenuated inversion recovery; M resonance image; SAH: subarachnoid hemorrhage; IVH: intraventricular hemorrhage. Graphic 108187 Version 1.0 https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 28/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate Hemorrhagic stroke etiologies (A) Lateral view of conventional cerebral angiogram demonstrating an extensive left parieto-occipital AVM (ar vessels from the left posterior cerebral, middle cerebral, and anterior cerebral arteries with early deep and su veins. (B) Axial T2/FLAIR (B, left panel) and susceptibility-weighted (B, right panel) MRI sequences showing a left fro malformation (arrows) with calcified components within the lesion (hyperintense punctate signals in (B, left p susceptibility (B, right panel) consistent with blood products. (C) Coronal views of a CT angiography (C, left panel) and conventional cerebral angiogram (C, right panel) dem irregular fusiform lobulated aneurysm of the mid-basilar artery (arrowheads). (D) Sagittal (D, left panel) and axial (D, right panel) T2/FLAIR-weighted MRI sequence of a patient with a large (arrowheads) with associated IVH from a posterior fossa primitive neuroectodermal tumor. AVM: arteriovenous malformation; CT: computed tomography; IPH: intraparenchymal hemorrhage; FLAIR: flu inversion recovery; MRI: magnetic resonance image; IVH: intraventricular hemorrhage. Graphic 108188 Version 1.0 https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 29/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate Differential diagnosis of hemorrhagic stroke in children Arterial ischemic stroke with or without hemorrhagic transformation Bell's palsy Brain tumor Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Cerebral infections including abscess, encephalitis, and meningitis Cerebral sinovenous thrombosis with or without venous infarction or hemorrhage Complications of migraine Conversion disorder Metabolic derangements such as hypoglycemia Methotrexate and other chemotherapeutic agent neurotoxicity Mitochondrial disease such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) Musculoskeletal disorders Organic or amino acidurias Posterior reversible encephalopathy syndrome (PRES) Postictal (Todd) paralysis White matter diseases including multiple sclerosis, acute disseminated encephalomyelitis, and leukodystrophies Graphic 108249 Version 1.0 https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 30/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate MRI algorithm for the diagnosis of white matter disorders https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 31/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate MRI: magnetic resonance imaging; PNS: peripheral nervous system; CADASIL: cerebral autosomal dominant Reproduced with permission from: Schi mann R, van der Knaap MS. Invited Article: An MRI-based approach to the diagnosis of white m Graphic 65871 Version 13.0 https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 32/33 7/5/23, 12:20 PM Hemorrhagic stroke in children - UpToDate Contributor Disclosures Evelyn K Shih, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Lauren A Beslow, MD, MSCE No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Douglas R Nordli, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 33/33
7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions : Claire L Shovlin, PhD, FRCP : Lawrence LK Leung, MD : Jennifer S Tirnauer, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Apr 26, 2022. INTRODUCTION Hereditary hemorrhagic telangiectasia (HHT; also called Osler-Weber-Rendu syndrome) is an autosomal dominant vascular disorder associated with a variety of clinical manifestations including mucocutaneous telangiectasia, epistaxis, gastrointestinal bleeding, and iron deficiency anemia. Arteriovenous malformations (AVMs) commonly occur in the pulmonary, hepatic, and cerebral circulations. This topic review discusses the management of vascular lesions in individuals with HHT, including epistaxis; gastrointestinal lesions; and pulmonary, hepatic, and cerebral AVMs. Other aspects of HHT care are discussed separately: Pathophysiology, epidemiology, and diagnosis (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".) Screening for asymptomatic AVMs and testing and counseling of family members (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs".) OVERVIEW Definition of terms The following vascular lesions are seen in individuals with HHT: https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 1/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Arteriovenous malformation An arteriovenous malformation (AVM) is an abnormal vascular structure that provides a direct communication between one or more arteries and one or more veins. These may be sacs (eg, for pulmonary AVMs), small collections of intervening vessels (nidal AVMs), or direct high-flow connections between the arterial and venous side (arteriovenous fistulas [AVFs]). AVMs result in arteriovenous shunting. Shunting may also be observed secondary to dilatation of existing normal capillaries (eg, intrapulmonary shunting in the hepatopulmonary syndrome and as part of normal physiologic responses). Telangiectasia A telangiectasia is a small, dilated blood vessel (arteriole, venule, or capillary). The term is descriptive and refers to telangiectasia of many anatomic types and etiologies. HHT telangiectasia usually contain small arteriovenous communications and are commonly located near the surface of skin or mucous membranes. These lesions are not specific for HHT; they can also be seen sporadically in otherwise healthy individuals, associated with other disorders, or as part of a syndrome. Additional vascular lesions are increasingly recognized, some seen more commonly in patients with HHT, and others, such as aneurysms, present at similar or only marginally increased rates to the general population. General principles of management Major management issues in individuals with HHT span the full range of clinical manifestations ( table 1) and have been summarized in International Guidelines published in 2020 [1] and Consensus Statements from the European Reference Network (ERN) and other groups [2-5]. Important general elements include: Patient educational materials for individuals with HHT, and the location of specialized centers for diagnostic testing and management, are available from the websites of Cure HHT, VASCERN (the European Reference Network on Rare Multisystemic Vascular Diseases), and country-specific patient groups. Clinician education regarding the importance of epistaxis as the main cause of anemia, the need for intervention for certain asymptomatic individuals, and the paucity of clinical signs in patients with genetically confirmed HHT with visceral AVMs [6]. HHT vascular lesions may mimic metastases to liver or lung. Individuals with epistaxis (and less frequently, gastrointestinal bleeding) from sites that are accessible can receive dedicated local therapies; however, systemic therapies are sometimes used very successfully. (See 'Epistaxis' below and 'Gastrointestinal lesions' below and 'Hepatic AVMs' below.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 2/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Other localized vascular lesions should be assessed and treated ( table 1). This may require subspecialist management. The interventions used are generally the same as the treatment of the lesion in the absence of HHT. (See 'Therapy for specific vascular lesions and iron deficiency' below.) Systemic treatments may be needed for those with refractory bleeding, usually manifested by requirements for multiple blood transfusions and/or iron infusions. When reviewing evidence for systemic therapies, it is important to prioritize data from randomized trials. Individuals on the placebo arm often experience improvement in symptoms, illustrating the challenges in using observational studies to ascribe benefit [7]. (See 'Tamoxifen and other non-guideline approaches' below and 'Bevacizumab and other systemic antiangiogenic therapies' below.) When anticoagulation or antiplatelet therapy is indicated (for prophylaxis or treatment of thromboembolic or cardiovascular disease), this therapy should not be denied simply due to the HHT diagnosis. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Individuals who require anticoagulation (VTE and AF)'.) An approach to screening for asymptomatic AVMs and other aspects of routine care are discussed separately. It is especially important to identify pulmonary AVMs (PAVMs) to prevent paradoxical emboli, strokes, and brain abscesses. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs".) Many management recommendations are based on expert opinion and observational studies; although data from randomized trials are emerging for several areas of management, randomized trials have not delivered statistical support for several proposed treatments, and larger and further studies are underway with results awaited. In the meantime, as described in the sections below, much of expert opinion and practice remains guided by observational studies [1,3-5]. The uniformity of expert opinion varies depending on the clinical situation and prevailing health care practices. The second International HHT Guideline, published in 2020 by an international consensus group, was updated to take into account changes in evidence and advances in genetic testing [1]. The first International Guideline for the management of HHT was developed by the same group in 2006, made available online in 2007, and published in print in 2011 [8]. The 2020 International Guideline addressed six topics: epistaxis, gastrointestinal bleeding, anemia/anticoagulation, hepatic vascular malformations, pediatrics, and pregnancy [1]. This Guideline was more nuanced in separating the severity of indications for elements of care https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 3/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate proposed in the first Guideline (presenting in a stepwise fashion according to the severity of the disease), and also incorporated some new recommendations. For evaluation and therapy, the main new item in the 2020 Guideline was the incorporation of systemic antiangiogenic therapies into the algorithms for epistaxis, gastrointestinal bleeding, and severe hepatic AVMs (data on antiangiogenic therapy in HHT was not available when the first Guideline was generated in 2006). (See 'Bevacizumab and other systemic antiangiogenic therapies' below.) While previous guidelines recommended referral to specialists with relevant expertise (eg, otorhinolaryngologists, centers with neurovascular expertise), the 2020 Guideline detailed structured approaches recommended for the specialty management. Anemia was discussed as a separate topic. Previous guidelines had discussed management with oral and intravenous iron: the 2020 Guideline included a specific recommendation for red blood cell transfusions in the settings of hemodynamic instability/shock; comorbidities that require a higher hemoglobin target; need to increase the hemoglobin acutely, such as prior to surgery or during pregnancy; and/or inability to maintain an adequate hemoglobin despite frequent iron infusions. (See 'Iron deficiency and iron deficiency anemia' below.) Consensus statements on good practice in HHT have also been developed by the European Reference Network (ERN) on Rare Multisystemic Vascular Diseases ( VASCERN). This group has identified core Outcome Measures suitable to be implemented by all clinicians evaluating a patient with HHT: PAVM screening, antibiotic prophylaxis prior to dental and surgical procedures for those with PAVMs, epistaxis advice, assessment of iron deficiency, and advice on pregnancy [3]. Subsequent manuscripts include evidence from HHT patients across the ERN [3,4,9,10]. Frameworks published in 2022 include guidance for general health care practitioners reviewing HHT patients in non-specialty care as well as providing summary data and pathophysiological integrations for HHT specialists [2]. Educational materials for patients with HHT and the location of specialized centers for diagnostic testing and management are available from the websites of Cure HHT, VASCERN, and country-specific patient groups. THERAPY FOR SPECIFIC VASCULAR LESIONS AND IRON DEFICIENCY Epistaxis Epistaxis is the most common site of blood loss in HHT, affecting more than 90 percent of patients. Very high proportions experience epistaxis on a daily or near-daily basis, https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 4/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate and the iron losses are often sufficient to cause iron deficiency anemia, even in the absence of additional gastrointestinal bleeding. Management of epistaxis and iron deficiency anemia are therefore cornerstones of HHT management. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Epistaxis'.) The 2020 International Guideline provides a stepwise approach to treatment of epistaxis, in the following sequence [1]: Topical therapies Oral tranexamic acid Ablative therapies by otorhinolaryngologists Systemic antiangiogenic therapy (eg, bevacizumab) Septal dermatoplasty Young's procedure (nostril closure) As discussed below, there is evidence from randomized controlled trials for tamoxifen and tranexamic acid in HHT, and randomized trials are especially important in HHT (see 'General principles of management' above). Although tamoxifen was not addressed in the 2020 guideline, we suggest tamoxifen for individuals who require systemic therapy. Tranexamic acid is another reasonable option. (See 'Tamoxifen and other non-guideline approaches' below and 'Oral tranexamic acid' below.) There has also been widespread adoption of bevacizumab, and two further drugs (raloxifene and thalidomide) have received European Medicine Agency orphan drug designation for use in HHT, despite not being the most commonly used agents and no supportive evidence from randomized trials. Bevacizumab can be useful for individuals with severe bleeding. However, the transiency of some responses, lack of randomized trial data, and adverse effects should also be considered. (See 'Bevacizumab and other systemic antiangiogenic therapies' below.) The decision to use particular approaches depends on risk-benefit evaluations individualized to incorporate potential benefits and risks for the specific patient, as discussed in more detail below. Potential beneficial effects from systemic agents need to be balanced against the risks, and this is ideally conducted by clinicians with expertise using these agents in HHT. When weighing risks and benefits, there are few randomized trials to guide care. Early randomized trials provided evidence of benefit for the following: Estrogen-progesterone [11] Tamoxifen [12,13] Tranexamic acid [14,15] https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 5/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Systemic propranolol [16] However, other randomized trials have not shown convincing evidence of benefit in the treatment arm [7,17-22]. For two of the trials, there was marked improvement in the placebo arm, reflecting the benefit of saline and gel administration [17,18]. The degree of ill health and/or compromised quality of life due to HHT-associated bleeding not responding to all other measures means that the risks of systemic therapies may be considered justifiable [9]. However, it is important to recognize that most HHT patients with nosebleeds and anemia will not require such treatments that should be reserved for severe cases. Although all drugs have their specific side effect profiles, the risk of venous thromboembolism (VTE) requires a special note. Concerns about VTE with systemic therapies have led to the development of investigational topical agents (see 'Topical therapies' below). The systemic agents used to treat HHT-related epistaxis also increase the risk of VTE; individuals who develop VTE would require full anticoagulation with its attendant risks [23-25]. Across Europe, these agents are therefore generally avoided in patients with a prior history of VTE and/or those at particularly high risk of cerebral sequelae (eg, due to concurrent atrial fibrillation). Topical therapies Additional information about local therapies for the management of epistaxis is presented separately. (See "Management of epistaxis in children" and "Approach to the adult with epistaxis".) In HHT, accumulating evidence encourages the use of local (topical) preventive therapies [1]: Nasal humidification Ointments Saline spray [17] Gel [18] These therapies are essentially free of significant adverse effects, although occasional individuals report that they seem to precipitate their nosebleeds, in which case they should be discontinued. Saline nasal sprays Saline nasal sprays can be used to prevent drying, especially during winter and in dry environments such as airplanes. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Air travel'.) Saline nasal sprays demonstrated significant benefits in two trials in which they were used as placebo: https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 6/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate In one trial from 2016 involving 80 patients with HHT randomly assigned to receive intranasal bevacizumab or a saline nasal spray, the epistaxis severity score (ESS) in the 27 patients receiving nasal saline was reduced from 5.7 (95% CI 5.0-6.3) to 3.7 (95% CI 3.2-4.3) [7]. Other studies have demonstrated that the minimally important difference in the ESS is 0.7 [26]. In a survey of 649 patients with HHT and epistaxis, there were positive (beneficial) scores for improvement of epistaxis with saline treatments, room humidification, and nasal lubrication [27]. In another trial from 2016 involving 121 patients with HHT who were randomly assigned to receive one of several nasal sprays (active agents bevacizumab, estriol, tranexamic acid, or saline [placebo]), there were no significant between-group differences [17]. Thermosensitive gel In a randomized trial of 27 patients, benefit was seen in the placebo arm, which used a thermosensitive gel [18]. The median reduction in ESS was 1.96 (range, -0.91 to 5.98), and 9 of 12 participants (75 percent) receiving the placebo gel experienced a clinically meaningful improvement in ESS. Topical beta blockers Topical betablockers have been shown to demonstrate efficacy in some but not all randomized controlled trials: Propranolol demonstrated efficacy in a 2020 trial in 20 participants with moderate- severe HHT-related epistaxis who were randomly assigned to eight weeks of propranolol gel (1.5%) or placebo [16]. Dosing used 0.5 mL, applied to each nostril twice daily; and propranolol was continued for eight weeks in an open-label study. For the propranolol group, the ESS improved significantly (-2.03 1.7, versus -0.35 0.68 for the placebo group, p = 0.009). Hemoglobin levels also improved significantly (10.5 2.6 to 11.4 2.02 g/dL, p = 0.009); and intravenous iron and blood transfusion requirement decreased. The change in nasal endoscopy findings was not significant. During the open-label period, the ESS score improved significantly in the former placebo group (-1.99 1.41, p = 0.005). There was not a significant benefit in a trial in which 27 participants were randomly assigned to use timolol gel or placebo gel; the median change in ESS was 2.32 (range, 0.22 to 5.97) with timolol gel versus 1.96 (-0.91 to 5.98) with placebo [18]. A clinically meaningful improvement in ESS was experienced by 9 of 11 (82 percent) in the timolol gel group versus 9 of 12 (75 percent) with placebo. In another trial that randomly assigned 58 individuals to receive timolol nasal spray (0.25 mg in each nostril twice a https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 7/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate day for 28 consecutive days) or placebo, ESS did not improve with timolol administration [19]. Topical estrogen or other agents A 2016 trial in which 121 patients were assigned to apply a 0.1 percent estriol ointment (a low potency metabolite of estradiol), topical bevacizumab, topical tranexamic acid, or placebo to the nasal mucosa found no benefit of any of the active treatments [17]. However, the study was not sufficiently powered to rule out an effect, and a larger study of topical therapy may be warranted. A 2018 meta-analysis that included eight randomized placebo-controlled clinical trials found that submucosal (delivered endoscopically) bevacizumab and oral tamoxifen delivered benefit [28]. All of the nasal sprays (bevacizumab, tranexamic acid, or estrogen) showed a trend towards reduced frequency of epistaxis that did not reach statistical significance. Despite these negative findings, responses vary in different individuals, and it is not possible to predict who will respond particularly well to a given intervention. A 2020 randomized trial found that tacrolimus nasal ointment, administered for six weeks, did not improve epistaxis in HHT patients after the end of the treatment [20]. Emergency nasal packing may be required for severe hemorrhage. (See "Approach to the adult with epistaxis", section on 'Nasal packing'.) Oral tranexamic acid Tranexamic acid is proposed in the 2020 HHT guidelines to be second- line therapy for HHT nosebleeds that do not respond to topical therapies. It can be taken orally two to three times per day. Randomized trial evidence for efficacy of tranexamic acid with long-term use in HHT includes the following: In the 2014 ATERO trial, 118 individuals with HHT who had epistaxis for more than 60 minutes or 28 days in a month were randomly assigned to receive placebo or tranexamic acid (1.5 g orally twice per day for three months) followed by crossover to the other arm [14]. Compared with placebo, tranexamic acid was associated with a reduced duration of nosebleeds (106 versus 129 minutes per month) but no change in the number of nosebleeds (mean, 23 versus 22 per month). A randomized crossover trial from 2014 in which 22 patients received placebo or tranexamic acid, 1 g orally three times a day for three months, also found a significant reduction in nosebleeds with tranexamic acid, although hemoglobin levels were not improved [15]. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 8/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Not all experts agree with such widespread use of tranexamic acid, given the generally lifelong nature of HHT nosebleeds and the possibility of side effects not captured by short-term clinical trial follow-up. In our experience, VTE has developed in patients with HHT, and ischemic strokes have occurred in patients with HHT and pulmonary AVMs (PAVMs) [24,29]. Aminocaproic acid is an antifibrinolytic agent with a similar mechanism of action as tranexamic acid, but the published clinical experience with aminocaproic acid in HHT is much less extensive [30]. Ablative therapies For patients who continue to experience significant nosebleeds, review by an ear nose and throat (ENT) surgeon with expertise in this area is advisable to optimize interventional treatments. Dedicated local ENT treatments are generally directed to patients experiencing frequent epistaxis or less frequent massive hemorrhages [31]. In one survey, 326 of 666 unselected respondents with HHT (49 percent) required specialist invasive treatments, often requiring multimodality therapy [27]. Different types of laser or argon plasma coagulation devices are available, with the choice of method depending on operator preference and availability. Laser therapy is generally preferred over cauterization, since cauterization can damage the nasal mucosa, which may prompt vascular regrowth; however, if cauterization is the only therapy available, it can have beneficial effects [27]. In a survey comparing 267 international HHT users of cauterization and 221 users of laser therapy, laser therapy was reported to be beneficial more frequently than cauterization [27]. Sclerotherapy is another treatment that may be effective. A randomized crossover trial involving 17 patients with HHT and epistaxis found that sclerotherapy with sodium tetradecyl sulfate resulted in a greater reduction in ESS than standard care (moisturization, cautery) [32]. A retrospective study evaluating 67 patients with HHT found that use of sclerotherapy with sodium tetradecyl sulfate resulted in similar efficacy in controlling epistaxis as laser cautery, with fewer procedures required [33]. However, the otorhinolaryngology experts within the European Reference Network have made the point that sclerotherapy carries well-documented risks of adverse events including blindness in the non-HHT population, and full-patient counseling seems appropriate [2]. Coblation therapy (a term derived from the words "controlled ablation") is another treatment reported to be effective; it involves use of radiofrequency ablation at low temperatures to remove problematic tissue. In a study that followed 57 patients with HHT who underwent 150 coblation treatments over the course of 12 years, the average duration of effectiveness was 25 months (range 1 to 86 months) [34]. Of the 26 patients (46 percent) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 9/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate who underwent multiple coblation treatments, the overall average duration of coblation effectiveness was 16.4 months (range, 1 to72 months). Bevacizumab and other systemic antiangiogenic therapies Bevacizumab Bevacizumab is an antiangiogenic agent that inhibits vascular endothelial growth factor (VEGF); it has been tested in retrospective studies of patients with HHT who have significant chronic blood loss (from epistaxis or gastrointestinal lesions) and/or high- output heart failure. It can be very useful for individuals with severe bleeding. However, some responses do not persist, and some individuals discontinue therapy due to adverse events. Additionally, evidence for efficacy only includes observational studies; randomized trial evidence is lacking. The second International HHT Guideline reports multiple uncontrolled series that demonstrated intravenous bevacizumab reduced epistaxis, improved anemia, reduced transfusion requirements, or improved quality of life [1,35-43]. Further observational studies and surveys have been published since those reviewed in the Guideline [44]. At the same time, adverse events have been reported with the use of these therapies [9,45]. Randomized trials are needed. While results of randomized trials are awaited, antiangiogenic therapies were prominent in the recommendations from the second International HHT Guideline recommendations for epistaxis and gastrointestinal bleeding [1]. Evidence from some of the larger studies in severely ill individuals includes the following: A multicenter retrospective study from 2021 that included data from 238 individuals with HHT treated with systemic bevacizumab found favorable safety and efficacy profiles [46]. Dosing protocols varied; the majority received four to six treatments of 5 mg/kg every two weeks, followed by maintenance treatments on a regular schedule (5 mg/kg once every 4 to 12 weeks). Responses were apparent within three months; hemoglobin levels increased by a mean of 3.2 g/dL, the mean ESS decreased by 3.4 points, and the median number of transfusions decreased from six units in six months to zero. In patients who required intravenous iron infusions, the number of infusions decreased from eight infusions in six months to two. Adverse effects included hypertension in 18 percent, fatigue in 10 percent, proteinuria in 9 percent, myalgia or arthralgia in 6 percent, and venous thromboembolism in 2 percent (none fatal). Five percent discontinued bevacizumab for adverse events. Previous smaller studies, some from the same authors who contributed to the 2021 study above, had also suggested efficacy [35-37,47]. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 10/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Adverse effects were evaluated in a 2019 study by the European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) in 69 individuals with HHT who were treated with bevacizumab for a mean of 11 months for bleeding or high-output cardiac failure due to hepatic AVMs [9]. Adverse events were reported in 33 patients, more commonly in females (27 adverse events in 46 women versus 6 events in 23 men). The most common of these were joint pain (10 percent), headache (4 percent), and proteinuria (3 percent). Bleeding occurred in two patients (3 percent); one was an episode of grade 3 gastrointestinal bleeding and one was a fatal event of catastrophic hemoptysis from a known but not monitored PAVM. This was considered possibly related to bevacizumab, as spontaneous rupture of PAVMs is highly unusual outside of pregnancy or pulmonary hypertension, which were absent in this individual. Across the ERN, bevacizumab is considered to be a choice of last resort in extremely ill individuals with compromised quality of life, based on the evidence available, which does not include randomized trials, and the known adverse effects in HHT and other settings [9]. Other potential toxicities of bevacizumab identified in the general population (including cardiovascular effects [hypertension, thromboembolism, left ventricular dysfunction], non- cardiovascular effects [proteinuria, bleeding, delayed wound healing, gastrointestinal perforation, fatigue, and dysphonia], and fatal adverse events) are presented in more detail separately. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects".) IMiDs Thalidomide and lenalidomide have antiangiogenic and immunomodulatory properties [48-51]. There have not been randomized controlled trials of these drugs in HHT. A 2018 systematic review of observational studies found an association between the use of low-dose thalidomide and reduced frequency and duration of epistaxis and need for transfusions [52]. Thalidomide had previously received EMA orphan drug designation for HHT [53,54]. This was based on two small series of individuals with HHT (12 and 7 patients) [48,55]. Patients reported reductions in epistaxis, but many patients (approximately two- thirds and one-third, respectively) discontinued the drug due to side effects that included drowsiness, peripheral neuropathy, nausea, and constipation. Only a minority of patients continued taking thalidomide, primarily due to these side effects [48]. The safety of thalidomide in HHT was specifically evaluated by the European Reference Network (ERN) on Rare Multisystemic Vascular Diseases (VASCERN) [9]. Sixty-seven HHT patients received thalidomide, all for bleeding, and for a mean of 13.4 months, totaling 75 person-years of treatment. Adverse events related to thalidomide were reported in 34 individuals (51 percent), with an average incidence rate of 45.3 per 100 person-years. These https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 11/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate were seen at similar rates in males and females. They were more common in individuals with an ENG mutation than an ACVRL1 mutation (all 17 with ENG versus 14 of 34 [41 percent] with ACVRL1). The most common reports were of peripheral neuropathy (18 percent), drowsiness (12 percent), and dizziness (9 percent). Three fatal, adverse events were possibly related to thalidomide (average incidence rate: 4 per 100 person-years). As noted above, systemic therapies have demonstrated adverse effects of which the clinician and patient should be aware. Individuals with HHT who have a history of thromboembolic disease are excluded from clinical trials using these agents [14,38]. Clinical studies using systemic bevacizumab in HHT have also excluded individuals with cerebral arteriovenous malformations (AVMs), thrombocytopenia, or anticoagulant therapy [38]. The use of these drugs remains off-label, and reported experience is still very limited. A number of additional antiangiogenic and other agents have appeared promising in uncontrolled studies, case reports, or preclinical models. Examples include the VEGF inhibitor pazopanib and the immunosuppressive agents sirolimus and interferon [56-60]. It has been suggested that their use should be restricted to selected, consenting individuals in randomized trials conducted at experienced HHT centers, due to the lack of evidence for benefit from randomized trials, potential side effects, and lack of long-term safety and efficacy data [61]. Further ENT options recommended in international guidelines Other directed therapies include septodermoplasty and/or unilateral or bilateral surgical closure of the nostrils [31,62-67]. These invasive treatments are almost always used in patients who have also received laser therapy and/or cauterization [27,31]. Young's procedure (bilateral surgical closure of the nostrils) has not been evaluated in a randomized trial, but as published in a series of 100 cases, many seen by us in subsequent years, it can have remarkable long-term success in alleviating major nosebleeds and reversing transfusion dependency, as long as there is complete closure of nasal flow [68]. However, a small proportion of patients cannot tolerate the procedure and request reversal, and a larger number decline as they are concerned about the implication of anosmia and mouth breathing. Some patients have been treated with submucosal injection of bevacizumab at the time of laser therapy; long-term results of this approach are awaited [69,70]. Tamoxifen and other non-guideline approaches Additional elements that can be incorporated as part of general care include: Dietary changes for prevention HHT nosebleeds usually come in clusters and vary in severity over a lifetime. A proportion of people with HHT (we estimate approximately one in https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 12/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate three) may be able to identify dietary triggers of nosebleeds that can be avoided without detrimentally impacting their lifestyle [27,62,71]. We suggest keeping a food diary of items ingested in the hours immediately prior to an unusually severe bleed to aid identification of potential precipitants. Avoidance of over-the-counter supplements Caution with over-the-counter dietary supplements offers another opportunity to avoid potential precipitants. An example is fish oil supplements, for which antiplatelet activity is not generally appreciated [72]. (See "Fish oil: Physiologic effects and administration".) For individuals who require systemic therapy, the 2020 International HHT Guideline discussions did not incorporate tamoxifen (with evidence from randomized trials) and the two European Medicines Agency (EMA)-recommended drugs raloxifene and thalidomide. Tamoxifen A 2018 meta-analysis of eight randomized placebo-controlled trials demonstrated that only tamoxifen was superior to placebo, reducing both the frequency and the severity of epistaxis [28]. Tamoxifen appears to be well tolerated, has evidence of efficacy from a double-blind, randomized controlled trial, and is our first treatment of choice when a systemic agent is used for treating epistaxis. In a 2018 meta-analysis of randomized, placebo-controlled trials, tamoxifen was the only systemic agent shown to be superior to placebo; it reduced epistaxis severity and frequency [28]. Tamoxifen also has a favorable side effect profile compared with tranexamic acid, bevacizumab, and raloxifene (wider HHT population use of raloxifene is awaited). However, tamoxifen would not be recommended for someone with a prior history of VTE, atrial fibrillation, or similar higher risk-factor status for venous or arterial thromboembolism. (See "Managing the side effects of tamoxifen and aromatase inhibitors".) A benefit from tamoxifen was demonstrated in a 2009 trial that randomly assigned 25 individuals with HHT (men and women) to receive placebo or tamoxifen (20 mg daily) for six months [12]. Compared with placebo, tamoxifen was associated with a reduction in epistaxis, based on self-report and nasal endoscopy (improvement in 18 versus 90 percent). Some individuals assigned to tamoxifen also had an improvement in hemoglobin level or reduction in transfusion requirements. In an extended follow-up of patients completing the trial arm, in a total of 46 patients with mean 23.4 months of treatment, there were improvements in bleeding score, quality-of-life score, and hemoglobin concentration; none required blood transfusions [13]. These and other extended follow-up studies, as well as our experience, suggest sustained benefits from tamoxifen, and therapy has been well tolerated [13,23,73]. In contrast to other agents discussed below, we have yet to see VTE developing in HHT patients using tamoxifen [23,73]. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 13/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Premenopausal women taking tamoxifen should be aware of the effects on other organ systems. (See "Managing the side effects of tamoxifen and aromatase inhibitors".) Raloxifene Raloxifene is a selective estrogen receptor modulator (SERM) that has received European Medicine Agency (EMA) orphan drug designation for HHT based on a small pilot study [74,75]. There is no evidence from randomized trials in HHT. Raloxifene is associated with an increased risk of VTE events, particularly during the first four months of treatment, and is contraindicated in people with a history of VTE, hepatic impairment, cholestasis, severe renal impairment, unexplained uterine bleeding, or endometrial cancer. Estrogens High-dose estrogens have been beneficial in the setting of gastrointestinal bleeding from AVMs (see 'Gastrointestinal lesions' below); however, we do not use high- dose estrogens due to their side effect profiles, particularly the increased risk of VTE. The 50 mg estradiol dose that was effective in one study is not tolerated by men, and we consider the risk of VTE too great to use systemic estrogens [11]. N-acetylcysteine A pilot study in 43 patients suggested a possible benefit of N- acetylcysteine [76]. Pazopanib A retrospective review of 13 patients who received pazopanib for transfusion- dependent anemia due to HHT bleeding reported that all 13 became transfusion independent, with evidence for reduction in ESS, decreased intravenous iron use, and improvement in hemoglobin [77]. Compared with pretreatment hemoglobin, those treated with pazopanib for 12 months had an increase in their mean hemoglobin by 4.8 g/dL (95% CI 3.6-5.9), from 7.8 to 12.7 g/dL, and decreased mean ESS by 4.77 points (95% CI 3.11-6.44 points; from 2.43 to 7.20 points). As stated by the authors, these findings require confirmation in a randomized trial. Oral itraconazole In an observational assessment of 21 patients treated with oral itraconazole, four discontinued therapy due to side effects; the remaining 17 had a decrease in mean ESS from 6.0 to 3.8 points (IQR decreased from 5.1-7.2 to 3.1-5.2) [78]. Hemoglobin levels did not change significantly. Gastrointestinal lesions Gastrointestinal lesions in HHT are common (seen in up to 20 percent of patients), but in the majority of cases, treatment is not required, as iron deficiency is primarily due to under-replacement of iron losses from nosebleeds. That said, a small population of patients with HHT have very severe, recurrent gastrointestinal bleeding, and some suggest this is more common in patients with SMAD4 HHT. (See "Hereditary hemorrhagic
uncontrolled studies, case reports, or preclinical models. Examples include the VEGF inhibitor pazopanib and the immunosuppressive agents sirolimus and interferon [56-60]. It has been suggested that their use should be restricted to selected, consenting individuals in randomized trials conducted at experienced HHT centers, due to the lack of evidence for benefit from randomized trials, potential side effects, and lack of long-term safety and efficacy data [61]. Further ENT options recommended in international guidelines Other directed therapies include septodermoplasty and/or unilateral or bilateral surgical closure of the nostrils [31,62-67]. These invasive treatments are almost always used in patients who have also received laser therapy and/or cauterization [27,31]. Young's procedure (bilateral surgical closure of the nostrils) has not been evaluated in a randomized trial, but as published in a series of 100 cases, many seen by us in subsequent years, it can have remarkable long-term success in alleviating major nosebleeds and reversing transfusion dependency, as long as there is complete closure of nasal flow [68]. However, a small proportion of patients cannot tolerate the procedure and request reversal, and a larger number decline as they are concerned about the implication of anosmia and mouth breathing. Some patients have been treated with submucosal injection of bevacizumab at the time of laser therapy; long-term results of this approach are awaited [69,70]. Tamoxifen and other non-guideline approaches Additional elements that can be incorporated as part of general care include: Dietary changes for prevention HHT nosebleeds usually come in clusters and vary in severity over a lifetime. A proportion of people with HHT (we estimate approximately one in https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 12/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate three) may be able to identify dietary triggers of nosebleeds that can be avoided without detrimentally impacting their lifestyle [27,62,71]. We suggest keeping a food diary of items ingested in the hours immediately prior to an unusually severe bleed to aid identification of potential precipitants. Avoidance of over-the-counter supplements Caution with over-the-counter dietary supplements offers another opportunity to avoid potential precipitants. An example is fish oil supplements, for which antiplatelet activity is not generally appreciated [72]. (See "Fish oil: Physiologic effects and administration".) For individuals who require systemic therapy, the 2020 International HHT Guideline discussions did not incorporate tamoxifen (with evidence from randomized trials) and the two European Medicines Agency (EMA)-recommended drugs raloxifene and thalidomide. Tamoxifen A 2018 meta-analysis of eight randomized placebo-controlled trials demonstrated that only tamoxifen was superior to placebo, reducing both the frequency and the severity of epistaxis [28]. Tamoxifen appears to be well tolerated, has evidence of efficacy from a double-blind, randomized controlled trial, and is our first treatment of choice when a systemic agent is used for treating epistaxis. In a 2018 meta-analysis of randomized, placebo-controlled trials, tamoxifen was the only systemic agent shown to be superior to placebo; it reduced epistaxis severity and frequency [28]. Tamoxifen also has a favorable side effect profile compared with tranexamic acid, bevacizumab, and raloxifene (wider HHT population use of raloxifene is awaited). However, tamoxifen would not be recommended for someone with a prior history of VTE, atrial fibrillation, or similar higher risk-factor status for venous or arterial thromboembolism. (See "Managing the side effects of tamoxifen and aromatase inhibitors".) A benefit from tamoxifen was demonstrated in a 2009 trial that randomly assigned 25 individuals with HHT (men and women) to receive placebo or tamoxifen (20 mg daily) for six months [12]. Compared with placebo, tamoxifen was associated with a reduction in epistaxis, based on self-report and nasal endoscopy (improvement in 18 versus 90 percent). Some individuals assigned to tamoxifen also had an improvement in hemoglobin level or reduction in transfusion requirements. In an extended follow-up of patients completing the trial arm, in a total of 46 patients with mean 23.4 months of treatment, there were improvements in bleeding score, quality-of-life score, and hemoglobin concentration; none required blood transfusions [13]. These and other extended follow-up studies, as well as our experience, suggest sustained benefits from tamoxifen, and therapy has been well tolerated [13,23,73]. In contrast to other agents discussed below, we have yet to see VTE developing in HHT patients using tamoxifen [23,73]. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 13/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Premenopausal women taking tamoxifen should be aware of the effects on other organ systems. (See "Managing the side effects of tamoxifen and aromatase inhibitors".) Raloxifene Raloxifene is a selective estrogen receptor modulator (SERM) that has received European Medicine Agency (EMA) orphan drug designation for HHT based on a small pilot study [74,75]. There is no evidence from randomized trials in HHT. Raloxifene is associated with an increased risk of VTE events, particularly during the first four months of treatment, and is contraindicated in people with a history of VTE, hepatic impairment, cholestasis, severe renal impairment, unexplained uterine bleeding, or endometrial cancer. Estrogens High-dose estrogens have been beneficial in the setting of gastrointestinal bleeding from AVMs (see 'Gastrointestinal lesions' below); however, we do not use high- dose estrogens due to their side effect profiles, particularly the increased risk of VTE. The 50 mg estradiol dose that was effective in one study is not tolerated by men, and we consider the risk of VTE too great to use systemic estrogens [11]. N-acetylcysteine A pilot study in 43 patients suggested a possible benefit of N- acetylcysteine [76]. Pazopanib A retrospective review of 13 patients who received pazopanib for transfusion- dependent anemia due to HHT bleeding reported that all 13 became transfusion independent, with evidence for reduction in ESS, decreased intravenous iron use, and improvement in hemoglobin [77]. Compared with pretreatment hemoglobin, those treated with pazopanib for 12 months had an increase in their mean hemoglobin by 4.8 g/dL (95% CI 3.6-5.9), from 7.8 to 12.7 g/dL, and decreased mean ESS by 4.77 points (95% CI 3.11-6.44 points; from 2.43 to 7.20 points). As stated by the authors, these findings require confirmation in a randomized trial. Oral itraconazole In an observational assessment of 21 patients treated with oral itraconazole, four discontinued therapy due to side effects; the remaining 17 had a decrease in mean ESS from 6.0 to 3.8 points (IQR decreased from 5.1-7.2 to 3.1-5.2) [78]. Hemoglobin levels did not change significantly. Gastrointestinal lesions Gastrointestinal lesions in HHT are common (seen in up to 20 percent of patients), but in the majority of cases, treatment is not required, as iron deficiency is primarily due to under-replacement of iron losses from nosebleeds. That said, a small population of patients with HHT have very severe, recurrent gastrointestinal bleeding, and some suggest this is more common in patients with SMAD4 HHT. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Individuals with SMAD4 HHT'.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 14/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Bleeding gastrointestinal lesions in HHT may be accessible for local therapies administered endoscopically. As for epistaxis, local treatments allow the patient to avoid systemic therapies with potential prothrombotic or other risks. Repeated endoscopic ablation of gastrointestinal lesions may be used to control bleeding in the short term ( picture 1), although the results are not as good as in the non-HHT population [79]. Additionally, local therapies carry a potential risk of causing visceral perforations and other complications. In a 2009 guidance, repeated therapies were therefore not recommended [8]. Embolization and/or surgery has limited success due to recurrent disease but may be useful for emergency control of hemorrhage from discrete lesions. This is also the preferred option for diffuse or endoscopically inaccessible severe gastrointestinal bleeding. Gastrointestinal bleeding requiring frequent endoscopic interventions, transfusions, or iron infusion may be treated with systemic agents, and additional studies are ongoing. (See 'Bevacizumab and other systemic antiangiogenic therapies' above and 'Tamoxifen and other non-guideline approaches' above.) Additional information about management of accessible vascular lesions in the gastrointestinal tract is presented separately. (See "Angiodysplasia of the gastrointestinal tract" and "Argon plasma coagulation in the management of gastrointestinal hemorrhage", section on 'Angiodysplasia'.) Where bleeding from an obscure source is considered (eg, due to iron deficiency anemia or a positive stool guaiac test), under-appreciated epistaxis loss is almost always the cause (see 'Epistaxis' above). The possibility of other hematologic causes of anemia should also be considered. Iron deficiency and iron deficiency anemia Iron deficiency and iron deficiency anemia are common in individuals with HHT. The usual cause is epistaxis due to the vascular lesions of HHT. Other common non-HHT-related causes include heavy menstrual bleeding, dietary iron insufficiency, regular blood donation, pregnancy, surgery, and other traumatic events, all of which increase the requirement for iron (the hemorrhage-adjusted iron requirement [HAIR]) [80]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler- Weber-Rendu syndrome)", section on 'Iron deficiency'.) Most patients with iron deficiency anemia secondary to blood loss from the vascular lesions of HHT are managed conservatively by repletion of the lost iron. Evidence for responses to 35 mg elemental iron tablets (ferrous gluconate) has been published, and this is our preference for https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 15/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate initial oral dosing for reasons described below [81]. Recommended treatment regimens for iron supplementation and education regarding supplementary ways to improve iron absorption, such as avoiding ingestion of absorption inhibitors such as tea within an hour of iron ingestion based on general population considerations, are discussed separately. If iron absorption is impaired due to concurrent inflammation or disease, and/or bleeding is severe enough, parenteral iron therapy and/or blood transfusions may be required. (See "Treatment of iron deficiency anemia in adults".) HHT patients have important additional considerations relative to the general population: Ongoing blood losses and higher HAIR should be expected in individuals with HHT [80]. Data indicate that treatment of anemia (together with treatment of AVMs) improves epistaxis in approximately one-third of patients with HHT [82]. Importantly, a smaller proportion of HHT patients (approximately 5 percent) report that iron treatments and blood transfusions make their nosebleeds worse [82,83]. We are concerned this may relate to supranormal serum iron concentrations evident in people ingesting iron tablets [72,83] and induction of endothelial injury [83,84], but this awaits clinical confirmation. Additional studies are ongoing. Heavy menstrual bleeding is a very common problem for the female HHT population and can exacerbate iron deficiency. Heavy menstrual bleeding in patients with HHT is generally managed the same as in patients without HHT, though applying the prothrombotic concerns outlined above for systemic therapies (see 'Bevacizumab and other systemic antiangiogenic therapies' above). This information is presented in detail separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis" and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management".) Iron deficiency is the most common form of anemia in HHT, but as for any population, individuals may also be at risk for concurrent pathologies causing anemia, and these should be evaluated as appropriate for the patient. (See "Diagnostic approach to anemia in adults".) Data from a series of HHT patients with severe anemia out of proportion to calculated hemorrhagic iron losses emphasize that low-grade hemolysis may contribute to severe anemia in HHT [85]. Pulmonary AVMs Potential complications of PAVMs Pulmonary AVMs (PAVMs) are of concern in HHT because patients can develop a number of potentially life-threatening and life-changing cerebral https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 16/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate complications including ischemic stroke caused by a paradoxical embolus to the brain and brain abscess caused by paradoxical septic emboli [86]. As noted, PAVMs affect over half of individuals with HHT. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pulmonary AVMs'.) Hypoxemia versus hypoxia PAVMs commonly cause hypoxemia (low partial pressure of oxygen [PaO ] and low hemoglobin saturation by oxygen [SaO ]) due to impaired gas 2 2 exchange, though this is usually asymptomatic [87]. These changes are due to hypoxemia and not hypoxia. Individuals with HHT maintain their arterial oxygen content (CaO ), and 2 they do not have the same physiology as patients who have low PaO /SaO due to 2 2 parenchymal lung disease [87]. Standard recommendations for individuals with hypoxic lung disease are not applicable since individuals with hypoxemia due to right to left shunting are not specifically at risk of hypoxic pulmonary hypertension [88]. Two studies evaluating exercise capacity in individuals with HHT-associated PAVMs demonstrated that reduced exercise capacity reflects low hemoglobin and/or airflow limitation rather than hypoxemia [89,90]. Nevertheless, it was a surprise when the evidence on how well airline flights were tolerated was published [91]. Using a retrospective questionnaire-based study, the authors examined in-flight complications and predictors in 145 HHT patients (96 with PAVMs) who reported 3950 flights, totaling 18,943 flight hours. Dyspnea and thrombotic complications were less common than expected and could not be predicted from sea-level oxygen saturations or hemoglobin concentrations (anemia) [91]. Where there are concurrent pathologies such as parenchymal lung disease or pulmonary hypertension, standard guidance should be followed; this may include supplemental oxygen in certain settings (as an example, airline flights) or continuously. Where patients with PAVMs have successfully traveled by air on many occasions when hypoxemic, and there is no change in their medical state, we do not prohibit flying, based on published evidence [91]. (See "Assessment of adult patients for air travel" and "Evaluation of patients for supplemental oxygen during air travel".) Silent cerebral infarcts and stroke Silent cerebral infarcts are also a concern; these silent infarcts have been identified on cerebral magnetic resonance images (MRIs) performed for another indication (cerebral AVM screening), emphasizing the risk in individuals with PAVMs [92,93]. In a study from the United States involving 353 individuals with HHT who had brain magnetic resonance imaging (MRI) for any reason, silent cerebral infarcts were more common in individuals with PAVMs than those without PAVMs (overall https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 17/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate prevalence, 10 percent; with PAVMs in 81 percent of the silent infarction patients and 53 percent of the individuals without silent infarction) [93]. In a study from Europe in a group of 29 individuals with PAVMs and no history of stroke, one to five silent infarcts were found in 16 individuals (55 percent) [92]. The most frequently affected sites were the cerebellum (40 percent) and thalamus (14.3 percent), and the age-adjusted odds ratio for an infarct was 21.6 (95% CI: 3.7, 126) [92]. Septic embolism to the brain causing brain abscess is also a risk. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults", section on 'Neurologic'.) Bleeding Occasionally, PAVMs may bleed; this event is rare unless PAVMs have developed a systemic arterial supply (spontaneously or post-treatment), the individual is pregnant, or the individual has pulmonary hypertension. PAVM hemorrhage may lead to hemoptysis or hemothorax. These and other complications of PAVMs are discussed in more detail separately. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pulmonary AVMs' and "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults".) PAVM screening PAVMs are present in over half of individuals with HHT. Any relevant symptoms should be investigated. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults", section on 'Clinical manifestations'.) The approach to screening is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'PAVM screening'.) Principles of PAVM management Management of PAVMs should be performed by clinicians with expertise in this area and should include the following, which are in keeping with a 2017 good practice statement from the British Thoracic Society and the European Reference Network for HHT (VASCERN HHT) [3,94]. Individuals with PAVMs should receive prophylactic antibiotics prior to dental procedures, other potentially nonsterile procedures (eg, endoscopy), and surgery, to reduce post- procedural bacteremias implicated in brain abscess pathogenesis [95]. This is one of the five VASCERN HHT Outcome Measures, where good practice is 100 percent of all PAVM patients advised in writing [3,95]. It is also important to maintain good dental care to reduce the risk of bacteremia. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Antibiotic prophylaxis'.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 18/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate For PAVMs of a size amenable to embolization, embolotherapy is recommended based on evidence from observational studies that suggests reduced morbidity and mortality [73,96- 99]. These data are also supported by practice standards from the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) and a Cochrane database review [5,99]. Information about the details of the procedure and evidence to support its efficacy in reducing cerebral complications are presented separately. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Patients suitable for embolotherapy'.) There are occasional circumstances (eg, severe pulmonary hypertension [PH]) when risk- benefit analyses are generally not in favor of embolization or where surgery may be preferred due to a greater likelihood of complete obliteration of shunting through the lesion [99-101]. Patients with in situ metallic coils and Amplatzer vascular plugs used to treat PAVMs can safely undergo MRI [102]. For PAVMs that are not amenable to embolization anatomically, surgery may occasionally be warranted. While the risks of removing normal lung in an individual likely to have multiple PAVMs may in the past have outweighed the benefits, parenchymal-sparing surgical techniques mean this is less of a concern, and at our center, surgery is increasingly offered to selected patients. Lung transplantation has been performed in very occasional cases, but in major HHT/PAVM centers, this has not been considered an option for even the majority of complicated PAVM cases, due to longevity of patients with severe hypoxemia who do not receive lung transplantation. Of five where transplantation was considered and not performed, by 2017, survival ranged from 16 to 27 (median 21) years, with surviving patients restating a preference for their ongoing medical issues [103]. Since that publication, at our institution, one patient has been referred and meets the criteria for lung transplantation; however, they are not actively transplant-listed as their quality of life is considered by the patient and the transplant team to be too high to justify the risks of lung transplantation. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Surgical excision'.) Experts in some countries have recommended filters to prevent paradoxical embolization of particulate material present in an intravenous solution. In other countries such as the United Kingdom, where air embolism is a "never event" (ie, one that should not occur if the available preventive measures have been implemented), insertion of such a filter is considered likely to be detrimental, compared with judicious following of safe practices for intravenous solutions [104]. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 19/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Individuals with PAVMs are generally advised to avoid scuba diving. Having been informed of the additional risks, in our experience, some patients choose to make an informed choice of the level of risk that they would consider acceptable to them. The field is awaiting formal guidance to take into account the one in three of the general population who will also shunt through a patent foramen ovale during a dive. Management of complications of PAVMs (eg, ischemic stroke, brain abscess) is discussed separately. Importantly, brain abscess is often not accompanied by leukocytosis, and a low threshold for making the diagnosis should be used to ensure that there is immediate referral for neurosurgical review and that appropriate intravenous antibiotics are given [73,105]. As noted above, MRI can be performed in patients who have undergone PAVM embolization and should not be delayed in emergency situations [102]. (See "Initial assessment and management of acute stroke" and "Treatment and prognosis of bacterial brain abscess".) Pulmonary hypertension is a separate pathology (usually, pulmonary artery [PA] pressures are low to normal in patients with PAVMs). Data from two large series published in 2017 (3176 HHT patients, pulmonary artery hypertension in <2 percent) demonstrated that when pulmonary hypertension was present, it was usually part of a broader picture of hepatic AVMs, anemia, atrial fibrillation, and symptoms [106,107]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pulmonary hypertension' and "Pulmonary arteriovenous malformations: Epidemiology, etiology, and pathology in adults".) Additional discussion of the management of PAVMs is presented separately. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".) Hepatic AVMs Hepatic AVM management has been assisted by the 2020 International HHT Guidelines where the expert panel recommended the following [1]: Screening for liver AVMs in adults with definite or suspected HHT. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Hepatic AVM screening'.) Diagnostic testing in HHT patients with symptoms and/or signs suggestive of complicated liver AVMs (including heart failure, pulmonary hypertension, abnormal cardiac biomarkers, abnormal liver function tests, abdominal pain, portal hypertension, or encephalopathy), using Doppler ultrasound, multiphase contrast CT scan, or contrast abdominal MRI. (See 'Identifying hepatic AVMs and determining need for treatment' below.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 20/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Estimation of the prognosis of liver AVMs using available predictors, to identify patients in need of closer monitoring. An intensive first-line management only for patients with complicated and/or symptomatic liver AVMs, tailored to the type of complication(s). (See 'Initial management of hepatic AVMs' below.) Co-management of HHT patients with high-output cardiac failure and pulmonary hypertension by an HHT Center of Excellence and an HHT cardiologist or pulmonary hypertension specialty clinic. Systemic bevacizumab is considered for patients with symptomatic high-output cardiac failure due to liver AVMs for whom first-line management is unsuccessful. For those with refractory high-output cardiac failure, biliary ischemia, or complicated portal hypertension, referral for consideration of liver transplantation is appropriate. (See 'Role of liver transplantation' below.) Liver biopsy should be avoided in any patient with proven or suspected HHT. Hepatic artery embolization be avoided in patients with liver AVMs as it is only a temporizing procedure associated with significant morbidity and mortality. Identifying hepatic AVMs and determining need for treatment Hepatic AVMs are common in HHT, identified in approximately 50 percent of people; they are substantially more prevalent in patients with HHT2 due to pathogenic variants in ACVRL1 [108,109]. Longitudinal series have shown that complications occur at an incidence of 3.6 percent per year and that 1 percent annual mortality is due to hepatic AVMs in HHT [110]. Hepatic AVMs vary in size from small telangiectasia to large AVMs and constitute three separate types of aberrant intrahepatic communications. The most common are between hepatic arteries and hepatic veins. Other types of communications include hepatic-portal shunts (between hepatic arteries and portal veins) and portohepatic shunts (between portal and hepatic veins). Typical symptoms include reduced exercise tolerance, dyspnea, edema, ascites, and/or other consequences from high-output cardiac failure. These symptoms should prompt hepatic imaging to identify these lesions. Despite the high prevalence of hepatic AVMs and the significant symptoms they cause, clinicians often do not suspect that the driving pathology leading to these symptoms is sited in the liver rather than the heart. Thus, diagnosis of hepatic AVMs may be delayed. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 21/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Other challenges related to identifying hepatic AVMs include the following: Such patients usually present to cardiologists, who may focus on a potential cardiac cause of their symptoms. Portal hypertension and its consequences including encephalopathy and varices and symptoms from mesenteric or biliary ischaemia (resulting from blood flow steal) are more likely to result in an acute picture within gastroenterology and hepatology disciplines. (See "Portal hypertension in adults", section on 'Clinical manifestations'.) Symptoms may differ according to the nature of the vascular malformations, particularly whether the portal vein is involved, and whether there is a blood flow steal through arteriovenous (AV) shunts. It may be difficult to separate out the majority of patients who will never require specific treatment of their hepatic AVMs, from the significant minority for whom the consequences of hepatic AVMs will come to dominate the clinical picture and who will require high-level specialist support that needs to be delivered in a timely fashion to intervene at the optimal time [111]. Clinicians may not recognize the importance of correcting anemia, atrial fibrillation, and otherwise modest cardiac pathologies to improve the clinical picture. Longitudinal studies have demonstrated that symptoms of hepatic AVMs can be exacerbated in the presence of concurrent anemia and/or atrial fibrillation [110]. Data from two large series published in 2017 (3176 HHT patients, pulmonary artery hypertension in <2 percent) demonstrated that hepatic AVMs may be accompanied by a constellation of findings including pulmonary hypertension, anemia, atrial fibrillation, and symptoms [106,107]. Hepatic AVMs (and resultant high-output cardiac states) are responsible for the most common form of pulmonary hypertension in HHT [106,107]. These data were reviewed in a consensus statement from the European Association for the Study of the Liver (EASL) and an HHT workshop held in 2017 [111]. Updated guidance from the HHT International Guidelines Committee is awaited. For any HHT patient undergoing imaging of the liver, it is most important for clinicians to be aware of the possibility that hepatic AVMs may occur in individuals with HHT. We are aware of three cases in which hepatic AVMs were initially mistaken for cancer metastases (in one case resulting in a fatal outcome) and of two further cases where liver biopsies (performed without appreciating the presence of AVMs) resulted in catastrophic hemorrhage. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 22/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Initial management of hepatic AVMs International consensus is that all patients with HHT should be offered screening for hepatic AVMs; however, only symptomatic hepatic AVMs should be treated [112,113]. A 2016 practice guideline from the EASL and a 2011 observational study involving 154 patients with HHT who had vascular malformations in the liver concluded that in the small proportion (approximately 8 percent) who became symptomatic, medical therapy was beneficial in most [110,111]. For most of the 39 individuals who had a clinical event related to a hepatic AVM, treatment resulted in complete response or stable disease, although eight individuals died of disease complications over the 15-year period of observation. For those who do require treatment, therapy is individualized and should be performed by clinicians with expertise in this area. First-line treatments involve the following, as detailed in selected case series [111,113]: Treatment of high-output heart failure, in a similar way to treatment of heart failure in non- HHT patients, with emphasis on escalating diuretics and correcting anemia [110,111,114]. Iron deficiency anemia was the precipitant of high-output cardiac failure in seven of the eight cases in the largest prospective series [110]. (See "Causes and pathophysiology of high-output heart failure" and "Evaluation and management of anemia and iron deficiency in adults with heart failure".) Treatment of portal hypertension, in a similar way to treatment of portal hypertension in other circumstances. (See "Portal hypertension in adults", section on 'Treatment'.) Antibiotics in case of cholangitis. (See "Acute cholangitis: Clinical manifestations, diagnosis, and management".) The efficacy of these treatments are evaluated within 6 to 12 months, although earlier assessments will be required in individuals with rapid clinical deterioration [111,113]. For complicated liver AVMs that are refractory to first-line treatment, interventions directed at the hepatic arterial bed such as embolization, ligation, or banding of the hepatic artery are generally no longer advised for the majority of patients because of the high rate of complications (including potentially fatal hepatic necrosis) and up to a 20 percent acute mortality rate compared with transplantation [111]; the 10-year survival rate for transplantation is 82.5 percent [115]. Options for severe patients not responding to therapy include bevacizumab and liver transplantation. (See 'Role of bevacizumab for liver AVMs' below and 'Role of liver transplantation' below.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 23/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Role of bevacizumab for liver AVMs Bevacizumab has observational studies of efficacy and is a first-line choice in many HHT centers in the United States. However, earlier suggestions that this reversed the need for liver transplantation have not been supported by longer-term follow- up studies in those individuals. Bevacizumab is usually reserved for individuals with severe liver disease for which management is ineffective and in many countries where liver transplantation is not possible. It is proposed for older patients (over age 65) who will not meet transplantation criteria (and for patients younger than 65 years who are not medically fit for transplantation) as a "bridge to transplantation" if patients experience a response [113]. The efficacy of bevacizumab in the setting of severe hepatic AVMs was demonstrated in a series of individuals with HHT who had hepatic AVMs and increased cardiac output [38]. Bevacizumab (5 mg/kg intravenously once every 14 days for a total of six doses) was associated with an improvement in cardiac index in 20 of 24 evaluable patients (83 percent); this included cardiac output normalization in five individuals and improvement in 15 others. Additional benefits included resolution of pulmonary hypertension in five of eight (63 percent) and improvement in epistaxis. Case reports and observational studies have also described improvements (in some cases dramatic) in disease manifestations attributable to hepatic AVMs (and pancreatic AVMs) with bevacizumab [38,111,116-118]. Benefits from continued use have been published [119]. Notably, the reported follow-up for these patients has been relatively short compared with the decades-long follow-up post-liver transplantation discussed below (see 'Role of liver transplantation' below). Thrombotic complications of bevacizumab have been reported in individuals with HHT [120]. These and other safety concerns such as those observed in a study from the European Reference Network (ERN) on Rare Multisystemic Vascular Diseases (VASCERN) are discussed above. (See 'Bevacizumab and other systemic antiangiogenic therapies' above.) Role of liver transplantation Liver transplantation in countries where very good long-term survival of HHT patients is reported can be lifesaving for those who develop acute hepatic failure (eg, acute biliary necrosis syndrome), intractable heart failure, or portal hypertension [115,121- 123]. Available data suggest that liver transplantation should be proposed in a timely fashion, before pulmonary resistances become fixed, and taking into account that complicated liver AVMs in HHT represent a model for end-stage liver disease (MELD) exception for transplantation [111,113]. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation".) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 24/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate A 2006 series from the European Liver Transplant Registry reported outcomes in 40 individuals with HHT and severe liver disease who underwent liver transplantation [115]. Ten-year actuarial patient and graft survival rates were 82.5 percent. There were seven perioperative deaths, six due to bleeding and one due to heart failure, and one late death (at 11 years) due to chronic rejection. Pulmonary involvement through portopulmonary hypertension is considered a transplant priority and proposed as a MELD exception [124]. Right-heart catheterization to evaluate the severity of pulmonary hypertension prior to transplant is advised [111]. Cerebral lesions Lesions in the cerebral (or spinal) vasculature in individuals with HHT may include telangiectasia, AVMs, and aneurysms. These lesions result in varying degrees of hemorrhagic risk. They may also cause symptoms related to their size or location such as headache, focal neurologic deficit, or seizures; however, the majority of patients will have no complications from cerebral lesions. Significant effort has been invested in trying to identify the patients at higher risk of future complications in whom the known risks of neurologic intervention are more justifiable. Most patients will never have a specific complication from their cerebral AVMs, but for others, the consequences of cerebral AVMs will lead to life-changing or life-limiting consequences. For a small group of patients, symptoms may be used to indicate a higher likelihood of AVM presence, and an AVM that has already bled is usually treated. For highly symptomatic or ruptured cerebral AV shunts for which treatment is appropriate and feasible, therapeutic options include surgical excision, a number of endovascular techniques, or stereotactic radiotherapy. The risks associated with these interventions should not be underestimated [125]. The risk of rupture and details of therapy are discussed separately. (See "Brain arteriovenous malformations", section on 'Acute management issues'.) Management of cerebral lesions that have not bled is complex and should be performed by
be treated [112,113]. A 2016 practice guideline from the EASL and a 2011 observational study involving 154 patients with HHT who had vascular malformations in the liver concluded that in the small proportion (approximately 8 percent) who became symptomatic, medical therapy was beneficial in most [110,111]. For most of the 39 individuals who had a clinical event related to a hepatic AVM, treatment resulted in complete response or stable disease, although eight individuals died of disease complications over the 15-year period of observation. For those who do require treatment, therapy is individualized and should be performed by clinicians with expertise in this area. First-line treatments involve the following, as detailed in selected case series [111,113]: Treatment of high-output heart failure, in a similar way to treatment of heart failure in non- HHT patients, with emphasis on escalating diuretics and correcting anemia [110,111,114]. Iron deficiency anemia was the precipitant of high-output cardiac failure in seven of the eight cases in the largest prospective series [110]. (See "Causes and pathophysiology of high-output heart failure" and "Evaluation and management of anemia and iron deficiency in adults with heart failure".) Treatment of portal hypertension, in a similar way to treatment of portal hypertension in other circumstances. (See "Portal hypertension in adults", section on 'Treatment'.) Antibiotics in case of cholangitis. (See "Acute cholangitis: Clinical manifestations, diagnosis, and management".) The efficacy of these treatments are evaluated within 6 to 12 months, although earlier assessments will be required in individuals with rapid clinical deterioration [111,113]. For complicated liver AVMs that are refractory to first-line treatment, interventions directed at the hepatic arterial bed such as embolization, ligation, or banding of the hepatic artery are generally no longer advised for the majority of patients because of the high rate of complications (including potentially fatal hepatic necrosis) and up to a 20 percent acute mortality rate compared with transplantation [111]; the 10-year survival rate for transplantation is 82.5 percent [115]. Options for severe patients not responding to therapy include bevacizumab and liver transplantation. (See 'Role of bevacizumab for liver AVMs' below and 'Role of liver transplantation' below.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 23/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Role of bevacizumab for liver AVMs Bevacizumab has observational studies of efficacy and is a first-line choice in many HHT centers in the United States. However, earlier suggestions that this reversed the need for liver transplantation have not been supported by longer-term follow- up studies in those individuals. Bevacizumab is usually reserved for individuals with severe liver disease for which management is ineffective and in many countries where liver transplantation is not possible. It is proposed for older patients (over age 65) who will not meet transplantation criteria (and for patients younger than 65 years who are not medically fit for transplantation) as a "bridge to transplantation" if patients experience a response [113]. The efficacy of bevacizumab in the setting of severe hepatic AVMs was demonstrated in a series of individuals with HHT who had hepatic AVMs and increased cardiac output [38]. Bevacizumab (5 mg/kg intravenously once every 14 days for a total of six doses) was associated with an improvement in cardiac index in 20 of 24 evaluable patients (83 percent); this included cardiac output normalization in five individuals and improvement in 15 others. Additional benefits included resolution of pulmonary hypertension in five of eight (63 percent) and improvement in epistaxis. Case reports and observational studies have also described improvements (in some cases dramatic) in disease manifestations attributable to hepatic AVMs (and pancreatic AVMs) with bevacizumab [38,111,116-118]. Benefits from continued use have been published [119]. Notably, the reported follow-up for these patients has been relatively short compared with the decades-long follow-up post-liver transplantation discussed below (see 'Role of liver transplantation' below). Thrombotic complications of bevacizumab have been reported in individuals with HHT [120]. These and other safety concerns such as those observed in a study from the European Reference Network (ERN) on Rare Multisystemic Vascular Diseases (VASCERN) are discussed above. (See 'Bevacizumab and other systemic antiangiogenic therapies' above.) Role of liver transplantation Liver transplantation in countries where very good long-term survival of HHT patients is reported can be lifesaving for those who develop acute hepatic failure (eg, acute biliary necrosis syndrome), intractable heart failure, or portal hypertension [115,121- 123]. Available data suggest that liver transplantation should be proposed in a timely fashion, before pulmonary resistances become fixed, and taking into account that complicated liver AVMs in HHT represent a model for end-stage liver disease (MELD) exception for transplantation [111,113]. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation".) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 24/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate A 2006 series from the European Liver Transplant Registry reported outcomes in 40 individuals with HHT and severe liver disease who underwent liver transplantation [115]. Ten-year actuarial patient and graft survival rates were 82.5 percent. There were seven perioperative deaths, six due to bleeding and one due to heart failure, and one late death (at 11 years) due to chronic rejection. Pulmonary involvement through portopulmonary hypertension is considered a transplant priority and proposed as a MELD exception [124]. Right-heart catheterization to evaluate the severity of pulmonary hypertension prior to transplant is advised [111]. Cerebral lesions Lesions in the cerebral (or spinal) vasculature in individuals with HHT may include telangiectasia, AVMs, and aneurysms. These lesions result in varying degrees of hemorrhagic risk. They may also cause symptoms related to their size or location such as headache, focal neurologic deficit, or seizures; however, the majority of patients will have no complications from cerebral lesions. Significant effort has been invested in trying to identify the patients at higher risk of future complications in whom the known risks of neurologic intervention are more justifiable. Most patients will never have a specific complication from their cerebral AVMs, but for others, the consequences of cerebral AVMs will lead to life-changing or life-limiting consequences. For a small group of patients, symptoms may be used to indicate a higher likelihood of AVM presence, and an AVM that has already bled is usually treated. For highly symptomatic or ruptured cerebral AV shunts for which treatment is appropriate and feasible, therapeutic options include surgical excision, a number of endovascular techniques, or stereotactic radiotherapy. The risks associated with these interventions should not be underestimated [125]. The risk of rupture and details of therapy are discussed separately. (See "Brain arteriovenous malformations", section on 'Acute management issues'.) Management of cerebral lesions that have not bled is complex and should be performed by clinicians with expertise in this area who are aware of the results of the ARUBA (A Randomized trial of Unruptured Brain AVM therapy) trial [126]. The interpretation of this trial and its applicability to the HHT population has remained highly controversial, and in our experience, it is applied differently in Europe and the United States. Across the ERN, cerebral AVMs that have not bled are usually not treated [127]. A 2020 position statement on cerebral screening in HHT published by VASCERN suggested that data do not support routine intervention for unruptured AVMs, acknowledging the controversies that may arise and individual patients may have different preferences [4]. Some clinicians may weigh the risks and benefits differently. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 25/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate The ARUBA trial randomly assigned individuals with a cerebral AVM (not knowingly HHT related) to receive or not to receive an interventional procedure (surgery, embolization, stereotactic radiotherapy) in addition to standard medical therapy [126]. The trial was halted early after accrual of 223 patients when the data and safety monitoring board noted a threefold increased risk of adverse outcomes in the intervention group. At a median follow-up of 33 months, the primary composite endpoint of death or symptomatic stroke was seen in 35 of 114 intervention patients (31 percent) versus 11 of 109 controls (10 percent). Individuals in the intervention group also had worse functional outcomes and a higher risk of hemorrhagic stroke. In a follow-up report that described an additional period of observation (mean follow-up of approximately 50 months total), there were 41 deaths or strokes in the intervention group and 15 deaths or strokes in the medical management group (incidence rate per 100 person-years, 12.3 versus 3.4, respectively) [128]. However, follow-up data were only available for half of the original participants. There is no evidence that the risks associated with cerebral AVMs in HHT are higher or lower than the risks in non-HHT cerebral AVMs [129]. There are other central nervous system vascular malformations that pose a very low risk of hemorrhage and usually no intervention is recommended. (See "Vascular malformations of the central nervous system", section on 'Capillary telangiectasias'.) For the HHT patients with cerebral vascular malformations who do not fall into either of these groups, assessments of the risks and benefits of intervention are based on clinical judgment, which can be highly specific to the individual. SPECIAL POPULATIONS Children Symptomatic children require specialist evaluation and treatment, as discussed in the sections above. It is important that neurologic symptoms are promptly investigated and that parents with HHT are educated about the potential significance of these symptoms or clinical signs of cardiac failure/hydrovenous dysfunction in their children [130]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Sites of large arteriovenous malformations'.) Issues related to screening of asymptomatic children are discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Children'.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 26/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Pregnancy Case reports have highlighted major complications of pregnancy in women with HHT. However, our series of 484 pregnancies in 199 women indicated that the vast majority are able to have a normal pregnancy. This is an important observation, since women with HHT are sometimes led to believe that pregnancy is too dangerous to undertake. That said, a small proportion of women did experience life-threatening complications, even in those who previously had only minor symptoms of HHT. In this series, the following complications were noted [131]: Pulmonary arteriovenous malformation (PAVM) hemorrhage 1.4 percent (95% CI 0.2-2.5) Stroke 1.2 percent (95% CI 0.3-2.2) Maternal deaths 1.0 percent (95% CI 0.1-1.9) Myocardial infarction 0.2 percent (one case) General recommendations for the management of pregnant women with HHT include: All pregnancies in women with HHT should be considered "high risk," and local obstetric services should be alerted to the need for greater than normal vigilance and pre-planning. All pregnant women with HHT should receive written advice on pregnancy management; this is one of European Reference Network (ERN) on Rare Multisystemic Vascular Diseases (VASCERN) HHT's five Outcome Measures defining good practice [3]. There is no evidence of hemorrhage from spinal AVMs in women with HHT who receive epidural anesthesia. Nevertheless, since spinal AVMs affect approximately 1 to 2 percent of HHT patients, some anesthetists will not perform epidural analgesia in HHT mothers unless magnetic resonance imaging (MRI) scans have excluded this possibility. PAVMs will enlarge during pregnancy, and fatal hemorrhage from maternal PAVMs has been described [131,132]. As a result, women with HHT should be screened for PAVMs and treated maximally before pregnancy, although treatment may be safely undertaken in late pregnancy if required [133]. Hemoptysis of any degree or sudden severe dyspnea should be considered a medical emergency, prompting urgent hospitalization and institution of appropriate treatment. In the series described above, hemorrhages occurred in both treated and untreated women, including four women who had previous PAVM embolization at four different institutions [131]. Obstetricians advise that a prolonged second stage of labor should be avoided in women in whom cerebral AVMs have not been excluded. In some countries, it is assumed that cerebral AVMs may be present, and this advice is given to all women with HHT. In others, or https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 27/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate if there would be specific separate recommendations were a cerebral AVM to be found, cerebral magnetic resonance imaging (MRI) is performed in pregnancy. In keeping with the general advice for patients with PAVMs and/or HHT, antibiotic prophylaxis should be provided during delivery [73,105,134]. Anecdotal data suggest that epistaxis may get worse and skin telangiectasia become more prominent during pregnancy; there are no firm data regarding effects on hepatic or cerebral AVMs. The patient should also be made aware that any offspring will have a 50 percent risk of inheriting HHT. Prenatal genetic testing is possible in families where the pathogenic variant has been identified in the family but is not necessary for proper pregnancy and delivery management [127]. Decisions about prenatal genetic testing are the choice of the parents, but discussion of all related issues is appropriate. The usual antenatal scans will be offered, and sonographers aware of the presence of HHT in the family will detect most major AVMs. PROGNOSIS When managed by treatment of nosebleeds, iron deficiency anemia, and screening/treatment for pulmonary arteriovenous malformations (PAVMs), life expectancy in individuals with HHT is normal on a population basis [135]. However, in settings in which optimal management is not pursued on a nationwide basis, life expectancy is modestly reduced. For example, in a 2015 case-control series from a primary care database, 675 individuals with HHT demonstrated a three-year reduction in survival (median age of death of 77 years, compared with 80 years in 6696 age- and sex-matched controls) [136]. An important limitation was that the rates were overall survival rather than disease-specific survival. Causes of death could not be confirmed, but the most frequent serious complications included stroke and heart disease. HHT can be life-limiting on an individual basis. Patients can die in childhood and young-adult life from HHT complications such as cerebral hemorrhage [137,138], pulmonary hemorrhage in pregnancy [131], and cerebral abscess from PAVMs [86,139]. Causes of death in older patients include sepsis and cardiac failure in studies from 2006 and 2018 that surveyed HHT patients asking for causes of death in their deceased relatives [140,141]. A reduced survival of 6.8 years in the affected parent compared with the non-affected parent was identified in the 2006 study, https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 28/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate based on median age at death of 63.2 years (HHT parent) versus 70.0 years (non-HHT parent) [141]. Where HHT does contribute to death, the mean life expectancy reduction has been calculated at 19 years (based on 55 of 73 deceased patients selected because HHT was considered implicated in the cause of death) [140]. We interpret these data for the patient, stating that while HHT can result in early deaths (that medical care strives to reduce), overall life expectancy is surprisingly good in HHT and is increasing with improved medical care. The reason for the good survival figures is that deaths due to HHT seem to be balanced by protection conferred by HHT from common causes of death in the general population such as certain cancers and myocardial infarction [135,142-145]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".) SUMMARY AND RECOMMENDATIONS Epistaxis Epistaxis affects over 95 percent of individuals with hereditary hemorrhagic telangiectasia (HHT) and is the usual cause of iron deficiency anemia. Topical, systemic, and surgical treatments are available. We generally try to avoid toxicity of systemic therapies by using local preventive therapies (nasal humidification, ointments) and dietary changes; however, management is individualized. Expert otorhinological review and management is important and often the only additional treatment required. (See 'Overview' above and 'Epistaxis' above.) Rarely, patients may require systemic therapies such as tamoxifen, tranexamic acid, or bevacizumab if epistaxis is recurrent or localized interventions are insufficient. For these individuals, we continue to suggest tamoxifen (Grade 2C). Other options are reasonable and may be preferred due to their differing side effect profiles or patient preference. Systemic agents are generally avoided in individuals with prior venous thromboembolism (VTE) and should be used with caution if there are additional risk factors for VTE or arterial thromboembolism. (See 'Bevacizumab and other systemic antiangiogenic therapies' above and 'Tamoxifen and other non-guideline approaches' above.) Gastrointestinal lesions Gastrointestinal lesions are present in up to 20 percent of patients but rarely require treatment. If bleeding occurs, local therapies may be https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 29/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate administered endoscopically, but gastrointestinal bleeding requiring transfusions or iron administration is often due to multiple lesions and is treated with systemic agents rather than frequent endoscopic interventions. (See 'Gastrointestinal lesions' above and 'Bevacizumab and other systemic antiangiogenic therapies' above.) Iron deficiency Iron deficiency and iron deficiency anemia are common, usually from epistaxis. Most individuals are treated with oral iron, but parenteral iron and/or blood transfusions may be required. (See 'Iron deficiency and iron deficiency anemia' above.) Pulmonary AVMs Pulmonary arteriovenous malformations (PAVMs) are especially concerning because of potentially life-threatening cerebral complications including ischemic stroke caused by a paradoxical embolus to the brain or brain abscess caused by a paradoxical septic embolus or hypoxia. Bleeding leading to hemoptysis or hemothorax is much less common but can occur. (See 'Pulmonary AVMs' above.) We screen all adults with HHT for PAVMs. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'PAVM screening'.) For PAVMs of a size amenable to embolization, we use embolotherapy, unless there are complications such as significant pulmonary hypertension that require more individualized therapy. (See 'Principles of PAVM management' above and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Patients suitable for embolotherapy'.) Antibiotic prophylaxis is required for all PAVM patients prior to dental and surgical procedures. PAVM management is discussed above and separately. (See 'Principles of PAVM management' above and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".) Hepatic AVMs Hepatic AVMs are usually asymptomatic but can require intense, informed specialist care. In our experience, one major risk is of misdiagnoses as metastases. Symptoms attributable to high-output heart failure (often indolent) are seen in <10 percent of patients; acute presentations with portal hypertension and/or biliary disease are less common. For symptomatic liver involvement, initial treatment includes optimizing cardiac status, iron stores, and emergency management as needed. If intense medical management fails, liver transplantation is the treatment of choice. Bevacizumab may also be helpful for nontransplant candidates. (See 'Hepatic AVMs' above.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 30/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Brain AVMs Management of cerebral lesions is complex. Symptomatic lesions and lesions that have bled are managed by specialized units with neurology expertise. For nonsymptomatic patients, management is more challenging since the ARUBA trial indicated that intervention results in worse outcomes than expectant management in unselected cases. Expertise in this area is required for optimal management. (See 'Cerebral lesions' above and "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Cerebral AVM screening'.) Children and pregnancy (See 'Special populations' above.) Prognosis Prognosis is variable. Most patients can expect very good life expectancy, and life expectancy continues to improve. (See 'Prognosis' above.) Diagnosis and routine screening (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)" and "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs".) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Vijeya Ganesan, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Faughnan ME, Mager JJ, Hetts SW, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. 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Cancer and hereditary haemorrhagic telangiectasia. J Cancer Res Clin Oncol 2017; 143:369. Topic 109902 Version 31.0 https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 42/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate GRAPHICS Overview of the incidence, presenting findings, evaluation, and management of the major clinical features of hereditary hemorrhagic telangiectasia (HHT) Presentation patterns Site Incidence Evaluation Treatment Nasal telangiectasia >90% Nose bleeds are usually the first History, inspection Routine therapy includes nasal lubrication and manifestation of treatment of iron deficiency when needed. HHT, frequently commencing in Laser treatment is generally preferred over childhood. cauterization. Surgery in expert hands offers good results for selected patients. Medical (systemic) treatments are an alternative and may be highly beneficial, but carry risks of prothrombotic side effects. Emergency treatments such as packing may be required. Mucocutaneous telangiectasia 50 to 80% Increase in size and number Inspection (oral, mucosa, Generally not indicated, but laser therapy can be with age. Main concerns are conjunctivae, face, trunk, used. cosmetic. May extremities, nail hemorrhage. beds) Gastrointestinal 11 to 40% Onset generally Flexible Iron supplementation telangiectasia over 30 years: Iron deficiency endoscopy, endoscopy and transfusion are the mainstays of treatment. anemia, angiogram, Medical (systemic) treatments are available occasionally acute capsule endoscopy and may be highly beneficial, but they carry gastrointestinal hemorrhage. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 43/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate risks of prothrombotic side effects. Pulmonary AVMs >50% Usually silent. Cyanosis, Chest radiography, Therapeutic embolization. clubbing, bruit, dyspnea, blood gas measurement, Antibiotic prophylaxis for dental and surgical paradoxical helical CT, procedures. embolism, cerebral angiography, chest Surgical resection may be indicated in highly abscess. echocardiography selected cases. Cerebral AVMs 10 to 15% Usually silent. Headache, CT, MRI, Doppler sonography, Most do not require treatment. epilepsy, angiography Therapeutic embolization, ischemia, intracerebral neurovascular surgery, or stereotactic radiosurgery hemorrhage. in highly selected cases. Hepatic AVMs 30 to 70% Usually silent. Hepatic artery- Doppler sonography, CT, Most do not require treatment. hepatic vein AVMs: MRI For the small proportion of patients who develop Hyperdynamic symptoms, standard hepatic medical care is circulation. Portasystemic often sufficient to resolve symptoms. shunts: Ascites and Liver transplantation in selected cases. encephalopathy. Embolization is a higher- risk procedure; some centers do not perform embolization unless the patient is accepted into a liver transplantation program. Less-common clinical manifestations include AVMs in other sites, high cardiac output states, and pulmonary hypertension. Refer to UpToDate for additional details of our approach. AVM: arteriovenous malformation; CT: computed tomography; MRI: magnetic resonance imaging. Adapted and updated from the original table in: Shovlin CL, Letarte M. Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms. Thorax 1999; https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 44/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate 54:714. Graphic 74593 Version 3.0 https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 45/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Arteriovenous malformation in the gastrointestinal tract Endoscopic views of arteriovenous malformations being treated with the argon plasma coagulator (APC). The top panels illustrate the appearance before and after APC coagulation. The bottom panels demonstrate the ability of APC to treat lesions tangentially. It is important to see the black portion of the APC cathether prior to initiating coagulation to prevent damage to the endoscope. Courtesy of Jonathan Cohen, MD. Graphic 79901 Version 2.0 https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 46/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Contributor Disclosures Claire L Shovlin, PhD, FRCP Patent Holder: Imperial College London [The use of trametinib for treatment of HHT bleeding is the subject of a patent application by my employer]. Grant/Research/Clinical Trial Support: National Institute for Health Research [Imaging angiogenesis by PET CT - A pilot study in patients with arteriovenous malformations and hereditary haemorrhagic telangiectasia]. Consultant/Advisory Boards: European Reference Network for Rare Multisystemic Vascular Diseases [HHT]; Genomics England Respiratory GeCIP [Genomic medicine]; International Guidelines Committee [Cure HHT]; NHS Genomic Medicine Service Alliance [Genomic medicine]; NIH ClinGen Expert Panel for hereditary haemorrhagic telangiectasia GRAMB [HHT]. All of the relevant financial relationships listed have been mitigated. Lawrence LK Leung, MD No relevant financial relationship(s) with ineligible companies to disclose. Jennifer S Tirnauer, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 47/47
7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs : Claire L Shovlin, PhD, FRCP : Lawrence LK Leung, MD : Jennifer S Tirnauer, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 17, 2023. INTRODUCTION Hereditary hemorrhagic telangiectasia (HHT; also called Osler-Weber-Rendu syndrome) is a vascular disorder inherited as an autosomal dominant trait, with a variety of clinical findings and range of severity, even within relatives who have the same HHT pathogenic gene variant. Arteriovenous malformations (AVMs) frequently affect the pulmonary, hepatic, and/or cerebral circulations, demanding knowledge of the risks and benefits of screening for these complications. Additional common problems include mucocutaneous telangiectasia, epistaxis, gastrointestinal bleeding, and iron deficiency anemia. Despite these disease manifestations, some patients may present with pulmonary AVMs only and have a paucity or absence of clinical signs and symptoms [1]. (See 'PAVM screening' below.) This topic review discusses an approach to screening of individuals with HHT for disease complications for which they are asymptomatic, as well as genetic testing and counseling of at- risk family members. Any symptoms related to HHT should be investigated, as discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) The pathophysiology, epidemiology, and diagnosis of HHT are also discussed separately. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler- https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 1/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Weber-Rendu syndrome)".) OVERVIEW Definition of terms Any vascular lesions can be observed in individuals with HHT. Vascular abnormalities seen at a higher prevalence than in the general population include: Arteriovenous malformation An arteriovenous malformation (AVM) is an abnormal vascular structure that provides a direct communication between one or more arteries and one or more veins. These may be sacs (eg, for pulmonary AVMs [PAVMs]), small collections of intervening vessels (nidal AVMs), or direct high-flow connections between the arterial and venous side (arteriovenous fistulas [AVFs]). AVMs result in arteriovenous shunting. Shunting may also be observed secondary to dilatation of existing normal capillaries (eg, intrapulmonary shunting in the hepatopulmonary syndrome and as part of normal physiologic responses). Telangiectasia A telangiectasia is a small, dilated blood vessel (arteriole, venule, or capillary). The term is descriptive and refers to telangiectasia of many anatomic types and etiologies. HHT telangiectasia usually contain small arteriovenous communications and are commonly located near the surface of the skin or mucous membranes. These lesions can also be seen in other disorders besides HHT, or in otherwise healthy individuals, as part of a syndrome or in isolation. As discussed in detail below, additional vascular lesions are increasingly recognized, some seen more commonly in patients with HHT and others, such as aneurysms, present at similar or only marginally increased rates to the general population. General principles of management Major management issues in individuals with HHT span the full range of clinical manifestations ( table 1) and include the following [2-13]: Patient education Educational materials for patients with HHT and the location of specialized centers for diagnostic testing and management are available from the websites of Cure HHT, VASCERN (the European Reference Network on Rare Multisystemic Vascular Diseases) and country-specific patient groups. VASCERN, formed in 2016, has created videos to provide a brief overview of HHT ( https://www.youtube.com/watch? v=0YjWf7Agn40) and a list of " Do's and Don'ts" that can be shared with patients [14]. Clinician education regarding the following: https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 2/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Possible sites of AVMs, typical symptoms attributable to these lesions, indications for treatment, and risks and benefits of local versus systemic therapies. Importance of epistaxis as the main cause of anemia, the need for intervention for certain asymptomatic individuals, and the possibility that HHT vascular lesions may radiologically-mimic metastases to liver or lung. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Therapy for specific vascular lesions and iron deficiency'.) Role of screening and treatment for asymptomatic AVMs in certain circulations. It is especially important to identify PAVMs to prevent paradoxical thromboemboli, strokes, and brain abscesses. (See 'Overview of screening strategy' below.) Screening for iron deficiency and supplementing iron as needed, ideally before the patient becomes symptomatic from anemia. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Iron deficiency and iron deficiency anemia'.) Awareness that patients who require antiplatelet and/or anticoagulation (eg, for treatment of thromboembolic disease) should not be denied this simply due to the diagnosis of HHT. (See 'Individuals who require anticoagulation (VTE and AF)' below.) Awareness that some individuals with genetically confirmed HHT have a paucity of clinical signs, and that absence of symptoms does not provide reassurance that someone does not have HHT [1]. Molecular (genetic) testing is required for minimally symptomatic relatives of an affected individuals and patients with isolated pulmonary AVMs. Many management recommendations are based on expert opinion and observational studies. Although randomized controlled trials are increasingly conducted, they have not delivered statistical support for several proposed treatments; results are awaited from larger studies and studies of longer duration that are underway. In the meantime, uniformity of expert opinion varies depending on the clinical situation and prevailing health care practices. Updated guidance from the second International Consensus Guidelines on management of HHT was published in 2020 [13]. This followed the first International Consensus Guidelines, which were developed in 2006, and published in print in 2011 [3]. The 2020 Guidelines focused on six topics and provided greater nuance than the first Guidelines in separating the severity of indications for elements of care and presenting guidance in a step- wise fashion, according to the severity of the disease [13]. The six topics addressed were: https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 3/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Epistaxis Gastrointestinal bleeding Anemia and anticoagulation Hepatic vascular malformations Pediatrics Pregnancy Several other recommendations from the first International Guideline were not reassessed and remain in place [3]. Details from these Guidelines, including new recommendations and affirmation of existing recommendations, are discussed below. (See 'Overview of screening strategy' below.) As noted above, consensus statements on good practice in HHT have also been developed by the European Reference Network (ERN) on Rare Multisystemic Vascular Diseases ( VASCERN). This group has identified core Outcome Measures suitable to be implemented by all clinicians evaluating a patient with HHT: pulmonary AVM (PAVM) screening, antibiotic prophylaxis prior to dental and surgical procedures for those with PAVMs, epistaxis advice, assessment of iron deficiency, and advice on pregnancy [15,16]. Subsequent manuscripts include evidence from HHT patients across the ERN [17,18], address nuances of cerebral screening [19], and are summarized in a single Frameworks manuscript targeting general and speciality care [20]. Overview of screening strategy Screening to diagnose AVMs in individuals at risk for HHT, or those with HHT but without symptoms relevant to the AVMs, is distinct from investigation of a symptomatic patient. Some countries have historically placed particular emphasis that screening within clinical practice should be clearly linked to a proven patient-recognizable benefit [21,22]. In some cases, such as identification of PAVMs, results of screening may lead to risk-reducing interventions. In other cases where risk cannot be altered, the stated or implied purpose of screening can be that it allows information considered valuable about the risk to be provided to the patient and/or family [21,22]. It is good practice, prior to screening patients, to counsel them on how the screening could impact their health and management. The challenge for all screening programs is to establish whether, across the selected population, the expected benefits are likely to outweigh the harms and burdens of screening. Clinicians should be cognizant of the significant radiation exposure that can occur during a lifetime of imaging studies [23] and should minimize these risks by restricting imaging studies to https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 4/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate individuals for which the results will affect evidence-based management [5]. (See "Radiation- related risks of imaging".) New recommendations for screening in the 2020 International Consensus Guidelines included a clearer recommendation for hepatic AVM screening for all adults and discussion of preconception and prenatal diagnostic options, including preimplantation genetic diagnosis [13]. Additional screening recommendations for children and during pregnancy were similar to the first International Consensus Guidelines, published in 2011, including cerebral and pulmonary screening and genetic testing [3]. There was no discussion of these topics for other adults, although cerebral AVMs have been addressed in a 2020 Position Statement from VASCERN on cerebral vascular malformations [19,20]. The British Thoracic Society provided a 2017 Position Statement on pulmonary AVMs [24]. Recommendations for evaluation of iron deficiency, anemia, and symptomatic lesions, as well as recommendations for therapy, are presented separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) In general, protocols for screening asymptomatic individuals depend upon the importance attached to the detection of asymptomatic lesions in particular viscera, the diagnostic and therapeutic expertise available locally, and the degree to which establishment of the extent of HHT is important in the particular health care system. Assuming the individual is in agreement, screening of adults with HHT typically consists of the following: Clinical evaluation History and physical examination may identify clinically significant features that would modify subsequent management [3]. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) Anemia and iron deficiency All individuals are evaluated for anemia and iron deficiency, with treatment if identified. This is an Outcome Measure to define good clinical HHT practice from VASCERN [16]. It was also recommended in the second International HHT Guidelines in 2020 [13]. (See 'Iron status' below.) Pulmonary AVMs (PAVMs) PAVMs are always considered worthy of treatment, and screening should be offered for all adult patients over 16 years with known or suspected HHT [13]. All individuals with PAVMs should receive advice on antibiotic prophylaxis and many proceed to interventions to occlude the AVMs, which have been shown to reduce PAVM complications [25-27]. This is an Outcome Measure to define good clinical HHT practice from VASCERN [16]. It was also addressed in a British Thoracic Society Clinical Statement in 2017 and recommended in the 2006 International HHT Guideline, published in 2011 [3,24]. (See 'PAVM screening' below.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 5/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Cerebral AVMs There is widespread agreement that any HHT patient with neurologic symptoms potentially attributable to a cerebral AVM should be investigated (see "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Cerebral lesions'). However there has been significant controversy and ongoing debate regarding the optimal management of asymptomatic cerebral vascular malformations and the role of cerebral screening in asymptomatic individuals with HHT. The first International Guidelines recommended brain AVM screening in adults, with lower agreement than most of the other recommendations; this recommendation was not reassessed and remains in place [3,13]. Important considerations were addressed in a 2020 Neurovascular-led Position Statement from VASCERN and are discussed in more detail below [19,20]. Hepatic AVMs There is consensus that any HHT patient with symptoms potentially attributable to hepatic AVMs should be investigated, and in the 2020 International Guidelines, this was extended to all adults [13]. Asymptomatic, incidentally discovered hepatic AVMs are not treated, but the value of early detection to guide management in symptomatic patients has been increasingly recognized. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Hepatic AVMs'.) Spinal AVMs Screening has performed in pregnancy in countries where epidurals may be withheld due to a perceived risk of spinal AVMs and often for patients undergoing surgery when epidural analgesia may be required [28]. The 2020 International HHT Guidelines recommended against withholding an epidural because of a diagnosis of HHT, and stated that screening for spinal vascular malformations is not required [13]. Additional investigations are performed based upon patient symptoms, results of the initial assessment, and sometimes specific family issues [3]. Screening in children is discussed below. (See 'Children' below.) Individuals with SMAD4 HHT Individuals with SMAD4-related HHT require more extensive surveillance due to the risk of juvenile polyposis and aortopathy [29,30]. A discussion of SMAD4- specific issues related to polyposis and aortopathy screening is presented separately. (See "Juvenile polyposis syndrome", section on 'Management'.) Other management does not differ from that for individuals with ENG or ACVRL1 HHT. Other elements of genomic variability A 2022 study highlighted that the severity of hemorrhage is higher in HHT patients with rare, high-impact deoxyribonucleic acid (DNA) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 6/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate variants in genes associated with bleeding diatheses [31]. HHT patients with concurrent changes in T-helper lymphocytes may be more at risk of infectious complications [32]. These associations may lead to additional investigation of patients with more severe phenotypes, but there has been no recommendation to screen all individuals with HHT for such changes. IRON STATUS Assessment of iron stores and optimization of iron status is crucial in HHT. As noted separately, the major cause of iron deficiency is bleeding, including bleeding from epistaxis and gastrointestinal arteriovenous malformations (AVMs), with insufficient iron supplementation for the degree of bleeding. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Iron deficiency'.) A survey of 50 individuals with HHT emphasized that epistaxis is usually sufficiently severe to account for the iron deficiency [33]. The approximate blood loss from epistaxis was in the order of 277 mL per month resulting in hemorrhage-adjusted iron requirements (HAIR) that could not be met from dietary sources alone in 80 percent of the study participants. Forty-three patients (86 percent) met their recommended dietary allowance of iron, but only 10 (20 percent) met their HAIR. Regular complete blood counts (CBCs) are recommended [3]. Review of other red blood cell (RBC) indices such as the mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC) are also important [34]. This is particularly true for patients who have hypoxemia due to pulmonary arteriovenous malformations (PAVMs), when a "normal" hemoglobin may be inappropriately low for the expected degree of polycythemia [34,35]. Regular assessment of iron status is recommended regardless of the hemoglobin level, to detect iron deficiency that is likely to progress to anemia if not treated [13,16]. We routinely measure serum iron and transferrin saturation index in addition to ferritin. While a low ferritin confirms the presence of iron deficiency, a normal or high ferritin does not exclude iron deficiency since it is an acute phase protein and can be elevated despite iron deficiency being present [36]. More information regarding the use of iron studies to assess iron status and thresholds for determining iron deficiency are presented separately. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Stages of iron deficiency' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.) Iron deficiency can lead to symptoms related to the deficiency and/or to anemia (eg, fatigue, lethargy, dyspnea); it is also associated with an increased risk of other complications of HHT https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 7/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate including venous thromboembolism (VTE), high-output cardiac failure and/or cardiac arrhythmias, and ischemic stroke [35,37-40]. Iron replacement and supplementation was also addressed in the 2020 Guideline [13]. This subject is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Iron deficiency and iron deficiency anemia' and "Treatment of iron deficiency anemia in adults".) PAVM SCREENING Adults with HHT should be screened for pulmonary arteriovenous malformations (PAVMs) because of the high incidence of unsuspected PAVMs and the high rates of complications in otherwise asymptomatic adults [41,42] and evidence that treatment reduces stroke and brain abscess risks in adults [25]. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Principles of PAVM management' and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Embolotherapy'.) Initial PAVM screening Adults (non-pregnant) One algorithm for PAVM screening is provided by the British Thoracic Society (BTS) following modification at public consultation [24]. The 2020 second International Consensus Guideline did not provide additional discussion of PAVM screening in non-pregnant adults [3,13]. Key points emphasized by the BTS include the following [24]: All adults over the age of 16 years with known or suspected HHT should be offered screening for PAVMs (this is also an Outcome Measure from the European Reference Network [ERN] for Rare Vascular Diseases [VASCERN] and a recommendation from the 2006 International HHT Guideline, which was published in 2011) [3,16]. Although trans-thoracic contrast echocardiography (TTCE; bubble echocardiography) is commonly recommended by international groups, the BTS Clinical Statement Group considered it was difficult to recommend contrast echocardiography as the preferred first-line screen, as a number of British Respiratory Medicine units noted that inexpert operators may miss clinically significant shunts. Thus, unless there is very strong local expertise in contrast echocardiography, the preference was for the definitive study to be by computed tomography (CT). However, the decision regarding the appropriate https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 8/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate screening approach is approached on a case-by-case basis, mindful of the prevailing expertise in detection of intrapulmonary shunts by contrast echocardiography. A positive CT scan is diagnostic for PAVMs, whereas contrast echocardiography is frequently positive for reasons unrelated to PAVMs (such as functional shunting in response to exercise or hypoxemia) and notably is positive in at least 8 percent of the general population at rest [3,43-45]. A normal chest radiograph does not exclude clinically significant PAVMs, even if accompanied by normal oxygen saturations and no clinical symptoms [3,16,24]. PAVMs are commonly seen "below the diaphragm" on posterior-anterior chest radiographs, due to their lower lobe predilection; their enlarged feeder arteries and draining veins may also be obscured. Either a negative thoracic CT scan, with or without contrast, or negative contrast echocardiography (if performed at a center with expertise in this type of study and no evidence of hypoxemia) excludes clinically significant PAVMs [3,16,24]. Radiation exposure from the recommended protocol screening is high, and a key component of the BTS statement was that CT scanning should not be repeated based on protocol alone, as this increases radiation exposure [3,24,46]. However, there may be an indication to perform a repeat CT scan, such as post-pregnancy (a time of PAVM growth), or based on other clinical concerns. It is considered particularly important that women with HHT undergo screening before becoming pregnant, since PAVMs can bleed in later pregnancy, leading to life-threatening hemoptysis or hemothorax [28,47-49]. In a series of 484 pregnancies, this occurred in 1 percent (95% CI 0.1-1.9 percent) [28]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pulmonary AVMs' and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Pregnancy'.) Pregnant women The 2020 HHT Guideline recommends screening of women for PAVMs during pregnancy if they have not been recently screened before becoming pregnant [13]. However, this is not our practice unless the tests are performed as investigations of symptoms or other abnormal findings, and in the United Kingdom, pregnant women are managed assuming PAVMs are present [28]. Children The 2020 International Guideline recommends screening of asymptomatic children for pulmonary AVMs, typically at five-year intervals, using various modalities https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 9/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate including CT, TTCE, and oximetry [13]. This is not the practice across many ERN HHT centers, based on clinical experience and the absence of any complications from PAVMs in asymptomatic children within extensive European cohorts and subsequent re-review of the pediatric data. A study cohort that followed 436 children from HHT families screened consecutively for HHT over a period of 18 years found that postponing transthoracic contrast echocardiography and subsequent chest CT scanning (to detect any smaller PAVMs) until adulthood did not appear to be associated with major risk [50]. Within this study, 175 of 436 children (40 percent) had a diagnosis of HHT. PAVMs were detected in 39 of these 175 (22 percent), and 33 of the 39 required treatment by embolotherapy. In the expert European HHT centers, PAVM investigations of younger children are generally performed only if there is a symptomatic concern after evaluation by a pediatrician. Reperfusion rates are higher in treated children who may then require further treatment as an adult; pediatric studies have also raised the possibility of additional complications [51]. Management of PAVMs is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Principles of PAVM management' and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".) Repeat screens The risk of subsequent PAVM development in an individual who previously screened negative by thoracic CT or contrast echocardiography in adult life is unclear, although accumulating evidence suggests that the risk is very small [24]. Key points from the BTS Clinical Statement include the following: For asymptomatic individuals with a negative initial screen during childhood, a repeat evaluation is needed in adulthood. For individuals with a negative screen during adulthood, we suggest review every five years (or if new symptoms develop). We initially evaluate using a history of the individual's symptoms and imaging with radiation-sparing strategies, restricting further thoracic CT scans for patients who have a specific clinical indication. Evaluation by CT may be reserved for those with signs or symptoms that suggest a PAVM. This practice is consistent with the BTS Clinical Statement [24]. Even if an initial screen was negative, PAVM reassessment is essential if the patient develops neurologic symptoms suggestive of a transient ischemic attack, or if they have a stroke or brain abscess. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 10/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate PAVM reassessment is also essential if there is a radiologic finding such as a new opacity on chest radiography, noting this is more likely to be a different pathology, and the importance is not to assume PAVMs are the cause. The approach is discussed separately. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults".) PAVM growth or development may be included in the differential diagnosis of new respiratory symptoms such as dyspnea or hemoptysis, again noting that these symptoms are more likely to be due to non-PAVM pathologies (eg, anemia, airflow obstruction) [52,53]. These other conditions may be more amenable to treatment than very small PAVMs. A normal chest radiograph does not exclude clinically significant PAVMs [24]. The details of contrast ("bubble") echocardiography and other tests for PAVMs are presented separately. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults".) CEREBRAL AVM SCREENING Evaluation of symptoms potentially attributable to a cerebral arteriovenous malformation (AVM) is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Cerebral lesions'.) The types of cerebral lesions include vascular malformations with a risk of hemorrhage and lesions with minimal risk, as detailed in data from the European Reference Network [19,20]. Discussions of these lesions and their prevalence are presented separately. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".) As with other complex decision-making, it is essential that cerebral screening is discussed so that each patient can make an informed decision, weighing risks and benefits, about whether to screen [19]. It may also be beneficial to consult with local neurosurgery or neuroradiology colleagues regarding whether they would treat an asymptomatic brain lesion and to share this information with the patient. For individuals who engage in shared decision-making and determine that brain imaging would be useful (even if it does not result in an invasive intervention), brain imaging is appropriate and reasonable and should be pursued. In contrast, if the perception is that at the current time, screening information would create more harms than benefits, we support the patient's decision to forgo imaging. This decision can be revisited if circumstances change. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 11/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate The role of screening for cerebral AVMs in asymptomatic individuals is more controversial than screening in other sites [19]. The controversy largely focuses on differing opinions about the risk-benefit ratio of screening, as discussed in a series of responses to the 2020 International Consensus Guidelines [54-56]. Considerations, advantages, and disadvantages of cerebral AVM screening in asymptomatic individuals with HHT include the following: Risk of bleeding Cerebral hemorrhages in HHT patients are usually life-changing and may be fatal. However, many HHT-related cerebral vascular malformations rarely bleed, including several types that may be identified by cerebral imaging [19]. The absolute risk of bleeding for any particular lesion has been evaluated across the European Centres of excellence in VASCERN and may be estimated from the literature [19,20]. Precise angioarchitecture and location of the lesion are also relevant [57,58]. Children are at a small risk of an arteriovenous fistula, which have higher hemorrhagic rates than the adult- type nidus AVMs. Younger individuals also have more life-years to live with their vascular abnormalities, with attendant hemorrhage risks per annum. Risks from imaging studies Computed tomography (CT) is not sufficiently sensitive, and CT carries risks of radiation. Magnetic resonance imaging (MRI) is the preferred screening modality, though while this eliminates the risk of radiation for the initial screen, radiation may be used for subsequent evaluations and treatment. Imaging in young children may require sedation or general anesthesia [19]. Outcomes following identification of different types of lesions: Brain AVF These are usually considered for treatment. Brain AVM Symptomatic cerebral AVMs are usually considered for treatment. Asymptomatic AVMs are less likely to be treated according to the results of a consensus from European interventional neuroradiologists and neurosurgeons in three specialist societies spanning the three forms of treatment: the European Association of Neurosurgical Societies (EANS), the European Society of Interventional Therapy (ESMINT), and the European Society for Radiosurgery (EGKS) [19,59]. The expert authors specifically integrated review of the ARUBA trial (A Randomized trial of Unruptured Brain AVM), which found that in unruptured cerebral AVMs, conservative management was less harmful than interventional treatments [60]. There were several concerns with this trial, and participants were mainly adults with non-HHT-related AVMs. (See "Brain arteriovenous malformations", section on 'Unruptured AVMs'.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 12/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Following expert joint review, neurosurgical, interventional neuroradiological, and radiosurgical teams may elect not to treat a lesion for other reasons [59]. However, those managing HHT families are aware there may be value in knowing of the presence of a cerebral AVM, either for early intervention should it become symptomatic, or for other aspects of health planning. There may also be negative implications from the awareness of a cerebral AVM for which treatment is not recommended. Other lesions Other lesions more commonly seen in HHT patients include capillary malformations/telangiectases (sometimes referred to incorrectly as "micro-AVMs"), cavernous malformations (formerly known as "cavernomas") and developmental venous anomalies (DVA) [19]. (See "Vascular malformations of the central nervous system".) For these, management in HHT patients follows general population guidance; these lesions are usually not treated due to low risks of hemorrhage [19]. Cerebral aneurysm The rate in HHT patients is similar to the general population [19,61] and management follows general population guidance. Across European expert centers, these issues are discussed with all patients as part of formal pretest counseling. Our preferred practice is to enable any HHT patient to have a screening brain MRI scan if that is their wish following pretest counseling [41]. A 2020 Position Statement from the European Reference Network stated that discussions of potential screening are undertaken for asymptomatic patients and noted that MRI scans are performed in only a proportion of patients having the screening discussions [19]. One center's experience stratifying 603 HHT patients with no neurologic symptoms of concern according to whether there was a positive family history of cerebral hemorrhage were reported in 2018 [41]. Screening scan uptake was higher after publication of the ARUBA trial, and patients with a family history of cerebral hemorrhage were 4-fold to 14-fold more likely to have a screening scan than patients with no such family history [41]. In a survey of 28 North American HHT Centers of Excellence, all reported screening adults with HHT for vascular lesions in the brain; 25 of 28 routinely screen children [62]. If screening is performed, brain MRI with contrast is recommended; this may entail general anesthesia in young children. The optimal timing and frequency of MRI is not established, and it is important to recognize that small lesions may be missed without catheter cerebral angiography. Other important considerations related to the incidence of cerebral AVMs include the following: The risk of a new AVM developing after a previous negative scan is unknown. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 13/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Screening scans commonly detect silent cerebral infarction due to pulmonary AVMs (PAVMs) [19]. At our institution, these considerations are openly discussed with the patient [41]. While cerebral AVMs lesions are more common in HHT1 (ENG) and SMAD4 families, they also are present and may hemorrhage in individuals from ACVRL1 families [29,63-68]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler- Weber-Rendu syndrome)", section on 'Genotype-phenotype correlations and variable penetrance'.) The lifelong risk of hemorrhage is higher for younger patients because of their longer predicted lifespan. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Cerebral vascular abnormalities' and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Children'.) HEPATIC AVM SCREENING Symptomatic liver lesions should be investigated, as discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Hepatic AVMs'.) Screening for liver lesions was recommended in the 2020 International Guideline on HHT [13]. Reasons included the fact that diagnosis of symptomatic hepatic AVMs may be delayed because symptoms are incorrectly attributed to other causes (eg, high output cardiac failure attributed to "heart" disease). Hepatic vascular malformations are most common in individuals with HHT2 due to ACVRL1 variants.(See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetics'.) In terms of approaches to hepatic AVM screening, data are not available to guide the choice of imaging modality or the frequency of monitoring; additional study of these questions is needed. The choice of imaging modality may depend on local expertise and should be discussed with the radiology team who will be performing liver imaging. A Practice Guideline from the French Association for the Study of the Liver (AFEF) and European Reference Network (ERN) provides details of the types of lesions that may be found [69]. Management is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Initial management of hepatic AVMs'.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 14/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate SPECIAL SCENARIOS Individuals who require anticoagulation (VTE and AF) Appropriate use of anticoagulation VTE prophylaxis Patients with HHT are at increased risk for venous thromboembolism (VTE) [37]. They should have prophylactic anticoagulation at high-risk times as for the general population. AF or VTE treatment Patients may also receive full anticoagulation if needed for conditions such as atrial fibrillation (AF) or VTE, or other indications; HHT is not an
abnormalities, with attendant hemorrhage risks per annum. Risks from imaging studies Computed tomography (CT) is not sufficiently sensitive, and CT carries risks of radiation. Magnetic resonance imaging (MRI) is the preferred screening modality, though while this eliminates the risk of radiation for the initial screen, radiation may be used for subsequent evaluations and treatment. Imaging in young children may require sedation or general anesthesia [19]. Outcomes following identification of different types of lesions: Brain AVF These are usually considered for treatment. Brain AVM Symptomatic cerebral AVMs are usually considered for treatment. Asymptomatic AVMs are less likely to be treated according to the results of a consensus from European interventional neuroradiologists and neurosurgeons in three specialist societies spanning the three forms of treatment: the European Association of Neurosurgical Societies (EANS), the European Society of Interventional Therapy (ESMINT), and the European Society for Radiosurgery (EGKS) [19,59]. The expert authors specifically integrated review of the ARUBA trial (A Randomized trial of Unruptured Brain AVM), which found that in unruptured cerebral AVMs, conservative management was less harmful than interventional treatments [60]. There were several concerns with this trial, and participants were mainly adults with non-HHT-related AVMs. (See "Brain arteriovenous malformations", section on 'Unruptured AVMs'.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 12/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Following expert joint review, neurosurgical, interventional neuroradiological, and radiosurgical teams may elect not to treat a lesion for other reasons [59]. However, those managing HHT families are aware there may be value in knowing of the presence of a cerebral AVM, either for early intervention should it become symptomatic, or for other aspects of health planning. There may also be negative implications from the awareness of a cerebral AVM for which treatment is not recommended. Other lesions Other lesions more commonly seen in HHT patients include capillary malformations/telangiectases (sometimes referred to incorrectly as "micro-AVMs"), cavernous malformations (formerly known as "cavernomas") and developmental venous anomalies (DVA) [19]. (See "Vascular malformations of the central nervous system".) For these, management in HHT patients follows general population guidance; these lesions are usually not treated due to low risks of hemorrhage [19]. Cerebral aneurysm The rate in HHT patients is similar to the general population [19,61] and management follows general population guidance. Across European expert centers, these issues are discussed with all patients as part of formal pretest counseling. Our preferred practice is to enable any HHT patient to have a screening brain MRI scan if that is their wish following pretest counseling [41]. A 2020 Position Statement from the European Reference Network stated that discussions of potential screening are undertaken for asymptomatic patients and noted that MRI scans are performed in only a proportion of patients having the screening discussions [19]. One center's experience stratifying 603 HHT patients with no neurologic symptoms of concern according to whether there was a positive family history of cerebral hemorrhage were reported in 2018 [41]. Screening scan uptake was higher after publication of the ARUBA trial, and patients with a family history of cerebral hemorrhage were 4-fold to 14-fold more likely to have a screening scan than patients with no such family history [41]. In a survey of 28 North American HHT Centers of Excellence, all reported screening adults with HHT for vascular lesions in the brain; 25 of 28 routinely screen children [62]. If screening is performed, brain MRI with contrast is recommended; this may entail general anesthesia in young children. The optimal timing and frequency of MRI is not established, and it is important to recognize that small lesions may be missed without catheter cerebral angiography. Other important considerations related to the incidence of cerebral AVMs include the following: The risk of a new AVM developing after a previous negative scan is unknown. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 13/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Screening scans commonly detect silent cerebral infarction due to pulmonary AVMs (PAVMs) [19]. At our institution, these considerations are openly discussed with the patient [41]. While cerebral AVMs lesions are more common in HHT1 (ENG) and SMAD4 families, they also are present and may hemorrhage in individuals from ACVRL1 families [29,63-68]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler- Weber-Rendu syndrome)", section on 'Genotype-phenotype correlations and variable penetrance'.) The lifelong risk of hemorrhage is higher for younger patients because of their longer predicted lifespan. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Cerebral vascular abnormalities' and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Children'.) HEPATIC AVM SCREENING Symptomatic liver lesions should be investigated, as discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Hepatic AVMs'.) Screening for liver lesions was recommended in the 2020 International Guideline on HHT [13]. Reasons included the fact that diagnosis of symptomatic hepatic AVMs may be delayed because symptoms are incorrectly attributed to other causes (eg, high output cardiac failure attributed to "heart" disease). Hepatic vascular malformations are most common in individuals with HHT2 due to ACVRL1 variants.(See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetics'.) In terms of approaches to hepatic AVM screening, data are not available to guide the choice of imaging modality or the frequency of monitoring; additional study of these questions is needed. The choice of imaging modality may depend on local expertise and should be discussed with the radiology team who will be performing liver imaging. A Practice Guideline from the French Association for the Study of the Liver (AFEF) and European Reference Network (ERN) provides details of the types of lesions that may be found [69]. Management is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Initial management of hepatic AVMs'.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 14/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate SPECIAL SCENARIOS Individuals who require anticoagulation (VTE and AF) Appropriate use of anticoagulation VTE prophylaxis Patients with HHT are at increased risk for venous thromboembolism (VTE) [37]. They should have prophylactic anticoagulation at high-risk times as for the general population. AF or VTE treatment Patients may also receive full anticoagulation if needed for conditions such as atrial fibrillation (AF) or VTE, or other indications; HHT is not an absolute contraindication, as discussed in the HHT 2020 Guideline and the 2022 VASCERN Framework manuscript [13,20]. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants" and "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management".) Cautions While some caution is required during anticoagulation (particularly because nosebleeds may increase), anticoagulant or antithrombotic therapy should not be withheld purely on a presumption of potential bleeding risk in HHT [13,18,70]. Patients can be alerted that for approximately one-half of individuals, nosebleed severity may increase, but there is no evidence that AVM hemorrhage has been precipitated by therapeutic anticoagulation [18,70]. Securing additional ear, nose, and throat (ENT) treatments may be required [18]. Occasionally patients report that their nosebleeds improve. Choice of anticoagulant Conventional heparin and warfarin have been first-choice anticoagulants in HHT in International and European guidance [13]. However, a 2023 study found rates of dose reduction or discontinuation with warfarin and direct oral anticoagulants (DOACs), and the consensus for anticoagulant choice may shift to include DOACs [71]. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Treatment of bleeding'.) If DOACs are considered, apixaban appears to be associated with less risk of bleeding complications than rivaroxaban. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 15/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate If an HHT patient has excessive nosebleeds with one particular anticoagulant, they may successfully switch to an alternate agent, although it is not possible to predict which agent will best suit any particular individual [18]. Supporting evidence Heparin and warfarin Several studies have reported that heparin and warfarin are generally well-tolerated [18,70,72,73]. DOACs In a detailed audit of the use of anticoagulants across the European Reference Network (ERN), none of the eight VASCERN HHT Reference Centers had recommended DOACs [18,70]. There were 32 reports of the use of a DOAC prescribed to HHT patients by other clinicians, 16 times for VTE and 16 times for AF (apixaban in 15, rivaroxaban in 14, and dabigatran in 3). HHT nosebleeds increased in severity in 24 of 32 treatment episodes (75 percent), leading to treatment discontinuation in 11 (34 percent); 8 (25 percent) patients had extreme hemorrhage with nosebleeds lasting hours and requiring hospital admissions, blood transfusions, and in all cases, anticoagulant discontinuation [18]. Discontinuation rates In a cohort of 119 individuals with HHT, 59 (50 percent) reduced the dose or prematurely discontinued therapy due to worsening bleeding [71]. Multivariable analysis identified prior gastrointestinal bleeding as a risk factor for discontinuation. The choice of anticoagulant (warfarin, heparin, or a DOAC) did not affect dose reduction or anticoagulant discontinuation. Air travel As noted separately, air travel is generally well-tolerated in HHT. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Potential complications of PAVMs'.) Traveling by air raises issues in the general population and these have particular relevance for people with HHT. VTE Individuals with HHT can follow advice for the general population regarding reducing the likelihood of VTE associated with prolonged immobility during air travel. It is important to recognize that HHT nosebleeds (that may prohibit flying) may occur before or during flights whether antiplatelet or anticoagulant agents are prescribed. (See "Prevention of venous thromboembolism in adult travelers".) Epistaxis The risk of nosebleeds during airline travel may be increased due to reduced humidity and air pressure: in a series of 145 individuals with HHT who replied to a questionnaire about airline flight-related complications, significant nosebleeds occurred in https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 16/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate approximately 14 percent of long-haul flights [74]. In our institution, we advise patients to use Vaseline or other nasal lubricants and to be prepared with tissues. SCREENING AND GENETIC TESTING OF AT-RISK FAMILY MEMBERS Data from a 2022 study emphasize the paucity of clinical symptoms in many patients with genetically-confirmed HHT [1]. Of 152 unrelated adults with genetically confirmed HHT due to a pathogenic variant in ACVRL1, ENG, or SMAD4, only 104 (68 percent) met a clinical diagnosis of HHT with three Cura ao criteria. Of 83 unrelated probands with one or more PAVMs and genetically-confirmed HHT, 20 (24 percent) had few, if any, features of HHT. Unaffected status should not be assumed based on the absence of nosebleeds or other HHT symptoms. Children Children in HHT families who have symptoms should be investigated, as discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) Determining what should happen to healthy children within HHT families is much more controversial. Genetic testing The 2020 second International Consensus HHT Guideline recommended genetic screening to be offered to all children of a parent with HHT (96 percent agreement) and all who are diagnosed with HHT based on clinical criteria [13]. Where genetic testing is offered, this should always be in the context of counseling and informed decision-making, with discussions of the potential implications for the child. If the familial disease-causing (pathogenic) variant is known and the child tests negative for that variant, parents can be reassured that the child does not have HHT. However, if the familial variant is not known, a negative test cannot exclude the diagnosis of HHT. Those who do not undergo genetic testing should be considered to have possible HHT. (See 'Genetic counseling and testing of family members' below and "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.) If formal genetic testing and exclusion of a familial variant has not (or cannot) be done, it is not possible to eliminate the possibility of HHT in a child, since symptoms and vascular lesions may not become apparent until later in life [13]. There are differences in practice for children for whom it is not possible to use formal genetic testing, ranging from screening for all manifestations of HHT to deferring any screening in asymptomatic children until after puberty, unless dictated otherwise by family history [57]. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 17/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Clinical evaluation Across practices, for children with HHT, recommendations range from evaluating for all manifestations of HHT to deferring the evaluation in most asymptomatic children until post-puberty, unless dictated otherwise by family history [57]. Similar variation in practices applies to children for whom it is not possible to use formal genetic testing [57]. Pulmonary AVMs For pulmonary arteriovenous malformations (PAVMs), the first International HHT Guideline recommended screening all patients with possible or confirmed HHT for PAVMs and included children in the screening recommendation [3]. The second International Guideline specifically addressed children and recommended pulmonary AVM screening at the time of diagnosis, and in those at risk for HHT based on a parent's diagnosis (94 percent agreement from the clinician and patient expert panel), and a repeat pulmonary AVM screening in children with an initial negative screen, at an interval of every five years (86 percent agreement) [13]. Cerebral AVMs For cerebral AVMs, the first International HHT Guideline recommended screening children with possible or definite HHT for CVMs in the first six months of life or at time of diagnosis (64 percent agreement) [3]. The second International HHT Guideline also recommended screening for brain vascular malformations in asymptomatic children with HHT or at risk for HHT, at the time of presentation or diagnosis (87 percent agreement) [13]. It should be noted that the pulmonary and cerebral screening recommendations contrast with other position statements (eg cerebral AVMs from the European Reference Network for Rare Vascular Diseases [VASCERN] [19]), particularly regarding the indication for repeated screening, imaging, and treatment of asymptomatic pulmonary AVMs. Further data on the outcomes post treatment are expected. Based on the latest evidence, pediatric-specific risks and benefits of screening include the following: Greater burdens and risks Burdens and risks of screening may be greater in children than in adults. Greater risks from exposure to ionizing radiation, including increased risk of cancer [23,75-77] Possible need for general anesthesia to enable imaging Inability to give full informed consent and/or to understand the implications of screening https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 18/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Less evidence for benefit There is less evidence for benefits of screening in children, especially for pulmonary AVMs. Risk of complications from pulmonary AVMs in children is less well-documented than risk of complications in adults. Some of these considerations are discussed in more detail separately. (See "Radiation-related risks of imaging", section on 'Children and adolescents' and "Genetic testing", section on 'Testing children'.) Briefly, as for adult screening, all experts are in agreement that decisions to screen children should be made with shared decision-making to allow all concerns and questions to be addressed and implications of screening decisions understood, including by the child when they are near the age of consent in the particular country (age varies from 16 to 21 years in different countries). The key considerations are: Whether asymptomatic children are at similar or different risks to asymptomatic adults if rationales for screening programs are based on data in adults (for example, pulmonary arteriovenous malformation [PAVM] screens given almost all complications occur in adult life). Whether treatment of asymptomatic children modifies the natural history of the development of their condition in a detrimental manner [51]. Practice variations in the aggressiveness of testing and screening reflect the uncertainty as to whether silent AVMs pose sufficient danger in childhood to balance the risks of childhood radiation exposure from imaging studies. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Onset of disease manifestations' and 'Cerebral AVM screening' above.) Pediatric treatment recommendations (as opposed to screening of asymptomatic children) are discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Children'.) Genetic counseling and testing of family members Individuals with HHT should be aware of the autosomal-dominant transmission and the possibility of having an affected child or other affected first-degree relative, which is approximately 50 percent. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetics'.) Individuals with HHT should be aware of that data [1] absence or paucity of nosebleeds does not exclude HHT: of 83 unrelated probands genetically screened for HHT due to the presence of PAVM(s), 20 (24 percent) had few, if any, features of HHT. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 19/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Genetic testing of family members is complicated in HHT because there are several potential genes involved, there are no common pathogenic variants, founder members may be mosaic with challenging molecular diagnostics, and the causative pathogenic variant is not identified in all families, highlighting that additional HHT genes or genomic regions are yet to be characterized [3]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetics'.) If genetic testing is pursued, an affected individual in the family should be tested first, followed by testing of selected family members for the specific variant that has been identified to be pathogenic or likely pathogenic in that family. If a familial disease-causing variant for HHT has been identified, genetic testing for this variant can reliably identify family members who have and have not inherited the variant. Individuals with the HHT genotype can be evaluated as described above. However, this is only possible if a specific familial gene variant has been tested [3]. Details of this testing are presented separately. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetics' and "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler- Weber-Rendu syndrome)", section on 'Diagnosis'.) Practices vary regarding the age at which to perform genetic testing, reflecting the ethical considerations involved in screening an asymptomatic child who is too young to give consent and will likely not understand the implications of testing. (See 'Children' above and "Genetic testing", section on 'Testing children'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".) SUMMARY AND RECOMMENDATIONS Symptomatic individuals Individuals with hereditary hemorrhagic telangiectasia (HHT) who are symptomatic should be investigated. Clinicians should be aware of typical arteriovenous malformation (AVM) symptoms. Many recommendations are based on expert opinion and observational studies; the uniformity of expert opinion varies depending on the clinical situation and prevailing practices. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 20/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Asymptomatic individuals; general principles Education and screening are important. Educational materials and specialized testing and management centers are available from the European Reference Network on Rare Multisystemic Vascular Diseases and country- specific patient groups. (See 'General principles of management' above.) Screening AVM screening in individuals at risk of HHT or asymptomatic individuals with HHT is recommended universally for PAVMs. For other AVMs, screening is more controversial than evaluating symptomatic lesions. It is good practice to counsel patients on risks and benefits prior to screening. Assuming the individual agrees, screening generally consists of an examination, evaluation for anemia and iron deficiency, pulmonary AVM (PAVM) screening, and discussions of screening for AVMs at other sites (hepatic, cerebral). Individuals with SMAD4-related HHT require more extensive surveillance due to the risk of juvenile polyposis and aortopathy. (See 'Overview of screening strategy' above and 'Cerebral AVM screening' above and 'Individuals with SMAD4 HHT' above.) Iron deficiency We obtain regular complete blood counts (CBC) and examine serial trends and red cell indices, particularly for patients who have hypoxemia due to PAVMs, for whom a "normal" hemoglobin may be inappropriately low for the expected degree of polycythemia. We regularly assess iron status regardless of the hemoglobin level, since iron deficiency is likely to progress to anemia if not treated. (See 'Iron status' above.) PAVMs Adults with HHT should be screened for PAVMs. Unsuspected PAVMs are common, and treatment reduces risks of stroke and brain abscess in adults. Females with HHT should undergo screening before becoming pregnant, since PAVMs can bleed in later pregnancy leading to life-threatening hemoptysis or hemothorax. Screening may consist of contrast (bubble) echocardiography in institutions with very strong local expertise, or with chest computed tomography (CT). Negative contrast echocardiography in experienced hands or negative CT can rule out PAVMs; a negative chest radiograph cannot. The timing and repeat screening in individuals with a negative initial screen depends on patient age and other findings. (See 'PAVM screening' above.) Cerebral AVMs Screening for cerebral arteriovenous (AV) shunts can be undertaken, noting the importance of shared decision-making and other considerations discussed above. (See 'Cerebral AVM screening' above.) Children Screening asymptomatic children within HHT families differs between institutions due to variable risk-benefit assessment. Evidence of benefit is generally lacking, and certain risks are recognized (radiation exposure from some imaging https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 21/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate studies). All specialists agree on the importance of informed consent that weighs risks and benefits for each individual. Other considerations include uncertainty about the risk of complications from silent AVMs in children, concerns about the ethics of screening children, and lack of information about how treatment affects the natural history of disease in children. (See 'Children' above.) VTE risk Individuals with HHT have an increased risk of venous thromboembolism (VTE) and should follow general population guidance for VTE treatment and prophylaxis. (See 'Individuals who require anticoagulation (VTE and AF)' above and 'Air travel' above.) Reproductive counseling and testing Individuals with HHT should be aware of the autosomal dominant transmission and possibility of having an affected child. Genetic testing of family members can be complicated. The possibility of disease can be excluded in relatives only if a familial pathogenic variant has been identified. (See 'Genetic counseling and testing of family members' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Vijeya Ganesan, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Anderson E, Sharma L, Alsafi A, Shovlin CL. Pulmonary arteriovenous malformations may be the only clinical criterion present in genetically confirmed hereditary haemorrhagic telangiectasia. Thorax 2022; 77:628. 2. Shovlin CL. Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev 2010; 24:203. 3. Faughnan ME, Palda VA, Garcia-Tsao G, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet 2011; 48:73. 4. Geisthoff UW, Nguyen HL, R th A, Seyfert U. How to manage patients with hereditary haemorrhagic telangiectasia. Br J Haematol 2015; 171:443. 5. Garg N, Khunger M, Gupta A, Kumar N. Optimal management of hereditary hemorrhagic telangiectasia. J Blood Med 2014; 5:191. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 22/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate 6. Shovlin CL. Circulatory contributors to the phenotype in hereditary hemorrhagic telangiectasia. Front Genet 2015; 6:101. 7. Labeyrie PE, Courth oux P, Babin E, et al. Neurological involvement in hereditary hemorrhagic telangiectasia. 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Faughnan ME, Mager JJ, Hetts SW, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med 2020; 173:989. 14. https://vascern.eu/wp-content/uploads/2018/09/Fiches_Hereditary-Haemorrhagic-Telangiec tasia_FINAL-web.pdf (Accessed on September 10, 2019). 15. Shovlin C, Bamford K, Sabb C, et al. Prevention of serious infections in hereditary hemorrhagic telangiectasia: roles for prophylactic antibiotics, the pulmonary capillaries-but not vaccination. Haematologica 2019; 104:e85. 16. Shovlin CL, Buscarini E, Kjeldsen AD, et al. European Reference Network For Rare Vascular Diseases (VASCERN) Outcome Measures For Hereditary Haemorrhagic Telangiectasia (HHT). Orphanet J Rare Dis 2018; 13:136. 17. Buscarini E, Botella LM, Geisthoff U, et al. Safety of thalidomide and bevacizumab in patients with hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis 2019; 14:28. 18. Shovlin CL, Millar CM, Droege F, et al. Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis 2019; 14:210. 19. Eker OF, Boccardi E, Sure U, et al. European Reference Network for Rare Vascular Diseases (VASCERN) position statement on cerebral screening in adults and children with hereditary haemorrhagic telangiectasia (HHT). Orphanet J Rare Dis 2020; 15:165. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 23/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate 20. Shovlin CL, Buscarini E, Sabb C, et al. The European Rare Disease Network for HHT Frameworks for management of hereditary haemorrhagic telangiectasia in general and speciality care. Eur J Med Genet 2022; 65:104370. 21. Wilson JMG, Jungner G. The principles and practice of screening for disease. Public Health P apers, no. 34, World Health Organization; Geneva, 1968. 22. Raffle AE, Gray JAM. Screening: Evidence and practice, Oxford University Press, Oxford 2007. 23. Hanneman K, Faughnan ME, Prabhudesai V. Cumulative radiation dose in patients with hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations. Can Assoc Radiol J 2014; 65:135. 24. Shovlin CL, Condliffe R, Donaldson JW, et al. British Thoracic Society Clinical Statement on Pulmonary Arteriovenous Malformations. Thorax 2017; 72:1154. 25. Shovlin CL, Jackson JE, Bamford KB, et al. Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax 2008; 63:259. 26. Vorselaars VM, Velthuis S, Mager JJ, et al. Direct haemodynamic effects of pulmonary arteriovenous malformation embolisation. Neth Heart J 2014; 22:328. 27. Post MC, Thijs V, Schonewille WJ, et al. Embolization of pulmonary arteriovenous malformations and decrease in prevalence of migraine. Neurology 2006; 66:202. 28. Shovlin CL, Sodhi V, McCarthy A, et al. Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services. BJOG 2008; 115:1108. 29. Jelsig AM, T rring PM, Kjeldsen AD, et al. JP-HHT phenotype in Danish patients with SMAD4 mutations. Clin Genet 2016; 90:55. 30. Heald B, Rigelsky C, Moran R, et al. Prevalence of thoracic aortopathy in patients with juvenile Polyposis Syndrome-Hereditary Hemorrhagic Telangiectasia due to SMAD4. Am J Med Genet A 2015; 167A:1758. 31. Joyce KE, Onabanjo E, Brownlow S, et al. Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variation. Blood Adv 2022; 6:3956. 32. Guilhem A, Portal s P, Dupuis-Girod S, et al. Altered expressions of CXCR4 and CD26 on T- helper lymphocytes in hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis 2021; 16:511. 33. Finnamore H, Le Couteur J, Hickson M, et al. Hemorrhage-adjusted iron requirements, hematinics and hepcidin define hereditary hemorrhagic telangiectasia as a model of https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 24/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate hemorrhagic iron deficiency. PLoS One 2013; 8:e76516. 34. Shovlin CL, Simeoni I, Downes K, et al. Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. Blood 2020; 136:1907. 35. Santhirapala V, Williams LC, Tighe HC, et al. Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations. PLoS One 2014; 9:e90777. 36. NICE Clinical Knowledge Summaries (CKS): Interpreting ferritin levels. http://cks.nice.org.uk/ anaemia-iron-deficiency#!diagnosissub:3 (Accessed on January 25, 2017). 37. Livesey JA, Manning RA, Meek JH, et al. Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia. Thorax 2012; 67:328. 38. Shovlin CL, Chamali B, Santhirapala V, et al. Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets. PLoS One 2014; 9:e88812. 39. Buscarini E, Leandro G, Conte D, et al. Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia. Dig Dis Sci 2011; 56:2166. 40. Shovlin CL, Awan I, Cahilog Z, et al. Reported cardiac phenotypes in hereditary hemorrhagic telangiectasia emphasize burdens from arrhythmias, anemia and its treatments, but suggest reduced rates of myocardial infarction. Int J Cardiol 2016; 215:179. 41. Fatania G, Gilson C, Glover A, et al. Uptake and radiological findings of screening cerebral magnetic resonance scans in patients with hereditary haemorrhagic telangiectasia. Intractable Rare Dis Res 2018; 7:236. 42. Brinjikji W, Nasr DM, Wood CP, Iyer VN. Pulmonary Arteriovenous Malformations Are Associated with Silent Brain Infarcts in Hereditary Hemorrhagic Telangiectasia Patients. Cerebrovasc Dis 2017; 44:179. 43. Romac R, Barak O, Glavas D, et al. Characterization of blood flow through intrapulmonary arteriovenous anastomoses and patent foramen ovale at rest and during exercise in stroke and transient ischemic attack patients. Echocardiography 2017; 34:676. 44. Laurie SS, Elliott JE, Goodman RD, Lovering AT. Catecholamine-induced opening of intrapulmonary arteriovenous anastomoses in healthy humans at rest. J Appl Physiol (1985) 2012; 113:1213. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 25/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate 45. Duke JW, Davis JT, Ryan BJ, et al. Decreased arterial PO2, not O2 content, increases blood flow through intrapulmonary arteriovenous anastomoses at rest. J Physiol 2016; 594:4981. 46. Yang W, Liu A, Hung AL, et al. Lower risk of intracranial arteriovenous malformation hemorrhage in patients with hereditary hemorrhagic telangiectasia. Neurosurgery 2016; 78:684. 47. Shovlin CL, Letarte M. Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms. Thorax 1999; 54:714. 48. Ference BA, Shannon TM, White RI Jr, et al. Life-threatening pulmonary hemorrhage with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia. Chest 1994; 106:1387. 49. Shovlin CL, Winstock AR, Peters AM, et al. Medical complications of pregnancy in hereditary haemorrhagic telangiectasia. QJM 1995; 88:879. 50. Hosman AE, de Gussem EM, Balemans WAF, et al. Screening children for pulmonary arteriovenous malformations: Evaluation of 18 years of experience. Pediatr Pulmonol 2017; 52:1206. 51. Arthur H, Geisthoff U, Gossage JR, et al. Executive summary of the 11th HHT international scientific conference. Angiogenesis 2015; 18:511. 52. Gawecki F, Strangeways T, Amin A, et al. Exercise capacity reflects airflow limitation rather than hypoxaemia in patients with pulmonary arteriovenous malformations. QJM 2019; 112:335. 53. Gawecki F, Myers J, Shovlin CL. Veterans Specific Activity Questionnaire (VSAQ): a new and efficient method of assessing exercise capacity in patients with pulmonary arteriovenous malformations. BMJ Open Respir Res 2019; 6:e000351. 54. Geisthoff U. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med 2021; 174:1034. 55. Faughnan ME, Mager JJ, Hetts SW, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med 2021; 174:1035. 56. Clancy MS, Palmer S, Olitsky S, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med 2021; 174:1036.
Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate 20. Shovlin CL, Buscarini E, Sabb C, et al. The European Rare Disease Network for HHT Frameworks for management of hereditary haemorrhagic telangiectasia in general and speciality care. Eur J Med Genet 2022; 65:104370. 21. Wilson JMG, Jungner G. The principles and practice of screening for disease. Public Health P apers, no. 34, World Health Organization; Geneva, 1968. 22. Raffle AE, Gray JAM. Screening: Evidence and practice, Oxford University Press, Oxford 2007. 23. Hanneman K, Faughnan ME, Prabhudesai V. Cumulative radiation dose in patients with hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations. Can Assoc Radiol J 2014; 65:135. 24. Shovlin CL, Condliffe R, Donaldson JW, et al. British Thoracic Society Clinical Statement on Pulmonary Arteriovenous Malformations. Thorax 2017; 72:1154. 25. Shovlin CL, Jackson JE, Bamford KB, et al. Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax 2008; 63:259. 26. Vorselaars VM, Velthuis S, Mager JJ, et al. Direct haemodynamic effects of pulmonary arteriovenous malformation embolisation. Neth Heart J 2014; 22:328. 27. Post MC, Thijs V, Schonewille WJ, et al. Embolization of pulmonary arteriovenous malformations and decrease in prevalence of migraine. Neurology 2006; 66:202. 28. Shovlin CL, Sodhi V, McCarthy A, et al. Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services. BJOG 2008; 115:1108. 29. Jelsig AM, T rring PM, Kjeldsen AD, et al. JP-HHT phenotype in Danish patients with SMAD4 mutations. Clin Genet 2016; 90:55. 30. Heald B, Rigelsky C, Moran R, et al. Prevalence of thoracic aortopathy in patients with juvenile Polyposis Syndrome-Hereditary Hemorrhagic Telangiectasia due to SMAD4. Am J Med Genet A 2015; 167A:1758. 31. Joyce KE, Onabanjo E, Brownlow S, et al. Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variation. Blood Adv 2022; 6:3956. 32. Guilhem A, Portal s P, Dupuis-Girod S, et al. Altered expressions of CXCR4 and CD26 on T- helper lymphocytes in hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis 2021; 16:511. 33. Finnamore H, Le Couteur J, Hickson M, et al. Hemorrhage-adjusted iron requirements, hematinics and hepcidin define hereditary hemorrhagic telangiectasia as a model of https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 24/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate hemorrhagic iron deficiency. PLoS One 2013; 8:e76516. 34. Shovlin CL, Simeoni I, Downes K, et al. Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. Blood 2020; 136:1907. 35. Santhirapala V, Williams LC, Tighe HC, et al. Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations. PLoS One 2014; 9:e90777. 36. NICE Clinical Knowledge Summaries (CKS): Interpreting ferritin levels. http://cks.nice.org.uk/ anaemia-iron-deficiency#!diagnosissub:3 (Accessed on January 25, 2017). 37. Livesey JA, Manning RA, Meek JH, et al. Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia. Thorax 2012; 67:328. 38. Shovlin CL, Chamali B, Santhirapala V, et al. Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets. PLoS One 2014; 9:e88812. 39. Buscarini E, Leandro G, Conte D, et al. Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia. Dig Dis Sci 2011; 56:2166. 40. Shovlin CL, Awan I, Cahilog Z, et al. Reported cardiac phenotypes in hereditary hemorrhagic telangiectasia emphasize burdens from arrhythmias, anemia and its treatments, but suggest reduced rates of myocardial infarction. Int J Cardiol 2016; 215:179. 41. Fatania G, Gilson C, Glover A, et al. Uptake and radiological findings of screening cerebral magnetic resonance scans in patients with hereditary haemorrhagic telangiectasia. Intractable Rare Dis Res 2018; 7:236. 42. Brinjikji W, Nasr DM, Wood CP, Iyer VN. Pulmonary Arteriovenous Malformations Are Associated with Silent Brain Infarcts in Hereditary Hemorrhagic Telangiectasia Patients. Cerebrovasc Dis 2017; 44:179. 43. Romac R, Barak O, Glavas D, et al. Characterization of blood flow through intrapulmonary arteriovenous anastomoses and patent foramen ovale at rest and during exercise in stroke and transient ischemic attack patients. Echocardiography 2017; 34:676. 44. Laurie SS, Elliott JE, Goodman RD, Lovering AT. Catecholamine-induced opening of intrapulmonary arteriovenous anastomoses in healthy humans at rest. J Appl Physiol (1985) 2012; 113:1213. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 25/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate 45. Duke JW, Davis JT, Ryan BJ, et al. Decreased arterial PO2, not O2 content, increases blood flow through intrapulmonary arteriovenous anastomoses at rest. J Physiol 2016; 594:4981. 46. Yang W, Liu A, Hung AL, et al. Lower risk of intracranial arteriovenous malformation hemorrhage in patients with hereditary hemorrhagic telangiectasia. Neurosurgery 2016; 78:684. 47. Shovlin CL, Letarte M. Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms. Thorax 1999; 54:714. 48. Ference BA, Shannon TM, White RI Jr, et al. Life-threatening pulmonary hemorrhage with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia. Chest 1994; 106:1387. 49. Shovlin CL, Winstock AR, Peters AM, et al. Medical complications of pregnancy in hereditary haemorrhagic telangiectasia. QJM 1995; 88:879. 50. Hosman AE, de Gussem EM, Balemans WAF, et al. Screening children for pulmonary arteriovenous malformations: Evaluation of 18 years of experience. Pediatr Pulmonol 2017; 52:1206. 51. Arthur H, Geisthoff U, Gossage JR, et al. Executive summary of the 11th HHT international scientific conference. Angiogenesis 2015; 18:511. 52. Gawecki F, Strangeways T, Amin A, et al. Exercise capacity reflects airflow limitation rather than hypoxaemia in patients with pulmonary arteriovenous malformations. QJM 2019; 112:335. 53. Gawecki F, Myers J, Shovlin CL. Veterans Specific Activity Questionnaire (VSAQ): a new and efficient method of assessing exercise capacity in patients with pulmonary arteriovenous malformations. BMJ Open Respir Res 2019; 6:e000351. 54. Geisthoff U. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med 2021; 174:1034. 55. Faughnan ME, Mager JJ, Hetts SW, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med 2021; 174:1035. 56. Clancy MS, Palmer S, Olitsky S, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med 2021; 174:1036. 57. Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet 2009; 17:860. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 26/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate 58. Ding D, Starke RM, Kano H, et al. International multicenter cohort study of pediatric brain arteriovenous malformations. Part 1: Predictors of hemorrhagic presentation. J Neurosurg Pediatr 2017; 19:127. 59. Cenzato M, Boccardi E, Beghi E, et al. European consensus conference on unruptured brain AVMs treatment (Supported by EANS, ESMINT, EGKS, and SINCH). Acta Neurochir (Wien) 2017; 159:1059. 60. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non- blinded, randomised trial. Lancet 2014; 383:614. 61. Ring NY, Latif MA, Hafezi-Nejad N, et al. Prevalence of and Factors Associated with Arterial Aneurysms in Patients with Hereditary Hemorrhagic Telangiectasia: 17-Year Retrospective Series of 418 Patients. J Vasc Interv Radiol 2021; 32:1661. 62. Kilian A, Clancy MS, Olitsky S, et al. Screening for pulmonary and brain vascular malformations is the North American standard of care for patients with hereditary hemorrhagic telangiectasia (HHT): A survey of HHT Centers of Excellence. Vasc Med 2021; 26:53. 63. Kjeldsen AD, M ller TR, Brusgaard K, et al. Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia. J Intern Med 2005; 258:349. 64. Letteboer TG, Mager JJ, Snijder RJ, et al. Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia. J Med Genet 2006; 43:371. 65. Sabb C, Pasculli G, Lenato GM, et al. Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. J Thromb Haemost 2007; 5:1149. 66. Lesca G, Olivieri C, Burnichon N, et al. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network. Genet Med 2007; 9:14. 67. Bossler AD, Richards J, George C, et al. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat 2006; 27:667. 68. Bayrak-Toydemir P, McDonald J, Markewitz B, et al. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet A 2006; 140:463. 69. Silvain C, Th venot T, Colle I, et al. Hereditary hemorrhagic telangiectasia and liver involvement: Vascular liver diseases: position papers from the francophone network for vascular liver diseases, the French Association for the Study of the Liver (AFEF), and ERN- rare liver. Clin Res Hepatol Gastroenterol 2020; 44:426. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 27/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate 70. Devlin HL, Hosman AE, Shovlin CL. Antiplatelet and anticoagulant agents in hereditary hemorrhagic telangiectasia. N Engl J Med 2013; 368:876. 71. Virk ZM, Zhang E, Rodriguez-Lopez J, et al. Safety, tolerability, and effectiveness of anticoagulation and antiplatelet therapy in hereditary hemorrhagic telangiectasia. J Thromb Haemost 2023; 21:26. 72. Edwards CP, Shehata N, Faughnan ME. Hereditary hemorrhagic telangiectasia patients can tolerate anticoagulation. Ann Hematol 2012; 91:1959. 73. Gaetani E, Agostini F, Porfidia A, et al. Safety of antithrombotic therapy in subjects with hereditary hemorrhagic telangiectasia: prospective data from a multidisciplinary working group. Orphanet J Rare Dis 2019; 14:298. 74. Mason CG, Shovlin CL. Flight-related complications are infrequent in patients with hereditary haemorrhagic telangiectasia/pulmonary arteriovenous malformations, despite low oxygen saturations and anaemia. Thorax 2012; 67:80. 75. Kmietowicz Z. Computed tomography in childhood and adolescence is associated with small increased risk of cancer. BMJ 2013; 346:f3348. 76. Mathews JD, Forsythe AV, Brady Z, et al. Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians. BMJ 2013; 346:f2360. 77. McDonald J, Wooderchak-Donahue W, VanSant Webb C, et al. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet 2015; 6:1. Topic 123017 Version 20.0 https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 28/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate GRAPHICS Overview of the incidence, presenting findings, evaluation, and management of the major clinical features of hereditary hemorrhagic telangiectasia (HHT) Presentation patterns Site Incidence Evaluation Treatment Nasal telangiectasia >90% Nose bleeds are usually the first History, inspection Routine therapy includes nasal lubrication and manifestation of treatment of iron deficiency when needed. HHT, frequently commencing in Laser treatment is generally preferred over childhood. cauterization. Surgery in expert hands offers good results for selected patients. Medical (systemic) treatments are an alternative and may be highly beneficial, but carry risks of prothrombotic side effects. Emergency treatments such as packing may be required. Mucocutaneous telangiectasia 50 to 80% Increase in size and number Inspection (oral, mucosa, Generally not indicated, but laser therapy can be with age. Main concerns are conjunctivae, face, trunk, used. cosmetic. May extremities, nail hemorrhage. beds) Gastrointestinal 11 to 40% Onset generally Flexible Iron supplementation telangiectasia over 30 years: endoscopy, and transfusion are the mainstays of treatment. Iron deficiency anemia, endoscopy angiogram, Medical (systemic) treatments are available occasionally acute capsule endoscopy and may be highly beneficial, but they carry gastrointestinal hemorrhage. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 29/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate risks of prothrombotic side effects. Pulmonary AVMs >50% Usually silent. Cyanosis, Chest radiography, Therapeutic embolization. clubbing, bruit, dyspnea, blood gas measurement, Antibiotic prophylaxis for dental and surgical paradoxical helical CT, procedures. embolism, cerebral angiography, chest Surgical resection may be indicated in highly selected cases. abscess. echocardiography Cerebral AVMs 10 to 15% Usually silent. Headache, CT, MRI, Doppler sonography, Most do not require treatment. epilepsy, angiography Therapeutic embolization, ischemia, intracerebral neurovascular surgery, or stereotactic radiosurgery hemorrhage. in highly selected cases. Hepatic AVMs 30 to 70% Usually silent. Hepatic artery- Doppler sonography, CT, Most do not require treatment. hepatic vein AVMs: MRI For the small proportion of patients who develop Hyperdynamic symptoms, standard hepatic medical care is circulation. Portasystemic often sufficient to resolve symptoms. shunts: Ascites and Liver transplantation in selected cases. encephalopathy. Embolization is a higher- risk procedure; some centers do not perform embolization unless the patient is accepted into a liver transplantation program. Less-common clinical manifestations include AVMs in other sites, high cardiac output states, and pulmonary hypertension. Refer to UpToDate for additional details of our approach. AVM: arteriovenous malformation; CT: computed tomography; MRI: magnetic resonance imaging. Adapted and updated from the original table in: Shovlin CL, Letarte M. Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms. Thorax 1999; https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 30/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate 54:714. Graphic 74593 Version 3.0 https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 31/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Contributor Disclosures Claire L Shovlin, PhD, FRCP Patent Holder: Imperial College London [The use of trametinib for treatment of HHT bleeding is the subject of a patent application by my employer]. Grant/Research/Clinical Trial Support: National Institute for Health Research [Imaging angiogenesis by PET CT - A pilot study in patients with arteriovenous malformations and hereditary haemorrhagic telangiectasia]. Consultant/Advisory Boards: European Reference Network for Rare Multisystemic Vascular Diseases [HHT]; Genomics England Respiratory GeCIP [Genomic medicine]; International Guidelines Committee [Cure HHT]; NHS Genomic Medicine Service Alliance [Genomic medicine]; NIH ClinGen Expert Panel for hereditary haemorrhagic telangiectasia GRAMB [HHT]. All of the relevant financial relationships listed have been mitigated. Lawrence LK Leung, MD No relevant financial relationship(s) with ineligible companies to disclose. Jennifer S Tirnauer, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 32/32
7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Intraventricular hemorrhage : Brett L Cucchiara, MD : Scott E Kasner, MD, Alejandro A Rabinstein, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 04, 2022. INTRODUCTION Intraventricular hemorrhage (IVH) confined to the ventricular system within the brain is uncommon, accounting for only about 3 percent of all spontaneous intracranial hemorrhage [1]. IVH more commonly occurs in the setting of intracerebral hemorrhage or subarachnoid hemorrhage. The assessment of the patient with IVH focuses on identifying the underlying cause of the hemorrhage, which may have significant treatment implications. Common to patients with IVH, regardless of etiology, is a risk for sudden and potentially fatal obstructive hydrocephalus, requiring acute clinical decision-making regarding the use of external ventricular drainage and other interventions. This topic discusses the causes, clinical presentation, diagnosis, and treatment of IVH. Intracerebral, subarachnoid, subdural, and epidural hemorrhage are discussed separately: (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) (See "Subdural hematoma in adults: Etiology, clinical features, and diagnosis".) (See "Subdural hematoma in adults: Management and prognosis".) (See "Intracranial epidural hematoma in adults".) https://www.uptodate.com/contents/intraventricular-hemorrhage/print 1/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate IVH in the newborn is also discussed separately. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis" and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome".) EPIDEMIOLOGY AND DEFINITIONS Primary IVH refers to bleeding confined to the ventricular system within the brain. Primary IVH is uncommon, accounting for only about 3 percent of all spontaneous intracerebral hemorrhage [1]. The following demographic characteristics were reported in a 2008 review of published cases series of primary IVH [2]: The median age is 55 years (range 9 to 91 years). Males and females are equally represented. Half of patients have a history of hypertension. Secondary IVH refers to the more common occurrence of IVH in the setting of intracerebral hemorrhage or subarachnoid hemorrhage. The epidemiology of intracerebral hemorrhage and subarachnoid hemorrhage is discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) ETIOLOGY IVH most commonly occurs as a secondary phenomenon when parenchymal or intracerebral hemorrhage (ICH) ruptures into the ventricular space or when subarachnoid hemorrhage (SAH) extends into the ventricles. IVH is estimated to complicate 40 to 60 percent of ICH and 10 percent of SAH cases [3-5]. In one retrospective review, warfarin therapy was associated with IVH risk, volume at presentation, and subsequent expansion in patients with deep or lobar ICH [6]. The underlying causes of ICH and SAH are discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Nonaneurysmal subarachnoid hemorrhage".) IVH can also complicate closed head injury. Usually, this is in the setting of other traumatic brain injury, including contusion and traumatic SAH; isolated IVH is a relatively rare complication of head trauma [7-9]. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 2/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate Primary IVH is uncommon; in consequence, studies estimating the frequency of various etiologies have been limited. Retrospective case series derived from tertiary referral centers are subject to ascertainment bias. Further, definitions of primary IVH have varied among different authors and studies. While most limit their use of the term to hemorrhages entirely localized within the ventricle, others have included hemorrhages that originate within 15 mm of the ependymal surface [10]. The latter criteria invariably classify thalamic, caudate, and medial putaminal bleeds (usually secondary to chronic hypertension) associated with IVH as primary IVH. Among series that more strictly limit the definition of IVH, vascular malformations are the most frequently identified cause of primary IVH. In small case series, vascular malformations have been identified in 14 to 58 percent of patients with primary IVH [2,10-15]. Reported causes of primary IVH include: Vascular malformations (usually arteriovenous malformations or arteriovenous fistulas) [1,2,10-19]. (See "Brain arteriovenous malformations".) Intraventricular tumors (papilloma, neurocytoma, meningioma, metastases, astrocytoma, ependymoma) [11,20-26]. (See "Overview of the clinical features and diagnosis of brain tumors in adults".) Intraventricular aneurysms developing within the distal lenticulostriate or choroidal arteries (occasionally reported in association with Moyamoya disease) [10,16,22,27]. Occasionally aneurysms of the anterior communicating artery, posterior inferior cerebellar artery, or basilar tip rupture into the ventricles without other overt subarachnoid blood [2,10,14]. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Moyamoya disease [1,2,16,22,28-31]. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) Coagulopathies, acquired or inherited [2,10,12,29,32-34]. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis".) Pituitary apoplexy [35]. (See "Causes, presentation, and evaluation of sellar masses", section on 'Causes'.) Vasculitis [36]. (See "Primary angiitis of the central nervous system in adults".) Fibromuscular dysplasia [10]. (See "Clinical manifestations and diagnosis of fibromuscular dysplasia".) https://www.uptodate.com/contents/intraventricular-hemorrhage/print 3/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate Sympathomimetic agents [37,38]. (See "Clinical manifestations, diagnosis, and management of the cardiovascular complications of cocaine abuse" and "Acute amphetamine and synthetic cathinone ("bath salt") intoxication", section on 'Central and peripheral nervous system'.) In approximately 20 to 50 percent of cases (depending in part on the intensity of the investigation), no cause is identified [11,12,16,33]. About half of these patients have chronic hypertension; this is believed, but not known, to cause primary IVH in the same way it is understood to cause ICH. It is speculated that some patients with IVH may have had a small hypertensive intraparenchymal hemorrhage, too small to see on computed tomography (CT) or magnetic resonance imaging (MRI), which arises in proximity to the ventricular system and produces IVH as its primary manifestation. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Pathogenesis and etiologies'.) CLINICAL FEATURES Clinical presentation Patients with secondary IVH present with clinical features typical of intracerebral hemorrhage or subarachnoid hemorrhage. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Patients with primary IVH typically present with abrupt headache, often associated with nausea, vomiting, and impaired consciousness (confusion, disorientation) [2,11,33,39]. A minority of patients have frank loss of consciousness at the onset [12]. Symptoms are usually sudden in onset; however, nearly a quarter of patients are reported to have progressive or fluctuating symptoms [11,12]. The degree of neurologic impairment, often measured as the Glasgow Coma Scale ( table 1) is an important prognostic indicator. (See 'Prognosis' below.) Focal neurologic findings are relatively uncommon with primary IVH and most typically involve cranial nerve abnormalities [10]. Such cranial nerve palsies are generally of the "false localizing" type due to stretching across the basilar skull surface and include dysfunction of the sixth and third nerves. Seizures are not common but can occur [1,10,11,17]. Most patients are hypertensive on presentation, and some will have an elevated body temperature or suffer cardiac arrhythmias [12]. Nuchal rigidity is inconsistently present. The clinical symptoms and signs of IVH reflect a sudden increase in intracranial pressure that results from sudden introduction of blood volume into the intracranial space [40]. In addition to pressure effects, it is speculated that blood products in the cerebrospinal fluid space may affect brain function. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 4/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate Complications Patients with primary or secondary IVH are at risk for sudden neurologic deterioration, which may result from obstructive hydrocephalus, recurrent hemorrhage, or other complications [12]: Hydrocephalus Acute obstructive hydrocephalus can result when cerebrospinal fluid circulation is obstructed by blood clots. Patients with blood in the third or fourth ventricle are at most risk of this complication [12]. One-half to two-thirds of patients with IVH have some degree of hydrocephalus on the initial computed tomography (CT) scan of the head [2,11,12,15,41]. This can be rapidly fatal and usually requires urgent intervention with insertion of an external ventricular drain [8,40]. (See 'External ventricular drain' below.) Patients may also develop communicating hydrocephalus as a delayed complication of IVH; this usually presents more gradually. (See 'Prognosis' below.) Hemorrhage extension Recurrent hemorrhage or hemorrhage extension occurs in 10 to 20 percent of patients with IVH [12,40]. The highest risk of this is in those with an underlying etiology of vascular malformation or aneurysm or in the setting of a coagulopathy. The presence of a coexisting intraparenchymal hemorrhage is also associated with an elevated risk of IVH expansion, especially those that have expanded on follow-up imaging or are located in the thalamus [42]. Cerebral vasospasm Cerebral ischemia due to arterial vasospasm is unusual in cases of primary IVH, but this complication has been described in isolated cases [19,43-45]. In contrast, vasospasm is a common complication of aneurysmal subarachnoid hemorrhage. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Other medical complications Neurologic deterioration due to medical complications is common in the setting of IVH. These include pulmonary embolism, pneumonia and other infections, and electrolyte imbalance. Other medical complications of IVH include cardiovascular instability, deep venous thrombosis, and gastrointestinal bleeding. DIFFERENTIAL DIAGNOSIS The presentation of primary IVH overlaps with those of aneurysmal subarachnoid hemorrhage and other forms of stroke. Urgent diagnostic evaluation, including head CT, is required to identify these alternative conditions to reduce risk of morbidity and initiate time-sensitive therapeutic interventions. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Approach to reperfusion therapy for acute ischemic stroke" and https://www.uptodate.com/contents/intraventricular-hemorrhage/print 5/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Cerebral venous thrombosis: Treatment and prognosis".) Other conditions that may present with a headache with sudden onset also include reversible cerebral vasoconstriction syndrome, cervical artery dissection, and posterior reversible leukoencephalopathy syndrome, among others ( table 2). A noncontrast head CT can distinguish IVH from these other entities. (See "Overview of thunderclap headache", section on 'Diagnostic evaluation'.) DIAGNOSTIC EVALUATION Imaging diagnosis Noncontrast head CT is the test of choice to diagnose IVH. CT rapidly and reliably identifies blood within the ventricular system, helps to identify parenchymal intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) associated with the IVH, and also identifies concurrent hydrocephalus. IVH may be identified infrequently by brain MRI or other neuroimaging studies, typically when these studies are performed to evaluate other conditions. Evaluation for underlying causes and monitoring Neuroimaging studies are typically required to define the etiology of a primary IVH. In the absence of an obvious precipitant such as trauma or coagulopathy, we recommend patients with primary IVH undergo neuroimaging to assess for underlying causes. Computed tomography Close examination of the initial head CT should be performed to identify secondary IVH due to ICH or aneurysmal SAH. Hemorrhagic findings in the brain regions surrounding the ventricles (caudate and thalamus, in particular) may identify ICH ( image 1). Similarly, the presence of subarachnoid blood in the basal cisterns or cortical sulci should raise concern for aneurysmal SAH with secondary IVH. If ICH or SAH is present, diagnostic evaluation should be pursued. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Evaluation and diagnosis' and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Identifying the source of bleeding'.) The extent of IVH can be graded by head CT. The Graeb score and other scoring systems have been proposed [46-48], but none are widely implemented in clinical practice. The CT scan should be repeated emergently for any neurologic deterioration to identify recurrent hemorrhage or obstructive hydrocephalus. CT scans are also used to monitor https://www.uptodate.com/contents/intraventricular-hemorrhage/print 6/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate hydrocephalus, particularly during attempts to clamp or remove a drain. Transcranial ultrasonography has been suggested as a possible alternative to serial CT to monitor ventricular size, but the reliability and reproducibility of this technique has yet to be independently validated [49]. Other neuroimaging studies For most patients with IVH, we typically start with MRI and magnetic resonance angiography (MRA) or CT angiography to investigate for underlying causes ( image 2). If the MRI/MRA or CT angiography is unrevealing, we recommend digital subtraction angiography, in agreement with guidelines from the American Heart Association/American Stroke Association [50]. In a prospective observational study of patients with IVH who underwent catheter angiography, vascular lesions were found in 11 of 17 (65 percent), including 10 patients with arteriovenous malformations, and one with aneurysm [14]. A retrospective review of published case series similarly estimated the yield of angiography at 56 percent, additionally identifying cases of Moyamoya and dural arteriovenous fistula [2]. If the cause of the IVH remains undetermined, it is reasonable in some cases to consider repeat contrast MRI and possibly catheter angiography one to two months following the initial studies after reabsorption of blood products has occurred. Other tests Other tests that are important to include are blood clotting studies (prothrombin time, partial thromboplastin time, and platelet count). A toxicology screen should also be considered. Because electrolyte imbalances can complicate IVH, these should be measured at baseline and followed regularly. MANAGEMENT General measures The treatment of IVH focuses on cessation of bleeding, relieving hydrocephalus, and controlling intracranial pressure (ICP). Specific therapy aimed at treating the underlying cause should be undertaken (aneurysm or arteriovenous malformation obliteration). (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Vascular malformations of the central nervous system".) Patients who have a moderate to severe IVH (impaired alertness and/or extensive intraventricular blood on imaging) should be followed in an intensive care setting. Medical complications are common (eg, pneumonia, deep venous thrombosis, gastrointestinal bleeding, https://www.uptodate.com/contents/intraventricular-hemorrhage/print 7/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate cardiovascular instability, supraventricular tachycardia, hypo- and hypernatremia) and require appropriate monitoring and treatment [1,11]. The head of the bed should be placed at 30 degrees or greater to decrease ICP and reduce the risk of aspiration. Euvolemia should be maintained using isotonic crystalloid solutions, and any elevations in body temperature should be treated aggressively. For prevention of deep venous thrombosis, mechanical thromboprophylaxis using intermittent pneumatic compression stockings is recommended until a bleeding source has been identified and secured. At that time, antithrombotic therapy can be used. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".) Because seizures are an infrequent complication of IVH, prophylactic antiseizure medications are not generally used but should be initiated immediately should seizures occur. Management of antithrombotic medications Reversing anticoagulation For most patients with IVH, we discontinue anticoagulant medications and give agents to reverse their effects. However, for some patients with small acute IVH and no signs of hydrocephalus who are receiving anticoagulation for a compelling indication such as a mechanical heart valve, the risk-benefit calculation may favor continued anticoagulation with close observation of neurologic status. In such circumstances, we generally use intravenous heparin during the acute period given the ability to rapidly reverse its anticoagulant effect. (See "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures", section on 'Management of bleeding'.) If reversal of anticoagulation is indicated, the appropriate intervention depends upon the anticoagulant the patient is taking, the time since last dose, and the urgency with which reversal is needed. Some patients prescribed anticoagulant medications may not require reversal agents if laboratory testing or the time interval since last dose indicates they are effectively not anticoagulated. The strategies used to reverse anticoagulation in patients with IVH are the same as those used for patients with intracerebral hemorrhage. These strategies are discussed separately. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Reversal strategy for specific anticoagulants'.) Patients on antiplatelets Antiplatelet medications are typically stopped at the time of diagnosis for most patients with acute IVH. However, we balance the thrombotic risks of discontinuation with the hemorrhagic risks of continuing antiplatelets at an individual level. We may continue antiplatelet medications during acute monitoring for selected patients at high risk https://www.uptodate.com/contents/intraventricular-hemorrhage/print 8/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate of thrombosis such as those with established atherosclerotic disease or who have undergone intravascular stent placement and who have small IVH. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Antithrombotic therapy for elective percutaneous coronary intervention: General use" and "Overview of carotid artery stenting" and "Endovascular techniques for lower extremity revascularization", section on 'Antiplatelet therapy'.) We reserve platelet transfusions for those with specific indications, including those with a thrombocytopenia (<100,000/microL) or a known platelet defect. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Platelet function disorders'.) Blood pressure management The optimal blood pressure management in patients with IVH remains undefined. Aggressive blood pressure lowering may minimize the risk of further hemorrhage but must be weighed against the risk of decreased cerebral perfusion in patients with increased ICP. It seems reasonable to gradually lower elevated blood pressure in patients with normal ICP. Intravenous antihypertensives such as labetalol or nicardipine are typically used, although other agents are acceptable [51]. In the absence of better data specific to IVH, the guidelines outlined for blood pressure management in the setting of ICH seem reasonable [50]. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management'.) External ventricular drain An external ventricular drain (EVD) is a small catheter inserted through the skull usually into the lateral ventricle, which is typically connected to a closed collecting device to allow for drainage of cerebrospinal fluid ( figure 1). The EVD can also be connected to a transducer that records ICP. We recommend an EVD for patients with IVH with hydrocephalus and neurologic decline [50]. Rarely, bilateral EVDs may be needed if hemorrhage obstructs the foramen of Monro [52]. The major complications associated with EVD are catheter occlusion due to clotted blood at the intraventricular orifice and infection. The former may be relieved by irrigation or catheter replacement. Symptoms suggestive of infection should prompt cerebrospinal fluid analysis for cell count and culture along with antibiotic therapy as appropriate. Staphylococci are the most common pathogens. Higher rates of bacterial ventriculitis/meningitis occur with longer duration of EVD placement [53]. Prophylactic catheter change does not reduce the risk of infection. The management and prevention of infections in patients with an EVD are discussed in greater detail separately. (See "Infections of cerebrospinal fluid shunts and other devices".) https://www.uptodate.com/contents/intraventricular-hemorrhage/print 9/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate Additional management options In addition to EVD placement, adjunctive approaches have also been used for selected patients with IVH for the prevention and treatment of hydrocephalus. Intraventricular thrombolysis The utility of intraventricular thrombolysis (IVT) for patients with IVH and an EVD is uncertain. IVT use involves shared decision-making and includes discussing individual risks and benefits. Instillation of thrombolytic agents into the ventricles may improve mortality by hastening clot resolution, thereby avoiding the morbidity associated with EVD occlusion and shortening the duration of EVD use. It is also possible, although unproven, that more rapid resolution of IVH may decrease the long-term incidence of communicating hydrocephalus. However, IVT use may increase the risk of bleeding and severe disability. Evidence supporting the use of IVT for EVD has been reported in case series, observational studies, and pooled analyses. These studies have suggested a benefit for IVT, showing increased clot resolution and, in some cases, decreased mortality [3,39,54-65]. The results of randomized clinical trials, on the other hand, have not shown clear benefit: The Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III) trial included 500 patients with IVH and compared treatment with 1 mg alteplase (tPA) or placebo injected through an EVD every eight hours until clot reduction or a clinical endpoint occurred, or 12 doses were given [66]. At 180 days, the primary efficacy outcome of a modified Rankin scale (mRS) score of 3 or less was similar in each group (48 versus 45 percent comparing alteplase to placebo; risk ratio [RR] 1.06, 95% CI 0.88-1.28). Patients who received IVT had a lower mortality (18 versus 29 percent; RR 0.60, 95% CI 0.41-0.86), but a higher rate of severe disability indicated by an mRS score of 5 (17 versus 9 percent; RR 1.99, 95% CI 1.22-3.26). Bleeding complication rates were similar (2 percent) in both groups. One criticism of the CLEAR-III trial is that only a minority of patients experienced substantial IVT removal, suggesting the possibility of benefit with more effective methods for clot removal. The Intraventricular Hemorrhage Thrombolysis Trial, a multicenter randomized controlled study, enrolled 48 patients and compared IVT (3 mg tPA) to control (normal saline); each treatment was injected through an EVD every 12 hours until clot reduction or a clinical endpoint occurred (median duration of dosing was 7.5 days for IVT) [67]. The rate of clot resolution was faster for IVT than placebo (18 versus 8 percent per day). Rates of death and ventriculitis were lower than expected and did not differ significantly between treatment groups. Symptomatic bleeding complications were more frequent in the tPA group (23 versus 5 percent), but this did not reach statistical significance. The dose used in this study was higher than that used in the CLEAR III trial. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 10/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate Bleeding complications are a concern with IVT; recurrent IVH and/or ICH expansion is reported in 8 to 20 percent of patients after IVT [16,40,56,57,67,68]. Typically, patients with known aneurysm or vascular malformation were excluded from early studies of IVT. However, IVT has been used without complication in a few reported cases after the vascular malformation or aneurysm was surgically treated [16,69-71], and even before surgery, in few patients with these lesions [17,72]. Systemic bleeding complications are unlikely to be significantly increased with IVT; in CLEAR IVH, systemic coagulation parameters were similar after administration of tPA and placebo [73]. It is also possible that the risk of bacterial meningitis/ventriculitis may be increased with IVT therapy, but this has not been demonstrated so far [40,56,66,67]. IVT has not been associated with systemic complications [74]. IVT is reserved for selected patients with acute IVH and an EVD at centers experienced with this approach. Lumbar drainage The use of lumbar drainage combined with IVT was studied in an open- label trial that was stopped early after 30 patients were enrolled; patients with severe IVH with tamponade of the third and fourth ventricles requiring EVD were treated with IVT (control group) or IVT combined with lumbar drainage [75]. The primary endpoint (need for permanent shunt placement of prolonged requirement for cerebrospinal fluid drainage) occurred more frequently in the control versus combined treatment groups (7 out of 16 versus 0 out of 14). In a meta- analysis that included patients in this study as well as an additional 67 patients treated outside of the clinical trial, the combined intervention was associated with a significant reduction (OR 0.24; 95% CI 0.01-0.36) for shunt dependency. This analysis found no significant differences in functional outcomes or cerebrospinal fluid infection rates at 90 days; bleeding complications were less frequent in the combined treatment group (odds ratio 0.4, 95% CI 0.30-0.53). PROGNOSIS The reported in-hospital mortality of IVH varies from 20 to 50 percent [1,2,4,10-12,33,56]. Secondary IVH carries a higher risk of death than primary IVH [15,33,74]. Advanced age, underlying coagulopathy, Glasgow Coma Scale score of 8 or less, and hydrocephalus at presentation are also associated with a higher risk of death [2,12,33,41,74]. While some studies have found that the extent of IVH correlates with prognosis [2,12,41,47], others have not [10,11,15]. The results of one study found that the volume of blood in the third ventricle was a strong and independent predictor of poor outcomes, while the volume of blood in the lateral ventricles, fourth ventricle, or entire ventricular system did not correlate significantly with https://www.uptodate.com/contents/intraventricular-hemorrhage/print 11/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate prognosis [76]. The authors speculated that blood in the third ventricle may affect critical contiguous structures in the midbrain. Other long-term complications of IVH include: Neurocognitive sequelae Patients with significant IVH are often confused, agitated, and disoriented [1]. These symptoms are often slow to recover and a significant proportion (about half of survivors) are left with disabling cognitive deficits [1,11,16]. Noncommunicating hydrocephalus IVH along with a secondary inflammatory/fibrotic response may lead to impaired absorption of cerebrospinal fluid at the arachnoid granulations. This may be manifest by a more subacute decline in cognition, gait, and urinary continence that can occur weeks or later after the initial IVH or as a failure to wean off EVD. Such patients may require permanent ventriculoperitoneal shunt [40]. Approximately 30 to 50 percent of patients with IVH require a shunt placement [16,56,63,70,77-80]. (See "Normal pressure hydrocephalus".) Late recurrence of intracerebral hemorrhage or IVH Recurrent hemorrhage is uncommonly reported after IVH. In one series, 2 of 14 survivors had a subsequent intracerebral hemorrhage [12], while in another series there was no recurrent bleeding in a group of 13 patients after 67 months [11]. The risk of this complication is likely highest in those with an unrecognized and/or unsecured vascular lesion (eg, Moyamoya) [27,81]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Terminology and etiologies Intraventricular hemorrhage (IVH) can complicate intracerebral hemorrhage or subarachnoid hemorrhage (secondary IVH). Less commonly, IVH occurs in isolation (primary IVH). The most commonly identified cause of primary IVH is a vascular malformation. Up to half of patients with primary IVH do not have a cause (other than hypertension) identified. (See 'Epidemiology and definitions' above and 'Etiology' above.) Clinical features Patients with IVH usually present with sudden headache, nausea and vomiting, and impaired alertness. (See 'Clinical features' above.) https://www.uptodate.com/contents/intraventricular-hemorrhage/print 12/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate Diagnostic evaluation Patients with a clinical presentation of IVH should undergo immediate noncontrast head computed tomography (CT). The primary purpose is to exclude subarachnoid hemorrhage and to identify the IVH and evaluate its severity and potential for obstructive hydrocephalus. (See 'Computed tomography' above.) Individuals with primary IVH should have magnetic resonance imaging with magnetic resonance angiography and/or conventional angiography to identify the underlying etiology, particularly a vascular malformation or aneurysm that may require surgical intervention. (See 'Other neuroimaging studies' above.) Management Monitoring Because acute obstructive hydrocephalus often complicates IVH that involves the third and fourth ventricles, such patients should be closely monitored. When neurologic deterioration occurs, emergent CT scan should be done to exclude the development of obstructive hydrocephalus or recurrent hemorrhage. (See 'General measures' above and 'Computed tomography' above.) Blood pressure The optimal blood pressure management in patients with IVH is uncertain. For patients with IVH and elevated blood pressure, intravenous antihypertensives such as labetalol or nicardipine may be used to lower blood pressure gradually while maintaining adequate cerebral perfusion. Aggressive blood pressure lowering may minimize the risk of further hemorrhage but must be weighed against the risk of decreased cerebral perfusion in patients with increased ICP. (See 'Blood pressure management' above.) External ventricular drain We recommend external ventricular drainage (EVD) for patients with neurologic deterioration that occurs with ventricular enlargement over conservative management (Grade 1B). An EVD can reduce clot burden, treat hydrocephalus, and facilitate ICP monitoring. (See 'External ventricular drain' above.) Additional management options The use of intraventricular thrombolysis involves shared decision-making and after assessing individual risks and benefits and is reserved for patients at experienced centers with established protocols. (See 'Intraventricular thrombolysis' above and 'Lumbar drainage' above.) ACKNOWLEDGMENT https://www.uptodate.com/contents/intraventricular-hemorrhage/print 13/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate The UpToDate editorial staff acknowledges James Pacelli Jr, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Darby DG, Donnan GA, Saling MA, et al. Primary intraventricular hemorrhage: clinical and neuropsychological findings in a prospective stroke series. Neurology 1988; 38:68. 2. Flint AC, Roebken A, Singh V. Primary intraventricular hemorrhage: yield of diagnostic angiography and clinical outcome. Neurocrit Care 2008; 8:330. 3. Hanley DF. Intraventricular hemorrhage: severity factor and treatment target in spontaneous intracerebral hemorrhage. Stroke 2009; 40:1533. 4. Nyquist P, Hanley DF. The use of intraventricular thrombolytics in intraventricular hemorrhage. J Neurol Sci 2007; 261:84. 5. Maas MB, Nemeth AJ, Rosenberg NF, et al. Delayed intraventricular hemorrhage is common and worsens outcomes in intracerebral hemorrhage. Neurology 2013; 80:1295. 6. Biffi A, Battey TW, Ayres AM, et al. Warfarin-related intraventricular hemorrhage: imaging and outcome. Neurology 2011; 77:1840. 7. LeRoux PD, Haglund MM, Newell DW, et al. Intraventricular hemorrhage in blunt head trauma: an analysis of 43 cases. Neurosurgery 1992; 31:678. 8. Inamasu J, Hori S, Aikawa N. Traumatic intraventricular hemorrhage causing talk and deteriorate syndrome. Am J Emerg Med 2001; 19:167. 9. Atzema C, Mower WR, Hoffman JR, et al. Prevalence and prognosis of traumatic intraventricular hemorrhage in patients with blunt head trauma. J Trauma 2006; 60:1010. 10. Angelopoulos M, Gupta SR, Azat Kia B. Primary intraventricular hemorrhage in adults: clinical features, risk factors, and outcome. Surg Neurol 1995; 44:433. 11. Mart -F bregas J, Piles S, Guardia E, Mart -Vilalta JL. Spontaneous primary intraventricular hemorrhage: clinical data, etiology and outcome. J Neurol 1999; 246:287. 12. Passero S, Ulivelli M, Reale F. Primary intraventricular haemorrhage in adults. Acta Neurol Scand 2002; 105:115. 13. Findlay JM. Intraventricular hemorrhage. Neurosurgery Quarterly 2000; 10:182. 14. Zhu XL, Chan MS, Poon WS. Spontaneous intracranial hemorrhage: which patients need diagnostic cerebral angiography? A prospective study of 206 cases and review of the literature. Stroke 1997; 28:1406. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 14/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate 15. Roos YB, Hasan D, Vermeulen M. Outcome in patients with large intraventricular haemorrhages: a volumetric study. J Neurol Neurosurg Psychiatry 1995; 58:622. 16. Goh KY, Poon WS. Recombinant tissue plasminogen activator for the treatment of spontaneous adult intraventricular hemorrhage. Surg Neurol 1998; 50:526. 17. Kumar K, Demeria DD, Verma A. Recombinant tissue plasminogen activator in the treatment of intraventricular hemorrhage secondary to periventricular arteriovenous malformation before surgery: case report. Neurosurgery 2003; 52:964. 18. Irie F, Fujimoto S, Uda K, et al. Primary intraventricular hemorrhage from dural arteriovenous fistula. J Neurol Sci 2003; 215:115. 19. Gerard E, Frontera JA, Wright CB. Vasospasm and cerebral infarction following isolated intraventricular hemorrhage. Neurocrit Care 2007; 7:257. 20. Okamura A, Goto S, Sato K, Ushio Y. Central neurocytoma with hemorrhagic onset. Surg Neurol 1995; 43:252. 21. Lee EJ, Choi KH, Kang SW, Lee IW. Intraventricular hemorrhage caused by lateral ventricular meningioma: a case report. Korean J Radiol 2001; 2:105. 22. Vates GE, Arthur KA, Ojemann SG, et al. A neurocytoma and an associated lenticulostriate artery aneurysm presenting with intraventricular hemorrhage: case report. Neurosurgery 2001; 49:721. 23. Lindboe CF, Stolt-Nielsen A, Dale LG. Hemorrhage in a highly vascularized subependymoma of the septum pellucidum: case report. Neurosurgery 1992; 31:741. 24. Smets K, Salgado R, Simons PJ, et al. Central neurocytoma presenting with intraventricular hemorrhage: case report and review of literature. Acta Neurol Belg 2005; 105:218. 25. Zuccaro G, Sosa F, Cuccia V, et al. Lateral ventricle tumors in children: a series of 54 cases. Childs Nerv Syst 1999; 15:774. 26. Akamatsu Y, Utsunomiya A, Suzuki S, et al. Subependymoma in the lateral ventricle manifesting as intraventricular hemorrhage. Neurol Med Chir (Tokyo) 2010; 50:1020. 27. Hamada J, Hashimoto N, Tsukahara T. Moyamoya disease with repeated intraventricular hemorrhage due to aneurysm rupture. Report of two cases. J Neurosurg 1994; 80:328. 28. Khan M, Novakovic RL, Rosengart AJ. Intraventricular hemorrhage disclosing neurofibromatosis 1 and moyamoya phenomena. Arch Neurol 2006; 63:1653. 29. Jabbour R, Taher A, Shamseddine A, Atweh SF. Moyamoya syndrome with intraventricular hemorrhage in an adult with factor V Leiden mutation. Arch Neurol 2005; 62:1144. 30. Nah HW, Kwon SU, Kang DW, et al. Moyamoya disease-related versus primary intracerebral hemorrhage: [corrected] location and outcomes are different. Stroke 2012; 43:1947. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 15/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate 31. Yu Z, Guo R, Zheng J, et al. Comparison of Acute Moyamoya Disease-Related and Idiopathic Primary Intraventricular Hemorrhage in Adult Patients. World Neurosurg 2019; 125:e313. 32. Ionita CC, Ferrara J, McDonagh DL, et al. Systemic hemostasis with recombinant-activated factor VII followed by local thrombolysis with recombinant tissue plasminogen activator in intraventricular hemorrhage. Neurocrit Care 2005; 3:246. 33. Kiymaz N, Demir O, Cirak B. Is external ventricular drainage useful in primary intraventricular hemorrhages? Adv Ther 2005; 22:447.
exclude subarachnoid hemorrhage and to identify the IVH and evaluate its severity and potential for obstructive hydrocephalus. (See 'Computed tomography' above.) Individuals with primary IVH should have magnetic resonance imaging with magnetic resonance angiography and/or conventional angiography to identify the underlying etiology, particularly a vascular malformation or aneurysm that may require surgical intervention. (See 'Other neuroimaging studies' above.) Management Monitoring Because acute obstructive hydrocephalus often complicates IVH that involves the third and fourth ventricles, such patients should be closely monitored. When neurologic deterioration occurs, emergent CT scan should be done to exclude the development of obstructive hydrocephalus or recurrent hemorrhage. (See 'General measures' above and 'Computed tomography' above.) Blood pressure The optimal blood pressure management in patients with IVH is uncertain. For patients with IVH and elevated blood pressure, intravenous antihypertensives such as labetalol or nicardipine may be used to lower blood pressure gradually while maintaining adequate cerebral perfusion. Aggressive blood pressure lowering may minimize the risk of further hemorrhage but must be weighed against the risk of decreased cerebral perfusion in patients with increased ICP. (See 'Blood pressure management' above.) External ventricular drain We recommend external ventricular drainage (EVD) for patients with neurologic deterioration that occurs with ventricular enlargement over conservative management (Grade 1B). An EVD can reduce clot burden, treat hydrocephalus, and facilitate ICP monitoring. (See 'External ventricular drain' above.) Additional management options The use of intraventricular thrombolysis involves shared decision-making and after assessing individual risks and benefits and is reserved for patients at experienced centers with established protocols. (See 'Intraventricular thrombolysis' above and 'Lumbar drainage' above.) ACKNOWLEDGMENT https://www.uptodate.com/contents/intraventricular-hemorrhage/print 13/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate The UpToDate editorial staff acknowledges James Pacelli Jr, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Darby DG, Donnan GA, Saling MA, et al. Primary intraventricular hemorrhage: clinical and neuropsychological findings in a prospective stroke series. Neurology 1988; 38:68. 2. Flint AC, Roebken A, Singh V. Primary intraventricular hemorrhage: yield of diagnostic angiography and clinical outcome. Neurocrit Care 2008; 8:330. 3. Hanley DF. Intraventricular hemorrhage: severity factor and treatment target in spontaneous intracerebral hemorrhage. Stroke 2009; 40:1533. 4. Nyquist P, Hanley DF. The use of intraventricular thrombolytics in intraventricular hemorrhage. J Neurol Sci 2007; 261:84. 5. 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Spontaneous primary intraventricular hemorrhage: clinical data, etiology and outcome. J Neurol 1999; 246:287. 12. Passero S, Ulivelli M, Reale F. Primary intraventricular haemorrhage in adults. Acta Neurol Scand 2002; 105:115. 13. Findlay JM. Intraventricular hemorrhage. Neurosurgery Quarterly 2000; 10:182. 14. Zhu XL, Chan MS, Poon WS. Spontaneous intracranial hemorrhage: which patients need diagnostic cerebral angiography? A prospective study of 206 cases and review of the literature. Stroke 1997; 28:1406. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 14/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate 15. Roos YB, Hasan D, Vermeulen M. Outcome in patients with large intraventricular haemorrhages: a volumetric study. J Neurol Neurosurg Psychiatry 1995; 58:622. 16. Goh KY, Poon WS. Recombinant tissue plasminogen activator for the treatment of spontaneous adult intraventricular hemorrhage. Surg Neurol 1998; 50:526. 17. Kumar K, Demeria DD, Verma A. 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J Neurosurg 2000; 93:976. Topic 1116 Version 23.0 https://www.uptodate.com/contents/intraventricular-hemorrhage/print 19/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate GRAPHICS Glasgow Coma Scale (GCS) Score Eye opening Spontaneous 4 Response to verbal command 3 Response to pain 2 No eye opening 1 Best verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible sounds 2 No verbal response 1 Best motor response Obeys commands 6 Localizing response to pain 5 Withdrawal response to pain 4 Flexion to pain 3 Extension to pain 2 No motor response 1 Total The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. Graphic 81854 Version 9.0 https://www.uptodate.com/contents/intraventricular-hemorrhage/print 20/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate Etiologies of thunderclap headache Most common causes of thunderclap headache: Subarachnoid hemorrhage Reversible cerebral vasoconstriction syndromes (RCVS) Conditions that less commonly cause thunderclap headache: Cerebral infection (eg, meningitis, acute complicated sinusitis) Cerebral venous thrombosis Cervical artery dissection Spontaneous intracranial hypotension Acute hypertensive crisis Posterior reversible leukoencephalopathy syndrome (PRES) Intracerebral hemorrhage Ischemic stroke Conditions that uncommonly or rarely cause thunderclap headache: Pituitary apoplexy Colloid cyst of the third ventricle Aortic arch dissection Aqueductal stenosis Brain tumor Giant cell arteritis Pheochromocytoma Pneumocephalus Retroclival hematoma Spinal epidural hematoma Varicella zoster virus vasculopathy Vogt-Koyanagi-Harada syndrome Disputed causes of thunderclap headache: Sentinel headache (unruptured intracranial aneurysm)* Primary thunderclap headache Sentinel headache due to an unruptured intracranial aneurysm is a possible cause of thunderclap headache, but supporting data are weak. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 21/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate There is controversy as to whether thunderclap headache can occur as a benign and potentially recurrent headache disorder in the absence of underlying organic intracranial pathology. Graphic 81710 Version 8.0 https://www.uptodate.com/contents/intraventricular-hemorrhage/print 22/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate Intracerebral hemorrhage with intraventricular hemorrhage due to moyamoya syndrome Noncontrast head CT (A) showing hematoma in the right corpus striatum and lateral ventricles. Digital subtraction angiogram (B) showing critical stenosis of proximal right middle cerebral artery (arrow), prominent collateralization of both lenticulostriate vessels (circle), and branches of the anterior cerebral artery (thick arrows). CT: computed tomography. Courtesy of Glenn A Tung, MD, FACR. Graphic 132277 Version 1.0 https://www.uptodate.com/contents/intraventricular-hemorrhage/print 23/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate Intraventricular hemorrhage due to ruptured periventricular arteriovenous malformation Noncontrast head CT (A) showing IVH. CT angiogram (B) showing abnormal tangle of vessels (circle) in the left perisplenial region. Digital subtraction angiogram (C) showing AVM nidus (circle). CT: computed tomography; IVH: intraventricular hemorrhage; AVM: arteriovenous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 132281 Version 1.0 https://www.uptodate.com/contents/intraventricular-hemorrhage/print 24/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate External ventricular drain An external ventricular drain (EVD) is a small catheter inserted through the skull usually into the lateral ventricle, which is typically connected to a closed collecting device to allow for drainage of cerebrospinal fluid. The EVD can also be connected to a transducer that records intracranial pressure. Graphic 56391 Version 2.0 https://www.uptodate.com/contents/intraventricular-hemorrhage/print 25/26 7/5/23, 12:22 PM Intraventricular hemorrhage - UpToDate Contributor Disclosures Brett L Cucchiara, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator-initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/intraventricular-hemorrhage/print 26/26
7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis : Nijasri Charnnarong Suwanwela, MD : Jos Biller, MD, FACP, FAAN, FAHA, Douglas R Nordli, Jr, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 08, 2022. INTRODUCTION Moyamoya is an uncommon cerebrovascular condition characterized by progressive narrowing of large intracranial arteries and the secondary development of prominent small-vessel collaterals. These collateral vessels produce a characteristic smoky appearance on angiography, which was first called "moyamoya," a Japanese word meaning puffy, obscure, or hazy like a puff of smoke in the air. Moyamoya is a progressive disorder that may lead to ischemic stroke or intracranial hemorrhage in children and adults. This topic will review the etiologies, clinical features, and diagnosis of moyamoya. The prognosis and treatment of moyamoya are discussed separately. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis".) CLASSIFICATION AND TERMINOLOGY The term "moyamoya" describes the specific angiographic findings of unilateral or bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation ( image 1). https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 1/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no associated conditions. This may also be called primary or idiopathic moyamoya disease as well as the descriptive "spontaneous occlusion of the circle of Willis" [1,2]. Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition as described below. (See 'Associated conditions' below.) These secondary forms of the condition have been termed "moyamoya phenomenon," "angiographic moyamoya," or "quasi-moyamoya disease" [1,3-5]. ETIOLOGY AND PATHOGENESIS The etiology of MMD is unknown, but genetic associations have been identified. MMS has been associated with multiple conditions, which may implicate diverse pathophysiologic processes leading to the characteristic vascular abnormalities. Genetic associations The high incidence among the Japanese population, together with a familial occurrence of approximately 10 to 15 percent of cases, strongly suggests a genetic etiology. Accumulating evidence suggests that the RNF213 gene on chromosome 17q25.3 is an important susceptibility factor for MMD in populations in several East Asian countries [6-14]. Several reports have also linked familial MMD to chromosomes 3p24.2, p26, 6q25, 8q23, and 12p12 [15-17]. Although the mode of inheritance is not established, one study suggested that familial moyamoya is an autosomal dominant disease with incomplete penetrance [18]. The authors proposed that genomic imprinting and epigenetic modification may account for the predominantly maternal transmission and elevated female-to-male incidence ratio. (See 'Epidemiology' below and "Inheritance patterns of monogenic disorders (Mendelian and non- Mendelian)", section on 'Parent-of-origin effects (imprinting)'.) A later genome-wide association study confirmed the relationship of MMD and a previously reported locus on chromosome 17q25 [19]. The study also identified 10 novel risk loci, including the genes regulating homocysteine metabolism, loci related to large vessel disease, and loci that are highly expressed in the immune system. Associated conditions There are many conditions associated with MMS. They may be causative or syndromic. Some of the conditions reported to be associated with MMS include: Disease affecting arteries around the circle of Willis https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 2/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Atherosclerosis [20] Radiation therapy to the base of the brain [21] (see "Delayed complications of cranial irradiation", section on 'Cerebrovascular effects') Cranial trauma [22] Brain tumors [23-25] Meningitis [26] Other viral or bacterial infection (eg, Cutibacterium acnes, leptospirosis, human immunodeficiency virus [HIV]) [27-29] Hematologic conditions Sickle cell disease [30-32] Beta thalassemia [33] Fanconi anemia [34] Hereditary spherocytosis [35] Homocystinuria and hyperhomocysteinemia [36] Factor XII deficiency [37] Essential thrombocythemia [38] Protein S deficiency [39-41] Pyruvate kinase deficiency [42] Vasculitis and autoimmune and multisystem diseases Systemic lupus erythematosus [43] Polyarteritis nodosa and postinfectious vasculopathy [44] Graves disease and thyroiditis [45-48] Sneddon syndrome and the antiphospholipid antibody syndrome [49,50] Anti-Ro and anti-La antibodies [51] Type 1 diabetes mellitus [48] Pulmonary sarcoidosis [52,53] Genetic and developmental disorders Alagille syndrome [54,55] Down syndrome [56,57] Hypomelanosis of Ito [58] Marfan syndrome [59] Microcephalic osteodysplastic primordial dwarfism type 2 [60] Multisystem disorder with short stature, hypergonadotropic hypogonadism, and dysmorphism [61,62] https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 3/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Neurofibromatosis type 1 [63-66] Noonan syndrome [67-69] Phakomatosis pigmentovascularis type IIIb [70] Prader-Willi syndrome [71] Pseudoxanthoma elasticum [72] Sturge-Weber syndrome [73] Tuberous sclerosis [74] Turner syndrome [75] Williams syndrome [76] Morning glory optic disc anomaly ( image 2), usually in conjunction with other craniofacial abnormalities [77-79] (see "Congenital and acquired abnormalities of the optic nerve", section on 'Morning glory disc') Other vasculopathies and extracranial cardiovascular diseases Coarctation of the aorta [80] Congenital heart disease [81] Fibromuscular dysplasia [82] Renal artery stenosis [83] Metabolic diseases Type I glycogenosis [84,85] Hyperphosphatasia [86] Primary oxalosis [87] Renal disorders Polycystic kidney disease [88-90] Wilms tumor [83,91-103] Pathogenesis The pathophysiologic processes leading to arterial stenosis and small vessel collateralization involve vessel wall thickening and angiogenesis. A genetic susceptibility may be implicated in MMD, while underlying associated conditions trigger the development of MMS. Vascular changes in moyamoya may be related to impaired response to inflammation or defects in cellular repair mechanisms [104]. Such changes have been associated with evidence of increased angiogenesis-related factors, including endothelial colony-forming cells, various cytokines, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) [105-107]. High levels of fibroblast growth factor, which may stimulate arterial growth, have been found in the vascular intima, media, and smooth muscle as well as cerebrospinal fluid https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 4/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate among patients with moyamoya [108,109]. Transforming growth factor beta-1 (TGFB1), which mediates neovascularization, may also contribute to the pathogenesis [110,111]. High levels of hepatocyte growth factor (a strong inducer of angiogenesis) have been detected in the carotid fork and cerebrospinal fluid in patients with moyamoya [112]. Pathologic findings Tissue analysis in patients with moyamoya shows evidence of arterial vessel narrowing and secondary vascular proliferation characteristic of the disease as well as tissue damage related to the vascular abnormalities. Stroke Brain tissue of patients with moyamoya usually reveals evidence of prior ischemic or hemorrhagic stroke. Multiple areas of cerebral infarction and focal cortical atrophy are commonly found. Although large-vessel stenosis and occlusion are the hallmark of this disease, extensive territorial infarction is uncommon. The brain infarcts are generally small and located in the basal ganglia, internal capsule, thalamus, and subcortical regions [113]. However, the cause of death in most autopsy cases is intracerebral hemorrhage [93]. The hemorrhage is commonly found in the basal ganglia, thalamus, hypothalamus, midbrain, and/or periventricular region. Bleeding into the intraventricular space is frequently observed. Vascular stenosis Pathologic vascular lesions appear in the large vessels of the circle of Willis and in the small collateral vessels [94]. The terminal portions of the internal carotid arteries as well as the proximal middle and anterior cerebral arteries are most commonly involved [114]. Some patients may have unilateral stenosis at presentation, although progression to bilateral involvement may occur [115,116]. Less frequently, the posterior circulation is affected, especially the posterior cerebral artery. In the affected large arteries, variable stenosis or occlusion is associated with intimal fibrocellular thickening, tortuosity or duplication of the internal elastic lamina, and attenuation of the media [91,117-119]. Collateral vessels One of the hallmarks of moyamoya is the presence of a collateral meshwork of overgrown and dilated small arteries, the moyamoya vessels, that branch from the circle of Willis ( image 3). The pathology of the smaller perforating vessels in moyamoya is variable. Morphometric analysis suggests that some are dilated with relatively thin walls, while others are stenotic with thick walls [117]. Dilated vessels, more common in younger patients than in adults, tend to show fibrosis with attenuation of the media and microaneurysm formation. Histologic study from autopsy specimens of aneurysms showed disappearance of internal https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 5/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate elastic lamina and media [92]. These findings are similar to those of the berry aneurysms commonly observed in primary subarachnoid hemorrhage. Leptomeningeal vessels are another source of collaterals in moyamoya. As a result of intracranial internal carotid artery stenosis, leptomeningeal anastomoses may develop from the three main cerebral arteries (middle, anterior, and posterior). These collaterals result from dilatation of preexisting arteries and veins. In addition, transdural anastomoses, termed vault moyamoya, may develop from extracranial arteries such as the middle meningeal and superficial temporal arteries [95]. Aneurysms Cerebral aneurysms have been associated with moyamoya in a number of reports [96-100]. Aneurysms can develop at vessel branching points in the circle of Willis or along collateral vessels [101,120]. In a review of 111 moyamoya patients with cerebral aneurysm, most presented with intracranial hemorrhage and were found to have a single aneurysm in 86 percent of cases. Aneurysms along the circle of Willis were found in 56 percent, of which almost 60 percent were in the posterior circulation [120]. Aneurysms can also arise from the small collateral moyamoya vessels, choroidal arteries, or other peripheral collateral arteries [101]. These small-vessel aneurysms are the major cause of parenchymal (intracerebral) hemorrhage in moyamoya. Extracranial involvement In patients with moyamoya, stenosis due to fibrocellular intimal thickening may also affect the extracranial and systemic arteries, including the cervical carotid, renal, pulmonary, and coronary vessels [91,102]. Involvement of the renal arteries has been most frequently reported. In one study of 86 patients with MMD, six had renal artery stenosis, two had associated renovascular hypertension, and one had a renal artery aneurysm [83]. Similarly, in a later study of 73 consecutive patients with MMD, four had renal artery stenosis [121]. EPIDEMIOLOGY Incidence and prevalence The relative prevalence of MMD and MMS vary geographically. MMD is more common in East Asian countries than elsewhere, with the highest prevalence found in Japan, China, and Korea [114,122,123]. In epidemiologic surveys conducted in Japan, the following observations have been made [124- 127]: The annual incidence of moyamoya is 0.35 to 0.94 per 100,000 population. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 6/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate The prevalence of moyamoya is 3.2 to 10.5 per 100,000 population. There is a female predominance, with a female-to-male ratio of 1.9. A family history of MMD is present in 10 to 12 percent of patients. Using hospital admissions data, a United States study found an incidence of 0.57 per 100,000 persons/year [128]. Among ethnic groups in California, the moyamoya incidence rate for Asian Americans was 0.28 per 100,000, similar to that in Japan. The incidence rates were lower for African American, White American, and Hispanic populations (0.13, 0.06, and 0.03 per 100,000, respectively). The incidence of MMS in Japan is approximately 10 times lower than MMD [129,130]. Age distribution MMD and MMS both occur in children and adults; presentation in infancy is uncommon [131,132]. Data from a nationwide registry in Japan, with 2545 cases of MMD, showed a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second broader peak at approximately 40 years of age [127]. A cohort study of 802 patients with MMD from China also demonstrated a bimodal age distribution, with a major peak at five to nine years of age and another peak at 35 to 39 years of age [133]. CLINICAL PRESENTATIONS Moyamoya has varying clinical presentations; the expression of disease and the age at presentation are influenced by regional and ethnic differences. Ischemic stroke and transient ischemic attack The most common initial presentation of moyamoya is ischemic stroke [134-138]. Transient ischemic attack (TIA) is also a frequent initial presentation and may be recurrent [134,138]. In one retrospective series from the United States, 61 percent of 31 adults with MMD or MMS presented with ischemic symptoms; in those with stroke, the predominant pattern was a border- zone pattern of infarction [137]. In another retrospective study, 21 German patients with MMD all presented with ischemic events, including 16 who were adults at symptom onset [136]. In children, symptomatic episodes of ischemia in the anterior and middle cerebral artery vascular territories may commonly be triggered by exercise, crying, coughing, straining, fever, or hyperventilation [104,139,140]. In the International Pediatric Stroke Study involving 174 children with moyamoya, ischemic stroke was the initial presentation in 90 percent of children and TIA in 7.5 percent [134]. Ischemic symptoms of hemiparesis or speech impairment predominated, reflecting the predilection for stenosis of the anterior cerebral circulation (anterior and middle https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 7/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate cerebral artery territories). In this series, 20 percent of children had recurrent symptoms in the median 13-month follow-up interval. Multiple recurrent events are common in other studies as well, likely reflecting the fixed stenosis susceptible to recurrent hypoperfusion. In one study from Korea of 88 children and adults who were followed for 6 to 216 months, multiple cerebrovascular events occurred in 55 percent [141]. Recurrences were most commonly ischemic. Intracerebral, intraventricular, and subarachnoid hemorrhage While ischemic symptoms may be more common at presentation, hemorrhagic complications of moyamoya, mainly intracerebral hemorrhage (ICH), represent a significant clinical burden. ICH is more common in adults than children [138,142]. In the International Pediatric Stroke Study, ICH was the presenting syndrome in 2.5 percent [134], while, in a series of adult patients, 10 percent of patients presented with intracranial hematoma [137]. In a systematic review, intracerebral hemorrhage at initial presentation was more frequent for patients in China and Taiwan than in the United States [135]. Intraventricular hemorrhage with or without ICH was a common presentation of MMD, according to one report from Korea [143]. In adults who presented with ICH or intraventricular hemorrhage, small aneurysms in the periventricular area have been reported ( image 4). Patients may also present with subarachnoid hemorrhage [144]. Seizures Patients with moyamoya present infrequently with seizures, often secondary to ischemic damage [145]. The rate of epilepsy may be more frequent in children than in adults [142]. Other manifestations Headache Headache is common in patients with moyamoya [146]. Migraine is the most common headache phenotype, but tension-type headache and cluster headache have also been reported [147,148]. Other neurologic symptoms There are case reports of patients with moyamoya who develop dystonia, chorea, or dyskinesia, but these appear to be uncommon manifestations [149-151]. Asymptomatic disease Moyamoya can be found incidentally in asymptomatic patients undergoing screening imaging for other conditions or because of family history [152,153]. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 8/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate A nationwide study in Japan using a questionnaire in 1994 identified 33 asymptomatic cases (1.5 percent) out of a total of 2193 patients [154]. INITIAL TEST FINDINGS Because patients with MMD or MMS may present with signs and symptoms of acute cerebrovascular disease, initial testing typically includes neuroimaging. Electroencephalography is often performed in patients with seizures and sometimes in those with transient ischemic attack (TIA). Specific findings on these tests may suggest moyamoya. Neuroimaging Cerebral infarction may involve cortical and subcortical regions ( image 5). Ischemic injury distal to the stenotic or occluded moyamoya vessel is common in superficial and deep border-zone regions most susceptible to hypoperfusion [155]. Patterns of infarction may be suggestive of moyamoya, but these features are not specific for this condition. In a retrospective series of 32 adults with first-ever ischemic stroke, patients with early-stage MMD had ischemic lesions involving only deep subcortical structures, while those with advanced stage had predominantly cortical lesions [156]. In patients with intracerebral hemorrhage (ICH), bleeding occurs in deep structures such as the basal ganglia, thalamus, and/or ventricular system. Bleeding in the cortical and subcortical regions has been reported with lower frequency [157,158]. Asymptomatic cerebral microbleeds were present on T2*-weighted gradient-echo magnetic resonance imaging (MRI) in 30 percent or more of adult patients with MMD [159-161]. One study of 50 patients with moyamoya found that the presence of multiple microbleeds was an independent risk factor for subsequent intracerebral hemorrhage (hazard ratio [HR] 2.89, 95% CI 1.001-13.24) [160]. Additional MRI findings have been implicated in identifying vascular changes consistent with moyamoya: Dilated collateral vessels in the basal ganglia or thalamus can be demonstrated as multiple punctate flow voids, a finding that is considered virtually diagnostic of moyamoya ( image 6) [162]. The "ivy sign" refers to focal, tubular, or serpentine hyperintensities on fluid-attenuated inversion recovery (FLAIR) or contrast-enhanced T1 images in the subarachnoid spaces that represent slow, retrograde collateral flow through engorged pial vessels via leptomeningeal anastomoses ( image 7) [163-165]. Observational data of 48 patients with ischemic symptoms and MMD showed the extent of the ivy sign was associated with a reduction in cerebral vascular reserve assessed by single-photon emission computed https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 9/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate tomography (SPECT) [166]. This sign is not specific for MMS/MMD and has been reported in association with large-vessel stenosis or occlusions, where it is referred to as FLAIR vascular hyperintensities or the hyperintense vessel sign [167]. The "brush sign" refers to prominent hypointensity in medullary veins draining areas of impaired cerebral perfusion on susceptibility-weighted imaging (SWI), a high-spatial- resolution 3D gradient-echo MRI technique that accentuates paramagnetic properties of blood products such as deoxyhemoglobin. In a group of 33 patients, the brush sign was identified more often in moyamoya patients with TIA and infarction than in asymptomatic patients. This sign was also more prominent in those with impaired cerebrovascular reserve ( image 8) [168]. Like the ivy sign, the "brush sign" is not specific for moyamoya and has been identified in patients with subacute stroke from many causes [169]. Post-contrast enhancement within the arterial wall may be seen using high-resolution MRI [170]. One study of 24 patients with moyamoya who underwent high-resolution vessel wall imaging protocol with 3-tesla MRI showed that patients with MMD demonstrated concentric enhancement of the distal internal carotid arteries, whereas patients with intracranial atherosclerotic disease generally had focal and eccentric enhancement of the symptomatic arterial segment [171]. In addition, at six-month follow-up, vessel wall enhancement was found in eight of the nine patients (odds ratio [OR] 36.2, 95% CI 2.8- 475.0), while absence of enhancement was associated with nonprogressive stenosis. This technique may be helpful if angiographic findings on other more routine testing are not diagnostic but may not be readily available in many centers. Electroencephalographic findings Children with MMD often exhibit abnormalities on electroencephalography (EEG). Hyperventilation, performed as a part of EEG protocol, induces generalized high-voltage slow waves (the "build-up" phenomenon) that resolve after hyperventilation stops. The reappearance of generalized or localized high-voltage slow waves on EEG 20 to 60 seconds after the end of hyperventilation (the "rebuild-up" phenomenon) is considered pathognomonic for moyamoya and occurs in approximately two-thirds of affected children [172,173]. Asymmetric posterior alpha activity and centrotemporal slowing have also been described in children with moyamoya. Background abnormalities in children and adults with MMD include nonspecific generalized, asymmetric, or localized slow-wave activity [173,174]. Of note, hyperventilation should be minimized in patients with a diagnosis of moyamoya since it may induce reflex cerebral vasoconstriction [175]. While EEG with hyperventilation was reported https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 10/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate to be safe in one series of 127 children [173], rare reports link hyperventilation to limb-shaking TIA and episodes of chorea and dystonia [176-178]. DIAGNOSIS The diagnosis of moyamoya is made by identifying the characteristic angiographic appearance of bilateral stenoses affecting the distal internal carotid arteries (or other proximal circle of Willis vessels) along with the presence of prominent collateral vessels ( image 5). MMS is diagnosed by identifying characteristic angiographic features in the setting of an associated condition. MMD is diagnosed in patients with a genetic susceptibility or family history of moyamoya after associated conditions have been excluded. (See 'Associated conditions' above.) Indications for vascular imaging The possibility of MMD disease should be considered in: Children or young adults with repeated symptoms of ischemic attacks resulting from low perfusion in the same arterial territory. Patients who lack common factors for primary intracerebral hemorrhage (ICH) but present with intracerebral hemorrhage in brain regions supplied by small vessels that branch from the circle of Willis (eg, caudate, thalamus, or intraventricular hemorrhage within the lateral ventricles) ( image 9). Children or young adults with ischemic or hemorrhagic stroke who may lack common cerebrovascular risk factors. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Differential diagnosis'.) Patients who undergo MRI, particularly in the context of evaluation for cerebral ischemia, that shows associated findings such as dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," the "brush sign," or enhancement of the arterial wall. (See 'Neuroimaging' above.) Diagnostic criteria Definitive diagnosis of moyamoya requires neurovascular imaging. Diagnostic criteria proposed by a Japanese research committee include the following major requirements [4]: Stenosis or occlusion at the terminal portion of the internal carotid artery and at the proximal portion of the anterior and middle cerebral arteries. Abnormal vascular networks in the basal ganglia; these networks can also be diagnosed by the presence of multiple flow voids on brain MRI. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 11/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Angiographic findings are present bilaterally; cases with unilateral angiographic findings are considered probable. For the diagnosis of MMD, underlying associated conditions (suggestive instead of MMS) are excluded. (See 'Further evaluation' below.) Angiography Stenotic distal internal carotid or proximal circle of Willis arteries and prominent collateral vessels can be identified by angiogram, computed tomography angiogram (CTA), or magnetic resonance angiography (MRA). Conventional digital subtraction angiography (DSA) is the gold standard for the diagnosis of MMD. Additionally, DSA is typically required for treatment planning. Characteristic angiographic findings include stenosis or occlusion at the distal internal carotid artery and the origin of the anterior cerebral and middle cerebral arteries on both sides, as well as abnormal vascular networks at the basal ganglia or moyamoya vessels ( image 1). Noninvasive imaging (CTA and MRA) can demonstrate stenotic or occlusive lesions in the distal internal carotid arteries ( image 10) and the arteries around the circle of Willis [179-181]. Although less sensitive than DSA for smaller vessels, noninvasive testing can also visualize the collateral "moyamoya vessels" in the basal ganglia ( image 11). Nevertheless, due to its high diagnostic yield and noninvasive nature, CTA and MRA have supplanted conventional DSA in many centers as the initial imaging modality to evaluate moyamoya [162,181]. Because the vascular changes and associated risks of ischemia or hemorrhage sequelae in MMD and MMS are often progressive, characterizing the degree of vascular abnormality is important. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis", section on 'Neuroimaging'.) Angiographic severity staging systems can provide insight and guidance. Suzuki followed patients with MMD and classified the angiographic progression [182,183]. Further evaluation In the absence of a known genetic predisposition to MMD or known diagnosis associated with MMS (eg, sickle cell anemia), patients should be further evaluated for underlying conditions in order to institute the most appropriate secondary prevention strategy. Evaluation for vasculitis and other metabolic conditions may be indicated when suggestive features of clinical presentation are present. In general, work-up for atherosclerotic risk factors such as diabetes, dyslipidemia, hyperhomocysteinemia, and alternative sources to large-vessel vasculopathy should be performed. (See "Primary angiitis of the central nervous system in adults", section on 'When to suspect the diagnosis' and "Intracranial large artery atherosclerosis: https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 12/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Epidemiology, clinical manifestations, and diagnosis", section on 'Identifying other causes of intracranial stenosis'.) Hemodynamic studies are useful both pre- and postoperatively to help determine cerebrovascular reserve and to assess disease severity and risk of ischemic morbidity. These topics are discussed elsewhere. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis", section on 'Neuroimaging'.) SCREENING IMAGING In general, we do not screen asymptomatic individuals for moyamoya; however, screening with a noninvasive angiographic modality may be reasonable in those with a family history of MMD, particularly individuals from or with families from Eastern Asia. The 2008 American Heart Association Stroke Council guidelines state that there is insufficient evidence to justify screening studies in asymptomatic individuals or in relatives of patients with MMS in the absence of a strong family history of MMD or medical conditions that predispose to MMS [162]. Even in individuals with a strong family history of MMD or those with medical conditions that predispose to MMS, the utility of angiographic screening is unclear, particularly since available medical and surgical treatment of asymptomatic MMD is of uncertain benefit. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Classification and terminology Moyamoya describes chronic progressive cerebrovascular diseases typically characterized by bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation. (See 'Classification and terminology' above.) Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no underlying risk factors. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 13/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition. (See 'Classification and terminology' above and 'Associated conditions' above.) Epidemiology MMD and MMS are rare. MMD is more common in East Asian countries than elsewhere. There is a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second, broader peak at approximately 40 years of age. (See 'Incidence and prevalence' above.) Clinical presentations Ischemic stroke and transient ischemic attack (TIA) affecting the anterior circulation are the most common clinical presentations. (See 'Ischemic stroke and transient ischemic attack' above and 'Neuroimaging' above.) Intracranial hemorrhage is less common and is rare in children. Hemorrhage usually affects deep structures such as the basal ganglia or thalamus but may also be intraventricular or subarachnoid. (See 'Intracerebral, intraventricular, and subarachnoid hemorrhage' above and 'Neuroimaging' above.) Clinical and imaging findings suggestive of underlying moyamoya pathology MRI findings that suggest the diagnosis of moyamoya include dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," or the "brush sign." (See 'Neuroimaging' above.) The diagnosis of moyamoya is most often considered in those with suggestive MRI findings in the context of evaluation for ischemic stroke. Other settings in which the diagnosis should be considered include repeated episodes of ischemia in the same arterial territory, deep intracerebral hemorrhage in the absence of hypertension or other known cause, and ischemic or hemorrhagic stroke in children or young adults who lack cerebrovascular risk factors. (See 'Indications for vascular imaging' above.) Diagnosis The diagnosis of moyamoya is made by angiographic demonstration of bilateral stenoses affecting the distal internal carotid arteries or proximal circle of Willis vessels along with the presence of prominent basal collateral vessels. (See 'Diagnosis' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Smith ER, Scott RM. Spontaneous occlusion of the circle of Willis in children: pediatric moyamoya summary with proposed evidence-based practice guidelines. A review. J https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 14/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Neurosurg Pediatr 2012; 9:353. 2. Fukui M. Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis ('moyamoya' disease). Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) of the Ministry of Health and Welfare, Japan. Clin Neurol Neurosurg 1997; 99 Suppl 2:S238. 3. Arias EJ, Derdeyn CP, Dacey RG Jr, Zipfel GJ. Advances and surgical considerations in the treatment of moyamoya disease. Neurosurgery 2014; 74 Suppl 1:S116. 4. Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis, Health Labour Sciences Research Grant for Research on Measures for Infractable Diseases. Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo) 2012; 52:245. 5. Kim JS, Bang OY, Oh CW. Moyamoya disease. In: Uncommon Causes of Stroke, 3rd ed, Capla n L, Biller J (Eds), Cambridge University Press, New York, NY 2018. p.545. 6. Kamada F, Aoki Y, Narisawa A, et al. A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet 2011; 56:34. 7. Liu W, Morito D, Takashima S, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One 2011; 6:e22542. 8. Miyatake S, Miyake N, Touho H, et al. Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology 2012; 78:803. 9. Yamauchi T, Tada M, Houkin K, et al. Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke 2000; 31:930. 10. Mineharu Y, Liu W, Inoue K, et al. Autosomal dominant moyamoya disease maps to chromosome 17q25.3. Neurology 2008; 70:2357. 11. Miyawaki S, Imai H, Takayanagi S, et al. Identification of a genetic variant common to moyamoya disease and intracranial major artery stenosis/occlusion. Stroke 2012; 43:3371. 12. Wu Z, Jiang H, Zhang L, et al. Molecular analysis of RNF213 gene for moyamoya disease in the Chinese Han population. PLoS One 2012; 7:e48179. 13. Bang OY, Ryoo S, Kim SJ, et al. Adult Moyamoya Disease: A Burden of Intracranial Stenosis in East Asians? PLoS One 2015; 10:e0130663. 14. Wang Y, Zhang Z, Wei L, et al. Predictive role of heterozygous p.R4810K of RNF213 in the phenotype of Chinese moyamoya disease. Neurology 2020; 94:e678. 15. Ikeda H, Sasaki T, Yoshimoto T, et al. Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet 1999; 64:533. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 15/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 16. Inoue TK, Ikezaki K, Sasazuki T, et al. Linkage analysis of moyamoya disease on chromosome 6. J Child Neurol 2000; 15:179. 17. Sakurai K, Horiuchi Y, Ikeda H, et al. A novel susceptibility locus for moyamoya disease on chromosome 8q23. J Hum Genet 2004; 49:278. 18. Mineharu Y, Takenaka K, Yamakawa H, et al. Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting. J Neurol Neurosurg Psychiatry 2006; 77:1025. 19. Duan L, Wei L, Tian Y, et al. Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study. Stroke 2018; 49:11. 20. Lee SJ, Ahn JY. Stenosis of the proximal external carotid artery in an adult with moyamoya disease: moyamoya or atherosclerotic change? Neurol Med Chir (Tokyo) 2007; 47:356. 21. Ullrich NJ, Robertson R, Kinnamon DD, et al. Moyamoya following cranial irradiation for primary brain tumors in children. Neurology 2007; 68:932. 22. Fernandez-Alvarez E, Pineda M, Royo C, Manzanares R. "Moya-moya' disease caused by cranial trauma. Brain Dev 1979; 1:133. 23. Kitano S, Sakamoto H, Fujitani K, Kobayashi Y. Moyamoya disease associated with a brain stem glioma. Childs Nerv Syst 2000; 16:251. 24. Arita K, Uozumi T, Oki S, et al. Moyamoya disease associated with pituitary adenoma report of two cases. Neurol Med Chir (Tokyo) 1992; 32:753. 25. Tsuji N, Kuriyama T, Iwamoto M, Shizuki K. Moyamoya disease associated with craniopharyngioma. Surg Neurol 1984; 21:588. 26. Czartoski T, Hallam D, Lacy JM, et al. Postinfectious vasculopathy with evolution to moyamoya syndrome. J Neurol Neurosurg Psychiatry 2005; 76:256. 27. Yamada H, Deguchi K, Tanigawara T, et al. The relationship between moyamoya disease and bacterial infection. Clin Neurol Neurosurg 1997; 99 Suppl 2:S221. 28. Sharfstein SR, Ahmed S, Islam MQ, et al. Case of moyamoya disease in a patient with advanced acquired immunodeficiency syndrome. J Stroke Cerebrovasc Dis 2007; 16:268.
cerebrovascular diseases typically characterized by bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation. (See 'Classification and terminology' above.) Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no underlying risk factors. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 13/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition. (See 'Classification and terminology' above and 'Associated conditions' above.) Epidemiology MMD and MMS are rare. MMD is more common in East Asian countries than elsewhere. There is a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second, broader peak at approximately 40 years of age. (See 'Incidence and prevalence' above.) Clinical presentations Ischemic stroke and transient ischemic attack (TIA) affecting the anterior circulation are the most common clinical presentations. (See 'Ischemic stroke and transient ischemic attack' above and 'Neuroimaging' above.) Intracranial hemorrhage is less common and is rare in children. Hemorrhage usually affects deep structures such as the basal ganglia or thalamus but may also be intraventricular or subarachnoid. (See 'Intracerebral, intraventricular, and subarachnoid hemorrhage' above and 'Neuroimaging' above.) Clinical and imaging findings suggestive of underlying moyamoya pathology MRI findings that suggest the diagnosis of moyamoya include dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," or the "brush sign." (See 'Neuroimaging' above.) The diagnosis of moyamoya is most often considered in those with suggestive MRI findings in the context of evaluation for ischemic stroke. Other settings in which the diagnosis should be considered include repeated episodes of ischemia in the same arterial territory, deep intracerebral hemorrhage in the absence of hypertension or other known cause, and ischemic or hemorrhagic stroke in children or young adults who lack cerebrovascular risk factors. (See 'Indications for vascular imaging' above.) Diagnosis The diagnosis of moyamoya is made by angiographic demonstration of bilateral stenoses affecting the distal internal carotid arteries or proximal circle of Willis vessels along with the presence of prominent basal collateral vessels. (See 'Diagnosis' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Smith ER, Scott RM. Spontaneous occlusion of the circle of Willis in children: pediatric moyamoya summary with proposed evidence-based practice guidelines. A review. 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Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke 2008; 39:2644. 163. Ohta T, Tanaka H, Kuroiwa T. Diffuse leptomeningeal enhancement, "ivy sign," in magnetic resonance images of moyamoya disease in childhood: case report. Neurosurgery 1995; 37:1009. 164. Maeda M, Tsuchida C. "Ivy sign" on fluid-attenuated inversion-recovery images in childhood moyamoya disease. AJNR Am J Neuroradiol 1999; 20:1836. 165. Chung PW, Park KY. Leptomeningeal enhancement in petients with moyamoya disease: correlation with perfusion imaging. Neurology 2009; 72:1872. 166. Mori N, Mugikura S, Higano S, et al. The leptomeningeal "ivy sign" on fluid-attenuated inversion recovery MR imaging in Moyamoya disease: a sign of decreased cerebral vascular reserve? AJNR Am J Neuroradiol 2009; 30:930. 167. Azizyan A, Sanossian N, Mogensen MA, Liebeskind DS. Fluid-attenuated inversion recovery vascular hyperintensities: an important imaging marker for cerebrovascular disease. AJNR Am J Neuroradiol 2011; 32:1771. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 25/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 168. Horie N, Morikawa M, Nozaki A, et al. "Brush Sign" on susceptibility-weighted MR imaging indicates the severity of moyamoya disease. AJNR Am J Neuroradiol 2011; 32:1697. 169. Yu X, Yuan L, Jackson A, et al. Prominence of Medullary Veins on Susceptibility-Weighted Images Provides Prognostic Information in Patients with Subacute Stroke. AJNR Am J Neuroradiol 2016; 37:423. 170. Muraoka S, Araki Y, Taoka T, et al. Prediction of Intracranial Arterial Stenosis Progression in Patients with Moyamoya Vasculopathy: Contrast-Enhanced High-Resolution Magnetic Resonance Vessel Wall Imaging. World Neurosurg 2018; 116:e1114. 171. Ryoo S, Cha J, Kim SJ, et al. High-resolution magnetic resonance wall imaging findings of Moyamoya disease. Stroke 2014; 45:2457. 172. Kodama N, Aoki Y, Hiraga H, et al. Electroencephalographic findings in children with moyamoya disease. Arch Neurol 1979; 36:16. 173. Cho A, Chae JH, Kim HM, et al. Electroencephalography in pediatric moyamoya disease: reappraisal of clinical value. Childs Nerv Syst 2014; 30:449. 174. Frechette ES, Bell-Stephens TE, Steinberg GK, Fisher RS. Electroencephalographic features of moyamoya in adults. Clin Neurophysiol 2015; 126:481. 175. Smith ER. Moyamoya arteriopathy. Curr Treat Options Neurol 2012; 14:549. 176. Kim HY, Chung CS, Lee J, et al. Hyperventilation-induced limb shaking TIA in Moyamoya disease. Neurology 2003; 60:137. 177. Spengos K, Tsivgoulis G, Toulas P, et al. Hyperventilation-enhanced chorea as a transient ischaemic phenomenon in a patient with moyamoya disease. Eur Neurol 2004; 51:172. 178. Bakdash T, Cohen AR, Hempel JM, et al. Moyamoya, dystonia during hyperventilation, and antiphospholipid antibodies. Pediatr Neurol 2002; 26:157. 179. Tsuchiya K, Makita K, Furui S. Moyamoya disease: diagnosis with three-dimensional CT angiography. Neuroradiology 1994; 36:432. 180. Hasuo K, Mihara F, Matsushima T. MRI and MR angiography in moyamoya disease. J Magn Reson Imaging 1998; 8:762. 181. Yamada I, Nakagawa T, Matsushima Y, Shibuya H. High-resolution turbo magnetic resonance angiography for diagnosis of Moyamoya disease. Stroke 2001; 32:1825. 182. Suzuki J, Kodama N. Moyamoya disease a review. Stroke 1983; 14:104. 183. Suzuki J, Takaku A. Cerebrovascular "moyamoya" disease. Disease showing abnormal net- like vessels in base of brain. Arch Neurol 1969; 20:288. Topic 1131 Version 41.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 26/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate GRAPHICS 40-year-old with moyamoya disease Digital subtraction angiogram shows stenosis of right supraclinoid carotid, proximal middle cerebral artery a artery (oval), and lenticulostriate moyamoya collateral vessels (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129102 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 27/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Morning glory disc anomaly The disc is large and there is a central, white tuft of glial tissue. The retinal vessels proceed radially from the disc. Courtesy of Karl C Golnik, MD. Graphic 55325 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 28/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 9-year-old with unilateral moyamoya disease Digital subtraction angiogram shows stenosis of right supraclinoid and proximal middle cerebral arteries (cir lenticulostriate moyamoya collateral vessels (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129103 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 29/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Aneurysm in moyamoya disease Cerebral angiogram showing aneurysm (arrow) in patient with moyamoya disease. Courtesy of Nijasri Suwanwela, MD. Graphic 64850 Version 4.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 30/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 9-year-old male with moyamoya disease who presented with repeated episodes of transient left hemiparesis (A) Noncontrast head CT scan shows low-density area of infarction in the right basal ganglia (arrow). (B) MRI FLAIR image depicting a high-signal-intensity area in the right basal ganglia and multiple small hyperintense areas in both basal ganglia consistent with infarction. (C, D) Selective intra-arterial DSA (anteroposterior projection) shows severe stenoses of the distal right and left internal carotid arteries. Abnormal network of blood vessels (puff of smoke or moyamoya vessels) in the vicinity of the stenotic areas were noted (arrows). CT: computed tomography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DSA: digital subtraction angiogram. Courtesy of Nijasri Suwanwela, MD. Graphic 74421 Version 8.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 31/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 54-year-old with moyamoya disease T2-weighted sequence on magnetic resonance imaging shows lenticulostriate moyamoya collateral vessels on right (arrow). Courtesy of Glenn A Tung, MD, FACR. Graphic 129104 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 32/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 40-year-old with moyamoya disease "ivy sign" Fluid-attenuated inversion recovery sequence magnetic resonance imaging shows linear and curvilinear hyperintensities in the cerebral sulci consistent with "ivy sign" (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129105 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 33/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya disease "brush sign" The conspicuity of multiple deep medullary veins on susceptibility- weighted imaging sequence (oval) from reduced oxygen supply relative to tissue demand resulting in an increase in the concentration of deoxyhemoglobin in venous blood. Republished with permission of the American Society of Neuroradiology, from: Horie N, Morikawa M, Nozaki A, et al. "Brush sign" on susceptibility-weighted MR imaging indicates the severity of moyamoya disease. Am J Neurorad 2011; 32:1697; permission conveyed through Copyright Clearance Center, Inc. Copyright 2011. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 34/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Graphic 129106 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 35/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Intracerebral hemorrhage with intraventricular hemorrhage due to moyamoya syndrome
25/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 168. Horie N, Morikawa M, Nozaki A, et al. "Brush Sign" on susceptibility-weighted MR imaging indicates the severity of moyamoya disease. AJNR Am J Neuroradiol 2011; 32:1697. 169. Yu X, Yuan L, Jackson A, et al. Prominence of Medullary Veins on Susceptibility-Weighted Images Provides Prognostic Information in Patients with Subacute Stroke. AJNR Am J Neuroradiol 2016; 37:423. 170. Muraoka S, Araki Y, Taoka T, et al. Prediction of Intracranial Arterial Stenosis Progression in Patients with Moyamoya Vasculopathy: Contrast-Enhanced High-Resolution Magnetic Resonance Vessel Wall Imaging. World Neurosurg 2018; 116:e1114. 171. Ryoo S, Cha J, Kim SJ, et al. High-resolution magnetic resonance wall imaging findings of Moyamoya disease. Stroke 2014; 45:2457. 172. Kodama N, Aoki Y, Hiraga H, et al. Electroencephalographic findings in children with moyamoya disease. Arch Neurol 1979; 36:16. 173. Cho A, Chae JH, Kim HM, et al. Electroencephalography in pediatric moyamoya disease: reappraisal of clinical value. Childs Nerv Syst 2014; 30:449. 174. Frechette ES, Bell-Stephens TE, Steinberg GK, Fisher RS. Electroencephalographic features of moyamoya in adults. Clin Neurophysiol 2015; 126:481. 175. Smith ER. Moyamoya arteriopathy. Curr Treat Options Neurol 2012; 14:549. 176. Kim HY, Chung CS, Lee J, et al. Hyperventilation-induced limb shaking TIA in Moyamoya disease. Neurology 2003; 60:137. 177. Spengos K, Tsivgoulis G, Toulas P, et al. Hyperventilation-enhanced chorea as a transient ischaemic phenomenon in a patient with moyamoya disease. Eur Neurol 2004; 51:172. 178. Bakdash T, Cohen AR, Hempel JM, et al. Moyamoya, dystonia during hyperventilation, and antiphospholipid antibodies. Pediatr Neurol 2002; 26:157. 179. Tsuchiya K, Makita K, Furui S. Moyamoya disease: diagnosis with three-dimensional CT angiography. Neuroradiology 1994; 36:432. 180. Hasuo K, Mihara F, Matsushima T. MRI and MR angiography in moyamoya disease. J Magn Reson Imaging 1998; 8:762. 181. Yamada I, Nakagawa T, Matsushima Y, Shibuya H. High-resolution turbo magnetic resonance angiography for diagnosis of Moyamoya disease. Stroke 2001; 32:1825. 182. Suzuki J, Kodama N. Moyamoya disease a review. Stroke 1983; 14:104. 183. Suzuki J, Takaku A. Cerebrovascular "moyamoya" disease. Disease showing abnormal net- like vessels in base of brain. Arch Neurol 1969; 20:288. Topic 1131 Version 41.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 26/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate GRAPHICS 40-year-old with moyamoya disease Digital subtraction angiogram shows stenosis of right supraclinoid carotid, proximal middle cerebral artery a artery (oval), and lenticulostriate moyamoya collateral vessels (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129102 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 27/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Morning glory disc anomaly The disc is large and there is a central, white tuft of glial tissue. The retinal vessels proceed radially from the disc. Courtesy of Karl C Golnik, MD. Graphic 55325 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 28/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 9-year-old with unilateral moyamoya disease Digital subtraction angiogram shows stenosis of right supraclinoid and proximal middle cerebral arteries (cir lenticulostriate moyamoya collateral vessels (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129103 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 29/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Aneurysm in moyamoya disease Cerebral angiogram showing aneurysm (arrow) in patient with moyamoya disease. Courtesy of Nijasri Suwanwela, MD. Graphic 64850 Version 4.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 30/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 9-year-old male with moyamoya disease who presented with repeated episodes of transient left hemiparesis (A) Noncontrast head CT scan shows low-density area of infarction in the right basal ganglia (arrow). (B) MRI FLAIR image depicting a high-signal-intensity area in the right basal ganglia and multiple small hyperintense areas in both basal ganglia consistent with infarction. (C, D) Selective intra-arterial DSA (anteroposterior projection) shows severe stenoses of the distal right and left internal carotid arteries. Abnormal network of blood vessels (puff of smoke or moyamoya vessels) in the vicinity of the stenotic areas were noted (arrows). CT: computed tomography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DSA: digital subtraction angiogram. Courtesy of Nijasri Suwanwela, MD. Graphic 74421 Version 8.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 31/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 54-year-old with moyamoya disease T2-weighted sequence on magnetic resonance imaging shows lenticulostriate moyamoya collateral vessels on right (arrow). Courtesy of Glenn A Tung, MD, FACR. Graphic 129104 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 32/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 40-year-old with moyamoya disease "ivy sign" Fluid-attenuated inversion recovery sequence magnetic resonance imaging shows linear and curvilinear hyperintensities in the cerebral sulci consistent with "ivy sign" (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129105 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 33/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya disease "brush sign" The conspicuity of multiple deep medullary veins on susceptibility- weighted imaging sequence (oval) from reduced oxygen supply relative to tissue demand resulting in an increase in the concentration of deoxyhemoglobin in venous blood. Republished with permission of the American Society of Neuroradiology, from: Horie N, Morikawa M, Nozaki A, et al. "Brush sign" on susceptibility-weighted MR imaging indicates the severity of moyamoya disease. Am J Neurorad 2011; 32:1697; permission conveyed through Copyright Clearance Center, Inc. Copyright 2011. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 34/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Graphic 129106 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 35/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Intracerebral hemorrhage with intraventricular hemorrhage due to moyamoya syndrome Noncontrast head CT (A) showing hematoma in the right corpus striatum and lateral ventricles. Digital subtraction angiogram (B) showing critical stenosis of proximal right middle cerebral artery (arrow), prominent collateralization of both lenticulostriate vessels (circle), and branches of the anterior cerebral artery (thick arrows). CT: computed tomography. Courtesy of Glenn A Tung, MD, FACR. Graphic 132277 Version 1.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 36/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Magnetic resonance angiography (MRA) of a patient with moyamoya disease A) There is severe narrowing of the distal part of the both carotid arteries (arrows). In addition, there is markedly reduced flow in the left middle cerebral artery and absence of both anterior cerebral arteries. B) Lateral projection MRA demonstrates severe narrowing of the distal internal carotid artery (arrow). Courtesy of Nijasri Suwanwela, MD. Graphic 51947 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 37/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 12-year-old with moyamoya syndrome secondary to neurofibromatosis type 1 Magnetic resonance angiogram shows occlusion of left supraclinoid internal carotid artery (circles) and lentic collateral vessels (arrow). Courtesy of Glenn A Tung, MD, FACR. Graphic 129107 Version 3.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 38/39 7/5/23, 12:23 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Contributor Disclosures Nijasri Charnnarong Suwanwela, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Douglas R Nordli, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 39/39
7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Reversal of anticoagulation in intracranial hemorrhage : W David Freeman, MD, Jeffrey I Weitz, MD : Lawrence LK Leung, MD, Scott E Kasner, MD : Richard P Goddeau, Jr, DO, FAHA, Jennifer S Tirnauer, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 17, 2023. INTRODUCTION Intracranial hemorrhage, which includes intracerebral, intraventricular, subarachnoid, subdural, and epidural bleeding, is a potentially devastating occurrence associated with anticoagulant therapy. Reversal of anticoagulation in patients with anticoagulant-associated intracranial hemorrhage is a medical emergency, as anticoagulation is associated with greater hematoma growth, neurologic deterioration, and increased risk of death and major disability compared with no anticoagulation. This topic discusses the reversal of anticoagulation in patients with anticoagulant-associated intracranial hemorrhage. Other aspects of the management and prevention of intracranial hemorrhage are presented separately. Risks and prevention (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Intracranial'.) (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Risk of recurrence'.) Management https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 1/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Intracerebral hemorrhage (ICH) (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) Intraventricular hemorrhage (IVH) (See "Intraventricular hemorrhage", section on 'Management'.) Subarachnoid hemorrhage (SAH) (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Subdural hematoma (SDH) (See "Subdural hematoma in adults: Management and prognosis".) Epidural hematoma (EDH) (See "Intracranial epidural hematoma in adults", section on 'Management'.) TERMINOLOGY The following terms are used herein: Intracranial hemorrhage Intracranial hemorrhage is the broadest term for bleeding; it includes bleeding anywhere inside the skull, including intracerebral, intraventricular, subarachnoid, and subdural hemorrhage. Intracerebral hemorrhage Intracerebral hemorrhage (ICH) is bleeding in the brain parenchyma. Intraventricular hemorrhage Intraventricular hemorrhage refers to bleeding within the ventricular system in the brain. Subarachnoid hemorrhage Subarachnoid hemorrhage is bleeding directly adjacent to the brain in the subarachnoid space (between the pia mater and arachnoid membrane); most of these are caused by ruptured saccular aneurysms. Subdural hematoma Subdural hematoma is bleeding outside the subarachnoid space directly beneath the dura mater. Epidural hematoma Epidural hematoma is bleeding in the potential space between the dura mater and the skull or in the epidural space in the spinal canal. URGENT EVALUATION The goal of the evaluation is to document as rapidly as possible, with brain imaging, whether the patient's symptoms are due to intracranial bleeding rather than another cause, such as https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 2/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate poisoning (related to a suicide attempt or other toxic exposure), encephalopathy, or ischemia; to document that the patient is in fact anticoagulated; and to confirm which anticoagulant is responsible. This information determines whether a reversal agent is needed, and if so, the specific agent. We request urgent evaluation by neurology and/or neurosurgery (and stroke team where available) when a patient presents with a suspected intracranial hemorrhage. Laboratory testing for anticoagulation status and brain imaging should be obtained immediately, notifying the laboratory and the radiology department of the emergency nature of the testing and imaging. Patient history can be obtained while the patient is being examined and blood for laboratory testing is being drawn. Often, the neurologist or stroke team can meet the patient in the radiology department and see the images as they are being obtained or review them immediately after. Rapid clinical assessment We rapidly obtain the relevant history, which includes the onset of symptoms, major neurologic abnormalities, which anticoagulant and dose the patient is taking and for what indication, and when they took the most recent dose. Presenting symptoms Patients with symptomatic intracranial hemorrhage generally present with acute onset of neurologic impairment consistent with stroke, although some patients with subarachnoid hemorrhage (SAH) may be neurologically intact and present with isolated sudden-onset, severe headache (ie, thunderclap headache). Subdural hematoma in the setting of anticoagulation may present with acute neurologic deterioration or milder symptoms initially, depending on the size and acuity. Clinical manifestations of epidural hematoma (EDH) are highly variable and include altered consciousness, headache, vomiting, drowsiness, confusion, aphasia, seizures, and hemiparesis. Some patients with acute EDH and transient loss of consciousness have a "lucid interval" with recovery of consciousness followed by deterioration due to hematoma enlargement. Symptoms of intracranial hemorrhage may include headache, nausea, vomiting, or neurologic deficit(s). It is important to distinguish between symptomatic hemorrhage and incidentally discovered hemorrhage on neuroimaging; both are potentially clinically serious, but the urgency and aggressiveness needed to manage symptomatic bleeding may be greater than that for an incidentally discovered subdural bleed that may already be stabilized or resolving. (See 'Neuroimaging' below.) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 3/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Additional details of the presentation and diagnosis of intracranial hemorrhage are reviewed separately by etiology: Intracerebral hemorrhage (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Clinical presentation' and "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Evaluation and diagnosis') Intraventricular hemorrhage (see "Intraventricular hemorrhage", section on 'Clinical presentation' and "Intraventricular hemorrhage", section on 'Diagnostic evaluation') Subarachnoid hemorrhage (see "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Clinical presentation' and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis') Subdural hematoma (see "Subdural hematoma in adults: Etiology, clinical features, and diagnosis", section on 'Clinical manifestations' and "Subdural hematoma in adults: Etiology, clinical features, and diagnosis", section on 'Diagnosis and evaluation') Epidural hematoma (see "Intracranial epidural hematoma in adults", section on 'Clinical manifestations' and "Intracranial epidural hematoma in adults", section on 'Diagnostic evaluation') Trauma We ask if there was direct trauma to the head. If the patient was injured in a motor vehicle accident or other trauma (eg, a fall), we determine how fast the vehicle was going and whether neurologic deterioration started before or after the accident. If the patient fell, we determine the distance fallen. Anticoagulant and other medications We ask the name of the anticoagulant and confirm that it is the same as that listed in the medical record. We also ask if the patient is taking other medication(s) that could affect hemostasis, such as an antiplatelet agent (eg, aspirin, clopidogrel) or a drug that may affect the metabolism of their anticoagulant. The tables provide examples of drug interactions for warfarin ( table 1) and the direct oral anticoagulants (DOACs) ( table 2). (See "Biology of warfarin and modulators of INR control", section on 'Drug interactions'.) Dose and timing The indication for the anticoagulant should be assessed as this helps in confirming the specific agent, the dose, and the risk of thrombosis if anticoagulation is stopped or reversed. We ask what anticoagulant dose the patient is using and when the last dose was taken. The strength and timing of the last dose taken may impact whether https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 4/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate reversal is necessary and, especially for andexanet alfa, the amount of reversal agent needed. We also assess whether it is possible that the patient may be anticoagulated to a greater degree than expected with routine dosing. This includes questioning about how they are taking the anticoagulant to ascertain possible overdose or incorrect dosing. For patients on warfarin, we ask about the timing and result of the most recent international normalized ratio (INR). Comorbidities We ask if the individual has renal or hepatic disease, which may affect clearance or metabolism of DOACs, as well as any intercurrent infection, which may affect the INR on warfarin. Disorders that alter gastrointestinal absorption of drugs may explain lack of anticoagulant effect in some cases. Concomitant uremia or thrombocytopenia may increase bleeding risk. The underlying condition necessitating anticoagulation may also be a factor in decision-making, especially for those at highest risk of thromboembolic complications (recent pulmonary embolism, mechanical heart valve). Patients with moderate-to-severe neurologic deficits due to acute stroke may be unable to provide a reliable history. In such cases, it is important to review the patient's medical record and ask family members, friends, and caregivers whether the patient is receiving an anticoagulant and if so, when it was last administered. In some cases, it may be reasonable to ask if there was a suspected suicide attempt. If no history is available, we base our assessment on the results of coagulation testing and imaging. Neuroimaging As noted above, neuroimaging is performed in individuals taking an anticoagulant who develop symptoms consistent with intracranial bleeding, including headache, nausea, vomiting, or neurologic defects. The need for intervention may be more urgent in those with symptomatic bleeding than for those with incidentally discovered bleeding. (See 'Rapid clinical assessment' above.) Acute intracranial hemorrhage must be confirmed by neuroimaging, typically with urgent noncontrast computed tomography (CT), or, less frequently, with magnetic resonance imaging (MRI), before undertaking interventions to reverse anticoagulation. It is not possible to distinguish bleeding from ischemia by history and physical examination alone. This is especially true for patients with atrial fibrillation, who are at increased risk for ischemic stroke, but it applies to all individuals. As an example, neurologic symptoms following a motor vehicle accident may be due to traumatic intracranial hemorrhage or due to an ischemic stroke leading to loss of control of the vehicle. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 5/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate In selected cases in which the time delay in obtaining intracranial imaging could be life threatening, the clinicians may decide to treat empirically; this is a challenging decision that weighs the risks and benefits of empiric treatment versus delaying therapy to confirm the diagnosis. As an example, anticoagulant reversal may be reasonable for an individual with head trauma who has papilledema and for whom brain imaging is not available. However, papilledema has causes aside from ICH and by itself (without brain imaging) is not enough evidence for reversal. Laboratory testing We perform the following testing as rapidly as possible: All patients PT with INR, activated partial thromboplastin time (aPTT), and complete blood count (CBC) with platelet count. Patients on dabigatran Thrombin time (TT); diluted thrombin time (dTT) or ecarin clotting time (ECT) may be performed but they are not widely available. Serum creatinine should also be measured, and creatinine clearance calculated, as dabigatran is primarily eliminated by renal clearance. Patients on an oral factor Xa inhibitor or low molecular weight (LMW) heparin Anti- factor Xa activity, creatinine, and calculated creatinine clearance. Selected patients Liver function tests, basic metabolic panel, and other testing to address suspected comorbidities or other causes of neurologic deterioration. TT and anti-factor Xa activity may not be routinely available at all institutions, although most hospitals can perform a TT. Obtaining a platelet count is important to ensure that the patient does not have concomitant thrombocytopenia, which might contribute to bleeding. The usefulness of these coagulation tests varies according to the anticoagulant agent: Warfarin A prolonged PT or INR (eg, INR 1.4) indicates that the patient is anticoagulated. The aPTT is also prolonged with warfarin. In some cases, an individual with a PT or INR at the high end of the normal range may be slightly anticoagulated, especially if the value is higher than his or her baseline before starting warfarin. The PT and INR are monitored daily to determine if the warfarin effect is persistent and additional vitamin K is needed. (See 'Warfarin' below.) Dabigatran High plasma levels of dabigatran may prolong the aPTT. However, the aPTT may be normal or near normal in patients with therapeutic levels of dabigatran. Therefore, https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 6/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate a prolonged aPTT indicates the need for reversal, but normal aPTT values cannot be used to establish the lack of dabigatran effect. The TT, dTT, and ECT are more sensitive to the anticoagulant effects of dabigatran than the aPTT. Therefore, we would not use a reversal agent if the TT, dTT, and/or ECT are normal. If the TT, dTT, or ECT are not available, anticoagulation status is determined from the history of dabigatran ingestion (eg, dose, time since last dose). (See 'Dabigatran' below.) Direct factor Xa inhibitors Direct factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) are detected by anti-factor Xa activity calibrated to the specific agent. In some cases, anti- factor Xa activity calibrated to a different agent may show drug effect, although this is not optimal. The PT and aPTT may be helpful if prolonged but are not considered reliable indicators of anticoagulant effect. An anti-factor Xa activity that indicates a drug level of >30 ng/mL is evidence of anticoagulation. If anti-factor Xa activity is not available and the PT and aPTT are normal, anticoagulation status is determined from the history of anticoagulant ingestion. (See 'Apixaban, edoxaban, and rivaroxaban' below.) Unfractionated heparin Unfractionated heparin prolongs the aPTT and has anti-factor Xa activity. Heparin has a short half-life of approximately one hour after intravenous infusion. A normal aPTT indicates that the anticoagulant effect has resolved. (See 'Unfractionated heparin' below.) LMW heparin LMW heparin has anti-factor Xa activity. The assay should be calibrated to LMW heparin. A detectable LMW heparin level 0.3 international units/mL indicates LMW heparin effect. There is no anticoagulant effect if there is no detectable anti-factor Xa activity or if the anti-factor Xa activity indicates a LMW heparin level less than 0.3 international units/mL. (See 'LMW heparin' below.) The expected effect of anticoagulants on commonly used clotting tests is summarized in the table ( table 3). For warfarin, the extent of INR prolongation at the time of warfarin-associated ICH correlates with initial hematoma size, progressive hematoma enlargement after admission, functional outcome, and mortality [1-6]. Most episodes of warfarin-associated ICH occur in patients with a therapeutic level of anticoagulation (INR 2.0 to 3.5) [1,7-11]. However, even patients with a therapeutic INR can have an increased risk of bleeding, especially those older than 70 years of age. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk'.) While similar data have not been obtained for all the other anticoagulants, it is likely that the intensity of the anticoagulant effect correlates with the severity of intracerebral bleeding, and https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 7/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate that any level of anticoagulation puts the patient at risk for adverse outcomes of intracranial bleeding compared with no anticoagulation. INDICATIONS FOR REVERSAL AND GOALS OF TREATMENT Acute intracranial hemorrhage Urgent anticoagulant reversal is indicated for patients with acute intracerebral (ICH), intraventricular, subarachnoid, or subdural hemorrhage associated with active anticoagulation. These types of hemorrhage are assumed to be life threating regardless of the extent of hemorrhage visible on initial brain imaging, since ongoing bleeding and hemorrhage enlargement can cause neurologic deterioration, elevation in intracranial pressure, and poor functional outcome or death [12]. An exception is that urgent reversal may not be necessary for a clinically stable patient with a small, chronic subdural hemorrhage and no evidence of elevated intracranial pressure; in such a case, the potential benefit of reversing anticoagulation (reduced risk of hematoma enlargement) must be weighed against the risk of thrombosis related to the underlying need for anticoagulation. As an example, anticoagulation with warfarin dose adjusted to achieve a therapeutic international normalized ratio (INR) may be continued in an individual with a mechanical heart valve and a small subdural hematoma with no signs of increased intracranial pressure, since the risk of valve thrombosis may be a greater concern than hematoma expansion. Another option in such an individual is to switch to heparin anticoagulation, which is easier to reverse quickly, while observing for clinical improvement. This subject is discussed in detail separately. (See "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures" and "Antithrombotic therapy for mechanical heart valves".) As noted above, reversal is only appropriate after intracerebral bleeding has been documented on an imaging study. Empiric treatment for suspected intracranial hemorrhage in the absence of confirmation by one of these methods is not advised unless the patient is in extremis and imaging is not available. This is because reversal agents are potentially prothrombotic, and their use may cause harms without benefit if they are given to an individual who did not actually have a hemorrhage [12]. As noted above, some patients who are receiving an anticoagulant may not actually be anticoagulated, especially if they are on a short-acting agent and took their last dose several half-lives ago. The lack of anticoagulation was demonstrated in some of the trials evaluating reversal agents for the direct oral anticoagulants. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Anticoagulant reversal'.) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 8/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate The main goals of treatment are to rapidly reverse anticoagulation effects and to maintain reversal for a minimum of 72 hours, thereby limiting hemorrhage enlargement. This is important because hematoma growth, particularly within the first 24 hours after ICH, is an independent predictor of mortality and poor outcome. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Predicting hemorrhage expansion' and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Clinical risk factors'.) Reversal of anticoagulation, along with blood pressure control, is believed to improve outcomes in warfarin-associated ICH. In one observational study, reduced rates of hematoma enlargement were noted for patients who had reversal of INR <1.3 within four hours of admission (20 versus 42 percent) [13]. The combination of successful reversal of INR <1.3 and blood pressure control <160 mmHg within four hours was associated with lowered rates of hematoma enlargement (18 versus 44 percent) and in-hospital mortality (13 versus 21 percent). Lumbar puncture in suspected subarachnoid hemorrhage When there is strong suspicion for subarachnoid hemorrhage (SAH) despite a normal head computed tomography (CT), lumbar puncture is generally required, except for selected patients with isolated headache, a normal neurologic examination, and high-quality brain imaging performed within six hours of headache onset that is negative for hemorrhage. The sensitivity of CT for detecting SAH decreases over the ensuing hours to days. The evaluation for SAH is discussed in detail separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.) Anticoagulation is considered a contraindication to lumbar puncture. Anticoagulation should be reversed for patients who require a lumbar puncture to rule out SAH while anticoagulated, as assessed by criteria described above (eg, INR 1.5 for warfarin; prolonged TT for dabigatran; anti-factor Xa activity assay that indicates a level of apixaban, rivaroxaban, or edoxaban over 30 ng/mL; history of ingestion in the preceding 24 to 48 hours if laboratory testing is inconclusive or unavailable). (See 'Laboratory testing' above.) GENERAL MEASURES FOR ALL ANTICOAGULANTS Discontinue all antithrombotic agents All anticoagulant and antiplatelet therapy should be discontinued. This includes discontinuation of the anticoagulant the patient is taking, and avoidance of other anticoagulants (eg, "routine" orders for heparin or low molecular weight (LMW) heparin administration for venous thromboembolism prophylaxis). These measures must be clearly stipulated in the medical record and ordering system. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 9/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate If an individual has another hemostatic defect such as moderate to severe thrombocytopenia (platelet count <50,000 to 100,000/microL) or use of dual antiplatelet therapy, consideration should be given to concomitant therapy for that defect as well. (See 'Other supportive care' below and 'Limited role of platelet transfusions' below.) Potential exceptions are noted above. (See 'Indications for reversal and goals of treatment' above.) Admit to intensive care Patients with acute anticoagulant-associated intracranial hemorrhage should be managed initially in an intensive care setting where frequent neurologic checks can detect neurologic deterioration, and hemodynamic monitoring can allow tighter blood pressure control and management. Control blood pressure Elevated blood pressure may predispose to hematoma expansion in patients with intracerebral hemorrhage (ICH), as already noted. (See 'Indications for reversal and goals of treatment' above.) We target a systolic blood pressure below 140 mmHg for ICH and below 160 mmHg for subarachnoid hemorrhage. Lower blood pressure targets in the acute setting increase the risk of hypoperfusion and infarction. We generally administer antihypertensive agents for those with a systolic blood pressure above 150 mmHg. Specific antihypertensive agents and the frequency of monitoring are discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management' and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Blood pressure control'.) Other supportive care Other interventions include rapid and regular assessment of hemodynamic status and airway, along with optimization of body temperature, pH, and electrolyte balance. Rarely, transfusions may be needed, such as platelet transfusions for thrombocytopenia or red blood cell transfusions for anemia. (See 'Limited role of platelet transfusions' below.) Supportive measures are discussed in more detail separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Overview of management'.) Supportive care related to the site of bleeding is presented elsewhere: Intracerebral hemorrhage (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 10/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Intraventricular hemorrhage (See "Intraventricular hemorrhage", section on 'Management'.) Subarachnoid hemorrhage (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Subdural hematoma (See "Subdural hematoma in adults: Management and prognosis".) Epidural hematoma (See "Intracranial epidural hematoma in adults", section on 'Management'.) Limited role of platelet transfusions Platelet transfusions generally are not indicated in the setting of intracranial bleeding, even for patients on concomitant antiplatelet therapy. Thrombocytopenia Platelet transfusion is appropriate for an individual with platelet counts <100,000/microL or with a known platelet function defect. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Actively bleeding patient' and "Platelet transfusion: Indications, ordering, and associated risks", section on 'Platelet function disorders'.) Antiplatelet agents The available data from trials of patients with spontaneous ICH (eg, the PATCH trial) suggest that empiric platelet transfusions in those without thrombocytopenia may be hazardous and should generally be avoided. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Antiplatelet agents'.) Some clinicians use platelet transfusions for patients taking long-acting antiplatelet agents such as clopidogrel or prasugrel, but there is limited evidence to support this approach. Input from the neurologist and hematologist may be helpful in determining an individualized approach. Platelet transfusion is not considered useful for patients taking ticagrelor because ticagrelor is a reversible inhibitor of the adenosine diphosphate (ADP) receptor on the platelet surface and will bind to transfused platelets. REVERSAL STRATEGY FOR SPECIFIC ANTICOAGULANTS The reversal agent depends on which anticoagulant the patient is receiving. This should be confirmed from the history and in some cases, the results of coagulation testing. (See 'Rapid clinical assessment' above and 'Laboratory testing' above.) As noted above, reversal should be done as rapidly as possible but should only be done when intracerebral bleeding is documented (see 'Neuroimaging' above), in order to avoid giving https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 11/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate potentially prothrombotic drugs unnecessarily to a person with an increased thrombosis risk. Our approach for specific anticoagulants (outlined in the following sections) is largely consistent with general guidelines for reversing anticoagulation in the setting of severe bleeding as well as guidelines specific to hemorrhagic stroke [14-19]. A complete listing of society guidelines is presented separately. (See "Society guideline links: Anticoagulation" and "Society guideline links: Stroke in adults".) Warfarin Intracranial bleeding associated with warfarin anticoagulation should be treated with a rapid source of functional clotting factors as well as vitamin K to allow endogenous production of functional vitamin K-dependent factors. Warfarin works by interfering with carboxylation of the vitamin K-dependent clotting factors (factors II [prothrombin], VII, IX, and X). Carboxylation of these factors is essential for their function. The principal means of reversing warfarin rapidly is to replace these fully functional factors. The most rapidly acting source of functional factors is a 4-factor prothrombin complex concentrate (4-factor PCC). Convincing evidence of warfarin anticoagulation is based on a prolonged prothrombin time (PT) and an international normalized ratio (INR) outside the normal range ( 1.4 in most cases). (See 'Laboratory testing' above.) Reversal and monitoring strategy Our approach (described in the following sections) is similar to the 2022 guideline from the American Heart Association (AHA)/American Stroke Association (ASA), the 2018 guideline from the American Society of Hematology (ASH), and the 2012 guideline from the American College of Chest Physicians (ACCP), which recommend the following for serious or life-threatening bleeding associated with warfarin ( table 4) [16,18,19]: Hold warfarin. We also make sure that warfarin has been discontinued and that this is clearly stated in the medical record. Administer a 4-factor PCC; if a PCC is not available, a plasma product such as Fresh Frozen Plasma (FFP) or Thawed Plasma may be used. (See 'Reversal agent' below.) Administer intravenous vitamin K. (See 'Intravenous vitamin K' below.) The effects of these treatments is summarized in the table ( table 5) and an overview of warfarin-associated bleeding and reversal is presented separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR".) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 12/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate We recheck the PT/INR at approximately 30 minutes following PCC (or plasma) administration and periodically thereafter (eg, INR checked every four to six hours for the first 24 hours, and then checked daily for a few days) to ensure that the INR has become normal (<1.4 in most laboratories) and is maintained in the normal range [11,20]. If the INR remains elevated, additional doses of PCC or plasma may be given [21,22]. Details are presented separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Serious/life-threatening bleeding'.) Reversal agent For warfarin-associated ICH, we recommend reversal with 4-factor prothrombin complex concentrate (4-factor PCC) rather than plasma. Options if 4-factor PCC is unavailable include 3-factor PCC supplemented with a source of factor VII, such as recombinant activated factor VII (rFVIIa), or a plasma product such as Fresh Frozen Plasma or Thawed Plasma. However, use of plasma may delay warfarin reversal, leading to a greater risk of complications of hematoma expansion, and may cause a transfusion reaction. We generally do not recommend the use of rFVIIa alone for treatment of warfarin-associated ICH because it does not replace factors II, IX, or X and may give a false sense of security by normalizing the INR without fully reversing warfarin effect. rFVIIa acts rapidly (eg, normalization of the INR within 10 minutes), but the half-life is only two to three hours, and repeated dosing or administration of another product would be required [23,24]. Although the INR is normalized rapidly with rFVIIa, the bleeding risk may persist due to dysfunction of other vitamin K- dependent factors. Thus, the normal INR may give a false sense of security and deprive the patient of other, more effective treatments. Additionally, 4-factor PCC is likely to carry a lower risk of thrombosis than products containing activated factors (rFVIIa or activated PCC, which contains activated factor VII). Prothrombin complex concentrate All four vitamin K-dependent factors are present in 4-factor PCC, which can be administered rapidly in a small volume ( table 6). Thus, 4-factor PCC is the preferred treatment ( table 4). Supporting evidence is summarized below. (See 'Efficacy of PCC versus plasma' below.) All institutions that treat patients with anticoagulant-associated hemorrhage should stock a 4- factor PCC. The available strategies for factor replacement are presented in order of preference; only one of these should be used, along with vitamin K: 4-factor PCC We generally give 4-factor PCC (Kcentra in the United States and Japan; Beriplex or Octaplex in Canada; Octaplex, Cofact, or Proplex in many European countries) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 13/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate as an initial fixed dose of 1500 to 2000 international units at a rate of 100 units/minute ( table 7). Fixed-dose PCC may be easier logistically to stock and deliver in emergencies, but supplemental PCC doses may be required for those with warfarin-associated ICH who have a higher INR (>3). Alternatively, the initial dose may be calculated by body weight and INR. If weight-based or INR-based dosing is used, institutional protocols should be followed. An example is 25 units/kg for INR 2 to 4; 35 units/kg for INR 4 to 6; and 50 units/kg for INR >6, with a maximum dose of 5000 units [25]. In a randomized trial involving 199 patients with warfarin-associated extracranial bleeding, the rate of effective hemostasis in those assigned to an initial fixed-dose PCC (1000 units) was similar to those assigned a calculated dose that incorporated body weight and INR (87 versus 90 percent) [26]. The median initial dose in the calculated dose group was 1750 units. An additional dose of PCC was given to four patients in the fixed-dose group compared with one in the weight-based group, but the door-to-needle time was shorter in the fixed-dose group (109 versus 142 minutes). The proportion of patients in each group reaching an INR 2.0 within 60 minutes was similar (91 versus 92 percent). 3-factor PCC plus a supplement If a 4-factor PCC is not available, a 3-factor PCC (Profilnine in the United States; Bebulin was discontinued in 2018) can be used. However, 3- factor PCC does not contain factor VII. Therefore, most experts recommend supplementing 3-factor PCC with rFVIIa at a dose of 20 mcg/kg or with plasma (eg, FFP, two units). If rFVIIa is used to supplement 3-factor PCC, we prefer a lower dose (20 mcg/kg) rather than higher doses. This is based on data from a randomized trial in 841 patients with spontaneous intracerebral hemorrhage (ICH; not warfarin-associated) that compared two doses of rFVIIa (80 and 20 mcg/kg) with placebo; PCC was not administered [27]. The primary outcome (severe disability or death) was similar among the three groups, despite less expansion of the hemorrhage in those receiving rFVIIa. Overall, thromboembolic events were similar in the three groups, but severe events (eg, cerebral infarction, myocardial infarction [MI]) were more common in those who received high-dose rFVIIa compared with placebo (8 versus 4 percent). Activated PCC Activated PCC (aPCC) contains factors II, VII, IX, and X; factor VII is mostly present in the activated form (VIIa). The only available aPCC is factor eight inhibitor bypassing activity (FEIBA). FEIBA generally is not used for reversing warfarin anticoagulation, because the activated factor VII is potentially more prothrombotic compared with the factor VII in 4-factor PCC (discussed above) that is not in the activated https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 14/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate state. However, retrospective data suggest that treatment with FEIBA does not increase the risk of thrombotic events compared with plasma products [28]. Plasma products if PCC is unavailable If prothrombin complex concentrate (PCC) is unavailable, a plasma product (eg, FFP, Thawed Plasma) can be used to provide clotting factors. However, plasma requires a much larger volume of administration, often delaying the time to normalization of the INR, during which time hemorrhage expansion can continue. This was illustrated in a series of 45 patients with ICH, in which the median time interval between admission to a neuro-intensive care unit and INR normalization with FFP was 30 hours (range: 14 to 50 hours) [29]. Thus, plasma is not a very effective intervention for reducing the expansion of the hemorrhage [12]. Plasma also carries risks of transfusion reactions. A reasonable approach is to give two units of plasma, recheck the INR, and give additional units if needed. The infusion rate for plasma depends on the patient's ability to tolerate the volume load. FFP and other plasma products such as Thawed Plasma are equally effective in reversing the effects of anticoagulation and are considered interchangeable. Thawed Plasma (FFP that has been stored by refrigeration at 1 to 6 degrees Celsius) has the advantage of being available for immediate use. Eight units (2 liters) of FFP or Thawed Plasma are often required to fully reverse anticoagulation in patients treated with warfarin or other vitamin K antagonists; the total number of units required depends on the extent of INR prolongation. (See "Clinical use of plasma components", section on 'Plasma products'.) Efficacy of PCC versus plasma Prothrombin complex concentrates (PCCs) normalize the INR more rapidly than infusion of plasma or vitamin K alone, often within 10 minutes of administration [11,21,30-33]. However, vitamin K should be administered concomitantly because the effect of PCC is transient (hours) [11]. (See "Plasma derivatives and recombinant DNA- produced coagulation factors", section on 'PCCs'.) Evidence supporting the use of 4-factor PCC in warfarin-associated intracranial bleeding mostly consists of small, randomized trials and observational studies in ICH. As examples: PCC versus plasma Two randomized trials comparing PCC with FFP in intracranial hemorrhage associated with vitamin K antagonists. One trial was stopped early due to safety concerns when the 4-factor PCC group appeared to have a lower rate of death (8 of
INR", section on 'Serious/life-threatening bleeding'.) Reversal agent For warfarin-associated ICH, we recommend reversal with 4-factor prothrombin complex concentrate (4-factor PCC) rather than plasma. Options if 4-factor PCC is unavailable include 3-factor PCC supplemented with a source of factor VII, such as recombinant activated factor VII (rFVIIa), or a plasma product such as Fresh Frozen Plasma or Thawed Plasma. However, use of plasma may delay warfarin reversal, leading to a greater risk of complications of hematoma expansion, and may cause a transfusion reaction. We generally do not recommend the use of rFVIIa alone for treatment of warfarin-associated ICH because it does not replace factors II, IX, or X and may give a false sense of security by normalizing the INR without fully reversing warfarin effect. rFVIIa acts rapidly (eg, normalization of the INR within 10 minutes), but the half-life is only two to three hours, and repeated dosing or administration of another product would be required [23,24]. Although the INR is normalized rapidly with rFVIIa, the bleeding risk may persist due to dysfunction of other vitamin K- dependent factors. Thus, the normal INR may give a false sense of security and deprive the patient of other, more effective treatments. Additionally, 4-factor PCC is likely to carry a lower risk of thrombosis than products containing activated factors (rFVIIa or activated PCC, which contains activated factor VII). Prothrombin complex concentrate All four vitamin K-dependent factors are present in 4-factor PCC, which can be administered rapidly in a small volume ( table 6). Thus, 4-factor PCC is the preferred treatment ( table 4). Supporting evidence is summarized below. (See 'Efficacy of PCC versus plasma' below.) All institutions that treat patients with anticoagulant-associated hemorrhage should stock a 4- factor PCC. The available strategies for factor replacement are presented in order of preference; only one of these should be used, along with vitamin K: 4-factor PCC We generally give 4-factor PCC (Kcentra in the United States and Japan; Beriplex or Octaplex in Canada; Octaplex, Cofact, or Proplex in many European countries) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 13/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate as an initial fixed dose of 1500 to 2000 international units at a rate of 100 units/minute ( table 7). Fixed-dose PCC may be easier logistically to stock and deliver in emergencies, but supplemental PCC doses may be required for those with warfarin-associated ICH who have a higher INR (>3). Alternatively, the initial dose may be calculated by body weight and INR. If weight-based or INR-based dosing is used, institutional protocols should be followed. An example is 25 units/kg for INR 2 to 4; 35 units/kg for INR 4 to 6; and 50 units/kg for INR >6, with a maximum dose of 5000 units [25]. In a randomized trial involving 199 patients with warfarin-associated extracranial bleeding, the rate of effective hemostasis in those assigned to an initial fixed-dose PCC (1000 units) was similar to those assigned a calculated dose that incorporated body weight and INR (87 versus 90 percent) [26]. The median initial dose in the calculated dose group was 1750 units. An additional dose of PCC was given to four patients in the fixed-dose group compared with one in the weight-based group, but the door-to-needle time was shorter in the fixed-dose group (109 versus 142 minutes). The proportion of patients in each group reaching an INR 2.0 within 60 minutes was similar (91 versus 92 percent). 3-factor PCC plus a supplement If a 4-factor PCC is not available, a 3-factor PCC (Profilnine in the United States; Bebulin was discontinued in 2018) can be used. However, 3- factor PCC does not contain factor VII. Therefore, most experts recommend supplementing 3-factor PCC with rFVIIa at a dose of 20 mcg/kg or with plasma (eg, FFP, two units). If rFVIIa is used to supplement 3-factor PCC, we prefer a lower dose (20 mcg/kg) rather than higher doses. This is based on data from a randomized trial in 841 patients with spontaneous intracerebral hemorrhage (ICH; not warfarin-associated) that compared two doses of rFVIIa (80 and 20 mcg/kg) with placebo; PCC was not administered [27]. The primary outcome (severe disability or death) was similar among the three groups, despite less expansion of the hemorrhage in those receiving rFVIIa. Overall, thromboembolic events were similar in the three groups, but severe events (eg, cerebral infarction, myocardial infarction [MI]) were more common in those who received high-dose rFVIIa compared with placebo (8 versus 4 percent). Activated PCC Activated PCC (aPCC) contains factors II, VII, IX, and X; factor VII is mostly present in the activated form (VIIa). The only available aPCC is factor eight inhibitor bypassing activity (FEIBA). FEIBA generally is not used for reversing warfarin anticoagulation, because the activated factor VII is potentially more prothrombotic compared with the factor VII in 4-factor PCC (discussed above) that is not in the activated https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 14/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate state. However, retrospective data suggest that treatment with FEIBA does not increase the risk of thrombotic events compared with plasma products [28]. Plasma products if PCC is unavailable If prothrombin complex concentrate (PCC) is unavailable, a plasma product (eg, FFP, Thawed Plasma) can be used to provide clotting factors. However, plasma requires a much larger volume of administration, often delaying the time to normalization of the INR, during which time hemorrhage expansion can continue. This was illustrated in a series of 45 patients with ICH, in which the median time interval between admission to a neuro-intensive care unit and INR normalization with FFP was 30 hours (range: 14 to 50 hours) [29]. Thus, plasma is not a very effective intervention for reducing the expansion of the hemorrhage [12]. Plasma also carries risks of transfusion reactions. A reasonable approach is to give two units of plasma, recheck the INR, and give additional units if needed. The infusion rate for plasma depends on the patient's ability to tolerate the volume load. FFP and other plasma products such as Thawed Plasma are equally effective in reversing the effects of anticoagulation and are considered interchangeable. Thawed Plasma (FFP that has been stored by refrigeration at 1 to 6 degrees Celsius) has the advantage of being available for immediate use. Eight units (2 liters) of FFP or Thawed Plasma are often required to fully reverse anticoagulation in patients treated with warfarin or other vitamin K antagonists; the total number of units required depends on the extent of INR prolongation. (See "Clinical use of plasma components", section on 'Plasma products'.) Efficacy of PCC versus plasma Prothrombin complex concentrates (PCCs) normalize the INR more rapidly than infusion of plasma or vitamin K alone, often within 10 minutes of administration [11,21,30-33]. However, vitamin K should be administered concomitantly because the effect of PCC is transient (hours) [11]. (See "Plasma derivatives and recombinant DNA- produced coagulation factors", section on 'PCCs'.) Evidence supporting the use of 4-factor PCC in warfarin-associated intracranial bleeding mostly consists of small, randomized trials and observational studies in ICH. As examples: PCC versus plasma Two randomized trials comparing PCC with FFP in intracranial hemorrhage associated with vitamin K antagonists. One trial was stopped early due to safety concerns when the 4-factor PCC group appeared to have a lower rate of death (8 of 23 [35 percent] receiving FFP versus 5 of 27 [19 percent] receiving PCC) and a lower rate of hematoma expansion [34]. The other trial, which randomly assigned 202 patients who presented with major bleeding associated with a vitamin K antagonist to receive 4-factor PCC or plasma, found that PCC was associated with a trend towards greater hemostatic https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 15/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate efficacy (72 percent with PCC versus 65 percent with plasma) and a greater likelihood of INR correction within the first half hour after the infusion (62 versus 10 percent); serious adverse events were similar [25]. Prospective and retrospective observational studies have consistently shown superior or equivalent outcomes with PCC compared with plasma; in some studies, PCCs were also associated with fewer serious adverse events [22,28,31,35- 39]. Despite the efficacy of PCC in reversing warfarin effect, the mortality of anticoagulant- associated ICH remains high (42 percent in one series) [40]. This is likely due to early hematoma expansion and the delay in anticoagulant reversal during transportation to the hospital, intracranial imaging, and administration of reversal products. 4-factor versus 3-factor PCC These two products have not been compared directly for patients with intracranial bleeding. The rate of INR normalization in patients with systemic bleeding appears higher with 4-factor PCC. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Evidence for efficacy'.) PCC versus rFVIIa or aPCC A case series of 101 patients with warfarin-associated intracranial hemorrhage treated with rFVIIa (mean dose 52 mcg/kg) reported thromboembolic complications in eight patients (seven deep vein thromboses, one stroke) [41]. Similar risks were found in a multicenter randomized trial of rFVIIa in 841 patients with ICH not associated with warfarin [27]. There was no benefit with treatment on the primary clinical outcomes of death and disability, and higher rates of arterial thromboembolic serious adverse events (eg, stroke, MI) were found in patients assigned to the higher dose (80 mcg/kg) treatment group. Other studies have also suggested an association between rFVIIa and serious thromboembolic events. These and other studies are discussed in more detail separately. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Thromboembolic complications' and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Reverse anticoagulation'.) In a retrospective study comparing outcomes with 4-factor PCC versus aPCC in 342 patients with ICH, treatment with 4-factor PCC was associated with a higher likelihood of an INR 1.5 [42]. Case reports suggest that incomplete INR correction is associated with clinical worsening in patients treated with PCC. Observational studies show that in some cases ICH can continue to expand, even in patients for whom anticoagulation is reversed, although more rapid reversal with a PCC appears to correlate with a lower risk of expansion [4,11,43]. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 16/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Additional supporting data for PCC are presented separately. (See "Management of warfarin- associated bleeding or supratherapeutic INR", section on 'PCC products'.) Thrombotic events have complicated infusion of PCC, but this risk is difficult to quantify due to varying preparations, doses, and differing patient populations in available reports. Among most series, thrombotic complications occurred in 1.5 to 10 percent of patients [20,31,40,44-46]. The risk may be substantially higher in individuals with prosthetic heart valves or valvular heart disease [43]. Intravenous vitamin K Vitamin K should be given because the half-life of PCC is very short (hours). Vitamin K 10 mg is given by slow intravenous infusion, no faster than 1 mg/min to minimize anaphylactic risk [11,31]. If the INR is 1.5, a lower dose (eg, 5 mg) may be given if desired. The effect of vitamin K on the INR takes approximately 12 to 24 hours; thus, all patients should also receive PCC. (See 'Prothrombin complex concentrate' above.) Intravenous vitamin K administration is preferred over oral or subcutaneous administration because it results in more rapid correction of the INR and because oral administration can be problematic in the setting of neurologic deficits or conditions that affect gastrointestinal absorption. Oral vitamin K may be used in individuals who are awake and have normal gastrointestinal function. Vitamin K administration can be repeated every 12 hours for persistent INR elevation, and daily INR should be obtained to assess for this need [47]. (See 'Laboratory testing' above.) Evidence supporting the efficacy of vitamin K and comparison of the routes of administration are presented separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Vitamin K dose, route, formulation'.) Dabigatran Intracranial bleeding associated with dabigatran can be treated with idarucizumab or aPCC. We make sure that dabigatran has been discontinued and that this is clearly stated in the medical record. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal'.) Convincing evidence of dabigatran anticoagulation may be based on a clinical history of ingestion within the previous 3.5 days and/or laboratory evidence of dabigatran effect (eg, prolonged activated partial thromboplastin time [aPTT], thrombin time [TT], diluted thrombin time [dTT], or ecarin clotting time [ECT]). An aPTT in the normal range cannot be used to justify withholding of idarucizumab, because drug effect may still be present. However, idarucizumab should not be given to patients who have a normal TT, dTT, and/or ECT. (See "Direct oral https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 17/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Laboratory testing and monitoring (dabigatran)'.) Idarucizumab Idarucizumab is an emergency reversal agent for dabigatran. It is an anti- dabigatran monoclonal antibody fragment. For patients with acute intracranial hemorrhage and convincing evidence of dabigatran anticoagulation, we suggest idarucizumab if available, rather than clotting factor products (aPCC, PCC, or plasma). The dose of idarucizumab is 5 grams (two 2.5-gram vials), administered either as two consecutive infusions or as a bolus (ie, injecting both vials consecutively via syringe). Repeat dosing is generally not required but may be appropriate in selected cases (eg, overdose, persistently prolonged aPTT), although data are limited. We do not combine idarucizumab with other prohemostatic products such as a PCC, aPCC, or rFVIIa. Treatment with idarucizumab may be associated with thrombosis due to the patient's underlying thrombotic risk factors. Evidence for the efficacy and safety of idarucizumab in dabigatran- associated bleeding is presented separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal'.) Alternative options Activated PCC If idarucizumab is not available, we suggest administering activated prothrombin complex concentrate (aPCC; FEIBA) at a dose of 50 to 80 units/kg. The activated factor VII in this product activates the free factor X and may be sufficient to bypass dabigatran and promote clotting. If aPCC is not available, 4-factor or 3-factor PCC at a dose of 50 units/kg would be reasonable. Three-factor PCC may be supplemented with rFVIIa or plasma. Dosing of these supplements is described above. (See 'Reversal agent' above.) Activated charcoal and dialysis Unabsorbed dabigatran can be removed from the gastrointestinal tract using oral activated charcoal. This is generally appropriate if the last dose was within the previous two hours. Dosing and contraindications are presented separately. (See "Gastrointestinal decontamination of the poisoned patient".) Dabigatran can also be removed by hemodialysis if the consulting specialist believes this would be useful. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 18/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate These interventions are discussed in more detail separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Overview of management'.) Apixaban, edoxaban, and rivaroxaban Intracranial bleeding associated with a direct oral factor Xa inhibitor (apixaban, edoxaban, or rivaroxaban) can be treated with andexanet alfa (a reversal agent for factor Xa inhibitors) or 4-factor PCC ( table 8). We make sure that the factor Xa inhibitor has been discontinued and that this is clearly stated in the medical record. Convincing evidence of factor Xa inhibitor anticoagulation may be based on a clinical history of ingestion within a period of five half-lives and/or laboratory evidence of anticoagulant effect (eg, increased anti-factor Xa activity, ideally calibrated for the specific drug). The PT, aPTT, and anti-Xa calibrated for other drugs may be useful if abnormal but are less reliable. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct factor Xa inhibitors'.) The half-lives of these agents and the number of days elapsed in five half-lives are listed separately (see "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Interval since last dose'); most are within two to three days. Reversal agent options For patients with acute intracranial hemorrhage and convincing evidence of anticoagulation with a factor Xa inhibitor, we suggest andexanet alfa or 4-factor PCC. These agents have not been directly compared in a randomized trial. We prefer andexanet alfa given the drug's specificity and available data [48,49]. However, some experts consider there to be more equipoise in the choice between andexanet alfa and PCC. In a retrospective chart review of 109 adults with intracranial hemorrhage who were taking either apixaban or rivaroxaban at presentation, the rate of effective hemostasis was similar (71 percent for patients who received andexanet alfa and those who received 4-factor PCC) [50]. At baseline, the mean intracerebral hemorrhage score was 1 and Glasgow Coma Scale score was 14. After treatment, the median change in hematoma volume on repeat brain imaging and the rate of thrombotic complications were also similar between groups, but the total cost of treatment was more than three times higher with andexanet alfa. These results are limited by the relative small sample size, the potential of treatment bias, and uncertain applicability to patients with more severe hemorrhagic events. A randomized trial comparing andexanet versus usual care in patients with intracranial bleeding is ongoing [51]. Further discussion of this subject and evidence for the efficacy and safety of andexanet are reviewed separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Andexanet alfa'.) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 19/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Andexanet alfa Andexanet alfa (andexanet) is an emergency reversal agent for factor Xa inhibitors. It is a recombinantly produced, catalytically inactive form of factor Xa that acts as a "decoy" to bind and sequester the factor Xa inhibitor anticoagulant. Andexanet alfa is given at one of two dose levels based on the dose and timing of the factor Xa inhibitor. The low dose is given as a bolus of 400 mg at 30 mg/min over 15 minutes, followed by an infusion of 480 mg given at 4 mg/min for up to 120 minutes. This is used in patients who received a lower dose of factor Xa inhibitor (eg, rivaroxaban 10 mg, apixaban 5 mg, or edoxaban 30 mg) or if eight hours or more have elapsed since the last dose of factor Xa inhibitor. The high dose is given as a bolus of 800 mg at 30 mg/min over 30 minutes, followed by an infusion at 960 mg given at 8 mg/min for up to 120 minutes. This is used for those who received a higher dose of factor Xa inhibitor (eg, rivaroxaban >10 mg, apixaban >5 mg, edoxaban >30 mg) or unknown dose within the previous eight hours. We do not use anti-factor Xa assays to assess the extent of anticoagulation reversal. Routine anti-factor Xa levels obtained after treatment with andexanet alfa may be falsely elevated due to dilutional effects [52]. We do not combine andexanet with other prohemostatic products such as PCC, aPCC or rFVIIa. 4-factor PCC A 4-factor prothrombin complex concentrate (PCC) is an alternative to andexanet for reversing factor Xa inhibitors. In a retrospective series involving 663 individuals who had an intracranial hemorrhage while receiving apixaban or rivaroxaban, 4-factor PCC was associated with good or excellent hemostasis in 354 of 433 evaluated for efficacy (82 percent) [53]. Thrombosis within 14 days of PCC administration occurred in 22 of the 663 (3.3 percent). These efficacy and safety outcomes are like those seen with andexanet and with 4-factor PCC in other studies of oral factor Xa inhibitor reversal after bleeding in other sites. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Overview of factor Xa inhibitor reversal'.) PCC can be given at a dose of 50 units/kg, or a fixed-dose regimen (2000 or 2500 units) can be used (eg, dosing like that used for warfarin reversal). (See 'Reversal agent' above.) If PCC is used, the patient should not be treated with andexanet. Activated charcoal Unabsorbed anticoagulant can be removed from the gastrointestinal tract using oral activated charcoal. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 20/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate We use the following intervals from the most recent dose to decide if charcoal may be helpful (see "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Factor Xa inhibitors'): Apixaban Within six hours Edoxaban Within two hours Rivaroxaban Within six to eight hours Dosing and contraindications to oral activated charcoal are presented separately. (See "Gastrointestinal decontamination of the poisoned patient".) Direct factor Xa inhibitors cannot be removed by hemodialysis. Unfractionated heparin For patients with intracranial bleeding associated with therapeutic doses of unfractionated heparin, protamine sulfate can be given for heparin reversal. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Unfractionated heparin'.) We make sure that all sources of heparin have been discontinued and that this is clearly stated in the medical record. Protamine sulfate Protamine sulfate (protamine) is an emergency reversal agent for unfractionated heparin. For patients with acute intracranial hemorrhage and convincing evidence of anticoagulation with unfractionated heparin (prolonged aPTT and/or administration within the previous two hours), we recommend protamine. A fixed dose of 50 mg or 25 mg may be given; some experts give 50 mg and others give 25 mg followed by an additional dose of 25 mg if needed (eg, based on a prolonged aPTT). The 50 mg dose would be more appropriate for an individual with a greater aPTT prolongation; however, this dose may be associated with a greater risk for relative hypotension. Alternatively, the dose can be calculated as 1 mg protamine per 100 units of heparin. The number of units of heparin is estimated based on the previous dose and the interval since it was administered, with an estimated half-life of heparin in the range of one to two hours (eg, if a dose of 5000 units was given one hour ago, the number of units would be 2500 and the dose of protamine would be 25 mg). Protamine must be given by slow intravenous infusion, as rapid infusion may cause hypotension, particularly at high doses (eg, 50 mg). The infusion rate should not exceed 20 mg/min and the total dose should not exceed 50 mg in any 10-minute period. Repeat doses may be given for a persistently prolonged aPTT. If heparin had been given by subcutaneous injection, https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 21/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate repeated small doses of protamine may be required because of prolonged heparin absorption from subcutaneous sites. Protamine is derived from fish sperm and may elicit an allergic reaction, especially in previously exposed individuals. In the United States, the protamine sulfate label contains a boxed warning that the drug can cause severe hypotension, cardiovascular collapse, noncardiogenic pulmonary edema, catastrophic pulmonary vasoconstriction, and pulmonary hypertension. Risk factors include high dose or overdose, rapid administration, repeated doses, previous administration of protamine or protamine-containing insulin (eg, neutral protamine hagedorn [NPH] or protamine zinc insulin [PZI]), and certain beta-blockers. Allergy to fish, previous vasectomy, severe left ventricular dysfunction, and abnormal preoperative pulmonary hemodynamics also may be risk factors. Vasopressors and resuscitation equipment should be immediately available in case of a severe reaction to protamine. Evidence for the efficacy and safety of protamine include a number of preclinical and observational studies that demonstrate effective reversal, as summarized in a 2016 guideline [14]. Studies evaluating clinically significant outcomes are lacking, as discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Urgent reversal (protamine)'.) LMW heparin Intracranial bleeding associated with low molecular weight (LMW) heparin (eg, enoxaparin, dalteparin, nadroparin, tinzaparin) is uncommon but can occur, particularly in patients with cancer and brain metastases. For intracranial bleeding associated with therapeutic dose LMW heparin, we suggest andexanet alfa rather than protamine sulfate. However, protamine sulfate is a reasonable alternative if andexanet is not available. Evidence of LMW heparin effect may be based on the interval since the last dose and/or anti- factor Xa activity indicating a LMW heparin level of 0.3 international units/mL. (See 'Laboratory testing' above.) We make sure that the LMW heparin has been discontinued and that this is clearly stated in the medical record. Andexanet alfa Despite limited data, andexanet alfa is a reasonable approach for the treatment of intracranial bleeding associated with LMW heparin anticoagulation. Studies evaluating andexanet alfa for reversal of anticoagulation suggested efficacy for achieving hemostasis in a small number of individuals receiving therapeutic dose LMW heparin (16 individuals receiving enoxaparin in the ANNEXA-4 study) [54]. Additional data are needed. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 22/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate For patients with bleeding associated with therapeutic dose LMW heparin, the dosing of andexanet alfa in ANNEXA-4 was the higher dose level, with an 800 mg bolus given at 30 mg/minute over 30 minutes, followed by an infusion of 960 mg given at 8 mg/minute for up to 120 minutes [54]. The lower dose level (400 mg bolus and 480 infusion at 4 mg/minute) may be sufficient in individuals receiving prophylactic dose LMW heparin, although this has not been demonstrated, and it may be safer to use the higher dose level. If andexanet is unavailable, protamine sulfate should be given. (See 'Protamine sulfate if andexanet alfa is unavailable' below.) Protamine sulfate if andexanet alfa is unavailable For patients with acute intracranial hemorrhage and evidence of LMW heparin anticoagulation (increased anti-factor Xa activity [preferred] or administration within the previous 12 hours), protamine sulfate is a reasonable treatment option if andexanet is not available. Unlike its effect with unfractionated heparin, protamine is less effective in reversing the effect of LMW heparin. This is because protamine acts by reversing the inhibitory effect of LMW heparin on thrombin but only reverses approximately 60 percent of the inhibitory effect on factor Xa due to decreased binding to the shorter heparin chains in LMW heparin. Dosing of protamine sulfate in LMW heparin-associated bleeding is discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Urgent reversal (protamine)'.) Fondaparinux Fondaparinux is a synthetic pentasaccharide analog of the natural pentasaccharide found in heparin. Fondaparinux acts by binding to and inducing a conformational change in antithrombin that causes selective inhibition of factor Xa. The half-life of fondaparinux is 17 to 21 hours. For patients with intracranial hemorrhage associated with fondaparinux anticoagulation, there is little information to guide management. Andexanet alfa is a reasonable option if it is available. Although data are limited, we would use the higher dose level, with an 800 mg bolus given at 30 mg/minute over 30 minutes, followed by an infusion of 960 mg given at 8 mg/minute for up to 120 minutes. Protamine sulfate is ineffective for fondaparinux reversal. Other options for reversal and additional information about the use of these agents are presented separately. (See "Fondaparinux: Dosing and adverse effects", section on 'Bleeding/emergency surgery'.) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 23/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate RESUMPTION OF ANTICOAGULATION In many cases, anticoagulation can be resumed after bleeding resolves, provided the patient remains stable and the risk-benefit calculation clearly favors reinitiating anticoagulation. However, the decision must be individualized. Considerations related to this decision and evidence to support the benefit of restarting anticoagulation are presented separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Resumption of anticoagulation'.) Likewise, the optimal timing for restarting anticoagulation therapy following an intracranial bleed is unknown. The size and cause of the bleeding (eg, traumatic versus atraumatic) and patient-specific factors that increase bleeding risk may play a role in the calculation. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Prognosis and reinitiation of anticoagulation'.) For individuals treated with high doses of vitamin K, there may be a period of refractoriness after resuming warfarin. The decision process to reinitiate anticoagulation and the timing of reinitiation are discussed separately. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Management of antithrombotic therapy'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation" and "Society guideline links: Stroke in adults" and "Society guideline links: COVID-19 Anticoagulation" and "Society guideline links: COVID-19 Index of guideline topics".) SUMMARY AND RECOMMENDATIONS Urgent evaluation We perform a rapid clinical assessment to identify important features of the history and neuroimaging to distinguish hemorrhage from ischemia. Lumbar puncture (LP) is generally required when there is strong suspicion for subarachnoid hemorrhage (SAH) despite a normal head computed tomography (CT). All patients should have a complete blood count (CBC) with platelet count, prothrombin time (PT) with international normalized ratio (INR), and activated partial thromboplastin https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 24/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate time (aPTT). Liver function tests and a metabolic panel may also be appropriate. (See 'Urgent evaluation' above.) Additional laboratory evaluation varies by anticoagulant: Dabigatran Thrombin time (TT), creatinine determination, and calculation of the creatinine clearance Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban, low molecular weight [LMW] heparin) Anti-factor Xa activity calibrated to the drug, creatinine, and calculated creatinine clearance TT and anti-factor Xa activity may not be immediately available. General measures for all patients General measures for anticoagulant-associated intracranial hemorrhage (ICH) include discontinuation of all antithrombotic agents, admission with intensive monitoring, and blood pressure control. Other interventions may be needed to treat severe thrombocytopenia, anemia, and metabolic abnormalities. (See 'General measures for all anticoagulants' above.) Indications for anticoagulant reversal Reversal of the anticoagulant effect is indicated in virtually all cases of documented acute ICH and in patients requiring an urgent LP to exclude SAH or infection. A rare exception is an individual for whom the risk of thrombosis is clinically more serious than the risk of hematoma expansion (eg, individual with a mechanical heart valve and a small, stable subdural hematoma). (See 'Indications for reversal and goals of treatment' above.) Specific reversal strategies Reversal should be done as rapidly as possible to limit hemorrhage enlargement, which can be fatal. Warfarin For warfarin-associated ICH, we recommend reversal with 4-factor prothrombin complex concentrate (4-factor PCC) rather than plasma (Grade 1B). PCC is typically given as a fixed dose of 1500 to 2000 international units at a rate of 100 units/minute ( table 7). (See 'Prothrombin complex concentrate' above.) Options if 4-factor PCC is unavailable include 3-factor PCC supplemented with a source of factor VII or a plasma product such as Fresh Frozen Plasma or Thawed Plasma. Use of plasma may delay warfarin reversal, leading to a greater risk of complications of hematoma expansion, and may cause a transfusion reaction. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 25/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Vitamin K is also given to all patients because PCC and plasma act transiently. The dose is 10 mg intravenously (which acts within several hours). Repeat vitamin K dosing may be appropriate if the PT or INR remains elevated. (See 'Intravenous vitamin K' above.) Dabigatran For dabigatran-associated ICH, we suggest idarucizumab (Grade 2C). The dose is 5 g (two 2.5 g vials). If idarucizumab is not available, activated PCC (aPCC; factor eight inhibitor bypassing activity [FEIBA]) may be used. Oral activated charcoal may be given if the patient can take oral medications and the last dose of dabigatran was within the prior two hours. Dabigatran may also be removed by hemodialysis. (See 'Dabigatran' above.) Direct factor Xa inhibitors (eg, apixaban, edoxaban, rivaroxaban) For direct factor Xa inhibitor-associated ICH, we suggest andexanet alfa rather than 4-factor PCC (Grade 2C). 4-factor PCC is a reasonable alternative if andexanet is unavailable. (See 'Apixaban, edoxaban, and rivaroxaban' above.) There are two dose levels for andexanet; the choice between them depends on the anticoagulant being reversed, how much was taken, and the timing of the most recent dose. (See 'Andexanet alfa' above.) The higher dose level uses a bolus of 800 mg at 30 mg/minute followed by an infusion of 960 mg at 8 mg/minute. The lower dose level uses a bolus of 400 mg at 30 mg/minute followed by an infusion of 480 mg at 4 mg/minute. Oral activated charcoal may be given if the patient can take oral medications and the last dose of the anticoagulant was recent (edoxaban within two hours; apixaban within six hours; rivaroxaban within eight hours). The direct factor Xa inhibitors cannot be dialyzed. (See 'Apixaban, edoxaban, and rivaroxaban' above.) UFH Unfractionated heparin (UFH)-associated ICH is treated with protamine sulfate (protamine). The dose is 1 mg protamine per 100 units of heparin; if rapid calculation is not possible, a single intravenous dose of 25 or 50 mg can be given by slow infusion over at least 20 or 30 minutes. Protamine can cause allergic reactions, particularly in individuals previously exposed to protamine sulfate, protamine-containing insulin, or those with a fish allergy. (See 'Unfractionated heparin' above.) LMW heparin (enoxaparin, dalteparin, tinzaparin) For LMW heparin-associated ICH, we suggest andexanet alfa rather than protamine (Grade 2C). The higher dose level (800 mg at 30 mg/minute followed by an infusion of 960 mg at 8 mg/minute) is https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 26/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate appropriate. Protamine sulfate is a reasonable alternative if andexanet is unavailable. (See 'LMW heparin' above.) Fondaparinux Treatment of fondaparinux-associated ICH is individualized. Andexanet alfa at the higher dose level is a reasonable option. (See 'Fondaparinux' above and "Fondaparinux: Dosing and adverse effects", section on 'Bleeding/emergency surgery'.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Maria I Aguilar, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Rosand J, Eckman MH, Knudsen KA, et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004; 164:880. 2. Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology 2008; 71:1084. 3. Berwaerts J, Dijkhuizen RS, Robb OJ, Webster J. Prediction of functional outcome and in- hospital mortality after admission with oral anticoagulant-related intracerebral hemorrhage. Stroke 2000; 31:2558. 4. Yasaka M, Minematsu K, Naritomi H, et al. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost 2003; 89:278. 5. Cucchiara B, Messe S, Sansing L, et al. Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke 2008; 39:2993. 6. Flibotte JJ, Hagan N, O'Donnell J, et al. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 2004; 63:1059. 7. Punthakee X, Doobay J, Anand SS. Oral-anticoagulant-related intracerebral hemorrhage. Thromb Res 2002; 108:31.
prognosis", section on 'Management of antithrombotic therapy'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation" and "Society guideline links: Stroke in adults" and "Society guideline links: COVID-19 Anticoagulation" and "Society guideline links: COVID-19 Index of guideline topics".) SUMMARY AND RECOMMENDATIONS Urgent evaluation We perform a rapid clinical assessment to identify important features of the history and neuroimaging to distinguish hemorrhage from ischemia. Lumbar puncture (LP) is generally required when there is strong suspicion for subarachnoid hemorrhage (SAH) despite a normal head computed tomography (CT). All patients should have a complete blood count (CBC) with platelet count, prothrombin time (PT) with international normalized ratio (INR), and activated partial thromboplastin https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 24/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate time (aPTT). Liver function tests and a metabolic panel may also be appropriate. (See 'Urgent evaluation' above.) Additional laboratory evaluation varies by anticoagulant: Dabigatran Thrombin time (TT), creatinine determination, and calculation of the creatinine clearance Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban, low molecular weight [LMW] heparin) Anti-factor Xa activity calibrated to the drug, creatinine, and calculated creatinine clearance TT and anti-factor Xa activity may not be immediately available. General measures for all patients General measures for anticoagulant-associated intracranial hemorrhage (ICH) include discontinuation of all antithrombotic agents, admission with intensive monitoring, and blood pressure control. Other interventions may be needed to treat severe thrombocytopenia, anemia, and metabolic abnormalities. (See 'General measures for all anticoagulants' above.) Indications for anticoagulant reversal Reversal of the anticoagulant effect is indicated in virtually all cases of documented acute ICH and in patients requiring an urgent LP to exclude SAH or infection. A rare exception is an individual for whom the risk of thrombosis is clinically more serious than the risk of hematoma expansion (eg, individual with a mechanical heart valve and a small, stable subdural hematoma). (See 'Indications for reversal and goals of treatment' above.) Specific reversal strategies Reversal should be done as rapidly as possible to limit hemorrhage enlargement, which can be fatal. Warfarin For warfarin-associated ICH, we recommend reversal with 4-factor prothrombin complex concentrate (4-factor PCC) rather than plasma (Grade 1B). PCC is typically given as a fixed dose of 1500 to 2000 international units at a rate of 100 units/minute ( table 7). (See 'Prothrombin complex concentrate' above.) Options if 4-factor PCC is unavailable include 3-factor PCC supplemented with a source of factor VII or a plasma product such as Fresh Frozen Plasma or Thawed Plasma. Use of plasma may delay warfarin reversal, leading to a greater risk of complications of hematoma expansion, and may cause a transfusion reaction. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 25/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Vitamin K is also given to all patients because PCC and plasma act transiently. The dose is 10 mg intravenously (which acts within several hours). Repeat vitamin K dosing may be appropriate if the PT or INR remains elevated. (See 'Intravenous vitamin K' above.) Dabigatran For dabigatran-associated ICH, we suggest idarucizumab (Grade 2C). The dose is 5 g (two 2.5 g vials). If idarucizumab is not available, activated PCC (aPCC; factor eight inhibitor bypassing activity [FEIBA]) may be used. Oral activated charcoal may be given if the patient can take oral medications and the last dose of dabigatran was within the prior two hours. Dabigatran may also be removed by hemodialysis. (See 'Dabigatran' above.) Direct factor Xa inhibitors (eg, apixaban, edoxaban, rivaroxaban) For direct factor Xa inhibitor-associated ICH, we suggest andexanet alfa rather than 4-factor PCC (Grade 2C). 4-factor PCC is a reasonable alternative if andexanet is unavailable. (See 'Apixaban, edoxaban, and rivaroxaban' above.) There are two dose levels for andexanet; the choice between them depends on the anticoagulant being reversed, how much was taken, and the timing of the most recent dose. (See 'Andexanet alfa' above.) The higher dose level uses a bolus of 800 mg at 30 mg/minute followed by an infusion of 960 mg at 8 mg/minute. The lower dose level uses a bolus of 400 mg at 30 mg/minute followed by an infusion of 480 mg at 4 mg/minute. Oral activated charcoal may be given if the patient can take oral medications and the last dose of the anticoagulant was recent (edoxaban within two hours; apixaban within six hours; rivaroxaban within eight hours). The direct factor Xa inhibitors cannot be dialyzed. (See 'Apixaban, edoxaban, and rivaroxaban' above.) UFH Unfractionated heparin (UFH)-associated ICH is treated with protamine sulfate (protamine). The dose is 1 mg protamine per 100 units of heparin; if rapid calculation is not possible, a single intravenous dose of 25 or 50 mg can be given by slow infusion over at least 20 or 30 minutes. Protamine can cause allergic reactions, particularly in individuals previously exposed to protamine sulfate, protamine-containing insulin, or those with a fish allergy. (See 'Unfractionated heparin' above.) LMW heparin (enoxaparin, dalteparin, tinzaparin) For LMW heparin-associated ICH, we suggest andexanet alfa rather than protamine (Grade 2C). The higher dose level (800 mg at 30 mg/minute followed by an infusion of 960 mg at 8 mg/minute) is https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 26/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate appropriate. Protamine sulfate is a reasonable alternative if andexanet is unavailable. (See 'LMW heparin' above.) Fondaparinux Treatment of fondaparinux-associated ICH is individualized. Andexanet alfa at the higher dose level is a reasonable option. (See 'Fondaparinux' above and "Fondaparinux: Dosing and adverse effects", section on 'Bleeding/emergency surgery'.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Maria I Aguilar, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Rosand J, Eckman MH, Knudsen KA, et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004; 164:880. 2. Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology 2008; 71:1084. 3. Berwaerts J, Dijkhuizen RS, Robb OJ, Webster J. Prediction of functional outcome and in- hospital mortality after admission with oral anticoagulant-related intracerebral hemorrhage. Stroke 2000; 31:2558. 4. Yasaka M, Minematsu K, Naritomi H, et al. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost 2003; 89:278. 5. Cucchiara B, Messe S, Sansing L, et al. Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke 2008; 39:2993. 6. Flibotte JJ, Hagan N, O'Donnell J, et al. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 2004; 63:1059. 7. Punthakee X, Doobay J, Anand SS. Oral-anticoagulant-related intracerebral hemorrhage. Thromb Res 2002; 108:31. 8. Sj blom L, H rdemark HG, Lindgren A, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke 2001; 32:2567. 9. Neau JP, Couderq C, Ingrand P, et al. Intracranial hemorrhage and oral anticoagulant treatment. 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Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy. Stroke 2021; 52:2096. 49. Cohen AT, Lewis M, Connor A, et al. Thirty-day mortality with andexanet alfa compared with prothrombin complex concentrate therapy for life-threatening direct oral anticoagulant- related bleeding. J Am Coll Emerg Physicians Open 2022; 3:e12655. 50. Pham H, Medford WG, Horst S, et al. Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhages. Am J Emerg Med 2022; 55:38. 51. https://clinicaltrials.gov/ct2/show/NCT03661528 (Accessed on November 18, 2021). 52. Bourdin M, Perrotin D, Mathieu O, et al. Measuring residual anti-Xa activity of direct factor Xa inhibitors after reversal with andexanet alfa. Int J Lab Hematol 2021; 43:795. 53. Panos NG, Cook AM, John S, et al. Factor Xa Inhibitor-Related Intracranial Hemorrhage: Results From a Multicenter, Observational Cohort Receiving Prothrombin Complex Concentrates. Circulation 2020; 141:1681. 54. Connolly SJ, Crowther M, Eikelboom JW, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med 2019; 380:1326. Topic 1325 Version 51.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 31/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate GRAPHICS Medications that interfere with the effect of warfarin May increase INR May decrease INR Acetaminophen Antibiotics Dicloxacillin Allopurinol Griseofulvin Amiodarone Nafcillin Androgens Rifampin Methyltestosterone Azathioprine Oxandrolone Cholestyramine Testosterone Enzyme-inducing antiseizure medications Antibiotics Carbamazepine Cephalosporins Phenobarbital Doxycycline Phenytoin (mixed effects described) Fluoroquinolones Ciprofloxacin Ritonavir Levofloxacin Saint John's wort Moxifloxacin Sucralfate Norfloxacin Vitamin K Macrolides Azithromycin Clarithromycin Erythromycin Metronidazole Penicillins (exceptions: dicloxacillin and nafcillin may decrease the INR) Amoxicillin Amoxicillin-clavulanate Trimethoprim-sulfamethoxazole Azole antifungals* Fluconazole Miconazole (oral) Voriconazole Cancer therapies Capecitabine Fluorouracil (5-FU) Imatinib https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 32/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Tamoxifen Cholesterol-lowering agents (exception: cholestyramine may decrease the INR) Fenofibrate Fluvastatin Gemfibrozil Lovastatin Rosuvastatin Simvastatin Cimetidine Glucocorticoids Methylprednisolone Prednisone Omeprazole (case reports with other proton pump inhibitors) Serotonin reuptake inhibitors Duloxetine Fluoxetine Fluvoxamine Venlafaxine Sitaxentan (not available in United States) Tramadol This is a partial list of medications that may increase or decrease warfarin effect on the INR. The patient's medications should be analyzed closely for drug interactions with warfarin, especially when initiating or altering therapy. The effect of a drug interaction can be unpredictable; thus, individuals receiving interacting medications are likely to require increased INR monitoring. Additional medications may increase bleeding risk independent of (or in addition to) effects on the INR (eg, NSAIDs, antiplatelet medications). Refer to UpToDate for additional details. Drug interactions may be evaluated using the Lexi-interact program included with UpToDate. INR: international normalized ratio; NSAIDs: nonsteroidal anti-inflammatory drugs. A more moderate effect on INR control may also be seen with posaconazole and itraconazole. In addition to potentially increasing the INR, serotonin reuptake inhibitors may also increase bleeding risk by inhibiting platelet reuptake of serotonin. References: 1. Greenblatt DJ, von Moltke L. Interaction of warfarin with drugs, natural substances, and foods. J Clin Pharmacol 2005; 45:127. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 33/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate 2. Holbrook A, Schulman S, Witt D, et al. Evidenced-based management of anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed. Chest 2012; 141:e152S. 3. Hazlewood KA, Fugate SE, Harrison DL. E ect of oral corticosteroids on chronic warfarin therapy. Ann Pharmacother 2006; 40:2101. 4. Lexi-Interact. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. Graphic 62697 Version 15.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 34/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Pharmacokinetics and drug interactions of direct oral anticoagulants Potential for Metabolism pharmacokinetic drug interactions* Anticoagulant Bioavailability and clearance* Half-life Dabigatran (Pradaxa) 3 to 7% bioavailable Over 80% cleared by the 12 to 17 hours P-gp inhibitors can increase kidney dabigatran effect Unaffected by food Prolonged with kidney P-gp P-gp inducers can substrate* impairment and in older decrease dabigatran Capsule must be taken intact adults effect and requires gastric acidity Avoidance of for absorption some combinations or dose adjustment may be needed Apixaban 50% 27% cleared 12 hours Strong dual (Eliquis) bioavailable by the kidney CYP3A4 and P-gp inhibitors can Prolonged in older adults Unaffected by Metabolized, increase food primarily by CYP3A4 apixaban effect Strong CYP3A4 P-gp substrate* inducers and/or P-gp inducers can decrease apixaban effect Avoidance of some combinations or dose adjustment may be needed Edoxaban (Savaysa, Lixiana) 62% bioavailable 50% cleared by the kidney 10 to 14 hours P-gp inhibitors can increase edoxaban effect Unaffected by food Reduced efficacy in Prolonged in renal P-gp inducers can patients with nonvalvular impairment decrease edoxaban effect atrial fibrillation Avoidance of some combinations or https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 35/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate and CrCl >95 mL/minute dose adjustment may be needed Undergoes minimal CYP metabolism P-gp substrate* Rivaroxaban (Xarelto) 10 mg dose: 36% cleared by the kidney 5 to 9 hours Strong dual CYP3A4 and P-gp 80 to 100% Prolonged to inhibitors can increase bioavailable Metabolized, primarily by 11 to 13 hours in Unaffected rivaroxaban CYP3A4 older adults by food effect P-gp 20 mg dose: Strong CYP3A4 substrate* 66% inducers and/or P-gp inducers can bioavailable if taken when decrease rivaroxaban fasting; increased if effect Avoidance of taken with food some combinations or dose adjustment may be needed Refer to UpToDate for dosing in specific clinical settings, including nonvalvular AF, VTE treatment, and VTE prophylaxis. Data on clearance may help assess the potential for accumulation in patients with kidney impairment. Data on metabolism may help assess potential drug interactions through alteration of CYP3A4 metabolism and/or P-gp-mediated drug efflux. Refer to Lexi-Interact, the drug interactions tool included with UpToDate, for specific drug interactions. Tables of P-gp inhibitors and inducers and CYP3A4 inhibitors and inducers are available separately in UpToDate. P-gp: P-glycoprotein drug efflux pump; CYP3A4: cytochrome p450 3A4 isoform; CrCl: creatinine clearance estimated by the Cockcroft-Gault equation; AF: atrial fibrillation; VTE: venous thromboembolism, includes deep vein thrombosis and pulmonary embolism; DOAC: direct oral anticoagulant. Examples of P-gp inhibitors that reduce metabolism of DOACs, leading to increased DOAC levels, include clarithromycin, ombitasvir- or ritonavir-containing combinations, and verapamil. Examples of P-gp inducers that increase DOAC metabolism, leading to lower DOAC levels, include phenytoin, rifampin, and St. John's wort. Refer to list available as a separate table in UpToDate. Examples of strong CYP3A4 inhibitors that reduce metabolism of some DOACs, leading to increased DOAC levels, include clarithromycin and ombitasvir- or ritonavir-containing combinations. Examples of strong CYP3A4 inducers that increase metabolism of some DOACs, leading to lower https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 36/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate DOAC levels, include carbamazepine, phenytoin, and rifampin. Refer to list available as a separate table in UpToDate. In patients with AF, combined use of levetiracetam or valproate with dabigatran, apixaban, or rivaroxaban was associated with an increased risk of ischemic stroke or systemic embolism. The [1] mechanism of this interaction is unknown. Inhibition of CYP3A4 (ie, without P-gp inhibition) may also increase apixaban and rivaroxaban effect, but to a lesser extent than dual inhibition of CYP3A4 and P-gp. Examples of CYP3A4 inhibitors that do not also inhibit P-gp include diltiazem, fluconazole, and voriconazole. Increased monitoring is advised. Blood levels of edoxaban were reduced and a higher rate of ischemic stroke was observed in patients with AF and CrCl >95 mL/minute who were treated with edoxaban compared with those receiving warfarin. Refer to the UpToDate topic on anticoagulation in AF for additional information. Reference: 1. Gronich N, Stein N, Muszkat M. Association between use of pharmacokinetic-interacting drugs and e ectiveness and safety of direct acting oral anticoagulants: Nested case-control study. Clin Pharmacol Ther 2021; 110:1526. Prepared with data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. Drugs@FDA: FDA-Approved Drugs. U.S. Food and Drug Administration. Available at: https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (Accessed on December 9, 2021). Graphic 112756 Version 19.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 37/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Expected effects of anticoagulant drugs on commonly used coagulation tests Brand Anti-factor Drug class Drug PT aPTT name(s) Xa activity / * Vitamin K Warfarin Jantoven antagonists / * Acenocoumarol Sintrom Heparins Unfractionated heparin / LMW heparins Enoxaparin Lovenox Dalteparin Fragmin Nadroparin Fraxiparine / Fondaparinux Arixtra Direct Argatroban Acova thrombin inhibitors / Dabigatran Pradaxa / / Direct factor Rivaroxaban Xarelto Xa inhibitors / / Apixaban Eliquis Edoxaban Lixiana, Savaysa PT and aPTT are measured in seconds; anti-factor Xa activity is measured in units/mL. Upward arrow ( ) signifies an increase above normal due to the anticoagulant (prolongation of PT or aPTT; increase in anti-factor Xa activity). The effect magnitude will vary depending on the reagent formulation and instrument used. Dash ( ) signifies no appreciable effect. Normal ranges for the PT, aPTT, and anti-factor Xa activity vary among laboratories and should be reported from the testing laboratory along with the patient result. Refer to the UpToDate topic on coagulation testing for details. PT: prothrombin time; aPTT: activated partial thromboplastin time; LMW heparin: low molecular weight heparin. Warfarin has a weak effect on most aPTT reagents. However, warfarin use will increase the sensitivity of the aPTT to heparin effect. While heparin, LMW heparin, and fondaparinux should, in theory, prolong the PT as indirect thrombin inhibitors, in practice most PT reagents contain heparin-binding chemicals that block any heparin effect below a concentration of 1 unit/mL. Above concentrations of 1 unit/mL, heparin effect on the PT may be observed. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 38/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Anti-factor Xa activity testing must be calibrated for the specific anticoagulant; this information should be verified with the clinical laboratory. Some of the data are from: Samuelson BT, Cuker A, Crowther M, Garcia DA. Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: A systematic review. Chest 2017; 151:127. Graphic 91267 Version 9.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 39/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Guideline recommendations for management of warfarin-associated bleeding and/or high INR Clinical setting 2018 ASH guideline 2012 ACCP guideline Serious or life-threatening 4-factor PCC 4-factor PCC* bleeding Vitamin K (intravenous) Vitamin K (intravenous) Any INR Hold warfarin Hold warfarin (No recommendations given) No bleeding Vitamin K (oral) INR >10 Hold warfarin No bleeding Hold warfarin Hold warfarin INR 4.5 to 10 No vitamin K Vitamin K (low dose, oral) is optional Clinical judgment is required to assess the severity of bleeding, urgency of warfarin reversal, and need for other interventions. Refer to UpToDate for details and additional advice such as the duration of warfarin interruption and repeat INR testing. INR: international normalized ratio; ASH: American Society of Hematology; ACCP: American College of Chest Physicians; PCC: prothrombin complex concentrate; FFP: fresh frozen plasma. A plasma product such as thawed plasma or FFP (approximately 10 mL/kg, depending on INR) can be used as an alternative if PCC is not available. References: 1. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv 2018; 2:3257. 2. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e152S. Graphic 119954 Version 2.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 40/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Reversing anticoagulation in warfarin-associated bleeding Management option Time to anticoagulation reversal Comments and cautions Discontinuing warfarin therapy 5 to 14 days Five days is typical for patients with an INR in the therapeutic range Vitamin K* 6 to 24 hours to correct the INR, longer Recovery of factors X and II to fully reverse anticoagulation (prothrombin) takes longer than 24 hours Risk of anaphylaxis with intravenous injection Impaired response to warfarin lasting up to one week may occur after large doses (ie, >5 mg) Fresh frozen Depends on the time it takes to Effect is transient and concomitant plasma complete the infusion; typically 12 to 32 hours for complete reversal vitamin K must be administered Potential for volume overload (2 to 4 L to normalize INR) Potential for TRALI Potential for viral transmission Prothrombin 15 minutes after 10-minute to 1-hour Effect is transient, and concomitant complex infusion vitamin K must be administered; concentrate limited availability Cost Variable factor VII content depending on the product: a 4-factor PCC is preferred Potentially prothrombotic Recombinant factor VIIa 15 minutes after bolus infusion Effect is transient, and concomitant vitamin K must be administered Cost Potentially prothrombotic Please refer to the UpToDate topic on warfarin reversal in intracerebral hemorrhage for further details of management. INR: international normalized ratio; TRALI: transfusion-related acute lung injury; PCC: prothrombin complex concentrate. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 41/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate A total of 10 mg intravenously by slow infusion given over 10 minutes. Adapted with permission from: Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intercerebral hemorrhage: Literature review and expert opinion. Mayo Clin Proc 2007; 82:82. Copyright 2007 Dowden Health Media. Graphic 79151 Version 16.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 42/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate PCC products available in the United States* Unactivated prothrombin complex concentrates (PCCs) 4 factor: Contains inactive forms of 4 factors: Factors II, VII, IX, and X Kcentra Also contains heparin 3 factor: Contains inactive forms of 3 factors: Factors II, IX, and X Profilnine Contains little or no factor VII Does not contain heparin Activated prothrombin complex concentrate (aPCC) 4 factor: Contains 4 factors: Factors II, VII, IX, and X. Of these, only factor VII is mostly the activated form FEIBA Does not contain heparin The table lists 4-factor and 3-factor PCC products available in the United States. Kcentra is available as Beriplex in Canada. Bebulin (a 3-factor PCC) was discontinued in 2018 due to decreased demand for the product. Potency is determined differently for different products; refer to product information. All PCCs are plasma derived and contain other proteins, including anticoagulant proteins (proteins C and S). Unactivated factors are proenzymes (inactive precursor proteins). Activated factors have higher enzymatic activity. Refer to UpToDate topics for use of these products. US: United States; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. Other 4-factor PCCs available outside the US include Octaplex and Cofact Proplex. Single-factor recombinant activated factor VII (rFVIIa) products are also available. Graphic 94210 Version 8.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 43/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Emergency reversal of anticoagulation from warfarin for life-threatening hemorrhage in adults: Suggested approaches based upon available resources A. If 4-factor prothrombin complex concentrate (4F PCC) is available (preferred approach): 1. Give 4F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 4F PCC (refer to topic or drug reference for details). 2. Give vitamin K 10 mg IV over 10 to 20 minutes. B. If 3-factor prothrombin complex concentrate (3F PCC) is available but 4F PCC is not available: 1. Give 3F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 3F PCC (refer to topic or drug reference for details). 2. Give Factor VIIa 20 mcg/kg IV OR give FFP 2 units IV by rapid infusion. Factor VIIa may be preferred if volume overload is a concern. 3. Give vitamin K 10 mg IV over 10 to 20 minutes. C. If neither 3F PCC nor 4F PCC is available: 1. Give FFP 2 units IV by rapid infusion. Check INR 15 minutes after completion of infusion. If INR 1.5, administer 2 additional units of FFP IV rapid infusion. Repeat process until INR 1.5. May wish to administer loop diuretic between FFP infusions if volume overload is a concern. 2. Give vitamin K 10 mg IV over 10 to 20 minutes. These products and doses are for use in life-threatening bleeding only. Evidence of life-threatening bleeding and over-anticoagulation with a vitamin K antagonist (eg, warfarin) are required. Anaphylaxis and transfusion reactions can occur. It may be reasonable to thaw 4 units of FFP while awaiting the PT/INR. The transfusion service may substitute other plasma products for FFP (eg, Plasma Frozen Within 24 Hours After Phlebotomy [PF24]); these products are considered clinically interchangeable. PCC will reverse anticoagulation within minutes of administration; FFP administration can take hours due to the volume required; vitamin K effect takes 12 to 24 hours, but administration of vitamin K is needed to counteract the long half-life of warfarin. Subsequent monitoring of the PT/INR is needed to guide further therapy. Refer to topics on warfarin reversal in individual situations for further management. PCC: unactivated prothrombin complex concentrate; 4F PCC: PCC containing coagulation factors II, VII, IX, X, protein S and protein C; 3F PCC: PCC containing factors II, IX, and X and only trace factor VII; FFP: fresh frozen plasma; PT: prothrombin time; INR: international normalized ratio; FEIBA: factor eight inhibitor bypassing agent. Before use, check product label to confirm factor types (3 versus 4 factor) and concentration. Activated complexes and single-factor IX products (ie, FEIBA, AlphaNine, Mononine, Immunine, BeneFix) are NOT used for warfarin reversal. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 44/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate PCC doses shown are those suggested for initial treatment of emergency conditions. Subsequent treatment is based on INR and patient weight if available. Refer to topic and Lexicomp drug reference included with UpToDate for INR-based dosing. Graphic 89478 Version 10.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 45/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Direct oral anticoagulant reversal agents for life-threatening bleeding (imminent risk of death from bleeding) Reversal agent (all are given intravenously) Anticoagulant Dabigatran (Pradaxa; oral thrombin inhibitor) Idarucizumab (Praxbind). Dose: 5 grams* Oral factor Xa inhibitors: Andexanet alfa (AndexXa). Dosing for the Apixaban (Eliquis) initial bolus and subsequent infusion depend on the dose level of the factor Xa inhibitor and Edoxaban (Lixiana, Savaysa) the interval since it was last taken. Rivaroxaban (Xarelto) OR- 4-factor PCC (Kcentra, Beriplex P/N, Octaplex). Dosing can be done with a fixed dose of 2000 units OR a weight-based dose of 25 to 50 units per kg.
Discontinuing warfarin therapy 5 to 14 days Five days is typical for patients with an INR in the therapeutic range Vitamin K* 6 to 24 hours to correct the INR, longer Recovery of factors X and II to fully reverse anticoagulation (prothrombin) takes longer than 24 hours Risk of anaphylaxis with intravenous injection Impaired response to warfarin lasting up to one week may occur after large doses (ie, >5 mg) Fresh frozen Depends on the time it takes to Effect is transient and concomitant plasma complete the infusion; typically 12 to 32 hours for complete reversal vitamin K must be administered Potential for volume overload (2 to 4 L to normalize INR) Potential for TRALI Potential for viral transmission Prothrombin 15 minutes after 10-minute to 1-hour Effect is transient, and concomitant complex infusion vitamin K must be administered; concentrate limited availability Cost Variable factor VII content depending on the product: a 4-factor PCC is preferred Potentially prothrombotic Recombinant factor VIIa 15 minutes after bolus infusion Effect is transient, and concomitant vitamin K must be administered Cost Potentially prothrombotic Please refer to the UpToDate topic on warfarin reversal in intracerebral hemorrhage for further details of management. INR: international normalized ratio; TRALI: transfusion-related acute lung injury; PCC: prothrombin complex concentrate. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 41/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate A total of 10 mg intravenously by slow infusion given over 10 minutes. Adapted with permission from: Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intercerebral hemorrhage: Literature review and expert opinion. Mayo Clin Proc 2007; 82:82. Copyright 2007 Dowden Health Media. Graphic 79151 Version 16.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 42/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate PCC products available in the United States* Unactivated prothrombin complex concentrates (PCCs) 4 factor: Contains inactive forms of 4 factors: Factors II, VII, IX, and X Kcentra Also contains heparin 3 factor: Contains inactive forms of 3 factors: Factors II, IX, and X Profilnine Contains little or no factor VII Does not contain heparin Activated prothrombin complex concentrate (aPCC) 4 factor: Contains 4 factors: Factors II, VII, IX, and X. Of these, only factor VII is mostly the activated form FEIBA Does not contain heparin The table lists 4-factor and 3-factor PCC products available in the United States. Kcentra is available as Beriplex in Canada. Bebulin (a 3-factor PCC) was discontinued in 2018 due to decreased demand for the product. Potency is determined differently for different products; refer to product information. All PCCs are plasma derived and contain other proteins, including anticoagulant proteins (proteins C and S). Unactivated factors are proenzymes (inactive precursor proteins). Activated factors have higher enzymatic activity. Refer to UpToDate topics for use of these products. US: United States; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. Other 4-factor PCCs available outside the US include Octaplex and Cofact Proplex. Single-factor recombinant activated factor VII (rFVIIa) products are also available. Graphic 94210 Version 8.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 43/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Emergency reversal of anticoagulation from warfarin for life-threatening hemorrhage in adults: Suggested approaches based upon available resources A. If 4-factor prothrombin complex concentrate (4F PCC) is available (preferred approach): 1. Give 4F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 4F PCC (refer to topic or drug reference for details). 2. Give vitamin K 10 mg IV over 10 to 20 minutes. B. If 3-factor prothrombin complex concentrate (3F PCC) is available but 4F PCC is not available: 1. Give 3F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 3F PCC (refer to topic or drug reference for details). 2. Give Factor VIIa 20 mcg/kg IV OR give FFP 2 units IV by rapid infusion. Factor VIIa may be preferred if volume overload is a concern. 3. Give vitamin K 10 mg IV over 10 to 20 minutes. C. If neither 3F PCC nor 4F PCC is available: 1. Give FFP 2 units IV by rapid infusion. Check INR 15 minutes after completion of infusion. If INR 1.5, administer 2 additional units of FFP IV rapid infusion. Repeat process until INR 1.5. May wish to administer loop diuretic between FFP infusions if volume overload is a concern. 2. Give vitamin K 10 mg IV over 10 to 20 minutes. These products and doses are for use in life-threatening bleeding only. Evidence of life-threatening bleeding and over-anticoagulation with a vitamin K antagonist (eg, warfarin) are required. Anaphylaxis and transfusion reactions can occur. It may be reasonable to thaw 4 units of FFP while awaiting the PT/INR. The transfusion service may substitute other plasma products for FFP (eg, Plasma Frozen Within 24 Hours After Phlebotomy [PF24]); these products are considered clinically interchangeable. PCC will reverse anticoagulation within minutes of administration; FFP administration can take hours due to the volume required; vitamin K effect takes 12 to 24 hours, but administration of vitamin K is needed to counteract the long half-life of warfarin. Subsequent monitoring of the PT/INR is needed to guide further therapy. Refer to topics on warfarin reversal in individual situations for further management. PCC: unactivated prothrombin complex concentrate; 4F PCC: PCC containing coagulation factors II, VII, IX, X, protein S and protein C; 3F PCC: PCC containing factors II, IX, and X and only trace factor VII; FFP: fresh frozen plasma; PT: prothrombin time; INR: international normalized ratio; FEIBA: factor eight inhibitor bypassing agent. Before use, check product label to confirm factor types (3 versus 4 factor) and concentration. Activated complexes and single-factor IX products (ie, FEIBA, AlphaNine, Mononine, Immunine, BeneFix) are NOT used for warfarin reversal. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 44/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate PCC doses shown are those suggested for initial treatment of emergency conditions. Subsequent treatment is based on INR and patient weight if available. Refer to topic and Lexicomp drug reference included with UpToDate for INR-based dosing. Graphic 89478 Version 10.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 45/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Direct oral anticoagulant reversal agents for life-threatening bleeding (imminent risk of death from bleeding) Reversal agent (all are given intravenously) Anticoagulant Dabigatran (Pradaxa; oral thrombin inhibitor) Idarucizumab (Praxbind). Dose: 5 grams* Oral factor Xa inhibitors: Andexanet alfa (AndexXa). Dosing for the Apixaban (Eliquis) initial bolus and subsequent infusion depend on the dose level of the factor Xa inhibitor and Edoxaban (Lixiana, Savaysa) the interval since it was last taken. Rivaroxaban (Xarelto) OR- 4-factor PCC (Kcentra, Beriplex P/N, Octaplex). Dosing can be done with a fixed dose of 2000 units OR a weight-based dose of 25 to 50 units per kg. Reversal agents carry a risk of life-threatening thrombosis and should only be used under the direction of a specialist with expertise in their use and/or in a patient at imminent risk of death from bleeding. In general, a single dose is given; dosing may be repeated in rare situations in which the oral anticoagulant persists for longer in the circulation, such as severe kidney dysfunction. Andexanet dosing is as follows: If the patient took rivaroxaban >10 mg, apixaban >5 mg, or dose unknown within the previous 8 hours: Andexanet 800 mg bolus at 30 mg/minute followed by 960 mg infusion at 8 mg/minute for up to 120 minutes. OR- If the patient took rivaroxaban 10 mg or apixaban 5 mg, or if 8 hours have elapsed since the last dose of a factor Xa inhibitor: Andexanet 400 mg bolus at 30 mg/minute followed by 480 mg infusion at 4 mg/minute for up to 120 minutes. Refer to UpToDate topics on treatment of bleeding in patients receiving a DOAC or perioperative management of patients receiving a DOAC for additional information on administration, risks, and alternative therapies. DOAC: direct oral anticoagulant; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. If idarucizumab is unavailable, an activated PCC (FEIBA, 50 to 80 units per kg intravenously) may be a reasonable alternative. Graphic 112299 Version 9.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 46/47 7/5/23, 12:24 PM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Contributor Disclosures W David Freeman, MD Other Financial Interest: Cambridge [Book royalties]; Oxford [Book royalties]. All of the relevant financial relationships listed have been mitigated. Jeffrey I Weitz, MD Consultant/Advisory Boards: Alnylam [Anticoagulation]; Anthos [Anticoagulation]; Bayer/Janssen [Anticoagulation]; Boehringer- Ingelheim [Anticoagulation]; Bristol Myers Squibb/Janssen [Anticoagulation]; Bristol Myers Squibb/Pfizer [Anticoagulation]; Daiichi-Sankyo [Anticoagulation]; Ionis Pharmaceuticals [Anticoagulation]; Merck [Anticoagulation]; Pfizer [Anticoagulation]; PhaseBio [Anti-platelet drug reversal]; Regeneron Pharmaceuticals [Anticoagulation]; Servier [Anticoagulation]; VarmX [Anticoagulant reversal]. All of the relevant financial relationships listed have been mitigated. Lawrence LK Leung, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Jennifer S Tirnauer, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 47/47
7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Spontaneous intracerebral hemorrhage: Acute treatment and prognosis : Guy Rordorf, MD, Colin McDonald, MD : Scott E Kasner, MD, Jonathan A Edlow, MD, FACEP, Alejandro A Rabinstein, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 30, 2023. INTRODUCTION Intracerebral hemorrhage (ICH) is the second most common cause of stroke, following ischemic stroke, but accounts for a disproportionate amount of cerebrovascular mortality and morbidity. The goals of initial treatment include preventing hemorrhage expansion, monitoring for and managing elevated intracranial pressure, and managing other neurologic and medical complications ( table 1). The acute treatment and prognosis of spontaneous (atraumatic) intracerebral hemorrhage will be reviewed here. Other aspects of ICH are discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis".) (See "Hemorrhagic stroke in children".) (See "Stroke in the newborn: Management and prognosis".) (See "Management of acute moderate and severe traumatic brain injury".) TRIAGE https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 1/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Prehospital management of acute ICH focuses on airway maintenance, cardiovascular support, and rapid transport to the nearest acute stroke care facility. Facilities without critical care units and expertise in stroke care should transfer stabilized patients with an acute ICH to an appropriate tertiary care center if possible. The initial steps of acute management in the emergency department include clinical evaluation and imaging-based diagnosis and are discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Evaluation and diagnosis' and "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Brain imaging'.) Admit to ICU or stroke unit Patients with acute ICH should be admitted to the hospital with expertise in neurology, neurosurgery, neuroradiology, and critical care to be monitored and managed in an intensive care unit (ICU) or dedicated stroke unit [1-5]. Multidisciplinary care and the use of ICH-specific treatment protocols can improve functional outcome in ICH [6]. Facilities without such expertise should transfer stabilized patients to an appropriate tertiary care center if possible. Patients with acute ICH are at risk for neurologic deterioration in the first several days due to complications including hematoma expansion, elevations in intracranial pressure, development of hydrocephalus, seizures, or brain herniation [7]. Initial aggressive care We generally provide initial aggressive care to all patients with acute ICH and delay prognostication or enacting new limitations in care for at least the first day. However, these measures do not apply to patients with preexisting "do not attempt resuscitation" (DNAR) orders nor to patients who present with catastrophic ICH and minimal brainstem function. There are inherent uncertainties in determining prognosis for individual patients with acute ICH. Severe neurologic impairment at initial evaluation may be due in part to reversible sources such as metabolic derangements or seizures. Additionally, early limitations to care including new DNAR orders may lead to a self-fulfilling prophecy of poor outcomes caused by clinical nihilism [8-10]. Clinical prediction scores may overestimate the likelihood of poor outcome due to these limitations [11]. MANAGEMENT OF ACUTE BLEEDING Cessation of bleeding occurs in ICH via intrinsic hemostatic pathways and vascular tamponade imposed by the rigid cranial vault [12]. Factors that delay this process by inhibiting hemostasis include exposure to antithrombotic medications and uncontrolled blood pressure. Prompt https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 2/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate control of these factors can reduce the risk of morbidity associated with hematoma enlargement. Reversal strategies differ by antithrombotic drug exposure. The management of uncontrolled blood pressure is reviewed below. (See 'Blood pressure management' below.) Reverse anticoagulation For patients who develop ICH, all anticoagulant and antiplatelet drugs should be discontinued initially. Medications to reverse the effects of anticoagulant drugs should be given immediately ( table 1). Medication-specific reversal agents include: Warfarin Four-factor prothrombin complex concentrate (4F PCC) is preferred for patients with acute ICH taking warfarin [5]. If 4F PCC is unavailable, three-factor prothrombin complex with recombinant activated factor VII or fresh frozen plasma (FFP) may be administered ( table 2). Intravenous vitamin K should also be given to sustain the short- acting effects of 4F PCC or FFP. Reversal of anticoagulation in this setting is discussed in detail separately. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Warfarin'.) Direct oral anticoagulants Reversal strategies for direct oral anticoagulants (DOACs) differ by agent and are presented separately ( table 3). (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Apixaban, edoxaban, and rivaroxaban' and "Reversal of anticoagulation in intracranial hemorrhage", section on 'Dabigatran'.) Heparin and low molecular weight heparins Protamine sulfate is recommended for urgent treatment of patients with heparin-associated ICH [5]. The appropriate dose of protamine sulfate is dependent upon the type of heparin (unfractionated or low molecular weight agents), the dose of heparin given, and the time elapsed since that dose. Andexanet alfa may be used for patients taking low molecular weight heparin. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Unfractionated heparin' and "Reversal of anticoagulation in intracranial hemorrhage", section on 'LMW heparin'.) Patients with severe coagulation factor deficiency or severe thrombocytopenia should receive appropriate factor replacement or platelet transfusion [5]. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Actively bleeding patient'.) Limited role of platelet transfusion For most ICH patients on antiplatelet therapy, we suggest not using platelet transfusions because available data indicate this may be hazardous [13,14]. Platelet transfusions may be given to selected patients with ICH undergoing emergency surgery to reduce the risk of postoperative bleeding [5]. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Antiplatelet agents'.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 3/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Other hemostatic strategies not recommended For ICH patients without coagulopathy and those not exposed to antithrombotic (anticoagulant or antiplatelet) therapy, we suggest not using specific hemostatic therapy outside the context of a clinical trial. While hemostatic therapy offers the theoretic potential to improve outcomes by stopping ongoing hemorrhage and preventing hemorrhage enlargement, the clinical benefits remain unproven [5,13] and these therapies may cause thromboembolic complications [15-17]. The two most studied hemostatic agents for use in spontaneous ICH are activated recombinant human factor VIIa (rFVIIa) and tranexamic acid. Recombinant factor VIIa rFVIIa promotes hemostasis by activating the extrinsic pathway of the coagulation cascade. Preliminary studies suggested that treatment with rFVIIa was safe and effective for ICH [18,19]. However, in the multicenter, double-blind Factor Seven for Acute Hemorrhagic Stroke (FAST) trial, rFVIIa failed to improve outcomes in patients with acute ICH [15]. The trial randomly assigned 841 patients with spontaneous ICH to receive either rFVIIa (20 or 80 mcg/kg) or placebo within four hours of symptom onset. Compared with placebo, treatment with rFVIIa produced a significant reduction in hematoma growth but did not result in improvement in death or severe disability at 90 days. Recombinant factor VIIa is associated with a risk of thrombosis from activation of the coagulation system [16]. In the FAST trial, the overall frequency of thromboembolic serious adverse events was similar among treatment groups, but the rate of arterial thromboembolic serious adverse events (myocardial infarction or cerebral infarction) was higher in the group assigned to 80 mcg/kg than those assigned to placebo (8 versus 4 percent) [15]. Similar findings were noted in an analysis of pooled data from three earlier randomized controlled trials of rFVIIa for spontaneous ICH [17]. Additionally, small open- label studies observed that rFVIIa treatment for ICH was associated with increased rates of troponin elevation and myocardial infarction [20] as well as higher-than-expected rates of posthemorrhagic hydrocephalus [21]. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Adverse events'.) The use of factor VIIa along with a prothrombin complex for patients with warfarin- associated ICH is discussed in detail separately. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Warfarin'.) Tranexamic acid Tranexamic acid inhibits fibrinolysis and the proteolytic activity of plasmin. Clinical trials have failed to show functional outcome or mortality benefit compared with placebo. The Tranexamic acid for hyperacute primary IntraCerebral Hemorrhage (TICH-2) trial randomly assigned over 2300 subjects with acute ICH to https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 4/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate treatment with tranexamic acid or matching placebo within eight hours of symptom onset [22]. At 90 days, there was no difference in functional status or mortality between the two treatment groups, despite early reductions in hematoma growth (at day 2) and death (at day 7). In another trial of patients with ICH who were treated within 4.5 hours of symptom onset, those assigned to tranexamic acid had a similar rate of ICH growth and functional outcomes as those assigned to placebo [23]. Managing hemorrhagic expansion Patients with acute ICH are at risk for hemorrhagic growth from continued or recurrent bleeding, most commonly within the first several hours after onset of ICH [24,25]. ICH growth can cause neurologic deterioration and increases the likelihood of developing elevated intracranial pressure (ICP). Medical and surgical strategies to manage patients with ICH growth and elevated ICP are discussed below. (See 'Intracranial pressure management' below.) Several imaging findings have been associated with the risk of ICH growth in the acute setting. These are discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Predicting hemorrhage expansion'.) BLOOD PRESSURE MANAGEMENT Elevated blood pressure is common in patients with acute ICH. Patients may develop elevated blood pressure due to an increase in intracranial pressure (ICP) and pain from the mass effect of the hemorrhage. Additionally, many patients with acute ICH have high blood pressure due to comorbid baseline hypertension. Uncontrolled elevations in blood pressure and blood pressure variability are risk factors for hemorrhagic expansion and poor outcome [26-28]. We manage elevated blood pressure in acute spontaneous ICH as follows, in agreement with guidelines from the American Heart Association ( table 1) [5]: For patients with acute ICH who present with systolic blood pressure (SBP) between 150 and 220 mmHg, we suggest lowering of SBP to a target of 140 mmHg, ideally within the first one hour of presentation, provided the patient remains clinically stable [5]. This degree of blood pressure reduction appears safe in most patients and may improve functional outcome. For patients with acute ICH who present with SBP >220 mmHg, we suggest rapid lowering of SBP to <220 mmHg. Thereafter, the blood pressure is gradually reduced (over a period of hours) to a target range of 140 to 160 mmHg, provided the patient remains clinically stable. Patients who deteriorate clinically during this period may require reduction of acute https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 5/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate antihypertensive therapy. The optimal blood pressure goal is uncertain, but an SBP of 140 to 160 mmHg is a reasonable target for patients who remain clinically stable [5]. Medication selection should account for the rapidity and extent of blood pressure reduction, method of delivery (bolus versus infusion), individual patient comorbidities, potential adverse effects, and local experience [5]. We monitor all patients for neurologic deterioration during treatment. Reducing SBP below 130 mmHg in the first hours after ICH onset has not been shown clearly beneficial for reducing death or disability and may increase the risk of adverse events, including cerebral hypoperfusion and kidney injury [5]. For most patients with an initial SBP 160 mmHg, we prefer nicardipine for initial treatment because it is fast-acting and can be quickly titrated. Blood pressure is monitored every five minutes and patients are monitored at least hourly to assess for neurologic deterioration. For most patients with an initial SBP <160 mmHg, we start with labetalol for its ease of administration and long duration of effect. However, the choice of antihypertensive agent and the optimal rate of reduction depend upon patient-level factors and local experience; data to guide selection in this setting are lacking. Several intravenous medications may be used to control blood pressure in this setting including nicardipine, labetalol, clevidipine, esmolol, enalaprilat, and fenoldopam ( table 4). Nitroprusside and nitroglycerin are typically avoided because they may increase intracranial pressure. (See "Drugs used for the treatment of hypertensive emergencies".) The relationship between blood pressure and outcome in patients with ICH is complex, and data to specify optimal treatment strategies are lacking. The potential benefits of treating elevated blood pressure in patients with ICH in the acute setting must be balanced with the potential risks. The key competing issues are: Severely elevated blood pressure can worsen ICH by inciting continued or recurrent bleeding and by causing hemorrhage expansion and potentially worse outcomes [29,30]. Conversely, lowering the arterial pressure might mitigate these risks and possibly improve outcomes. Lowering blood pressure rapidly could cause further injury by promoting cerebral and systemic hypoperfusion [31]. Conversely, reducing elevated blood pressure slowly with stepwise reductions while monitoring for clinical deterioration might help prevent these complications by maintaining adequate cerebral and systemic perfusion. Clinical studies to assess these issues have shown that aggressive blood pressure lowering in acute ICH is associated with reduced hematoma growth [32-34]. Additionally, blood pressure https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 6/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate lowering does not appear to impair cerebral blood flow within the perihematomal region [35- 37]. The ischemic-appearing rim of low attenuation surrounding the hemorrhage visible on computed tomography imaging is caused by extravasated plasma and is not associated with markers of ischemia visible on magnetic resonance imaging [37]. Data from clinical trials have not demonstrated consistent safety and outcome benefits from acute blood pressure reduction. In the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2) trial, 2839 patients with acute ICH were assigned (within six hours of symptom onset) either to intensive blood pressure lowering or traditional management (target SBP <140 mmHg versus SBP <180 mmHg) [38]. The mean baseline SBP was 179 mmHg. There was a trend toward lower rates of death and severe disability at 90 days with intensive blood pressure lowering, although this was not statistically significant (52 versus 55.6 percent). In addition, intensive blood pressure lowering was associated with improved measures of disability according to modified Rankin scale scores. The rates of acute neurologic deterioration and other adverse events were similar in the patient groups. The Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial found no differences in death or disability rates among 1000 patients with acute ICH assigned in an earlier time window (within 4.5 hours) to a more intensive target SBP of 110 to 139 mmHg versus a standard target SBP of 140 to 179 mmHg (39 versus 38 percent) [31]. Additionally, the rate of acute neurologic deterioration in patients assigned to intensive treatment was similar to those assigned standard treatment. However, the rate of adverse kidney events was higher in the intensive treatment group (9 versus 4 percent). Failure to achieve goal blood pressure was also more frequent in the intensive group (12 versus 1 percent). In a subsequent analysis of patients by actual blood pressure attained, the rates of neurologic deterioration at 24 hours and cardiac- related adverse events were higher among patients who achieved and sustained SBP <140 mmHg [39]. In a post-hoc analysis using individual patient data of the INTERACT2 and ATACH-2 trials, each 10 mmHg reduction in SBP in the first 24 hours was associated with a 10 percent increased odds of better functional recovery, down to a threshold as low as 120 to 130 mmHg [40]. In this analysis, the combined mean baseline blood pressure was 178 mmHg and the mean ICH volume was 11 mL. It is unclear if these improved outcomes would be applicable to patients with more severe elevations in baseline blood pressure, those with more severe ICH, or those treated beyond the acute time intervals applied in the trials. INTRACRANIAL PRESSURE MANAGEMENT https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 7/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Patients with space-occupying lesions such as acute ICH are at risk for progressive neurologic impairment from brain compression due to increased intracranial pressure (ICP). Acute ICH may lead to elevated ICP due to several mechanisms. These include: Mass effect of the initial hematoma Expansion or rebleeding of the ICH Cerebral edema surrounding the hemorrhage Hydrocephalus from ventricular outflow obstruction The risk of developing increased ICP is highest in the first several days after ICH but may vary depending on the size and location of the hemorrhage and patient-level factors. (See 'Assessing elevated ICP' below.) Basic measures outlined below should be instituted initially for all patients with ICH; indications for ICP monitoring and treatment interventions (eg, cerebrospinal fluid drainage and osmotic therapy) are discussed in the sections that follow ( algorithm 1). Select patients with ICH may benefit from surgical interventions ( table 1). Identifying patients with an indication for emergent surgery Some patients with ICH may present with clinical evidence of, or imaging features concerning for, rapidly progressive neurological impairment due to elevated ICP. For these selected patients, emergent surgical consultation is indicated to assess whether surgery may be lifesaving. Such ICH features may include: Cerebellar hemorrhage that is either greater than 3 cm in diameter or associated with acute neurological deterioration, brainstem compression, or hydrocephalus due to ventricular obstruction. (See 'Cerebellar hemorrhage' below.) Intraventricular hemorrhage with ventricular enlargement associated with acute neurologic deterioration. (See 'Cerebrospinal fluid drainage for obstructive hydrocephalus' below.) Supratentorial (hemispheric) hemorrhage associated with acute neurological deterioration and life-threatening brain compression or hydrocephalus; however, not all patients will benefit from surgery. Treatment decisions for these patients should be individualized based on assessments of prognosis with and without surgical therapy. (See 'Supratentorial hemorrhage' below.) Preventive measures for all other patients For patients who do not require immediate surgical evaluation, preventive measures should be enacted to mitigate the morbidity associated https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 8/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate with elevated ICP. The following measures should be initiated unless a specific contraindication exists [5]: Elevation of the head of the bed to 30 degrees Mild sedation for agitated patients, typically to a goal Richmond Agitation-Sedation Scale (RASS) score of 0 to -2 ( table 5) (see "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal") Antipyretic medications if core temperature is >38 degrees Celsius Head positioning and device placement at the neck to facilitate cerebral venous outflow; these include avoiding neck rotation, internal jugular central line placement, and tight device securement (eg, device ties, endotracheal tube holder, or intravenous line dressings) Isotonic solutions such as normal saline for maintenance and replacement fluids; hypotonic fluids are contraindicated Maintain serum sodium >135 mEq/L Assessing elevated ICP Patients with acute ICH should be monitored until improvement in or stabilization of the neurologic exam and imaging findings (eg, hemorrhage and associated edema). The risk of neurologic deterioration from elevated ICP is typically highest in the first several days after ICH onset but may vary depending upon the presence of associated risks including the size and location of the ICH, ICH extension or rebleeding, or comorbid features (eg, fever, hyperglycemia, hypervolemia, and/or hypoosmolar fluid status). ICP is typically assessed and monitored by serial clinical examinations. We repeat urgent imaging with computed tomography (CT) of the head for deteriorating patients with suspected ICP elevation to help guide treatment and evaluate for an indication for surgery. Serial imaging is also sometimes used to monitor changes that may indicate progressive elevation of ICP; however, other modalities are preferred because progressive elevation of ICP may occur in the setting of a stable head CT. Invasive ICP monitoring is used for some deteriorating patients when the neurologic examination may be unreliable due to baseline deficits or other treatments (eg, sedative medications). (See 'Invasive ICP monitoring when clinical exam is unreliable' below.) For patients with rapid, life-threatening clinical deterioration or when imaging may be delayed, we give an initial dose of osmotic therapy prior to imaging. (See 'Identifying patients with an indication for emergent surgery' above and 'Osmotic therapy' below.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 9/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Clinical exam findings Serial examinations to identify progressive neurologic impairment are generally performed hourly for the initial few days or otherwise when the risk of deterioration is highest. Serial examinations may be less useful for comatose patients and others with severe baseline impairment (eg, hemiplegia). For these patients, we use invasive monitors and imaging to evaluate for elevated ICP. (See 'Invasive ICP monitoring when clinical exam is unreliable' below and 'Serial imaging for other patients' below.) Examination findings in a patient with acute ICH concerning for a progressive elevation in ICP include new or worsening: Pupillary changes, including impaired reactivity to light Abducens nerve (cranial nerve VI) palsy; alert patients may report horizontal diplopia Progressive drowsiness Cushing triad consisting of bradycardia, respiratory depression, and hypertension Focal symptoms related to herniation syndromes ( table 6) The clinical manifestations of elevated intracranial pressure are also discussed separately. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Clinical manifestations'.) Invasive ICP monitoring when clinical exam is unreliable We use invasive monitoring for select deteriorating patients unable to participate in serial clinical examinations due to severe baseline deficits or sedation (eg, those with Glasgow Coma Scale score <8 ( table 7)), those with clinical evidence of transtentorial herniation, and those with midline lesions or otherwise at risk for developing obstructive hydrocephalus [5]. Measuring ICP directly allows directed treatment of ICP and blood pressure with a goal of maintaining a cerebral perfusion pressure (CPP) of 50 to 70 mmHg. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Physiology'.) However, there are no high-quality data showing that ICP monitoring or management of elevated ICP improves outcomes in patients with ICH [41,42]. In addition, the use of invasive monitors is associated with a small risk of infection and intracranial bleeding. Noninvasive ICP monitoring techniques such as transcranial doppler, optic nerve sheath diameter analysis, and ocular ultrasound have been used as alternatives when invasive options are contraindicated or unavailable. However, these techniques have not been shown effective in large trials [43-45]. ICP monitoring is discussed in detail separately. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'ICP monitoring'.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 10/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Serial imaging for other patients We typically repeat imaging for deteriorating patients with suspected ICP elevation to help guide treatment and evaluate for an indication for surgery. (See 'Identifying patients with an indication for emergent surgery' above.) Serial imaging may also be used to monitor some patients for changes in the first days after acute ICH related to a progressive elevation of ICP. As examples, repeat surveillance imaging may be performed for patients who are deeply sedated to treat coexisting status epilepticus, patients receiving neuromuscular blocking medications, and those with a poor baseline neurologic exam due to a brainstem hemorrhage. However, serial neurologic examination or direct ICP monitoring are preferred strategies when feasible because progressive elevation of ICP may occur in the setting of a stable head CT. Such imaging findings that may be suggestive of a progressive elevation in ICP and associated with neurologic deterioration include: Increasing shift of brain tissue beyond midline Ventricular or brainstem compression Obstructive hydrocephalus Herniation (transtentorial, parafalcine, uncal, central, tonsillar) of brain structures ( figure 1) For most patients, we prefer head CT because it is typically more readily available and a faster imaging modality compared with brain magnetic resonance imaging (MRI). However, MRI may be performed as an alternative modality and may be preferred in circumstances where other causes of neurological deterioration may be not be adequately assessed by head CT. Such circumstances include assessing acute ischemic stroke and measuring interval changes in cerebral edema volume. Surgical approaches vary by specific imaging findings including the location of the ICH. (See 'Surgical approaches for selected patients' below.) Treatment measures for patients who have severe or progressive ICP elevation For patients who have severe signs or symptoms of elevated ICP or for those with milder symptoms that progress despite initial measures, we use osmotic therapy. We also repeat imaging to assess for structural sources that may be corrected with invasive and surgical options. For patients with rapid, life-threatening clinical deterioration or when imaging may be delayed, we give an initial dose of osmotic therapy prior to imaging. (See 'Assessing elevated ICP' above and 'Surgical approaches for selected patients' below.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 11/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Glucocorticoids should not be used to lower the ICP in most patients with ICH due to lack of benefit and risk of infection and hyperglycemia [46]. Osmotic therapy Acute ICP elevation or life-threatening mass effect can be treated with hypertonic saline or mannitol [47]. Osmotic therapy is effective for lowering ICP but has not been shown to improve outcomes in patients with acute ICH [48]. There is no compelling evidence to support the superiority of either agent, although some studies in patients with traumatic brain injury suggest that hypertonic saline may be more effective [49-52]. Either agent may be used depending upon local protocol and physician experience. Hypertonic saline is an effective hyperosmolar agent for the control of elevated ICP [52]. For patients with evidence of life-threatening or progressive deterioration (including patients with herniation syndromes and those awaiting emergent surgery), we use high- concentration (23.4 percent) saline as an intermittent bolus via a central intravenous line, typically 15 to 30 mL every six hours. For other patients with milder signs or symptoms, we use a continuous infusion of 3 percent saline (via peripheral or central intravenous line) titrated to a sodium goal of approximately 145 to 155 mEq/L. (See "Management of acute moderate and severe traumatic brain injury", section on 'Osmotic therapy'.) Serial measurement of electrolytes is performed at six-hour intervals to monitor and prevent excessive elevation of sodium and chloride levels and to detect and correct other derangements such as hypokalemia. Other potential adverse effects include circulatory overload, pulmonary edema, and a non-anion gap metabolic acidosis. Intravenous mannitol has also been shown to effectively lower ICP [53]. For initial therapy and for patients with evidence of life-threatening or progressive deterioration (including patients with herniation syndromes and those awaiting emergent surgery), we use mannitol 1 g/kg as a bolus via a central intravenous line. For other patients, we use mannitol at a dose of 0.25 to 0.5 g/kg every six hours. The goal of therapy is to force water to exit the brain while maintaining an adequate plasma volume [54]. The plasma osmolal gap should not be allowed to exceed 55 mosmol/kg; higher doses can cause reversible acute kidney injury. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Osmotic therapy and diuresis' and "Complications of mannitol therapy".) The osmolal gap peaks rapidly after mannitol infusion and typically normalizes from diuresis within hours. Therefore, the serum osmolality and electrolytes to calculate the osmolal gap should be drawn prior to subsequent doses to verify renal clearance of the previous dose as well as to monitor, prevent, and correct metabolic derangements and https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 12/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate acute kidney injury. Other potential adverse effects of mannitol therapy include hypotension and intravascular volume depletion [55]. (See "Complications of mannitol therapy" and "Serum osmolal gap".) Surgical approaches for selected patients The role of surgery in patients with acute ICH varies with the site of the bleed. Cerebrospinal fluid drainage for obstructive hydrocephalus Ventricular drainage of cerebrospinal fluid (CSF) with an external ventricular drain can help reduce elevated ICP for selected patients with hydrocephalus, particularly when associated with a decreased level of consciousness [5]. Obstructive hydrocephalus may occur when hemorrhage or mass effect obstructs CSF ventricular outflow. This may commonly be seen with ICH in the following locations: Thalamic hemorrhage (with third ventricle compression) Cerebellar hemorrhage (with fourth ventricle compression) (see 'Cerebellar hemorrhage' below) ICH with intraventricular extension (see "Intraventricular hemorrhage", section on 'External ventricular drain') For patients with neurologic deterioration who develop ventricular enlargement due to a large cerebellar hemorrhage, craniectomy with hematoma evacuation along with CSF drainage is the preferred intervention to treat both hydrocephalus and brainstem compression. In this setting, external drainage alone, without posterior fossa decompression, may create the theoretical risk of upward herniation of the cerebellar mass. (See 'Cerebellar hemorrhage' below.) For other ICH patients, a ventriculostomy catheter may be used with an external ventricular drainage to remove CSF and intraventricular blood to lower and monitor ICP. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Removal of CSF'.) The management of patients with intraventricular hemorrhage is discussed in greater detail separately. (See "Intraventricular hemorrhage", section on 'Management'.) Surgical decompression Cerebellar hemorrhage The indications for evacuation of a cerebellar hematoma depend on the ICH size and location, the time since onset, and the clinical status of the patient [5,56,57]. As examples, patients presenting acutely with a cerebellar hemorrhage greater than 3 3 cm in diameter (volume of at least 14 cm ) and brainstem compression will typically require https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 13/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate urgent surgical decompression of the cerebellum with craniectomy and hematoma evacuation. Some patients with smaller acute cerebellar hematomas may also warrant surgical decompression if they are deteriorating neurologically or have brainstem compression and/or hydrocephalus due to ventricular obstruction. Other patients with small, subacute cerebellar hematomas that do not exert mass effect on the brainstem may be managed medically with close monitoring. These recommendations are in broad agreement with published guidelines. Patients with cerebellar hemorrhage are at risk for rapid deterioration and fatal herniation due to the bony and tentorial confines of the posterior fossa. For patients selected for surgical decompression of a cerebellar hematoma, we suggest craniectomy and hematoma evacuation rather than ventriculostomy without posterior fossa decompression. External drainage alone may create the theoretical risk of upward herniation of the cerebellar mass. Observational evidence suggests that surgical evacuation of hematoma is associated with decreased mortality in patients with cerebellar hemorrhage. In a 2019 meta-analysis with individual patient data from four observational studies including 304 patients with cerebellar hemorrhage, surgical hematoma evacuation was associated with an increased probability of survival at three months compared with conservative treatment (78 versus 61 percent; absolute risk difference [ARD] 18.5 percent, 95% CI 13.8-23.2) [58]. This association was sustained at 12 months. The overall likelihood of a favorable functional outcome was similar for patients who had a hematoma evacuation or conservative treatment (31 versus 36 percent; ARD -3.7 percent, 3 95% CI -8.7 to 1.2). However, for patients with a hematoma volume of 12 cm , the likelihood of a favorable outcome was lower with surgical evacuation (31 versus 62 percent; ARD 35 percent). 3 By contrast, in the subgroup of patients with a hematoma volume of 15 cm , a favorable outcome was more likely with hematoma evacuation than with conservative treatment (75 versus 45 percent). Limitations to this meta-analysis include retrospective design, lack of randomization, small sample size for subgroup analyses, and a high number of patients on oral anticoagulant therapy at baseline, which impacts the generalizability of the findings. Supratentorial hemorrhage Surgical hematoma evacuation for supratentorial ICH is controversial because the potential benefits of hematoma evacuation may be offset by surgical morbidity in many cases. The subset of patients who may benefit from surgical treatment have not been conclusively defined [5]. We reserve surgical therapy for patients with life-threatening mass effect from supratentorial ICH, individualizing treatment decisions based on assessments of prognosis with and without surgical therapy. Limited data suggest that supratentorial hematoma evacuation might reduce mortality for patients who are comatose, have a large hematoma with significant midline shift, or have elevated ICP refractory to medical management [5]. Supratentorial decompression with https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 14/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate hematoma evacuation and/or decompressive hemicraniectomy may reduce mortality but not improve functional outcomes. It should only be considered as a life-saving procedure to treat refractory increases in ICP; even in these instances, decisions should be addressed on an individual basis: Surgery should not be considered for patients who are either fully alert or deeply comatose. Patients with intermediate levels of arousal (obtundation-stupor) are more
derangements such as hypokalemia. Other potential adverse effects include circulatory overload, pulmonary edema, and a non-anion gap metabolic acidosis. Intravenous mannitol has also been shown to effectively lower ICP [53]. For initial therapy and for patients with evidence of life-threatening or progressive deterioration (including patients with herniation syndromes and those awaiting emergent surgery), we use mannitol 1 g/kg as a bolus via a central intravenous line. For other patients, we use mannitol at a dose of 0.25 to 0.5 g/kg every six hours. The goal of therapy is to force water to exit the brain while maintaining an adequate plasma volume [54]. The plasma osmolal gap should not be allowed to exceed 55 mosmol/kg; higher doses can cause reversible acute kidney injury. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Osmotic therapy and diuresis' and "Complications of mannitol therapy".) The osmolal gap peaks rapidly after mannitol infusion and typically normalizes from diuresis within hours. Therefore, the serum osmolality and electrolytes to calculate the osmolal gap should be drawn prior to subsequent doses to verify renal clearance of the previous dose as well as to monitor, prevent, and correct metabolic derangements and https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 12/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate acute kidney injury. Other potential adverse effects of mannitol therapy include hypotension and intravascular volume depletion [55]. (See "Complications of mannitol therapy" and "Serum osmolal gap".) Surgical approaches for selected patients The role of surgery in patients with acute ICH varies with the site of the bleed. Cerebrospinal fluid drainage for obstructive hydrocephalus Ventricular drainage of cerebrospinal fluid (CSF) with an external ventricular drain can help reduce elevated ICP for selected patients with hydrocephalus, particularly when associated with a decreased level of consciousness [5]. Obstructive hydrocephalus may occur when hemorrhage or mass effect obstructs CSF ventricular outflow. This may commonly be seen with ICH in the following locations: Thalamic hemorrhage (with third ventricle compression) Cerebellar hemorrhage (with fourth ventricle compression) (see 'Cerebellar hemorrhage' below) ICH with intraventricular extension (see "Intraventricular hemorrhage", section on 'External ventricular drain') For patients with neurologic deterioration who develop ventricular enlargement due to a large cerebellar hemorrhage, craniectomy with hematoma evacuation along with CSF drainage is the preferred intervention to treat both hydrocephalus and brainstem compression. In this setting, external drainage alone, without posterior fossa decompression, may create the theoretical risk of upward herniation of the cerebellar mass. (See 'Cerebellar hemorrhage' below.) For other ICH patients, a ventriculostomy catheter may be used with an external ventricular drainage to remove CSF and intraventricular blood to lower and monitor ICP. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Removal of CSF'.) The management of patients with intraventricular hemorrhage is discussed in greater detail separately. (See "Intraventricular hemorrhage", section on 'Management'.) Surgical decompression Cerebellar hemorrhage The indications for evacuation of a cerebellar hematoma depend on the ICH size and location, the time since onset, and the clinical status of the patient [5,56,57]. As examples, patients presenting acutely with a cerebellar hemorrhage greater than 3 3 cm in diameter (volume of at least 14 cm ) and brainstem compression will typically require https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 13/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate urgent surgical decompression of the cerebellum with craniectomy and hematoma evacuation. Some patients with smaller acute cerebellar hematomas may also warrant surgical decompression if they are deteriorating neurologically or have brainstem compression and/or hydrocephalus due to ventricular obstruction. Other patients with small, subacute cerebellar hematomas that do not exert mass effect on the brainstem may be managed medically with close monitoring. These recommendations are in broad agreement with published guidelines. Patients with cerebellar hemorrhage are at risk for rapid deterioration and fatal herniation due to the bony and tentorial confines of the posterior fossa. For patients selected for surgical decompression of a cerebellar hematoma, we suggest craniectomy and hematoma evacuation rather than ventriculostomy without posterior fossa decompression. External drainage alone may create the theoretical risk of upward herniation of the cerebellar mass. Observational evidence suggests that surgical evacuation of hematoma is associated with decreased mortality in patients with cerebellar hemorrhage. In a 2019 meta-analysis with individual patient data from four observational studies including 304 patients with cerebellar hemorrhage, surgical hematoma evacuation was associated with an increased probability of survival at three months compared with conservative treatment (78 versus 61 percent; absolute risk difference [ARD] 18.5 percent, 95% CI 13.8-23.2) [58]. This association was sustained at 12 months. The overall likelihood of a favorable functional outcome was similar for patients who had a hematoma evacuation or conservative treatment (31 versus 36 percent; ARD -3.7 percent, 3 95% CI -8.7 to 1.2). However, for patients with a hematoma volume of 12 cm , the likelihood of a favorable outcome was lower with surgical evacuation (31 versus 62 percent; ARD 35 percent). 3 By contrast, in the subgroup of patients with a hematoma volume of 15 cm , a favorable outcome was more likely with hematoma evacuation than with conservative treatment (75 versus 45 percent). Limitations to this meta-analysis include retrospective design, lack of randomization, small sample size for subgroup analyses, and a high number of patients on oral anticoagulant therapy at baseline, which impacts the generalizability of the findings. Supratentorial hemorrhage Surgical hematoma evacuation for supratentorial ICH is controversial because the potential benefits of hematoma evacuation may be offset by surgical morbidity in many cases. The subset of patients who may benefit from surgical treatment have not been conclusively defined [5]. We reserve surgical therapy for patients with life-threatening mass effect from supratentorial ICH, individualizing treatment decisions based on assessments of prognosis with and without surgical therapy. Limited data suggest that supratentorial hematoma evacuation might reduce mortality for patients who are comatose, have a large hematoma with significant midline shift, or have elevated ICP refractory to medical management [5]. Supratentorial decompression with https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 14/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate hematoma evacuation and/or decompressive hemicraniectomy may reduce mortality but not improve functional outcomes. It should only be considered as a life-saving procedure to treat refractory increases in ICP; even in these instances, decisions should be addressed on an individual basis: Surgery should not be considered for patients who are either fully alert or deeply comatose. Patients with intermediate levels of arousal (obtundation-stupor) are more appropriate candidates. Features that support performing surgery include a recent onset of hemorrhage, ongoing clinical deterioration, and location of the hematoma near the cortical surface. Features in favor of less aggressive therapy include serious concomitant medical problems, advanced age, stable clinical condition, remote onset of hemorrhage, and inaccessibility of the hemorrhage. Open craniotomy with craniectomy is the most widely studied surgical technique in patients with supratentorial ICH. Other methods using craniotomy include endoscopic hemorrhage aspiration, use of fibrinolytic therapy to dissolve the hematoma followed by aspiration, and CT- guided stereotactic aspiration (ie, minimally invasive surgery) [5,59-62]. The role of surgery for patients with supratentorial ICH was evaluated in the International Surgical Trial in IntraCerebral Hemorrhage (STICH) trial. Among 1033 patients with supratentorial ICH, those assigned to early (median time to surgery was 30 hours after hemorrhage onset) surgical hematoma evacuation had similar rates of favorable outcome compared with those assigned initial conservative treatment (24 versus 26 percent; odds ratio [OR] 0.89, 95% CI 0.66-1.19) [63]. There was a trend toward favorable outcome among patients assigned to early surgery who had craniotomy as opposed to alternate techniques, and in those with hematoma located 1 cm or less from the cortical surface. However, substantial cross-over (26 percent of patients initially assigned to conservative medical management underwent surgical evacuation) limits the strength of these results [64-66]. Subsequently, the STICH II trial evaluated the role of early surgery for 601 conscious patients presenting with a supratentorial ICH within 1 cm of the cortical surface. Unfavorable functional outcome at six months was similar in those assigned surgery versus conservative treatment (59 versus 62 percent; OR 0.86, 95% CI 0.62-1.2) [67]. However, there was a trend toward reduced mortality among those assigned early surgery (18 versus 24 percent; OR 0.71, 95% CI 0.48-1.06). Limitations in interpreting the results of this study include the clinical and imaging status of the patients selected for treatment (conscious, without intraventricular extension), as well as a high https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 15/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate crossover rate; 21 percent of patients assigned to conservative therapy did undergo surgery [68]. In a systematic review of individual patient data of 15 trials including more than 3000 patients with ICH, surgery was associated with reduced mortality (OR 0.74, 95% CI 0.64-0.86) and a trend toward improved functional outcomes (OR 0.78, 95% CI 0.59-1.02). This benefit appeared highest among those with poorer prognosis on presentation, those who deteriorated after presentation, and those with superficial ICH and no intraventricular extension [67,69]. However, heterogeneity in patient selection, ICH size, and surgical techniques limit generalizability of these results. Salvage therapies Salvage therapies may be used when other therapies to control elevated ICP are insufficient to improve symptoms or reduce ICP. They may be used in conjunction with or in place of other therapies. Hyperventilation causes a rapid lowering of ICP by inducing cerebral vasoconstriction to reduce cerebral blood volume. The effect of hyperventilation on ICP only lasts for a few hours. We generally reserve hyperventilation for the urgent treatment of a patient with acute brain herniation until more definitive therapies can be implemented. This may include deteriorating patients awaiting either urgent surgery or central venous access for osmotherapy. We aim for a target partial pressure of carbon dioxide (PaCO ) goal of 30 to 2 35 mmHg [47]. More aggressive hyperventilation (ie, a PaCO of 26 to 30 mmHg) may 2 result in brain ischemia and worse outcomes [70]. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Hyperventilation'.) Pharmacologic coma acts by reducing cerebral metabolism, which lowers cerebral blood flow and reduces ICP. Barbiturate coma, most often induced with pentobarbital, is of variable benefit for the treatment of elevated ICP from a variety of causes and is associated with a high rate of severe side effects, especially arterial hypotension [71]. Pentobarbital is typically loaded at 5 to 20 mg/kg and infused at 1 to 4 mg/kg per hour. Continuous monitoring with electroencephalography is suggested during high-dose barbiturate treatment, with the dose titrated to a burst-suppression pattern of electrical activity. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Barbiturates'.) Propofol is an alternative sedative agent used to reduce intracranial pressure. Unlike pentobarbital, it has a short half-life and may be more easily titrated or temporarily held to permit arousal for serial neurologic examinations. Propofol is given intravenously to ventilated patients with a loading dose of 1 to 3 mg/kg and continued as an infusion with titration to achieve the desired sedation level, typically at 5 to 50 mcg/kg per minute, with a https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 16/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate maximum dose of 200 mcg/kg per minute [47]. Hypotension is a common adverse effect of propofol infusion; treatment involves intravenous fluids and/or vasopressors to maintain cerebral perfusion pressure. Propofol infusion syndrome is a rare complication associated with high doses (>4 mg/kg per hour or >67 mcg/kg per minute) and prolonged use (>48 hours), though it has been reported with short-term infusions. It is characterized by acute refractory bradycardia, metabolic acidosis, cardiovascular collapse, rhabdomyolysis, hyperlipidemia, renal failure, and hepatomegaly. (See "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects", section on 'Propofol'.) Neuromuscular blockade may be used to reduce ICP in patients who are not responsive to analgesia and sedation alone, as muscle activity can contribute to increased ICP by raising intrathoracic pressure, thereby reducing cerebral venous outflow. Drawbacks of neuromuscular blockade include an increased risk of pneumonia and sepsis. In addition, the ability to evaluate the neurologic status is lost once the patient is paralyzed. (See "Neuromuscular blocking agents in critically ill patients: Use, agent selection, administration, and adverse effects".) Hypothermia can reduce ICP through reduction in cerebral blood flow and metabolism. The benefit for patients with acute ICH has not been demonstrated. Adverse effects include electrolyte abnormalities, pneumonia, coagulopathy, and cardiac arrhythmias. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Therapeutic hypothermia'.) SEIZURE MANAGEMENT Patients with acute ICH are at risk for early seizures (within one to two weeks of ICH) and late (post-stroke) seizures. Early seizures may be self-limited, attributed to transient neurochemical changes associated with the acute ICH. By contrast, late seizures are felt to be due to structural changes from gliosis and are likelier to become recurrent, as poststroke epilepsy ( 2 unprovoked seizures occurring after the acute phase) [72]. For patients with acute ICH who have a seizure, immediate intravenous antiseizure medication treatment should be initiated to reduce the risk of a recurrent seizure [5]. (See "Evaluation and management of the first seizure in adults".) The optimal duration of antiseizure medication therapy for patients with ICH and a seizure is uncertain. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 17/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate For patients who have an early seizure (<14 days from ICH onset), we typically continue treatment for several days and then wean when patients are clinically stable if seizures do not recur. For patients who have a late seizure (>14 days from ICH onset), we typically continue long-term seizure therapy. (See "Overview of the management of epilepsy in adults", section on 'Poststroke seizures'.) The choice of the initial antiseizure medication is guided by medical comorbidities, drug interactions, side effect drug profile, and contraindications ( table 8). (See "Initial treatment of epilepsy in adults".) For patients with acute ICH who do not have a seizure, we do not start antiseizure medication prophylaxis, in agreement with guidelines from the American Heart Association [5]. Early seizures are more common than poststroke epilepsy [73]. In various studies, the risk of seizure within two weeks of acute ICH was 8 to 15 percent but may be up to approximately 30 percent when including patients with electrographic (nonconvulsive) seizures captured by routine continuous electroencephalogram (EEG) monitoring [73-75]. The incidence of poststroke epilepsy at one year was 2.6 to 4 percent in cohort studies but may be higher with longer follow- up [73,74,76]. Antiseizure medications may reduce the rate of early seizures in patients with lobar ICH but have not been shown to improve functional outcome or reduce the rate of poststroke epilepsy [74,77]. In a small trial of 50 patients with ICH, patients were assigned to prophylactic use of levetiracetam or placebo within 24 hours of ICH onset [78]. The rate of electrographic seizures within the first 72 hours was lower among the levetiracetam group (16 versus 43 percent). However, the seizure rate at 1 and 12 months and the functional outcomes were similar between groups. In a 2019 systematic review and meta-analysis evaluating antiseizure medication prophylaxis, antiseizure medication prophylaxis was not associated with a reduction in disability, mortality, or incident seizures [79]. The one trial included in the meta-analysis found that seizure prophylaxis with valproate starting immediately after ICH and continued for one month reduced the rate of early seizures but did not reduce incident seizures at one year [80]. Some other studies have found that prophylactic antiseizure medications were associated with worse outcome in patients with acute ICH [81,82]. PREVENTION AND MANAGEMENT OF MEDICAL COMPLICATIONS https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 18/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Patients with acute ICH are at risk for medical complications due to comorbid medical conditions as well as from immobility related to the neurologic injury. These complications may prolong hospitalization, delay recovery, and increase the risk of in-hospital and long-term mortality [83,84]. (See "Complications of stroke: An overview".) Specific interventions to prevent or manage common medical complications for patients with acute ICH include [85,86]: Prevention of aspiration Dysphagia is a common complication of ICH and a major risk factor for aspiration pneumonia. Patients with acute ICH at risk for aspiration should be given no oral nutrition (initial nil per os [NPO] status) until swallowing function is evaluated. For patients unable to take oral nutrition due to dysphagia from acute ICH, we give enteral nutrition and maintain the head of the bed positioned up at 30 to 45 degrees, whenever possible. (See "Complications of stroke: An overview", section on 'Dysphagia' and "Risk factors and prevention of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Preventing aspiration'.) Prevention of venous thromboembolism Patients hospitalized with an acute illness are at risk for venous thromboembolism and those with acute ICH are also at risk due to immobility. Intermittent pneumatic compression should be started on the first day of hospital admission for patients with ICH and impaired mobility [5]. We add chemical prophylaxis for most patients one to four days after ICH stability is documented. An exception would be some patients with elevated intracranial pressure being evaluated for urgent surgery for whom chemical prophylaxis may be temporarily withheld. In a 2022 meta-analysis of 28 studies that included nearly 3700 patients with acute ICH, chemical prophylaxis was associated with a lower rate of deep venous thrombosis than controls (3.4 versus 14.7 percent) [87]. Treatment was typically started within four days of ICH onset and continued for 10 to 14 days. The rate of hematoma expansion was similar between groups (2.4 versus 2.8 percent). (See "Prevention and treatment of venous thromboembolism in patients with acute stroke", section on 'Approach in intracerebral hemorrhage' and "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".) Prevention of pressure-induced skin injury Patients with impaired mobility are at risk for pressure-induced skin injuries, including ulcers. Strategies to reduce skin injury include cushioned bed surfaces, frequent repositioning, and proper skin care. (See "Prevention of pressure-induced skin and soft tissue injury".) Isotonic fluid replacement Isotonic fluids, such as normal saline, should be used for maintenance and replacement fluids in the acute setting. Hypotonic fluids are https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 19/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate contraindicated in the first several days after ICH as they may exacerbate cerebral edema and intracranial pressure. We also avoid hypervolemia as it may worsen cerebral edema. (See 'Intracranial pressure management' above and "Maintenance and replacement fluid therapy in adults".) Fever management Fever is common in acute ICH and may frequently be due to systemic infections such as aspiration pneumonia. Central (noninfectious) fever may also occur in acute ICH and has been associated with large hemorrhages and those with intraventricular extension [88]. Fever has been associated with poor outcomes in patients with ICH [89]. Sources of fever should be investigated and treated, and fevers should be treated with antipyretic medications. We do not use prophylactic antibiotics as they have not been shown to improve clinical outcomes [90]. (See "Initial assessment and management of acute stroke", section on 'Fever'.) Management of hyperglycemia and hypoglycemia Hyperglycemia after stroke is associated with adverse outcomes. We treat hyperglycemia in agreement with guidelines [5]. (See "Initial assessment and management of acute stroke", section on 'Hyperglycemia' and "Glycemic control in critically ill adult and pediatric patients".) Hypoglycemia should be avoided as it may cause neurologic deficits acutely and lead to permanent neurologic injury if uncorrected. (See "Initial assessment and management of acute stroke", section on 'Hypoglycemia' and "Glycemic control in critically ill adult and pediatric patients", section on 'Our approach'.) Avoiding routine gastric acid suppression Patients with acute ICH are at high risk of aspiration pneumonia due to dysphagia. We avoid routine use of agents to suppress gastric acid (ie, proton pump inhibitors, histamine-2 receptor antagonists) because they are associated with an increased risk of hospital-acquired pneumonia, Clostridioides di cile infection, and other enteric infections. We reserve gastrointestinal (GI) stress ulcer prophylaxis for high-risk patients, such as those on mechanical ventilation or with a history of recent GI bleeding. (See "Complications of stroke: An overview", section on 'Gastrointestinal bleeding' and "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention", section on 'High-risk patients'.) EARLY PROGNOSIS The main determinants of functional outcome and mortality in the first 90 days after acute ICH include clinical risk factors and specific features seen on neuroimaging. The long-term prognosis https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 20/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate among survivors of ICH is discussed separately. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Long-term prognosis'.) Functional outcome may be assessed at different times after the ICH and using varying performance thresholds or clinical scoring tools. The modified Rankin Scale (mRS) is frequently used ( table 9). In several trials, patients with ICH achieving a score of 0 to 3 have been described as having a good functional outcome; poor outcome included those scoring 4 to 6. Mortality rates In various studies, the 30-day mortality rate from ICH ranged from 32 to 52 percent [91-98]; one-half of these deaths occurred within the first two days [94,99,100]. Some evidence suggests that the mortality rate has decreased since the early 2000s, possibly because of better supportive care and secondary prevention [101]. However, this mortality reduction may be partially attributed to an increased proportion of survivors with disability [102]. Mortality rates differ by clinical features and underlying etiology. Mortality among patients with lobar ICH, most commonly associated with cerebral amyloid angiopathy, has been reported from 10 to 30 percent, varying with patient comorbidities and ICH size [103,104]. Several studies suggest that hemorrhage due to vascular malformations is associated with lower mortality than other causes of ICH [105-108]. (See 'Clinical risk factors' below and 'Imaging risk factors' below.) [92,109] Risk factors for poor outcomes Several risk factors have been associated with poor functional outcome and mortality in patients with acute ICH. They include clinical risk factors and imaging features associated with the ICH. Clinical risk factors Increasing age Advanced age is associated with a reduced likelihood of good functional outcome and an elevated risk of early mortality among patients with acute ICH [110,111]. Severe impairment on baseline exam or early neurologic deterioration Patients with baseline functional impairment and those with more severe impairment from the ICH on initial clinical examination, as measured by the Glasgow Coma Scale (GCS) score, have elevated mortality rates [99,111]. (See 'Clinical prediction scores' below.) Early neurologic deterioration within 48 hours after ICH onset is common and is associated with a poor prognosis. Potential mechanisms include hemorrhage enlargement, development of hydrocephalus, perilesional edema, and the inflammatory response to the hemorrhage [112-114]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 21/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Early withdrawal of support The early use of "do not attempt resuscitation" (DNAR) orders, along with decisions to limit aggressive treatments and/or withdraw medical care may negatively influence outcome in patients with ICH and may even invalidate some prognostic models that do not control for this variable [9,11,115-118]. (See 'Initial aggressive care' above.) Preceding antithrombotic use In the setting of an acute ICH, patients with preceding use of anticoagulants or antiplatelet agents appear to have larger initial hematoma volumes or greater hemorrhage enlargement leading to worse outcomes [119-121]. Patients on oral anticoagulant therapy have a mortality rate of 38 to 73 percent after ICH [119,122-124]. These rates appear to be three to four times higher than in those not on anticoagulation therapy [119,122]. This increased risk may be mitigated but not eliminated by rapid reversal of anticoagulation [125]. (See "Reversal of anticoagulation in intracranial hemorrhage".) Patients with direct oral anticoagulant (DOAC)-associated ICH may have better outcomes than those with warfarin-associated ICH. In some small observational studies, patients with DOAC-associated ICH were found to have smaller ICH volumes and better clinical outcomes than those with warfarin-associated ICH [126,127]; other studies failed to show this difference [128,129]. However, in a large registry-based cohort study including nearly 20,000 patients with anticoagulation-associated ICH, the risk of in-hospital mortality or discharge to hospice was lower in those taking a DOAC than those taking warfarin (38 versus 43 percent) [124]. Additionally, the rate of disability or dependence at discharge was lower and the rate of discharge to home was higher for patients with DOAC-associated ICH than those with warfarin-associated ICH and similar to those taking no anticoagulation at the time of the ICH. Antiplatelet use is associated with hematoma enlargement and worse prognosis after ICH in some [120,122,130-132] but not all [24,123,133-136] studies. A 2010 systematic review of 25 cohort studies concluded that prior antiplatelet use was associated with increased mortality (odds ratio [OR] 1.3) but not poor functional outcome after ICH [137]. In a 2021 large observational study of more than 13,000 patients with ICH, the 90-day mortality rate was 44 percent among both ICH patients taking anticoagulants and those taking antiplatelets compared with 26 percent among those not taking antithrombic medications at the time of the ICH [138]. A good functional outcome at 90-days was achieved by 27 percent of patients taking anticoagulants and 25 percent of those taking antiplatelets compared with 40 percent of those on no antithrombotic therapy. Patients taking antithrombotic medications were older and had more comorbidities. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 22/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Combination antithrombotic therapy has been associated with a worse prognosis and larger initial ICH volume than single-agent therapy. In a pooled analysis of three German observational studies including 3545 patients with ICH, a favorable functional outcome at three months was less frequent in those taking warfarin and an antiplatelet compared with those taking warfarin alone (24 versus 32 percent) [139]. Similarly, the rates of achieving a favorable outcome were numerically lower for patients taking a DOAC and antiplatelet compared with those taking a DOAC alone (21 versus 33 percent), although this difference was not statistically significant. In addition, patients taking an antiplatelet agent and warfarin or a DOAC had larger initial ICH volumes than those taking either anticoagulant alone (warfarin and antiplatelet OR 1.8, 95% CI 1.2-2.7; DOAC and antiplatelet OR 3.75, 95% CI 1.13-12.44). There was a trend toward larger ICH volumes in those on dual- versus single-antiplatelet therapy. Other laboratory markers Multiple laboratory test results have been associated with poor outcome in patients with acute ICH. Several studies have identified that an elevated admission blood glucose may be associated with a poor outcome [85,91,140-145]. Additionally, elevated C-reactive protein levels, lower serum levels of low-density lipoprotein cholesterol (LDL-C), and lower total cholesterol have been linked to a risk of neurologic deterioration and mortality in patients with acute ICH [146,147]. Imaging risk factors Initial ICH volume The ICH volume on initial head computed tomography (CT) scan at admission may be a particularly important prognostic indicator [99,107,111,148]. In a study of 188 patients, the initial ICH volume was associated with 30-day mortality rate. Among patients with a GCS score 9, the probability of death by 30 days was 19 percent when the ICH volume was 30 mL and 75 percent when the ICH volume was 60 mL [99]. The method for calculating ICH volume from head CT is discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Estimating hemorrhage volume'.) ICH location Patients with ICH located in the infratentorial brainstem or cerebellar regions have worse prognosis than those with supratentorial ICH [149]. Intraventricular extension Intraventricular and subarachnoid extension of ICH may be present on initial evaluation or occur subsequently. Data from a number of studies suggest that extension of blood into the ventricles and/or subarachnoid space is an independent predictor of poor outcome in patients with spontaneous ICH [107,150-156]. One of the largest of these reports evaluated 406 patients with ICH, 45 percent of whom had https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 23/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate intraventricular extension of hemorrhage [154]. After controlling for age and ICH volume, a poor outcome at discharge (defined as an mRS score of 4 to 6 ( table 9)) was significantly more likely in patients with intraventricular hemorrhage than in those without intraventricular hemorrhage (OR 2.25, 95% CI 1.40-3.64). Intraventricular hemorrhage is discussed in detail separately. (See "Intraventricular hemorrhage".) Hematoma shape and features ICH shape irregularity and heterogeneity on head CT and the spot sign on CT angiography suggest ongoing bleeding or risk of hematoma expansion and have been associated with poor functional outcome ( image 1 and image 2) [157]. These are discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Predicting hemorrhage expansion'.) Hematoma growth Hematoma growth, particularly within the first 24 hours, is also an independent predictor of mortality and poor outcome [112,157,158]. In a meta-analysis of 218 patients with spontaneous ICH who had a head CT scan within three hours of onset and follow-up head CT within 24 hours, for each 10 percent increase in hematoma volume, patients were 5 percent more likely to die (hazard ratio 1.05, 95% CI 1.03-1.08) and 16 percent less likely to have a good outcome as measured by the modified Rankin scale (cumulative OR 0.84, 95% CI 0.75-0.92) [25]. Risk factors for hematoma enlargement (eg, contrast extravasation or "spot sign" on CT angiography, hemorrhage volume on baseline imaging, antithrombotic therapy) are discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Predicting hemorrhage expansion'.) Other factors Other imaging such as extensive white matter lesions on CT or magnetic resonance imaging (MRI) have been associated with poor outcome and mortality after ICH in various studies [159-161]. Some studies have found that a significant number of patients with ICH have acute ischemic lesions on diffusion-weighted MRI sequence that are not contiguous to the hematoma [162]. The implication for these findings for prognosis is as yet undefined, although one study found that the presence of these lesions was associated with increased odds of death and disability [163]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Mechanisms of brain injury'.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 24/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Clinical prediction scores Multiple clinical scores have been developed to help approximate the risk of 30-day mortality or likelihood of good functional recovery for patients with acute ICH. These clinical scoring systems can be used in the acute setting to assist clinicians, patients, and caregivers gauge the expected severity of the ICH. They should be used along with overall clinical judgement, incorporating patient values and preferences to guide treatment decisions or limitations of care in the acute settings. Patients with acute ICH should be offered full treatment, and new limitations of care should be delayed at least until the second hospital day for most patients. (See 'Initial aggressive care' above.) ICH score A simple six-point clinical and radiographic grading scale called the ICH score has been devised to predict 30-day mortality after ICH [149]. This scale incorporates several clinical components that may be independent predictors of outcome ( table 10). The ICH score is determined by adding the score from each component as follows: GCS ( - - - table 7) score at presentation 3 to 4 (= 2 points) 5 to 12 (= 1 point) 13 to 15 (= 0 points) ICH volume on initial imaging - 3 30 cm (= 1 point) 3 <30 cm (= 0 points) Intraventricular extension of ICH - Present (= 1 point) Absent (= 0 points) Infratentorial origin of ICH - Yes (= 1 point) No (= 0 points) Age - - 80 (= 1 point) <80 (= 0 points) Thirty-day mortality rates increased steadily with ICH score. The mortality rates were: ICH score 1 (13 percent) ICH score 2 (26 percent) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 25/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate ICH score 3 (72 percent) ICH score 4 (97 percent) ICH score 5 (100 percent) No patient with an ICH score of 0 died, and none had a score of 6 in the initial cohort. The ICH score has been validated by multiple analyses [164-166]. A modified ICH score using the National Institutes of Health Stroke Scale (NIHSS) score ( table 11) in place of the GCS score performed similar to the original ICH score for mortality prediction but was a better predictor of outcome in one study [164]. FUNC score The FUNC score ( table 12) rates prognosis for good functional (neurologic) outcome at 90 days using an 11-point scale [167]. Components include age, ICH volume, ICH location, GCS score, and history of prior cognitive impairment. The proportion of patients who achieved functional independence increased steadily with FUNC score [167]. In the study cohort, functional independence rates were: FUNC scores 0 to 4 (none) FUNC scores 5 to 7 (13 percent) FUNC score 8 (42 percent) FUNC scores 9 to 10 (66 percent) FUNC score 11 (82 percent) These results have also been independently validated [168]. One study found that GCS score at presentation alone is a useful predictor of 30-day mortality [169]. However, the GCS score is insufficient for clinical prognostication after ICH because some patients with acute ICH and reversible causes to stupor may have a low GCS score at admission but still achieve a good functional outcome. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS
Additionally, elevated C-reactive protein levels, lower serum levels of low-density lipoprotein cholesterol (LDL-C), and lower total cholesterol have been linked to a risk of neurologic deterioration and mortality in patients with acute ICH [146,147]. Imaging risk factors Initial ICH volume The ICH volume on initial head computed tomography (CT) scan at admission may be a particularly important prognostic indicator [99,107,111,148]. In a study of 188 patients, the initial ICH volume was associated with 30-day mortality rate. Among patients with a GCS score 9, the probability of death by 30 days was 19 percent when the ICH volume was 30 mL and 75 percent when the ICH volume was 60 mL [99]. The method for calculating ICH volume from head CT is discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Estimating hemorrhage volume'.) ICH location Patients with ICH located in the infratentorial brainstem or cerebellar regions have worse prognosis than those with supratentorial ICH [149]. Intraventricular extension Intraventricular and subarachnoid extension of ICH may be present on initial evaluation or occur subsequently. Data from a number of studies suggest that extension of blood into the ventricles and/or subarachnoid space is an independent predictor of poor outcome in patients with spontaneous ICH [107,150-156]. One of the largest of these reports evaluated 406 patients with ICH, 45 percent of whom had https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 23/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate intraventricular extension of hemorrhage [154]. After controlling for age and ICH volume, a poor outcome at discharge (defined as an mRS score of 4 to 6 ( table 9)) was significantly more likely in patients with intraventricular hemorrhage than in those without intraventricular hemorrhage (OR 2.25, 95% CI 1.40-3.64). Intraventricular hemorrhage is discussed in detail separately. (See "Intraventricular hemorrhage".) Hematoma shape and features ICH shape irregularity and heterogeneity on head CT and the spot sign on CT angiography suggest ongoing bleeding or risk of hematoma expansion and have been associated with poor functional outcome ( image 1 and image 2) [157]. These are discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Predicting hemorrhage expansion'.) Hematoma growth Hematoma growth, particularly within the first 24 hours, is also an independent predictor of mortality and poor outcome [112,157,158]. In a meta-analysis of 218 patients with spontaneous ICH who had a head CT scan within three hours of onset and follow-up head CT within 24 hours, for each 10 percent increase in hematoma volume, patients were 5 percent more likely to die (hazard ratio 1.05, 95% CI 1.03-1.08) and 16 percent less likely to have a good outcome as measured by the modified Rankin scale (cumulative OR 0.84, 95% CI 0.75-0.92) [25]. Risk factors for hematoma enlargement (eg, contrast extravasation or "spot sign" on CT angiography, hemorrhage volume on baseline imaging, antithrombotic therapy) are discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Predicting hemorrhage expansion'.) Other factors Other imaging such as extensive white matter lesions on CT or magnetic resonance imaging (MRI) have been associated with poor outcome and mortality after ICH in various studies [159-161]. Some studies have found that a significant number of patients with ICH have acute ischemic lesions on diffusion-weighted MRI sequence that are not contiguous to the hematoma [162]. The implication for these findings for prognosis is as yet undefined, although one study found that the presence of these lesions was associated with increased odds of death and disability [163]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Mechanisms of brain injury'.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 24/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Clinical prediction scores Multiple clinical scores have been developed to help approximate the risk of 30-day mortality or likelihood of good functional recovery for patients with acute ICH. These clinical scoring systems can be used in the acute setting to assist clinicians, patients, and caregivers gauge the expected severity of the ICH. They should be used along with overall clinical judgement, incorporating patient values and preferences to guide treatment decisions or limitations of care in the acute settings. Patients with acute ICH should be offered full treatment, and new limitations of care should be delayed at least until the second hospital day for most patients. (See 'Initial aggressive care' above.) ICH score A simple six-point clinical and radiographic grading scale called the ICH score has been devised to predict 30-day mortality after ICH [149]. This scale incorporates several clinical components that may be independent predictors of outcome ( table 10). The ICH score is determined by adding the score from each component as follows: GCS ( - - - table 7) score at presentation 3 to 4 (= 2 points) 5 to 12 (= 1 point) 13 to 15 (= 0 points) ICH volume on initial imaging - 3 30 cm (= 1 point) 3 <30 cm (= 0 points) Intraventricular extension of ICH - Present (= 1 point) Absent (= 0 points) Infratentorial origin of ICH - Yes (= 1 point) No (= 0 points) Age - - 80 (= 1 point) <80 (= 0 points) Thirty-day mortality rates increased steadily with ICH score. The mortality rates were: ICH score 1 (13 percent) ICH score 2 (26 percent) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 25/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate ICH score 3 (72 percent) ICH score 4 (97 percent) ICH score 5 (100 percent) No patient with an ICH score of 0 died, and none had a score of 6 in the initial cohort. The ICH score has been validated by multiple analyses [164-166]. A modified ICH score using the National Institutes of Health Stroke Scale (NIHSS) score ( table 11) in place of the GCS score performed similar to the original ICH score for mortality prediction but was a better predictor of outcome in one study [164]. FUNC score The FUNC score ( table 12) rates prognosis for good functional (neurologic) outcome at 90 days using an 11-point scale [167]. Components include age, ICH volume, ICH location, GCS score, and history of prior cognitive impairment. The proportion of patients who achieved functional independence increased steadily with FUNC score [167]. In the study cohort, functional independence rates were: FUNC scores 0 to 4 (none) FUNC scores 5 to 7 (13 percent) FUNC score 8 (42 percent) FUNC scores 9 to 10 (66 percent) FUNC score 11 (82 percent) These results have also been independently validated [168]. One study found that GCS score at presentation alone is a useful predictor of 30-day mortality [169]. However, the GCS score is insufficient for clinical prognostication after ICH because some patients with acute ICH and reversible causes to stupor may have a low GCS score at admission but still achieve a good functional outcome. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 26/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Hemorrhagic stroke (The Basics)") Beyond the Basics topic (see "Patient education: Hemorrhagic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Goals of acute care The goals of initial treatment include preventing hemorrhage extension, monitoring for and managing elevated intracranial pressure, and managing other neurologic and medical complications ( table 1). We generally provide initial aggressive care to patients with acute ICH and delay prognostication or enacting new limitations in care for at least the first day. (See 'Introduction' above and 'Triage' above.) Management of antithrombotic medications For patients with acute ICH, all anticoagulant and antiplatelet drugs should be discontinued acutely. Medications to reverse the effects of anticoagulant drugs should be given immediately. (See 'Management of acute bleeding' above.) Blood pressure management For patients with acute ICH who present with systolic blood pressure (SBP) between 150 and 220 mmHg, we suggest rapid lowering of SBP to a target of 140 mmHg, provided the patient remains clinically stable (Grade 2C). (See 'Blood pressure management' above.) For patients with acute ICH who present with SBP >220 mmHg, we suggest rapid lowering of SBP to <220 mmHg. Thereafter, the blood pressure is gradually reduced (over a period of https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 27/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate hours) to a target range of 140 to 160 mmHg, provided the patient remains clinically stable (Grade 2C). Management of ICP Preventive measures should be enacted in all patients with ICH to mitigate risk of morbidity associated with elevated intracranial pressure (ICP) ( algorithm 1). (See 'Intracranial pressure management' above.) Osmotic therapy For patients who have severe signs or symptoms of elevated ICP or for those with milder symptoms that progress despite initial measures, we use osmotic therapy with either hypertonic saline or mannitol. (See 'Osmotic therapy' above.) Ventricular drainage Ventricular drainage of cerebrospinal fluid with an external ventricular drain can help reduce elevated ICP for selected patients with hydrocephalus, particularly when associated with a decreased level of consciousness. (See 'Cerebrospinal fluid drainage for obstructive hydrocephalus' above.) Surgical approaches The role of surgery in patients with acute ICH varies with the site of the bleed. The indications for evacuation of a cerebellar hematoma depend on the ICH size and location, the time since onset, and the clinical status of the patient. Patients presenting acutely with a large cerebellar hemorrhage and brainstem compression will typically require urgent surgical decompression of the cerebellum with craniectomy and hematoma evacuation. Other patients with small, subacute cerebellar hematomas that do not exert mass effect on the brainstem may be managed medically with close monitoring. (See 'Cerebellar hemorrhage' above.) For patients selected for surgical decompression of a cerebellar hematoma, we suggest craniectomy and hematoma evacuation rather than ventriculostomy without posterior fossa decompression (Grade 2C). External drainage alone may create the theoretical risk of upward herniation of the cerebellar mass. We reserve surgical therapy for patients with life-threatening mass effect from supratentorial ICH, individualizing treatment decisions based on assessments of prognosis with and without surgical therapy. (See 'Supratentorial hemorrhage' above.) Seizure management For patients with acute ICH who have a seizure, immediate intravenous antiseizure medication treatment should be initiated to reduce the risk of a recurrent seizure. For patients with acute ICH who do not have a seizure, we do not start antiseizure medication prophylaxis. (See 'Seizure management' above.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 28/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Medical complications of acute ICH General medical management issues include (see 'Prevention and management of medical complications' above): Prevention of aspiration (see "Complications of stroke: An overview", section on 'Dysphagia' and "Risk factors and prevention of hospital-acquired and ventilator- associated pneumonia in adults", section on 'Preventing aspiration') Prevention of venous thromboembolism (see "Prevention and treatment of venous thromboembolism in patients with acute stroke", section on 'Approach in intracerebral hemorrhage' and "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults") Prevention of pressure-induced skin injury (see "Prevention of pressure-induced skin and soft tissue injury") Isotonic fluid replacement (see 'Intracranial pressure management' above and "Maintenance and replacement fluid therapy in adults") Fever management (see "Initial assessment and management of acute stroke", section on 'Fever') Management of hyperglycemia and hypoglycemia (see "Initial assessment and management of acute stroke", section on 'Hyperglycemia' and "Glycemic control in critically ill adult and pediatric patients") Avoiding routine gastric acid suppression (see "Complications of stroke: An overview", section on 'Gastrointestinal bleeding' and "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention", section on 'High-risk patients') Prognosis The 30-day mortality rate from ICH ranges from 32 to 52 percent but differs by clinical and imaging features as well as underlying etiology. 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Di Napoli M, Godoy DA, Campi V, et al. C-reactive protein level measurement improves mortality prediction when added to the spontaneous intracerebral hemorrhage score. Stroke 2011; 42:1230. 148. Jordan LC, Kleinman JT, Hillis AE. Intracerebral hemorrhage volume predicts poor neurologic outcome in children. Stroke 2009; 40:1666. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 39/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate 149. Hemphill JC 3rd, Bonovich DC, Besmertis L, et al. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001; 32:891. 150. Portenoy RK, Lipton RB, Berger AR, et al. Intracerebral haemorrhage: a model for the prediction of outcome. J Neurol Neurosurg Psychiatry 1987; 50:976. 151. Young WB, Lee KP, Pessin MS, et al. Prognostic significance of ventricular blood in supratentorial hemorrhage: a volumetric study. Neurology 1990; 40:616. 152. Lisk DR, Pasteur W, Rhoades H, et al. Early presentation of hemispheric intracerebral hemorrhage: prediction of outcome and guidelines for treatment allocation. Neurology 1994; 44:133. 153. Tuhrim S, Horowitz DR, Sacher M, Godbold JH. Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage. Crit Care Med 1999; 27:617. 154. Hallevi H, Albright KC, Aronowski J, et al. Intraventricular hemorrhage: Anatomic relationships and clinical implications. Neurology 2008; 70:848. 155. Staykov D, Volbers B, Wagner I, et al. Prognostic significance of third ventricle blood volume in intracerebral haemorrhage with severe ventricular involvement. J Neurol Neurosurg Psychiatry 2011; 82:1260. 156. Maas MB, Nemeth AJ, Rosenberg NF, et al. Subarachnoid extension of primary intracerebral hemorrhage is associated with poor outcomes. Stroke 2013; 44:653. 157. Morotti A, Arba F, Boulouis G, Charidimou A. Noncontrast CT markers of intracerebral hemorrhage expansion and poor outcome: A meta-analysis. Neurology 2020; 95:632. 158. Dowlatshahi D, Demchuk AM, Flaherty ML, et al. Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes. Neurology 2011; 76:1238. 159. Lee SH, Kim BJ, Ryu WS, et al. White matter lesions and poor outcome after intracerebral hemorrhage: a nationwide cohort study. Neurology 2010; 74:1502. 160. Caprio FZ, Maas MB, Rosenberg NF, et al. Leukoaraiosis on magnetic resonance imaging correlates with worse outcomes after spontaneous intracerebral hemorrhage. Stroke 2013; 44:642. 161. Uniken Venema SM, Marini S, Lena UK, et al. Impact of Cerebral Small Vessel Disease on Functional Recovery After Intracerebral Hemorrhage. Stroke 2019; 50:2722. 162. Menon RS, Burgess RE, Wing JJ, et al. Predictors of highly prevalent brain ischemia in intracerebral hemorrhage. Ann Neurol 2012; 71:199. 163. Garg RK, Liebling SM, Maas MB, et al. Blood pressure reduction, decreased diffusion on MRI, and outcomes after intracerebral hemorrhage. Stroke 2012; 43:67. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 40/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate 164. Cheung RT, Zou LY. Use of the original, modified, or new intracerebral hemorrhage score to predict mortality and morbidity after intracerebral hemorrhage. Stroke 2003; 34:1717. 165. Godoy DA, Pi ero G, Di Napoli M. Predicting mortality in spontaneous intracerebral hemorrhage: can modification to original score improve the prediction? Stroke 2006; 37:1038. 166. Hemphill JC 3rd, Farrant M, Neill TA Jr. Prospective validation of the ICH Score for 12-month functional outcome. Neurology 2009; 73:1088. 167. Rost NS, Smith EE, Chang Y, et al. Prediction of functional outcome in patients with primary intracerebral hemorrhage: the FUNC score. Stroke 2008; 39:2304. 168. Garrett JS, Zarghouni M, Layton KF, et al. Validation of clinical prediction scores in patients with primary intracerebral hemorrhage. Neurocrit Care 2013; 19:329. 169. Parry-Jones AR, Abid KA, Di Napoli M, et al. Accuracy and clinical usefulness of intracerebral hemorrhage grading scores: a direct comparison in a UK population. Stroke 2013; 44:1840. Topic 1084 Version 62.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 41/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate GRAPHICS Acute spontaneous intracerebral hemorrhage: Rapid overview of emergency management Clinical features Stroke symptoms: sudden onset loss of function in speech, vision, movement, sensation, balance Features suggestive of ICH over ischemic stroke: progressive worsening of acute symptoms; severely elevated SBP (eg, >220 mmHg); patient taking anticoagulant Signs of elevated ICP (mass effect from ICH): Dilated pupil Progressive drowsiness Cushing triad (bradycardia, respiratory depression, hypertension) Evaluation Assess airway, breathing, circulation, and disability to initiate supportive care Determine GCS, neurologic deficits Obtain emergency imaging (eg, head CT or fast MRI) Initial laboratory evaluation: complete blood count, PT, PTT, INR, basic electrolytes, glucose, cardiac-specific troponin, pregnancy test in females of childbearing age Serial monitoring (hourly) for neurologic deterioration or signs of elevated ICP Treatment* Perform tracheal intubation for any patient unable to protect their airway or with rapidly deteriorating mental status or GCS 8 Obtain immediate neurosurgical consultation for imaging findings indicating need for emergency surgery: 3 Cerebellar ICH that is either 3 cm diameter or causing brainstem compression IVH with obstructive hydrocephalus and neurologic deterioration Hemispheric ICH with life-threatening brain compression or obstructive hydrocephalus Reverse anticoagulation (agent specific): Warfarin (4-factor PCC with IV vitamin K) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 42/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Dabigatran (idaricizumab) Factor Xa inhibitors: apixaban, edoxaban, rivaroxaban (4-factor PCC or andexanet alfa) Unfractionated heparin (protamine sulfate) Low molecular weight heparin (andexanet alfa; protamine sulfate is an alternative) Manage hypertension: Immediate treatment to reduce SBP below 220 mmHg: nicardipine starting at 5 mg/hour IV; alternate: labetalol 20 mg IV bolus, may repeat every 10 minutes Subsequent, stepwise treatment, typically over first 1 to 2 hours, to reduce SBP to 140 to 160 mmHg; monitor for neurologic deterioration Manage elevated intracranial pressure: General preventive measures: Elevate head of bed >30 degrees Give mild sedation as needed for comfort for intubated patients (eg, midazolam) Give antipyretics for temperature >38 C (eg, acetaminophen [paracetamol] 325 to 650 mg orally or PR every 4 to 6 hours or 650 mg IV every 4 hours) Maintain neutral head positioning; avoid rotating the neck or placing IV lines or devices in or at the neck that may impede venous outflow Use isotonic solutions for volume resuscitation and maintenance fluids; maintain serum sodium >135 mEq/L Repeat imaging (eg, head CT) for neurologic deterioration or signs of elevated ICP: Obtain immediate neurosurgical consultation for surgical indications (refer to above) Give osmotic therapy via central venous catheter for clinical signs or imaging findings of elevated ICP: Hypertonic saline 23.4%: 15 to 30 mL IV bolus every 6 hours, or Mannitol: 0.25 to 1 g/kg IV bolus every 6 hours ICH: intracerebral hemorrhage; SBP: systolic blood pressure; ICP: intracranial pressure; GCS: Glasgow coma scale; CT: computed tomography; MRI: magnetic resonance imaging; PT: prothrombin time; PTT: partial thromboplastin time; INR: international normalized ratio; IVH: intraventricular hemorrhage; PCC: prothrombin complex concentrate; IV: intravenous; PR: per rectum. Treatment steps for the acute management of ICH may be performed in parallel if resources are available. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 43/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Graphic 132288 Version 5.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 44/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Emergency reversal of anticoagulation from warfarin for life-threatening hemorrhage in adults: Suggested approaches based upon available resources A. If 4-factor prothrombin complex concentrate (4F PCC) is available (preferred approach): 1. Give 4F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 4F PCC (refer to topic or drug reference for details). 2. Give vitamin K 10 mg IV over 10 to 20 minutes. B. If 3-factor prothrombin complex concentrate (3F PCC) is available but 4F PCC is not available: 1. Give 3F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 3F PCC (refer to topic or drug reference for details). 2. Give Factor VIIa 20 mcg/kg IV OR give FFP 2 units IV by rapid infusion. Factor VIIa may be preferred if volume overload is a concern. 3. Give vitamin K 10 mg IV over 10 to 20 minutes. C. If neither 3F PCC nor 4F PCC is available: 1. Give FFP 2 units IV by rapid infusion. Check INR 15 minutes after completion of infusion. If INR 1.5, administer 2 additional units of FFP IV rapid infusion. Repeat process until INR 1.5. May wish to administer loop diuretic between FFP infusions if volume overload is a concern. 2. Give vitamin K 10 mg IV over 10 to 20 minutes. These products and doses are for use in life-threatening bleeding only. Evidence of life-threatening bleeding and over-anticoagulation with a vitamin K antagonist (eg, warfarin) are required. Anaphylaxis and transfusion reactions can occur. It may be reasonable to thaw 4 units of FFP while awaiting the PT/INR. The transfusion service may substitute other plasma products for FFP (eg, Plasma Frozen Within 24 Hours After Phlebotomy [PF24]); these products are considered clinically interchangeable. PCC will reverse anticoagulation within minutes of administration; FFP administration can take hours due to the volume required; vitamin K effect takes 12 to 24 hours, but administration of vitamin K is needed to counteract the long half-life of warfarin. Subsequent monitoring of the PT/INR is needed to guide further therapy. Refer to topics on warfarin reversal in individual situations for further management. PCC: unactivated prothrombin complex concentrate; 4F PCC: PCC containing coagulation factors II, VII, IX, X, protein S and protein C; 3F PCC: PCC containing factors II, IX, and X and only trace factor VII; FFP: fresh frozen plasma; PT: prothrombin time; INR: international normalized ratio; FEIBA: factor eight inhibitor bypassing agent. Before use, check product label to confirm factor types (3 versus 4 factor) and concentration. Activated complexes and single-factor IX products (ie, FEIBA, AlphaNine, Mononine, Immunine, BeneFix) are NOT used for warfarin reversal. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 45/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate PCC doses shown are those suggested for initial treatment of emergency conditions. Subsequent treatment is based on INR and patient weight if available. Refer to topic and Lexicomp drug reference included with UpToDate for INR-based dosing. Graphic 89478 Version 10.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 46/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Direct oral anticoagulant reversal agents for life-threatening bleeding (imminent risk of death from bleeding) Reversal agent (all are given Anticoagulant intravenously) Dabigatran (Pradaxa; oral thrombin inhibitor) Idarucizumab (Praxbind). Dose: 5 grams* Oral factor Xa inhibitors: Andexanet alfa (AndexXa). Dosing for the initial bolus and subsequent infusion depend Apixaban (Eliquis) on the dose level of the factor Xa inhibitor and the interval since it was last taken. Edoxaban (Lixiana, Savaysa) Rivaroxaban (Xarelto) OR- 4-factor PCC (Kcentra, Beriplex P/N, Octaplex). Dosing can be done with a fixed dose of 2000 units OR a weight-based dose of 25 to 50 units per kg. Reversal agents carry a risk of life-threatening thrombosis and should only be used under the direction of a specialist with expertise in their use and/or in a patient at imminent risk of death from bleeding. In general, a single dose is given; dosing may be repeated in rare situations in which the oral anticoagulant persists for longer in the circulation, such as severe kidney dysfunction. Andexanet dosing is as follows: If the patient took rivaroxaban >10 mg, apixaban >5 mg, or dose unknown within the previous 8 hours: Andexanet 800 mg bolus at 30 mg/minute followed by 960 mg infusion at 8 mg/minute for up to 120 minutes. OR- If the patient took rivaroxaban 10 mg or apixaban 5 mg, or if 8 hours have elapsed since the last dose of a factor Xa inhibitor: Andexanet 400 mg bolus at 30 mg/minute followed by 480 mg infusion at 4 mg/minute for up to 120 minutes. Refer to UpToDate topics on treatment of bleeding in patients receiving a DOAC or perioperative management of patients receiving a DOAC for additional information on administration, risks, and alternative therapies. DOAC: direct oral anticoagulant; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. If idarucizumab is unavailable, an activated PCC (FEIBA, 50 to 80 units per kg intravenously) may be a reasonable alternative. Graphic 112299 Version 9.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 47/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Parenteral drugs for treatment of hypertensive emergencies in adults* Onset of Duration of Dose Drug action action Adverse effects Role range (minutes) (minutes) Vasodilators Clevidipine Initially 1 to 2 mg/hour as 2 to 4 5 to 15 Atrial fibrillation, nausea, lipid Hypertensive emergencies IV infusion formulation contains including with rapid titration. potential allergens (eg, soy, egg) postoperative hypertension. Most patients respond to 4 to 6 mg/hour and are treated with maximum doses of 21 mg/hour or less. NOTE: Delivered in lipid emulsion. 1000 mL maximum per 24 hours (equivalent to 21 mg/hour) due to lipid load. Enalaprilat 1.25 to 5 mg 15 to 30 approximately Precipitous fall in Acute left every 6 hours IV 6 to >12 hours pressure in high- renin states; variable ventricular fail Due to slow on response, headache, dizziness and long durat of effect, rarely used. Avoid use in AM kidney function https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 48/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate impairment, or pregnancy. Fenoldopam Initially 0.1 5 to 10 30 to 60 Tachycardia, Most hyperten mcg/kg per minute as headache, nausea, flushing emergencies. Use caution or IV infusion titrated to a avoid with glaucoma or maximum of 1.6 mcg/kg increased intracranial per minute pressure. 1 to 4 hours IV Hydralazine 10 to 20 mg IV 10 to 20 IV Sudden precipitous drop in blood In general, hydralazine sh pressure, tachycardia, flushing, be avoided due its prolonged a headache, vomiting, aggravation of angina unpredictable hypotensive ef 10 to 20 mg 20 to 30 IM 4 to 6 hours IM (40 mg maximum per labeling) IM Labetalol and nicardipine are generally prefe choices for treatment of eclampsia. Nicardipine 5 to 15 mg/hour as IV infusion. 5 to 15 approximately 1.5 to 4 hours Tachycardia, headache, dizziness, nausea, flushing, local phlebitis, edema Most hyperten emergencies, including pregnancy indu Some patients may require up to 30 mg/hour. Avoid use in ac heart failure. Caution with coronary ische Nitroglycerin 5 to 100 2 to 5 5 to 10 Hypoxemia, Potential adjun (glyceryl trinitrate) mcg/minute as IV infusion tachycardia (reflex sympathetic other IV antihypertensiv activation), therapy in pati headache, vomiting, flushing, with coronary ischemia (ACS) methemoglobinemia, tolerance with acute pulmona edema. prolonged use Nitroprusside 0.25 to 10 0.5 to 1 1 to 10 Elevated intracranial Due to its toxic mcg/kg per minute as IV pressure, decreased cerebral blood flow, nitroprusside should genera infusion. reduced coronary avoided if pref https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 49/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate To minimize blood flow in CAD, agents are risk of cyanide and available. cyanide toxicity, thiocyanate toxicity, nausea, vomiting, Nitroprusside should be avoi in patients with infusion duration muscle spasm, flushing, sweating AMI, CAD, CVA, should be as short as elevated intracranial possible and generally not pressure, kidne function exceed 2 impairment, or hepatic mcg/kg per minute. Use impairment. of maximal dose (ie, 8 to 10 mcg/kg per minute) should not exceed 10 minutes. Patients who receive higher doses (ie, >500 mcg/kg at a rate exceeding 2 mcg/kg per minute) should receive sodium thiosulfate infusion to avoid cyanide toxicity. Adrenergic inhibitors Esmolol 500 mcg/kg is typical 1 to 2 10 to 30 Nausea, flushing, bronchospasm, first- Perioperative hypertension. loading dose degree heart block, Avoid use in ac decompensate given over 1 minute; then infusion-site pain; half-life prolonged in heart failure. initiate IV infusion at setting of anemia https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 50/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate 25 to 50 mcg/kg per minute; titrate incrementally up to maximum of 300 mcg/kg per minute. May consider repeating a loading dose (eg, 500 mcg/kg) prior to each up-titration step. Labetalol Initial bolus of 20 mg IV followed by 20 to 80 mg IV bolus 5 to 10 2 to 4 hours Nausea/vomiting, paresthesias (eg, scalp tingling), bronchospasm, dizziness, nausea, Most hyperten emergencies including myocardial ischemia, every 10 minutes (maximum 300 mg) heart block hypertensive encephalopath pregnancy, and postoperative hypertension. or Avoid use in ac decompensate heart failure. 0.5 to 2 mg/minute as IV loading infusion following an initial 20 mg Use cautiously obstructive or reactive airway IV bolus (maximum 300 mg) Metoprolol Initially 1.25 20 5 to 8 hours Refer to labetalol Myocardial to 5 mg IV followed by ischemia, perioperative 2.5 to 15 mg IV every 3 to hypertension. Avoid use in ac 6 hours decompensate heart failure. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 51/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Phentolamine 5 to 15 mg IV bolus every 5 1 to 2 10 to 30 Tachycardia, flushing, headache, Alternative opt for catecholam to 15 minutes nausea/vomiting excess (eg, adrenergic cris secondary to pheochromocy or cocaine overdose). IV: intravenous injection; AMI: acute myocardial infarction; IM: intramuscular injection; ACS: acute coronary syndrome; CAD: coronary artery disease; CVA: cerebrovascular accident. The treatment of acute aortic syndromes (eg, acute aortic dissection, aortic intramural hematoma) requires specific medication management to minimize disease extension and is presented separately. Refer to UpToDate topics discussing acute aortic syndromes and acute aortic dissection. Hypotension may occur with all agents. IV short-acting agents for treatment of hypertensive emergency should be administered immediately by clinicians who are trained and experienced in their titration using continuous noninvasive electronic monitoring of blood pressure, heart rate, and cardiac rhythm. Patients should be admitted to an intensive care unit as rapidly as possible. A combination of IV agents is often selected depending upon the acute indication. Refer to appropriate UpToDate clinical topic for suggested combinations. Initial fenoldopam doses in range of 0.01 to 0.3 mcg/kg per minute have been described. References: 1. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Hypertension 2018; 71:e140-e144]. Hypertension 2018; 71:e13-e115. 2. Marik PE, Varon J. Hypertensive crises: Challenges and management. Chest 2007; 131:1949. 3. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42:1206. 4. Varon J. Treatment of acute severe hypertension: Current and newer agents. Drugs 2008; 68:283. Graphic 64066 Version 36.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 52/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Management of intracranial pressure for patients with acute intracerebral hemorrhage* ICH: intracerebral hemorrhage; ICP: intracranial pressure. For patients with ICH without premorbid advanced directives specifying limitations of invasive care. Hemostatic and blood pressure issues should be addressed simultaneously. Refer to the UpToDate topic for additional details. Maintain midline head position, avoid internal jugular catheters, and avoid tight device securement (eg, device ties, endotracheal tube holder, or intravenous line dressings). Graphic 132294 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 53/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Richmond Agitation-Sedation Scale (RASS) Score Term Description +4 Combative Overtly combative or violent, immediate danger to staff +3 Very agitated Pulls on or removes tubes or catheters, aggressive behavior toward staff +2 Agitated Frequent nonpurposeful movement or patient-ventilator dyssynchrony +1 Restless Anxious or apprehensive but movements not aggressive or vigorous 0 Alert and calm 1 Drowsy Not fully alert, sustained (>10 seconds) awakening, eye contact to voice 2 Light sedation Briefly (<10 seconds) awakens with eye contact to voice 3 Moderate sedation Any movement (but no eye contact) to voice 4 Deep sedation No response to voice, any movement to physical stimulation 5 Unarousable No response to voice or physical stimulation Procedure 1. Observe patient. Is patient alert and calm (score 0)? 2. Does patient have behavior that is consistent with restlessness or agitation? Assign score +1 to +4 using the criteria listed above. 3. If patient is not alert, in a loud speaking voice state patient's name and direct patient to open eyes and look at speaker. Repeat once if necessary. Can prompt patient to continue looking at speaker. Patient has eye opening and eye contact, which is sustained for more than 10 seconds (score -1). Patient has eye opening and eye contact, but this is not sustained for 10 seconds (score -2). Patient has any movement in response to voice, excluding eye contact (score -3). 4. If patient does not respond to voice, physically stimulate patient by shaking shoulder and then rubbing sternum if there is no response. Patient has any movement to physical stimulation (score -4). Patient has no response to voice or physical stimulation (score -5). Reproduced with permission from: Sessler C, Gosnell M, Grap MJ, et al. The Richmond agitation-sedation scale. Validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002; 166:1338. Copyright 2002 American https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 54/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Thoracic Society. Graphic 57874 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 55/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Clinical progression of transtentorial herniation Headache Altered level of consciousness Dilation of ipsilateral pupil Cranial nerve III palsy Ptosis Loss of medial gaze Decerebrate posturing Hemiparesis Dilation of opposite pupil Alteration of respiration Bradycardia Hypertension Respiratory arrest Graphic 70683 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 56/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Glasgow Coma Scale (GCS) Score Eye opening Spontaneous 4 Response to verbal command 3 Response to pain 2 No eye opening 1 Best verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible sounds 2 No verbal response 1 Best motor response Obeys commands 6 Localizing response to pain 5 Withdrawal response to pain 4 Flexion to pain 3 Extension to pain 2 No motor response 1 Total The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. Graphic 81854 Version 9.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 57/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Transtentorial herniation Data from: Plum F, Posner JB. The Diagnosis of Stupor and Coma III. FA Davis, Philadelphia 1995. p. 103. Graphic 76974 Version 5.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 58/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Pharmacologic properties of antiseizure medications Enzyme or Metabolism and Protein binding Half-lif transporter clearance (%) adults (h induction/inhibition* 20 Brivaracetam Metabolized Inhibits epoxide 9 primarily by CYP- independent hydroxylase hydrolysis (60%) and CYP2C19 (30%) Dose adjustment is needed in hepatic impairment Cannabidiol Hepatic (primarily) and gut by CYP2C19, CYP3A4, UGT1A7, UGT1A9, and UGT2B7 to Inhibits BCRP/ABCG2, BSEP/ABCB11, CYP2C19 (moderate) >94 56 to 61 May increase serum concentration of clobazam and the active metabolite(s) of clobazam active metabolite 7- OH-CBD and then to inactive metabolite 7-COOH-CBD Dose adjustment is needed in moderate to severe hepatic impairment Carbamazepine >90% metabolized by CYPs 3A4 (major) Potent and broad- spectrum inducer of CYP, 75 25 to 65 (init enzyme-ind and 1A2/2C8 (minor) to active (epoxide) UGT-glucuronidation, and P-gp naive patien 8 to 22 (afte and inactive weeks due t induction) metabolites Dose adjustment is needed in severe renal impairment; use is not recommended in moderate or severe hepatic impairment Cenobamate Primarily May increase serum 60 50 to 60 hou metabolized by glucuronidation via concentrations of clobazam, phenobarbital, https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 59/79 7/5/23, 12:24 PM
Initial fenoldopam doses in range of 0.01 to 0.3 mcg/kg per minute have been described. References: 1. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Hypertension 2018; 71:e140-e144]. Hypertension 2018; 71:e13-e115. 2. Marik PE, Varon J. Hypertensive crises: Challenges and management. Chest 2007; 131:1949. 3. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42:1206. 4. Varon J. Treatment of acute severe hypertension: Current and newer agents. Drugs 2008; 68:283. Graphic 64066 Version 36.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 52/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Management of intracranial pressure for patients with acute intracerebral hemorrhage* ICH: intracerebral hemorrhage; ICP: intracranial pressure. For patients with ICH without premorbid advanced directives specifying limitations of invasive care. Hemostatic and blood pressure issues should be addressed simultaneously. Refer to the UpToDate topic for additional details. Maintain midline head position, avoid internal jugular catheters, and avoid tight device securement (eg, device ties, endotracheal tube holder, or intravenous line dressings). Graphic 132294 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 53/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Richmond Agitation-Sedation Scale (RASS) Score Term Description +4 Combative Overtly combative or violent, immediate danger to staff +3 Very agitated Pulls on or removes tubes or catheters, aggressive behavior toward staff +2 Agitated Frequent nonpurposeful movement or patient-ventilator dyssynchrony +1 Restless Anxious or apprehensive but movements not aggressive or vigorous 0 Alert and calm 1 Drowsy Not fully alert, sustained (>10 seconds) awakening, eye contact to voice 2 Light sedation Briefly (<10 seconds) awakens with eye contact to voice 3 Moderate sedation Any movement (but no eye contact) to voice 4 Deep sedation No response to voice, any movement to physical stimulation 5 Unarousable No response to voice or physical stimulation Procedure 1. Observe patient. Is patient alert and calm (score 0)? 2. Does patient have behavior that is consistent with restlessness or agitation? Assign score +1 to +4 using the criteria listed above. 3. If patient is not alert, in a loud speaking voice state patient's name and direct patient to open eyes and look at speaker. Repeat once if necessary. Can prompt patient to continue looking at speaker. Patient has eye opening and eye contact, which is sustained for more than 10 seconds (score -1). Patient has eye opening and eye contact, but this is not sustained for 10 seconds (score -2). Patient has any movement in response to voice, excluding eye contact (score -3). 4. If patient does not respond to voice, physically stimulate patient by shaking shoulder and then rubbing sternum if there is no response. Patient has any movement to physical stimulation (score -4). Patient has no response to voice or physical stimulation (score -5). Reproduced with permission from: Sessler C, Gosnell M, Grap MJ, et al. The Richmond agitation-sedation scale. Validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002; 166:1338. Copyright 2002 American https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 54/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Thoracic Society. Graphic 57874 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 55/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Clinical progression of transtentorial herniation Headache Altered level of consciousness Dilation of ipsilateral pupil Cranial nerve III palsy Ptosis Loss of medial gaze Decerebrate posturing Hemiparesis Dilation of opposite pupil Alteration of respiration Bradycardia Hypertension Respiratory arrest Graphic 70683 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 56/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Glasgow Coma Scale (GCS) Score Eye opening Spontaneous 4 Response to verbal command 3 Response to pain 2 No eye opening 1 Best verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible sounds 2 No verbal response 1 Best motor response Obeys commands 6 Localizing response to pain 5 Withdrawal response to pain 4 Flexion to pain 3 Extension to pain 2 No motor response 1 Total The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. Graphic 81854 Version 9.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 57/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Transtentorial herniation Data from: Plum F, Posner JB. The Diagnosis of Stupor and Coma III. FA Davis, Philadelphia 1995. p. 103. Graphic 76974 Version 5.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 58/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Pharmacologic properties of antiseizure medications Enzyme or Metabolism and Protein binding Half-lif transporter clearance (%) adults (h induction/inhibition* 20 Brivaracetam Metabolized Inhibits epoxide 9 primarily by CYP- independent hydroxylase hydrolysis (60%) and CYP2C19 (30%) Dose adjustment is needed in hepatic impairment Cannabidiol Hepatic (primarily) and gut by CYP2C19, CYP3A4, UGT1A7, UGT1A9, and UGT2B7 to Inhibits BCRP/ABCG2, BSEP/ABCB11, CYP2C19 (moderate) >94 56 to 61 May increase serum concentration of clobazam and the active metabolite(s) of clobazam active metabolite 7- OH-CBD and then to inactive metabolite 7-COOH-CBD Dose adjustment is needed in moderate to severe hepatic impairment Carbamazepine >90% metabolized by CYPs 3A4 (major) Potent and broad- spectrum inducer of CYP, 75 25 to 65 (init enzyme-ind and 1A2/2C8 (minor) to active (epoxide) UGT-glucuronidation, and P-gp naive patien 8 to 22 (afte and inactive weeks due t induction) metabolites Dose adjustment is needed in severe renal impairment; use is not recommended in moderate or severe hepatic impairment Cenobamate Primarily May increase serum 60 50 to 60 hou metabolized by glucuronidation via concentrations of clobazam, phenobarbital, https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 59/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate UGT2B7 and to a phenytoin, and CYP2C19 lesser extent by substrates UGT2B4, and by oxidation via May decrease serum concentrations of carbamazepine, CYP2E1, CYP2A6, CYP2B6, and to a lamotrigine, and CYP2B6 lesser extent by CYP2C19 and and CYP3A substrates CYP3A4/5 Dose adjustment is needed for hepatic impairment; not recommended for patients with severe hepatic impairment or end-stage renal disease Clobazam >90% metabolized by CYPs 3A4, 2C19, 2B6 and non-CYP transformations to active (N- Inhibits CYP2D6 (weak) 80 to 90 (clobazam, parent drug) 36 to 42 (clo parent drug 70 (N- 71 to 82 (N- desmethylclobazam, active metabolite) desmethylcl active metab desmethylclobazam) and inactive metabolites Active metabolite is primarily metabolized by CYP2C19 Dose adjustment is needed in hepatic impairment Eslicarbazepine Prodrug; <33% of active form Induces CYP3A4 (moderate) <40 13 to 20 (pro in renal undergoes UGT- insufficiency Inhibits CYP2C19 (weak) glucuronidation (including <5% metabolized to oxcarbazepine); 66% is excreted renally as unchanged drug Dose adjustment is needed for renal impairment; not https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 60/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate recommended in patients with severe hepatic impairment Ethosuximide ~80% metabolized by CYP3A4 (major) None <5 40 to 60 and non-CYP transformations to inactive metabolites Felbamate 50% metabolized by Increases conversion of 25 13 to 22 (pro CYPs 3A4, 2E1 (minor); ~50% renally excreted as carbamazepine to active epoxide metabolite; mechanism not in renal insufficiency unchanged drug established Dose adjustment is Inhibits CYP2C19 (weak) needed in renal impairment Gabapentin >95% renally None <5 5 to 7 (prolo excreted as unchanged drug (ie, does not undergo hepatic metabolism) renal insuffi >130 hours anuria) Dose adjustment is needed in renal impairment Lacosamide 40% renally excreted as unchanged drug; 30% metabolized by non-CYP transformations None <15 13 (including methylation) to inactive metabolite Dose adjustment is needed in hepatic and renal impairment Lamotrigine >90% metabolized by UGT- May induce its own metabolism by UGT- 55 12 to 62 glucuronidation and other non-CYP glucuronidation (minor) transformations to inactive metabolites https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 61/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Dose adjustment is needed in moderate to severe renal or hepatic impairment Levetiracetam >65% renally None <10 6 to 8 excreted as unchanged drug; 24% metabolized by non-CYP transformation (including amidase hydrolysis) to inactive metabolites Dose adjustment is needed in renal impairment Oxcarbazepine Prodrug; 70% of Induces CYP3A4 (weak) 40 9 (active me active (MHD) form undergoes UGT- glucuronidation; 30% is renally excreted as unchanged active drug and UGT-glucuronidation but does not induce its own metabolism prolonged in insufficiency Dose adjustment is needed in severe renal impairment Perampanel >70% metabolized Appears to induce 95 105 by CYPs 3A4, 3A5 and non-CYP transformations to metabolism of progestin- containing hormonal contraceptives inactive metabolites Dose adjustment is needed in mild or moderate hepatic impairment Phenobarbital 75% metabolized by Potent and broad- 55 75 to 110 CYPs 2C19, 2C9 (minor) and spectrum inducer of CYP and UGT-glucuronidation glucosidase hydrolysis and 2E1 (minor) to inactive metabolites; 25% https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 62/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate excreted renally as unchanged drug Dose adjustment is needed in severe renal or hepatic impairment Phenytoin >90% metabolized Potent and broad- 90 to 95 9 to >42 (do by CYPs 2C9, 2C19, 3A4 (minor) and spectrum inducer of CYP and UGT-glucuronidation dependent) non-CYP transformations to inactive metabolites; clearance is dose dependent, saturable, and may be subject to genetic polymorphism Dose adjustment is needed in severe renal or hepatic insufficiency; monitoring of free (unbound) concentrations also suggested Pregabalin >95% excreted None <5 6 renally as unchanged drug Dose adjustment is needed in renal impairment Primidone 75% metabolized by CYPs 2C19, 2C9 Potent and broad- spectrum inducer of CYP 0 to 20 10 to 15 (pa 29 to 100 (ac (minor) and 2E1 metabolite) (minor) to active intermediates; ~25% excreted renally as unchanged drug Dose adjustment is needed in moderate and severe renal or hepatic impairment; https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 63/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate close monitoring of plasma levels suggested Rufinamide >90% metabolized by non-CYP Induces CYP3A4 (weak) 35 6 to 10 transformations (hydrolysis) to inactive metabolites Stiripentol Metabolized Inhibits CYP3A4, 99 4.5 to 13 primarily in the liver by CYP450 enzymes CYP2C19, CYP3A4, CYP2C19, P-gp, and BCRP and glucuronidation Tiagabine >90% metabolized None 95 7 to 9 by CYP3A4 and non- CYP transformations to inactive metabolites 2 to 5 (with inducing an medications Topiramate >65% excreted renally as unchanged drug; None 9 to 17 12 to 24 <30% metabolized by non-CYP transformations to inactive metabolites; extent of metabolism is increased ~50% in patients receiving enzyme-inducing antiseizure medications Dose adjustment is needed in moderate and severe renal or hepatic impairment Valproate >95% undergoes None 80 to 95 7 to 16 complex transformations including CYPs 2C9, 2C19, 2A6, UGT- glucuronidation and other non-CYP transformation https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 64/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Dose adjustment is needed in hepatic impairment Vigabatrin >90% excreted renally as None 0 5 to 13 (unre duration of unchanged drug Dose adjustment is needed in renal impairment Zonisamide >65% metabolized None 50 63 by CYPs 3A4, 2C19 (minor) and non- CYP transformations Dose adjustment and/or slower titration is needed in mild renal impairment or hepatic impairment; not recommended in patients with moderate or severe renal impairment CYP: cytochrome P450; MHD: monohydroxy derivative active form of oxcarbazepine; P-gp: membrane P-glycoprotein multidrug resistance transporter; UGT-glucuronidation: metabolism by uridine 5'diphosphate-glucuronyltransferases. The inhibitors and inducers of CYP or UGT drug metabolism and P-gp transporters listed in this table can alter serum concentrations of drugs that are dependent upon these enzymes or transporters for elimination, activation, or bioavailability. Classifications are based on US Food and Drug Administration guidance [4, 5]. Other sources may use a different classification system resulting in some agents being classified differently. Specific interactions should be assessed using a drug interaction program such as Lexicomp interactions included within UpToDate. Highly protein-bound antiseizure medications exhibit altered pharmacokinetics, including greater therapeutic and toxic effects and drug interactions, when given in usual doses to patients with low serum albumin or protein-binding affinity (eg, due to nephrotic syndrome or acidosis). Dose alteration is needed and monitoring of unbound (free) antiseizure medication serum concentrations is suggested. Refer to UpToDate topic for additional information. Inhibitors of epoxide hydroxylase (eg, brivaracetam) can decrease metabolism of phenytoin and active metabolite of carbamazepine; refer to UpToDate topic. Data from: Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. Additional data from: https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 65/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate 1. Bazil CW. Antiepileptic drugs in the 21st century. CNS Spectr 2001; 6:756. 2. Lacerda G, Krummel T, Sabourdy C, et al. Optimizing therapy of seizures in patients with renal or hepatic dysfunction. Neurology 2006; 67:S28. 3. Anderson GD, Hakimian S. Pharmacokinetic of antiepileptic drugs in patients with hepatic or renal impairment. Clin Pharmacokinet 2014; 53:29. 4. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 5. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug- interactions-table-substrates-inhibitors-and-inducers (Accessed on June 12, 2019). Graphic 60182 Version 35.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 66/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 67/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate CT angiography "spot sign" Patient with spot sign, demonstrating extravasation and hematoma expansion. CT slice selection has been optimized for hematoma configuration, not for head position. (A) Unenhanced CT demonstrates left posterior putaminal and internal capsule hematoma with mild surrounding edema. An old parieto-occipital infarct is seen posterior to this. (B) A small focus of enhancement is seen peripherally on CTA source images, consistent with the spot sign (arrow). https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 68/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate (C) Post-contrast CT demonstrates enlargement of the spot sign, consistent with extravasation (thick arrow). (D) Unenhanced CT image one day after presentation reveals hematoma enlargement and intraventricular hemorrhage. CT: computed tomography; CTA: computed tomography angiography. From: Wada R, Aviv RI, Fox AJ, et al. CT angiography "spot sign" predicts hematoma expansion in acute intracerebral hemorrhage. Stroke 2007; 38:1257. Copyright 2007 American Heart Association, Inc. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 118220 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 69/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate ICH features on head CT associated with the risk of hematoma expansion Noncontrast head CT showing acute ICH with signs associated with the risk of subsequent hematoma expansion: irregular shape (A), island sign (B; arrow), hypodensity (C; dashed arrow), heterogeneity (D), black hole sign (E; thick arrow), swirl sign (F), and blend sign (G; arrowhead). ICH: intracerebral hemorrhage; CT: computed tomography. Courtesy of Glenn A Tung, MD, FACR. Graphic 132280 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 70/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate ICH score to predict 30-day mortality after spontaneous ICH Component ICH score points GCS score* at presentation 3 to 4 2 5 to 12 1 13 to 15 0 ICH volume on initial imaging 3 30 cm 1 3 <30 cm 0 Intraventricular extension of ICH Present 1 Absent 0 Infratentorial origin of ICH Yes 1 No 0 Age (years) 80 1 <80 0 Total 0 to 6 The ICH score results range from 0 to 6, with higher scores being associated with higher predicted mortality risk. The predicted 30 day mortality is 13% for an ICH score of 1, 26% for score of 2, 72% for a score of 3, 97% for a score of 4, and 100% for a score of 5. In the initial cohort, no patient with an ICH score of 0 died and none had a score of 6. ICH: intracerebral hemorrhage; GCS: Glasgow coma scale. Refer to the separate UpToDate table on Glasgow coma scale. From: From: Hemphill JC 3rd, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001; 32:891. DOI: 10.1161/01.str.32.4.891. Copyright 2001 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 132292 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 71/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The 0 = Alert; keenly responsive. investigator must choose a response if a full 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. evaluation is prevented by such obstacles as an endotracheal tube, language barrier, 2 = Not alert; requires repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement _____ (other than reflexive posturing) in response to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from 1 = Answers one question correctly. 2 = Answers neither question correctly. _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The 0 = Performs both tasks correctly. _____ patient is asked to open and close the eyes and then to grip and release the non-paretic 1 = Performs one task correctly. 2 = Performs neither task correctly. hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 72/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If one or both eyes, but forced deviation or total gaze paresis is not present. the patient has a conjugate deviation of the 2 = Forced deviation, or total gaze paresis eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a not overcome by the oculocephalic maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. Gaze is testable in all aphasic patients. _____ Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat, as appropriate. Patients may be encouraged, 0 = No visual loss. 1 = Partial hemianopia. 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut 3 = Bilateral hemianopia (blind including cortical blindness). _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score symmetry of grimace in response to noxious fold, asymmetry on smiling). 2 = Partial paralysis (total or near-total paralysis of lower face). stimuli in the poorly responsive or non- comprehending patient. If facial trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 73/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not falls before 10 seconds. The aphasic patient is encouraged using urgency in the voice hit bed or other support. 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in degrees, drifts down to bed, but has some _____ effort against gravity. the case of amputation or joint fusion at the shoulder, the examiner should record the score as untestable (UN), and clearly write 3 = No effort against gravity; limb falls. 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The 0 = No drift; leg holds 30-degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. Only in the case of amputation or joint fusion at the hip, the examiner should 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. _____ 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding 0 = Absent. _____ evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, 1 = Present in one limb. 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 74/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick when tested, or withdrawal from noxious 0 = Normal; no sensory loss. 1 = Mild-to-moderate sensory loss; patient stimulus in the obtunded or aphasic patient. feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of should test as many body areas (arms [not being touched. hands], legs, trunk, face) as needed to accurately check for hemisensory loss. A 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, score of 2, "severe or total sensory loss," should only be given when a severe or total loss of sensation can be clearly and leg. _____ demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of 0 = No aphasia; normal. _____ information about comprehension will be obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the attached picture, to name 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant limitation on ideas expressed or form of expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. conversation about provided materials Comprehension is judged from responses here, as well as to all of the commands in difficult or impossible. For example, in conversation about provided materials, the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the 2 = Severe aphasia; all communication is through fragmentary expression; great need hand, repeat, and produce speech. The intubated patient should be asked to write. for inference, questioning, and guessing by the listener. Range of information that can The patient in a coma (item 1a=3) will automatically score 3 on this item. The be exchanged is limited; listener carries burden of communication. Examiner cannot examiner must choose a score for the patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 75/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be 0 = Normal. normal, an adequate sample of speech must be obtained by asking patient to read or 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of 2 = Severe dysarthria; patient's speech is so articulation of spontaneous speech can be rated. Only if the patient is intubated or has _____ slurred as to be unintelligible in the absence of or out of proportion to any dysphasia, or is mute/anarthric. other physical barriers to producing speech, the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explain:________________ explanation for this choice. Do not tell the patient why he or she is being tested. 11. Extinction and inattention (formerly 0 = No abnormality. neglect): Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient has aphasia but does appear to attend to 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. 2 = Profound hemi-inattention or extinction to more than one modality; does not recognize own hand or orients to only one side of space. _____ both sides, the score is normal. The presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 76/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate FUNC score to predict functional outcome at 90-days after spontaneous intracerebral hemorrhage Component FUNC score points 3 ICH volume, cm <30 4 30-60 2 >60 0 Age, years <70 2 70-79 1 80 0 ICH location Lobar 2 Deep 1 Infratentorial 0 GCS score* 9 2 8 0 Pre-ICH cognitive impairment No 1 Yes 0 Total FUNC score 0-11 The FUNC score results range from 0 to 11, with 0 being the worst and 11 the best. Points are given for favorable predictors of functional 90-day outcome. The predicted likelihood of favorable outcome was 0 percent for FUNC scores 0 to 4, 13 percent for scores 5 to 7, 42 percent for score of 8, 66 percent for scores 9 to 10, and 82 percent for a score of 11. GCS: Glasgow coma scale; ICH: intracerebral hemorrhage hemorrhage. GCS scored at presentation. From: Rost NS, Smith EE, Chang Y, et al. Prediction of Functional Outcome in Patients with Primary Intracerebral Hemorrhage: The FUNC score. Stroke 2008; 39:2304. DOI: 10.1161/STROKEAHA.107.512202. Reproduced with permission from Lippincott https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 77/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Williams & Wilkins. Copyright 2008 American Heart Association. Unauthorized reproduction of this material is prohibited. Graphic 97671 Version 5.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 78/79 7/5/23, 12:24 PM Spontaneous intracerebral hemorrhage: Acute treatment and prognosis - UpToDate Contributor Disclosures Guy Rordorf, MD No relevant financial relationship(s) with ineligible companies to disclose. Colin McDonald, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Jonathan A Edlow, MD, FACEP No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator-initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-acute-treatment-and-prognosis/print 79/79
7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis : Guy Rordorf, MD, Colin McDonald, MD : Scott E Kasner, MD, Jonathan A Edlow, MD, FACEP, Alejandro A Rabinstein, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 11, 2023. INTRODUCTION Intracerebral hemorrhage (ICH) is the second most common cause of stroke after ischemic stroke and is a substantial cause of morbidity and mortality. ICH may be categorized as either spontaneous or traumatic. ICH following traumatic brain injury is reviewed separately. (See "Traumatic brain injury: Epidemiology, classification, and pathophysiology", section on 'Primary brain injury'.) The pathogenesis, epidemiology, clinical features, and diagnosis of spontaneous (atraumatic) ICH will be reviewed here. Other aspects of ICH are discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis".) (See "Hemorrhagic stroke in children".) (See "Stroke in the newborn: Management and prognosis".) PATHOGENESIS AND ETIOLOGIES Mechanisms of brain injury There are several mechanisms of brain injury in ICH. These include: https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 1/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Primary mechanical injury to brain parenchyma occurs via hematoma expansion and perilesional edema. Both hematoma volume and edema contribute to the mass effect and increased intracranial pressure (ICP), which in turn can cause reduced cerebral perfusion and ischemic injury, and, in very large ICH, cerebral herniation [1]. Secondary brain injury from the breakdown of the blood-brain barrier after the initial hemorrhage includes excitotoxic and inflammatory processes; however, the exact mechanism(s) underlying this remain uncertain. Enlargement of the hemorrhage is associated with neurologic deterioration, the development of increased intracranial pressure, and worse outcomes. In most cases, the bulk of hemorrhage expansion occurs in the first several hours after onset of ICH [2-5]. Perihematomal edema is frequent in ICH and may be related to mass effect, local neuronal ischemia, or the accumulation of cytotoxic factors [6]. Edema is present on computed tomography (CT) or magnetic resonance imaging (MRI) in at least half of patients when the patient is first imaged and progresses, reaching maximum volume 7 to 12 days after onset; the most rapid expansion occurs in the first 48 hours [7-9]. Hemorrhage volume, higher admission hematocrit, and a prolonged partial thromboplastin time appear to correlate with peak edema volume. The perihematomal region exhibits delayed perfusion and increased diffusivity mixed with areas of reduced diffusion, suggesting the presence of both vasogenic and cytotoxic (ischemic) edema [10]. Acute blood pressure changes with impaired cerebral autoregulation in patients with ICH may contribute to perihematomal ischemia [11]. Underlying hypertensive vasculopathy or cerebral amyloid angiopathy (CAA) may also affect autoregulation in some patients. Increased intracranial pressure and the resulting reduction in cerebral perfusion pressure may play a role; this phenomenon may be exacerbated by blood pressure lowering. Breakdown of the blood-brain barrier due to an inflammatory response to the ICH may be identified by contrast enhancement of brain tissue. In patients with acute and subacute ICH, postcontrast enhancement may be noted in the perihematomal area on CT and MRI [12,13]. Contrast enhancement remote from the hematoma may also be identified on imaging. One MRI study described a pattern of punctate areas of contrast enhancement in the sulcal areas both contiguous and remote from the hemorrhage suggesting that acute ICH may be associated with a more diffuse inflammatory process leading to widespread breakdown of the blood-brain barrier [14]. MRI hyperintensities on diffusion-weighted imaging (DWI) may also be seen with ICH. In some cases, restricted diffusion adjacent to the acute hematoma may be due to distortion of the https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 2/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate magnetic field from paramagnetic blood products [15]. However, acute ischemic lesions discontiguous with the hemorrhage may also be identified on DWI [16-19]. In a 2019 meta- analysis of 11 studies and 1910 patients with ICH, the prevalence of diffusion lesions was approximately 20 percent and did not differ between ICH related to hypertensive vasculopathy or ICH related to CAA [20]. The mechanism causing this phenomenon and the implication of these findings for clinical brain injury and prognosis are as yet undefined [21]. One study with follow-up imaging identified new ischemic lesions beyond the acute ICH period [19]. Specific etiologies There are several underlying pathological conditions associated with ICH; hypertension, amyloid angiopathy, and ruptured vascular malformation are most common [22,23]. Hypertensive vasculopathy Hypertensive hemorrhages occur in the territory of penetrator arteries that branch off major intracerebral arteries, often at 90 degree angles to the parent vessel ( image 1). These small penetrating arteries may be particularly susceptible to the effects of hypertension, as they are directly exposed to the pressure of the much larger parent vessel, without the protection of a preceding gradual decrease in vessel caliber [24]. The blood vessels that give rise to hypertensive hemorrhage are generally the same as those affected by hypertensive occlusive disease and diabetic vasculopathy, which cause lacunar strokes. These vessels supply the pons and midbrain (penetrators branching from the basilar artery), thalamus (thalamostriate and thalamogeniculate penetrators branching from the P1 and P2 segments of the posterior cerebral arteries), putamen, caudate, and globus pallidus (lenticulostriate penetrators branching from the M1 segment of the middle cerebral artery), and cerebellar nuclei (dentate nucleus penetrators branching from the cerebellar arteries). Cerebellar hemorrhage is more common than lacunar infarction in the cerebellum. Hypertensive vasculopathy is also believed to play a role in the development of white matter small vessel disease (leukoaraiosis), which may account for the association between white matter disease and risk of ICH [25]. Pathologic examination of the blood vessels in patients with chronic hypertension and in those with ICH has led to a theory of how hypertensive hemorrhage occurs. The penetrator vessels in patients with chronic hypertension develop intimal hyperplasia with hyalinosis in the vessel wall; this predisposes to focal necrosis, causing injury to the wall of the vessel. These microscopic "pseudoaneurysms" have been associated with small amounts of blood identified in the extravascular space. Pseudoaneurysm formation with subclinical leaks of blood may be relatively common; massive hemorrhage can occur when the clotting system is unable to compensate for these disruptions in the vessel wall. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 3/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Cerebral microbleeds (CMBs) are markers of bleeding-prone microangiopathy that may be found on imaging of patients with ICH due to hypertensive vasculopathy. T2*-weighted gradient echo and susceptibility-weighted MRI sequences can detect CMBs as punctate foci of hemosiderin deposition that represent remnants of clinically silent cerebral microhemorrhage [26,27]. The anatomic distribution of microbleeds varies with their etiology, with hypertensive microbleeds arising in the basal ganglia, thalamus, pons, and cerebellar nuclei in contrast with CAA-related microbleeds, which are found in more superficial lobar regions of the cerebral hemispheres ( image 2). This regional distribution is consistent with the usual location of ICH in these conditions. Cerebral amyloid angiopathy CAA is an important cause of primary lobar ICH in older adults. CAA is characterized by the deposition of congophilic material in small- to medium-sized blood vessels of the brain and leptomeninges. This weakens the structure of the vessel walls and makes them prone to bleeding. CAA usually manifests with spontaneous lobar hemorrhage ( image 3). The presence of CMBs restricted to the lobar region is associated with CAA. CAA is described in detail separately. (See "Cerebral amyloid angiopathy".) Other etiologies Several other less common underlying etiologies of nontraumatic ICH include [23,28-32]: Arteriovenous and other vascular malformations Rupture of vascular malformations including arteriovenous malformations (AVMs) and cavernous malformations (CMs) may be the cause of ICH. AVMs are characterized by connection of high-flow arterial pressure to the venous circulation without intervening capillary network. The hemorrhage is thought to result from rupture of a weakened vascular segment such as an intranidal aneurysm and most frequently occurs in lobar, intraventricular, or subarachnoid regions ( image 4 and image 5). Perilesional brain ischemia from vascular steal may also occur in patients with AVMs. By contrast, the hemorrhage due to spontaneous rupture of a CM is less common than with AVMs because these lesions are slow-flow vascular malformations comprised of thin-walled capillaries. ICH due to CMs commonly occurs in the brainstem, juxtacortical regions, or intraventricular space. (See "Brain arteriovenous malformations", section on 'Pathogenesis and pathology' and "Vascular malformations of the central nervous system", section on 'Cavernous malformations'.) Cerebral venous thrombosis Obstruction of the cerebral veins or venous sinuses results in increased venous pressure and leads to venous or capillary rupture with hemorrhage, often with simultaneous venous infarction ( image 6). Cerebral venous thrombosis most often occurs in individuals with a prothrombotic state. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Pathogenesis'.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 4/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Hemorrhagic infarction Breakdown of the structural integrity of the neurovascular unit accompanies tissue death during ischemic infarction. Blood extravasation during acute infarction may be visible on imaging as acute hemorrhagic infarction (or hemorrhagic transformation) ( image 7). Hemorrhagic infarction is common in ischemic infarcts that are large or associated with cerebral edema and those from an embolic source. Reperfusion injury after thrombolytic therapy or thrombectomy may also be a source of hemorrhagic infarction. (See "Pathophysiology of ischemic stroke".) Reversible cerebral vasoconstriction syndrome (RCVS) The transient multifocal cerebral arterial narrowing frequently seen with RCVS may also be associated with cerebral insults, including ischemic infarction or ICH ( image 8). ICH may be accompanied by subarachnoid hemorrhage in patients with RCVS. The typical clinical presentation includes recurrent thunderclap headaches. (See "Reversible cerebral vasoconstriction syndrome".) Primary or metastatic tumor Primary brain tumors such as high-grade gliomas and several metastatic brain tumors such as melanoma, choriocarcinoma, and lung, renal cell, and thyroid carcinomas may cause intratumoral hemorrhage, often associated with a large amount of surrounding edema ( image 9). (See "Overview of the clinical features and diagnosis of brain tumors in adults" and "Epidemiology, clinical manifestations, and diagnosis of brain metastases", section on 'Pathogenesis'.) Central nervous system infection Bacterial infections may cause brain abscess leading to ICH via mass effect or vessel wall erosion. Hemorrhagic necrosis of brain tissue may also occur with various viral infection (eg, herpes simplex encephalitis). (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess" and "Viral encephalitis in adults".) Mycotic intracranial aneurysm Cerebral emboli occurring as a complication of infective endocarditis may infect the arterial wall causing weakening and dilation, termed a mycotic aneurysm. They typically occur in distal arterioles and may be more likely to rupture when associated with a low platelet count or acute ischemic embolic stroke. ICH from this source may be intraparenchymal as well as subarachnoid ( image 10). (See "Complications and outcome of infective endocarditis", section on 'Neurologic complications'.) Moyamoya disease Progressive arterial narrowing and prominent collateral vessel formation around the circle of Willis in patients with moyamoya disease ( image 11 and image 12) can lead to ICH with or without subarachnoid hemorrhage. Hemorrhage frequently involves the basal ganglia, thalamus, and/or ventricular system ( image 13). ICH from moyamoya disease is more common in adults than children and more frequent in the carotid than vertebrobasilar arterial territories. (See "Moyamoya disease and https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 5/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Intracerebral, intraventricular, and subarachnoid hemorrhage'.) Cerebral vasculitis Multiple abnormalities on brain MRI may be found in patients with primary central nervous system or systemic vasculitides including T2 hyperintensities, ischemic infarcts, and hemorrhage. Vascular imaging frequently features multifocal segmental narrowing of inflamed blood vessels. (See "Primary angiitis of the central nervous system in adults" and "Overview of and approach to the vasculitides in adults".) Cerebral hyperperfusion syndrome After carotid revascularization procedures, the previously hypoperfused tissue may be unable to accommodate initially to the significant increase in cerebral perfusion pressure. Ipsilateral cerebral edema and hemorrhage typically occur within the first week after revascularization; elevated post-procedural blood pressure is an associated risk factor. (See "Complications of carotid endarterectomy", section on 'Hyperperfusion syndrome'.) Sickle cell disease Arterial wall thickening and progressive fragility as well as impaired cerebrovascular autoregulation can lead to ICH in patients with sickle cell disease (SCD). The vasculopathy with SCD is also associated with the development of moyamoya syndrome or cerebral aneurysms. ICH in patients with SCD is more common in adults than children and more frequent in those with coexisting hypertension or coagulopathy. (See "Prevention of stroke (initial or recurrent) in sickle cell disease".) Bleeding disorders Acquired or genetic bleeding disorders and conditions that impair hemostasis such as liver disease, antithrombotic therapy, or thrombolytic therapy are risk factors for ICH or systemic hemorrhage but may also be identified as the underlying cause when coagulopathy is severe and when evaluation excludes other sources. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis" and "Hemostatic abnormalities in patients with liver disease" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use", section on 'Intracerebral hemorrhage'.) EPIDEMIOLOGY Spontaneous (atraumatic) ICH is the cause of 9 to 27 percent of all strokes globally [33,34]. The overall incidence of ICH ranges from 12 to 31 per 100,000 people and varies by race [35-40]. The incidence of ICH increases with age, doubling every 10 years after age 35 [41,42]. A 2013 systematic review found that the global burden of brain hemorrhage (mainly ICH but also subarachnoid hemorrhage) was greater than that of ischemic stroke in terms of death and https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 6/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate disability, even though the incidence of ischemic stroke was twice as great [43]. The highest incidence of brain hemorrhage was found in Asia and southern sub-Saharan Africa, while the lowest incidence was found in North America, western Europe, Latin America, and Oceana. In the United States, ICH incidence varies by race. The rate of occurrence is highest in Chinese and Japanese patients, intermediate in Black Americans, and lowest in White Americans. The higher rate of ICH in Black compared with White Americans is predominately attributable to excess ICH in deep cerebral and brainstem locations where hypertension is the major risk factor [37]. Mexican Americans also have a higher incidence of ICH than non-Hispanic White Americans [44,45]. Data about the association of sex with the incidence of ICH are inconclusive [46]. A 2010 systematic review and meta-analysis found no significant difference in incidence between male and female patients [39], while a 2009 systematic review found that the incidence of ICH was higher in males [47]. RISK FACTORS Major risk factors for spontaneous ICH include older age, hypertension, and the use of antithrombotic (antiplatelet and anticoagulant) therapy. Age The risk of ICH increases with advancing age. A meta-analysis of more than 8100 patients with ICH assessed the age-related incidence of ICH over a 28-year period [39]. Using the age group of 45 to 54 years as reference, the incidence ratio increased from 0.10 (95% CI 0.06-0.14) for those under 45 years up to 9.6 (95% CI 6.6-13.9) for patients older than 85 years. Hypertension In addition to being the most common etiology of spontaneous ICH (see 'Hypertensive vasculopathy' above), hypertension is the most important risk factor for the development of ICH [40,48-51]. Hypertension more than doubles the risk of ICH [52-55]. The relative contribution of hypertension may be greater for deep than for lobar ICH [51,52,55,56]. In a meta-analysis that pooled data from 28 studies, hypertension was twice as common in patients with deep ICH as in patients with lobar ICH (odds ratio [OR] 2.1, 95% CI 1.82- 2.42) [56]. In data from a subset of three studies in the meta-analysis meeting more rigorous methodologic criteria, the association of hypertension with deep ICH remained significant (OR 1.5, 95% CI 1.09-2.07). In at least some studies, hypertension has also been shown to be a risk factor for ICH in the setting of other underlying etiologies for ICH (eg, cerebral amyloid angiopathy, antithrombotic- https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 7/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate associated ICH) [57-59]. (See "Cerebral amyloid angiopathy".) Antithrombotic medications Anticoagulant therapy, particularly warfarin, is associated with an increased risk of ICH, whereas the risk of ICH with antiplatelet monotherapy appears to be minimal [60]. Warfarin Anticoagulation with warfarin increases the risk of ICH two- to five-fold, depending upon the intensity of anticoagulation. This is discussed separately. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Risk factors related to the anticoagulant'.) In addition to an increased risk of ICH, retrospective evidence suggests that warfarin therapy with an international normalized ratio (INR) >3 is a risk factor for larger initial hemorrhage volume as well as poorer outcomes after ICH. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Risk factors for poor outcomes'.) Direct oral anticoagulants The risk of ICH is approximately 30 to 60 percent lower with the direct oral anticoagulants (DOACs; dabigatran, apixaban, edoxaban, rivaroxaban) than with warfarin in patients with nonvalvular atrial fibrillation, even when compared with well- controlled warfarin [61]. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Risk factors related to the anticoagulant'.) Parenteral anticoagulants Heparin products, including unfractionated and low- molecular weight heparins, are associated with an elevated risk of ICH. In general, the risk of bleeding rises with the intensity of anticoagulation, duration of therapy, and associated patient-level risk factors. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Bleeding'.) Thrombolytic agents The risk of ICH associated with thrombolytic medications such as alteplase or tenecteplase varies by dosage and indications. As examples, the rate of ICH was 1.3 percent in a trial of patients receiving thrombolysis for myocardial infarction; whereas, for patients with acute brain ischemia receiving thrombolytic therapy for acute ischemic stroke, the rate of symptomatic ICH was 6 percent [62,63]. (See "Acute ST- elevation myocardial infarction: The use of fibrinolytic therapy", section on 'Stroke' and "Approach to reperfusion therapy for acute ischemic stroke", section on 'Risk of intracerebral hemorrhage'.) Antiplatelet agents There is probably a small absolute increased risk of primary ICH associated with aspirin or antiplatelet agent monotherapy, based on meta-analyses of randomized trials [60,64,65], although other case-control studies have not found an https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 8/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate increased risk [66,67]. A subsequent review estimated the absolute risk of ICH attributed to the use of aspirin for primary and secondary prevention of coronary heart disease to be 0.2 events per 1000 patient years [68]. Dual antiplatelet therapy likely confers a higher risk compared with monotherapy. In a trial of over 7500 patients with atrial fibrillation for whom warfarin therapy was considered unsuitable, antiplatelet therapy with aspirin plus clopidogrel increased the risk of ICH twofold compared with aspirin alone (0.4 versus 0.2 percent) [69]. However, in another randomized trial of over 4800 adults with minor stroke or transient ischemic attack (TIA), short-term (90-day) treatment with clopidogrel plus aspirin did not increase the risk of ICH compared with aspirin alone [70]. Nonsteroidal anti-inflammatory drugs (NSAIDs) do not appear to increase the risk of ICH [71-74]. Prasugrel and ticagrelor have been associated with higher rates of major bleeding when used during percutaneous coronary intervention procedures in patients with acute coronary syndromes. (See "Periprocedural bleeding in patients undergoing percutaneous coronary intervention", section on 'Antithrombotic therapy'.) Other risk factors Obesity and inactivity Inactivity and obesity are comorbidities that can lead to increased risk for ICH. In one study including 777 ICH cases and 2083 control subjects, obesity had a small effect on the risk of ICH (OR 1.28, 95% CI 1.03-1.57), mostly through an indirect effect on hypertension [75]. Additionally, obesity is associated with the risk of obstructive sleep apnea, which is related to an increased prevalence of atrial fibrillation, higher use of anticoagulants, and a surge in nocturnal blood pressure [76]. High alcohol intake Heavy alcohol use is associated with an approximately threefold increased risk of ICH [53,55,77]. In a meta-analysis including 11 prospective studies in patients with ICH, heavy alcohol consumption (>4 drinks/day) was associated with risk for ICH (relative risk 1.67, 95% CI 1.25-2.23) [78]. The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study found a similar association (OR 1.77, 95% CI 1.30-2.41) at the threshold of 5 drinks per day [79]. Heavy alcohol consumption can also contribute to the risk of ICH indirectly due to its contribution to hypertension [80]. Race and ethnicity Race appears to be associated with an increased risk of ICH that is age related. Findings from a surveillance study and a prospective cohort have found that https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 9/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate the risk factors of race and age appear to interact, such that young (45- to 60-year-old) Black Americans have a higher risk of ICH than White Americans, but this increased risk declines with increasing age [54,81]. Lower cholesterol and lower low-density lipoprotein cholesterol A systematic review and meta-analysis of 23 prospective studies found low cholesterol was associated with an increased ICH risk [82]. However, the available data suggest that treatment with statins does not clearly increase the risk of ICH [83-88]. One meta-analysis of randomized trials did not find a higher risk of ICH in patients on statins (OR 1.08, 95% CI 0.88-1.32) [85]. However, another meta-analysis of randomized trials involving patients treated with high-dose statins did find an increased risk of ICH (risk ratio 1.53, 95% CI 1.16-2.01) [89]. Genetic variation Specific genetic features may contribute to as much as 44 percent of ICH risks [90]. However, most cases of ICH are not believed to have a monogenetic component. One exception is cerebral amyloid angiopathy-related ICH, which has been shown to have an association with apolipoprotein E (APOE) genotype. A large-scale genetic association study of 2189 ICH cases and 4041 controls revealed that the APOE allele epsilon 4 was also associated with deep ICH (OR 1.21), a location not typical for cerebral amyloid angiopathy [91]; however, in another large study, APOE epsilon 2 or epsilon 4 allele was specifically associated with lobar and not deep ICH [52]. (See "Cerebral amyloid angiopathy", section on 'Genetic susceptibilities'.) Small-vessel vascular disease Evidence of small-vessel disease may be seen on brain magnetic resonance imaging studies as lacunar infarcts, white matter hyperintensities on T2 sequences, or microbleeds. These markers of blood vessel fragility or atherosclerosis within the small vessels of the brain are associated with an elevated risk of ICH. In an observational study involving nearly 1500 patients with prior ischemic stroke and atrial fibrillation taking anticoagulation, the rate of ICH was higher in those with evidence of small-vessel disease than those without (0.6 versus 0.1 percent/year) [92,93]. Tobacco use Tobacco use may be associated with the risk of ICH, presumably by contributing to elevated blood pressure secondary to an increase in cardiac output and total peripheral vascular resistance and arterial wall damage, which predispose to rupture of small vessels in the brain. In the Physicians Health Study, active smokers had a relative ICH risk of 2.06 percent (95% CI 1.08-3.96) compared with nonsmokers [94]. Stimulant drug use The use of stimulant medications has been associated with a risk of ICH due to possible spikes in blood pressure and vasospasm. Appetite suppressant or https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 10/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate cough medications that contain sympathomimetic properties such as phenylpropanolamine are associated with an elevated risk of ICH [95]. Likewise, cocaine use has been associated with the risk of incidence ICH. Caffeine-containing medications have also been associated with ICH [96]. Infections Several infectious pathogens have been associated with the risk of incident ICH. These include HIV [97], hepatitis C virus [98,99], and the varicella-zoster virus [100,101] as well as the spirochete from the Leptospira genus that causes leptospirosis [102]. Less-certain risk factors Other risk factors for ICH are supported by observational data, including chronic kidney disease [103-105], diabetes [106], use of selective serotonin reuptake inhibitors [107,108], migraine [109], and systemic amyloidosis [110]. CLINICAL PRESENTATION The signs and symptoms of ICH vary according to the location and size of the hemorrhage ( table 1). Onset and progression In most circumstances, ICH onset occurs during routine activity. However, some hypertensive hemorrhages occur with exertion or intense emotional activity [111]. The neurologic symptoms and signs may be progressive over minutes or a few hours ( figure 1), in contrast with brain embolism and subarachnoid hemorrhage, where the neurologic symptoms and signs are often maximal at onset. However, some patients with large ICH are obtunded or comatose when first discovered or at first evaluation upon arrival to the emergency department. Headache, vomiting, and a decreased level of consciousness may develop if the hemorrhage is large. This symptom complex is typically absent with small hemorrhages. However, headache and vomiting occur in approximately one-half of patients with ICH ( figure 2). Headache may be due to traction on meningeal pain fibers, increased intracranial pressure (ICP), or blood in the cerebrospinal fluid; it is most common with cerebellar and lobar hemorrhages. Patients may complain of a stiff neck and have meningismus on physical examination if there is intraventricular blood. Stupor or coma attributed to the ICH is often an ominous sign. Exceptions include patients with thalamic hemorrhage with involvement of the reticular activating system who may recover after acute blood is resorbed and those with acute hydrocephalus who might improve if treated with https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 11/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate an external ventricular drain. Patients may also present with stupor or coma due to reversible causes such as acute metabolic derangements or seizure. Neurologic signs and ICH location Neurologic signs vary depending upon the location of the hemorrhage ( image 1). In one study, bleeding involved the putamen in approximately 35 percent of cases, cerebral lobes in 30 percent, cerebellum in 16 percent, thalamus in 15 percent, and pons in 5 to 12 percent [112]. In the subsequent Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) of over 2000 subjects with imaging-confirmed ICH and hypertension, the frequency of affected brain structures was as follows [113]: Putamen/globus pallidus 56 percent Posterior limb of internal capsule 46 percent Anterior limb of internal capsule 5 percent Thalamus 31 percent External capsule 27 percent Lobar 14 percent Cerebellum or brainstem 7 percent Caudate head 2 percent Intraventricular extension of the ICH was identified in 29 percent in this study. Neurologic exam deficits typically correspond to the location of the hemorrhage and associated edema. Patients with deficits not attributable to the hemorrhage should be evaluated for other causes, such as expansion of the hemorrhage, post-ictal symptoms after a seizure, or increased intracranial pressure. The localization of ICH may be associated with typical neurologic exam findings: Putaminal hemorrhage Spread of hemorrhage into the putamen most commonly occurs along white matter fiber tracts, causing hemiplegia, hemisensory loss, homonymous hemianopsia, and gaze palsy. Stupor and coma may develop if the hemorrhage is large. Caudate hemorrhage Hemorrhage typically originating within the head of the caudate nucleus may cause acute-onset confusion, personality changes, or memory impairment as well as transient contralateral weakness or numbness [114]. Headache and drowsiness may also occur, especially if bleeding extends into the adjacent intraventricular space. Internal capsule hemorrhage Small hemorrhages restricted to the internal capsule may cause mild dysarthria, contralateral hemiparesis, and sensory deficit [115]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 12/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Cerebellar hemorrhage Cerebellar hemorrhage usually originates in the dentate nucleus and may extend into the hemisphere and fourth ventricle and possibly into the pontine tegmentum. These bleeds typically cause an inability to walk due to imbalance, vomiting, and occipital headache. Some patients have referred pain to the neck or shoulder, neck stiffness, gaze palsy, and/or facial weakness. Notably, there is often no hemiparesis. The patient may become stuporous due to obstructive hydrocephalus or brainstem compression. Patients with acute cerebellar hemorrhage may frequently deteriorate and require surgery. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Surgical approaches for selected patients' and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Cerebellar hemorrhage'.) Thalamic hemorrhage Thalamic hemorrhages may extend in a transverse direction to the posterior limb of the internal capsule, downward to put pressure on the tectum of the midbrain, or medially to rupture into the third ventricle. Symptoms include hemiparesis, hemisensory loss, and occasionally transient homonymous hemianopsia. Pupils may be miotic and unreactive along with a gaze palsy (eg, peering at the tip of the nose, skewed, or "wrong-way eyes" toward the weak side [in contrast with hemispheric cortical injury in which the eyes are deviated away from the hemiparesis]). Aphasia may occur if the bleed affects the dominant hemisphere, while neglect may develop if the bleed affects the nondominant hemisphere. Patients with small anterior thalamic hemorrhages may present with drowsiness, acute confusion, or neuropsychiatric symptoms. Lobar hemorrhage Lobar hemorrhages vary in their neurologic signs depending upon location. They most often affect the parietal and occipital lobes. These bleeds are associated with a higher incidence of seizures. Occipital hemorrhages frequently present with a very dense contralateral homonymous hemianopsia. Hemorrhages in the frontoparietal region will produce a contralateral plegia or paresis of the leg with relative sparing of the arm. Pontine hemorrhage Pontine hemorrhages typically originate in brainstem nuclei and may extend into the base of the pons. These often lead to deep coma over the first few minutes following the hemorrhage, probably due to disruption of the reticular activating system. The motor examination may be marked by bilateral paralysis. The pupils are pinpoint and react to a strong light source. Horizontal eye movements are often absent, and there may be ocular bobbing, facial palsy, deafness, and dysarthria if the patient is awake. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 13/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Seizures Seizures may accompany acute ICH. Seizures in the first days after ICH occur approximately 15 percent of patients [116,117]; they are more common in lobar hemorrhages (affecting cortical tissue) than in deep or cerebellar ICH [118-121]. (See "Overview of the management of epilepsy in adults", section on 'Poststroke seizures'.) Cardiac abnormalities Cardiac abnormalities are commonly associated with spontaneous ICH [122]. The most frequently associated electrocardiographic (ECG) changes are prolonged QT interval and ST-T wave changes. These changes may reflect catecholamine-induced cardiac injury, which is most likely due to a centrally mediated release of excess catecholamines caused by increased intracranial pressure or autonomic disturbance [123]. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy" and "Complications of stroke: An overview", section on 'Neurogenic cardiac damage'.) Mild elevations in serum myocardial enzymes often accompany the ECG changes, including cardiac troponin and beta natriuretic peptide [122]. Echocardiographic abnormalities may involve global or regional wall motion abnormalities and reduced ejection fraction. Ventricular arrhythmias may occur with brainstem compression [124]. BRAIN IMAGING Both computed tomography (CT) or magnetic resonance imaging (MRI) are considered first- choice imaging options for the emergency diagnosis and assessment of ICH ( image 14) [125]. Clinical deficits on neurologic examination can be correlated with impacted brain regions apparent on CT or MRI. Acute imaging also provides information about extension into the ventricular system, the presence of surrounding edema, shifts in brain contents (herniation), impending expansion, and underlying etiology. ICH severity can be assessed by calculating the volume of the hemorrhage. (See 'Estimating hemorrhage volume' below.) Head CT Noncontrast head computed tomography (CT) accurately identifies the presence of acute ICH, distinguishing it from ischemic stroke. Hyperacute blood will appear hyperdense except in rare cases of severe anemia when it might appear isodense. Over weeks, the blood from an acute hemorrhage will typically become isodense and may have a ring-enhancement appearance. Chronically, the blood is hypodense ( image 15). CT angiography that may be performed along with a noncontrast head CT may identify an underlying vascular cause to the ICH [29,126]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 14/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Noncontrast head CT and CT angiography may also provide additional information regarding propensity for hemorrhagic expansion [127]. (See 'Predicting hemorrhage expansion' below.)
and pons in 5 to 12 percent [112]. In the subsequent Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) of over 2000 subjects with imaging-confirmed ICH and hypertension, the frequency of affected brain structures was as follows [113]: Putamen/globus pallidus 56 percent Posterior limb of internal capsule 46 percent Anterior limb of internal capsule 5 percent Thalamus 31 percent External capsule 27 percent Lobar 14 percent Cerebellum or brainstem 7 percent Caudate head 2 percent Intraventricular extension of the ICH was identified in 29 percent in this study. Neurologic exam deficits typically correspond to the location of the hemorrhage and associated edema. Patients with deficits not attributable to the hemorrhage should be evaluated for other causes, such as expansion of the hemorrhage, post-ictal symptoms after a seizure, or increased intracranial pressure. The localization of ICH may be associated with typical neurologic exam findings: Putaminal hemorrhage Spread of hemorrhage into the putamen most commonly occurs along white matter fiber tracts, causing hemiplegia, hemisensory loss, homonymous hemianopsia, and gaze palsy. Stupor and coma may develop if the hemorrhage is large. Caudate hemorrhage Hemorrhage typically originating within the head of the caudate nucleus may cause acute-onset confusion, personality changes, or memory impairment as well as transient contralateral weakness or numbness [114]. Headache and drowsiness may also occur, especially if bleeding extends into the adjacent intraventricular space. Internal capsule hemorrhage Small hemorrhages restricted to the internal capsule may cause mild dysarthria, contralateral hemiparesis, and sensory deficit [115]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 12/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Cerebellar hemorrhage Cerebellar hemorrhage usually originates in the dentate nucleus and may extend into the hemisphere and fourth ventricle and possibly into the pontine tegmentum. These bleeds typically cause an inability to walk due to imbalance, vomiting, and occipital headache. Some patients have referred pain to the neck or shoulder, neck stiffness, gaze palsy, and/or facial weakness. Notably, there is often no hemiparesis. The patient may become stuporous due to obstructive hydrocephalus or brainstem compression. Patients with acute cerebellar hemorrhage may frequently deteriorate and require surgery. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Surgical approaches for selected patients' and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Cerebellar hemorrhage'.) Thalamic hemorrhage Thalamic hemorrhages may extend in a transverse direction to the posterior limb of the internal capsule, downward to put pressure on the tectum of the midbrain, or medially to rupture into the third ventricle. Symptoms include hemiparesis, hemisensory loss, and occasionally transient homonymous hemianopsia. Pupils may be miotic and unreactive along with a gaze palsy (eg, peering at the tip of the nose, skewed, or "wrong-way eyes" toward the weak side [in contrast with hemispheric cortical injury in which the eyes are deviated away from the hemiparesis]). Aphasia may occur if the bleed affects the dominant hemisphere, while neglect may develop if the bleed affects the nondominant hemisphere. Patients with small anterior thalamic hemorrhages may present with drowsiness, acute confusion, or neuropsychiatric symptoms. Lobar hemorrhage Lobar hemorrhages vary in their neurologic signs depending upon location. They most often affect the parietal and occipital lobes. These bleeds are associated with a higher incidence of seizures. Occipital hemorrhages frequently present with a very dense contralateral homonymous hemianopsia. Hemorrhages in the frontoparietal region will produce a contralateral plegia or paresis of the leg with relative sparing of the arm. Pontine hemorrhage Pontine hemorrhages typically originate in brainstem nuclei and may extend into the base of the pons. These often lead to deep coma over the first few minutes following the hemorrhage, probably due to disruption of the reticular activating system. The motor examination may be marked by bilateral paralysis. The pupils are pinpoint and react to a strong light source. Horizontal eye movements are often absent, and there may be ocular bobbing, facial palsy, deafness, and dysarthria if the patient is awake. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 13/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Seizures Seizures may accompany acute ICH. Seizures in the first days after ICH occur approximately 15 percent of patients [116,117]; they are more common in lobar hemorrhages (affecting cortical tissue) than in deep or cerebellar ICH [118-121]. (See "Overview of the management of epilepsy in adults", section on 'Poststroke seizures'.) Cardiac abnormalities Cardiac abnormalities are commonly associated with spontaneous ICH [122]. The most frequently associated electrocardiographic (ECG) changes are prolonged QT interval and ST-T wave changes. These changes may reflect catecholamine-induced cardiac injury, which is most likely due to a centrally mediated release of excess catecholamines caused by increased intracranial pressure or autonomic disturbance [123]. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy" and "Complications of stroke: An overview", section on 'Neurogenic cardiac damage'.) Mild elevations in serum myocardial enzymes often accompany the ECG changes, including cardiac troponin and beta natriuretic peptide [122]. Echocardiographic abnormalities may involve global or regional wall motion abnormalities and reduced ejection fraction. Ventricular arrhythmias may occur with brainstem compression [124]. BRAIN IMAGING Both computed tomography (CT) or magnetic resonance imaging (MRI) are considered first- choice imaging options for the emergency diagnosis and assessment of ICH ( image 14) [125]. Clinical deficits on neurologic examination can be correlated with impacted brain regions apparent on CT or MRI. Acute imaging also provides information about extension into the ventricular system, the presence of surrounding edema, shifts in brain contents (herniation), impending expansion, and underlying etiology. ICH severity can be assessed by calculating the volume of the hemorrhage. (See 'Estimating hemorrhage volume' below.) Head CT Noncontrast head computed tomography (CT) accurately identifies the presence of acute ICH, distinguishing it from ischemic stroke. Hyperacute blood will appear hyperdense except in rare cases of severe anemia when it might appear isodense. Over weeks, the blood from an acute hemorrhage will typically become isodense and may have a ring-enhancement appearance. Chronically, the blood is hypodense ( image 15). CT angiography that may be performed along with a noncontrast head CT may identify an underlying vascular cause to the ICH [29,126]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 14/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Noncontrast head CT and CT angiography may also provide additional information regarding propensity for hemorrhagic expansion [127]. (See 'Predicting hemorrhage expansion' below.) Brain MRI Brain magnetic resonance imaging (MRI) is similarly sensitive as CT for detecting acute ICH. Acute ICH can be diagnosed by MRI with up to 100 percent sensitivity and accuracy by experienced readers [128]. In the Hemorrhage and Early MRI Evaluation (HEME) study, 200 patients presenting with focal stroke symptoms were evaluated with MRI including gradient recall echo (GRE) and diffusion-weighted imaging (DWI) sequences within six hours of symptom onset followed by CT [129]. MRI and CT were equivalent for the detection of acute ICH, and MRI was significantly more accurate than CT for the detection of chronic ICH. However, MRI is contraindicated for patients with some metallic implants [130]. Additionally, MRIs are not as readily available on an emergent basis as CT and conventional protocols take longer than CT protocols. Age of hemorrhagic findings MRI may also provide information about the age of the ICH ( table 2). The appearance of intracerebral blood on MRI images varies with time depending on the paramagnetic properties of the various stages of hemoglobin and on the mode of imaging acquisition [131,132]. Of note, these imaging features do not apply to extra-axial or intraventricular hemorrhage. Hyperacute hemorrhage (0 to 3 hours) A hyperacute parenchymal hematoma contains oxyhemoglobin and appears hypo- to isointense on T1-weighted images, hyperintense on T2-weighted images, and hypointense on T2-weighted (GRE or susceptibility-weighted imaging) sequences ( image 14) [133]. Acute hemorrhage (3 hours to 3 days) Acute ICH can be accurately detected due to the magnetic susceptibility of deoxygenated hemoglobin (deoxyhemoglobin) [128,129,132-136]. This property of superparamagnetic deoxyhemoglobin results in rapid dephasing of proton spins causing signal loss (darkening or hypointensity) that is best seen in T2-weighted images. Subacute hemorrhage (3 days to 3 weeks) Subacute ICH is recognized by the presence of diamagnetic methemoglobin, which appears as a T1-hyperintense signal, often first along the periphery of the hemorrhage. The appearance on T2-weighted imaging is hypointense in the first week due to magnetic susceptibility but becomes T2 hyperintense in the late subacute stage (one to three weeks) as red blood cells lyse and methemoglobin becomes extracellular. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 15/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Chronic hemorrhage (>3 weeks) The presence of superparamagnetic hemosiderin and ferritin in chronic ICH causes marked hypointensity on T2- and T2-weighted images. On T1-weighted images, chronic hemorrhage is isointense compared with brain tissue. Nonhemorrhagic findings in acute ICH Brain MRI may show other findings associated with acute ICH. Cerebral edema Tissue damage and subsequent inflammatory response to the presence of intracranial blood can lead to perilesional cerebral edema in ICH [137]. Edema can compress adjacent intracranial structures, causing elevated intracranial pressure (ICP) and leading to hydrocephalus. Cerebral edema may be seen in acute and subacute ICH and typically appears hypointense on T1-weighted images and hyperintense on T2-weighted images. ICH-related cerebral edema often peaks two to three weeks after hemorrhage [7,138]. Acute imaging showing prominent edema along with ICH may indicate subacute age of bleeding or suggest ICH may be due to a specific underlying cause such as cerebral sinus thrombosis ( image 6) or tumor ( image 9). (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Follow-up neuroimaging'.) Diffusion-weighted imaging lesions Brain MRI may show hyperintense diffusion- weighted imaging (DWI) lesions associated with acute ICH. These may indicate hemorrhagic transformation of a primary ischemic infarct ( image 7) or embolism such as from infective endocarditis ( table 3). (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Follow-up neuroimaging'.) Small DWI hyperintense lesions may also be found in patients with primary acute ICH. These lesions are often punctate in size, multifocal in number, and remote from and contralateral to the site of hemorrhage in location ( image 16). They appear to occur most frequently during the first several days after ICH but can also be found on subsequent nonacute imaging [19]. In a systematic review of observational studies that included 5211 patients with acute ICH, the pooled prevalence of DWI lesions on acute brain MRI was 24 percent [139]. DWI lesions are associated with larger ICH volume, subarachnoid bleeding, and elevated blood pressure, suggesting acute changes in cerebral perfusion and/or ICP may contribute to their development [139,140]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 16/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate MRI may also demonstrate imaging findings that may suggest a specific underlying cause. (See 'Subsequent imaging' below.) Estimating hemorrhage volume An estimate of ICH volume is useful to communicate hemorrhage severity and make early assessments of prognosis. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Clinical prediction scores'.) The formula is calculated using the centimeter scale on the CT (or MRI) images as follows [141]: A is the greatest hemorrhage diameter on the CT slice with the largest area of hemorrhage. B is the largest diameter 90 degrees to A on the same (index) CT slice ( image 17). C is the approximate number of CT slices with hemorrhage multiplied by the slice thickness in centimeters. To calculate C, each CT slice with hemorrhage is visually compared with the index CT slice [141]. An individual hemorrhage slice is counted as one full slice for determining C if the hemorrhage area is >75 percent of the area on the slice with the largest hemorrhage. A slice is counted as one-half if the hemorrhage area is approximately 25 to 75 percent of the area on the largest hemorrhage slice. The slice is not counted if the area is <25 percent of the largest hemorrhage slice. ABC/2 gives the ICH volume in cubic centimeters. In children, ICH volume may instead be measured as a percent of total brain volume as ABC/XYZ, where X is the largest midline axial diameter of supratentorial brain, Y is the largest axial diameter perpendicular to X, and Z is the brain vertical diameter [142]. Predicting hemorrhage expansion Enlargement of the hemorrhage is associated with neurologic deterioration and worse outcomes. These observations indicate that significant improvements in patient outcome from ICH may be achieved by minimizing both secondary brain ischemia and hemorrhage enlargement in the early hours following the onset of bleeding. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Managing hemorrhagic expansion'.) Serial CT scans in patients with hypertensive hemorrhage have shown that the hemorrhage enlarges in the first few hours after presentation in a subset of patients [2,6,143]. In most but not all cases, the bulk of hemorrhage expansion occurs in the first three hours after onset of ICH [2-5,144]. In a prospective series of 103 patients with ICH, significant hemorrhage growth (a >33 percent volume increase) occurred in 38 percent of patients over the first 24 hours [2]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 17/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate In a patient-level meta-analysis of studies reporting ICH growth, with data on over 5400 subjects, several independent predictors of hemorrhage growth identified [145]: Shorter time from symptom onset to initial imaging ICH volume Antiplatelet or anticoagulant use Contrast extravasation (eg, "spot sign") on initial CT angiography ( image 18) While all patients with ICH should be treated to limit risk for hemorrhage expansion, the presence of specific radiologic findings may trigger a somewhat more aggressive approach to monitoring and treatment. (See 'Subsequent imaging' below and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) Spot sign on CT angiography The spot sign ( image 18) describes the appearance of small focal or multifocal areas of contrast enhancement within a hemorrhage on CT angiography source images [146]. The spot sign has been linked to hemorrhage expansion and poor outcomes, including mortality [127,147]. In a retrospective analysis of 367 patients with acute ICH, a spot sign was found in 19 percent of patients and was independently associated with hemorrhage expansion [148]. Accumulation of contrast extravasation within the hemorrhage on postcontrast CT also predicts subsequent hemorrhage expansion [149]. Although less well-studied, tiny spots of contrast extravasation within the hemorrhage on MRI (the MRI spot sign) have also been detected on postcontrast T1-weighted and dynamic T1-weighted images, particularly when performed in the first six hours after ICH onset [150]. This "MRI spot sign" may be associated with hematoma growth and worse clinical outcomes, but definitive data are lacking [151]. A spot sign score that grades the number of spot signs, their maximum dimension, and attenuation has been found to be a strong predictor of hemorrhage expansion; of these features, the number of spot signs appears to be most predictive [148,152,153]. Signs on noncontrast head CT Irregularity or heterogeneity of the hematoma on noncontrast head CT also suggests ongoing bleeding or risk of hematoma expansion [154,155]. In a systematic review including 25 studies and 10,650 patients with ICH, several imaging features visible on CT were associated with subsequent risk of poor functional outcome [156]. These include ( image 19): Irregular hematoma shape Island sign ( 3 scattered hematomas separate from the main hematoma) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 18/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Hypodensity (any hypodense focus within the hematoma) Heterogeneous density ( 3 foci of hypodensity within the hematoma) Black-hole sign (focus of hypodensity with a difference of >28 Hounsfield units [HU] from the hematoma) Swirl sign (hypodense region within the hematoma) Blend sign (focus of hypodensity with a difference of >18 HU adjacent to the hematoma) Subarachnoid extension In one study, extension of hemorrhage into the subarachnoid space was associated with subsequent hemorrhagic expansion in patients with acute lobar ICH but not in patients with nonlobar ICH [157]. Intraventricular extension Expansion of ICH into the intraventricular space has been reported in up to 40 to 60 percent of patients in various studies and is associated with neurologic complications and worse outcomes [158-160]. EVALUATION AND DIAGNOSIS ICH is a neurologic and medical emergency because it is associated with a high risk of ongoing bleeding, progressive neurologic deterioration, permanent disability, and death [161,162]. As the diagnostic evaluation is proceeding, patients with ICH may also need acute interventions, possibly including intubation and mechanical ventilation, anticoagulation reversal, blood pressure control, intracranial pressure monitoring and treatment, and consideration of the need for ventriculostomy or surgical hematoma evacuation ( table 1). These issues are discussed in detail separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) Initial evaluation Clinical suspicion for ICH is based upon features such as acute onset of gradually worsening symptoms and increasing neurologic deficit, particularly if accompanied by severe headache, vomiting, severe hypertension, and decreased level of consciousness or coma. However, the distinction between brain hemorrhage and ischemia cannot be made on the basis of clinical characteristics alone [162]. Importantly, headache may be absent in some cases of ICH. (See 'Clinical presentation' above.) Neuroimaging with brain computed tomography (CT) or magnetic resonance imaging (MRI) is mandatory to confirm the diagnosis of ICH and to exclude ischemic stroke and stroke mimics as possible causes [162]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 19/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Laboratory and other dignostic testing Routine laboratory evaluation to evaluate for underlying causes or associated risks in patients with ICH includes [162]: Complete blood count, electrolytes, blood urea nitrogen, creatinine, and glucose Prothrombin time (with international normalized ratio [INR]) and activated partial thromboplastin time for all patients; thrombin clotting time for patients taking direct oral anticoagulants (and/or ecarin clotting time where available for patients known or suspected to be taking direct thrombin inhibitors) Cardiac-specific troponin Toxicology screen to detect cocaine and other sympathomimetic drugs Urinalysis Pregnancy test in a female of childbearing age An electrocardiogram (ECG) obtained at baseline may help identify patients with ICH and coexistent cardiac dysfunction [163,164]. A repeat ECG is also typically obtained along with an echocardiogram for those with heart failure or hemodynamic instability. (See "Electrocardiogram in the diagnosis of myocardial ischemia and infarction" and "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy".) An electroencephalogram is reserved for patients with seizures or those with encephalopathy not explained by the location or size of the ICH. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis", section on 'When to suspect NCSE' and 'Neurologic signs and ICH location' above.) Subsequent imaging Once ICH is confirmed by head CT or MRI, additional imaging is warranted in the event of clinical deterioration to evaluate for ICH expansion or rebleeding. A follow-up imaging study may also be performed to document that the bleeding has stabilized. Subsequent imaging is also typically performed to identify an underlying cause of the ICH to help guide preventive measures to reduce the risk of recurrent hemorrhage. The necessity for further evaluation to determine the cause of ICH varies with the clinical setting. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Follow-up neuroimaging'.) For some patients, the etiology of the ICH is identified with initial neuroimaging studies, and further imaging studies are not required. An example may include a stable patient with an acute ICH in the putamen suggestive of hypertensive vasculopathy who has a history of longstanding hypertension. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 20/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate For other patients, initial imaging studies do not sufficiently exclude other causes of ICH and follow-up evaluation is required. We obtain follow-up imaging when an underlying cause is suspected by clinical features or initial imaging findings ( table 3) [162]. Initial imaging findings that may suggest a specific underlying cause include: Early perihematomal edema out of proportion to the underlying ICH ( image 9) [165] ICH within arterial vascular territory suggesting primary ischemic infarction ( image 7) Multifocal hemorrhage ( image 20) Isolated intraventricular hemorrhage ( image 21) The assessment of the possible underlying structural pathology may be shrouded and distorted by the hematoma or surrounding edema. In these cases, delayed imaging performed after bleeding and edema have resolved may identify patients with underlying structural abnormalities at high risk for ICH recurrence ( algorithm 1). (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Follow-up neuroimaging'.) Brain MRI with contrast is the preferred modality to help identify the underlying cause of ICH for most patients. For patients who are unable to undergo MRI, head CT with contrast is a less sensitive alternative option. Vascular imaging (eg, CT or MR angiography or digital subtraction angiography) is performed when an underlying vascular lesion is suspected [29,30,126,166]. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Follow-up neuroimaging'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 21/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient education: Arteriovenous malformations in the brain (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Hemorrhagic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Underlying causes Injury to brain parenchyma occurs via hematoma expansion and perilesional edema as well as secondary excitotoxic and inflammatory injury from the breakdown of the blood-brain barrier. Common conditions associated with intracerebral hemorrhage (ICH) include hypertension, cerebral amyloid angiopathy, and ruptured vascular malformation. Other etiologies include cerebral venous thrombosis, vasculopathies, primary or metastatic tumors, and coagulopathies. (See 'Pathogenesis and etiologies' above.) Risk factors Major risk factors for spontaneous ICH include older age, hypertension, and the use of antithrombotic (antiplatelet and anticoagulant) therapy. (See 'Risk factors' above.) Presenting signs and symptoms The signs and symptoms of ICH vary according to the location and size of the hemorrhage ( table 1). Patients typically present with an acute onset of a focal neurologic deficit such as hemiparesis, aphasia, or visual impairment corresponding to the part of the brain affected. The neurologic symptoms and signs may be progressive over minutes or a few hours ( figure 1). Headache, vomiting, and a decreased level of consciousness develop if the hemorrhage is large. Patients may also present with stupor or coma due to associated reversible causes such as acute metabolic derangements or seizure. (See 'Clinical presentation' above.) Initial diagnostic imaging Neuroimaging with head computed tomography (CT) or magnetic resonance imaging (MRI) is mandatory to confirm the diagnosis of ICH and to https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 22/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate exclude ischemic stroke and stroke mimics as alternative causes to symptoms. Acute imaging also provides information about the severity of the hemorrhage, the risk of expansion of bleeding, and the underlying cause of the ICH ( image 19 and table 3). (See 'Evaluation and diagnosis' above and 'Brain imaging' above.) Both CT or MRI are considered first-choice imaging options for the emergency diagnosis and assessment of ICH. CT angiography may be performed along with a noncontrast head CT to help identify an underlying vascular cause to the ICH. (See 'Brain imaging' above.) Predictors of hemorrhage growth associated with neurologic deterioration include a shorter time from symptom onset to initial imaging, initial ICH volume, antithrombotic medication use, and imaging signs of ICH heterogeneity on noncontrast CT or focal contrast extravasation on CT angiography ( image 18 and image 19). (See 'Predicting hemorrhage expansion' above.) Subsequent imaging evaluation Additional imaging may be warranted after the diagnosis of ICH in the event of clinical deterioration to evaluate for ICH expansion or rebleeding and to document that the bleeding has stabilized. (See 'Subsequent imaging' above.) We also obtain follow-up imaging when an underlying cause is suspected by clinical features or initial imaging findings to help guide preventive measures to reduce the risk of recurrent hemorrhage ( table 3). Brain MRI with contrast is the preferred modality to help identify the underlying cause of ICH for most patients. 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Susceptibility-weighted imaging is more reliable than T2-weighted gradient-recalled echo MRI for detecting microbleeds. Stroke 2013; 44:2782. 28. Meretoja A, Strbian D, Putaala J, et al. SMASH-U: a proposal for etiologic classification of intracerebral hemorrhage. Stroke 2012; 43:2592. 29. Delgado Almandoz JE, Schaefer PW, Goldstein JN, et al. Practical scoring system for the identification of patients with intracerebral hemorrhage at highest risk of harboring an underlying vascular etiology: the Secondary Intracerebral Hemorrhage Score. AJNR Am J Neuroradiol 2010; 31:1653. 30. van Asch CJ, Velthuis BK, Greving JP, et al. External validation of the secondary intracerebral hemorrhage score in The Netherlands. Stroke 2013; 44:2904. 31. Gross BA, Jankowitz BT, Friedlander RM. Cerebral Intraparenchymal Hemorrhage: A Review. JAMA 2019; 321:1295. 32. Mallon D, Doig D, Dixon L, et al. Neuroimaging in Sickle Cell Disease: A Review. J Neuroimaging 2020; 30:725. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 25/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate 33. Steiner T, Al-Shahi Salman R, Beer R, et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke 2014; 9:840. 34. Feigin VL, Lawes CM, Bennett DA, et al. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 2009; 8:355. 35. Sacco S, Marini C, Toni D, et al. Incidence and 10-year survival of intracerebral hemorrhage in a population-based registry. Stroke 2009; 40:394. 36. Gebel JM, Broderick JP. Intracerebral hemorrhage. Neurol Clin 2000; 18:419. 37. Flaherty ML, Woo D, Haverbusch M, et al. Racial variations in location and risk of intracerebral hemorrhage. Stroke 2005; 36:934. 38. Labovitz DL, Halim A, Boden-Albala B, et al. The incidence of deep and lobar intracerebral hemorrhage in whites, blacks, and Hispanics. Neurology 2005; 65:518. 39. van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010; 9:167. 40. Poon MT, Bell SM, Al-Shahi Salman R. Epidemiology of Intracerebral Haemorrhage. Front Neurol Neurosci 2015; 37:1. 41. Broderick JP, Brott T, Tomsick T, et al. Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg 1993; 78:188. 42. Stein M, Misselwitz B, Hamann GF, et al. Intracerebral hemorrhage in the very old: future demographic trends of an aging population. Stroke 2012; 43:1126. 43. Krishnamurthi RV, Feigin VL, Forouzanfar MH, et al. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet Glob Health 2013; 1:e259. 44. Bruno A, Carter S, Qualls C, Nolte KB. Incidence of spontaneous intracerebral hemorrhage among Hispanics and non-Hispanic whites in New Mexico. Neurology 1996; 47:405. 45. Morgenstern LB, Smith MA, Lisabeth LD, et al. Excess stroke in Mexican Americans compared with non-Hispanic Whites: the Brain Attack Surveillance in Corpus Christi Project. Am J Epidemiol 2004; 160:376. 46. Gokhale S, Caplan LR, James ML. Sex differences in incidence, pathophysiology, and outcome of primary intracerebral hemorrhage. Stroke 2015; 46:886. 47. Appelros P, Stegmayr B, Ter nt A. Sex differences in stroke epidemiology: a systematic review. Stroke 2009; 40:1082. 48. Woo D, Sauerbeck LR, Kissela BM, et al. Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. Stroke 2002; https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 26/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate 33:1190. 49. Woo D, Haverbusch M, Sekar P, et al. Effect of untreated hypertension on hemorrhagic stroke. Stroke 2004; 35:1703. 50. Feldmann E, Broderick JP, Kernan WN, et al. Major risk factors for intracerebral hemorrhage in the young are modifiable. Stroke 2005; 36:1881. 51. Zia E, Hedblad B, Pessah-Rasmussen H, et al. Blood pressure in relation to the incidence of
perihematomal edema after intracerebral hemorrhage measured by serial magnetic resonance imaging. Stroke 2011; 42:73. 8. Staykov D, Wagner I, Volbers B, et al. Natural course of perihemorrhagic edema after intracerebral hemorrhage. Stroke 2011; 42:2625. 9. Li N, Worthmann H, Heeren M, et al. Temporal pattern of cytotoxic edema in the perihematomal region after intracerebral hemorrhage: a serial magnetic resonance imaging study. Stroke 2013; 44:1144. 10. Olivot JM, Mlynash M, Kleinman JT, et al. MRI profile of the perihematomal region in acute intracerebral hemorrhage. Stroke 2010; 41:2681. 11. Oeinck M, Neunhoeffer F, Buttler KJ, et al. Dynamic cerebral autoregulation in acute intracerebral hemorrhage. Stroke 2013; 44:2722. 12. Murai Y, Ikeda Y, Teramoto A, Tsuji Y. Magnetic resonance imaging-documented extravasation as an indicator of acute hypertensive intracerebral hemorrhage. J Neurosurg 1998; 88:650. 13. Aksoy D, Bammer R, Mlynash M, et al. Magnetic resonance imaging profile of blood-brain barrier injury in patients with acute intracerebral hemorrhage. J Am Heart Assoc 2013; 2:e000161. 14. Kidwell CS, Burgess R, Menon R, et al. Hyperacute injury marker (HARM) in primary hemorrhage: a distinct form of CNS barrier disruption. Neurology 2011; 77:1725. 15. Silvera S, Oppenheim C, Touz E, et al. Spontaneous intracerebral hematoma on diffusion- weighted images: influence of T2-shine-through and T2-blackout effects. AJNR Am J Neuroradiol 2005; 26:236. 16. Menon RS, Burgess RE, Wing JJ, et al. Predictors of highly prevalent brain ischemia in intracerebral hemorrhage. Ann Neurol 2012; 71:199. 17. Garg RK, Liebling SM, Maas MB, et al. Blood pressure reduction, decreased diffusion on MRI, and outcomes after intracerebral hemorrhage. Stroke 2012; 43:67. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 24/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate 18. Kang DW, Han MK, Kim HJ, et al. New ischemic lesions coexisting with acute intracerebral hemorrhage. Neurology 2012; 79:848. 19. Auriel E, Gurol ME, Ayres A, et al. Characteristic distributions of intracerebral hemorrhage- associated diffusion-weighted lesions. Neurology 2012; 79:2335. 20. Boulanger M, Schneckenburger R, Join-Lambert C, et al. Diffusion-Weighted Imaging Hyperintensities in Subtypes of Acute Intracerebral Hemorrhage. Stroke 2018; :STROKEAHA118021407. 21. Prabhakaran S, Naidech AM. Ischemic brain injury after intracerebral hemorrhage: a critical review. Stroke 2012; 43:2258. 22. Beslow LA, Licht DJ, Smith SE, et al. Predictors of outcome in childhood intracerebral hemorrhage: a prospective consecutive cohort study. Stroke 2010; 41:313. 23. Cordonnier C, Demchuk A, Ziai W, Anderson CS. Intracerebral haemorrhage: current approaches to acute management. Lancet 2018; 392:1257. 24. Garcia JH, Ho KL. Pathology of hypertensive arteriopathy. Neurosurg Clin N Am 1992; 3:497. 25. Folsom AR, Yatsuya H, Mosley TH Jr, et al. Risk of intraparenchymal hemorrhage with magnetic resonance imaging-defined leukoaraiosis and brain infarcts. Ann Neurol 2012; 71:552. 26. Offenbacher H, Fazekas F, Schmidt R, et al. MR of cerebral abnormalities concomitant with primary intracerebral hematomas. AJNR Am J Neuroradiol 1996; 17:573. 27. Cheng AL, Batool S, McCreary CR, et al. Susceptibility-weighted imaging is more reliable than T2-weighted gradient-recalled echo MRI for detecting microbleeds. Stroke 2013; 44:2782. 28. Meretoja A, Strbian D, Putaala J, et al. SMASH-U: a proposal for etiologic classification of intracerebral hemorrhage. Stroke 2012; 43:2592. 29. Delgado Almandoz JE, Schaefer PW, Goldstein JN, et al. Practical scoring system for the identification of patients with intracerebral hemorrhage at highest risk of harboring an underlying vascular etiology: the Secondary Intracerebral Hemorrhage Score. AJNR Am J Neuroradiol 2010; 31:1653. 30. van Asch CJ, Velthuis BK, Greving JP, et al. External validation of the secondary intracerebral hemorrhage score in The Netherlands. Stroke 2013; 44:2904. 31. Gross BA, Jankowitz BT, Friedlander RM. Cerebral Intraparenchymal Hemorrhage: A Review. JAMA 2019; 321:1295. 32. Mallon D, Doig D, Dixon L, et al. Neuroimaging in Sickle Cell Disease: A Review. J Neuroimaging 2020; 30:725. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 25/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate 33. Steiner T, Al-Shahi Salman R, Beer R, et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke 2014; 9:840. 34. Feigin VL, Lawes CM, Bennett DA, et al. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 2009; 8:355. 35. Sacco S, Marini C, Toni D, et al. Incidence and 10-year survival of intracerebral hemorrhage in a population-based registry. Stroke 2009; 40:394. 36. Gebel JM, Broderick JP. Intracerebral hemorrhage. Neurol Clin 2000; 18:419. 37. Flaherty ML, Woo D, Haverbusch M, et al. Racial variations in location and risk of intracerebral hemorrhage. Stroke 2005; 36:934. 38. Labovitz DL, Halim A, Boden-Albala B, et al. The incidence of deep and lobar intracerebral hemorrhage in whites, blacks, and Hispanics. Neurology 2005; 65:518. 39. van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010; 9:167. 40. Poon MT, Bell SM, Al-Shahi Salman R. Epidemiology of Intracerebral Haemorrhage. Front Neurol Neurosci 2015; 37:1. 41. Broderick JP, Brott T, Tomsick T, et al. Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg 1993; 78:188. 42. Stein M, Misselwitz B, Hamann GF, et al. Intracerebral hemorrhage in the very old: future demographic trends of an aging population. Stroke 2012; 43:1126. 43. Krishnamurthi RV, Feigin VL, Forouzanfar MH, et al. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet Glob Health 2013; 1:e259. 44. Bruno A, Carter S, Qualls C, Nolte KB. Incidence of spontaneous intracerebral hemorrhage among Hispanics and non-Hispanic whites in New Mexico. Neurology 1996; 47:405. 45. Morgenstern LB, Smith MA, Lisabeth LD, et al. Excess stroke in Mexican Americans compared with non-Hispanic Whites: the Brain Attack Surveillance in Corpus Christi Project. Am J Epidemiol 2004; 160:376. 46. Gokhale S, Caplan LR, James ML. Sex differences in incidence, pathophysiology, and outcome of primary intracerebral hemorrhage. Stroke 2015; 46:886. 47. Appelros P, Stegmayr B, Ter nt A. Sex differences in stroke epidemiology: a systematic review. Stroke 2009; 40:1082. 48. Woo D, Sauerbeck LR, Kissela BM, et al. Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. 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Oleinik A, Romero JM, Schwab K, et al. CT angiography for intracerebral hemorrhage does not increase risk of acute nephropathy. Stroke 2009; 40:2393. Topic 1133 Version 39.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 34/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate GRAPHICS Typical locations of intracerebral hemorrhage Typical locations of hypertensive ICH are putamen (A), thalamus (B), subcortical white matter (C), pons (D) and cerebellum (E). Thalamic and subcortical hemorrhages often extend into ventricles (B and C). Cerebral amyloid angiopathy, drug abuse, or vascular anomaly often causes lobar hemorrhage (F). ICH: intracerebral hemorrhage. Reproduced with permission from: Dastur CK, Yu W. Current management of spontaneous intracerebral haemorrhage. Stroke Vasc Neurol 2017; 2(1):21-29. Copyright 2017 BMJ Publishing Group Ltd. Graphic 118071 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 35/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Distinctive distribution of cerebral microbleeds (A-C) CMBs on T2-weighted gradient echo MRI sequences suggestive of deep penetrating (hypertensive) vasculopathy. CMBs predominate in bilateral thalami (A), brainstem (B), and dentate nucleus of cerebellum (C). (D-F) CMBs on T2-weighted gradient echo MRI sequences suggestive of cerebral amyloid angiopathy. CMBs predominate in cerebral hemispheres (D, E). Associated findings include lobar hemorrhage (D; arrow and thick arrow) and superficial siderosis (F; circles). CMB: cerebral microbleeds; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 36/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Graphic 132282 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 37/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Lobar hemorrhage in cerebral amyloid angiopathy Acute superficial lobar hemorrhage in the left frontal lobe seen on computed tomography scan in a patient with cerebral amyloid angiopathy (A). Flair magnetic resonance image performed one week later shows the high signal intensity of subacute hemorrhage with surrounding edema extending into the subcortical white matter (B). Hemorrhage (now low signal intensity consistent with hemosiderin) and edema are mostly resolved on a three-month follow-up study (C). Courtesy of Eric D Schwartz, MD. Graphic 50480 Version 4.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 38/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate MRI of brain arteriovenous malformation T2-weighted MRI of the brain demonstrates multiple flow voids in the right hemisphere, suggestive of a large arteriovenous malformation. MRI: magnetic resonance imaging. From: Flemming KD, Lanzino G. Management of Unruptured Intracranial Aneurysms and Cerebrovascular Malformations. Continuum (Minneap Minn) 2017; 23:181. DOI: 10.1212/CON.0000000000000418. Copyright 2017 American Academy of Neurology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 53992 Version 6.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 39/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Cerebellar hematoma due to ruptured AVM (A) Noncontrast head CT showing acute right cerebellar ICH with smaller adjacent focus of hemorrhage (black arrow). (B) Subsequent FLAIR sequence on brain MRI after decompressive craniectomy showing flow void (white arrow) adjacent to ICH (white dashed arrow). (C) Digital subtraction angiogram subsequently identified an AVM with a nidus (white arrowhead), feeding artery (white thick arrow), and draining vein (white short arrow). CT: computed tomography; ICH: intracerebral hemorrhage; FLAIR: fluid-attenuated inversion recovery; MRI: magnetic resonance imaging; AVM: arteriovenous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 132273 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 40/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Intracerebral hemorrhage due to cerebral sinus thrombosis Noncontrast head CT showing left frontal ICH (arrow) and vasogenic edema (arrowhead) (A). Mid-sagittal plane on CT angiography (B) and MRV (C) showing filling defect (thick arrows) in superior sagittal sinus (B). Subsequent brain MRI with FLAIR (D) and T2 gradient recall echo (E) imaging showing larger ICH (arrows) and associated edema (arrowheads). ICH: intracerebral hemorrhage; CT: computed tomography; MRV: magnetic resonance venography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery. Courtesy of Glenn A Tung, MD, FACR. Graphic 132274 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 41/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Hemorrhagic transformation of ischemic infarction Noncontrast head CT (A) shows heterogeneous hyperdensity within hypodense region involving right frontal and insular lobes. On subsequent MRI of the brain, FLAIR (B), T2* gradient recall echo (C), and DWI (D) sequences show hypointense ICH (thin arrows) and hyperintensities consistent with acute infarction in the distribution of the right middle cerebral artery (thick arrows). CT: computed tomography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted imaging; ICH: intracerebral hemorrhage. Courtesy of Glenn A Tung, MD, FACR. Graphic 132275 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 42/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Brain lesions in reversible cerebral vasoconstriction syndrome Representative brain images from patients with RCVS are shown to highlight different lesion patterns. The numbers in parenthesis show the percentages of the lesion patterns; totals exceed 100% due to lesion combinations. (A) No acute parenchymal lesion (24%). Normal axial DWI, GRE, and FLAIR images are shown. The hyperintense dot sign is present on FLAIR (far right, arrow). (B) Border zone/watershed infarcts (25%). On the far left, DWI shows typical symmetric, posterior infarcts that spare the cortical ribbon. In https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 43/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate the middle and on the far right, DWI shows widespread watershed infarcts. (C) Vasogenic edema (28%). Subcortical crescent-shaped T2- hyperintense lesions consistent with the posterior reversible encephalopathy syndrome are seen on FLAIR. (D) Hemorrhagic lesions (42%). The two images on the left (axial GRE) show simultaneous lobar and deep intraparenchymal hemorrhages. The two images on the right show convexal subarachnoid hemorrhages on CT and axial GRE. (E) Lesion combinations (28%). The two images on the left show bilateral watershed infarcts on DWI and the two images on the right show lobar as well as convexal subarachnoid hemorrhages on axial FLAIR and CT, all in the same patient. RCVS: reversible cerebral vasoconstriction syndrome; DWI: diffusion- weighted images; GRE: gradient-echo; FLAIR: fluid-attenuated inversion recovery; CT: computed tomography. From: Singhal AB, Topcuoglu MA, Fok JW, et al. Reversible cerebral vasoconstriction syndromes and primary angiitis of the central nervous system: clinical, imaging, and angiographic comparison. Ann Neurol 2016; 79:882. http://onlinelibrary.wiley.com/wol1/doi/10.1002/ana.24652/abstract. Copyright 2016 American Neurological Association. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: permissions@wiley.com or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (http://onlinelibrary.wiley.com). Graphic 109962 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 44/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Excessive perihematomal edema in a patient with hemorrhagic lung metastasis Noncontrast head CT showing left frontal ICH surrounded by excessive volume of hypodense vasogenic edema (A, B). MRI performed one day later shows hyperintense vasogenic edema on T2*-weighted gradient echo image (C). Pre- (D) and post-contrast (E) T1-weighted MRI images demonstrate enhancement (arrows) consistent with underlying tumor. CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132284 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 45/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Intracerebral hemorrhage due to mycotic aneurysm Noncontrast head CT (A) showing small right parietal ICH (circle). CT angiogram in axial (B) and coronal (C) planes showing small mycotic aneurysm (arrow) adjacent to ICH (circle). CT: computed tomography; ICH: intracerebral hemorrhage. Courtesy of Glenn A Tung, MD, FACR. Graphic 132276 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 46/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate 12-year-old with moyamoya syndrome secondary to neurofibromatosis type 1 Magnetic resonance angiogram shows occlusion of left supraclinoid internal carotid artery (circles) and lentic collateral vessels (arrow). Courtesy of Glenn A Tung, MD, FACR. Graphic 129107 Version 3.0
MRI: magnetic resonance imaging. From: Flemming KD, Lanzino G. Management of Unruptured Intracranial Aneurysms and Cerebrovascular Malformations. Continuum (Minneap Minn) 2017; 23:181. DOI: 10.1212/CON.0000000000000418. Copyright 2017 American Academy of Neurology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 53992 Version 6.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 39/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Cerebellar hematoma due to ruptured AVM (A) Noncontrast head CT showing acute right cerebellar ICH with smaller adjacent focus of hemorrhage (black arrow). (B) Subsequent FLAIR sequence on brain MRI after decompressive craniectomy showing flow void (white arrow) adjacent to ICH (white dashed arrow). (C) Digital subtraction angiogram subsequently identified an AVM with a nidus (white arrowhead), feeding artery (white thick arrow), and draining vein (white short arrow). CT: computed tomography; ICH: intracerebral hemorrhage; FLAIR: fluid-attenuated inversion recovery; MRI: magnetic resonance imaging; AVM: arteriovenous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 132273 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 40/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Intracerebral hemorrhage due to cerebral sinus thrombosis Noncontrast head CT showing left frontal ICH (arrow) and vasogenic edema (arrowhead) (A). Mid-sagittal plane on CT angiography (B) and MRV (C) showing filling defect (thick arrows) in superior sagittal sinus (B). Subsequent brain MRI with FLAIR (D) and T2* gradient recall echo (E) imaging showing larger ICH (arrows) and associated edema (arrowheads). ICH: intracerebral hemorrhage; CT: computed tomography; MRV: magnetic resonance venography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery. Courtesy of Glenn A Tung, MD, FACR. Graphic 132274 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 41/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Hemorrhagic transformation of ischemic infarction Noncontrast head CT (A) shows heterogeneous hyperdensity within hypodense region involving right frontal and insular lobes. On subsequent MRI of the brain, FLAIR (B), T2* gradient recall echo (C), and DWI (D) sequences show hypointense ICH (thin arrows) and hyperintensities consistent with acute infarction in the distribution of the right middle cerebral artery (thick arrows). CT: computed tomography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted imaging; ICH: intracerebral hemorrhage. Courtesy of Glenn A Tung, MD, FACR. Graphic 132275 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 42/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Brain lesions in reversible cerebral vasoconstriction syndrome Representative brain images from patients with RCVS are shown to highlight different lesion patterns. The numbers in parenthesis show the percentages of the lesion patterns; totals exceed 100% due to lesion combinations. (A) No acute parenchymal lesion (24%). Normal axial DWI, GRE, and FLAIR images are shown. The hyperintense dot sign is present on FLAIR (far right, arrow). (B) Border zone/watershed infarcts (25%). On the far left, DWI shows typical symmetric, posterior infarcts that spare the cortical ribbon. In https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 43/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate the middle and on the far right, DWI shows widespread watershed infarcts. (C) Vasogenic edema (28%). Subcortical crescent-shaped T2- hyperintense lesions consistent with the posterior reversible encephalopathy syndrome are seen on FLAIR. (D) Hemorrhagic lesions (42%). The two images on the left (axial GRE) show simultaneous lobar and deep intraparenchymal hemorrhages. The two images on the right show convexal subarachnoid hemorrhages on CT and axial GRE. (E) Lesion combinations (28%). The two images on the left show bilateral watershed infarcts on DWI and the two images on the right show lobar as well as convexal subarachnoid hemorrhages on axial FLAIR and CT, all in the same patient. RCVS: reversible cerebral vasoconstriction syndrome; DWI: diffusion- weighted images; GRE: gradient-echo; FLAIR: fluid-attenuated inversion recovery; CT: computed tomography. From: Singhal AB, Topcuoglu MA, Fok JW, et al. Reversible cerebral vasoconstriction syndromes and primary angiitis of the central nervous system: clinical, imaging, and angiographic comparison. Ann Neurol 2016; 79:882. http://onlinelibrary.wiley.com/wol1/doi/10.1002/ana.24652/abstract. Copyright 2016 American Neurological Association. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: permissions@wiley.com or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (http://onlinelibrary.wiley.com). Graphic 109962 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 44/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Excessive perihematomal edema in a patient with hemorrhagic lung metastasis Noncontrast head CT showing left frontal ICH surrounded by excessive volume of hypodense vasogenic edema (A, B). MRI performed one day later shows hyperintense vasogenic edema on T2-weighted gradient echo image (C). Pre- (D) and post-contrast (E) T1-weighted MRI images demonstrate enhancement (arrows) consistent with underlying tumor. CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132284 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 45/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Intracerebral hemorrhage due to mycotic aneurysm Noncontrast head CT (A) showing small right parietal ICH (circle). CT angiogram in axial (B) and coronal (C) planes showing small mycotic aneurysm (arrow) adjacent to ICH (circle). CT: computed tomography; ICH: intracerebral hemorrhage. Courtesy of Glenn A Tung, MD, FACR. Graphic 132276 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 46/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate 12-year-old with moyamoya syndrome secondary to neurofibromatosis type 1 Magnetic resonance angiogram shows occlusion of left supraclinoid internal carotid artery (circles) and lentic collateral vessels (arrow). Courtesy of Glenn A Tung, MD, FACR. Graphic 129107 Version 3.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 47/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate 40-year-old with moyamoya disease Digital subtraction angiogram shows stenosis of right supraclinoid carotid, proximal middle cerebral artery a artery (oval), and lenticulostriate moyamoya collateral vessels (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129102 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 48/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Intracerebral hemorrhage with intraventricular hemorrhage due to moyamoya syndrome Noncontrast head CT (A) showing hematoma in the right corpus striatum and lateral ventricles. Digital subtraction angiogram (B) showing critical stenosis of proximal right middle cerebral artery (arrow), prominent collateralization of both lenticulostriate vessels (circle), and branches of the anterior cerebral artery (thick arrows). CT: computed tomography. Courtesy of Glenn A Tung, MD, FACR. Graphic 132277 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 49/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Acute spontaneous intracerebral hemorrhage: Rapid overview of emergency management Clinical features Stroke symptoms: sudden onset loss of function in speech, vision, movement, sensation, balance Features suggestive of ICH over ischemic stroke: progressive worsening of acute symptoms; severely elevated SBP (eg, >220 mmHg); patient taking anticoagulant Signs of elevated ICP (mass effect from ICH): Dilated pupil Progressive drowsiness Cushing triad (bradycardia, respiratory depression, hypertension) Evaluation Assess airway, breathing, circulation, and disability to initiate supportive care Determine GCS, neurologic deficits Obtain emergency imaging (eg, head CT or fast MRI) Initial laboratory evaluation: complete blood count, PT, PTT, INR, basic electrolytes, glucose, cardiac-specific troponin, pregnancy test in females of childbearing age Serial monitoring (hourly) for neurologic deterioration or signs of elevated ICP Treatment Perform tracheal intubation for any patient unable to protect their airway or with rapidly deteriorating mental status or GCS 8 Obtain immediate neurosurgical consultation for imaging findings indicating need for emergency surgery: 3 Cerebellar ICH that is either 3 cm diameter or causing brainstem compression IVH with obstructive hydrocephalus and neurologic deterioration Hemispheric ICH with life-threatening brain compression or obstructive hydrocephalus Reverse anticoagulation (agent specific): Warfarin (4-factor PCC with IV vitamin K) Dabigatran (idaricizumab) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 50/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Factor Xa inhibitors: apixaban, edoxaban, rivaroxaban (4-factor PCC or andexanet alfa) Unfractionated heparin (protamine sulfate) Low molecular weight heparin (andexanet alfa; protamine sulfate is an alternative) Manage hypertension: Immediate treatment to reduce SBP below 220 mmHg: nicardipine starting at 5 mg/hour IV; alternate: labetalol 20 mg IV bolus, may repeat every 10 minutes Subsequent, stepwise treatment, typically over first 1 to 2 hours, to reduce SBP to 140 to 160 mmHg; monitor for neurologic deterioration Manage elevated intracranial pressure: General preventive measures: Elevate head of bed >30 degrees Give mild sedation as needed for comfort for intubated patients (eg, midazolam) Give antipyretics for temperature >38 C (eg, acetaminophen [paracetamol] 325 to 650 mg orally or PR every 4 to 6 hours or 650 mg IV every 4 hours) Maintain neutral head positioning; avoid rotating the neck or placing IV lines or devices in or at the neck that may impede venous outflow Use isotonic solutions for volume resuscitation and maintenance fluids; maintain serum sodium >135 mEq/L Repeat imaging (eg, head CT) for neurologic deterioration or signs of elevated ICP: Obtain immediate neurosurgical consultation for surgical indications (refer to above) Give osmotic therapy via central venous catheter for clinical signs or imaging findings of elevated ICP: Hypertonic saline 23.4%: 15 to 30 mL IV bolus every 6 hours, or Mannitol: 0.25 to 1 g/kg IV bolus every 6 hours ICH: intracerebral hemorrhage; SBP: systolic blood pressure; ICP: intracranial pressure; GCS: Glasgow coma scale; CT: computed tomography; MRI: magnetic resonance imaging; PT: prothrombin time; PTT: partial thromboplastin time; INR: international normalized ratio; IVH: intraventricular hemorrhage; PCC: prothrombin complex concentrate; IV: intravenous; PR: per rectum. Treatment steps for the acute management of ICH may be performed in parallel if resources are available. Graphic 132288 Version 5.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 51/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Time course of neurologic changes in intracerebral hemorrhage Schematic representation of rapid downhill course in terms of unusual behavior (solid line), hemimotor function (dotted line), and consciousness (dash-dotted line) in a patient with intracerebral (intraparenchymal) hemorrhage. Graphic 61491 Version 3.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 52/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Headache and vomiting in stroke subtypes The frequency of sentinel headache, onset headache, and vomiting in three subtypes of stroke: subarachnoid hemorrhage, intraparenchymal (intracerebral) hemorrhage, and ischemic stroke. Onset headache was present in virtually all patients with SAH and about one-half of those with IPH; all of these symptoms were infrequent in patients with IS. SAH: subarachnoid hemorrhage; IPH: intraparenchymal (intracerebral) hemorrhage; IS: ischemic stroke. Data from: Gorelick PB, Hier DB, Caplan LR, Langenberg P. Headache in acute cerebrovascular disease. Neurology 1986; 36:1445. Graphic 60831 Version 4.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 53/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate CT and MRI scans of hyperacute intracerebral hemorrhage CT and MRI studies were obtained less than six hours from symptom onset in a patient with spontaneous acute intracerebral hemorrhage. The CT scan shows a hyperdense hemorrhage predominantly in the left frontal lobe. On MRI, the central portion of the hematoma is isointense to brain parenchyma on the T1-weighted image and hyperintense on the T2-weighted and T2* gradient echo images, consistent with hemorrhage containing oxyhemoglobin. On the T2-weighted and T2* gradient echo images, the periphery of the hemorrhage is hypointense, consistent with deoxygenation that occurs more rapidly at the borders. On the T2 weighted image, tissue adjacent to and surrounding the hematoma is hyperintense, consistent with vasogenic edema. CT: computed tomography; MRI: magnetic resonance imaging; ICH: https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 54/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate intracerebral hemorrhage. Graphic 81767 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 55/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Evolution of intracerebral hemorrhage on head CT over time Noncontrast head CT (A-F) of putaminal ICH with IVH showing typical reduced centripetal density and size over time. Imaging performed at days 1 (A), 14 (B), 19 (C), 24 (D), 40 (E), and 50 (F). ICH: intracerebral hemorrhage; CT: computed tomography; IVH: intraventricular hemorrhage. Courtesy of Glenn A Tung, MD, FACR. Graphic 132278 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 56/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Temporal evolution of intracerebral hematoma on MRI Hemoglobin Descriptor Approximate age T1 T2 moiety iso or Hyperacute Oxy <3 hours iso or Acute Deoxy <3 days Early subacute Intracellular met 3 to 13 days Late subacute Extracellular met <3 weeks iso or Chronic Hemosiderin/ferritin >3 weeks MRI: magnetic resonance imaging; T1: T1-weighted sequence; T2: T2-weighted sequence; oxy: oxyhemoglobin; iso: isointense or same signal intensity as brain; : hypointense compared with normal brain; : hyperintense compared with normal brain; deoxy: deoxyhemoglobin; met: methemoglobin. Courtesy of Glenn A Tung, MD, FACR. Graphic 132279 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 57/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Clinical and neuroimaging features of intracerebral hemorrhage associated with underlying causes Alternative Specifying ICH Characteristic Other associated features underlying feature underlying cause causes Basal ganglia or Deep perforating CMBs in basal ganglia, thalamus, pons, cerebellar brainstem location vasculopathy (HTN) nuclei Subcortical white matter lesions on MRI Deep perforating territory ischemic infarcts Clinical history of HTN or diabetes mellitus Lobar location Cerebral amyloid angiopathy Deep penetrating vasculopathy (HTN) Cortico-subcortical CMBs Convexal superficial siderosis Clinical history of cognitive impairment Intraventricular hemorrhage Arteriovenous malformation Deep penetrating vasculopathy (HTN) Flow voids within or adjacent to ICH Calcification within or adjacent to ICH Cavernous malformation Small ICH with adjacent calcification Cavernous malformation Deep penetrating vasculopathy (HTN) T2-weighted image hyperintensity at center on MRI Peripheral rim of T2- weighted gradient echo image hypointensity on MRI Subarachnoid Ruptured cerebral Perimesencephalic SAH predominates over basal surfaces hemorrhage Basal cisterns aneurysm hemorrhage Clinical history of Non-aneurysmal SAH thunderclap headache Subarachnoid hemorrhage Reversible cerebral vasoconstriction Trauma Hemispheric or cortical ICH Clinical history of recurrent thunderclap headache Cerebral amyloid Convexity syndrome angiopathy Cerebral venous thrombosis https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 58/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Arteriovenous malformation Simultaneous Infective endocarditis Cerebral amyloid CMBs acute infarcts angiopathy Mycotic aneurysms (typically distal arterial locations) Deep penetrating vasculopathy (HTN) Systemic/cutaneous evidence of embolism New heart murmur Cerebral vasculitis Multifocal segmental narrowing on vascular imaging Clinical history of new persistent headaches Progressive cognitive or other neurologic impairment Prominent edema Cerebral sinus thrombosis Subacute ICH of other etiologies Edema/hemorrhage extends to cortical surface Venous flow void (eg, delta and empty-delta signs) Clinical history of seizure or progressive headache Tumor (primary/metastatic) Multifocal lesions Contrast enhancement Clinical history of new persistent headaches Clinical exam findings may be milder than imaging abnormalities Hemorrhagic transformation of (Cytotoxic) Edema appears in distribution of arterial territory infarct Arterial stenosis or occlusion proximal to territory of hemorrhage Clinical history of ischemic risk factors Flow voids Moyamoya Arteriovenous malformation Basal ganglia or hemispheric location Bilateral (but may be asymmetric) narrowing of distal internal carotid or https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 59/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate proximal anterior/middle cerebral arteries Clinical history of episodes of transient weakness with vigorous laughing/crying (Prominent cause of ICH and infarcts in children) ICH: intracerebral hemorrhage; HTN: hypertension; CMB: cerebral microbleeds; MRI: magnetic resonance imaging; SAH: subarachnoid hemorrhage. Graphic 132289 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 60/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Restricted diffusion associated with acute ICH Axial diffusion-weighted image (DWI) on brain MRI (A) and corresponding apparent diffusion coefficient (ADC image (B) showing hyperintense DWI and hypointense ADC foci (arrows) suggestive of acute ischemia associ with acute ICH (arrowheads). ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging. Courtesy of Scott A Kasner, MD. Graphic 141459 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 61/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate ABC/2 method for estimating intracerebral hemorrhage volume Acute left basal ganglia hemorrhage measured by the ABC/2 method. A is 6 cm, B is 4 cm, and C is 3 cm (hematoma is seen on 12 slices [10 full and 4 half] with a slice thickness of 0.25 cm). Hematoma volume is 36 cc ([6 4 3]/2). rd Reproduced from: Thabet AM, Kottapally M, Hemphill JC 3 . Management of intracerebral hemorrhage. Handb Clin Neurol 2017; 140:177. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 118213 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 62/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate CT angiography "spot sign" Patient with spot sign, demonstrating extravasation and hematoma expansion. CT slice selection has been optimized for hematoma configuration, not for head position. (A) Unenhanced CT demonstrates left posterior putaminal and internal capsule hematoma with mild surrounding edema. An old parieto-occipital infarct is seen posterior to this. (B) A small focus of enhancement is seen peripherally on CTA source images, consistent with the spot sign (arrow). https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 63/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate (C) Post-contrast CT demonstrates enlargement of the spot sign, consistent with extravasation (thick arrow). (D) Unenhanced CT image one day after presentation reveals hematoma enlargement and intraventricular hemorrhage. CT: computed tomography; CTA: computed tomography angiography. From: Wada R, Aviv RI, Fox AJ, et al. CT angiography "spot sign" predicts hematoma expansion in acute intracerebral hemorrhage. Stroke 2007; 38:1257. Copyright 2007 American Heart Association, Inc. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 118220 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 64/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate ICH features on head CT associated with the risk of hematoma expansion Noncontrast head CT showing acute ICH with signs associated with the risk of subsequent hematoma expansion: irregular shape (A), island sign (B; arrow), hypodensity (C; dashed arrow), heterogeneity (D), black hole sign (E; thick arrow), swirl sign (F), and blend sign (G; arrowhead). ICH: intracerebral hemorrhage; CT: computed tomography. Courtesy of Glenn A Tung, MD, FACR. Graphic 132280 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 65/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Multifocal intracerebral hemorrhage from thyroid cancer Noncontrast head CT (A) shows multiple hyperdensities (arrows). T2-weighted gradient echo MRI images show that some but not all lesions are hypointense hemorrhages (B, C). Pre- (D) and post-contrast (E) T1- weighted MRI images show contrast enhancement consistent with metastases. ICH: intracerebral hemorrhage; CT: computed tomography; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132287 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 66/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Intraventricular hemorrhage due to ruptured periventricular arteriovenous malformation Noncontrast head CT (A) showing IVH. CT angiogram (B) showing abnormal tangle of vessels (circle) in the left perisplenial region. Digital subtraction angiogram (C) showing AVM nidus (circle). CT: computed tomography; IVH: intraventricular hemorrhage; AVM: arteriovenous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 132281 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 67/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Evaluating the underlying etiology of nontraumatic intracerebral hemorrhage This is an algorithm to guide etiologic testing; additional testing may be indicated for patients who develop new or worsening symptoms during recovery period. Refer to the UpToDate topic on secondary prevention and long-term prognosis of spontaneous intracerebral hemorrhage for additional details. ICH: intracerebral hemorrhage. Refer to the separate UpToDate table on clinical and neuroimaging features of intracerebral hemorrhage associated with underlying causes. Lobar or cortical ICH, evidence of multifocal superficial siderosis, age 55 years, and other sources for hemorrhagic features excluded. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 68/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Refer to the UpToDate topic on cerebral amyloid angiopathy for additional details. Graphic 132295 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 69/70 7/5/23, 12:25 PM Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis - UpToDate Contributor Disclosures Guy Rordorf, MD No relevant financial relationship(s) with ineligible companies to disclose. Colin McDonald, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Jonathan A Edlow, MD, FACEP No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator-initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis/print 70/70
7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis : Magdy Selim, MD, PhD : Scott E Kasner, MD, Alejandro A Rabinstein, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 07, 2022. INTRODUCTION Spontaneous intracerebral hemorrhage (ICH) is often associated with long-term neurologic symptoms, and patients with ICH have an elevated risk of recurrence. Prevention of recurrent ICH (ie, secondary prevention) may reduce accumulating neurologic disability as well as societal burden of ICH. ICH may be categorized as either spontaneous or traumatic. ICH following traumatic brain injury is reviewed separately. (See "Traumatic brain injury: Epidemiology, classification, and pathophysiology".) This topic will review the epidemiology, secondary prevention, and long-term prognosis in adults with spontaneous ICH. Other aspects of ICH are discussed elsewhere. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) (See "Cerebral amyloid angiopathy".) (See "Hemorrhagic stroke in children".) (See "Stroke in the newborn: Management and prognosis".) RISK OF RECURRENCE https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 1/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Incidence The incidence of recurrent ICH varies from 2 to 7 percent per year, depending on risk factors [1,2]. Patients with a history of ICH have a risk of recurrent ICH that is higher than the risk of recurrence in patients with ischemic stroke [1-3]. In addition, the rate of recurrent ICH was 6.6-fold higher than for a first ICH in a study of patients with prior ischemic stroke [1]. The risk of ICH recurrence may be highest in the first 12 months after the initial ICH but persists for years after the first event, particularly after lobar ICH [4]. The cumulative risk of ICH recurrence varies from 1.3 to 8.9 percent after one year and ranges from 7.4 to 13.7 percent after five years in different populations [2,3,5,6]. Risk factors Initial ICH location and etiology Deep (nonlobar) ICH involving the basal ganglia, thalamus, cerebellum, or brainstem is associated with a lower risk of recurrence than ICH in lobar locations. The annual risk of ICH recurrence after deep ICH is approximately 2 to 3 percent, versus 7 to 14 percent after lobar ICH [2,7-9]. ICH involving deep nuclei is often attributed to hypertensive microvascular disease and lobar ICH is often attributed to cerebral amyloid angiopathy (CAA), but the risk of recurrence appears to be independent of ICH etiology, at least in part. CAA is a major cause of incident and recurrent lobar ICH [10]. A meta-analysis of 10 prospective cohorts of ICH patients found that the annual risk of ICH recurrence after CAA- related ICH was 7.4 percent (95% CI 3.2-12.6), versus 1.1 percent (95% CI 0.5-1.7) for non- CAA-related ICH [11]. (See "Cerebral amyloid angiopathy".) Other secondary causes of ICH, such as brain arteriovenous malformation, moyamoya syndrome, sickle cell disease, and brain tumors are also associated with elevated risks of recurrent ICH based on the nature of the underlying causes and the presence of specific associated high-risk features. These are discussed separately. (See "Brain arteriovenous malformations" and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis" and "Prevention of stroke (initial or recurrent) in sickle cell disease" and "Overview of the clinical features and diagnosis of brain tumors in adults".) Other imaging features The presence and number of cerebral microbleeds (CMBs) and/or superficial siderosis on brain magnetic resonance imaging (MRI) identifies patients at high risk for recurrent ICH [11,12]. In one study, the presence of >1 CMB was associated with increased risk of recurrent ICH in patients with CAA-related ICH while a higher threshold, >10 CMBs, identified increased risk of a recurrent event in patients with non- CAA-related ICH [11]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 2/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Hyperintensities on diffusion-weighted imaging (DWI) brain MRI sequences found in some patients with ICH may be a marker of severe small-vessel disease associated with the risk of ICH recurrence [13,14]. In one study of 247 patients with ICH, those with DWI hyperintensities had a higher risk of recurrent ICH but not subsequent ischemic stroke at two years [15]. Hypertension Hypertension (HTN) is the most consistent risk factor for ICH recurrence. HTN predisposes to ICH recurrence of both deep and lobar ICH [4]. Inadequate control of HTN is common and increases the risk of recurrent ICH [4,16,17]. In a longitudinal study of 1145 patients with ICH, each 10 mmHg increase in systolic blood pressure was associated with an incremental increase in risk of recurrent lobar ICH (hazard ratio [HR] 1.33, 95% CI 1.02-1.76) and recurrent deep ICH (HR 1.54, 95% CI 1.03-2.30) [18]. The risks of ICH related to inadequate blood pressure control and management to mitigate these risks are discussed below. (See 'Blood pressure management' below.) Age The risk of ICH recurrence with age is based largely on the association of advancing age with the risk of initial ICH [19]. A meta-analysis of more than 8100 patients with ICH assessed the age-related incidence of ICH over a 28-year period [20]. Using the age group of 45 to 54 years as reference, the incidence ratio increased from 0.10 (95% CI 0.06-0.14) for those under 45 years up to 9.6 (95% CI 6.6-13.9) for patients older than 85 years. These findings are likely true for ICH recurrence as well. Older age is also associated with higher prevalence of CAA and higher use of antithrombotic drugs for accumulating cardiovascular comorbidities. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) Medications Antithrombotic medications (including antiplatelet agents and anticoagulants) and statins may be associated with risk of ICH recurrence. In addition, several other substances including selective serotonin reuptake inhibitors and nonsteroidal anti-inflammatory drugs have been linked to increased risk of bleeding in general, including ICH and ICH recurrence ( table 1). However, studies examining the associations between these drugs and risk of ICH recurrence have yielded inconsistent results [3,18,21,22]. The potential risks of recurrent ICH due to antithrombotic and statin medications are discussed below. (See 'Management of antithrombotic therapy' below and 'Management of statins' below.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 3/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Other risk factors Race and ethnicity There are racial and ethnic disparities in the risk of ICH recurrence. Black American, Hispanic American, and Asian American patients with a history of ICH seem to be at higher risk for a recurrent event than White American patients [16,23]. The prevalence of HTN in these groups does not fully account for this elevated risk of ICH. In one study, patients remained at higher risk of ICH recurrence after adjusting for blood pressure measurements and variability [16]. Chronic kidney disease Chronic kidney disease can be a marker of atherosclerotic disease and may further contribute to the risk of ICH through renally mediated impairment of cerebral autoregulation [24]. A large population-based study in Denmark evaluated 15,270 patients with ICH and found that patients with kidney failure at the time of the initial ICH were at higher risk for ICH recurrence (relative risk 1.72, 95% CI 1.34-2.17) [3]. Prior ischemic stroke or ICH The risk of a future ICH is higher in patients with history of prior ICH and those with history of a prior ischemic stroke [1]. Genetic features Certain genetic features associated with CAA are associated with increased risk of ICH recurrence [25]. Patients with ICH who are carriers of apolipoprotein-E (APOE) e2 or e4 genotypes, frequently associated with CAA, are at elevated risk of ICH [9]. Additionally, patients with genetic bleeding disorders also are at risk for ICH. These disorders are discussed separately. (See "Clinical presentation and diagnosis of von Willebrand disease" and "Clinical manifestations and diagnosis of hemophilia" and "Rare inherited coagulation disorders".) FOLLOW-UP NEUROIMAGING All patients whose symptoms unexpectedly fail to improve or worsen during the recovery period require neuroimaging to evaluate for a recurrent hemorrhage. In addition, follow-up imaging studies can help to identify or confirm the cause of the ICH, which in turn determines the risk of recurrence and may help guide preventive measures. For some patients, neuroimaging studies performed during the acute hospitalization identify the etiology such that further imaging studies are not required. For other patients, the initial imaging study does not sufficiently exclude other causes of ICH and follow-up studies are required. When acute https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 4/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate bleeding and surrounding edema from the acute ICH shroud and distort underlying brain structures, delayed imaging performed after bleeding and edema have resolved may identify patients who are at high risk for recurrence due to an underlying structural cause ( algorithm 1). (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Subsequent imaging'.) Patients with suspected hypertensive ICH Patients with ICH attributed to hypertension (HTN) who continue to improve clinically during recovery may not warrant additional imaging. Clinical and imaging features on head computed tomography (CT) or brain magnetic resonance imaging (MRI) suggestive of hemorrhage related to HTN or other atherosclerotic risk factors associated with deep penetrating vasculopathy include: Hematoma or cerebral microbleeds (CMBs) in basal ganglia or thalamus, cerebellar nuclei, or brainstem ( image 1) Known history or new diagnosis of HTN No prior ICH (unless in setting of uncontrolled HTN) No atypical clinical or neuroimaging features ( table 2) Patient age 65 years Clinically stable patients who meet most or all of the criteria listed above likely do not require a follow-up imaging study. For patients with only some of these features, we suggest repeating a brain MRI with gadolinium contrast in 12 to 16 weeks after the ICH to assess for alternative secondary causes. Additional associated imaging features found in some patients with a hypertensive ICH include evidence of prior chronic ischemic stroke attributed to small vessel (penetrating artery) and CMBs located in the basal ganglia or thalamus evident on T2-weighted brain MRI sequences. Patients with suspected CAA-related ICH Some patients with ICH attributed to cerebral amyloid angiopathy (CAA) whose symptoms continue to improve during recovery may not require additional imaging in the ambulatory setting. Imaging features on brain MRI suggestive of ICH related to CAA include lobar location and evidence of lobar CMBs or cortical superficial siderosis in an older patient ( image 1 and image 2). The approach to confirming that diagnosis is discussed separately. (See "Cerebral amyloid angiopathy", section on 'Diagnostic approach'.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 5/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Other patients We obtain follow-up imaging for patients with clinical or imaging features of the ICH suggestive of an underlying cause but not identified or excluded during the acute hospitalization ( table 2). Clinical features that raise suspicion for an underlying cause of ICH include: Age <65 years No history or new diagnosis of HTN History of protracted new-onset headaches History of new-onset neurologic symptoms preceding ICH Thunderclap headache at onset of hemorrhage History of prior ICH (unless attributed to uncontrolled HTN or CAA) Imaging features of the hemorrhage on imaging (head CT or brain MRI) raising suspicion for other secondary causes of ICH (such as a vascular lesion, primary or metastatic brain tumor, cerebral venous thrombosis, or hemorrhagic transformation of ischemic infarct) include: Early perihematomal edema out of proportion to the size of the ICH ( image 3) Hemorrhage appears to be in arterial vascular territory suggesting primary ischemic infarction ( image 4) Enhancement of intracranial vessels around ICH ( image 5) Multifocal hemorrhage ( image 6) Isolated intraventricular hemorrhage ( image 7) Specific underlying etiologies of nontraumatic ICH are discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Specific etiologies'.) We prefer brain MRI with gadolinium for most patients who undergo post-acute testing to identify underlying cause of ICH. MRI should include T2-weighted (gradient echo [GRE] or susceptibility-weighted imaging [SWI]) sequences. In an observational study in 400 patients with spontaneous ICH, MRI performed within 30 days improved diagnostic accuracy regarding ICH etiology over CT, changing the diagnostic impression in approximately 14 percent and management in 20 percent of cases [26]. These findings were confirmed in a subsequent study of 123 patients where MRI was most useful for establishing the diagnosis of ICH secondary to cerebral venous sinus thrombosis, hemorrhagic transformation of an ischemic infarct, neoplasms, and vascular malformations [27]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 6/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate For patients who are unable to undergo MRI, head CT with contrast is a reasonable but less sensitive alternative. When an underlying vascular cause is suspected, additional noninvasive vascular imaging with CT or MR angiogram should be performed. Digital subtraction angiography (DSA) is performed when CT or MR angiography is inconclusive or is negative and clinical suspicion for an underlying vascular lesion remains high ( image 5) [28,29]. In addition, we generally obtain DSA to evaluate for a vascular lesion such as an arteriovenous malformation. CT or MR venography is performed for suspected venous lesions, such as cerebral venous thrombosis. (See "Brain arteriovenous malformations" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) The optimal time to obtain follow-up imaging depends on the indication and the clinical recovery of the patient. For patients who did not undergo evaluation during the acute hospitalization for potential underlying secondary causes of the ICH, we obtain early imaging in four weeks to identify potential underlying structural sources amenable to early treatment. For other patients with a suspected secondary cause where the acute evaluation did not identify or exclude an underlying source, we obtain imaging after six to eight weeks to allow for better visualization of underlying brain tissue after some resorption of the hematoma. For patients without worrisome clinical or imaging features of the ICH for whom the acute evaluation for underlying causes did not identify the etiology, repeat imaging is indicated to exclude underlying structural sources. For these patients, we typically delay repeat imaging for 12 to 16 weeks after the ICH to promote optimal visualization of underlying brain tissue and reduce the risk of identifying confounding abnormal imaging findings that may be attributed to healing of the ICH in the late subacute time period. BLOOD PRESSURE MANAGEMENT Blood pressure (BP) control is an important aspect of reducing the risk of recurrent ICH. Hypertension (HTN) is one of the single most important modifiable risk factors for initial ICH and ICH recurrence. (See 'Risk factors' above.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 7/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Small improvements in BP control help to reduce the risk of ICH. The relationship between BP control and ICH recurrence has been studied somewhat indirectly in patients with either ischemic stroke or ICH. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, patients with prior stroke (hemorrhage or infarction) were randomly assigned to an angiotensin-converting enzyme inhibitor (perindopril) with or without a diuretic (indapamide) versus placebo. A modest BP reduction rate by 9/4 mmHg in patients assigned to active treatment reduced the risk of ICH from 2.4 to 1.2 percent, corresponding to a 50 percent relative risk reduction (95% CI 26-67 percent) [30]. The relative risk reduction for recurrent stroke was 49 percent (95% CI 18-68 percent) among patients whose qualifying event was ICH [30-32]. Blood pressure goals We suggest aiming for BP <130/80 mmHg as a long-term target to reduce the risk of recurrence after ICH ( table 3) [33]. The risk of ICH is reduced with each incremental reduction in BP, but the benefit may be greatest for patients whose BP reaches intensive BP-lowering targets [18,31]. The benefit for intensive BP reduction has not been demonstrated specifically for ICH recurrence; however, indirect evidence from patients with other cerebrovascular conditions suggests a likely benefit. In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, 3020 patients with prior ischemic stroke were assigned either to a systolic BP target of 130 to 149 mmHg or <130 mmHg [34]. During a mean follow-up of 3.7 years, there were fewer ICH events in those assigned to the intensive BP target (6 versus 16), corresponding to a lower rate of ICH at 0.1 percent per patient-year in the intensive group compared with 0.3 percent per patient-year in the higher target. A more intensive BP target was assessed in the Recurrent Stroke Prevention Clinical Outcome (RESPECT) trial, in which 1266 patients with ischemic stroke were randomly assigned to intensive BP control (<120/80 mmHg) or to standard treatment (<140/90 mmHg) [35]. There was a trend toward fewer strokes in patients assigned to the intensive group; however, limitations in this study prevent firm conclusions. The actual mean BP achieved in the intensive group was 127/77, not very different from 133/78 mmHg in the standard group. The trial was stopped early with relatively few (12) ICH events, most in the standard treatment group (11 versus 1). In a meta-analysis of these studies along with two additional trials in patients after ischemic stroke, more intensive BP lowering (variably defined) was associated with a reduced risk of ICH (relative risk [RR] 0.25, 95% CI 0.07-0.90) [35]. Blood pressure lowering has additional benefits in reducing the risk of other vascular events including ischemic stroke, although in the population of patients with prior ICH, the absolute benefits in this regard are likely to be small [35]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 8/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate When to begin antihypertensive therapy The approach to BP control after ICH is stepwise. However, high quality data to specify when to safely implement BP control after ICH are lacking. In the acute (typically hospital) setting, initial steps to control the BP are begun immediately to prevent hematoma expansion. The benefit of acute control of elevated blood pressure must be balanced against the competing risk of cerebral or other organ hypoperfusion. Initial target systolic blood pressure is 140 to 160 mmHg for most patients. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management'.) Further reductions in BP toward normotension are made in a stepwise fashion. For most patients, we aim to achieve the BP target of <130/80 mmHg within 10 to 14 days after the onset of ICH. We also advise close outpatient monitoring to ensure that BP control is maintained. Selection of antihypertensive agent For patients without a clinical indication for a specific agent, we typically start an angiotensin-converting enzyme (ACE) inhibitor. For those unable to tolerate or who prefer an agent other than an ACE inhibitor, we offer an angiotensin receptor blocker, thiazide diuretic, or calcium channel blocker, based on analyses of risk reduction in patients with atherosclerotic disease [36,37]. The choice of agent should be guided by efficacy in achieving target BP. Clinical indications to guide individualized medication selection are discussed elsewhere ( table 4). (See "Choice of drug therapy in primary (essential) hypertension".) The use of combination antihypertensive regimen (ie, multiple antihypertensive drugs, instead of a single drug) may decrease the risk of adverse effects and improves tolerability and compliance [38]. (See "Choice of drug therapy in primary (essential) hypertension".) Education of patients and their caregivers about target BP and their engagement in self- monitoring at home and communications with their medical providers are also key to achieve better BP control and to improve adherence to therapy [39]. Lifestyle modifications and management of obstructive sleep apnea and obesity are fundamental components of BP management. (See 'Lifestyle modifications' below.) MANAGEMENT OF ANTITHROMBOTIC THERAPY Many patients with ICH have comorbid cardiovascular conditions and may have indications for antiplatelet or oral anticoagulant agents. Whether to resume or discontinue these medications after ICH requires weighing the competing risks of thromboembolic events versus ICH recurrence. In the absence of high-quality trial data, observational reports and expert opinion guide risk/benefit assessment and decision-making. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 9/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Antiplatelet therapy Antiplatelet therapy is typically withheld in the acute setting to mitigate the risk of hemorrhage expansion. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Reverse anticoagulation'.) We suggest resuming antiplatelet therapy after ICH for most patients who have a specific indication for such therapy. However, it is important to balance individual risks and benefits. Patients with established atherosclerotic disease We resume antiplatelet therapy for most patients with nonlobar ICH and those with lobar ICH attributed to cerebral amyloid angiopathy (CAA) who have established atherosclerotic disease, in agreement with guidelines from the American Heart Association (AHA) [33]. Such indications may include prior cardiovascular disease, ischemic stroke, or peripheral arterial disease. These indications are discussed separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".) The risks and benefits of resuming antiplatelet medications for patients with CAA are discussed in detail separately. (See "Cerebral amyloid angiopathy", section on 'Prevention of recurrent hemorrhage'.) If lobar ICH was attributed to an alternative source, we base decisions on resuming antiplatelet therapy on the individual risks associated with the underlying etiology. We prefer low-dose aspirin (81 mg per day), typically starting a few days after ICH, if neuroimaging confirms stability. Low-dose aspirin has been most studied in relationship to ICH recurrence. Some [4,40-42] but not all [43] small studies have reported no difference in the rates of ICH recurrence among patients with ICH who continued aspirin and those who discontinued it. In the Restart or Stop Antithrombotics Randomized Trial (RESTART), 537 patients who developed ICH while taking antithrombotic therapy were assigned either to continue or discontinue antiplatelet therapy [44]. Most patients (88 percent) were taking antithrombotic therapy for secondary prevention of atherosclerotic disease; 25 percent had atrial fibrillation, either as a comorbid condition or as their primary indication. After a median two years of follow-up, the risk of recurrent ICH was similar (nonsignificantly lower) in patients who continued versus discontinued antiplatelet therapy (4 versus 9 percent; adjusted hazard ratio [aHR] 0.51, 95% CI 0.25-1.03), while rates of major occlusive and thromboembolic events were higher and were similar among treatment groups (15 versus 14 percent; aHR 1.02, 95% CI 0.65-1.60). These findings were sustained in an extended follow-up at a median time of three years (interquartile range two to five years) [45]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 10/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Hemorrhagic and thromboembolic outcomes were similar among patients who continued versus those who discontinued antiplatelet therapy, and the rate of recurrent ICH remained lower than the rate of major vascular events (9 versus 30 percent). Primary prevention of atherosclerotic disease For patients with ICH without established atherosclerotic disease, we consider individual risk factors to weigh overall benefits of antiplatelet therapy against the risk of hemorrhage. As examples, we typically would resume aspirin for patients with ICH and hypertension (HTN), hyperlipidemia, and diabetes mellitus or those with carotid atherosclerotic disease. For such patients, ICH may be a marker of atherosclerotic risk. In a Danish cohort study, patients with prior ICH had a higher risk of subsequent cardiovascular events than age- and sex-matched controls, including ischemic stroke (1.5 versus 0.6 per 100 person-years) and major adverse cardiovascular events (4.2 versus 1.4 per 100 person-years) [46]. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".) For most of these patients in whom antiplatelet therapy is resumed, we prefer low-dose aspirin and restart such therapy several days after the ICH has stabilized. For patients with lobar ICH and suspected CAA without high risk of ischemic stroke or cardiovascular events, we avoid antiplatelet therapy. (See "Cerebral amyloid angiopathy".) Patients with intravascular stents Patients with symptomatic atherosclerotic disease who have undergone intravascular stent placement are typically prescribed antiplatelet therapy for several months to prevent vascular occlusion from thrombosis at the site of the stent. We typically resume these medications in patients with ICH because of the thrombotic risks related to their discontinuation and typically start within a few days after ICH if neuroimaging confirms stability. Whenever feasible, we prefer single antiplatelet therapy over dual antiplatelet therapy. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use" and "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Overview of carotid artery stenting" and "Endovascular techniques for lower extremity revascularization", section on 'Antiplatelet therapy'.) Patients taking nonsteroidal antiinflammatory drugs We prefer nonacetylated salicylates (eg, magnesium salicylate) over other nonsteroidal antiinflammatory medications with antithrombotic properties that impair platelet function. Anticoagulation Anticoagulation is typically withheld, and the effects are reversed acutely for patients with ICH, to reduce the risks of hemorrhagic expansion and associated morbidity. (See https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 11/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Reverse anticoagulation'.) Many patients with ICH benefit from resuming anticoagulation when the thromboembolic risk is higher than the risk of recurrent ICH. However, it is important to balance individual risks and benefits. Individualize decision to resume or discontinue We balance the risks of recurrent ICH with the risk of thromboembolism to help make decisions about resuming anticoagulation for individual patients ( algorithm 2). Only limited observational data and expert opinion are available to support clinical decisions regarding resuming or withholding anticoagulation [47-50]. These decisions should be made along with the patient after weighing the individualized risks, benefits, and exploring alternative options whenever possible. Timing of resumption The optimal time for restarting oral anticoagulation after ICH has not been established and may depend on the underlying indication for anticoagulation. Early resumption of anticoagulation within several days after stabilization of the ICH may be indicated for select patients with a compelling indication (eg, mechanical prosthetic heart valve) [33]. (See 'Mechanical prosthetic heart valves' below.) For most other patients who resume anticoagulation, we generally suggest delaying restarting oral anticoagulants for four to eight weeks after onset of the ICH, in agreement with AHA guidelines [33]. We use hemorrhage size and thromboembolic risks to guide the specific timing of resumption for an individual patient. In one study of 177 patients with intracranial hemorrhage and an indication for anticoagulation, the combined risk of recurrent intracranial hemorrhage or ischemic stroke reached a nadir when warfarin was resumed after 10 weeks, suggesting that the optimal timing for resumption of oral anticoagulation is after 10 weeks [51]. The risk of ischemic stroke was lowest and the risk of recurrent hemorrhage was highest within the first five weeks after the initial hemorrhage, suggesting anticoagulation may be delayed during this time interval. Mechanical prosthetic heart valves Resumption of warfarin is recommended for most patients with mechanical prosthetic valves who develop ICH while taking warfarin because the ongoing risk of thromboembolic events is higher than the risk of recurrent ICH, regardless of hemorrhage etiology. In a meta-analysis of more than 13,000 patients with mechanical heart valves, the incidence of major embolism was four times higher among those not on antithrombotic therapy versus those taking warfarin (4 versus 1 per 100 patient-years) [52]. A https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 12/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate prosthesis in the mitral position increased the thromboembolic risk almost twice as compared with the aortic position. (See "Antithrombotic therapy for mechanical heart valves".) CAA-related ICH Many patients with lobar ICH do not resume anticoagulation because of the associated risk of recurrent ICH attributed to CAA outside a compelling indication such as a mechanical heart valve. The specific risks of future ICH for individual patients with CAA should be weighed against the benefits of resuming anticoagulation. These risks and benefits of anticoagulation for patients with CAA are discussed separately. (See "Cerebral amyloid angiopathy", section on 'Prevention of recurrent hemorrhage'.) Atrial fibrillation In the absence of high-quality trial data, the decision to resume or withhold anticoagulation in patients with ICH and atrial fibrillation requires balancing future hemorrhagic and thromboembolic risks at an individual level. For many patients with atrial fibrillation, ischemic stroke is more common than recurrent ICH and the risk-benefit analysis favors resuming anticoagulation after ICH [6]. In a 2017 meta- analysis of eight studies including 5306 patients with anticoagulation-associated ICH, restarting anticoagulation after ICH was associated with a lower risk of thromboembolic complications and no excess risk of ICH recurrence [53]. Most patients resumed warfarin and atrial fibrillation was the most common indication for restarting anticoagulation. Resumption of oral anticoagulation was also associated with reduced risk of all-cause stroke and mortality at 12 months in an analysis of 1012 patients with warfarin-associated lobar and nonlobar ICH [54]. Another meta- analysis of 50,470 patients with spontaneous or anticoagulation-associated intracranial hemorrhage and atrial fibrillation also found that resuming anticoagulation was associated with lower risk of subsequent thromboembolism without excess risk of recurrent intracranial hemorrhage [55]. However, interpretation of these meta-analyses is limited by heterogeneity of included studies, their retrospective and observational nature, and inherent selection, indication, and prescription biases. Estimating bleeding and thromboembolic risks Several clinical prediction scores have been developed to help quantify individual risks of future bleeding and thromboembolism. The CHADS2 or CHA2DS2-VASc scores to assess thromboembolic risks are used widely ( table 5 and algorithm 2). Other scores have been developed to help estimate bleeding risk. Among these, the HAS-BLED score incorporates clinical risk factors associated with bleeding to help to assess initial hemorrhagic risk (scored 1 to 9) in patients with atrial fibrillation ( table 6) [56]. However, its generalizability is limited by the small number of patients with risks who scored 5 to 9 and may also be restricted to the assessment of initial ICH risk among patients taking warfarin. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 13/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Additionally, subjective clinical assessment of bleeding risk may have a similar predictive accuracy to bleeding scores [57]. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores' and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.) As examples: For a typical patient with nonlobar ICH attributed to HTN without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may resume anticoagulation once HTN is controlled. For a typical patient with lobar ICH attributed to CAA without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may pursue alternatives to anticoagulation. For a typical patient with non-lobar ICH of undetermined source who has atrial fibrillation a CHA2DS2-VASc score 2, we would exclude underlying sources prior to considering resuming anticoagulation. One study using a decision-analysis model to compare warfarin resumption versus discontinuation after ICH found that resumption improves quality-adjusted life (QoL) expectancy in some patients. For patients with lobar ICH, warfarin discontinuation improves QoL expectancy by 1.9 years and is therefore preferred unless the rate of ICH recurrence is estimated to be <1.4 percent per year [58]. By contrast, for patients with deep ICH, resumption of warfarin may be preferred if the rate of recurrent ICH is low (eg, <1.6 percent per year) and the rate of ischemic stroke is high (eg, >7 percent per year). This analysis was limited to patients taking warfarin. Therapeutic options Therapeutic options for patients with ICH and atrial fibrillation include: Resumption of anticoagulation For patients with ICH who have atrial fibrillation, anticoagulation may be resumed when the associated risk of thromboembolism is higher than the future hemorrhagic risk. (See 'Estimating bleeding and thromboembolic risks' above.) For long-term anticoagulation, options include a direct oral anticoagulant (DOAC) or a vitamin K antagonist, such as warfarin. For most patients with atrial fibrillation who develop ICH while on an oral anticoagulant and in whom oral anticoagulation is resumed, we suggest a DOAC over warfarin because of a favorable hemorrhagic risk profile. For select patients, warfarin may be preferred for specific indications, described immediately below. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 14/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Direct oral anticoagulants DOACs are at least as effective as warfarin for prevention of thromboembolic events in patients with atrial fibrillation [59]. Because they are associated with a lower risk for ICH, they are an appealing option to help reduce the risk of recurrent ICH [60]. In a study of patients with atrial fibrillation or venous thromboembolism resuming anticoagulation, there was a trend toward fewer ICH recurrences in those taking a DOAC [61]. The incidence rate of recurrent ICH was 2.5 per 100 patient-years with warfarin and 1.3 per 100-patient years with a DOAC (risk ratio 1.9, 95% CI 0.6-7.4) [61]. There were too few recurrent events to assess a difference among specific DOACs. Warfarin Much of the experience with resumption of anticoagulation has been from patients taking warfarin [48,50,51]. Warfarin may be chosen based on cost or availability and is indicated for patients with specific indications, including some patients with atrial
anticoagulation is after 10 weeks [51]. The risk of ischemic stroke was lowest and the risk of recurrent hemorrhage was highest within the first five weeks after the initial hemorrhage, suggesting anticoagulation may be delayed during this time interval. Mechanical prosthetic heart valves Resumption of warfarin is recommended for most patients with mechanical prosthetic valves who develop ICH while taking warfarin because the ongoing risk of thromboembolic events is higher than the risk of recurrent ICH, regardless of hemorrhage etiology. In a meta-analysis of more than 13,000 patients with mechanical heart valves, the incidence of major embolism was four times higher among those not on antithrombotic therapy versus those taking warfarin (4 versus 1 per 100 patient-years) [52]. A https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 12/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate prosthesis in the mitral position increased the thromboembolic risk almost twice as compared with the aortic position. (See "Antithrombotic therapy for mechanical heart valves".) CAA-related ICH Many patients with lobar ICH do not resume anticoagulation because of the associated risk of recurrent ICH attributed to CAA outside a compelling indication such as a mechanical heart valve. The specific risks of future ICH for individual patients with CAA should be weighed against the benefits of resuming anticoagulation. These risks and benefits of anticoagulation for patients with CAA are discussed separately. (See "Cerebral amyloid angiopathy", section on 'Prevention of recurrent hemorrhage'.) Atrial fibrillation In the absence of high-quality trial data, the decision to resume or withhold anticoagulation in patients with ICH and atrial fibrillation requires balancing future hemorrhagic and thromboembolic risks at an individual level. For many patients with atrial fibrillation, ischemic stroke is more common than recurrent ICH and the risk-benefit analysis favors resuming anticoagulation after ICH [6]. In a 2017 meta- analysis of eight studies including 5306 patients with anticoagulation-associated ICH, restarting anticoagulation after ICH was associated with a lower risk of thromboembolic complications and no excess risk of ICH recurrence [53]. Most patients resumed warfarin and atrial fibrillation was the most common indication for restarting anticoagulation. Resumption of oral anticoagulation was also associated with reduced risk of all-cause stroke and mortality at 12 months in an analysis of 1012 patients with warfarin-associated lobar and nonlobar ICH [54]. Another meta- analysis of 50,470 patients with spontaneous or anticoagulation-associated intracranial hemorrhage and atrial fibrillation also found that resuming anticoagulation was associated with lower risk of subsequent thromboembolism without excess risk of recurrent intracranial hemorrhage [55]. However, interpretation of these meta-analyses is limited by heterogeneity of included studies, their retrospective and observational nature, and inherent selection, indication, and prescription biases. Estimating bleeding and thromboembolic risks Several clinical prediction scores have been developed to help quantify individual risks of future bleeding and thromboembolism. The CHADS2 or CHA2DS2-VASc scores to assess thromboembolic risks are used widely ( table 5 and algorithm 2). Other scores have been developed to help estimate bleeding risk. Among these, the HAS-BLED score incorporates clinical risk factors associated with bleeding to help to assess initial hemorrhagic risk (scored 1 to 9) in patients with atrial fibrillation ( table 6) [56]. However, its generalizability is limited by the small number of patients with risks who scored 5 to 9 and may also be restricted to the assessment of initial ICH risk among patients taking warfarin. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 13/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Additionally, subjective clinical assessment of bleeding risk may have a similar predictive accuracy to bleeding scores [57]. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores' and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.) As examples: For a typical patient with nonlobar ICH attributed to HTN without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may resume anticoagulation once HTN is controlled. For a typical patient with lobar ICH attributed to CAA without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may pursue alternatives to anticoagulation. For a typical patient with non-lobar ICH of undetermined source who has atrial fibrillation a CHA2DS2-VASc score 2, we would exclude underlying sources prior to considering resuming anticoagulation. One study using a decision-analysis model to compare warfarin resumption versus discontinuation after ICH found that resumption improves quality-adjusted life (QoL) expectancy in some patients. For patients with lobar ICH, warfarin discontinuation improves QoL expectancy by 1.9 years and is therefore preferred unless the rate of ICH recurrence is estimated to be <1.4 percent per year [58]. By contrast, for patients with deep ICH, resumption of warfarin may be preferred if the rate of recurrent ICH is low (eg, <1.6 percent per year) and the rate of ischemic stroke is high (eg, >7 percent per year). This analysis was limited to patients taking warfarin. Therapeutic options Therapeutic options for patients with ICH and atrial fibrillation include: Resumption of anticoagulation For patients with ICH who have atrial fibrillation, anticoagulation may be resumed when the associated risk of thromboembolism is higher than the future hemorrhagic risk. (See 'Estimating bleeding and thromboembolic risks' above.) For long-term anticoagulation, options include a direct oral anticoagulant (DOAC) or a vitamin K antagonist, such as warfarin. For most patients with atrial fibrillation who develop ICH while on an oral anticoagulant and in whom oral anticoagulation is resumed, we suggest a DOAC over warfarin because of a favorable hemorrhagic risk profile. For select patients, warfarin may be preferred for specific indications, described immediately below. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 14/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Direct oral anticoagulants DOACs are at least as effective as warfarin for prevention of thromboembolic events in patients with atrial fibrillation [59]. Because they are associated with a lower risk for ICH, they are an appealing option to help reduce the risk of recurrent ICH [60]. In a study of patients with atrial fibrillation or venous thromboembolism resuming anticoagulation, there was a trend toward fewer ICH recurrences in those taking a DOAC [61]. The incidence rate of recurrent ICH was 2.5 per 100 patient-years with warfarin and 1.3 per 100-patient years with a DOAC (risk ratio 1.9, 95% CI 0.6-7.4) [61]. There were too few recurrent events to assess a difference among specific DOACs. Warfarin Much of the experience with resumption of anticoagulation has been from patients taking warfarin [48,50,51]. Warfarin may be chosen based on cost or availability and is indicated for patients with specific indications, including some patients with atrial fibrillation associated with valvular heart disease and those with mechanical prosthetic heart valves. (See 'Mechanical prosthetic heart valves' above and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Patients with valvular heart disease'.) Warfarin may be preferred by patients previously taking the medication whose international normalized ratio (INR) is well-controlled. Additionally, warfarin may be preferred for other patients, including some with bodyweight <60 kg or age 80 years, and those unable to take a DOAC (eg, drug interaction, creatinine clearance <30 mL/minute). (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Settings in which a heparin or vitamin K antagonist may be preferable'.) Left atrial appendage occlusion Percutaneous left atrial appendage occlusion (LAAO) may be a viable treatment option for patients with ICH and nonvalvular atrial fibrillation who are at high risk for recurrent ICH and thromboembolic events and in whom resumption of oral anticoagulation is not resumed or contraindicated [33]. In a meta- analysis of trials comparing LAAO closure with oral anticoagulation, the rates of both systemic embolism and major bleeding were similar after a mean follow-up of 39 months [62]. The risk of ICH was lower for patients assigned to LAAO (0.5 versus 2.4 percent; relative risk 0.22, 95% CI 0.02-0.58). In the Amplatzer Cardiac Plug multicenter registry, the subsequent annual major bleeding rate was 0.7 percent, corresponding to a relative risk reduction of 89 percent in patients with prior intracranial hemorrhage compared with those with other indications for LAAO [63,64]. LAAO is discussed in further detail separately. (See "Risks and prevention of bleeding with oral anticoagulants" and "Atrial fibrillation: Left atrial appendage occlusion".) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 15/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Antiplatelet therapy For patients with ICH and atrial fibrillation in whom anticoagulation is not resumed, antiplatelet therapy is used as an alternative. Because the benefit of aspirin to prevent thromboembolism in this population has not been established, we reserve antiplatelet therapy for patients with other indications. (See 'Antiplatelet therapy' above.) Other patients Anticoagulation may be used for patients with selected indications associated with a very high risk of thromboembolism and inadequate alternative choices. In these circumstances, risks and benefits should be discussed with patients and decisions should be individualized based on risk analysis and patient values. Such indications may include: Cancer-related thrombophilia with high risk of or prior venous thromboembolism (see "Risk and prevention of venous thromboembolism in adults with cancer") Hypercoagulable (acquired or inherited) conditions (see "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors") Venous thromboembolism with high risk of recurrence (see "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation") Other forms of cardiovascular disease (see "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Antithrombotic therapy in patients with heart failure") Other temporary high-risk indications for anticoagulation (see "Atrial fibrillation: Left atrial appendage occlusion", section on 'Postprocedure management' and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement" and "Left ventricular thrombus after acute myocardial infarction") Alternatives to intravenous thrombolytic therapy We do not routinely offer intravenous thrombolytic therapy to patients with ICH who develop conditions such as ischemic stroke, myocardial infarction, or pulmonary embolism, consistent with AHA guideline recommendations [65]. Endovascular and mechanical thrombectomy procedures may be an option for such patients. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) MANAGEMENT OF STATINS https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 16/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate The decision to resume statins (hydroxymethylglutaryl [HMG] CoA reductase inhibitors) for patients with ICH requires balancing the benefits of therapy with the potential hemorrhagic risks. We suggest resuming statins in most patients with ICH who have a strong indication for therapy. This includes patients with diabetes and coronary artery disease and those with recent myocardial infarction or baseline severe atherosclerotic arterial disease. We discontinue statins for patients with ICH with less compelling indications such as isolated dyslipidemia and for those with multiple (recurrent) lobar ICHs who are at high risk for ICH recurrence [66]. For patients with ICH who resume statins, we avoid high doses and prefer hydrophilic statins (eg, pravastatin or rosuvastatin). For patients who discontinue statins after ICH, we use the indication for therapy to help select an alternative medication. (See "Statins: Actions, side effects, and administration" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Hypertriglyceridemia in adults: Management".) Statins appear to increase the propensity for ICH by inhibiting platelets, decreasing thrombus formation, and enhancing fibrinolysis [67,68]. In addition, hyperlipidemia appears to be protective against ICH. In a case-control study including 3492 patients with ICH, a reduced risk of ICH was associated with each increase in serum cholesterol by 5 mg/dL (odds ratio 0.87, 95% CI 0.86-0.88) [69]. Additionally, lower levels of low-density lipoprotein cholesterol are also associated with increased risk for ICH [70,71]. The contribution of statin drugs to the risk of initial ICH is supported by trials and several observational studies [69,72,73]. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, patients with prior transient ischemic attack or ischemic stroke assigned to atorvastatin had fewer major cardiovascular events than those assigned to placebo (3.5 percent absolute risk reduction) [74]. However, the incidence rate of ICH was significantly higher in patients who received atorvastatin 80 mg daily (2.3 versus 1.4 percent; risk ratio [RR] 1.68, 95% CI 1.09-2.5). However, data on the risk of recurrent ICH are less certain [75,76]. Outcomes associated with statin use were evaluated in a 2018 systematic review of 15 studies that included more than 50,000 patients with prior ICH [25]. Among studies reporting ICH recurrence, the risk associated with statin use was similar to controls (RR 1.04, 95% CI 0.86-1.25). However, statin use was associated with improved functional outcome and reduced mortality in patients with prior ICH. These findings may reflect variability of individual risk related to several factors including statin dose or formulation, prescription bias, the burden of atherosclerotic disease, and the cause of the prior ICH. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 17/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Effect of statin dose Statin dose may modify the risk of hemorrhagic complications such as ICH [77]. A meta-analysis of seven randomized controlled trials found that higher doses of statins were associated with increased risk for ICH compared with placebo (RR 1.53, 95% CI 1.16-2.01) [78]. However, a large 10-year nationwide cohort study from Taiwan found no association between statin dose and risk of recurrent ICH [79]. Effect of statin formulation Statins with lipophilic solubility (atorvastatin, lovastatin, simvastatin, cerivastatin, and fluvastatin) have a greater ability to penetrate across blood- brain barrier and have been associated with increased odds of recurrent ICH compared with hydrophilic statins [79]. Cause of incident ICH Some cohorts suggest the hemorrhagic risk with statin use is associated with patients with lobar ICH [80-82]. The protective effect of hyperlipidemia also appears to be higher for patients with lobar versus nonlobar ICH [69]. LIFESTYLE MODIFICATIONS We advise lifestyle modifications based on their association as risk factors of stroke, including ICH [33]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) These include: Regular physical activity (see "The benefits and risks of aerobic exercise") Maintenance of healthy body weight (see "Obesity in adults: Overview of management") Healthy diet (see "Healthy diet in adults") Cessation of smoking and excessive alcohol use (see "Cardiovascular risk of smoking and benefits of smoking cessation") Avoidance of sympathomimetic medications (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors') LONG-TERM PROGNOSIS Prognosis after ICH involves both initial prognosis and long-term prognosis. The clinical and imaging determinants of initial prognosis occur within the acute hospitalization and recovery periods, typically comprising the first 180 days after ICH. Long-term prognosis focuses on sequelae of ICH, which persist beyond 180 days. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 18/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Acute prognosis in ICH is discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Early prognosis'.) Functional recovery The rate of recovery after ICH may be highest in the first few weeks to months. In one study, recovery was greatest within the first 30 days after ICH [83]. However, recovery after ICH is often delayed and can be slow; many patients report functional improvements for 6 to 12 months [84,85]. In a post-hoc analysis of individual patient data from two clinical trials of patients with intracerebral or intraventricular hemorrhage, poor functional outcome at 30 days was reported in 715 of 999 patients (72 percent) [86]. By one year, 308 of these patients (46 percent) had achieved good functional outcome, including 30 percent who were functionally independent. Older age, larger hemorrhage volumes, and baseline conditions such as diabetes mellitus and severe leukoaraiosis on imaging were associated with poor one- year outcomes. In addition, common complications of acute ICH were also predictors of poor outcome at one year including sepsis, new ischemic stroke, prolonged mechanical ventilation, hydrocephalus, and the need for gastrostomy feeding tube. Aggressive acute treatment to prevent these acute complications may help avoid premature withdrawal of support and improve long-term outcomes. Early rehabilitation and sustained support are recommended to maximize functional recovery [83,87,88]. Educating patients and caregivers regarding secondary prevention strategies and addressing lifestyle changes, depression, and caregiver burden is an important part of post-ICH rehabilitation program. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Initial aggressive care'.) The main clinical determinants associated with reduced functional recovery after ICH include increasing age, baseline comorbidities, and severity of ICH as assessed by Glasgow Coma Scale score at presentation. Key imaging determinants include ICH volume, the presence of intraventricular hemorrhage, and specific ICH locations (including brainstem, posterior limb of internal capsule, or thalamus) [89,90]. Functional outcome may be assessed using varying performance thresholds or clinical scoring tools. The modified Rankin Scale (mRS) is frequently used ( table 7). In several trials, patients with ICH achieving a score of 0 to 3 have been described as having a good functional outcome; poor outcome included those scoring 4 to 6. In a retrospective study of 1499 patients, 51 percent of patients with a first ICH had good functional recovery after 90 days, compared with 31 percent of patients after recurrent ICH [91]. A decline in long-term functional status has been observed among patients after ICH. In a single-center observational study of 560 patients, 23 percent of those with a good functional outcome at six months had declined over a median nine-year follow-up [92]. Advanced age, https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 19/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate higher initial ICH volume, lower six-month functional status, and new diagnoses of dementia or stroke during follow-up were predictors of functional decline. Cognitive impairment Cognitive impairment is frequent among patients after ICH [93,94]. A systematic review reported that the prevalence of cognitive impairment ranged between 14 and 88 percent after ICH [95]. Predictive factors were previous stroke, ICH volume and location, and markers of cerebral amyloid angiopathy. Cognitive deficits after ICH were common across multiple domains. The most frequently impaired domains were naming, processing speed, executive functioning, memory, visuospatial abilities, and attention. Long-term mortality In population-based cohorts of patients hospitalized after ICH the 10- year survival rate ranged from 18 to 25 percent [5,96]. Life expectancy among patients after ICH was decreased compared with age- and sex-matched controls in the general population [97-99]. In a cohort of 219 patients with ICH, the major cause of death within five years was cardiovascular disease, largely due to recurrent ICH and its sequelae (10 percent) irrespective of ICH location [5]. The risk of death was similar in patients with lobar versus nonlobar ICH and higher in patients with anticoagulation-associated ICH. A retrospective multicenter 10-year study of 1499 patients with ICH reported recurrent ICH in 9.5 percent of patients and found that 30-day mortality was similar (approximately 14 percent) after first and recurrent ICH [91]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 20/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Hemorrhagic stroke (The Basics)") Beyond the Basics topic (see "Patient education: Hemorrhagic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Risk factors for recurrent ICH Several risk factors have been implicated in the risk of recurrent intracerebral hemorrhage (ICH). These include the location and etiology of the initial ICH, hypertension, older age, several medications ( table 1), race/ethnicity, chronic kidney disease, prior stroke, and specific genetic features. (See 'Risk of recurrence' above.) Follow-up imaging to evaluate for underlying causes We obtain follow-up imaging for patients with clinical or imaging features of the ICH suggestive of an underlying cause ( algorithm 1 and table 2). For most patients, we prefer brain magnetic resonance imaging (MRI) with gadolinium to evaluate for an underlying cause. (See 'Follow-up neuroimaging' above.) Blood pressure management Blood pressure control is an important feature of secondary prevention for all patients with ICH. We suggest a long-term target <130/80 mmHg to lower the risk of ICH recurrence (Grade 2B). (See 'Blood pressure management' above.) Management of antiplatelet therapy We suggest resuming antiplatelet therapy for most patients with ICH who have a specific indication for such therapy (Grade 2C). For patients with ICH in whom antiplatelet therapy is being resumed, we typically start aspirin within a few days after the ICH has stabilized. (See 'Antiplatelet therapy' above.) Management of anticoagulation We balance the risks of recurrent ICH and thromboembolism to help make decisions about resuming anticoagulation for each patient ( algorithm 2). (See 'Anticoagulation' above.) Early resumption of anticoagulation may be indicated for select patients with a compelling indication (eg, mechanical prosthetic heart valve). For most other patients who resume anticoagulation, we generally suggest waiting for at least four weeks after onset of the ICH to restart the anticoagulant (Grade 2C). https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 21/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate For patients with atrial fibrillation, prediction models such as the HAS-BLED score may be used to help assess bleeding risk ( table 6) and CHADS2 or CHA2DS2-VASc scores used to help assess thromboembolic risks ( table 5). For many patients with atrial fibrillation, the risk-benefit analysis favors resuming anticoagulation after ICH. For most patients with atrial fibrillation who develop ICH while on warfarin and in whom oral anticoagulation is resumed, we suggest a direct oral anticoagulant (DOAC) over warfarin (Grade 2B). DOACs generally have a lower risk of bleeding, including ICH, than warfarin. Warfarin may be selected for patients with valvular atrial fibrillation, a mechanical heart valve, or an inability to take a DOAC. Management of statins We suggest resuming statins for most patients with lobar and nonlobar ICH who have atherosclerotic disease (Grade 2C). We discontinue statins for most patients with multiple (recurrent) lobar ICHs. (See 'Management of statins' above.) Long-term prognosis The rate of recovery after ICH may be highest in the first few months. However, the greatest extent of recovery may not be evident until 6 to 12 months after ICH. (See 'Functional recovery' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Arima H, Tzourio C, Butcher K, et al. Prior events predict cerebrovascular and coronary outcomes in the PROGRESS trial. Stroke 2006; 37:1497. 2. Poon MT, Fonville AF, Al-Shahi Salman R. 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Long term (13 years) prognosis after primary intracerebral haemorrhage: a prospective population based study of long term mortality, prognostic factors and causes of death. J Neurol Neurosurg Psychiatry 2013; 84:1150. Topic 129071 Version 14.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 29/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate GRAPHICS Medications and other substances that may increase the risk of bleeding or bruising Drug class or substance Mechanism Anticoagulants Interfere with clot formation (secondary hemostasis) Antiplatelet agents, including NSAIDs Interfere with platelet function (primary hemostasis) Glucocorticoids Interfere with vascular integrity Antibiotics Cause vitamin K deficiency, especially with longer use Some interfere with platelet function SSRIs Interfere with platelet function (primary hemostasis) Alcohol Complications of liver disease may affect clot formation and may cause thrombocytopenia May cause thrombocytopenia due to direct marrow toxicity Vitamin E Interferes with vitamin K metabolism in some individuals Garlic Interferes with platelet function in some individuals Gingko biloba Unknown This is a partial list that does not include drugs used for cancer therapy or drugs that alter the metabolism of anticoagulants. The magnitude of increased bleeding risk depends on many factors including the patient's other bleeding risk factors and the specific drug, dose, and duration of use. Fish oil is often cited, but bleeding risk does not appear to be increased. Refer to drug information monographs and UpToDate topics for further information. NSAIDs: nonsteroidal antiinflammatory drugs; SSRIs: selective serotonin reuptake inhibitors. Graphic 120264 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 30/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Evaluating the underlying etiology of nontraumatic intracerebral hemorrhage This is an algorithm to guide etiologic testing; additional testing may be indicated for patients who develop new or worsening symptoms during recovery period. Refer to the UpToDate topic on secondary prevention and long-term prognosis of spontaneous intracerebral hemorrhage for additional details. ICH: intracerebral hemorrhage. Refer to the separate UpToDate table on clinical and neuroimaging features of intracerebral hemorrhage associated with underlying causes. Lobar or cortical ICH, evidence of multifocal superficial siderosis, age 55 years, and other sources for hemorrhagic features excluded. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 31/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Refer to the UpToDate topic on cerebral amyloid angiopathy for additional details. Graphic 132295 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 32/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Distinctive distribution of cerebral microbleeds (A-C) CMBs on T2-weighted gradient echo MRI sequences suggestive of deep penetrating (hypertensive) vasculopathy. CMBs predominate in bilateral thalami (A), brainstem (B), and dentate nucleus of cerebellum (C). (D-F) CMBs on T2-weighted gradient echo MRI sequences suggestive of cerebral amyloid angiopathy. CMBs predominate in cerebral hemispheres (D, E). Associated findings include lobar hemorrhage (D; arrow and thick arrow) and superficial siderosis (F; circles). CMB: cerebral microbleeds; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 33/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Graphic 132282 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 34/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Clinical and neuroimaging features of intracerebral hemorrhage associated with underlying causes Alternative Specifying ICH Characteristic Other associated features underlying feature underlying cause causes Basal ganglia or brainstem Deep perforating vasculopathy (HTN) CMBs in basal ganglia, thalamus, pons, cerebellar location nuclei Subcortical white matter lesions on MRI Deep perforating territory ischemic infarcts Clinical history of HTN or diabetes mellitus Lobar location Cerebral amyloid angiopathy Deep penetrating vasculopathy (HTN) Cortico-subcortical CMBs Convexal superficial siderosis Clinical history of cognitive impairment Intraventricular hemorrhage Arteriovenous malformation Deep penetrating vasculopathy (HTN) Flow voids within or adjacent to ICH Calcification within or adjacent to ICH Cavernous malformation Small ICH with adjacent calcification Cavernous malformation Deep penetrating vasculopathy (HTN) T2-weighted image hyperintensity at center on MRI Peripheral rim of T2- weighted gradient echo image hypointensity on MRI Subarachnoid Ruptured cerebral Perimesencephalic SAH predominates over basal surfaces hemorrhage Basal cisterns aneurysm hemorrhage Clinical history of Non-aneurysmal SAH thunderclap headache Subarachnoid hemorrhage Reversible cerebral vasoconstriction Trauma Hemispheric or cortical ICH Clinical history of recurrent thunderclap headache Cerebral amyloid Convexity syndrome angiopathy Cerebral venous thrombosis https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 35/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Arteriovenous malformation Simultaneous Infective endocarditis Cerebral amyloid CMBs acute infarcts angiopathy Mycotic aneurysms (typically distal arterial locations) Deep penetrating vasculopathy (HTN) Systemic/cutaneous evidence of embolism New heart murmur Cerebral vasculitis Multifocal segmental narrowing on vascular imaging Clinical history of new persistent headaches Progressive cognitive or other neurologic impairment Prominent edema Cerebral sinus thrombosis Subacute ICH of other etiologies Edema/hemorrhage extends to cortical surface Venous flow void (eg, delta and empty-delta signs) Clinical history of seizure or progressive headache Tumor (primary/metastatic) Multifocal lesions Contrast enhancement Clinical history of new persistent headaches Clinical exam findings may be milder than imaging abnormalities Hemorrhagic transformation of (Cytotoxic) Edema appears in distribution of arterial territory infarct Arterial stenosis or occlusion proximal to territory of hemorrhage Clinical history of ischemic risk factors Flow voids Moyamoya Arteriovenous malformation Basal ganglia or hemispheric location Bilateral (but may be asymmetric) narrowing of distal internal carotid or https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 36/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate proximal anterior/middle cerebral arteries Clinical history of episodes of transient weakness with vigorous laughing/crying (Prominent cause of ICH and infarcts in children) ICH: intracerebral hemorrhage; HTN: hypertension; CMB: cerebral microbleeds; MRI: magnetic resonance imaging; SAH: subarachnoid hemorrhage. Graphic 132289 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 37/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Acute and subacute lobar hemorrhage Noncontrast head CT shows acute right parietal ICH (A). T2 susceptibility-weighted sequence on MRI performed one day later shows an acute ICH in the right frontal and parietal hemisphere (B) as well as a subacute hemorrhage in the left occipital lobe (thick arrow) and chronic ICH in right inferior parietal lobule (C; arrow). In addition, multiple microbleeds at cerebral corticomedullary junctions (B, C) are consistent with cerebral amyloid angiopathy. CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132283 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 38/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Excessive perihematomal edema in a patient with hemorrhagic lung metastasis Noncontrast head CT showing left frontal ICH surrounded by excessive volume of hypodense vasogenic edema (A, B). MRI performed one day later shows hyperintense vasogenic edema on T2-weighted gradient echo image (C). Pre- (D) and post-contrast (E) T1-weighted MRI images demonstrate enhancement (arrows) consistent with underlying tumor. CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132284 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 39/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Hemorrhagic transformation of ischemic infarction Noncontrast head CT (A) shows heterogeneous hyperdensity within hypodense region involving right frontal and insular lobes. On subsequent MRI of the brain, FLAIR (B), T2 gradient recall echo (C), and DWI (D) sequences show hypointense ICH (thin arrows) and hyperintensities consistent with acute infarction in the distribution of the right middle cerebral artery (thick arrows). CT: computed tomography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted imaging; ICH: intracerebral hemorrhage. Courtesy of Glenn A Tung, MD, FACR. Graphic 132275 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 40/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Enhancing intracranial vessels associated with ICH due to AVM Noncontrast head CT showing right posterior frontal ICH (A, B). T2- weighted MRI images (C, D) and post-contrast T1-weighted MRI image (E) show flow voids and focal enhancement (arrows), both suspicious for AVM nidus. Subsequent digital subtraction angiograms images (F, G) show both pial AVM nidus (thick arrows). https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 41/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging; AVM: arteriovenous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 132285 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 42/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Multifocal intracerebral hemorrhage from thyroid cancer Noncontrast head CT (A) shows multiple hyperdensities (arrows). T2-weighted gradient echo MRI images show that some but not all lesions are hypointense hemorrhages (B, C). Pre- (D) and post-contrast (E) T1- weighted MRI images show contrast enhancement consistent with metastases. ICH: intracerebral hemorrhage; CT: computed tomography; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132287 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 43/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Intraventricular hemorrhage due to ruptured periventricular arteriovenous malformation Noncontrast head CT (A) showing IVH. CT angiogram (B) showing abnormal tangle of vessels (circle) in the left perisplenial region. Digital subtraction angiogram (C) showing AVM nidus (circle). CT: computed tomography; IVH: intraventricular hemorrhage; AVM: arteriovenous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 132281 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 44/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Goal blood pressure according to baseline risk for cardiovascular disease and method of measuring blood pressure Routine/conventional office blood pressure Unattended AOBPM, (manual measurement daytime ABPM, or home with stethoscope or blood pressure oscillometric device) Higher-risk population 125 to 130/<80 120 to 125/<80 Known ASCVD Heart failure Diabetes mellitus Chronic kidney disease Age 65 years Calculated 10-year risk of ASCVD event 10% Lower-risk 130 to 139/<90 125 to 135/<90 None of the above risk factors All target ranges presented above are in mmHg. On average, blood pressure readings are 5 to 10 mmHg lower with digital, unattended, or out-of- office methods of measurement (ie, AOBPM, daytime ABPM, home blood pressure) than with routine/standard methods of office measurement (ie, manual auscultatory or oscillometric measurement), presumably due to the "white coat effect." However, it is critical to realize that this average difference in blood pressures according to the methodology of measurement applies to the population and not the individual. Some patients do not experience a white coat effect, and, therefore, there is some uncertainty in setting goals that are specific to the method of measurement. When treating to these goals, a patient may (inadvertently) attain a blood pressure below the given target. Provided the patient does not develop symptoms, side effects, or adverse events as a result of the treatment regimen, then reducing or withdrawing antihypertensive medications is unnecessary. Less aggressive goals than those presented in the table may be appropriate for specific groups of patients, including those with postural hypotension, the frail older adult patient, and those with side effects to multiple antihypertensive medications. AOBPM: automated oscillometric blood pressure monitoring; ABPM: ambulatory blood pressure monitoring; ASCVD: atherosclerotic cardiovascular disease; ACC/AHA: American College of Cardiology/American Heart Association. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 45/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Office blood pressure must be performed adequately in order to use such measurements to manage patients. Critical to an adequate office assessment of blood pressure are proper patient positioning (eg, seated in a chair, feet flat on the floor, arm supported, remove clothing covering the location of cuff placement) and proper technique (eg, calibrated device, proper-sized cuff). The average of multiple measurements should be used for management. Refer to UpToDate topics on measurement of blood pressure. Office readings should not be used to manage blood pressure unless it is performed adequately. Home blood pressure, like office blood pressure, must be performed adequately in order for the measurements to be used to manage patients. First, the accuracy of the home blood pressure device must be verified in the clinician's office. Second, the clinician should verify that the cuff and bladder that the patient will use are the appropriate size. Third, patients should measure their pressure after several minutes of rest and while seated in a chair (back supported and feet flat on the floor) with their arm supported (eg, resting on a table). Fourth, the blood pressure should be measured at different times per day and over multiple days. The average value of these multiple measurements is used for management. Home blood pressure readings should not be used to manage blood pressure unless it is performed adequately and in conjunction with office blood pressure or ambulatory blood pressure. The level of evidence supporting the lower goal in higher-risk individuals is stronger for some risk groups (eg, patients with known coronary heart disease, patients with a calculated 10-year risk 15%, chronic kidney disease) than for other risk groups (eg, patients with diabetes, patients with a prior stroke). Refer to UpToDate topics on goal blood pressure for a discussion of the evidence. Prior history of coronary heart disease (acute coronary syndrome or stable angina), prior stroke or transient ischemic attack, prior history of peripheral artery disease. In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized (eg, reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers, rather than targeting one of the blood pressure goals in the table. The 2013 ACC/AHA cardiovascular risk assessment calculator should be used to estimate 10-year cardiovascular disease risk. In the large subgroup of patients who have an initial (pretreatment) blood pressure 140/ 90 mmHg, but who do not have any of the other listed cardiovascular risk factors, some experts would set a more aggressive blood pressure goal of <130/<80 mmHg rather than those presented in the table. This more aggressive goal would likely reduce the chance of developing severe hypertension and ultimately lower the relative risk of cardiovascular events in these lower-risk patients over the long term. However, the absolute benefit of more aggressive blood pressure lowering in these patients is comparatively small, and a lower goal would require more intensive pharmacologic therapy and corresponding side effects. Graphic 117101 Version 3.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 46/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Considerations for individualizing antihypertensive therapy Indication or Antihypertensive drugs contraindication Compelling indications (major improvement in outcome independent of blood pressure) Heart failure with reduced ejection fraction ACE inhibitor or ARB, beta blocker, diuretic, aldosterone antagonist* Postmyocardial infarction ACE inhibitor or ARB, beta blocker, aldosterone antagonist Proteinuric chronic kidney ACE inhibitor or ARB disease Angina pectoris Beta blocker, calcium channel blocker Atrial fibrillation rate control Beta blocker, nondihydropyridine calcium channel blocker Atrial flutter rate control Beta blocker, nondihydropyridine calcium channel blocker Likely to have a favorable effect on symptoms in comorbid conditions Benign prostatic hyperplasia Alpha blocker Essential tremor Beta blocker (noncardioselective) Hyperthyroidism Beta blocker Migraine Beta blocker, calcium channel blocker Osteoporosis Thiazide diuretic Raynaud phenomenon Dihydropyridine calcium channel blocker Contraindications Angioedema Do not use an ACE inhibitor Bronchospastic disease Do not use a non-selective beta blocker Liver disease Do not use methyldopa Pregnancy (or at risk for) Do not use an ACE inhibitor, ARB, or renin inhibitor (eg, aliskiren) Second- or third-degree heart block Do not use a beta blocker, nondihydropyridine calcium channel blocker unless a functioning ventricular pacemaker Drug classes that may have adverse effects on comorbid conditions Depression Generally avoid beta blocker, central alpha-2 agonist Gout Generally avoid loop or thiazide diuretic Hyperkalemia Generally avoid aldosterone antagonist, ACE inhibitor, ARB, renin inhibitor Hyponatremia Generally avoid thiazide diuretic https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 47/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Renovascular disease Generally avoid ACE inhibitor, ARB, or renin inhibitor ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker. A benefit from an aldosterone antagonist has been demonstrated in patients with NYHA class III-IV heart failure or decreased left ventricular ejection fraction after a myocardial infarction. Adapted from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003; 289:2560. Graphic 63628 Version 15.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 48/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Can anticoagulation be resumed after intracerebral hemorrhage*? ICH: intracerebral hemorrhage. Applicable only for patients with a persistent thromboembolic indication for anticoagulation. Timing of initiating/resuming medication depends on strength of indication and ICH features. Refer to the UpToDate topic on secondary prevention and long-term prognosis of spontaneous intracerebral hemorrhage for additional details. Cerebral vascular malformation, ruptured cerebral aneurysm or intracranial dissection, primary or metastatic tumor, cerebral venous thrombosis, cerebral vasculitis, or other cerebral vasculopathy. Refer to the UpToDate topic on secondary prevention and long-term https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 49/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate prognosis of spontaneous intracerebral hemorrhage for additional details. Examples include recurrent deep venous thrombosis or pulmonary embolus. Known bleeding diathesis, severe thrombocytopenia (<50,000/microL), abnormal liver or kidney function, or uncontrolled hypertension; patient prioritizes prevention of hemorrhagic over thromboembolic complications. Graphic 132293 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 50/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted [1] CHADS acronym Score CHADS acronym ischemic stroke rate (% per year) 2 2 Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc acronym 2 2 [2] CHA DS -VASc acronym Score 2 2 (% per year) Congestive HF 1 0 0.2
Home blood pressure, like office blood pressure, must be performed adequately in order for the measurements to be used to manage patients. First, the accuracy of the home blood pressure device must be verified in the clinician's office. Second, the clinician should verify that the cuff and bladder that the patient will use are the appropriate size. Third, patients should measure their pressure after several minutes of rest and while seated in a chair (back supported and feet flat on the floor) with their arm supported (eg, resting on a table). Fourth, the blood pressure should be measured at different times per day and over multiple days. The average value of these multiple measurements is used for management. Home blood pressure readings should not be used to manage blood pressure unless it is performed adequately and in conjunction with office blood pressure or ambulatory blood pressure. The level of evidence supporting the lower goal in higher-risk individuals is stronger for some risk groups (eg, patients with known coronary heart disease, patients with a calculated 10-year risk 15%, chronic kidney disease) than for other risk groups (eg, patients with diabetes, patients with a prior stroke). Refer to UpToDate topics on goal blood pressure for a discussion of the evidence. Prior history of coronary heart disease (acute coronary syndrome or stable angina), prior stroke or transient ischemic attack, prior history of peripheral artery disease. In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized (eg, reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers, rather than targeting one of the blood pressure goals in the table. The 2013 ACC/AHA cardiovascular risk assessment calculator should be used to estimate 10-year cardiovascular disease risk. In the large subgroup of patients who have an initial (pretreatment) blood pressure 140/ 90 mmHg, but who do not have any of the other listed cardiovascular risk factors, some experts would set a more aggressive blood pressure goal of <130/<80 mmHg rather than those presented in the table. This more aggressive goal would likely reduce the chance of developing severe hypertension and ultimately lower the relative risk of cardiovascular events in these lower-risk patients over the long term. However, the absolute benefit of more aggressive blood pressure lowering in these patients is comparatively small, and a lower goal would require more intensive pharmacologic therapy and corresponding side effects. Graphic 117101 Version 3.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 46/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Considerations for individualizing antihypertensive therapy Indication or Antihypertensive drugs contraindication Compelling indications (major improvement in outcome independent of blood pressure) Heart failure with reduced ejection fraction ACE inhibitor or ARB, beta blocker, diuretic, aldosterone antagonist* Postmyocardial infarction ACE inhibitor or ARB, beta blocker, aldosterone antagonist Proteinuric chronic kidney ACE inhibitor or ARB disease Angina pectoris Beta blocker, calcium channel blocker Atrial fibrillation rate control Beta blocker, nondihydropyridine calcium channel blocker Atrial flutter rate control Beta blocker, nondihydropyridine calcium channel blocker Likely to have a favorable effect on symptoms in comorbid conditions Benign prostatic hyperplasia Alpha blocker Essential tremor Beta blocker (noncardioselective) Hyperthyroidism Beta blocker Migraine Beta blocker, calcium channel blocker Osteoporosis Thiazide diuretic Raynaud phenomenon Dihydropyridine calcium channel blocker Contraindications Angioedema Do not use an ACE inhibitor Bronchospastic disease Do not use a non-selective beta blocker Liver disease Do not use methyldopa Pregnancy (or at risk for) Do not use an ACE inhibitor, ARB, or renin inhibitor (eg, aliskiren) Second- or third-degree heart block Do not use a beta blocker, nondihydropyridine calcium channel blocker unless a functioning ventricular pacemaker Drug classes that may have adverse effects on comorbid conditions Depression Generally avoid beta blocker, central alpha-2 agonist Gout Generally avoid loop or thiazide diuretic Hyperkalemia Generally avoid aldosterone antagonist, ACE inhibitor, ARB, renin inhibitor Hyponatremia Generally avoid thiazide diuretic https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 47/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Renovascular disease Generally avoid ACE inhibitor, ARB, or renin inhibitor ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker. A benefit from an aldosterone antagonist has been demonstrated in patients with NYHA class III-IV heart failure or decreased left ventricular ejection fraction after a myocardial infarction. Adapted from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003; 289:2560. Graphic 63628 Version 15.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 48/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Can anticoagulation be resumed after intracerebral hemorrhage? ICH: intracerebral hemorrhage. Applicable only for patients with a persistent thromboembolic indication for anticoagulation. Timing of initiating/resuming medication depends on strength of indication and ICH features. Refer to the UpToDate topic on secondary prevention and long-term prognosis of spontaneous intracerebral hemorrhage for additional details. Cerebral vascular malformation, ruptured cerebral aneurysm or intracranial dissection, primary or metastatic tumor, cerebral venous thrombosis, cerebral vasculitis, or other cerebral vasculopathy. Refer to the UpToDate topic on secondary prevention and long-term https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 49/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate prognosis of spontaneous intracerebral hemorrhage for additional details. Examples include recurrent deep venous thrombosis or pulmonary embolus. Known bleeding diathesis, severe thrombocytopenia (<50,000/microL), abnormal liver or kidney function, or uncontrolled hypertension; patient prioritizes prevention of hemorrhagic over thromboembolic complications. Graphic 132293 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 50/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted [1] CHADS acronym Score CHADS acronym ischemic stroke rate (% per year) 2 2 Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc acronym 2 2 [2] CHA DS -VASc acronym Score 2 2 (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. 2 2 2 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 51/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 52/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Clinical characteristics comprising the HAS-BLED bleeding risk score Letter Clinical characteristic Points H Hypertension (ie, uncontrolled blood pressure) 1 A Abnormal renal and liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding tendency or predisposition 1 L Labile INRs (for patients taking warfarin) 1 E Elderly (age greater than 65 years) 1 D Drugs (concomitant aspirin or NSAIDs) or excess alcohol use (1 point each) 1 or 2 Maximum 9 points HAS-BLED score (total points) Bleeds per 100 patient-years 0 1.13 1 1.02 2 1.88 3 3.74 4 8.70 5 to 9 Insufficient data The HAS-BLED bleeding risk score has only been validated in patients with atrial fibrillation receiving warfarin. Refer to UpToDate topics on anticoagulation in patients with atrial fibrillation and on specific anticoagulants for further information and other bleeding risk scores and their performance relative to clinical judgment. INR: international normalized ratio; NSAIDs: nonsteroidal antiinflammatory drugs. Hypertension is defined as systolic blood pressure >160 mmHg. Abnormal renal function is defined as the presence of chronic dialysis, renal transplantation, or serum creatinine 200 micromol/L. Abnormal liver function is defined as chronic hepatic disease (eg, cirrhosis) or biochemical evidence of significant hepatic derangement (eg, bilirubin more than 2 times the upper limit of normal, plus 1 or more of aspartate transaminase, alanine transaminase, and/or alkaline phosphatase more than 3 times the upper limit of normal). Bleeding predisposition includes chronic bleeding disorder or https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 53/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate previous bleeding requiring hospitalization or transfusion. Labile INRs for a patient on warfarin include unstable INRs, excessively high INRs, or <60% time in therapeutic range. Based on initial validation cohort from Pisters R. A novel-user-friendly score (HAS-BLED) to assess 1- year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093. Actual rates of bleeding in contemporary cohorts may vary from these estimates. Original gure modi ed for this publication. Lip GY. Implications of the CHA2DS2-VASc and HAS-BLED Scores for thromboprophylaxis in atrial brillation. Am J Med 2011; 124:111. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 75259 Version 16.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 54/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 55/56 7/5/23, 12:26 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Contributor Disclosures Magdy Selim, MD, PhD Grant/Research/Clinical Trial Support: NIH/NINDS [Intracerebral hemorrhage]. Consultant/Advisory Boards: MedRhythm, Inc [Neurological recovery]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator-initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 56/56
7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Stroke: Etiology, classification, and epidemiology : Louis R Caplan, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 15, 2022. INTRODUCTION The two broad categories of stroke, hemorrhage and ischemia, are diametrically opposite conditions: hemorrhage is characterized by too much blood within the closed cranial cavity, while ischemia is characterized by too little blood to supply an adequate amount of oxygen and nutrients to a part of the brain [1]. Each of these categories can be divided into subtypes that have somewhat different causes, clinical pictures, clinical courses, outcomes, and treatment strategies. As an example, intracranial hemorrhage can be caused by intracerebral hemorrhage (ICH, also called parenchymal hemorrhage), which involves bleeding directly into brain tissue, and subarachnoid hemorrhage (SAH), which involves bleeding into the cerebrospinal fluid that surrounds the brain and spinal cord [1]. This topic will review the classification of stroke. The clinical diagnosis of stroke subtypes and an overview of stroke evaluation are discussed separately. (See "Clinical diagnosis of stroke subtypes" and "Overview of the evaluation of stroke".) DEFINITIONS Stroke is classified into two major types: Brain ischemia due to thrombosis, embolism, or systemic hypoperfusion https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 1/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Brain hemorrhage due to intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) A stroke is the acute neurologic injury that occurs as a result of one of these pathologic processes. Approximately 80 percent of strokes are due to ischemic cerebral infarction and 20 percent to brain hemorrhage. (See 'Epidemiology' below.) An infarcted brain is pale initially. Within hours to days, the gray matter becomes congested with engorged, dilated blood vessels and minute petechial hemorrhages. When an embolus blocking a major vessel migrates, lyses, or disperses within minutes to days, recirculation into the infarcted area can cause a hemorrhagic infarction and may aggravate edema formation due to disruption of the blood-brain barrier. Transient ischemic attack (TIA) is defined clinically by the temporary nature of the associated neurologic symptoms, which last less than 24 hours by the classic definition. The definition is changing with recognition that transient neurologic symptoms are frequently associated with permanent brain tissue injury. The definition of TIA is discussed in more detail separately. (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Definition of TIA'.) A primary ICH damages the brain directly at the site of the hemorrhage by compressing the surrounding tissue. Physicians must initially consider whether the patient with suspected cerebrovascular disease is experiencing symptoms and signs suggestive of ischemia or hemorrhage. The great majority of ischemic strokes are caused by a diminished supply of arterial blood, which carries sugar and oxygen to brain tissue. Another cause of stroke that is difficult to classify is stroke due to occlusion of veins that drain the brain of blood. Venous occlusion causes a backup of fluid resulting in brain edema, and in addition it may cause both brain ischemia and hemorrhage into the brain. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) BRAIN ISCHEMIA There are three main subtypes of brain ischemia [2]: Thrombosis (see 'Thrombosis' below) generally refers to local in situ obstruction of an artery. The obstruction may be due to disease of the arterial wall, such as arteriosclerosis, dissection, or fibromuscular dysplasia; there may or may not be superimposed thrombosis. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 2/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Embolism (see 'Embolism' below) refers to particles of debris originating elsewhere that block arterial access to a particular brain region [3]. Since the process is not local (as with thrombosis), local therapy only temporarily solves the problem; further events may occur if the source of embolism is not identified and treated. Systemic hypoperfusion (see 'Systemic hypoperfusion' below) is a more general circulatory problem, manifesting itself in the brain and perhaps other organs. Blood disorders (see 'Blood disorders' below) are an uncommon primary cause of stroke. However, increased blood coagulability can result in thrombus formation and subsequent cerebral embolism in the presence of an endothelial lesion located in the heart, aorta, or large arteries that supply the brain. Thrombosis Thrombotic strokes are those in which the pathologic process giving rise to thrombus formation in an artery produces a stroke either by reduced blood flow distally (low flow) or by an embolic fragment that breaks off and travels to a more distant vessel (artery-to- artery embolism). Thrombotic strokes can be divided into either large or small vessel disease ( table 1). These two subtypes of thrombosis are worth distinguishing since the causes, outcomes, and treatments are different. Large vessel disease Large vessels include both the extracranial (common and internal carotids, vertebral) and intracranial arterial system (Circle of Willis and proximal branches) ( figure 1 and figure 2). Intrinsic lesions in large extracranial and intracranial arteries cause symptoms by reducing blood flow beyond obstructive lesions, and by serving as the source of intra-arterial emboli. At times a combination of mechanisms is operant. Severe stenosis promotes the formation of thrombi which can break off and embolize, and the reduced blood flow caused by the vascular obstruction makes the circulation less competent at washing out and clearing these emboli. Pathologies affecting large extracranial vessels include: Atherosclerosis Dissection Takayasu arteritis Giant cell arteritis Fibromuscular dysplasia Pathologies affecting large intracranial vessels include: Atherosclerosis https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 3/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Dissection Arteritis/vasculitis Noninflammatory vasculopathy Moyamoya syndrome Vasoconstriction Atherosclerosis is by far the most common cause of in situ local disease within the large extracranial and intracranial arteries that supply the brain. White platelet-fibrin and red erythrocyte-fibrin thrombi are often superimposed upon the atherosclerotic lesions, or they may develop without severe vascular disease in patients with hypercoagulable states. Vasoconstriction (eg, with migraine) is probably the next most common, followed in frequency by arterial dissection (a disorder much more common than previously recognized) and traumatic occlusion. Fibromuscular dysplasia is an uncommon arteriopathy, while arteritis is frequently mentioned in the differential diagnosis, but it is an extremely rare cause of thrombotic stroke. Aortic disease is really a form of proximal extracranial large vessel disease, but it is often considered together with cardioembolic sources because of anatomic proximity. (See 'Aortic atherosclerosis' below.) Identification of the specific focal vascular lesion, including its nature, severity, and localization, is important for treatment since local therapy may be effective (eg, surgery, angioplasty, intraarterial thrombolysis). It should be possible clinically in most patients to determine whether the local vascular disease is within the anterior (carotid) or posterior (vertebrobasilar) circulation and whether the disorder affects large or penetrating arteries. (See "Clinical diagnosis of stroke subtypes", section on 'Neurologic examination'.) Delivery of adequate blood through a blocked or partially blocked artery depends upon many factors, including blood pressure, blood viscosity, and collateral flow. Local vascular lesions also may throw off emboli, which can cause transient symptoms. In patients with thrombosis, the neurologic symptoms often fluctuate, remit, or progress in a stuttering fashion ( figure 3). (See "Clinical diagnosis of stroke subtypes", section on 'Clinical course of symptoms and signs' and "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Mechanisms and clinical manifestations'.) Small vessel disease Small vessel disease affects the intracerebral arterial system, specifically penetrating arteries that arise from the distal vertebral artery, the basilar artery, the middle cerebral artery stem, and the arteries of the circle of Willis. These arteries thrombose due to: https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 4/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Lipohyalinosis (a lipid hyaline build-up distally secondary to hypertension) and fibrinoid degeneration Atheroma formation at their origin or in the parent large artery The most common cause of obstruction of the smaller arteries and arterioles that penetrate at right angles to supply the deeper structures within the brain (eg, basal ganglia, internal capsule, thalamus, pons) is lipohyalinosis (ie, blockage of an artery by medial hypertrophy and lipid admixed with fibrinoid material in the hypertrophied arterial wall). A stroke due to obstruction of these vessels is referred to as a lacunar stroke (see "Lacunar infarcts"). Lipohyalinosis is most often related to hypertension, but aging may play a role. Microatheromas can also block these small penetrating arteries, as can plaques within the larger arteries that block or extend into the orifices of the branches (called atheromatous branch disease) [1]. Penetrating artery occlusions usually cause symptoms that develop during a short period of time, hours or at most a few days ( figure 4), compared with large artery-related brain ischemia, which can evolve over a longer period. Embolism Embolic strokes are divided into four categories ( table 1) [3]. Those with a known source that is cardiac Those with a possible cardiac or aortic source based upon transthoracic and/or transesophageal echocardiographic findings Those with an arterial source (artery to artery embolism) Those with a truly unknown source in which tests for embolic sources are negative The symptoms depend upon the region of brain rendered ischemic [4,5]. The embolus suddenly blocks the recipient site so that the onset of symptoms is abrupt and usually maximal at the start ( figure 5). Unlike thrombosis, multiple sites within different vascular territories may be affected when the source is the heart (eg, left atrial appendage or left ventricular thrombus) or aorta. Treatment will depend upon the source and composition of the embolus. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) Cardioembolic strokes usually occur abruptly, although they occasionally present with stuttering, fluctuating symptoms. The symptoms may clear entirely since emboli can migrate and lyse, particularly those composed of thrombus. When this occurs, infarction generally also occurs but is silent; the area of infarction is smaller than the area of ischemia that gave rise to the https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 5/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate symptoms. This process is often referred to as a TIA due to embolism, although it is more correctly termed an embolic infarction or stroke in which the symptoms clear within 24 hours. High-risk cardiac source The diagnosis of embolic strokes with a known cardiac source is generally agreed upon by physicians ( table 2) [6,7]; included in this category are those due to: Atrial fibrillation and paroxysmal atrial fibrillation Rheumatic mitral or aortic valve disease Bioprosthetic and mechanical heart valves Atrial or ventricular thrombus Sinus node dysfunction Sustained atrial flutter Recent myocardial infarction (within one month) Chronic myocardial infarction together with ejection fraction <28 percent Symptomatic congestive heart failure with ejection fraction <30 percent Dilated cardiomyopathy Fibrous nonbacterial endocarditis as found in patients with systemic lupus (ie, Libman- Sacks endocarditis), antiphospholipid syndrome, and cancer (marantic endocarditis) Infective endocarditis Papillary fibroelastoma Left atrial myxoma Coronary artery bypass graft (CABG) surgery With CABG, for example, the incidence of postoperative neurologic sequelae is approximately 2 to 6 percent, most of which is due to stroke [8]. Atheroemboli associated with ascending aortic atherosclerosis is probably the most common cause. (See "Neurologic complications of cardiac surgery".) Potential cardiac source Embolic strokes considered to have a potential cardiac source ( table 2) are ones in which a possible source is detected (usually) by echocardiographic methods [6,7,9], including: Patent foramen ovale Atrial septal aneurysm Atrial septal aneurysm with patent foramen ovale Atrial cardiopathy (large or malfunctioning left atrium) Left ventricular aneurysm without thrombus Isolated left atrial smoke on echocardiography (no mitral stenosis or atrial fibrillation) https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 6/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Complex atheroma in the ascending aorta or proximal arch (see 'Aortic atherosclerosis' below) In this group, the association of the cardiac or aortic lesion and the rate of embolism is often uncertain, since some of these lesions do not have a high frequency of embolism and are often incidental findings unrelated to the stroke event [10]. Thus, they are considered potential sources of embolism. A truly unknown source represents embolic strokes in which no clinical evidence of heart disease is present ( table 1). Aortic atherosclerosis In longitudinal population studies with nonselected patients, complex aortic atherosclerosis does not appear to be associated with any increased primary ischemic stroke risk [11-13]. However, most studies evaluating secondary stroke risk have found that complex aortic atherosclerosis is a risk factor for recurrent stroke [14-17]. The range of findings is illustrated by the following studies: A prospective case-control study examined the frequency and thickness of atherosclerotic plaques in the ascending aorta and proximal arch in 250 patients admitted to the hospital with ischemic stroke and 250 consecutive controls, all over the age of 60 years [15]. Atherosclerotic plaques 4 mm in thickness were found in 14 percent of patients compared with 2 percent of controls, and the odds ratio for ischemic stroke among patients with such plaques was 9.1 after adjustment for atherosclerotic risk factors. In addition, aortic atherosclerotic plaques 4 mm were much more common in patients with brain infarcts of unknown cause (relative risk 4.7). In contrast, a population-based study of 1135 subjects who had transesophageal echocardiography (TEE) found that complex atherosclerotic plaque (>4 mm with or without mobile debris) in the ascending and transverse aortic arch was not a significant risk factor for cryptogenic ischemic stroke or TIA after adjusting for age, sex, and other clinical risk factors [12]. However, there was an association between complex aortic plaque and noncryptogenic stroke. The investigators concluded that complex aortic arch debris is a marker for the presence of generalized atherosclerosis. Methodologic differences are a potential explanation for the discrepant results of these reports assessing the risk of ischemic stroke related to aortic atherosclerosis, as the earlier case-control studies may have been skewed by selection and referral bias. However, many patients with aortic atherosclerosis also have cardiac or large artery lesions, a problem that may confound purely epidemiologic studies. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 7/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate In the author's opinion, there is no question that large protruding plaques in the ascending aorta and arch, particularly mobile plaques, are an important cause of stroke [18]. (See "Thromboembolism from aortic plaque".) Systemic hypoperfusion Reduced blood flow is more global in patients with systemic hypoperfusion and does not affect isolated regions. The reduced perfusion can be due to cardiac pump failure caused by cardiac arrest or arrhythmia, or to reduced cardiac output related to acute myocardial ischemia, pulmonary embolism, pericardial effusion, or bleeding. Hypoxemia may further reduce the amount of oxygen carried to the brain. Symptoms of brain dysfunction typically are diffuse and nonfocal in contrast to the other two categories of ischemia. Most affected patients have other evidence of circulatory compromise and hypotension such as pallor, sweating, tachycardia or severe bradycardia, and low blood pressure. The neurologic signs are typically bilateral, although they may be asymmetric when there is preexisting asymmetrical craniocerebral vascular occlusive disease. The most severe ischemia may occur in border zone (watershed) regions between the major cerebral supply arteries since these areas are most vulnerable to systemic hypoperfusion. The signs that may occur with borderzone infarction include cortical blindness, or at least bilateral visual loss; stupor; and weakness of the shoulders and thighs with sparing of the face, hands, and feet (a pattern likened to a "man-in-a-barrel"). Blood disorders Blood and coagulation disorders are an uncommon primary cause of stroke and TIA, but they should be considered in patients younger than age 45, patients with a history of clotting dysfunction, and in patients with a history of cryptogenic stroke [10]. The blood disorders associated with arterial cerebral infarction include: Sickle cell anemia Polycythemia vera Essential thrombocytosis Heparin induced thrombocytopenia Protein C or S deficiency, acquired or congenital Prothrombin gene mutation Factor V Leiden (resistance to activated protein C) Antithrombin III deficiency Antiphospholipid syndrome Hyperhomocysteinemia Thrombotic thrombocytopenic purpura (TTP) https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 8/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Factor V Leiden mutation and prothrombin 20210 mutations are associated mostly with venous rather than arterial thrombosis. They can result in cerebral venous thrombosis or deep venous thrombosis with paradoxical emboli. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) Infectious and inflammatory disease such as pneumonia, urinary tract infections, Crohn disease, ulcerative colitis, HIV/AIDS, and cancers result in a rise in acute phase reactants such as fibrinogen, C-reactive protein, and coagulation factors VII and VIII. In the presence of an endothelial cardiac or vascular lesion, this increase can promote active thrombosis and embolism. CLASSIFICATION SYSTEMS FOR ISCHEMIC STROKE TOAST classification The TOAST classification scheme for ischemic stroke is widely used and has good interobserver agreement [19]. The TOAST system ( table 3) attempts to classify ischemic strokes according to the major pathophysiologic mechanisms that are recognized as the cause of most ischemic strokes ( table 1). It assigns ischemic strokes to five subtypes based upon clinical features and the results of ancillary studies including brain imaging, neurovascular evaluations, cardiac tests, and laboratory evaluations for a prothrombotic state. The five TOAST subtypes of ischemic stroke are: Large artery atherosclerosis Cardioembolism Small vessel occlusion Stroke of other determined etiology Stroke of undetermined etiology The last subtype, stroke of undetermined etiology, involves cases where the cause of a stroke cannot be determined with any degree of confidence, and by definition includes those with two or more potential causes identified, those with a negative evaluation, and those with an incomplete evaluation. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) SSS-TOAST and CCS classification Since the original TOAST classification scheme was developed in the early 1990s, advances in stroke evaluation and diagnostic imaging have allowed more frequent identification of potential vascular and cardiac causes of stroke [6]. These advances could cause an increasing proportion of ischemic strokes to be classified as https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 9/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate "undetermined" if the strict definition of this category (cases with two or more potential causes) is applied. As a result, an evidenced-based modification of the TOAST criteria called SSS-TOAST was developed [6]. The SSS-TOAST system divides each of the original TOAST subtypes into three subcategories as "evident," "probable," or "possible" based upon the weight of diagnostic evidence as determined by predefined clinical and imaging criteria. In a further refinement, an automated version of the SSS-TOAST called the Causative Classification System (CCS) was devised ( table 4) to improve its usefulness and accuracy for stroke subtyping [20]. The CCS is a computerized algorithm that consists of questionnaire-style classification scheme. The CCS appears to have good inter-rater reliability among multiple centers [21]. It is available online at https://ccs.mgh.harvard.edu/ccs_title.php. The overall agreement between the original TOAST and CCS classification systems appears to be moderate at best, suggesting that two methods often classify stroke cases into different categories despite having categories with similar names [22]. BRAIN HEMORRHAGE There are two main subtypes of brain hemorrhage [2]: Intracerebral hemorrhage (ICH) refers to bleeding directly into the brain parenchyma Subarachnoid hemorrhage (SAH) refers to bleeding into the cerebrospinal fluid within the subarachnoid space that surrounds the brain Intracerebral hemorrhage Bleeding in ICH is usually derived from arterioles or small arteries. The bleeding is directly into the brain, forming a localized hematoma that spreads along white matter pathways. Accumulation of blood occurs over minutes or hours; the hematoma gradually enlarges by adding blood at its periphery like a snowball rolling downhill. The hematoma continues to grow until the pressure surrounding it increases enough to limit its spread or until the hemorrhage decompresses itself by emptying into the ventricular system or into the cerebrospinal fluid (CSF) on the pial surface of the brain [23,24]. The most common causes of ICH are hypertension, trauma, bleeding diatheses, amyloid angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations [23,24] (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis"). Less frequent causes include bleeding into tumors, aneurysmal rupture, and vasculitis. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 10/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate The earliest symptoms of ICH relate to dysfunction of the portion of the brain that contains the hemorrhage [23,24]. As examples: Bleeding into the right putamen and internal capsule region causes left limb motor and/or sensory signs Bleeding into the cerebellum causes difficulty walking Bleeding into the left temporal lobe presents as aphasia The neurologic symptoms usually increase gradually over minutes or a few hours. In contrast to brain embolism and SAH, the neurologic symptoms related to ICH may not begin abruptly and are not maximal at onset ( figure 6) (and see below). Headache, vomiting, and a decreased level of consciousness develop if the hematoma becomes large enough to increase intracranial pressure or cause shifts in intracranial contents ( figure 7) [23,24]. These symptoms are absent with small hemorrhages; the clinical presentation in this setting is that of a gradually progressing stroke. ICH destroys brain tissue as it enlarges. The pressure created by blood and surrounding brain edema is life threatening; large hematomas have a high mortality and morbidity. The goal of treatment is to contain and limit the bleeding. Recurrences are unusual if the causative disorder is controlled (eg, hypertension or bleeding diathesis). Subarachnoid hemorrhage The two major causes of SAH are rupture of arterial aneurysms that lie at the base of the brain and bleeding from vascular malformations that lie near the pial surface. Bleeding diatheses, trauma, amyloid angiopathy, and illicit drug use are less common. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Rupture of an aneurysm releases blood directly into the CSF under arterial pressure. The blood spreads quickly within the CSF, rapidly increasing intracranial pressure. Death or deep coma ensues if the bleeding continues. The bleeding usually lasts only a few seconds but rebleeding is very common. With causes of SAH other than aneurysm rupture, the bleeding is less abrupt and may continue over a longer period of time. Symptoms of SAH begin abruptly in contrast to the more gradual onset of ICH. The sudden increase in pressure causes a cessation of activity (eg, loss of memory or focus or knees buckling). Headache is an invariable symptom and is typically instantly severe and widespread; the pain may radiate into the neck or even down the back into the legs. Vomiting occurs soon after onset. There are usually no important focal neurologic signs unless bleeding occurs into the brain and CSF at the same time (meningocerebral hemorrhage). Onset headache is more common than in ICH, and the combination of onset headache and vomiting is infrequent in https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 11/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate ischemic stroke ( figure 7) [25]. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Approximately 30 percent of patients have a minor hemorrhage manifested only by sudden and severe headache (the so-called sentinel headache) that precedes a major SAH ( figure 7) [25]. The complaint of the sudden onset of severe headache is sufficiently characteristic that SAH should always be considered. In a prospective study of 148 patients presenting with sudden and severe headache, for example, SAH was present in 25 percent overall and 12 percent in patients in whom headache was the only symptom [26]. EPIDEMIOLOGY Globally, ischemia accounts for 62 percent, intracerebral hemorrhage 28 percent, and subarachnoid hemorrhage 10 percent of all incident strokes, reflecting a higher incidence of hemorrhagic stroke in low- and middle-income countries [27,28]. In the United States, the proportion of all strokes due to ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage is 87, 10, and 3 percent, respectively [29]. The lifetime risk of stroke for adult men and women (25 years of age and older) is approximately 25 percent [30]. The highest risk of stroke is found in East Asia, Central Europe, and Eastern Europe. Worldwide, stroke is the second most common cause of mortality and the second most common cause of disability [31]. In China, which has the greatest burden of stroke in the world, the age-standardized prevalence, incidence, and mortality rates are estimated to be 1115, 247, and 115 per 100,000 person-years, respectively [32]. These data suggest that the stroke prevalence in China is relatively low compared with the prevalence in high-income countries, but the stroke incidence and mortality rates in China are among the highest in the world. While the incidence of stroke is decreasing in high-income countries, including the United States [33-35], the incidence is increasing in low-income countries [36]. The overall rate of stroke-related mortality is decreasing in high and low income countries, but the absolute number of people with stroke, stroke survivors, stroke-related deaths, and the global burden of stroke-related disability is high and increasing [37]. In the United States, the annual incidence of new or recurrent stroke is about 795,000, of which about 610,000 are first-ever strokes, and 185,000 are recurrent strokes [29]. There is a higher regional incidence and prevalence of stroke and a higher stroke mortality rate in the southeastern United States (sometimes referred to as the "stroke belt") than in the rest of the country [38-42]. The lifetime risk of stroke is higher for females compared with males [29]. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 12/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Black and Hispanic Americans have an increased risk of stroke compared with White Americans, as illustrated by the following observations: The Northern Manhattan Study reported that the age-adjusted incidence of first ischemic stroke among White, Hispanic, and Black Americans was 88, 149, and 191 per 100,000 respectively [43]. Among Black compared with White Americans, the relative rate of stroke attributed to intracranial atherosclerosis, extracranial atherosclerosis, lacunes, and cardioembolism was 5.85, 3.18, 3.09, and 1.58 respectively. Among Hispanic compared with White Americans, the relative rate of stroke attributed to intracranial atherosclerosis, extracranial atherosclerosis, lacunes, and cardioembolism was 5.00, 1.71, 2.32, and 1.42. The Greater Cincinnati/Northern Kentucky Stroke Study showed that small vessel strokes and strokes of undetermined origin were nearly twice as common, and large vessel strokes were 40 percent more common, among Black compared with White patients [44]. The incidence of cardioembolic strokes was not significantly different. An increased incidence of stroke has also been found among Mexican Americans compared with non-Hispanic White Americans [45]. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 13/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate SUMMARY Classification Stroke is classified into two major types (see 'Definitions' above): Brain ischemia due to thrombosis, embolism, or systemic hypoperfusion Brain hemorrhage due to intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) Ischemia - There are three main subtypes of brain ischemia ( table 1): Thrombosis generally refers to local in situ obstruction of an artery. The obstruction may be due to disease of the arterial wall, such as atherosclerosis, arteriosclerosis, dissection, or fibromuscular dysplasia; there may or may not be superimposed thrombosis. Thrombotic strokes can be divided into either large or small vessel disease. These two subtypes of thrombosis are worth distinguishing since the causes, outcomes, and treatments are different. (See 'Thrombosis' above.) Embolism refers to particles of debris originating elsewhere that block arterial access to a particular brain region. The source of embolism is most often from the heart or from an artery (artery-to-artery embolism). (See 'Embolism' above.) Systemic hypoperfusion is a more general circulatory problem, manifesting itself in the brain and perhaps other organs. (See 'Systemic hypoperfusion' above.) Blood disorders are an uncommon primary cause of stroke. However, increased blood coagulability can result in thrombus formation and subsequent cerebral embolism in the presence of an endothelial lesion located in the heart, aorta, or large arteries that supply the brain. (See 'Blood disorders' above.) Ischemic stroke classification The TOAST classification scheme for ischemic stroke ( table 3) is widely used and has good interobserver agreement. The SSS-TOAST system divides each of the original TOAST subtypes into three subcategories as "evident," "probable," or "possible" based upon the weight of diagnostic. The Causative Classification System (CCS) ( table 4) is an automated version of the SSS-TOAST. (See 'Classification systems for ischemic stroke' above.) Brain hemorrhage There are two main subtypes of brain hemorrhage: ICH refers to bleeding directly into the brain parenchyma. Accumulation of blood occurs over minutes or hours. The most common causes of ICH are hypertension, trauma, https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 14/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate bleeding diatheses, amyloid angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations. Less frequent causes include bleeding into tumors, aneurysmal rupture, and vasculitis. (See 'Intracerebral hemorrhage' above.) SAH refers to bleeding into the cerebrospinal fluid within the subarachnoid space that surrounds the brain. The two major causes of SAH are rupture of arterial aneurysms that lie at the base of the brain and bleeding from vascular malformations that lie near the pial surface. Bleeding diatheses, trauma, amyloid angiopathy, and illicit drug use are less common. Rupture of an aneurysm releases blood directly into the cerebrospinal fluid (CSF) under arterial pressure. The blood spreads quickly within the CSF, rapidly increasing intracranial pressure. Death or deep coma ensues if the bleeding continues. (See 'Subarachnoid hemorrhage' above.) Epidemiology Globally, ischemia accounts for 62 percent, intracerebral hemorrhage 28 percent, and subarachnoid hemorrhage 10 percent of all incident strokes, reflecting a higher incidence of hemorrhagic stroke in low- and middle-income countries. In the United States, the proportion of all strokes due to ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage is 87, 10, and 3 percent, respectively. (See 'Epidemiology' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Caplan LR. Intracranial branch atheromatous disease: a neglected, understudied, and underused concept. Neurology 1989; 39:1246. 2. Caplan LR. Basic pathology, anatomy, and pathophysiology of stroke. In: Caplan's Stroke: A Clinical Approach, 4th ed, Saunders Elsevier, Philadelphia 2009. p.22. 3. Brain embolism, Caplan LR, Manning W (Eds), Informa Healthcare, New York 2006. 4. Caplan LR. Brain embolism, revisited. Neurology 1993; 43:1281. 5. Caplan LR. Brain embolism. In: Clinical Neurocardiology, Caplan LR, Hurst JW, Chimowitz M (Eds), Marcel Dekker, New York 1999. p.35. 6. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. 7. Doufekias E, Segal AZ, Kizer JR. Cardiogenic and aortogenic brain embolism. J Am Coll Cardiol 2008; 51:1049. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 15/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate 8. Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996; 335:1857. 9. Kamel H, Bartz TM, Elkind MSV, et al. Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). Stroke 2018; 49:980. 10. Flemming KD, Brown RD Jr, Petty GW, et al. Evaluation and management of transient ischemic attack and minor cerebral infarction. Mayo Clin Proc 2004; 79:1071. 11. Meissner I, Khandheria BK, Sheps SG, et al. Atherosclerosis of the aorta: risk factor, risk marker, or innocent bystander? A prospective population-based transesophageal echocardiography study. J Am Coll Cardiol 2004; 44:1018. 12. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between atherosclerotic aortic debris and cerebrovascular ischemic events. Mayo Clin Proc 2006; 81:609. 13. Russo C, Jin Z, Rundek T, et al. Atherosclerotic disease of the proximal aorta and the risk of vascular events in a population-based cohort: the Aortic Plaques and Risk of Ischemic Stroke (APRIS) study. Stroke 2009; 40:2313. 14. Amarenco P, Duyckaerts C, Tzourio C, et al. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992; 326:221. 15. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474. 16. Cohen A, Tzourio C, Bertrand B, et al. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke. FAPS Investigators. French Study of Aortic Plaques in Stroke. Circulation 1997; 96:3838. 17. Di Tullio MR, Russo C, Jin Z, et al. Aortic arch plaques and risk of recurrent stroke and death. Circulation 2009; 119:2376. 18. Caplan LR. The aorta as a donor source of brain embolism. In: Brain embolism, Caplan, LR, Manning, WJ (Eds), Informa Healthcare, New York 2006. p.187. 19. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic
th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 13/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate SUMMARY Classification Stroke is classified into two major types (see 'Definitions' above): Brain ischemia due to thrombosis, embolism, or systemic hypoperfusion Brain hemorrhage due to intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) Ischemia - There are three main subtypes of brain ischemia ( table 1): Thrombosis generally refers to local in situ obstruction of an artery. The obstruction may be due to disease of the arterial wall, such as atherosclerosis, arteriosclerosis, dissection, or fibromuscular dysplasia; there may or may not be superimposed thrombosis. Thrombotic strokes can be divided into either large or small vessel disease. These two subtypes of thrombosis are worth distinguishing since the causes, outcomes, and treatments are different. (See 'Thrombosis' above.) Embolism refers to particles of debris originating elsewhere that block arterial access to a particular brain region. The source of embolism is most often from the heart or from an artery (artery-to-artery embolism). (See 'Embolism' above.) Systemic hypoperfusion is a more general circulatory problem, manifesting itself in the brain and perhaps other organs. (See 'Systemic hypoperfusion' above.) Blood disorders are an uncommon primary cause of stroke. However, increased blood coagulability can result in thrombus formation and subsequent cerebral embolism in the presence of an endothelial lesion located in the heart, aorta, or large arteries that supply the brain. (See 'Blood disorders' above.) Ischemic stroke classification The TOAST classification scheme for ischemic stroke ( table 3) is widely used and has good interobserver agreement. The SSS-TOAST system divides each of the original TOAST subtypes into three subcategories as "evident," "probable," or "possible" based upon the weight of diagnostic. The Causative Classification System (CCS) ( table 4) is an automated version of the SSS-TOAST. (See 'Classification systems for ischemic stroke' above.) Brain hemorrhage There are two main subtypes of brain hemorrhage: ICH refers to bleeding directly into the brain parenchyma. Accumulation of blood occurs over minutes or hours. The most common causes of ICH are hypertension, trauma, https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 14/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate bleeding diatheses, amyloid angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations. Less frequent causes include bleeding into tumors, aneurysmal rupture, and vasculitis. (See 'Intracerebral hemorrhage' above.) SAH refers to bleeding into the cerebrospinal fluid within the subarachnoid space that surrounds the brain. The two major causes of SAH are rupture of arterial aneurysms that lie at the base of the brain and bleeding from vascular malformations that lie near the pial surface. Bleeding diatheses, trauma, amyloid angiopathy, and illicit drug use are less common. Rupture of an aneurysm releases blood directly into the cerebrospinal fluid (CSF) under arterial pressure. The blood spreads quickly within the CSF, rapidly increasing intracranial pressure. Death or deep coma ensues if the bleeding continues. (See 'Subarachnoid hemorrhage' above.) Epidemiology Globally, ischemia accounts for 62 percent, intracerebral hemorrhage 28 percent, and subarachnoid hemorrhage 10 percent of all incident strokes, reflecting a higher incidence of hemorrhagic stroke in low- and middle-income countries. In the United States, the proportion of all strokes due to ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage is 87, 10, and 3 percent, respectively. (See 'Epidemiology' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Caplan LR. Intracranial branch atheromatous disease: a neglected, understudied, and underused concept. Neurology 1989; 39:1246. 2. Caplan LR. Basic pathology, anatomy, and pathophysiology of stroke. In: Caplan's Stroke: A Clinical Approach, 4th ed, Saunders Elsevier, Philadelphia 2009. p.22. 3. Brain embolism, Caplan LR, Manning W (Eds), Informa Healthcare, New York 2006. 4. Caplan LR. Brain embolism, revisited. Neurology 1993; 43:1281. 5. Caplan LR. Brain embolism. In: Clinical Neurocardiology, Caplan LR, Hurst JW, Chimowitz M (Eds), Marcel Dekker, New York 1999. p.35. 6. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. 7. Doufekias E, Segal AZ, Kizer JR. Cardiogenic and aortogenic brain embolism. J Am Coll Cardiol 2008; 51:1049. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 15/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate 8. Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996; 335:1857. 9. Kamel H, Bartz TM, Elkind MSV, et al. Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). Stroke 2018; 49:980. 10. Flemming KD, Brown RD Jr, Petty GW, et al. Evaluation and management of transient ischemic attack and minor cerebral infarction. Mayo Clin Proc 2004; 79:1071. 11. Meissner I, Khandheria BK, Sheps SG, et al. Atherosclerosis of the aorta: risk factor, risk marker, or innocent bystander? A prospective population-based transesophageal echocardiography study. J Am Coll Cardiol 2004; 44:1018. 12. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between atherosclerotic aortic debris and cerebrovascular ischemic events. Mayo Clin Proc 2006; 81:609. 13. Russo C, Jin Z, Rundek T, et al. Atherosclerotic disease of the proximal aorta and the risk of vascular events in a population-based cohort: the Aortic Plaques and Risk of Ischemic Stroke (APRIS) study. Stroke 2009; 40:2313. 14. Amarenco P, Duyckaerts C, Tzourio C, et al. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992; 326:221. 15. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474. 16. Cohen A, Tzourio C, Bertrand B, et al. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke. FAPS Investigators. French Study of Aortic Plaques in Stroke. Circulation 1997; 96:3838. 17. Di Tullio MR, Russo C, Jin Z, et al. Aortic arch plaques and risk of recurrent stroke and death. Circulation 2009; 119:2376. 18. Caplan LR. The aorta as a donor source of brain embolism. In: Brain embolism, Caplan, LR, Manning, WJ (Eds), Informa Healthcare, New York 2006. p.187. 19. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24:35. 20. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke 2007; 38:2979. 21. Arsava EM, Ballabio E, Benner T, et al. The Causative Classification of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 16/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate 22. McArdle PF, Kittner SJ, Ay H, et al. Agreement between TOAST and CCS ischemic stroke classification: the NINDS SiGN study. Neurology 2014; 83:1653. 23. Caplan LR. Intracerebral haemorrhage. Lancet 1992; 339:656. 24. Kase CS, Caplan LR. Intracerebral Hemorrhage, Butterworth-Heinemann, Boston 1996. 25. Gorelick PB, Hier DB, Caplan LR, Langenberg P. Headache in acute cerebrovascular disease. Neurology 1986; 36:1445. 26. Linn FH, Wijdicks EF, van der Graaf Y, et al. Prospective study of sentinel headache in aneurysmal subarachnoid haemorrhage. Lancet 1994; 344:590. 27. Krishnamurthi RV, Feigin VL, Forouzanfar MH, et al. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet Glob Health 2013; 1:e259. 28. GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol 2021; 20:795. 29. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation 2022; 145:e153. 30. GBD 2016 Lifetime Risk of Stroke Collaborators, Feigin VL, Nguyen G, et al. Global, Regional, and Country-Specific Lifetime Risks of Stroke, 1990 and 2016. N Engl J Med 2018; 379:2429. 31. GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18:459. 32. Wang W, Jiang B, Sun H, et al. Prevalence, Incidence, and Mortality of Stroke in China: Results from a Nationwide Population-Based Survey of 480 687 Adults. Circulation 2017; 135:759. 33. Koton S, Schneider AL, Rosamond WD, et al. Stroke incidence and mortality trends in US communities, 1987 to 2011. JAMA 2014; 312:259. 34. Vangen-L nne AM, Wilsgaard T, Johnsen SH, et al. Declining Incidence of Ischemic Stroke: What Is the Impact of Changing Risk Factors? The Troms Study 1995 to 2012. Stroke 2017; 48:544. 35. Madsen TE, Khoury JC, Leppert M, et al. Temporal Trends in Stroke Incidence Over Time by Sex and Age in the GCNKSS. Stroke 2020; 51:1070. 36. Feigin VL, Forouzanfar MH, Krishnamurthi R, et al. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet 2014; 383:245. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 17/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate 37. GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18:439. 38. Lanska DJ. Geographic distribution of stroke mortality in the United States: 1939-1941 to 1979-1981. Neurology 1993; 43:1839. 39. Casper ML, Wing S, Anda RF, et al. The shifting stroke belt. Changes in the geographic pattern of stroke mortality in the United States, 1962 to 1988. Stroke 1995; 26:755. 40. Centers for Disease Control and Prevention (CDC). Disparities in deaths from stroke among persons aged <75 years United States, 2002. MMWR Morb Mortal Wkly Rep 2005; 54:477. 41. Rich DQ, Gaziano JM, Kurth T. Geographic patterns in overall and specific cardiovascular disease incidence in apparently healthy men in the United States. Stroke 2007; 38:2221. 42. Glymour MM, Kosheleva A, Boden-Albala B. Birth and adult residence in the Stroke Belt independently predict stroke mortality. Neurology 2009; 73:1858. 43. White H, Boden-Albala B, Wang C, et al. Ischemic stroke subtype incidence among whites, blacks, and Hispanics: the Northern Manhattan Study. Circulation 2005; 111:1327. 44. Schneider AT, Kissela B, Woo D, et al. Ischemic stroke subtypes: a population-based study of incidence rates among blacks and whites. Stroke 2004; 35:1552. 45. Morgenstern LB, Smith MA, Lisabeth LD, et al. Excess stroke in Mexican Americans compared with non-Hispanic Whites: the Brain Attack Surveillance in Corpus Christi Project. Am J Epidemiol 2004; 160:376. Topic 1089 Version 33.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 18/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate GRAPHICS Pathophysiologic ischemic stroke classification Large vessel atherothrombotic stroke More common Bifurcation of the common carotid artery Siphon portion of the common carotid artery Middle cerebral artery stem Intracranial vertebral arteries proximal to middle basilar artery Origin of the vertebral arteries Less common Origin of the common carotid artery Posterior cerebral artery stem Origin of the major branches of the basilar-vertebral arteries Origin of the branches of the anterior, middle, and posterior cerebral arteries Small vessel (lacunar) stroke Mechanism Lipohyalinotic occlusion Less frequently proximal atherothrombotic occlusion Least likely embolic occlusion Most common locations Penetrating branches of the anterior, middle, and posterior cerebral and basilar arteries Cardioaortic embolic stroke Cardiac sources definite - antithrombotic therapy generally used Left atrial thrombus Left ventricular thrombus Atrial fibrillation and paroxysmal atrial fibrillation Sustained atrial flutter Recent myocardial infarction (within one month) Rheumatic mitral or aortic valve disease Bioprosthetic and mechanical heart valve https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 19/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Chronic myocardial infarction with ejection fraction <28 percent Symptomatic heart failure with ejection fraction <30 percent Dilated cardiomyopathy Cardiac sources definite - anticoagulation hazardous Bacterial endocarditis (exception nonbacterial) Atrial myxoma Cardiac sources possible Mitral annular calcification Patent foramen ovale Atrial septal aneurysm Atrial septal aneurysm with patent foramen ovale Left ventricular aneurysm without thrombus Isolated left atrial spontaneous echo contrast ("smoke") without mitral stenosis or atrial fibrillation Mitral valve strands Ascending aortic atheromatous disease (>4 mm) True unknown source embolic stroke Other Dissection Moyamoya Binswanger's disease Primary thrombosis Cerebral mass Graphic 55099 Version 4.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 20/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Anatomy of the cerebral arterial circulation Frontal view of the carotid arteries, vertebral arteries, and intracranial vessels and their communication with each other via the circle of Willis. Reproduced with permission from: U acker R. Atlas Of Vascular Anatomy: An Angiographic Approach, Second Edition. Philadelphia: Lippincott Williams & Wilkins, 2006. Copyright 2006 Lippincott Williams & Wilkins. Graphic 51410 Version 6.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 21/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Major cerebral vascular territories Representation of the territories of the major cerebral vessels shown in a coronal section of the brain. Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases. Harrison's Principles of Internal Medicine, 13th ed, McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 65199 Version 2.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 22/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Stuttering time course of thrombotic stroke The course of weakness of the right limb in a patient with a thrombotic stroke reveals fluctuating symptoms, varying between normal and abnormal, progressing in a stepwise or stuttering fashion with some periods of improvement. Graphic 64107 Version 2.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 23/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Time course of lacunar infarction Penetrating artery occlusions usually cause symptoms that develop over a short period of time, hours or at most a few days, compared to large artery-related brain ischemia which can evolve over a longer period. A stuttering course may ensue, as with large artery thrombosis. This patient had a pure motor hemiparesis. Graphic 52246 Version 1.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 24/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Time course of embolic stroke Embolic stroke occurs suddenly, with symptoms maximal at onset. This patient had multiple embolic events with different clinical symptoms (initially weakness, followed by paresthesias). Graphic 73261 Version 1.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 25/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Cardioaortic sources of cerebral embolism Sources with high primary risk for ischemic stroke Sources with low or uncertain primary risk for ischemic stroke Atrial fibrillation Cardiac sources of embolism: Paroxysmal atrial fibrillation Mitral annular calcification Left atrial thrombus Patent foramen ovale Left ventricular thrombus Atrial septal aneurysm Sick sinus syndrome Atrial septal aneurysm and patent foramen ovale Atrial flutter Left ventricular aneurysm without thrombus Recent myocardial infarction (within one month prior to stroke) Left atrial spontaneous echo contrast ("smoke") Mitral stenosis or rheumatic valve disease Congestive heart failure with ejection fraction <30% Mechanical heart valves Bioprosthetic heart valves Chronic myocardial infarction together with low ejection fraction (<28%) Apical akinesia Dilated cardiomyopathy (prior established Wall motion abnormalities (hypokinesia, diagnosis or left ventricular dilatation with an akinesia, dyskinesia) other than apical akinesia ejection fraction of <40% or fractional shortening of <25%) Nonbacterial thrombotic endocarditis Hypertrophic cardiomyopathy Infective endocarditis Left ventricular hypertrophy Papillary fibroelastoma Left ventricular hypertrabeculation/non- compaction Left atrial myxoma Recent aortic valve replacement or coronary artery bypass graft surgery Presence of left ventricular assist device Paroxysmal supraventricular tachycardia Aortic sources of embolism: Complex atheroma in the ascending aorta or proximal arch (protruding with >4 mm thickness, or mobile debris, or plaque ulceration) The high- and low-risk cardioaortic sources in this table are separated using an arbitrary 2% annual https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 26/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate or one-time primary stroke risk threshold. Data from: 1. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. 2. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. 3. Arsava EM, Ballabio E, Benner T, et al. The Causative Classi cation of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. 4. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 2013; 44:1550. 5. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017; 36:1080. Reproduced and modi ed with permission from: Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. Copyright 2005 American Neurological Association. Graphic 60843 Version 11.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 27/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate TOAST classification of subtypes of acute ischemic stroke Large-artery atherosclerosis Cardioembolism Small-vessel occlusion Stroke of other determined etiology Stroke of undetermined etiology Two or more causes identified Negative evaluation Incomplete evaluation Graphic 62571 Version 1.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 28/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Causative Classification System (CCS) of ischemic stroke etiology Stroke Level of Criteria mechanism confidence 1. Either occlusive or stenotic ( 50 percent diameter reduction or <50 percent diameter reduction with plaque ulceration or Large artery Evident atherosclerosis thrombosis) vascular disease judged to be caused by atherosclerosis in the clinically relevant extracranial or intracranial arteries, and 2. The absence of acute infarction in vascular territories other than the stenotic or occluded artery 1. History of 1 transient monocular blindness (TMB), TIA, or stroke from the territory of index artery affected by atherosclerosis within the last month, or Probable 2. Evidence of near-occlusive stenosis or nonchronic complete occlusion judged to be caused by atherosclerosis in the clinically relevant extracranial or intracranial arteries (except for the vertebral arteries), or 3. The presence of ipsilateral and unilateral internal watershed infarctions or multiple, temporally separate, infarctions exclusively within the territory of the affected artery Possible 1. The presence of an atherosclerotic plaque protruding into the lumen and causing mild stenosis (<50 percent) in the absence of any detectable plaque ulceration or thrombosis in a clinically relevant extracranial or intracranial artery and history of 2 TMB, TIA, or stroke from the territory of index artery affected by atherosclerosis, at least one event within the last month, or 2. Evidence for evident large artery atherosclerosis in the absence of complete diagnostic investigation for other mechanisms https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 29/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Cardio-aortic embolism Evident The presence of a high-risk cardiac source of cerebral embolism Probable 1. Evidence of systemic embolism, or 2. The presence of multiple acute infarctions that have occurred closely related in time within both right and left anterior or both anterior and posterior circulations in the absence of occlusion or near-occlusive stenosis of all relevant vessels. Other diseases that can cause multifocal ischemic brain injury such as vasculitides, vasculopathies, and hemostatic or hemodynamic disturbances must not be present. Possible 1. The presence of a cardiac condition with low or uncertain primary risk of cerebral embolism, or 2. Evidence for evident cardio-aortic embolism in the absence of complete diagnostic investigation for other mechanisms Small artery Evident Imaging evidence of a single and clinically relevant acute infarction occlusion <20 mm in greatest diameter within the territory of basal or brainstem penetrating arteries in the absence of any other pathology in the parent artery at the site of the origin of the penetrating artery (focal atheroma, parent vessel dissection, vasculitis, vasospasm, etc) Probable 1. The presence of stereotypic lacunar transient ischemic attacks within the past week, or 2. The presence of a classical lacunar syndrome Possible 1. Presenting with a classical lacunar syndrome in the absence of imaging that is sensitive enough to detect small infarctions, or 2. Evidence for evident small artery occlusion in the absence of complete diagnostic investigation for other mechanisms Other causes Evident The presence of a specific disease process that involves clinically appropriate brain arteries Probable A specific disease process that has occurred in clear and close temporal or spatial relationship to the onset of brain infarction such as arterial dissection, cardiac or arterial surgery, and cardiovascular interventions Possible Evidence for an evident other cause in the absence of complete diagnostic investigation for mechanisms listed above https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 30/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Undetermined Unknown (no Cryptogenic embolism: causes evident, probable, or 1. Angiographic evidence of abrupt cut-off consistent with a blood clot within otherwise angiographically normal looking intracranial arteries, or possible criteria for 2. Imaging evidence of complete recanalization of previously the causes occluded artery, or above) 3. The presence of multiple acute infarctions that have occurred closely related in time without detectable abnormality in the relevant vessels Other cryptogenic: Those not fulfilling the criteria for cryptogenic embolism Incomplete evaluation: The absence of diagnostic tests that, under the examiner's judgment, would have been essential to uncover the underlying etiology Unclassified The presence of >1 evident mechanism in which there is either probable evidence for each, or no probable evidence to be able to establish a single cause Reproduced with permission from: Ay H, Benner T, Arsava EM. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. Graphic 57732 Version 4.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 31/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Time course of neurologic changes in intracerebral hemorrhage Schematic representation of rapid downhill course in terms of unusual behavior (solid line), hemimotor function (dotted line), and consciousness (dash-dotted line) in a patient with intracerebral (intraparenchymal) hemorrhage. Graphic 61491 Version 3.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 32/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Headache and vomiting in stroke subtypes The frequency of sentinel headache, onset headache, and vomiting in three subtypes of stroke: subarachnoid hemorrhage, intraparenchymal (intracerebral) hemorrhage, and ischemic stroke. Onset headache was present in virtually all patients with SAH and about one-half of those with IPH; all of these symptoms were infrequent in patients with IS. SAH: subarachnoid hemorrhage; IPH: intraparenchymal (intracerebral) hemorrhage; IS: ischemic stroke. Data from: Gorelick PB, Hier DB, Caplan LR, Langenberg P. Headache in acute cerebrovascular disease. Neurology 1986; 36:1445. Graphic 60831 Version 4.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 33/34 7/5/23, 12:26 PM Stroke: Etiology, classification, and epidemiology - UpToDate Contributor Disclosures Louis R Caplan, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 34/34
7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Vascular malformations of the central nervous system : Robert J Singer, MD, Christopher S Ogilvy, MD, Guy Rordorf, MD : Jos Biller, MD, FACP, FAAN, FAHA, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 08, 2023. INTRODUCTION AND TERMINOLOGY Cerebral vascular malformations refer to a group of conditions characterized by abnormal vascular configurations occurring within the brain (and spinal cord). As a group, they occur in 0.1 to 4.0 percent of the general population [1-3]. Four general subtypes of congenital malformations include: Arteriovenous malformations (AVMs) Cavernous malformations (CMs) Developmental venous anomalies (DVAs) Capillary telangiectasias AVMs may be subcategorized into pial AVMs and dural arteriovenous fistulas. Cavernous malformations have also been called cavernous angiomas, cavernous hemangiomas, and cavernomas. Developmental venous anomalies were previously also called venous angiomas. Developmental venous anomalies are most common in autopsy series, with an incidence of 2 percent [4,5]. This is followed by arteriovenous malformations (1 percent), capillary telangiectasias (0.7 percent), and cavernous malformations (0.4 percent). Developmental venous anomalies and capillary telangiectasia are usually benign, while cavernous malformations and arteriovenous malformations have a greater tendency toward neurologic sequelae. This topic will review cavernous malformations, developmental venous anomalies, and capillary telangiectasias. Cerebral and spinal cord arteriovenous malformations and carotid-cavernous https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 1/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate fistulas are discussed separately. (See "Brain arteriovenous malformations" and "Disorders affecting the spinal cord", section on 'Vascular malformations' and "Carotid-cavernous fistulas".) ARTERIOVENOUS MALFORMATIONS Arteriovenous malformations are the most dangerous congenital vascular malformations. This topic is discussed separately. (See "Brain arteriovenous malformations".) CAVERNOUS MALFORMATIONS Pathogenesis Cavernous malformations (CMs) may occur sporadically or in a familial pattern [6]. Familial CMs Familial CM cases have an autosomal dominant inheritance pattern and are estimated to account for approximately 20 percent of all cases of CMs. Most familial cases have multiple CMs. Pathogenic variants in CCM1 (KRIT1), CCM2, and CCM3 (PDCD10) are known to cause familial CMs [7-9]. The CCM proteins encoded by these three genes interact with each other and are involved with cellular signaling pathways, including formation of a CCM complex signaling platform. Loss of CCM proteins results in the dysregulation of signaling pathways in brain endothelial cells and eventual lesion formation [10,11]. Most of the pathogenic variants constitute loss-of-function mutations involving nonsense, frameshift, or splice site mutations, but larger deletions and duplications have also been reported [6,9,12]. Nearly all familial cases of cerebral CMs among Hispanic Americans have been linked to a founder variant of KRIT1 [13-15]. Familial cases in non-Hispanic White families have been linked to CCM2 [16] and PDCD10 [16,17]. CM may also be found in some patients with genetic conditions such as hereditary hemorrhagic telangiectasia. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pathophysiology'.) Sporadic CMs Approximately 80 percent of CMs are sporadic [18]. Most sporadic cerebral CMs present as solitary lesions and are often associated with a developmental venous anomaly (DVA), but sporadic CMs occasionally present as multiple lesions around the periphery of a DVA [6]. Sporadic CMs appear to be acquired lesions. De novo CMs have been demonstrated on serial magnetic resonance imaging (MRI) [19]. CMs may also develop after cranial radiation therapy [20]. Genetic susceptibilities may underly the development of CMs in some patients [21,22]. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 2/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Novel genetic variants in the CCM pathway were identified in one series of patients with sporadic CMs [23]. In a cohort of 88 patients with sporadic CM, nearly 40 percent were found to have a somatic variant in the PIK3CA oncogene, compared with 10 percent with a variant in a CCM gene [21]. Neuropathology On gross examination, CMs have a characteristic "mulberry" or "popcorn" appearance with engorged purplish clusters. They vary from 2 mm to several centimeters in diameter. Microscopic examination reveals that CMs are composed of dilated, thin-walled capillaries with a simple endothelial lining and a thin, fibrous adventitia. Elastic fibers and smooth muscle are not present in the vessel walls. In the classic description of CMs, there is no intervening brain tissue between the channels of the lesion [24]. However, this may not be an essential criterion of CMs, as one histopathologic study of 71 CM cases noted intervening brain parenchyma in 50 (70 percent) [25], and others have also noted intervening brain tissue in some fraction of cases [26,27]. The immediately surrounding tissue is usually gliotic and hemosiderin laden due to previous hemorrhages. It contains dilated capillaries that may represent telangiectasias; this finding supports the integrative concept of capillary telangiectasias and CMs representing two ends of a spectrum in the development of CMs [26]. Inflammation, calcification, and, rarely, ossification may be identified with CMs, usually in larger lesions [28]. The cerebrum is the most common location for CMs (70 to 90 percent) [29]. They have been reported throughout the supratentorial compartment, but most commonly are subcortical and predisposed to the rolandic and temporal areas. Posterior fossa lesions comprise approximately 25 percent of CMs in most large series, with the majority located in the pons and cerebellar hemispheres. Spinal cord CMs are intramedullary lesions and predominantly involve the cervical and thoracic regions [30,31]. Intramedullary spinal cord CMs are more common than once recognized, with over 600 cases reported in a meta-analysis published in 2014 [30]. DVAs may be associated with CMs, particularly in sporadic cases [32-35]. In a series of 102 patients, DVAs associated with CMs were found in 23 percent; these occurred more often with lesions in the posterior fossa than the supratentorial compartment [32]. A later series of 57 patients with CMs found associated DVAs in 25 percent, and atypical patterns of venous drainage associated with CMs were seen in an additional 35 percent [33]. (See 'Developmental venous anomalies' below.) Epidemiology The incidence of CMs is 0.15 to 0.56 per 100,000 in various populations [36]. CMs occur with equal frequency in males and females, with a mean age of 30 to 40, although females more commonly present with hemorrhage and neurologic deficits [37-39]. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 3/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate CMs may occur sporadically or in a familial pattern. (See 'Familial CMs' above and 'Sporadic CMs' above.) Clinical presentation The presentation of CMs is specific to their location. A substantial proportion are asymptomatic and are found incidentally on brain MRI [40,41]. Supratentorial CMs commonly present with hemorrhage, seizures, and progressive neurologic deficits. Annual bleeding rates of 0.25 to 1.1 percent have been reported in several large series [38,42]. Seizures and progressive neurologic deficits may be the result of mass effect and secondary compromise of the microcirculation or the result of microhemorrhages with local hemosiderin deposition irritating cortical or subcortical tissue. Infratentorial CMs commonly present with hemorrhage and progressive neurologic deficits. Lesions in the brainstem present with cranial neuropathies and long-tract signs that cause progressive neurologic decline due to the high volume of critical nuclei and fiber tracts in this area. Thus, the natural history of brainstem lesions is worse than that of lesions in other areas. The annual bleeding rate for brainstem lesions is 2 to 3 percent per year, with recurrent hemorrhage rates approaching 17 to 21 percent [19]. Progressive neurologic decline is observed in 39 percent. Neuroimaging MRI plays a key role in the identification and diagnosis of CMs [43]. (See 'Confirming the diagnosis' below.) MRI Characteristic findings on T1- and T2-weighted images include a "popcorn" pattern of variable image intensities consistent with evolving blood products ( image 1 and image 2). A dark hemosiderin ring, best seen on T2 or gradient echo sequences at the periphery of the lesion, is suggestive of remote hemorrhage ( image 3). MRI should include gradient echo or susceptibility-weighted imaging ( image 4), which may detect smaller CMs that are not visible on conventional MRI sequences [6,44,45]. Contrast-enhanced images should be obtained once a CM is identified in order to delineate any potential associated DVAs [32]. Contrast-enhanced and susceptibility-weighted imaging sequences often demonstrate DVAs since they are associated with a classic "caput medusae" morphology and draining (or "collector") vein ( image 5 and image 6). On the other hand, CMs may have only scattered enhancement that is variable and inconsequential. This is critical in surgical planning since the resection of DVAs may compromise normal cortical venous drainage patterns and lead to venous infarction [46]. (See 'Developmental venous anomalies' below.) https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 4/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate CT Computed tomography (CT) usually demonstrates a nonspecific, irregular, hyperdense mass from variable degrees of calcification ( image 6). A faint perilesional blush with contrast administration is a variable and nonspecific finding. Evaluation and diagnosis Confirming the diagnosis The diagnosis of CMs is based upon the characteristic radiologic appearance on MRI (see 'Neuroimaging' above). The diagnosis of familial CM is based upon detection of a pathogenic variant in one of the three genes (KRIT1, CCM2, or PDCD10) [6]. Catheter angiography is generally not recommended for the detection of CMs unless arteriovenous malformation is a diagnostic consideration [6]. Blood flow through CMs is minimal. Thus, they may not be seen on angiography and have been referred to as "angiographically occult." CMs demonstrate a capillary blush or early draining vein in approximately 10 percent of patients [29]. These findings may be similar to the angiographic appearance of meningiomas. Genetic testing Genetic testing for pathogenic variants in CCM1 (KRIT1), CCM2, and CCM3 (PDCD10) is indicated for patients with multiple CMs on imaging, a history of brain radiation therapy, or a positive family history of CMs [6]. Testing should include direct sequencing and deletion/duplication analysis. For new cases of CMs, clinicians should obtain a three-generation family history at the time of diagnosis, with particular attention to family members with a history of hemorrhagic stroke, abnormal MRI scan, epilepsy, or other neurologic complications [6]. However, family history may be confounded by the incomplete penetrance and variable presentation, even within families, of familial CMs. Differential diagnosis Lesions that mimic CMs on MRI include hemorrhagic or calcified neoplastic lesions, particularly hemorrhagic metastases (eg, melanoma, renal cell carcinoma), oligodendrogliomas, pleomorphic xanthoastrocytomas, polymorphous low-grade neuroepithelial tumor of the young, and cerebral microbleeds [6,47]. Metastases Radiologic features more suggestive of metastases include associated extensive cerebral edema compared with the size of the lesion, localization at the junction of the gray and white matter, and/or heterogeneous contrast enhancement. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases", section on 'Imaging studies'.) Gliomas Low-grade gliomas in adults generally are expansile lesions involving both cortex and underlying white matter that appear hyperintense on MRI T2/fluid-attenuated https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 5/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate inversion recovery (FLAIR) sequences. Vasogenic edema is usually absent, and most low- grade gliomas are nonenhancing. Calcification is sometimes present. (See "Clinical features, diagnosis, and pathology of IDH-mutant, 1p/19q-codeleted oligodendrogliomas", section on 'Neuroimaging'.) Pleomorphic xanthoastrocytomas Pleomorphic xanthoastrocytoma is a rare type of brain tumor; the few reported lesions with MRI imaging were cortical with leptomeningeal involvement and either a solid or mixed solid-cystic appearance, with the solid component generally hypo- or isointense on T1 sequences, iso- or hyperintense on T2 sequences, and with postcontrast enhancement [48]. (See "Uncommon brain tumors", section on 'Pleomorphic xanthoastrocytoma'.) Polymorphous low-grade neuroepithelial tumors Polymorphous low-grade neuroepithelial tumor of the young is an epileptogenic tumor characterized by oligodendroglioma-like morphology, aberrant expression of CD34 and genetic alterations in the MAP kinase pathway. It is typically a well-circumscribed lesion with macroscopic calcification and cystic component located peripherally in the posteroinferior temporal lobe in children and young adults (median age of 16 years) [49]. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'Polymorphous low-grade neuroepithelial tumor of the young'.) Cerebral microbleeds Multiple cerebral microbleeds can be seen with multiple CMs as well as cerebral amyloid angiopathy or hypertensive vasculopathy. These conditions generally can be distinguished from multiple CMs by the clinical setting and distribution of microbleeds. Microbleeds restricted to the cerebral cortex or superficial cerebellar regions (cerebellar cortex and vermis) suggest cerebral amyloid angiopathy, while microbleeds that primarily arise from the basal ganglia, thalamus, or pons suggest hypertensive vasculopathy. (See "Cerebral amyloid angiopathy", section on 'Microbleeds'.) Management The general management of CMs involves assessing the individual risk of future bleeding or other neurologic sequela. Most CMs are treated conservatively. The routine care and additional screening for patients with CM associated with other conditions are discussed separately. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis" and "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs" and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) Asymptomatic lesions Asymptomatic CMs are observed, irrespective of location [6]. Management of asymptomatic CMs involves annual clinical follow-up with a specialist (eg, https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 6/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate neurologist or neurosurgeon) [9]. Some experts advocate annual imaging with brain MRI [50], but such an approach would not change management for patients who are asymptomatic. Immediate brain MRI is indicated for those who develop symptoms possibly related to CMs (eg, seizure, new headache, or new or progressive neurologic deficit) to evaluate for new hemorrhage or new CM [6]. We agree that surgical resection is not recommended for asymptomatic CMs. However, some experts advise that surgical resection of a solitary asymptomatic cerebral CM located in an easily accessible noneloquent area may be considered for various reasons including prevention of future hemorrhage, reduction of burden caused by associated psychological disability and/or expensive and time-consuming follow-up visits, facilitation of lifestyle or career decisions, or risk reduction for patients who need anticoagulation [6]. Symptomatic lesions In general, acute intracerebral hemorrhage (ICH) due to a CM is evaluated and managed in the same way as ICH from other causes. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) A summary of the general approach to symptomatic CMs according to presentation is as follows [6,10]: First-time seizure Medical therapy with antiseizure medication. Medically refractory epilepsy Surgical resection. Supratentorial CM with first ICH Surgical resection if accessible lesion and symptomatic hemorrhage. Consideration for conservative management is given based on comorbidities. Brainstem or deep nucleus CM with first ICH Conservative management. Brainstem or deep nucleus CM with second or greater ICH Surgical resection (or possibly stereotactic radiosurgery, except for familial cases). Indications for surgical resection of accessible symptomatic cerebral and cerebellar lesions include progressive neurologic deficit, intractable epilepsy, and recurrent hemorrhage. Risk of new or recurrent hemorrhage Decisions about CM management should be guided by risk estimates of new or recurrent CM-related symptoms. A 2016 meta-analysis of individual data from 1620 patients with cerebral CMs reported the clinical course from CM diagnosis to the first CM treatment or last available follow-up. With a https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 7/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate median follow-up of 3.5 years, symptomatic ICH developed in 204 patients, with an estimated five-year risk of 15.8 percent (95% CI 13.7-17.9) [51]. Presentation with ICH and brainstem location appear to be risk factors for subsequent hemorrhage [51,52]. According to the meta- analysis, the estimated five-year risk of ICH in these risk categories are: Nonbrainstem CMs presenting without ICH or focal neurologic deficit 3.8 percent (95% CI 2.1-5.5) Brainstem CMs presenting without ICH or focal neurologic deficit 8 percent (95% CI 0.1- 15.9) Nonbrainstem CMs presenting with ICH or focal neurologic deficits 18.4 percent (95% CI 13.3.-23.5) Brainstem CMs presenting with ICH or focal neurologic deficits 30.8 percent (95% CI 26.3- 35.2) There was no independent prognostic significance for risk related to age, sex, or CM multiplicity [51]. It is uncertain if the presence of a DVA is a risk factor for future hemorrhage. Retrospective studies have suggested that an associated DVA is a risk factor for hemorrhage at presentation [33,53]. However, in one registry of 731 patients with sporadic cerebral CM, associated DVAs were negatively correlated with initial ICH (odds ratio [OR] 0.635, 95% CI 0.459-0.878) and were also not predictive of subsequent hemorrhage [52]. Efficacy of surgery There are no randomized controlled trials of interventions for CMs, but observational data from uncontrolled case series suggest that surgical resection is beneficial for select patients with CMs. A 2022 systematic review and meta-analysis identified 100 cohorts with nearly 9000 patients who had treatment of cerebral CMs [54]. With a mean follow-up of 4 years, the mean hemorrhage rate was lower for patients who underwent surgery (2.6 percent) compared with those treated with radiosurgery or conservative treatment (14 and 22 percent, respectively). Prior hemorrhage and brainstem location were associated with higher bleeding risk in both nonsurgical patients and those treated with surgery or radiosurgery. In an earlier systematic review involving over 3400 patients with CM, the incidence of the composite outcome (death, nonfatal intracranial hemorrhage, or new/worse persistent focal neurological deficit) after neurosurgical resection was 6.6 per 100 person-years (95% CI 5.7-7.5) [55]. The incidence increased with each percentage point increase in patients with brainstem CMs (rate ratio [RR] 1.03, 95% CI 1.01-1.05) and decreased with each percentage point increase in patients who presented with hemorrhage (RR 0.98, 95% CI 0.96-1.00) and with each more https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 8/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate recent study midyear, defined as the middle of the time frame of the year in which treatment took place (RR 0.91, 95% CI 0.85-0.98). Thus, although direct comparisons are lacking and data are observational, indirect comparisons suggest that the overall risks at approximately three years of surgical excision (approximately 7 percent risk of death, nonfatal stroke, or neurologic deficit) compares favorably to the overall estimated five-year ICH recurrence risk, which in one cohort was as high as 29.5 percent [56]. The inherent risks of surgery are higher with CMs removed from eloquent ares of the brain (ie, brain regions that directly control neurologic functions such as language, vision, movement, or sensation) or deep brain regions, particularly with brainstem lesions. In a 2019 systematic review of surgical resection of brainstem CMs involving 2493 adult and pediatric patients, the rate of early postoperative morbidity was 35 percent; at last follow-up, neurologic function was improved in 58 percent, stable in 26 percent, and worse in 12 percent, with a mortality rate of approximately 2 percent [57]. Therefore, surgery is typically reserved for patients with a second symptomatic hemorrhage involving brainstem or deep CMs, whereas surgery is usually recommended after a first symptomatic hemorrhage for CMs in noneloquent, superficial locations [6]. However, due to their aggressive natural history, some experts advise treating brainstem CMs even in the absence of recurrent hemorrhage when there is neurologic deterioration if the lesion is surgically accessible (ie, near the pial surface or via a noneloquent tissue corridor to the lesion) [58]. Microsurgical techniques are also being used with success in some centers for patients with several hemorrhages or progression of symptoms [59]. Role of stereotactic radiosurgery We suggest not using stereotactic radiosurgery as the primary treatment for CMs. Stereotactic radiosurgery is a potential alternative to conservative therapy in patients with such surgically inaccessible lesions, and the available evidence suggests that it does lead to a reduction in hemorrhage, especially two years or more after radiosurgery [60]. Nevertheless, high complication rates in available published series coupled with clinical experience has dissuaded many from using stereotactic radiosurgery for the treatment of CMs. In addition, there is concern that radiation exposure may promote the development of new CMs in familial cases [6]. (See "Stereotactic cranial radiosurgery".) As an example, one retrospective analysis of 95 patients with 98 lesions found that stereotactic radiosurgery was associated with a significant drop in the annualized hemorrhage rate from 17 to 5 percent after a two-year post-treatment latency period [61]. However, at an average follow- up of 5.4 years, the incidence of permanent neurologic deficit and mortality was 16 and 3 percent, respectively, and these complications were attributed to radiation-induced injury. In addition, the combined effects of radiation-related injury and clinical progression of the lesion led to a significant decline in neurologic function during follow-up. In a 2019 systematic review https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 9/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate and meta-analysis of 14 observational studies with 576 patients who had stereotactic radiosurgery for brainstem CMs, symptomatic adverse radiation effects developed in 7.3 percent, and permanent adverse radiation effects were noted in 2.2 percent [60]. However, data regarding the long-term safety and adverse effects of stereotactic radiosurgery remain sparse [55]. Management of epilepsy Patients with a first seizure related to cerebral CM should be managed with medical therapy using antiseizure medication. In one prospective report of patients with a first CM-related seizure, the risk of developing epilepsy was 94 percent [62], warranting the diagnosis of probable epilepsy after a single seizure and supporting the use of antiseizure medication treatment [63]. In contrast, prophylactic antiseizure medication treatment is not indicated for patients with asymptomatic or symptomatic CMs who do not have seizures [63]. Medically refractory epilepsy is an indication for surgical resection [6,63]. In a case series of 168 patients with symptomatic epilepsy attributed to CM, more than two-thirds of patients were seizure free at three years after surgery [64]. Predictors for good outcome included mesiotemporal location, size <1.5 cm, and the absence of secondarily generalized seizures. Another series identified a long preoperative seizure history and poorer preoperative seizure control as unfavorable prognostic indicators [65]. Epilepsy surgery is reviewed in greater detail separately. (See "Surgical treatment of epilepsy in adults", section on 'Vascular malformations'.) Management during pregnancy Observational data from several large series suggest that the risk of developing clinical symptoms due to cerebral CMs during pregnancy is similar to the baseline risk before pregnancy [6,66-68], but this view is not universally held [69]. For patients with cerebral CMs who develop new focal neurologic deficit, acute severe headache, or worsening seizures during pregnancy, a brain MRI is indicated to determine if the symptoms are related to CMs or another intracranial etiology [6]. The approach to managing a new CM- related brain hemorrhage during pregnancy should account for the additional risk that surgical intervention may have on the pregnancy and the unborn child, but otherwise is similar to that in the nonpregnant state [70]. Females with epilepsy related to cerebral CMs should be evaluated and counseled, ideally before conception, about the risks associated with epilepsy during pregnancy. These include the potential for perinatal complications, seizure worsening, and adverse effects of antiseizure medications on the fetus and later development. These risks may be minimized by interventions https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 10/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate before and during pregnancy, as reviewed elsewhere. (See "Risks associated with epilepsy during pregnancy and postpartum period" and "Management of epilepsy during preconception, pregnancy, and the postpartum period".) The mode of delivery should be dictated by obstetrical indications; most patients can have a normal vaginal delivery unless there is a recent intracranial hemorrhage or a precluding neurologic deficit [6,68]. Safety of antithrombotic therapy In contrast to conventional wisdom, the available data suggest that the bleeding risk associated with CMs is not increased with the use of antithrombotic or oral anticoagulant therapy [71,72]. In a population-based cohort study of 300 prospectively identified people (age 16 years and older) in Scotland who were diagnosed with a cerebral CM, there were 61 who used antithrombotic therapy (including 10 who used anticoagulant therapy) [73]. Compared with no antithrombotics, the use of antithrombotics was associated with a lower risk of subsequent intracranial hemorrhage or focal neurologic deficit (2 versus 12 percent; adjusted hazard ratio [HR] 0.12, 95% CI 0.02-0.88). Similarly, in a meta- analysis performed by the same investigators of six studies, mainly retrospective, with over 1300 patients, antithrombotic therapy use was associated with a lower risk of intracranial hemorrhage (3 versus 14 percent; incidence rate ratio 0.25, 95% CI 0.13-0.51). It is likely that the indication for antithrombotic therapy in the patients so treated was the prevention of arterial or venous occlusive disease, but individual patient data were not available; these results do not provide a rationale for treating CMs with antithrombotic therapy. Use of contraceptive and menopausal hormonal medications Limited data suggest use of hormonal contraception or menopausal therapy is associated with an elevated risk of hemorrhage [74,75]. In a multicenter cohort study of 722 female patients with CM, the incidence rate of symptomatic hemorrhage was elevated among patients using hormonal therapy (7.4 versus 5.1 per 100 person-years) [75]. Mean follow-up was 3.3 years. Hormonal therapy included estrogen and/or progesterone and most patients were taking an oral agent. This elevated risk of hemorrhage was present among both patients <45 years old taking oral contraception (aHR 2.0, 95% CI 1.3-3.2) and those 45 years old taking menopausal therapy (aHR 2.4, 95% CI 1.1-5.1). These data are limited by nonrandomized study design, relatively short-term follow-up, and heterogeneity of both hormonal therapy and CM features. The use of hormonal contraceptive or menopausal therapy in patients with CM should be individualized, after informed discussion of risks and benefits. Nonhormonal options may be preferred for patients with CM to reduce the risk of hemorrhage. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 11/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate DEVELOPMENTAL VENOUS ANOMALIES Developmental venous anomalies (DVAs) are composed of a radially arranged configuration of medullary veins ("caput medusae") separated by normal brain parenchyma (most commonly white matter) [76]. These small venous conduits empty into a dilated superficial or deep vein that drains normal brain. A stenosis is common on the collecting vein at the point of penetration into the draining dural sinus. Microscopically, the venous structures appear largely normal with rare degenerative changes consisting of thickening and hyalinization. The lesions are common in supratentorial regions of the brain, with a frontal lobe predominance, but may also be found in the cerebellum and basis pontis. DVAs most often are solitary, although multiple lesions have been described in association with other clinical syndromes (eg, the blue rubber bleb nevus syndrome) [77]. DVAs also may occur concurrently with cavernous malformations (CMs) in 13 to 40 percent, as well as with other intracranial vascular malformations and with superficial venous malformations of the head and neck [32,78,79]. Clinical presentation DVAs are considered benign lesions, although they may uncommonly present with seizures, progressive neurologic deficits, and hemorrhage [52,76,80-83]. Headache is the most common presenting complaint, followed by seizures and sensory-motor phenomena. However, a direct correlation between these symptoms and the DVA is uncertain [84,85]. In a 10-year prospective clinical and MRI study involving 80 patients, a symptomatic hemorrhage rate of 0.34 percent per year was observed [84]. In another study of 93 patients with 492 person- years of follow-up, no symptomatic hemorrhages occurred [83]. The hemorrhages were usually minor, although fatal intracranial hemorrhages have been described [82]. A retrospective case series reviewed the clinical presentations of 68 patients with imaging findings suggestive of DVAs whose symptoms could not be attributed to other pathologies [86]. Cases with associated CMs were excluded. Two major pathophysiologic mechanisms were reported: Mechanical compression of intracranial structures by a component of the vein was seen in 21 percent. The most common associated symptoms were hydrocephalus, tinnitus, brainstem deficits, hemifacial spasm, and trigeminal neuralgia. Flow-related symptoms were present in 72 percent. Increased inflow was present in 28 percent, typically related to an arteriovenous malformation (AVM) draining via dilated and ectatic medullary veins, resulting parenchymal and/or intraventricular hemorrhage, or https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 12/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate venous infarction. Symptoms included headaches, neurologic deficits, seizures, and coma. Restricted outflow, either by an anatomic obstruction (eg, stenosis or thrombosis of the vein) in 38 percent or by a physiologic obstruction (eg, increased venous pressure secondary to a distal arteriovenous shunt or AVM) was observed in 6 percent. Patients presented with variable combinations of neurologic deficits, headaches, seizures, and altered mentation, a clinical picture that resembled that of cerebral venous thrombosis, with increased intracranial pressure, venous congestive edema, and/or intraparenchymal or subarachnoid hemorrhage. No obvious alteration was found to explain symptoms in 9 percent. Diagnosis Cerebral angiography is considered the gold standard for the diagnosis of DVAs, but they are usually identified with contrast-enhanced cross-sectional imaging modalities such as CT, MRI, and magnetic resonance angiography (MRA) [78]. Computed tomography Nonenhanced CT scans do not usually demonstrate DVAs unless there is an associated cavernous malformation. After contrast administration, the enlarged vein is all that is typically identified. CT angiography (CTA) has also been used to identify DVAs ( image 6) [87]. Magnetic resonance imaging and angiography MRI with gadolinium typically shows medullary veins in "caput medusae" pattern that converge on a dilated transcerebral draining vein. A characteristic "sunburst" pattern is seen on enhanced T1-weighted images ( image 7) [88]. Gradient echo sequences should be included to increase sensitivity for detecting associated CMs [78]. White matter abnormalities and/or calcifications may be observed in the parenchyma adjacent to the DVA. MRA usually demonstrates the dilated venous channel with variable depiction of the smaller medullary veins. Catheter angiography Cerebral angiography usually is not needed for the diagnosis of DVA since MRI is often sufficient to make the diagnosis. In atypical cases, angiographic findings are pathognomonic; during the late capillary or venous phase there is a paucity of normal veins in the region of the lesion and a characteristic "caput medusae" appearance of the radially arranged small medullary veins ( image 8). The arterial phase is typically normal; however, so-called arterialized DVAs have been described with early-phase opacification on angiography and/or enlarged arterial feeders [78]. These lesions may have a bleeding risk that is more similar to an arteriovenous malformation. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 13/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Management DVAs should be treated conservatively in the vast majority of cases, with associated symptoms such as headaches and seizures managed medically [85]. Obliteration may be considered in the rare patient with hemorrhage or uncontrolled seizures associated with a DVA [82]. However, surgical or endovascular obliteration is associated with a risk of venous infarction [76]. In patients who undergo surgery, preoperative MRI with gadolinium is required to identify an associated cavernous malformation [32]. Venous infarction has been reported with DVA resection [46]; thus, it is reasonable to simply evacuate the hematoma and leave the DVA in situ. Radiosurgical and endovascular techniques do not have a defined role in the management of these lesions. In rare patients who present with symptomatic thrombosis of a DVA, there is anecdotal support for considering the use of systematic anticoagulation [78]. (See "Cerebral venous thrombosis: Treatment and prognosis".) CAPILLARY TELANGIECTASIAS Capillary telangiectasias are small lesions most commonly found in the pons, middle cerebellar peduncles, and cerebellar dentate nuclei. Multiple lesions are common. The lesions are composed of small, dilated capillaries devoid of smooth muscle or elastic fibers. The intervening brain is often normal; it may also demonstrate areas of microhemorrhage or gliosis. A common histopathological feature of these lesions is a dilated efferent system, probably representing a venous channel. An argument has been made for these lesions representing the early stage in the spectrum of development of cavernous malformations and other "mixed" vascular malformations [26,89]. Although not proven, angiogenesis is believed to play a role in lesion evolution. Most telangiectasias represent an angiodysplastic phenomenon resulting from faulty embryogenesis of the vascular wall and have been associated with angiomatous phacomatoses such as Osler- Weber-Rendu (hereditary hemorrhagic telangiectasia), Louis-Bar (ataxia-telangiectasia), and Wyburn-Mason (unilateral retinocephalic vascular malformation) syndromes [90]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Cerebral vascular abnormalities' and "Ataxia-telangiectasia", section on 'Neuroimaging features'.) Clinical presentation Capillary telangiectasias are usually clinically silent, found incidentally on neuroimaging studies or at postmortem examination. In a systematic review of 10 series and https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 14/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate 203 patients with capillary telangiectasias, symptomatic cases accounted for 6 percent [91]; headache, nausea, and seizures have been described in patients with these lesions, although a causal relationship is unclear. Diagnosis MRI with gadolinium contrast is the most sensitive imaging modality for the identification of brain capillary telangiectasias, but the lesions may be inconspicuous on precontrast MRI. Small lesions that are hypo- to isointense on T1-weighted sequences and iso- to
other clinical syndromes (eg, the blue rubber bleb nevus syndrome) [77]. DVAs also may occur concurrently with cavernous malformations (CMs) in 13 to 40 percent, as well as with other intracranial vascular malformations and with superficial venous malformations of the head and neck [32,78,79]. Clinical presentation DVAs are considered benign lesions, although they may uncommonly present with seizures, progressive neurologic deficits, and hemorrhage [52,76,80-83]. Headache is the most common presenting complaint, followed by seizures and sensory-motor phenomena. However, a direct correlation between these symptoms and the DVA is uncertain [84,85]. In a 10-year prospective clinical and MRI study involving 80 patients, a symptomatic hemorrhage rate of 0.34 percent per year was observed [84]. In another study of 93 patients with 492 person- years of follow-up, no symptomatic hemorrhages occurred [83]. The hemorrhages were usually minor, although fatal intracranial hemorrhages have been described [82]. A retrospective case series reviewed the clinical presentations of 68 patients with imaging findings suggestive of DVAs whose symptoms could not be attributed to other pathologies [86]. Cases with associated CMs were excluded. Two major pathophysiologic mechanisms were reported: Mechanical compression of intracranial structures by a component of the vein was seen in 21 percent. The most common associated symptoms were hydrocephalus, tinnitus, brainstem deficits, hemifacial spasm, and trigeminal neuralgia. Flow-related symptoms were present in 72 percent. Increased inflow was present in 28 percent, typically related to an arteriovenous malformation (AVM) draining via dilated and ectatic medullary veins, resulting parenchymal and/or intraventricular hemorrhage, or https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 12/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate venous infarction. Symptoms included headaches, neurologic deficits, seizures, and coma. Restricted outflow, either by an anatomic obstruction (eg, stenosis or thrombosis of the vein) in 38 percent or by a physiologic obstruction (eg, increased venous pressure secondary to a distal arteriovenous shunt or AVM) was observed in 6 percent. Patients presented with variable combinations of neurologic deficits, headaches, seizures, and altered mentation, a clinical picture that resembled that of cerebral venous thrombosis, with increased intracranial pressure, venous congestive edema, and/or intraparenchymal or subarachnoid hemorrhage. No obvious alteration was found to explain symptoms in 9 percent. Diagnosis Cerebral angiography is considered the gold standard for the diagnosis of DVAs, but they are usually identified with contrast-enhanced cross-sectional imaging modalities such as CT, MRI, and magnetic resonance angiography (MRA) [78]. Computed tomography Nonenhanced CT scans do not usually demonstrate DVAs unless there is an associated cavernous malformation. After contrast administration, the enlarged vein is all that is typically identified. CT angiography (CTA) has also been used to identify DVAs ( image 6) [87]. Magnetic resonance imaging and angiography MRI with gadolinium typically shows medullary veins in "caput medusae" pattern that converge on a dilated transcerebral draining vein. A characteristic "sunburst" pattern is seen on enhanced T1-weighted images ( image 7) [88]. Gradient echo sequences should be included to increase sensitivity for detecting associated CMs [78]. White matter abnormalities and/or calcifications may be observed in the parenchyma adjacent to the DVA. MRA usually demonstrates the dilated venous channel with variable depiction of the smaller medullary veins. Catheter angiography Cerebral angiography usually is not needed for the diagnosis of DVA since MRI is often sufficient to make the diagnosis. In atypical cases, angiographic findings are pathognomonic; during the late capillary or venous phase there is a paucity of normal veins in the region of the lesion and a characteristic "caput medusae" appearance of the radially arranged small medullary veins ( image 8). The arterial phase is typically normal; however, so-called arterialized DVAs have been described with early-phase opacification on angiography and/or enlarged arterial feeders [78]. These lesions may have a bleeding risk that is more similar to an arteriovenous malformation. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 13/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Management DVAs should be treated conservatively in the vast majority of cases, with associated symptoms such as headaches and seizures managed medically [85]. Obliteration may be considered in the rare patient with hemorrhage or uncontrolled seizures associated with a DVA [82]. However, surgical or endovascular obliteration is associated with a risk of venous infarction [76]. In patients who undergo surgery, preoperative MRI with gadolinium is required to identify an associated cavernous malformation [32]. Venous infarction has been reported with DVA resection [46]; thus, it is reasonable to simply evacuate the hematoma and leave the DVA in situ. Radiosurgical and endovascular techniques do not have a defined role in the management of these lesions. In rare patients who present with symptomatic thrombosis of a DVA, there is anecdotal support for considering the use of systematic anticoagulation [78]. (See "Cerebral venous thrombosis: Treatment and prognosis".) CAPILLARY TELANGIECTASIAS Capillary telangiectasias are small lesions most commonly found in the pons, middle cerebellar peduncles, and cerebellar dentate nuclei. Multiple lesions are common. The lesions are composed of small, dilated capillaries devoid of smooth muscle or elastic fibers. The intervening brain is often normal; it may also demonstrate areas of microhemorrhage or gliosis. A common histopathological feature of these lesions is a dilated efferent system, probably representing a venous channel. An argument has been made for these lesions representing the early stage in the spectrum of development of cavernous malformations and other "mixed" vascular malformations [26,89]. Although not proven, angiogenesis is believed to play a role in lesion evolution. Most telangiectasias represent an angiodysplastic phenomenon resulting from faulty embryogenesis of the vascular wall and have been associated with angiomatous phacomatoses such as Osler- Weber-Rendu (hereditary hemorrhagic telangiectasia), Louis-Bar (ataxia-telangiectasia), and Wyburn-Mason (unilateral retinocephalic vascular malformation) syndromes [90]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Cerebral vascular abnormalities' and "Ataxia-telangiectasia", section on 'Neuroimaging features'.) Clinical presentation Capillary telangiectasias are usually clinically silent, found incidentally on neuroimaging studies or at postmortem examination. In a systematic review of 10 series and https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 14/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate 203 patients with capillary telangiectasias, symptomatic cases accounted for 6 percent [91]; headache, nausea, and seizures have been described in patients with these lesions, although a causal relationship is unclear. Diagnosis MRI with gadolinium contrast is the most sensitive imaging modality for the identification of brain capillary telangiectasias, but the lesions may be inconspicuous on precontrast MRI. Small lesions that are hypo- to isointense on T1-weighted sequences and iso- to slightly hyperintense on T2-weighted sequences with faint enhancement on postcontrast T1- weghted sequences are suggestive, although not diagnostic, of these lesions [92]. Compared with other precontrast MRI sequences, sensitivity for the detection of capillary telangiectasias is increased with the use of gradient echo and especially with susceptibility-weighted imaging (SWI) ( image 9) [92,93]. Telangiectasias can be identified in the late arterial/early capillary phase of angiography as a faint blush with an associated venous channel. Thus, these lesions can be distinguished from developmental venous anomalies that are visualized during the venous phase of the study. Management Capillary telangiectasias are nonoperable lesions. Management is conservative, particularly since most lesions are asymptomatic. The routine care and additional screening for patients with capillary telangiectasias associated with other conditions are discussed separately. (See "Ataxia-telangiectasia", section on 'Management' and "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs" and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 15/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Arteriovenous malformations in the brain (The Basics)") SUMMARY AND RECOMMENDATIONS Brain arteriovenous malformations Arteriovenous malformations are the most dangerous cerebral vascular malformation and can cause hemorrhage, seizures, headaches, and focal neurologic deficits. These lesions are discussed in detail separately. (See "Brain arteriovenous malformations".) Cavernous malformations Cavernous malformations are thin-walled dilated capillaries with a simple endothelial lining ( image 1). They may occur as a sporadic or familial condition and may be associated with developmental venous anomalies in about 25 percent. (See 'Cavernous malformations' above.) Cavernous malformations may be found incidentally on neuroimaging or may present with neurologic symptoms such as hemorrhage, seizures, and/or progressive neurologic deficits ( image 3 and image 2). Recurrent hemorrhage is more common after an initial bleed and may be as high as 5 percent per year for supratentorial lesions and 21 percent for brainstem lesions. Cavernous malformations are typically identified on MRI and are often angiographically occult. They can occur throughout the brain but are most common in the subcortical rolandic and temporal areas. Asymptomatic cavernous malformations are generally followed without intervention. Surgical resection may be indicated for accessible symptomatic lesions associated with progressive neurologic deficits, intractable epilepsy, and/or hemorrhage. Stereotactic radiosurgery is an option for nonoperable lesions, but long-term safety is uncertain. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 16/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Developmental venous anomalies Developmental venous anomalies (DVAs) consist of a radially arranged configuration of medullary veins separated by normal brain parenchyma ( image 7). The lesions are usually solitary but can be multiple and occur with cavernous malformations. (See 'Developmental venous anomalies' above.) DVAs are usually an incidental finding but may rarely present with seizures or hemorrhage. They are usually identified on MRI. Cerebral angiography is considered the gold standard for diagnosis of a DVA. After diagnosis, hemorrhage is unusual. Most patients with DVAs are followed without intervention; rarely, surgery is required for hemorrhage or intractable epilepsy. Capillary telangiectasias Capillary telangiectasias are small, dilated capillaries devoid of smooth muscle or elastic fibers. (See 'Capillary telangiectasias' above.) MRI is the most sensitive imaging modality for the identification of brain capillary telangiectasias ( image 9). They are most commonly found in the pons, middle cerebellar peduncles, and dentate nuclei. Multiple lesions are common. Capillary telangiectasias are usually clinically silent, found incidentally on neuroimaging studies. They are not associated with morbidity, and intervention is not required. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. el-Gohary EG, Tomita T, Gutierrez FA, McLone DG. Angiographically occult vascular malformations in childhood. Neurosurgery 1987; 20:759. 2. McCormick WF. The pathology of vascular ("arteriovenous") malformations. J Neurosurg 1966; 24:807. 3. Al-Shahi R, Bhattacharya JJ, Currie DG, et al. 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Susceptibility-weighted imaging and quantitative susceptibility mapping in the brain. J Magn Reson Imaging 2015; 42:23. 46. Senegor M, Dohrmann GJ, Wollmann RL. Venous angiomas of the posterior fossa should be considered as anomalous venous drainage. Surg Neurol 1983; 19:26. 47. Sze G, Krol G, Olsen WL, et al. Hemorrhagic neoplasms: MR mimics of occult vascular malformations. AJR Am J Roentgenol 1987; 149:1223. 48. Gon alves VT, Reis F, Queiroz Lde S, Fran a M Jr. Pleomorphic xanthoastrocytoma: magnetic resonance imaging findings in a series of cases with histopathological confirmation. Arq https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 20/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Neuropsiquiatr 2013; 71:35. 49. Johnson DR, Giannini C, Jenkins RB, et al. Plenty of calcification: imaging characterization of polymorphous low-grade neuroepithelial tumor of the young. Neuroradiology 2019; 61:1327. 50. 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AJNR Am J Neuroradiol 2014; 35:2302. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 23/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Topic 1129 Version 24.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 24/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate GRAPHICS MRI of a cerebral cavernous malformation Cavernous malformations appear characteristically on MRI as a "popcorn" pattern of variable image intensities. Courtesy of Guy Rordorf, MD. Graphic 80348 Version 4.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 25/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Cavernous malformation of the spinal cord on MRI (A) Sagittal T2-weighted MRI sequence shows target-like lesion (thick arrow) with hypointense core consistent with CM. Note both rostral and caudal ill-defined T2-hypointense acute hemorrhage (arrows), as well as more rostral cord edema (bracket). https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 26/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate (B) Magnified pre-contrast sagittal T1-weighted sequence shows hyperdensity consistent with hemorrhage (thick arrow). (C) Magnified sagittal and (D) axial post-contrast T1-weighted MRI sequences show mild contrast enhancement of CM (thick arrows). MRI: magnetic resonance imaging; CM: cavernous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 139103 Version 1.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 27/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate MRI of a cerebral cavernous malformation with old hemorrhage A dark hemosiderin ring around the cavernous malformation is evident on this T-2 weighted MR image, suggestive of old hemorrhage. MRI: magnetic resonance imaging. Courtesy of Guy Rordorf, MD. Graphic 68000 Version 5.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 28/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Cerebral cavernous malformations (CCM) on CT and MRI sequences SWI is very sensitive to slow-flow vascular malformations such as CCM, as in this child with a large left temporal CCM (dashed arrows), with a characteristic "popcorn" appearance on CT and MRI. There are typical internal calcifications on CT (A), hyperintense subacute blood products on T1-weighted imaging (B), mild internal enhancement on postcontrast T1-weighted imaging (C), and peripheral hypointense hemosiderin on FLAIR (D) and T2-weighted imaging (E). The lesion appears larger on SWI (F) due to blooming artifact. More important, additional smaller CCMs are detected (arrows), which indicate that the patient likely has multiple familial CCM syndrome (which can occur in as many as one-third of patients with CCM). SWI parameters are: 3 Tesla, TE = 20 milliseconds, TR = 29 milliseconds, FA = 15 , field of vision 250 mm 188 mm, matrix 448 336, 2 mm thick acquisition displayed with 16 mm minimum intensity projection. SWI: Susceptibility-weighted imaging; CCM: cerebral cavernous malformations; CT: computed tomography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; TE: echo time; TR: repetition time; FA: flip angle. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 29/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate From: Liu C, Li W, Tong KA, et al. Susceptibility-weighted imaging and quantitative susceptibility mapping in the brain. J Magn Reson Imaging 2015; 42(1):23-41. https://onlinelibrary.wiley.com/doi/abs/10.1002/jmri.24768. Copyright 2014 Wiley Periodicals, Inc. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: permissions@wiley.com or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (https://onlinelibrary.wiley.com/). Graphic 122720 Version 1.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 30/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Sporadic CCM with a DVA Sporadic CCM with a very large DVA. (A) Axial T2 SE of a 26-year-old female patient shows a CCM near the left lateral ventricle. (B) Postgadolinium T1 shows a large DVA involving much of the left frontal lobe. (C and D) SWI demonstrates very clearly the CCM and DVA without gadolinium administration. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 31/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate CCM: cerebral cavernous malformation; DVA: developmental venous anomaly; SE: spin echo; SWI: susceptibility-weighted imaging. Republished with permission of the American Society of Neuroradiology, from: Petersen TA, Morrison LA, Schrader RM, Hart BL. Familial versus sporadic cavernous malformations: di erences in developmental venous anomaly association and lesion phenotype. AJNR Am J Neuroradiol 2010; 31:377; permission conveyed through Copyright Clearance Center, Inc. Copyright 2010. Graphic 122722 Version 2.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 32/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Developmental venous anomaly with dystrophic calcification (A) Axial and (B) coronal non-contrast CT images show hyperdense linear calcification in left lateral putamen. (C) Axial and (D) sagittal images from CT angiography show classic caput medusae and dilated vein (circles) characteristic of DVA. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 33/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate CT: computed tomography; DVA: developmental venous anomaly. Courtesy of Glenn A Tung, MD, FACR. Graphic 139104 Version 1.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 34/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Left frontal DVA on MRI A DVA accompanied by a small cyst and loco-regional atrophy localized in the left frontal deep and subcortica white matter of a 45-year-old patient with headache. (A) Thin venous stems and veins in the center, leading to the caput medusae imaging on axial contrast- enhanced 3D SPGR maximum intensity projection image, are visualized. (B) Loco-regional atrophy in the frontal lobe and a millimetric cyst (arrow) adjacent to the DVA caput on a coronal contrast-enhanced 3D SPGR image are visualized. 3D SPRG: three-dimensional spoiled gradient recalled echo; DVA: developmental venous anomaly; MRI: magnetic resonance imaging. Reprinted by permission from Springer: Clinical Neuroradiology. G k e E, Acu B, Beyhan M, et al. Magnetic resonance imaging ndings of developmental venous anomalies. Clin Neuroradiol 2014; 24:135. Copyright 2014. https://link.springer.com/journal/62. Graphic 122040 Version 5.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 35/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Cerebral angiography of a developmental venous anomaly During the late capillary or venous phase of angiography, there is a paucity of normal veins in the region of a developmental venous anomaly and a characteristic "caput medusae" appearance of the radially arranged small medullary veins (arrow). Courtesy of Guy Rordorf, MD. Graphic 56038 Version 4.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 36/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate MRI of brain capillary telangiectasia A brain capillary telangiectasia (circle) seen in the pons on both GRE (A) and SWI (B) and confirmed on postcontrast T1-weighted image (C). GRE: gradient echo; MRI: magnetic resonance imaging; SWI: susceptibility-weighted imaging. Republished with permission of the American Society of Neuroradiology, from: Chaudhry US, De Bruin DE, Policeni BA. Susceptibility- weighted MR imaging: a better technique in the detection of capillary telangiectasia compared with T2* gradient-echo. AJNR Am J Neuroradiol 2014; 35:2302; permission conveyed through Copyright Clearance Center, Inc. Copyright 2014. Graphic 122043 Version 1.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 37/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Contributor Disclosures
(B) Magnified pre-contrast sagittal T1-weighted sequence shows hyperdensity consistent with hemorrhage (thick arrow). (C) Magnified sagittal and (D) axial post-contrast T1-weighted MRI sequences show mild contrast enhancement of CM (thick arrows). MRI: magnetic resonance imaging; CM: cavernous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 139103 Version 1.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 27/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate MRI of a cerebral cavernous malformation with old hemorrhage A dark hemosiderin ring around the cavernous malformation is evident on this T-2 weighted MR image, suggestive of old hemorrhage. MRI: magnetic resonance imaging. Courtesy of Guy Rordorf, MD. Graphic 68000 Version 5.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 28/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Cerebral cavernous malformations (CCM) on CT and MRI sequences SWI is very sensitive to slow-flow vascular malformations such as CCM, as in this child with a large left temporal CCM (dashed arrows), with a characteristic "popcorn" appearance on CT and MRI. There are typical internal calcifications on CT (A), hyperintense subacute blood products on T1-weighted imaging (B), mild internal enhancement on postcontrast T1-weighted imaging (C), and peripheral hypointense hemosiderin on FLAIR (D) and T2-weighted imaging (E). The lesion appears larger on SWI (F) due to blooming artifact. More important, additional smaller CCMs are detected (arrows), which indicate that the patient likely has multiple familial CCM syndrome (which can occur in as many as one-third of patients with CCM). SWI parameters are: 3 Tesla, TE = 20 milliseconds, TR = 29 milliseconds, FA = 15 , field of vision 250 mm 188 mm, matrix 448 336, 2 mm thick acquisition displayed with 16 mm minimum intensity projection. SWI: Susceptibility-weighted imaging; CCM: cerebral cavernous malformations; CT: computed tomography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; TE: echo time; TR: repetition time; FA: flip angle. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 29/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate From: Liu C, Li W, Tong KA, et al. Susceptibility-weighted imaging and quantitative susceptibility mapping in the brain. J Magn Reson Imaging 2015; 42(1):23-41. https://onlinelibrary.wiley.com/doi/abs/10.1002/jmri.24768. Copyright 2014 Wiley Periodicals, Inc. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: permissions@wiley.com or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (https://onlinelibrary.wiley.com/). Graphic 122720 Version 1.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 30/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Sporadic CCM with a DVA Sporadic CCM with a very large DVA. (A) Axial T2 SE of a 26-year-old female patient shows a CCM near the left lateral ventricle. (B) Postgadolinium T1 shows a large DVA involving much of the left frontal lobe. (C and D) SWI demonstrates very clearly the CCM and DVA without gadolinium administration. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 31/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate CCM: cerebral cavernous malformation; DVA: developmental venous anomaly; SE: spin echo; SWI: susceptibility-weighted imaging. Republished with permission of the American Society of Neuroradiology, from: Petersen TA, Morrison LA, Schrader RM, Hart BL. Familial versus sporadic cavernous malformations: di erences in developmental venous anomaly association and lesion phenotype. AJNR Am J Neuroradiol 2010; 31:377; permission conveyed through Copyright Clearance Center, Inc. Copyright 2010. Graphic 122722 Version 2.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 32/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Developmental venous anomaly with dystrophic calcification (A) Axial and (B) coronal non-contrast CT images show hyperdense linear calcification in left lateral putamen. (C) Axial and (D) sagittal images from CT angiography show classic caput medusae and dilated vein (circles) characteristic of DVA. https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 33/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate CT: computed tomography; DVA: developmental venous anomaly. Courtesy of Glenn A Tung, MD, FACR. Graphic 139104 Version 1.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 34/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Left frontal DVA on MRI A DVA accompanied by a small cyst and loco-regional atrophy localized in the left frontal deep and subcortica white matter of a 45-year-old patient with headache. (A) Thin venous stems and veins in the center, leading to the caput medusae imaging on axial contrast- enhanced 3D SPGR maximum intensity projection image, are visualized. (B) Loco-regional atrophy in the frontal lobe and a millimetric cyst (arrow) adjacent to the DVA caput on a coronal contrast-enhanced 3D SPGR image are visualized. 3D SPRG: three-dimensional spoiled gradient recalled echo; DVA: developmental venous anomaly; MRI: magnetic resonance imaging. Reprinted by permission from Springer: Clinical Neuroradiology. G k e E, Acu B, Beyhan M, et al. Magnetic resonance imaging ndings of developmental venous anomalies. Clin Neuroradiol 2014; 24:135. Copyright 2014. https://link.springer.com/journal/62. Graphic 122040 Version 5.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 35/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Cerebral angiography of a developmental venous anomaly During the late capillary or venous phase of angiography, there is a paucity of normal veins in the region of a developmental venous anomaly and a characteristic "caput medusae" appearance of the radially arranged small medullary veins (arrow). Courtesy of Guy Rordorf, MD. Graphic 56038 Version 4.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 36/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate MRI of brain capillary telangiectasia A brain capillary telangiectasia (circle) seen in the pons on both GRE (A) and SWI (B) and confirmed on postcontrast T1-weighted image (C). GRE: gradient echo; MRI: magnetic resonance imaging; SWI: susceptibility-weighted imaging. Republished with permission of the American Society of Neuroradiology, from: Chaudhry US, De Bruin DE, Policeni BA. Susceptibility- weighted MR imaging: a better technique in the detection of capillary telangiectasia compared with T2* gradient-echo. AJNR Am J Neuroradiol 2014; 35:2302; permission conveyed through Copyright Clearance Center, Inc. Copyright 2014. Graphic 122043 Version 1.0 https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 37/38 7/5/23, 12:27 PM Vascular malformations of the central nervous system - UpToDate Contributor Disclosures Robert J Singer, MD No relevant financial relationship(s) with ineligible companies to disclose. Christopher S Ogilvy, MD Consultant/Advisory Boards: Cerevasc [Hydrocephalus]; Contour [Aneurysms]; Medtronic [Chronic subdural hematoma]. All of the relevant financial relationships listed have been mitigated. Guy Rordorf, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/vascular-malformations-of-the-central-nervous-system/print 38/38
7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease : Alex George, MD, PhD, Lori Jordan, MD, PhD : Douglas R Nordli, Jr, MD, Michael R DeBaun, MD, MPH : Jennifer S Tirnauer, MD, John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 16, 2023. INTRODUCTION Stroke is a common and devastating manifestation of sickle cell disease (SCD) that can affect children and adults. This topic discusses assessment and treatment of acute stroke in children and adults with SCD. Risk stratification and stroke prevention are presented separately. (See "Prevention of stroke (initial or recurrent) in sickle cell disease".) PRESENTATION Stroke subtypes Ischemic stroke Central nervous system ischemia is defined as brain, spinal cord, or retinal cell death attributable to ischemia; ischemic stroke is defined as brain infarction accompanied by sudden onset of overt stroke symptoms. Hemorrhagic stroke Represents one-third of acute neurologic events in patients with SCD. ICH Intracerebral hemorrhage (ICH) involves bleeding directly into the brain parenchyma and formation of hematoma. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 1/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate IVH Intraventricular hemorrhage (IVH) involves bleeding into the ventricles, excluding IVH in preterm infants. SAH Subarachnoid hemorrhage (SAH) involves bleeding that occurs directly into the subarachnoid space under arterial pressure. The blood spreads quickly within the cerebrospinal fluid (CSF), leading to a rapid increase in intracranial pressure. When to suspect Acute ischemic stroke due to vaso-occlusion in cerebral vessels is the first consideration in a patient with SCD who presents with new neurologic findings or severe headache. However, it is important not to overlook other potential causes of neurologic deterioration. (See 'Differential diagnoses' below.) Presenting features may suggest certain stroke subtypes or stroke mimics, though no clinical features are pathognomonic for distinguishing among types of stroke: Ischemic stroke Infants may present with focal weakness but are more likely than older children to present with seizures and altered mental status. Older children usually have hemiparesis or other focal neurologic signs such as aphasia, or visual disturbance; other symptoms may include seizures, headache, and lethargy. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors" and "Overview of the evaluation of stroke".) The most common locations for an acute ischemic stroke in patients with SCD include large vessel territories and borderzone regions ( figure 1). Hemorrhagic transformation of infarcts can occur in these sites [1]. Transient ischemic attack (TIA) Stroke symptoms or signs lasting <24 hours have been historically defined as a TIA. However, when appropriate neuroimaging is completed, up to 33 percent of patients with stroke symptoms lasting <24 hours are found to have an infarct [2]. In a small study in children with TIA, 16 percent had infarcts on follow-up magnetic resonance imaging (MRI) [3]. This has led to a tissue-based definition of TIA as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction on neuroimaging [4]. (See "Definition, etiology, and clinical manifestations of transient ischemic attack".) During a TIA or acute ischemic infarct, blood transfusion may hasten recovery to baseline. The traditional threshold for distinguishing stroke from TIA is therefore somewhat arbitrary. Cerebral venous thrombosis Cerebral venous thrombosis (CVT; also called cerebral venous sinus thrombosis [CVST]) has a highly variable presentation, since there may be https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 2/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate associated brain swelling, edema, venous infarction, or hemorrhagic venous infarction caused by venous occlusion. The onset can be acute, subacute, or chronic. Headache (of gradual, acute, or thunderclap onset) is the most frequent symptom and may occur as part of an isolated intracranial hypertension syndrome, with or without vomiting, papilledema, and visual problems. In other cases, headache may be accompanied by focal neurologic deficits, focal or generalized seizures, papilledema, and encephalopathy with altered mental status or coma. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) ICH The presentation of ICH depends primarily on the size of the hematoma, anatomic location, and whether the hemorrhage extends into the ventricles. Typical findings include rapid onset of neurologic dysfunction and signs of increased intracranial pressure such as headache, vomiting, and decreased level of consciousness. For patients with large volume hemorrhage, stupor or coma is typical. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) SAH The primary symptom of aneurysmal SAH is a sudden, severe headache, which may or may not be associated with a brief loss of consciousness, nausea or vomiting, and meningismus. Restricted SAH may manifest with transient motor or sensory symptoms that suggest epileptic phenomena and/or frank seizures. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Nonaneurysmal subarachnoid hemorrhage".) Age may be somewhat helpful for predicting the ultimate diagnosis. Ischemic stroke is more common than hemorrhagic stroke in children and adolescents with SCD. Hemorrhagic stroke is more common than ischemic stroke in adults with SCD [1]. TIA is rare in children. However, individuals of all ages with SCD may have any of these diagnoses. The epidemiology of stroke in SCD, which may differ according to the age of the patient, is discussed separately. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Incidence'.) Differential diagnoses The following alternative diagnoses warrant consideration [1]: Infection, including acute meningitis, brain abscess, meningoencephalitis, or cerebral malaria (in endemic areas) Seizure, particularly when associated with prolonged postictal paralysis (Todd paralysis) Migraine (especially hemiplegic migraine) Tumors and other structural brain lesions https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 3/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Alternating hemiplegia of childhood Posterior reversible leukoencephalopathy syndrome (PRES) Metabolic derangements Demyelinating conditions such as acute disseminated encephalomyelitis (ADEM) Idiopathic intracranial hypertension Drug toxicity, including opioid overdose for patients on chronic opioid therapy Musculoskeletal conditions Psychogenic conditions Distinguishing characteristics and laboratory findings are discussed separately. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Differential diagnosis' and "Differential diagnosis of transient ischemic attack and acute stroke".) IMMEDIATE EVALUATION AND MANAGEMENT Evaluation and treatment proceed in parallel Initial stabilization with a rapid clinical assessment should occur simultaneously with prompt simple transfusion and neuroimaging to differentiate ischemia from hemorrhage and to exclude stroke mimics. In practice, this means that labs required for transfusion are sent while rapid neuroimaging is requested ( algorithm 1). Initial stabilization All patients with SCD and possible stroke should have [1,5]: Immediate assessment by clinicians with expertise in stroke and SCD management, typically from the neurology and hematology services. Monitoring of oxygen saturation. Supplemental oxygen to maintain saturation >95 percent. Airway protection from aspiration. Baseline laboratory testing. (See 'Laboratory and other testing' below.) Urgent simple transfusion to reduce the percent sickle hemoglobin and to raise the hemoglobin to approximately 10 g/dL, but not higher. (See 'Simple transfusion for all patients' below and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".) Brain imaging. (See 'Neuroimaging' below.) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 4/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Precautions to minimize crying and hyperventilation (treat pain, minimize the number of medical personnel in the room, have a parent or caregiver keep the patient calm). In some patients, crying and hyperventilation can lower the PaCO and thereby induce or worsen 2 cerebral ischemia by causing vasoconstriction. Avoidance of hypotension, hypovolemia, hyperthermia, hyperglycemia, and hypocarbia. Intravenous hydration with isotonic fluids, typically at the normal maintenance rate, holding fluids during transfusion. Volume depletion should be avoided, but fluid overload can contribute to hypertension and pulmonary edema. Blood pressure control. (See "Initial assessment and management of acute stroke", section on 'Blood pressure management'.) Identification and treatment of concurrent infection, with antipyretics if fever is present. Management of seizures if present. Intensive monitoring and care in a dedicated stroke unit when possible. Management of acute stroke in SCD requires specialized expertise in exchange transfusion. Transfer to another facility may be required if needed to provide access to exchange transfusion. (See 'Exchange transfusion' below.) Oxygenation and treatment of infection can reduce sickling, which could further worsen cerebral ischemia and other vaso-occlusive complications. Maximizing cerebral perfusion, ventilation, and normoglycemia is also critical. Hydration with normal saline rather than hypotonic saline will avoid the potential worsening of cerebral edema; excessive fluids should be avoided. (See "Initial assessment and management of acute stroke" and "Ischemic stroke in children: Management and prognosis", section on 'Initial management'.) Patients with fever Fever can occur with infection (meningitis, acute chest syndrome, sepsis) or with stroke in the absence of infection. Distinguishing between these is critical. Individuals with SCD are immunocompromised due to functional asplenia and are at high risk of sepsis from encapsulated organisms. Prompt institution of broad-spectrum antibiotics may be lifesaving. All patients with SCD who present with fever and acute neurologic findings should be treated presumptively for a bacterial infection until this possibility is eliminated, unless there is a good rationale not to do so. (See "Evaluation and management of fever in children and adults with sickle cell disease".) Laboratory and other testing Laboratory testing should include [1]: https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 5/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Complete blood count (CBC) Reticulocyte count Type and crossmatch for transfusion Percent hemoglobin S, to facilitate exchange transfusion Prothrombin time (PT) and activated partial thromboplastin time (aPTT) Basic metabolic profile with electrolytes, urea nitrogen, creatinine, and glucose Blood cultures if fever is present The role of these studies is discussed in more detail separately. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis".) Simple transfusion for all patients Red blood cell (RBC) transfusion is the cornerstone of treatment for acute ischemic stroke because it treats anemia and lowers the percent sickle hemoglobin. The role in acute hemorrhagic stroke is less clear; however, simple transfusion is recommended for all patients. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.) Simple transfusion is a temporizing measure until exchange transfusion can be performed. Exchange transfusion is much more effective at lowering the percent hemoglobin S while avoiding hyperviscosity. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Risk of hyperviscosity syndrome from simple transfusion'.) If clinical suspicion for an acute stroke is high and the patient's hemoglobin level is 8.5 g/dL, a simple transfusion should be given rapidly, within two hours of clinical presentation. Raising the hemoglobin to 10 g/dL also facilitates sedation for neuroimaging and central venous catheter placement if necessary. Overtransfusion (to hemoglobin >10 g/dL) is avoided since it may cause hyperviscosity, which decreases oxygen delivery. If the hemoglobin level is <5 g/dL, it can be raised to 10 g/dL with sequential simple transfusions of 5 to 10 mL/kg, and the hemoglobin S concentration can then be determined to assess the need for exchange transfusion. Neuroimaging Neuroimaging (brain and neurovascular) is critical for all patients with suspected stroke in order to: Differentiate ischemia from hemorrhage Exclude stroke mimics, such as tumor Assess the status of large cervical and intracranial arteries The major management implication of the distinction between ischemia and hemorrhage is in helping to decide whether urgent exchange transfusion is appropriate. Urgent exchange https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 6/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate transfusion is indicated for patients with acute ischemic stroke, TIA, and/or hemorrhagic transformation of an acute ischemic stroke. The role of exchange transfusion in the management of hemorrhagic stroke is less clear. Imaging methods are reviewed here briefly and presented separately. (See "Neuroimaging of acute stroke".) MRI versus CT Brain magnetic resonance imaging (MRI) is preferred if it can be obtained rapidly. Brain MRI is more sensitive for acute ischemia than computed tomography (CT), particularly with diffusion-weighted imaging (DWI) in the hyperacute time period. Brain MRI provides better visualization of the posterior fossa and detects intracerebral hemorrhage (ICH) with good sensitivity using high susceptibility sequences. Limitations of MRI include availability and cost. Young children and other individuals who cannot cooperate with lying still may require sedation for MRI, which carries additional risks and costs. Head CT typically takes <5 minutes and thus is easier to obtain, and unenhanced CT has a high sensitivity for hemorrhage. However, CT is a source of radiation exposure. Children Head CT is generally not considered adequate to diagnose ischemic stroke; MRI may be required to reliably exclude stroke mimics. CT should be used if MRI is not rapidly available or if a child is not stable for (or cannot tolerate) MRI. If CT is unrevealing, MRI can be obtained once the patient is stabilized [1]. Adults Either CT or MRI may be used as the initial study. Brain MRI with DWI is typically preferred if available because it is more sensitive for acute ischemic stroke. For older adults with risk factors for embolic stroke such as atrial fibrillation, head CT with CT angiography (CTA) of the head and neck will rapidly diagnose large vessel occlusion. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Brain imaging' and "Neuroimaging of acute stroke".) Given these considerations, the imaging approach and local institutional practices may vary. MRA and CTA Magnetic resonance angiography (MRA) or CTA should be obtained in all adults and children with acute stroke to evaluate large vessel arteriopathy (large vessel stenosis, dissection, moyamoya, atherosclerosis) and to exclude aneurysm. In a patient whose clinical picture is not concerning for arterial dissection or aneurysm, vascular imaging can be deferred until after the patient has been stabilized. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 7/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate MRV Brain MRI with magnetic resonance venography (MRV) is the most sensitive technique for demonstrating cerebral venous sinus thrombosis (CVST). Some experts recommend obtaining MRV with the initial MRI to reduce the likelihood of missing a cerebral venous thrombosis (CVT), particularly those with altered mental status and headache [1]. Clinical features and evaluation for CVST are presented separately. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Neuroimaging'.) Lack of access to imaging A large portion of the world's SCD population may not have immediate access to neuroimaging. For these individuals, it is necessary to make a presumptive diagnosis of stroke based on clinical features alone, as discussed separately. (See "Sickle cell disease in sub-Saharan Africa", section on 'Stroke'.) Supportive care Venous thromboembolism (VTE) prophylaxis Prophylaxis for deep venous thrombosis and pulmonary embolism is indicated for patients with acute stroke who have restricted mobility or other risk factors for VTE, such as an indwelling central venous catheter, significant inflammation, or high body mass index. VTE prophylaxis in younger children is determined on a case-by-case basis; sequential compression devices may be preferred to anticoagulation in some children. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke".) Swallowing assessment Dysphagia is common after stroke and is a major risk factor for developing aspiration pneumonia. Swallowing function should be assessed prior to administering oral medications or food. Nothing should be administered orally until swallowing function is evaluated. (See "Complications of stroke: An overview", section on 'Dysphagia'.) TIA AND ISCHEMIC STROKE MANAGEMENT Transfusion For patients with SCD who have a clinically and/or radiologically confirmed acute ischemic stroke or TIA, we suggest exchange transfusion ( algorithm 1). Goals The goals of transfusion in ischemic stroke are: Lower the percentage of sickle hemoglobin to <30 percent of total hemoglobin (typically 15 to 20 percent). https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 8/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Aim for a total hemoglobin of approximately 10 g/dL. This is best achieved using exchange transfusion. However, it takes time to mobilize resources and possibly transfer to another facility for exchange transfusion. When exchange transfusion is not available within two hours of presentation and the hemoglobin is 8.5 g/dL, simple transfusion can be performed, with careful estimation of the transfusion volume so as not to raise the post-transfusion hemoglobin above 10 g/dL, often while awaiting the results of the clinical assessment and neuroimaging and possibly the placement of an apheresis catheter. (See 'Immediate evaluation and management' above.) Exchange transfusion Rationale We use exchange transfusion rather than simple transfusion alone or other interventions for children and adults with SCD who have confirmed ischemic stroke or TIA. The rationale is that reducing the percentage of hemoglobin S decreases vaso-occlusion and further ischemia, and that children who have early exchange transfusion have a lower rate of recurrent stroke compared with those who receive only simple transfusion [6]. A high percentage of adults with TIA have an ischemic stroke within seven days, and exchange transfusion is protective [7]. Simple transfusion cannot provide a sufficient volume of allogeneic red blood cells (RBCs) to lower the percentage of hemoglobin S sufficiently without causing hyperviscosity or transfusion-associated circulatory overload. Procedure Exchange transfusion involves a type of apheresis (erythrocytapheresis) in which blood removed from the patient is depleted of RBCs, reconstituted with donor RBCs, and retransfused in a continuous circuit. This procedure typically requires placement of a double-lumen apheresis catheter. If equipment for automated exchange is not available, manual exchange can be performed. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Exchange blood transfusion'.) A single exchange transfusion is usually sufficient to lower the hemoglobin S concentration to the desired level. The apheresis catheter can be removed after the exchange transfusion is completed unless it is absolutely required for venous access. Total hemoglobin and percent hemoglobin S are monitored during the exchange. The usual post-transfusion targets are: Total hemoglobin approximately 10 g/dL (not higher) Hemoglobin S <30 percent of total hemoglobin (target, 15 to 20 percent) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 9/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate This should maintain the hemoglobin S concentration <30 percent of total hemoglobin for two to four weeks until another transfusion is needed. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Exchange blood transfusion'.) Supporting evidence There are no randomized trials comparing exchange transfusion with simple transfusion or other interventions for acute stroke in SCD. Evidence for the benefit of transfusion in patients with SCD and acute stroke includes our clinical experience and studies revealing improved cerebral perfusion with transfusion [8,9]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Mechanisms'.) Evidence for the superiority of exchange transfusion in secondary prevention (reducing the risk of stroke recurrence) includes a 2006 retrospective study of 137 children with SCD and acute stroke [6]. For the 52 patients who presented within 24 hours of onset of initial stroke symptom for whom treatment information was available, second strokes were more likely in those who received simple transfusions (8 of 14 patients [57 percent]) compared with those who were treated with exchange transfusions (8 of 38 patients [21 percent]; RR 5.0, 95% CI 1.3-18.6), despite similar baseline risk factors. Our approach is consistent with a 2014 consensus report on SCD management from the National Heart, Lung, and Blood Institute (NHLBI) in the United States [10,11], and with 2020 guidelines from the American Society of Hematology [5]. Additional information on risks and benefits of simple versus exchange transfusion are presented separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".) Reperfusion therapy Reperfusion therapy (intravenous thrombolysis with tissue plasminogen activator [tPA] and/or mechanical thrombectomy) for acute ischemic stroke associated with SCD is controversial, and data are sparse. For adults with a high likelihood of a non-SCD-related cause of ischemic stroke, such as embolism in the setting of atrial fibrillation or large artery stenosis or occlusion, it is logical to consider reperfusion therapies unless there is a strong reason not to do so ( algorithm 1). Patients most likely to benefit are older adults with conventional stroke risk factors such as hypertension, diabetes, hyperlipidemia, and/or atrial fibrillation [12]. Intravenous thrombolysis Adults with SCD presenting with symptoms of acute ischemic stroke should be considered for intravenous tPA [5]. They should meet typical criteria: https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 10/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Age 18 years No hemorrhage on brain imaging Within 4.5 hours of stroke symptom onset No contraindications for thrombolysis Full inclusion and exclusion criteria are listed in the table ( table 1). For children <18 years with SCD, intravenous tPA is not recommended [5]. There is a concern that the use of thrombolytic agents could precipitate intracranial hemorrhage (ICH) at a higher rate in individuals with SCD. However, the risk of ICH in SCD appears to be due to an increased prevalence of aneurysm rather than increased bleeding tendency specific to SCD. Thus, SCD is not an exclusion criterion for tPA treatment of adults with ischemic stroke. An observational study using administrative data to compare 832 adults with stroke and SCD versus 3328 adults with stroke who did not have SCD found no difference in the percentage treated with thrombolytic therapy (8.2 versus 9.4 percent) or in the incidence of symptomatic ICH complicating thrombolysis (4.9 versus 3.2 percent) [13]. Thrombolysis was felt to be safe; however, the effect on functional outcomes was not reported. Administration of tPA should not replace or delay typical SCD-related acute stroke care, specifically simple blood transfusion [5]. Since tPA guidelines require the placement of two intravenous lines, tPA infusion and transfusion could be concurrent. Importantly, the apheresis catheter for exchange transfusion must be placed before tPA is administered. Older adults with typical stroke risk factors such as atrial fibrillation, diabetes, hypertension, or hyperlipidemia may be viewed as more likely to benefit from tPA than younger adults without these risk factors [5,12]. Moyamoya disease is a relative contraindication to tPA. (See 'Moyamoya syndrome' below.) Mechanical thrombectomy (MT) MT is not well-studied for the treatment of stroke in patients with SCD [5]. In the general population, mechanical thrombectomy is indicated for patients with acute ischemic stroke due to a large artery occlusion in the anterior circulation who meet eligibility criteria and can be treated within 24 hours of the time last known to be at their neurologic baseline (last time known well), regardless of whether they receive intravenous thrombolysis for the same ischemic stroke event. (See "Mechanical thrombectomy for acute ischemic stroke".) Patient selection for MT is reviewed in the figure ( algorithm 2) and discussed separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 11/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Patients and their families/caregivers must be counseled about the limited evidence for reperfusion therapies in SCD [5,12,14]. These therapies should only be used in centers with significant experience and in consultation with the appropriate specialists from neurology, hematology, and interventional radiology. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) Evaluation for the cause Additional evaluation for causes of ischemic stroke and TIA other than vaso-occlusive vasculopathy may be appropriate in select cases, particularly in adults with typical stroke risk factors. (see "Overview of the evaluation of stroke") These may include: Cardioembolic sources such as atrial fibrillation or patent foramen ovale (PFO) Vasospasm in association with drug use (eg, from cocaine or amphetamines) Vascular disease associated with hypercholesterolemia or diabetes Appropriate history, brain and blood vessel imaging, cardiac monitoring, echocardiography, and laboratory testing (fasting lipids, hemoglobin A1c) are essential for the evaluation for these risk factors In principle, any of these conditions could affect patients of any age. However, their likelihood is age-dependent. Additional information on possible etiologies and evaluation in children is presented separately. Newborns (see "Stroke in the newborn: Classification, manifestations, and diagnosis" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis") Children (see "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis") Other rare stroke mimics must be considered if the initial evaluation and imaging do not reveal a cause. (See 'Differential diagnoses' above and "Differential diagnosis of transient ischemic attack and acute stroke".) Treatment for specific causes Moyamoya syndrome For patients with moyamoya syndrome (bilateral or unilateral internal carotid artery stenosis with prominent collateral vessels) and acute stroke, acute treatment is mainly symptomatic and directed towards improving cerebral blood flow with fluids and https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 12/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate transfusion and controlling seizures. In moyamoya disease, tPA should not be used due to the increased risk of bleeding. Some clinicians start antiplatelet therapy for children and adults with moyamoya syndrome; however, evidence is lacking for prevention of infarct recurrence. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis".) Cerebral venous thrombosis The main treatment for symptomatic cerebral venous thrombosis (CVT, also called central venous sinus thrombosis [CVST]) is anticoagulation with heparin (unfractionated or low molecular weight [LMW] heparin). Hemorrhagic venous infarction, intracerebral hemorrhage (ICH), or isolated subarachnoid hemorrhage (SAH) are not contraindications to anticoagulation in CVT, including in patients with SCD [1]. (See "Cerebral venous thrombosis: Treatment and prognosis".) Testing for hypercoagulable conditions and COVID-19 is appropriate when CVT is found. (See "Overview of the causes of venous thrombosis" and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".) Other causes Other defined traditional stroke mechanisms may be present in patients with SCD. Management is reviewed separately: Small vessel disease (see "Lacunar infarcts") Large vessel atherosclerosis (see "Management of symptomatic carotid atherosclerotic disease" and "Intracranial large artery atherosclerosis: Treatment and prognosis") Cardiogenic embolism (see "Stroke in patients with atrial fibrillation") Role of antiplatelet agents and anticoagulation Antiplatelet agents The efficacy of antiplatelet agents has not been studied for acute treatment or secondary prevention of SCD-associated TIA or ischemic stroke in children or adults [15]. In the general population, aspirin or short-term dual antiplatelet therapy (DAPT) are indicated for most adults with acute TIA or acute ischemic stroke, and antiplatelet therapy may be appropriate for adults with SCD who have an acute TIA or ischemic stroke, particularly if they have traditional stroke risk factors, especially intracranial atherosclerosis. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 13/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Antiplatelet therapy may also be appropriate for secondary stroke prevention in adults with SCD who have traditional stroke risk factors, similar to the general population [16]. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Anticoagulation We generally do not use anticoagulation for ischemic stroke in patients with SCD. However, SCD is a hypercoagulable state, and prophylactic dose anticoagulation may be appropriate for venous thromboembolism (VTE) prophylaxis in those admitted with an acute medical illness, especially adults and those with decreased mobility. (See 'Supportive care' above and "Prevention and treatment of venous thromboembolism in patients with acute stroke".) Anticoagulation may be appropriate for: CVT (see "Cerebral venous thrombosis: Treatment and prognosis") Increased probability of thromboembolic disease, after the immediate risk of hemorrhagic conversion has receded (see "Stroke in patients with atrial fibrillation" and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome") Administration and adverse events are discussed separately. (see "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management") INTRACRANIAL HEMORRHAGE MANAGEMENT Intracranial hemorrhage (ICH), also called hemorrhagic stroke, accounts for approximately one- third of cerebrovascular events in patients with SCD and is more common in older individuals [17]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Incidence' and "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Risk factors: Hemorrhagic stroke'.) Urgent interventions In addition to acute stabilization of the patient as described above (see 'Immediate evaluation and management' above), the following should be done immediately ( algorithm 1): Discontinue all anticoagulants and antiplatelet agents, unless the benefits of continuing are thought to outweigh their risks for that patient, such as in the setting of CVST and hemorrhagic venous infarction or a prosthetic heart valve where anticoagulation might be held briefly for stabilization and then restarted. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 14/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate For patients receiving an anticoagulant, decide whether a reversal agent is needed. For those who have received a short-acting anticoagulant for which several half-lives have passed, reversal may not be required. For patients with thrombocytopenia, administer platelet transfusions as necessary to maintain the platelet count 100,000/microL. Obtain neurosurgical consultation if a procedure may be required to reduce intracranial pressure or to treat a bleeding aneurysm. Obtain imaging such as CT- or MR-angiography to guide further therapy in most cases. Management of ICH and subarachnoid hemorrhage (SAH) in the general population is discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Nonaneurysmal subarachnoid hemorrhage".) Additional therapy according to type of bleed Hemorrhagic transformation of arterial ischemic stroke Hemorrhagic transformation of an ischemic stroke should be managed as with other causes of hemorrhagic stroke, including stopping and reversing any anticoagulation, correcting any coagulopathy, and transfusing platelets as needed. Transfusion is appropriate. (See 'Transfusion' above.) Cerebral venous sinus thrombosis (CVST) Management is similar to individuals without SCD. (See "Cerebral venous thrombosis: Treatment and prognosis".) SAH from aneurysmal bleeding Initial treatment of SAH includes intensive care monitoring, analgesia, and close attention to blood pressure control; as well as ventriculostomy for those with increased intracranial pressure. Aneurysm repair should be attempted if possible. Details are presented separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Treatment of cerebral aneurysms" and "Nonaneurysmal subarachnoid hemorrhage".) Patients with SAH who are undergoing surgery should have exchange transfusion if possible prior to surgery, to reduce sickle hemoglobin to <30 percent of total hemoglobin; ideally surgery is performed within a week of exchange transfusion. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Prophylactic preoperative transfusion'.) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 15/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Intraventricular hemorrhage (IVH) IVH may occur when subarachnoid or intraparenchymal hemorrhage extends into the ventricles [18]. Patients with prior ischemic stroke may be at risk for IVH and intraparenchymal hemorrhage, even months to years later [19]. Hemorrhage into the third ventricle or cerebral aqueduct confers a high risk for late deterioration. Patients may be awake and alert immediately following the bleed and become comatose over the ensuing 48 hours because of obstructive hydrocephalus and ventricular dilation. Emergency ventricular drainage may be necessary [20]. Management is discussed separately. (See "Intraventricular hemorrhage".) Despite these interventions, mortality from ICH in SCD is as high as 24 to 30 percent [14,17]. Deaths generally occur within the first two weeks, many on the first day [17]. Some individuals have moderate to severe residual disability [21]. FOLLOW-UP AFTER THE ACUTE EVENT Repeat imaging If the initial magnetic resonance imaging (MRI) study does not show ischemic injury and clinically the patient seemed to have a stroke or transient ischemic attack (TIA), we perform a repeat MRI of the brain two to four weeks after the initial presentation, since diffusion weighted images of the brain may rarely be negative upon presentation and may still demonstrate very small areas of ischemic injury upon
"Overview of the causes of venous thrombosis" and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".) Other causes Other defined traditional stroke mechanisms may be present in patients with SCD. Management is reviewed separately: Small vessel disease (see "Lacunar infarcts") Large vessel atherosclerosis (see "Management of symptomatic carotid atherosclerotic disease" and "Intracranial large artery atherosclerosis: Treatment and prognosis") Cardiogenic embolism (see "Stroke in patients with atrial fibrillation") Role of antiplatelet agents and anticoagulation Antiplatelet agents The efficacy of antiplatelet agents has not been studied for acute treatment or secondary prevention of SCD-associated TIA or ischemic stroke in children or adults [15]. In the general population, aspirin or short-term dual antiplatelet therapy (DAPT) are indicated for most adults with acute TIA or acute ischemic stroke, and antiplatelet therapy may be appropriate for adults with SCD who have an acute TIA or ischemic stroke, particularly if they have traditional stroke risk factors, especially intracranial atherosclerosis. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 13/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Antiplatelet therapy may also be appropriate for secondary stroke prevention in adults with SCD who have traditional stroke risk factors, similar to the general population [16]. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Anticoagulation We generally do not use anticoagulation for ischemic stroke in patients with SCD. However, SCD is a hypercoagulable state, and prophylactic dose anticoagulation may be appropriate for venous thromboembolism (VTE) prophylaxis in those admitted with an acute medical illness, especially adults and those with decreased mobility. (See 'Supportive care' above and "Prevention and treatment of venous thromboembolism in patients with acute stroke".) Anticoagulation may be appropriate for: CVT (see "Cerebral venous thrombosis: Treatment and prognosis") Increased probability of thromboembolic disease, after the immediate risk of hemorrhagic conversion has receded (see "Stroke in patients with atrial fibrillation" and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome") Administration and adverse events are discussed separately. (see "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management") INTRACRANIAL HEMORRHAGE MANAGEMENT Intracranial hemorrhage (ICH), also called hemorrhagic stroke, accounts for approximately one- third of cerebrovascular events in patients with SCD and is more common in older individuals [17]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Incidence' and "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Risk factors: Hemorrhagic stroke'.) Urgent interventions In addition to acute stabilization of the patient as described above (see 'Immediate evaluation and management' above), the following should be done immediately ( algorithm 1): Discontinue all anticoagulants and antiplatelet agents, unless the benefits of continuing are thought to outweigh their risks for that patient, such as in the setting of CVST and hemorrhagic venous infarction or a prosthetic heart valve where anticoagulation might be held briefly for stabilization and then restarted. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 14/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate For patients receiving an anticoagulant, decide whether a reversal agent is needed. For those who have received a short-acting anticoagulant for which several half-lives have passed, reversal may not be required. For patients with thrombocytopenia, administer platelet transfusions as necessary to maintain the platelet count 100,000/microL. Obtain neurosurgical consultation if a procedure may be required to reduce intracranial pressure or to treat a bleeding aneurysm. Obtain imaging such as CT- or MR-angiography to guide further therapy in most cases. Management of ICH and subarachnoid hemorrhage (SAH) in the general population is discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Nonaneurysmal subarachnoid hemorrhage".) Additional therapy according to type of bleed Hemorrhagic transformation of arterial ischemic stroke Hemorrhagic transformation of an ischemic stroke should be managed as with other causes of hemorrhagic stroke, including stopping and reversing any anticoagulation, correcting any coagulopathy, and transfusing platelets as needed. Transfusion is appropriate. (See 'Transfusion' above.) Cerebral venous sinus thrombosis (CVST) Management is similar to individuals without SCD. (See "Cerebral venous thrombosis: Treatment and prognosis".) SAH from aneurysmal bleeding Initial treatment of SAH includes intensive care monitoring, analgesia, and close attention to blood pressure control; as well as ventriculostomy for those with increased intracranial pressure. Aneurysm repair should be attempted if possible. Details are presented separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Treatment of cerebral aneurysms" and "Nonaneurysmal subarachnoid hemorrhage".) Patients with SAH who are undergoing surgery should have exchange transfusion if possible prior to surgery, to reduce sickle hemoglobin to <30 percent of total hemoglobin; ideally surgery is performed within a week of exchange transfusion. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Prophylactic preoperative transfusion'.) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 15/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Intraventricular hemorrhage (IVH) IVH may occur when subarachnoid or intraparenchymal hemorrhage extends into the ventricles [18]. Patients with prior ischemic stroke may be at risk for IVH and intraparenchymal hemorrhage, even months to years later [19]. Hemorrhage into the third ventricle or cerebral aqueduct confers a high risk for late deterioration. Patients may be awake and alert immediately following the bleed and become comatose over the ensuing 48 hours because of obstructive hydrocephalus and ventricular dilation. Emergency ventricular drainage may be necessary [20]. Management is discussed separately. (See "Intraventricular hemorrhage".) Despite these interventions, mortality from ICH in SCD is as high as 24 to 30 percent [14,17]. Deaths generally occur within the first two weeks, many on the first day [17]. Some individuals have moderate to severe residual disability [21]. FOLLOW-UP AFTER THE ACUTE EVENT Repeat imaging If the initial magnetic resonance imaging (MRI) study does not show ischemic injury and clinically the patient seemed to have a stroke or transient ischemic attack (TIA), we perform a repeat MRI of the brain two to four weeks after the initial presentation, since diffusion weighted images of the brain may rarely be negative upon presentation and may still demonstrate very small areas of ischemic injury upon subsequent imaging [22]. Secondary stroke prevention Secondary stroke prevention is critical, typically involving chronic transfusions. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of recurrent ischemic stroke (secondary stroke prophylaxis)' and "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of hemorrhagic strokes'.) Cognitive or behavioral dysfunction (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Management of cognitive and behavioral dysfunction'.) Motor deficits (See "Overview of geriatric rehabilitation: Patient assessment and common indications for rehabilitation", section on 'Stroke' and "Overview of ischemic stroke prognosis in adults", section on 'Interventions that improve outcomes'.) SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 16/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias" and "Society guideline links: Stroke in children".) PATIENT PERSPECTIVE TOPIC Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".) SUMMARY AND RECOMMENDATIONS Presentation Acute ischemic stroke due to cerebral vaso-occlusion is the first consideration in patients with sickle cell disease (SCD) who present with new neurologic findings or severe headache. Hemorrhagic stroke accounts for one-third of events. It is important not to overlook other potential causes of neurologic deterioration, including transient ischemic attack (TIA), cerebral venous thrombosis (CVT), seizure, infection, and other stroke mimics. (See 'Presentation' above.) Immediate measures Management involves initial stabilization by clinicians with expertise in stroke and SCD, supplemental oxygen to maintain saturation >95 percent, rapid clinical assessment and baseline laboratory testing, and simple transfusion, followed by neuroimaging ( algorithm 1). Patients with fever should receive empiric broad- spectrum antibiotics and antipyretics. (See 'Immediate evaluation and management' above.) Neuroimaging Brain and neurovascular imaging is essential to differentiate ischemia from hemorrhage, exclude stroke mimics, and assess large cervical and intracranial arteries. Magnetic resonance imaging (MRI) is generally preferred. (See 'Neuroimaging' above.) Transfusion For patients with SCD who have a suspected or confirmed stroke (ischemic or hemorrhagic) or TIA, we suggest exchange transfusion (Grade 2C). The goal is to lower the percentage of sickle hemoglobin to <30 percent of total hemoglobin (typically to 15 to 20 percent) without raising the total hemoglobin >10 g/dL and causing hyperviscosity. Simple transfusion is used as a temporizing measure until exchange transfusion can be instituted. (See 'Transfusion' above.) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 17/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Reperfusion Adults with SCD and acute ischemic stroke should be evaluated for intravenous thrombolysis and mechanical thrombectomy. (See 'Reperfusion therapy' above.) Mechanism-specific treatment The following is appropriate in addition to immediate assessment, stabilization, and other standard acute stroke management ( algorithm 1): Ischemic stroke or TIA Antiplatelet therapy may be appropriate for adults with SCD who have an acute TIA or ischemic stroke, particularly if they have traditional stroke risk factors. (See 'Role of antiplatelet agents and anticoagulation' above.) Intracranial hemorrhage Neurosurgical evaluation and angiography to guide therapy. Additional interventions for specific types of hemorrhagic stroke are discussed above. (See 'Intracranial hemorrhage management' above.) Moyamoya syndrome Some clinicians start antiplatelet therapy. (See 'Moyamoya syndrome' above.) CVT Heparin anticoagulation, even if hemorrhagic transformation occurs. (See 'Cerebral venous thrombosis' above.) Follow-up Secondary stroke prevention is critical. Repeat imaging, cognitive assistance, and rehabilitation services may be appropriate. (See 'Follow-up after the acute event' above.) ACKNOWLEDGMENTS UpToDate acknowledges ZoAnn Dreyer, MD, who contributed to earlier versions of this topic review. The UpToDate editorial staff also acknowledge the extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kassim AA, Galadanci NA, Pruthi S, DeBaun MR. How I treat and manage strokes in sickle cell disease. Blood 2015; 125:3401. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 18/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate 2. Ovbiagele B, Kidwell CS, Saver JL. Epidemiological impact in the United States of a tissue- based definition of transient ischemic attack. Stroke 2003; 34:919. 3. Lehman LL, Watson CG, Kapur K, et al. Predictors of Stroke After Transient Ischemic Attack in Children. Stroke 2016; 47:88. 4. Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke 2009; 40:2276. 5. DeBaun MR, Jordan LC, King AA, et al. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv 2020; 4:1554. 6. Hulbert ML, Scothorn DJ, Panepinto JA, et al. Exchange blood transfusion compared with simple transfusion for first overt stroke is associated with a lower risk of subsequent stroke: a retrospective cohort study of 137 children with sickle cell anemia. J Pediatr 2006; 149:710. 7. Giles MF, Rothwell PM. Risk of stroke early after transient ischaemic attack: a systematic review and meta-analysis. Lancet Neurol 2007; 6:1063. 8. Guilliams KP, Fields ME, Ragan DK, et al. Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia. Blood 2018; 131:1012. 9. Juttukonda MR, Lee CA, Patel NJ, et al. Differential cerebral hemometabolic responses to blood transfusions in adults and children with sickle cell anemia. J Magn Reson Imaging 2019; 49:466. 10. https://www.nhlbi.nih.gov/sites/default/files/media/docs/Evd-Bsd_SickleCellDis_Rep2014.pd f (Accessed on July 20, 2018). 11. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014; 312:1033. 12. Alakbarzade V, Maduakor C, Khan U, et al. Cerebrovascular disease in sickle cell disease. Pract Neurol 2023; 23:131. 13. Adams RJ, Cox M, Ozark SD, et al. Coexistent Sickle Cell Disease Has No Impact on the Safety or Outcome of Lytic Therapy in Acute Ischemic Stroke: Findings From Get With The Guidelines-Stroke. Stroke 2017; 48:686. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 19/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate 14. Strouse JJ, Lanzkron S, Urrutia V. The epidemiology, evaluation and treatment of stroke in adults with sickle cell disease. Expert Rev Hematol 2011; 4:597. 15. Guilliams KP, Kirkham FJ, Holzhauer S, et al. Arteriopathy Influences Pediatric Ischemic Stroke Presentation, but Sickle Cell Disease Influences Stroke Management. Stroke 2019; 50:1089. 16. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 17. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998; 91:288. 18. Adams RJ, Nichols FT. Sickle cell anemia, sickle cell trait and thalassemia. In: Handbook of Cli nical Neurology, Vascular Disease Part III, Vinken PJ, Bruyn GW, Klawans HL (Eds), Elsevier, A msterdam 1989. p.503. 19. Powars D, Adams RJ, Nichols FT, et al. Delayed intracranial hemorrhage following cerebral infarction in sickle cell anemia. J Assoc Acad Minor Phys 1990; 1:79. 20. Adams RJ. Neurologic complications. In: Sickle Cell Disease: Basic Principles and Clinical Prac tice, Embury SH, Robert P, Hebbel RP, et al (Eds), Raven Press, Ltd, New York 1994. p.599. 21. Oyesiku NM, Barrow DL, Eckman JR, et al. Intracranial aneurysms in sickle-cell anemia: clinical features and pathogenesis. J Neurosurg 1991; 75:356. 22. Makin SD, Doubal FN, Dennis MS, Wardlaw JM. Clinically Confirmed Stroke With Negative Diffusion-Weighted Imaging Magnetic Resonance Imaging: Longitudinal Study of Clinical Outcomes, Stroke Recurrence, and Systematic Review. Stroke 2015; 46:3142. Topic 5926 Version 52.0 https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 20/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate GRAPHICS Cerebrovascular complications with their locations in sickle cell disease Cerebrovascular complications of the large and small vessels of the brain and their corresponding territories are shown. The most common complications are cerebral infarcts in major vessels and "borderzone" infarctions. Borderzone infarctions are most common in the areas between the middle and anterior cerebral arteries, and between the middle and posterior cerebral arteries. Fat embolism and venous side abnormalities are the least common lesions. Small white matter lesions visualized on magnetic resonance imaging can be seen in asymptomatic patients. Multiple cerebral aneurysms can be present within the branches of the circle of Willis. ICA: internal carotid artery; MCA: middle cerebral artery; ACA: anterior cerebral artery; MRI: magnetic resonance imaging; BA: basilar artery. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 21/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Modi ed from: Adams RJ. Neurologic complications. In: Sickle Cell Disease: Basic Principles and Clinical Practice, Embury SH, Robert P, Hebbel RP, et al (Eds), Raven Press, New York 1994. Graphic 50288 Version 4.0 https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 22/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Management of acute stroke in sickle cell disease SCD: sickle cell disease; IV: intravenous; Hb: hemoglobin; RBC: red blood cell; TIA: transient ischemic attack; I magnetic resonance angiography; CTA: CT angiography; CBC: complete blood count; PT: prothrombin time; a DBP: diastolic blood pressure; ICH: intracerebral hemorrhage; SAH: subarachnoid hemorrhage; MAP: mean a resonance venography; CT: computed tomography. Initial stabilization with a rapid clinical assessment should occur simultaneously with prompt RBC transfusi transfusion are sent while rapid neuroimaging is ordered. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 23/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate IVT can proceed concurrently with RBC transfusion but should not replace or delay transfusion. Importantl IVT is administered. Graphic 140156 Version 1.0 https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 24/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 25/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 26/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 27/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Indications for mechanical thrombectomy to treat patients with acute ischemic IV: intravenous; tPA: tissue plasminogen activator (alteplase or tenecteplase); CTA: computed tomography an artery occlusion; MT: mechanical thrombectomy; ASPECTS: Alberta Stroke Program Early CT Score; NIHSS: Na tomography; MRI: magnetic resonance imaging; mRS: modified Rankin Scale; MCA: middle cerebral artery; IC recovery. Patients are not ordinarily eligible for IV tPA unless the time last known to be well is <4.5 hours. However, im that is diffusion positive and FLAIR negative) is an option at expert stroke centers to select patients with wake associated UpToDate topics for details. Usually assessed with MRA or CTA, less often with digital subtraction angiography. There is intracranial arterial occlusion of the distal ICA, middle cerebral (M1/M2), or anterior cerebral (A1/A2 MT may be a treatment option for patients with acute ischemic stroke caused by occlusion of the basilar ar stroke centers, but benefit is uncertain. [1] Based upon data from the Aurora study . Reference: https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 28/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate 1. Albers GW, Lansberg MG, Brown S, et al. Assessment of Optimal Patient Selection for Endovascular Thrombectomy Beyond 6 Hou Neurol 2021; 78:1064. Graphic 117086 Version 3.0 https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 29/30 7/5/23, 12:33 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Contributor Disclosures Alex George, MD, PhD Grant/Research/Clinical Trial Support: Forma Pharmaceuticals [Sickle cell disease]. Consultant/Advisory Boards: Agios Pharmaceuticals [Sickle cell disease]; Chiesi USA [Transfusional iron overload]; GBT Pharmaceuticals [Sickle cell disease]. Speaker's Bureau: GBT Pharmaceuticals [Sickle cell disease]. All of the relevant financial relationships listed have been mitigated. Lori Jordan, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Douglas R Nordli, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Michael R DeBaun, MD, MPH Consultant/Advisory Boards: Forma therapeutics [Sickle cell disease]; Global Blood Therapeutics [Sickle cell disease]; Novartis [Priapism in sickle cell disease]; Vertex/CRISPR Therapeutics [Sickle cell disease, beta thalassemia]. All of the relevant financial relationships listed have been mitigated. Jennifer S Tirnauer, MD No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. 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7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Approach to reperfusion therapy for acute ischemic stroke : Jamary Oliveira-Filho, MD, MS, PhD, Owen B Samuels, MD : Jos Biller, MD, FACP, FAAN, FAHA, Jonathan A Edlow, MD, FACEP, Alejandro A Rabinstein, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 30, 2023. INTRODUCTION The most important factor in successful reperfusion therapy of acute ischemic stroke is early treatment. Nonetheless, selection of appropriate candidates for reperfusion demands a neurologic evaluation and a neuroimaging study. In addition, reperfusion therapy for acute stroke requires a system that coordinates pre-hospital emergency services, emergency medicine, stroke neurology, intensive care services, interventional neuroradiology, and neurosurgery to provide optimal treatment. This topic will review the use of reperfusion therapy for patients with acute ischemic stroke, focusing on early thrombolytic therapy with intravenous thrombolysis (IVT). The administration of IVT for acute ischemic stroke, including dosing, monitoring, and complications, is reviewed in detail separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) Mechanical thrombectomy is reviewed in detail elsewhere. (See "Mechanical thrombectomy for acute ischemic stroke".) REPERFUSION THERAPIES The immediate goal of reperfusion therapy for acute ischemic stroke is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. The long-term goal is to improve https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 1/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate outcome by reducing stroke-related disability and mortality. Options for reperfusion therapy that are proven effective include intravenous thrombolysis (IVT) and mechanical thrombectomy (MT). Intravenous thrombolysis Alteplase IVT with alteplase is the mainstay of treatment for acute ischemic stroke, provided that treatment is initiated within 4.5 hours of the time last known well. Eligibility criteria are outlined in the table ( table 1). Because the benefit of alteplase is time dependent, it is critical to treat patients as quickly as possible. Alteplase, a recombinant tissue plasminogen activator (tPA), initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converting entrapped plasminogen to plasmin. In turn, plasmin breaks up the thrombus. Benefit by time to treatment IVT with alteplase improves functional outcome at three to six months when given within 4.5 hours of ischemic stroke onset [1-8]. The benefit of IVT for acute ischemic stroke decreases continuously over time from symptom onset, as shown in meta-analyses of randomized trials [1,3,4,9] and a registry that analyzed data from over 58,000 patients treated with IVT within 4.5 hours of ischemic stroke symptom onset [2]. In the registry, each 15-minute reduction in the time to initiation of IVT treatment was associated with an increase in the odds of walking independently at discharge (4 percent) and being discharged to home rather than an institution (3 percent) and a decrease in the odds of death before discharge (4 percent) and symptomatic hemorrhagic transformation of infarction (4 percent) [2]. Similarly, another study of over 61,000 patients treated with IVT found that shorter door-to-needle times were associated with lower all-cause mortality at one year and a reduced risk of hospital readmission at one year [10]. A 2014 meta-analysis evaluated individual patient data from 6756 patients (including more than 1700 who were older than age 80 years) with acute ischemic stroke who were allocated to IVT or control in the NINDS, ATLANTIS, ECASS (1, 2, and 3), EPITHET, and IST-3 trials [4]. The primary outcome measure was the proportion of patients achieving a good stroke outcome at three or six months as defined by a modified Rankin scale score ( table 2) of 0 or 1 (ie, no significant disability). The following observations were reported: For treatment within 3 hours of stroke onset, alteplase led to a good outcome for 33 percent, versus 23 percent for control (odds ratio [OR] 1.75, 95% CI 1.35-2.27). The number needed to treat (NNT) for one additional patient to achieve a good outcome was 10. For treatment from 3 to 4.5 hours, the proportion with a good outcome in the alteplase and control groups was 35 and 30 percent (OR 1.26, 95% CI 1.05-1.51, NNT 20). https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 2/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate For treatment beyond 4.5 hours, the proportion with a good outcome in the alteplase and control groups was no longer significant at 33 and 31 percent (OR 1.15, 95% CI 0.95-1.40, NNT 50). The benefit of alteplase was similar regardless of patient age or stroke severity. Alteplase increased the risk of symptomatic intracranial hemorrhage (6.8 percent, versus 1.3 percent for control, OR 5.55, 95% CI 4.01-7.70); the number needed to harm (NNH) for one additional patient to have a symptomatic intracranial hemorrhage was 18. Alteplase also increased the risk of fatal intracranial hemorrhage within seven days (2.7 versus 0.4 percent, OR 7.14, 95% CI 3.98-12.79, NNH 44); this risk was similar regardless of age, stroke severity, or treatment delay. Alteplase treatment had no significant effect on other early or late causes of death. Death at 90 days was slightly higher in the alteplase group (17.9 percent, versus 16.5 percent in the control group, hazard ratio 1.11, 95% CI 0.99-1.25), a result that just missed statistical significance. In agreement with other meta-analyses [1,3,7], these observations confirm that the sooner IVT is initiated, the more likely it is to be beneficial, and that the benefit extends to treatment started within 4.5 hours of stroke onset [4]. The results also show that alteplase is beneficial regardless of patient age, stroke severity, or the associated increased risk of symptomatic or fatal intracranial hemorrhage in the first days after alteplase treatment. The odds of a favorable three-month outcome decrease as the interval from stroke onset to start of alteplase treatment increases ( figure 1) [1]. Beyond 4.5 hours, harm may exceed benefit. Benefit with imaging selection of patients IVT may be beneficial for select patients who wake-up with stroke more than 4.5 hours after they were last known well or those who have unknown time of symptom onset, if they have an acute ischemic brain lesion detected on diffusion magnetic resonance imaging (MRI) but no corresponding hyperintensity on fluid- attenuated inversion recovery (FLAIR) MRI. This imaging mismatch (diffusion positive/FLAIR negative) correlates with a stroke onset time of 4.5 hours or less [11]. Limited clinical trial evidence suggests that IVT is beneficial for select patients who meet imaging criteria indicative of recent cerebral infarction and/or significant salvageable brain tissue, even if they do not qualify based upon traditional time windows, although results have been inconsistent: The placebo-controlled Wake-Up Stroke trial selected 500 adults with unwitnessed stroke onset who had an ischemic parenchymal brain lesion on MRI diffusion-weighted imaging https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 3/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate but no corresponding hyperintensity on FLAIR [12]. Nearly 90 percent of enrolled patients awoke from sleep with stroke symptoms. The trial excluded patients last known to be well within 4.5 hours, since they would fulfill standard eligibility criteria for alteplase; the trial also excluded patients who were to receive MT. At 90 days, a favorable outcome (defined by a score of 0 or 1 on the modified Rankin Scale [mRS]) was more likely for patients assigned to intravenous alteplase compared with those assigned to placebo (53 versus 42 percent, adjusted OR 1.61, 95% CI 1.09-2.36). However, the mortality rate was nonsignificantly higher in the alteplase group (4 versus 1 percent, OR 3.38, 95% CI 0.92-12.52), as was the rate of symptomatic intracranial hemorrhage (2.0 versus 0.4 percent, OR 4.95, 95% CI 0.57- 42.87). Limitations to the trial include stopping early (for lack of funding) and exclusion of patients planned for MT. The EXTEND trial was stopped early after publication of the Wake-Up Stroke trial. EXTEND enrolled 225 adults (of a planned 310) who had hypoperfused but salvageable brain tissue on automated perfusion imaging (with computed tomography [CT] or MRI) and could be treated between 4.5 and 9 hours after the onset of ischemic stroke or awoke with stroke symptoms, if within 9 hours from the midpoint of sleep [13]. Patients were randomly assigned to intravenous alteplase or to placebo. At 90 days, a favorable outcome (defined by a score of 0 or 1 on the mRS) was more likely for the intravenous alteplase group compared with the placebo group, after adjustment for age and clinical severity at baseline (35 versus 30 percent, risk ratio [RR] 1.44, 95% CI 1.01-2.06). However, there was no difference between treatment groups in unadjusted analysis (RR 1.2, 95% CI 0.82-1.76). Symptomatic intracranial hemorrhage within 36 hours of treatment was increased with alteplase (6 versus 1 percent) and mortality was nonsignificantly higher with alteplase (12 versus 9 percent). Limitations to the trial include stopping early and lack of efficacy in unadjusted analyses. In the ECASS 4 trial, stopped early for slow recruitment, 119 patients (of a planned 264) with acute ischemic stroke and salvageable brain tissue identified by MRI were randomly assigned to treatment with alteplase or placebo between 4.5 and 9 hours after the onset of symptoms [14]. At 90 days, there was no difference between the alteplase and placebo groups in the mRS distribution (OR 1.20, 95% CI 0.63-2.27); mortality was nonsignificantly higher with alteplase (12 versus 7 percent). A meta-analysis pooled individual patient data (n = 414) from three trials (EXTEND, ECASS 4, and EPITHET) of intravenous alteplase that used imaging to identify and treat patients with salvageable brain tissue who had ischemic stroke 4.5 to 9 hours after onset or had wake-up stroke [15]. There was a higher rate of excellent functional outcome (defined by a mRS score 0 of 1) at three months for patients assigned to alteplase compared with those assigned to placebo https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 4/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate (36 versus 29 percent, adjusted odds ratio [OR] 1.86, 95% CI 1.15-2.99). Symptomatic intracerebral hemorrhage was more frequent in the alteplase group (5 versus 0.5 percent), but this result did not nullify the overall benefit of alteplase. Limitations to this meta-analysis include small sample size and early stopping of two of the included trials (EXTEND and ECASS 4). Another meta-analysis of four trials (including Wake-Up Stroke, EXTEND, and ECASS 4) with individual patient data from over 843 patients reported similar findings [16]. Although this approach seems promising, additional trials are needed to confirm the efficacy and safety of IVT using imaging selection of patients with a stroke onset time >4.5 hours or an unknown stroke onset time [17]. Imaging with MRI or CT perfusion appears to be essential to determine if the cerebral infarction is recent and if there is significant salvageable brain tissue. Results of the TWIST trial suggest that selecting patients with noncontrast head CT alone (to exclude hemorrhage or large infarction) is unlikely to identify patients with wake-up stroke who will benefit from IVT [18]. Risk of intracerebral hemorrhage Treatment with IVT within 4.5 hours of acute ischemic stroke onset is associated with an increased early risk of intracerebral hemorrhage, but this risk is offset by later benefit in the form of reduced disability (see 'Benefit by time to treatment' above) [4]. In clinical trials of intravenous alteplase, the rates of symptomatic intracerebral hemorrhage were 5 to 7 percent [4,19], using the National Institute of Neurological Disorders and Stroke (NINDS) definition. In addition, most community-based studies of intravenous alteplase have shown similar rates [20-24]. These studies suggest that IVT can be used safely to treat acute ischemic stroke in routine clinical practice. The number needed to harm (NNH) with IVT is very high, because most cases of symptomatic intracerebral hemorrhage occur in patients with severe deficits and poor anticipated prognosis before lysis [25]. Also, some hemorrhages occur in areas of the brain that are already infarcted and so do not result in additional measurable deficits. As an example from the NINDS trials, for an outcome of severely disabled or dead (defined by an mRS score 4) with IVT-related symptomatic hemorrhage, the NNH was 126, and for a worsened outcome (defined by an mRS score 1), the NNH ranged from approximately 30 to 40. Differences in the criteria used to define symptomatic intracerebral hemorrhage likely account for much of the variability in the rates of hemorrhage reported in different trials [26]. The NINDS trial definition of symptomatic intracerebral hemorrhage includes any hemorrhagic transformation temporally related to any neurologic worsening [19], which may be overly inclusive because it captures small petechial hemorrhages associated with minimal neurologic deterioration that are unlikely to have altered long-term functional outcome [27,28]. By contrast, the ECASS 2, ECASS-3 and SITS-MOST definitions of symptomatic intracerebral hemorrhage include only hemorrhage associated with substantial clinical worsening of 4 points on the https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 5/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate National Institutes of Health Stroke Scale (NIHSS) stroke scale [24,29,30], which may be more predictive of intracerebral hemorrhages that adversely affect long-term outcome. As an example, the SITS-MOST study enrolled over 30,000 patients, mainly from Europe, who were treated with intravenous alteplase at 669 centers [24]. Symptomatic intracerebral hemorrhage by the NINDS definition occurred in 7.4 percent, and by the SITS-MOST definition in 1.8 percent. Lower rates have also been reported in other trials using stricter definitions of symptomatic intracerebral hemorrhage, including ECASS 3 [29]. Several risk assessment methods, including the HAT score, DRAGON score, SEDAN score, Stroke- Thrombolytic Predictive Instrument, SPAN-100 index, and the SITS SICH risk score, have been devised to predict the risk of intracerebral hemorrhage and/or prognosis for patients with acute stroke who are treated with IVT [24,31-39]. However, additional validation studies are needed to confirm the utility of these methods before they should be used in clinical practice. Recanalization Full or partial recanalization up to 24 hours after onset of acute stroke is associated with a more favorable outcome than persistent occlusion after thrombolysis [40-44]. In a prospective, multicenter study of 575 patients with acute ischemic stroke and intracranial arterial occlusion on baseline CT angiography (CTA), the rate of successful recanalization detected on repeat CTA was greater for patients who received IVT compared with those who did not (30 versus 13 percent, absolute difference 17 percent, 95% CI 10-26 percent) [45]. As observed in this and other studies, factors associated with the response to thrombolytic therapy include location of the symptomatic occlusive thrombus in the arterial tree, and clot-specific features such as size, composition, and source: Clot size and site Larger clots and more proximal clots (versus more distal location) are more resistant to thrombolysis [45-50]. As an example, internal carotid artery occlusions are more resistant than middle cerebral artery occlusions to IVT treatment. This may be due at least in part to the larger size of clots that lodge in larger vessels [51]. Clot occluding the cervical internal carotid artery may promote adjacent thrombosis extending to the intracranial internal carotid artery, resulting in a very long thrombus that is unlikely to be lysed by IVT alone. In large vessels, in situ thromboses associated with atherosclerotic lesions may be more resistant to recanalization than fibrin rich embolic occlusions arising from the heart [52]. In addition, higher residual flow (a measure of thrombus permeability) of intracranial arteries on baseline angiography is associated with successful recanalization [45]. Clot age and composition The age and composition of thromboembolic material likely affect its response to thrombolytic therapy [53,54]. The ability to recanalize in experimental embolic stroke is related to the amount of red cells in the emboli and inversely related to https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 6/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate the volume of emboli and to the fibrin content and density of the clots [55]. Thrombolytic drugs are unlikely to disrupt other types of embolic material, such as calcific plaque and fat. Other variables affecting outcome Early recanalization is probably the most important determinant of good outcome after thrombolysis, but a number of additional variables may impact neurologic outcome and the risk of intracerebral hemorrhage [56,57]. These include age, sex, stroke severity, availability of collateral blood supply, and early ischemic change on CT or MRI. However, these factors do not necessarily predict which patients will or will not benefit from IVT. The only factor known to independently alter response to IVT is time to treatment. (See 'Benefit by time to treatment' above.) Whenever possible, the potential risks and benefits of thrombolysis should be discussed objectively with the patient and/or family or health care proxy prior to initiating treatment. (See 'Issues regarding consent' below.) Age Patients age 80 years or older appear to benefit from IVT despite a higher mortality rate compared with younger patients. (See 'Age 80 years and older' below.) Stroke severity The severity of neurologic deficit as measured on the NIHSS score ( table 3) is associated with an increased risk of intracerebral hemorrhage [6,58]. However, stroke severity alone cannot be used to select or exclude patients for IVT. A 2014 meta-analysis of individual patient data from 6756 subjects found that the benefit of alteplase was similar regardless of stroke severity [4]. Early ischemic changes on CT The presence of extensive regions of obvious hypodensity consistent with irreversible injury on initial head CT suggests a longer time since stroke onset and is an exclusion for use of IVT ( table 1). This finding should be distinguished from milder early ischemic edema as discussed below. (See 'Early ischemic changes on neuroimaging' below.) Hyperglycemia Hyperglycemia before reperfusion in patients with acute ischemic stroke has been associated with diminished neurologic improvement, greater infarct size, and worse clinical outcome at three months after treatment with IVT [59-61]. Cerebral microbleeds Cerebral microbleeds are small chronic hemorrhages that are best visualized on susceptibility-weighted MRI sequences. Meta-analyses published in 2015 [62], 2016 [63], and 2017 [64] found that the presence of cerebral microbleeds on pretreatment brain MRI was associated with an increased risk of intracerebral hemorrhage (ICH) in patients treated with IVT for acute ischemic stroke. In https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 7/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate one of these reports, the risk of symptomatic ICH was significantly greater for patients with a high burden of cerebral microbleeds (>10) compared with patients who had a lower burden of microbleeds (1 to 10 or 0 to 10) [63]. However, the small number of patients in the subgroup with >10 microbleeds (n = 15) limits the strength of this conclusion. In another meta-analysis, the presence of cerebral microbleeds was not associated with symptomatic ICH but was associated with an increased risk of parenchymal hemorrhage, and the presence of >5 cerebral microbleeds was associated with poor functional outcome at three to six months [64]. Since decisions to proceed IVT treatment are usually made based upon CT imaging without MRI, these results should not affect patient selection or mandate additional imaging that will prolong the time to treatment. Sex There are conflicting data regarding whether benefit from early IVT of acute ischemic stroke differs by sex [65-67]. Tenecteplase Tenecteplase, a type of recombinant tissue plasminogen activator (tPA), is a modified version of alteplase, the only approved tPA for treating acute ischemic stroke. Tenecteplase differs from human tPA by having three amino acid substitutions. Because of the modifications, tenecteplase is more fibrin-specific and has a longer duration of action compared with alteplase. The single bolus dosing of tenecteplase is far easier to give in an emergency department and translates into faster door-to-needle times compared with alteplase [68]. Although not licensed in the US for IVT in acute ischemic stroke treatment, there is moderate- to high-quality evidence that intravenous tenecteplase, given in a single bolus at 0.25 mg/kg (maximum 25 mg), has similar efficacy and safety outcomes compared with alteplase, including rates of excellent functional outcome, symptomatic intracerebral hemorrhage, and mortality at 90 days [68-81]. As an example, the EXTEND-IA TNK trial found that tenecteplase led to better functional outcomes compared with alteplase and higher rates of reperfusion of the involved ischemic territory [70]. Furthermore, in an analysis of pooled individual patient data from several trials and a registry of patients with large vessel occlusion who were treated with intravenous thrombolysis, tenecteplase treatment (n = 492) compared with alteplase treatment (n = 401) was associated with higher rates of prethrombectomy reperfusion, which in turn was associated with improved outcomes [82]. However, higher doses of tenecteplase ( 0.4 mg/kg) should not be used for IVT because such doses may be associated with harm, although the evidence is inconsistent. In the original NOR- TEST trial, most of the 1100 patients had minor strokes (the median NIHSS score was 4), and the https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 8/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate tenecteplase group, treated with 0.4 mg/kg, had similar safety and efficacy outcomes compared with the alteplase group [69]. However, the NOR-TEST 2, part A trial was stopped early, after enrolling only 204 patients, due to higher numbers of symptomatic intracranial hemorrhage in the tenecteplase group [83]. NOR-TEST 2 included patients with moderate to severe ischemic stroke (the median NIHSS was 11) who were within 4.5 hours of the time last known well; the patients were randomly assigned to tenecteplase 0.4 mg/kg or alteplase 0.9 mg/kg. At three months, compared with the alteplase group, the tenecteplase group showed a trend toward an increased rate of symptomatic intracranial hemorrhage (6 versus 1 percent, OR 6.57, 95% CI 0.78-55.62). Furthermore, the tenecteplase group had a lower rate of a favorable outcome, defined as an mRS score of 0 to 1 (32 versus 51 percent, OR 0.45, 95% CI 0.25-0.80), and a higher rate of mortality (16 versus 5 percent, OR 3.56, 95% CI 1.24-10.21). Mechanical thrombectomy (MT) Mechanical thrombectomy is indicated for patients with acute ischemic stroke due to a large artery occlusion in the anterior circulation who meet eligibility criteria and can be treated within 24 hours of the time last known to be well (ie, at neurologic baseline), regardless of whether they receive IVT for the same ischemic stroke event. (See "Mechanical thrombectomy for acute ischemic stroke".) Patient selection for MT is discussed in detail separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) IVT followed by MT Treatment with IVT prior to MT, known as bridging therapy, is recommended for most patients who are candidates for both reperfusion therapies. Patients with ischemic stroke from large vessel occlusion should receive IVT without delay, if eligible, even if MT is being considered [84]. Mechanical thrombectomy treatment should then be started as quickly as possible [85,86], and should not be delayed to assess the response to IVT. Potential advantages of IVT before MT include complete or partial lysis of the thrombus causing the large vessel occlusion (the target of MT), lysis of thrombotic emboli in distal vessels beyond the reach of MT, and faster resolution of brain ischemia [87]. Potential disadvantages of giving IVT first include a delay in the time to the start of the MT procedure, an increased risk of symptomatic brain hemorrhage, and partial lysis of the large vessel thrombus that allows it to travel to more distal vessels beyond the reach of MT. MT alone (without preceding IVT) is an alternative strategy, but the available data, while inconsistent, have not proven the efficacy of this approach compared with the combination of IVT and MT for improved clinical outcomes or safety [88-98]. Rather, the preponderance of the evidence favors bridging therapy over MT alone. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 9/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate RAPID EVALUATION All adult patients with a clinical diagnosis of acute ischemic stroke should be rapidly screened for treatment with intravenous thrombolysis (IVT). Simultaneously, patients with suspected acute ischemic stroke involving the anterior circulation should be evaluated for mechanical thrombectomy (MT). (See "Mechanical thrombectomy for acute ischemic stroke".) Prehospital recognition and management Emergency medical responders should identify patients with a suspected stroke, preferably using a validated stroke screening tool (see "Use and utility of stroke scales and grading systems", section on 'Stroke diagnosis'), and transport them rapidly to the nearest medical facility that can provide urgent stroke care with the capability to treat with IVT, or IVT and MT. The use of mobile stroke units (MSUs) offers the potential for more rapid identification and treatment of acute ischemic stroke [99,100]. MSUs are ambulances equipped with point-of-care laboratory testing and a CT scanner; they are staffed by medical personnel trained to diagnose and treat patients in the ambulance using thrombolytic therapy and to make triage decisions for mechanical thrombectomy, in conjunction with telemedicine communication to hospital stroke experts. However, MSUs are expensive, and availability is limited to only a few metropolitan areas throughout the world. The potential benefit of MSUs for improving outcome from acute ischemic stroke is illustrated by two prospective, nonrandomized controlled studies. One was a multicenter study from the United States of 1047 patients who were within 4.5 hours after stroke symptom onset; patients were assigned by week of enrollment to receive MSU or standard emergency medical services (EMS) care [101]. Among patients eligible for intravenous thrombolysis, the rate of thrombolysis was higher in the MSU group compared with the EMS group (97.1 versus 79.5 percent), and the median time to thrombolysis was shorter (72 versus 108 minutes). At 90 days, the proportion of patients with no or minimal disability (ie, a score of 0 to 1 on the modified Rankin Scale [mRS]) was greater in the MSU group (55.0 versus 44.4 percent), while mortality was lower (8.9 versus 11.9 percent). The rate of symptomatic intracerebral hemorrhage in each group was 2 percent. In a similar prospective study of over 1500 patients from Berlin, Germany, dispatch of an MSU compared with EMS was associated with a shorter median time to treatment with thrombolysis (50 versus 70 minutes) and a lower level of global disability at 90 days [102]. In a 2022 meta- analysis that included these two nonrandomized studies, MSU use was associated with higher rates of excellent outcome, defined by an mRS score of 0 to 1 at 90 days, compared with usual care (adjusted odds ratio [OR] 1.64, 95% CI 1.27-2.13) [103]. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 10/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Further confirmation of clinical benefit along with evidence of cost-effectiveness will be needed before widespread use of MSUs can be considered. Other unproven strategies to reduce time to treatment with MT are being explored, including direct transport to a thrombectomy-capable center [104], and even flying the thrombectomy intervention clinical team to the local stroke center [105]. In-hospital timeline A door-to-needle time of 60 minutes is the benchmark for achieving rapid treatment with IVT [84]. The following in-hospital timeline is suggested as a goal for all patients with acute ischemic stroke who are eligible for treatment with IVT: Evaluation by physician 10 minutes elapsed from arrival Stroke or neurologic expertise contacted (ie, stroke team) 15 minutes elapsed Head CT or MRI scan 25 minutes elapsed Interpretation of neuroimaging scan 45 minutes elapsed Start of IVT 60 minutes elapsed Although IVT is the first priority, evaluation and preparation for possible MT should proceed during and after IVT. Patients with suspected infarction involving the anterior circulation should have cerebral angiography (eg, CT angiography [CTA] or magnetic resonance angiography [MRA]) as soon as possible to determine whether they have a proximal intracranial large artery occlusion that might also benefit from MT. However, IVT should not be delayed by angiography or MT. The administration of IVT for acute ischemic stroke, including dosing, monitoring, and complications, is reviewed in detail separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) Investigations Diagnostic neuroimaging is essential before considering reperfusion therapy for acute ischemic stroke. The only other test that is mandatory for all patients before initiation of IVT is blood glucose. In most cases, the results of routine laboratory tests including coagulation parameters and platelet count are not required to proceed with IVT. Thrombolytic therapy with alteplase (or tenecteplase) should not be delayed while results are pending unless one of the following conditions is present [84]: Clinical suspicion of a bleeding abnormality or thrombocytopenia Current or recent use of anticoagulants (eg, heparin, warfarin, direct oral anticoagulants [DOACs]) Use of anticoagulants is not known https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 11/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Potential exclusions to treatment Exclusion criteria for IVT are listed in the table ( table 1); these criteria have evolved with time as experience with IVT has increased. Several clinical issues may complicate the decision to use reperfusion therapy for acute ischemic stroke. Among these are rapidly improving stroke symptoms and early ischemic changes on neuroimaging. Patients on anticoagulants Current anticoagulant use with evidence of anticoagulant effect by laboratory tests is a contraindication to IVT. Coagulation tests For patients without recent use of oral anticoagulants or heparin, treatment with IVT can be started before availability of coagulation test results if there is no reason to suspect a coagulopathy (ie, patients not on anticoagulant therapy who have no known liver disease, hematologic disease, or advanced kidney disease). In such cases, alteplase treatment should be discontinued if the international normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (aPTT) are excessively elevated ( table 1). For patients with inadequate historical information, IVT should not be started until the aPTT and either the PT or the INR are available. Preliminary data suggest that normal coagulation parameters can be predicted on arrival to the emergency department by assessing three questions [106]: Is the patient taking an oral anticoagulant? Is the patient taking heparin or low molecular weight heparin? Is the patient on hemodialysis? In a retrospective study from 2006 (prior to the advent of direct oral anticoagulants) that included 299 patients, "no" answers to all three questions predicted normal range PT and aPTT with a sensitivity of 100 percent, suggesting that this simple screen may permit earlier treatment with alteplase in selected patients with acute stroke [106]. Other data suggest that unsuspected coagulopathy is rarely detected among patients evaluated for IVT [107]. Patients on DOACs Accumulating evidence suggests that recent use of a DOAC is not associated with an increased risk of symptomatic intracerebral hemorrhage following IVT [108,109]. Nevertheless, DOAC use remains a contraindication to IVT unless laboratory tests such as aPTT, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal or the patient has not received a DOAC dose for more than 48 hours, assuming normal renal function [84]. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 12/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate DOAC reversal DOAC reversal may provide an option to safely treat with thrombolysis, although this approach is not yet established as safe [110]. An observational cohort study identified 51 patients treated with idarucizumab for dabigatran reversal prior to thrombolysis and found that idarucizumab-treated patients had similar rates of symptomatic intracerebral hemorrhage, early neurologic improvement, and mortality compared with patients not treated with idarucizumab [111]. Rapidly improving stroke symptoms Rapidly improving stroke symptoms (RISS) should be considered an exclusion for reperfusion therapy only for patients who improve to the degree that any remaining deficits are nondisabling [112]. The decision regarding use of IVT or MT should be made based upon monitoring neurologic deficits for no longer than the time needed to prepare and begin treatment; treatment should not be delayed by continued monitoring for improvement. Disabling versus nondisabling stroke deficits Qualifying patients who have an acute ischemic stroke causing a persistent neurologic deficit that is potentially disabling, despite improvement of any degree while being evaluated, should be treated urgently with IVT and/or MT as appropriate. Any of the following should be considered disabling deficits [112]: Complete hemianopia: 2 on the National Institutes of Health Stroke Scale (NIHSS) question 3 ( table 3) Severe aphasia: 2 on NIHSS question 9 ( table 3) Visual extinction: 1 on NIHSS question 11 ( table 3) Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6 ( table 3) Any deficits that lead to a total NIHSS >5 (calculator 1) Any remaining deficit considered potentially disabling by the patient, family, or the treating practitioner For patients with an NIHSS score of 0 to 5, a clearly disabling deficit has also been defined as one that would prevent the patient from performing basic activities of daily living (ie, bathing, walking, toileting, and eating) or returning to work [113]. Whether IVT is beneficial for patients with mild, nondisabling ischemic stroke is unknown, and data are limited. The PRISMS trial enrolled patients with acute ischemic stroke within three hours of symptom onset who had an NIHSS score of 0 to 5 and deficits judged not clearly disabling; there was no difference in the rate of a favorable functional outcome (defined as a modified Rankin Scale score of 0 or 1 at 90 days) for patients assigned to treatment with IVT or to aspirin (78.2 versus 81.5 percent) [113]. However, the trial was stopped very early solely because of slow https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 13/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate recruitment, having enrolled only 313 of a planned 948 subjects, and therefore its findings are not definitive. Early ischemic changes on neuroimaging Minor ischemic changes on CT are not a contraindication to treatment; these include subtle or small areas of hypodensity, loss of gray- white distinction, obscuration of the lentiform nucleus, or the presence of a hyperdense artery sign ( image 1). We suggest withholding thrombolytic therapy with alteplase for patients with extensive regions of obvious hypodensity consistent with irreversible injury on initial head CT ( table 1), although there are few data to determine a threshold of ischemic severity or extent that modifies treatment response to alteplase [114]. Patient selection for MT is reviewed separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Role of ASPECTS method'.) Issues regarding consent Alteplase is an approved therapy for acute ischemic stroke because of substantial evidence of safety and efficacy. Consent is not required to administer alteplase as an emergent therapy for an otherwise eligible adult patient with a disabling acute ischemic stroke if patient or surrogate consent is not possible [84]. In such cases, the need for informed consent is outweighed by the need for urgent intervention, and the patient can be treated under the principle of presumption of consent. Furthermore, given the lack of clinical equipoise (the benefit of alteplase clearly outweighs the harms), shared decision-making is not appropriate [115]. Whether to proceed to thrombolysis in an individual patient should be based upon a brief discussion of the risks and benefits with the patient and family or health care proxy, if possible.
coagulation parameters and platelet count are not required to proceed with IVT. Thrombolytic therapy with alteplase (or tenecteplase) should not be delayed while results are pending unless one of the following conditions is present [84]: Clinical suspicion of a bleeding abnormality or thrombocytopenia Current or recent use of anticoagulants (eg, heparin, warfarin, direct oral anticoagulants [DOACs]) Use of anticoagulants is not known https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 11/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Potential exclusions to treatment Exclusion criteria for IVT are listed in the table ( table 1); these criteria have evolved with time as experience with IVT has increased. Several clinical issues may complicate the decision to use reperfusion therapy for acute ischemic stroke. Among these are rapidly improving stroke symptoms and early ischemic changes on neuroimaging. Patients on anticoagulants Current anticoagulant use with evidence of anticoagulant effect by laboratory tests is a contraindication to IVT. Coagulation tests For patients without recent use of oral anticoagulants or heparin, treatment with IVT can be started before availability of coagulation test results if there is no reason to suspect a coagulopathy (ie, patients not on anticoagulant therapy who have no known liver disease, hematologic disease, or advanced kidney disease). In such cases, alteplase treatment should be discontinued if the international normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (aPTT) are excessively elevated ( table 1). For patients with inadequate historical information, IVT should not be started until the aPTT and either the PT or the INR are available. Preliminary data suggest that normal coagulation parameters can be predicted on arrival to the emergency department by assessing three questions [106]: Is the patient taking an oral anticoagulant? Is the patient taking heparin or low molecular weight heparin? Is the patient on hemodialysis? In a retrospective study from 2006 (prior to the advent of direct oral anticoagulants) that included 299 patients, "no" answers to all three questions predicted normal range PT and aPTT with a sensitivity of 100 percent, suggesting that this simple screen may permit earlier treatment with alteplase in selected patients with acute stroke [106]. Other data suggest that unsuspected coagulopathy is rarely detected among patients evaluated for IVT [107]. Patients on DOACs Accumulating evidence suggests that recent use of a DOAC is not associated with an increased risk of symptomatic intracerebral hemorrhage following IVT [108,109]. Nevertheless, DOAC use remains a contraindication to IVT unless laboratory tests such as aPTT, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal or the patient has not received a DOAC dose for more than 48 hours, assuming normal renal function [84]. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 12/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate DOAC reversal DOAC reversal may provide an option to safely treat with thrombolysis, although this approach is not yet established as safe [110]. An observational cohort study identified 51 patients treated with idarucizumab for dabigatran reversal prior to thrombolysis and found that idarucizumab-treated patients had similar rates of symptomatic intracerebral hemorrhage, early neurologic improvement, and mortality compared with patients not treated with idarucizumab [111]. Rapidly improving stroke symptoms Rapidly improving stroke symptoms (RISS) should be considered an exclusion for reperfusion therapy only for patients who improve to the degree that any remaining deficits are nondisabling [112]. The decision regarding use of IVT or MT should be made based upon monitoring neurologic deficits for no longer than the time needed to prepare and begin treatment; treatment should not be delayed by continued monitoring for improvement. Disabling versus nondisabling stroke deficits Qualifying patients who have an acute ischemic stroke causing a persistent neurologic deficit that is potentially disabling, despite improvement of any degree while being evaluated, should be treated urgently with IVT and/or MT as appropriate. Any of the following should be considered disabling deficits [112]: Complete hemianopia: 2 on the National Institutes of Health Stroke Scale (NIHSS) question 3 ( table 3) Severe aphasia: 2 on NIHSS question 9 ( table 3) Visual extinction: 1 on NIHSS question 11 ( table 3) Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6 ( table 3) Any deficits that lead to a total NIHSS >5 (calculator 1) Any remaining deficit considered potentially disabling by the patient, family, or the treating practitioner For patients with an NIHSS score of 0 to 5, a clearly disabling deficit has also been defined as one that would prevent the patient from performing basic activities of daily living (ie, bathing, walking, toileting, and eating) or returning to work [113]. Whether IVT is beneficial for patients with mild, nondisabling ischemic stroke is unknown, and data are limited. The PRISMS trial enrolled patients with acute ischemic stroke within three hours of symptom onset who had an NIHSS score of 0 to 5 and deficits judged not clearly disabling; there was no difference in the rate of a favorable functional outcome (defined as a modified Rankin Scale score of 0 or 1 at 90 days) for patients assigned to treatment with IVT or to aspirin (78.2 versus 81.5 percent) [113]. However, the trial was stopped very early solely because of slow https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 13/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate recruitment, having enrolled only 313 of a planned 948 subjects, and therefore its findings are not definitive. Early ischemic changes on neuroimaging Minor ischemic changes on CT are not a contraindication to treatment; these include subtle or small areas of hypodensity, loss of gray- white distinction, obscuration of the lentiform nucleus, or the presence of a hyperdense artery sign ( image 1). We suggest withholding thrombolytic therapy with alteplase for patients with extensive regions of obvious hypodensity consistent with irreversible injury on initial head CT ( table 1), although there are few data to determine a threshold of ischemic severity or extent that modifies treatment response to alteplase [114]. Patient selection for MT is reviewed separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Role of ASPECTS method'.) Issues regarding consent Alteplase is an approved therapy for acute ischemic stroke because of substantial evidence of safety and efficacy. Consent is not required to administer alteplase as an emergent therapy for an otherwise eligible adult patient with a disabling acute ischemic stroke if patient or surrogate consent is not possible [84]. In such cases, the need for informed consent is outweighed by the need for urgent intervention, and the patient can be treated under the principle of presumption of consent. Furthermore, given the lack of clinical equipoise (the benefit of alteplase clearly outweighs the harms), shared decision-making is not appropriate [115]. Whether to proceed to thrombolysis in an individual patient should be based upon a brief discussion of the risks and benefits with the patient and family or health care proxy, if possible. However, neurologic deficits caused by acute stroke often preclude the ability of the patient to participate in the decision. Explaining benefits and risks Procedures for informed decision-making and informed consent vary among different centers; we explain the risks and benefits of alteplase as follows [115]: "There is a treatment for your stroke called alteplase that must be given within 4.5 hours after the stroke started. It is a 'clot-buster' drug. Getting alteplase reduces your risk of being disabled. People who get alteplase for stroke have a better chance of recovering without disability and getting back to the activities they enjoy compared to people who do not receive the treatment. All medicines have some risk. With alteplase, there is a risk of serious bleeding. However, time is https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 14/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate important as well. We know that the sooner we start treatment with alteplase, the greater the chance that patients will have a good outcome." Some patients will accept any risk, including an increased risk of intracranial bleeding, for an increased chance of avoiding severe permanent disability. Others are more risk averse and prefer to accept disability, especially if there is a chance of recovery over time. Need for transfer to stroke center Most hospitals in more economically developed countries are able to treat acute ischemic stroke with IVT. In situations where local stroke expertise is not routinely or immediately available, accumulating data suggest that the decision to administer IVT can be guided safely and effectively via telemedicine (telestroke) [116]. By contrast, MT is not as widely available. Transfer to an expert stroke center may be necessary for patients with acute ischemic stroke in the anterior circulation who present to medical facilities that lack resources and expertise to deliver MT. However, eligible patients can receive standard treatment with IVT if they present to hospitals where thrombectomy is not an option, and those with qualifying anterior circulation strokes can then be transferred to stroke centers where intra-arterial thrombectomy is available, a strategy called "drip and ship" [117,118]. Screening of patients for transfer is aided by the ability of networked hospitals to share brain and neurovascular imaging studies via cloud computing, which allows the stroke center hub to read a CTA (or MRA) done locally and thereby determine whether the patient has a large vessel occlusion, a key requirement for MT. Reducing delay Inordinate treatment delay can occur during any of the steps involved in reperfusion therapy, including emergency department triaging, initial telephone triage by the stroke physician, physician evaluation, neuroimaging, obtaining and waiting for results of blood and laboratory tests, obtaining consent, treating hypertension that would otherwise exclude the use of IVT (ie, systolic blood pressure 185 mmHg or diastolic 110 mmHg), and delivery of alteplase from the pharmacy to the bedside. Expedited stroke protocols may reduce treatment delays and improving patient outcomes. Such protocols may include the following features [119,120]: Prehospital notification by emergency medical personnel/ambulance of a patient with a possible stroke Blast paging of all relevant hospital stroke personnel, including CT technicians In-person triage of all code strokes without telephone triage; the stroke physician on-call proceeds immediately to the bedside Direct transfer of the patient, without fully undressing, from triage onto the CT scanner table via the ambulance stretcher https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 15/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate No delays pending formal neuroimaging interpretation; the on-call stroke physician reads the brain CT or MRI scan Unmixed alteplase is available at the bedside during the evaluation No delays pending electrocardiogram (ECG), coagulation tests, chest radiograph, or stool guaiac unless specifically indicated No delays pending written consent; verbal consent is obtained if the patient is able to consent or if family members or health care proxy are nearby While an expedited evaluation might increase the risk of giving IVT in cases of stroke mimics, data suggest that the intracranial hemorrhage rate in patients who later are diagnosed with a stroke mimic is approximately 1 percent [121,122]. TREATMENT BY TIME FROM SYMPTOM ONSET "Time is brain." The sooner intravenous thrombolysis (IVT) treatment with alteplase is initiated after ischemic stroke, the more likely it is to be beneficial [123-125]. Eligible patients should start treatment as quickly as possible within the appropriate 3- or 4.5-hour time window from stroke onset; treatment should not be delayed until the end of the time window. Mechanical thrombectomy (MT) is also time-dependent, with clear benefit for patients with acute ischemic stroke caused by an intracranial large artery occlusion in the proximal anterior circulation who are treated within 6 hours of symptom onset. Beyond 6 hours, MT may be an option at specialized stroke centers using imaging-based selection of patients with anterior circulation stroke who have symptom onset 6 to 24 hours before treatment. (See "Mechanical thrombectomy for acute ischemic stroke".) Less than 3 hours For eligible patients with acute ischemic stroke causing a potentially disabling neurologic deficit, we recommend IVT with intravenous alteplase (or intravenous tenecteplase) when treatment is initiated within 3 hours of the time last known well. Patients in this time window should also be evaluated to determine if they are candidates for MT. (See 'Benefit by time to treatment' above.) 3 to 4.5 hours The benefit of alteplase extends to 4.5 hours, as discussed above. For otherwise eligible patients who cannot be treated in less than 3 hours, we suggest (ie, a weak recommendation) IVT with alteplase provided that treatment is initiated within 3 to 4.5 hours of the time last known well. Patients in this time window should also be evaluated to determine if they are candidates for MT. (See 'Benefit by time to treatment' above.) https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 16/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate There are additional exclusion criteria ( table 1) for IVT in the 3- to 4.5-hour time window (age >80 years old, an National Institutes of Health Stroke Scale (NIHSS) score >25, a combination of previous stroke and diabetes, and oral anticoagulant use regardless of INR). However, we do not consider these as absolute contraindications to IVT in the 3- to 4.5-hour time window, given evidence that alteplase is still beneficial in patients who would otherwise be excluded by these criteria [4,114,126,127]. The additional exclusions from 3 to 4.5 hours were made to satisfy safety concerns from the European regulatory agency and were employed to select patients for treatment in the ECASS 3 trial [29], which established the benefit of IVT in the 3- to 4.5-hour time window. 4.5 to 6 hours Patients within 4.5 to 6 hours from stroke symptom onset should not routinely receive IVT because harm may exceed benefit, but they should be evaluated to determine if they are candidates for MT. (See 'Benefit by time to treatment' above.) 6 to 24 hours Patients beyond 6 hours from ischemic stroke symptom onset are not eligible for treatment with IVT. However, MT is an option at specialized stroke centers using imaging- based selection of patients with anterior circulation stroke who have were last known to be well at 6 to 24 hours before treatment. This is discussed in detail separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Benefit of later (6 to 24 hours) treatment'.) Beyond 24 hours Patients beyond 24 hours from ischemic stroke symptom onset generally are not eligible for treatment with IVT or MT. Limited retrospective data suggest possible benefit for selected patients treated with MT beyond 24 hours of last known well, but confirmation from prospective trials is needed [128]. Unwitnessed stroke onset and "wake-up" stroke When the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal. For patients whose stroke symptoms are first noted upon awakening from sleep, the last time known to be normal may be the time they went to bed (if the patient can report this reliably) or the last time seen normal by a friend or family member. Such patients are not ordinarily eligible for IVT unless the time last known to be normal is less than 4.5 hours. However, imaging-based criteria (ie, MRI showing an acute ischemic lesion that is diffusion positive and fluid-attenuated inversion recovery [FLAIR] negative) is an option at expert stroke centers to select patients with wake-up stroke or unknown stroke onset time for IVT. (See 'Benefit with imaging selection of patients' above.) Imaging-based selection of patients for treatment with MT who were last known to be normal 6 to 24 hours before treatment is an option at specialized stroke centers. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Benefit of later (6 to 24 hours) treatment'.) https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 17/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate SPECIAL POPULATIONS Different clinical presentations and patient populations may affect the decision to use intravenous thrombolysis (IVT) or mechanical thrombectomy (MT) for acute ischemic stroke, as discussed below. Posterior circulation stroke All eligible patients with acute ischemic stroke should be treated with IVT, including those with stroke in the posterior circulation. Mechanical thrombectomy is beneficial for select patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion in the anterior circulation, but trials that established the benefit of MT largely excluded patients with posterior circulation infarcts. However, endovascular interventions for vertebrobasilar occlusions, including MT, may be treatment options stroke centers with appropriate expertise. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Posterior circulation stroke'.) Age 80 years and older Patients age 80 years or older appear to benefit from IVT despite a higher mortality rate compared with younger patients. Therefore, we do not consider age to be a contraindication to IVT treatment for otherwise eligible patients. However, age >80 years is a relative contraindication in the 3- to 4.5-hour time window. (See '3 to 4.5 hours' above.) A 2014 meta-analysis of individual patient data from 6756 subjects (including more than 1700 subjects older than age 80 years) found that benefit of alteplase was similar regardless of patient age [4]. In a prespecified secondary analysis of individual participant data (n = 6756) from a 2016 meta-analysis of nine trials of alteplase versus control for acute ischemic stroke, the increased risk of intracerebral hemorrhage with alteplase in the first seven days after treatment did not differ by age [6]. Older age is not an exclusion for MT [129]. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) Prestroke disability or dementia Treatment decisions regarding IVT or MT for patients with significant prestroke disability or dementia should be individualized using shared decision- making that incorporates patient values and preferences [130]. Such patients were largely excluded from randomized trials of reperfusion therapies for acute ischemic stroke. However, observational data suggest that patients with disability or dementia at baseline may still benefit from reperfusion for acute stroke, despite an overall worse prognosis and possibly higher mortality [130]. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 18/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Pregnancy Although pregnancy has been considered a relative contraindication to the use of thrombolysis for acute stroke, IVT can be given in pregnancy after careful discussion of the potential risks and benefits. The use of thrombolytic therapy in pregnancy is discussed separately. (See "Cerebrovascular disorders complicating pregnancy", section on 'Acute ischemic stroke'.) Children Safety and efficacy data for reperfusion therapy of acute ischemic stroke are lacking in patients younger than 18 years of age. However, IVT and MT may be options for some children, particularly adolescents (age 13 years), with acute ischemic stroke on neuroimaging who are evaluated and treated at pediatric stroke centers. (See "Ischemic stroke in children: Management and prognosis", section on 'Reperfusion with thrombolysis and thrombectomy'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Goals and options for reperfusion The immediate goal of reperfusion therapy for acute ischemic stroke is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. Intravenous thrombolysis (IVT) is the mainstay of reperfusion therapy for acute ischemic stroke. Mechanical thrombectomy (MT) is indicated for patients with acute ischemic stroke caused by an intracranial large artery occlusion in the proximal anterior circulation. (See 'Reperfusion therapies' above.) Benefit of reperfusion therapy IVT improves functional outcome at three to six months for appropriately selected patients when given within 4.5 hours of ischemic stroke onset. (See 'Alteplase' above and 'Tenecteplase' above.) MT improves functional outcome at three months for appropriately selected patients if treatment is started within 24 hours from the time the patient was last known well. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Efficacy of mechanical thrombectomy'.) Evaluation All adult patients with a clinical diagnosis of acute ischemic stroke should be rapidly evaluated for treatment with IVT. Simultaneously, patients with suspected acute https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 19/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate ischemic stroke involving the anterior circulation should be evaluated for MT. (See 'Rapid evaluation' above.) Patient selection For IVT Eligibility criteria for treatment with IVT are outlined in the table ( table 1). For eligible patients with acute ischemic stroke causing a potentially disabling neurologic deficit, we recommend IVT with alteplase, provided that treatment is initiated within 3 hours of the time last known well (Grade 1A). For otherwise eligible patients who cannot be treated in less than 3 hours, we suggest IVT, provided that treatment is initiated within 3 to 4.5 hours of the time last known well (Grade 2A). For patients with wake-up stroke or unknown stroke onset time, imaging-based criteria (ie, MRI showing an acute ischemic lesion that is diffusion positive and fluid-attenuated inversion recovery [FLAIR] negative) is an option at expert stroke centers to determine eligibility for IVT. (See 'Less than 3 hours' above and '3 to 4.5 hours' above and 'Unwitnessed stroke onset and "wake-up" stroke' above.) For MT Intra-arterial mechanical thrombectomy is recommended for patients with ischemic stroke caused by a large artery occlusion in the proximal anterior circulation who can start treatment within 24 hours of the time last known well. Indications and eligibility criteria for MT are discussed in detail elsewhere. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) IVT administration The administration of IVT for acute ischemic stroke, including dosing, monitoring, and complications, is reviewed in detail separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) MT procedure Procedural details for MT are discussed in detail elsewhere. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Procedure'.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010; 375:1695. 2. Saver JL, Fonarow GC, Smith EE, et al. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. JAMA 2013; 309:2480. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 20/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate 3. Wardlaw JM, Murray V, Berge E, et al. 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Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute ischemic stroke before and after a quality improvement initiative. JAMA 2014; 311:1632. 126. Cronin CA, Shah N, Morovati T, et al. No increased risk of symptomatic intracerebral hemorrhage after thrombolysis in patients with European Cooperative Acute Stroke Study (ECASS) exclusion criteria. Stroke 2012; 43:1684. 127. Hill MD, Coutts SB. Alteplase in acute ischaemic stroke: the need for speed. Lancet 2014; 384:1904. 128. Sarraj A, Kleinig TJ, Hassan AE, et al. Association of Endovascular Thrombectomy vs Medical Management With Functional and Safety Outcomes in Patients Treated Beyond 24 Hours of Last Known Well: The SELECT Late Study. JAMA Neurol 2023; 80:172. 129. McDonough RV, Ospel JM, Campbell BCV, et al. Functional Outcomes of Patients 85 Years With Acute Ischemic Stroke Following EVT: A HERMES Substudy. Stroke 2022; 53:2220. 130. Ganesh A, Fraser JF, Gordon Perue GL, et al. Endovascular Treatment and Thrombolysis for Acute Ischemic Stroke in Patients With Premorbid Disability or Dementia: A Scientific Statement From the American Heart Association/American Stroke Association. Stroke 2022; 53:e204. Topic 115775 Version 43.0 https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 30/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate GRAPHICS Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 31/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 32/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 33/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 34/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Stroke treatment delay and outcome Relation of stroke onset to start of treatment (OTT) with treatment effect after adjustment for prognostic variables assessed by A) day 90 modified Rankin score 0-1 versus 2-6 (interaction p=0.0269, n=3530 [excluding EPITHET data p=0.0116, n=3431]); B) global test that incorporates modified Rankin score 0-1 versus 2-6, Barthel Index score 95-100 versus 90 or lower and NIHSS score 0-1 versus 2 or more (interaction p=0.0111, n=3535 [excluding EPITHET data p=0.0049, n=3436]); C) mortality (interaction p=0.0444, n=3530 [excluding EPITHET data p=0.0582, n=3431]); and D) parenchymal hemorrhage type 2 (interaction p=0.4140, n=3531 [excluding EPITHET data p=0.4578, n=3431]). Thus, for parenchymal hemorrhage type 2, the fitted line is not statistically distinguishable from a horizontal line. For each graph, the adjusted odds ratio is shown with the 95% CIs. CIs from the models will differ from those shown in the tables because the model uses data from all patients treated within 0-360 min whereas the categorized analyses in the tables are based on subsets of patients: the modeled CIs are deemed to be more reliable. %: percent. Lees, KR, Bluhmki, E, von Kummer, R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010; 375:1695. Illustration used https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 35/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate with permission of Elsevier Inc. All rights reserved. Graphic 66764 Version 2.0 https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 36/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The 0 = Alert; keenly responsive. investigator must choose a response if a full evaluation is prevented by such obstacles as 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. an endotracheal tube, language barrier, 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). _____ (other than reflexive posturing) in response to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from 1 = Answers one question correctly. 2 = Answers neither question correctly. _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The 0 = Performs both tasks correctly. _____ patient is asked to open and close the eyes and then to grip and release the non-paretic 1 = Performs one task correctly. 2 = Performs neither task correctly. hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 37/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in reflexive (oculocephalic) eye movements will one or both eyes, but forced deviation or total gaze paresis is not present. be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat, as appropriate. Patients may be encouraged, 0 = No visual loss. 1 = Partial hemianopia. 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut 3 = Bilateral hemianopia (blind including cortical blindness). _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score symmetry of grimace in response to noxious fold, asymmetry on smiling). 2 = Partial paralysis (total or near-total paralysis of lower face). stimuli in the poorly responsive or non- comprehending patient. If facial trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 38/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not falls before 10 seconds. The aphasic patient hit bed or other support. is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) degrees, drifts down to bed, but has some stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in _____ effort against gravity. the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The 0 = No drift; leg holds 30-degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. Only in the case of amputation or joint fusion at the hip, the examiner should 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. _____ 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding 0 = Absent. _____ evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, 1 = Present in one limb. 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 39/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of being touched.
to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). _____ (other than reflexive posturing) in response to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from 1 = Answers one question correctly. 2 = Answers neither question correctly. _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The 0 = Performs both tasks correctly. _____ patient is asked to open and close the eyes and then to grip and release the non-paretic 1 = Performs one task correctly. 2 = Performs neither task correctly. hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 37/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in reflexive (oculocephalic) eye movements will one or both eyes, but forced deviation or total gaze paresis is not present. be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat, as appropriate. Patients may be encouraged, 0 = No visual loss. 1 = Partial hemianopia. 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut 3 = Bilateral hemianopia (blind including cortical blindness). _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score symmetry of grimace in response to noxious fold, asymmetry on smiling). 2 = Partial paralysis (total or near-total paralysis of lower face). stimuli in the poorly responsive or non- comprehending patient. If facial trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 38/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not falls before 10 seconds. The aphasic patient hit bed or other support. is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) degrees, drifts down to bed, but has some stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in _____ effort against gravity. the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The 0 = No drift; leg holds 30-degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. Only in the case of amputation or joint fusion at the hip, the examiner should 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. _____ 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding 0 = Absent. _____ evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, 1 = Present in one limb. 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 39/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of being touched. should test as many body areas (arms [not hands], legs, trunk, face) as needed to 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, accurately check for hemisensory loss. A score of 2, "severe or total sensory loss," should only be given when a severe or total loss of sensation can be clearly and leg. _____ demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of 0 = No aphasia; normal. _____ information about comprehension will be obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the attached picture, to name 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant limitation on ideas expressed or form of expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. conversation about provided materials Comprehension is judged from responses here, as well as to all of the commands in difficult or impossible. For example, in conversation about provided materials, the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the 2 = Severe aphasia; all communication is through fragmentary expression; great need hand, repeat, and produce speech. The intubated patient should be asked to write. for inference, questioning, and guessing by the listener. Range of information that can The patient in a coma (item 1a=3) will automatically score 3 on this item. The be exchanged is limited; listener carries burden of communication. Examiner cannot examiner must choose a score for the patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 40/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal, an adequate sample of speech must 0 = Normal. 1 = Mild-to-moderate dysarthria; patient be obtained by asking patient to read or slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of 2 = Severe dysarthria; patient's speech is so slurred as to be unintelligible in the absence articulation of spontaneous speech can be rated. Only if the patient is intubated or has _____ of or out of proportion to any dysphasia, or is mute/anarthric. other physical barriers to producing speech, the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the patient why he or she is being tested. explain:________________ 11. Extinction and inattention (formerly 0 = No abnormality. neglect): Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient has aphasia but does appear to attend to 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. 2 = Profound hemi-inattention or extinction to more than one modality; does not recognize own hand or orients to only one side of space. _____ both sides, the score is normal. The presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 41/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Early ischemic changes on noncontrast head CT scan Findings of EIC in a 59-year-old man who presented with acute left hemiparesis. (A and B) NCCT 3.5 hours after symptom onset shows hypodensity and cortical swelling with sulcal effacement. There is loss of gray- white matter differentiation in the right frontal operculum, right temporal operculum, right insular cortex, and right frontoparietal lobes (arrowheads). CT: computed tomography; EIC: early ischemic changes; NCCT: noncontrast-enhanced computed tomography. From: Prakkamakul S, Yoo AJ. ASPECTS CT in Acute Ischemia: Review of Current Data. Top Magn Reson Imaging 2017; 26:103. DOI: 10.1097/RMR.0000000000000122. Copyright 2017. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 121623 Version 2.0 https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 42/43 7/5/23, 12:33 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Contributor Disclosures Jamary Oliveira-Filho, MD, MS, PhD No relevant financial relationship(s) with ineligible companies to disclose. Owen B Samuels, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Jonathan A Edlow, MD, FACEP No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 43/43
7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults : Steven R Mess , MD, Naser M Ammash, MD : Scott E Kasner, MD, Heidi M Connolly, MD, FACC, FASE : John F Dashe, MD, PhD, Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 10, 2023. INTRODUCTION Stroke can be associated with abnormalities of the atrial septum, specifically patent foramen ovale (PFO), atrial septal defect (ASD), and atrial septal aneurysm (ASA). The relationship between PFO, ASD, or ASA and ischemic neurologic complications will be reviewed here. Treatment is reviewed separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) PFO AND ASD The foramen ovale and its flap-like valve between the right and left atrium are important components of the fetal circulation. In the developing fetus, oxygenated blood from the umbilical vein enters the right atrium via the inferior vena cava and is shunted into the left atrium, circumventing the noninflated lungs. After birth, a relative increase in left atrial pressure closes the flap, and adhesions frequently result in a structurally intact atrial septum. However, in approximately 25 percent of adults, the foramen ovale remains patent and acts as a potential interatrial shunt ( movie 1 and movie 2). (See "Patent foramen ovale".) Less commonly, an open communication called an ASD persists between the atria after septation. The majority of these are secundum ASD defects caused by deficiency in the septum https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 1/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate primum. This may be visualized on transthoracic ( movie 3 and movie 4) or transesophageal echocardiography ( movie 5). The pathophysiology and clinical features of PFOs and ASDs are discussed in detail separately. (See "Clinical manifestations and diagnosis of atrial septal defects in adults", section on 'Embryology and classification'.) SOURCES OF EMBOLI Some patients with ischemic stroke and no other evident source cause for stroke have a PFO, ASD, or an ASA that can be identified by transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE). Alternatively, a right-to-left shunt (RLS; most of which are caused by PFO) can be identified by contrast-enhanced transcranial Doppler (TCD). (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism" and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) These structures have been implicated in the pathogenesis of embolic events, primarily by causing paradoxical embolization from the systemic venous circulation. However, identification of one or more of these atrial septal abnormalities in a patient with an ischemic event does not prove a causal relationship since other, more common, sources or conduits of embolism may also be present. Paradoxical emboli A paradoxical embolus originates in the systemic venous circulation and enters the systemic arterial circulation through a PFO, ASD, ventricular septal defect, or extracardiac communication such as a pulmonary arteriovenous malformation [1-6]. Paradoxical embolism is a potential cause of embolic stroke of undetermined source (ESUS), which is defined as a nonlacunar brain infarct without proximal arterial stenosis or cardioembolic source. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Embolic stroke of undetermined source'.) Case reports have described patients with an "impending" paradoxical embolus due to a trapped embolus in a PFO [7-9]. Increased risk of decompression sickness complicating SCUBA diving in individuals at risk for paradoxical emboli (including those with PFO or ASD) is discussed separately. (See "Complications of SCUBA diving", section on 'Right-to-left shunt'.) Right-sided sources Thromboemboli can originate from lower extremity or pelvic veins, right-sided valve (tricuspid) vegetations, a papillary fibroelastoma or other cardiac tumor, an https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 2/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate ASA, or thrombi (in transit or in situ) within the PFO [10,11]. Air emboli can arise from intravenous lines. Fat emboli can complicate trauma or orthopedic procedures. Thromboembolism from a right-sided source can result in concurrent pulmonary embolism and stroke. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Early'.) Transvenous cardiac device (pacemaker or defibrillator) leads, which are most commonly placed in right-sided heart chambers, are another potential nidus for the formation of mobile thrombi that can be a source of pulmonary emboli [12] or, via paradoxical embolization, can result in cerebral or other systemic emboli [13,14]. Small mobile thrombi are frequently observed by echocardiography attached to the right atrial segments of these leads. Although data are limited, a retrospective study of patients with transvenous cardiac device leads in the right atrium or right ventricle found that the presence of PFO was associated with a significantly increased risk of cardioembolic stroke [15]. Further data are needed to confirm this finding and determine how this compares with the risk of cardioembolic stroke in patients with PFO who do not have intracardiac device leads. Right-to-left shunting Right-to-left shunting through a PFO or an ASD can result in a paradoxical embolus (see 'Paradoxical emboli' above). Since a transient right-to-left atrial pressure gradient is sufficient to induce right-to-left shunting across a PFO (or ASD), such shunts commonly occur in individuals with no significant net right- to-left shunting between the atria (ie, those with no net intracardiac shunt or with a net left-to- right shunt). Chronic elevation in right heart pressures (eg, Eisenmenger syndrome) is not required for paradoxical embolism to occur. Transient right-to-left shunting across a PFO is a dynamic phenomenon given the significant variability of both right and left atrial pressures. Transient increases in right atrial pressure occur in normal individuals during early ventricular systole ( movie 1 and movie 2), during the Valsalva maneuver, and with repetitive cough [16]. In addition, a persistent, large Eustachian valve or a Chiari network may direct inferior vena caval blood toward the atrial septum where a PFO or ASD is located and potentially into the left atrium and systemic circulation. (See "Patent foramen ovale", section on 'Eustachian valve and Chiari network'.) With the Valsalva maneuver, transient right-to-left shunting in patients with a PFO or an ASD can be induced particularly during Valsalva release. During the straining phase, the right atrial pressure rises disproportionately, and during release there is a sudden increase in systemic venous return into the right atrium. Physiologic conditions associated with a Valsalva maneuver include straining to defecate, lifting or pushing heavy objects, and vigorous repetitive cough. In https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 3/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate one series of 148 patients with a PFO, 84 (57 percent) had right-to-left shunting at rest, and 136 (92 percent) had right-to-left shunting with straining or coughing [17]. (See "Contrast echocardiography: Clinical applications", section on 'Shunt detection' and "Clinical manifestations and diagnosis of atrial septal defects in adults", section on 'Agitated saline contrast'.) An uncommon consequence of intermittent right-to-left shunting is the platypnea-orthodeoxia syndrome [5]. This disorder is defined as an orthostatic right-to-left shunt across an ASD or PFO resulting in decreases in oxygen saturation when changing position from prone to upright, leading to significant positional dyspnea. (See "Patent foramen ovale", section on 'Platypnea- orthodeoxia syndrome'.) ASA An ASA is defined as redundant and mobile interatrial septal tissue in the region of the fossa ovalis with phasic excursion of at least 10 to 15 mm during the cardiorespiratory cycle. ASAs have been classified according to their oscillation (intrusion) into the left or right atrium and according to their motion during the respiratory cycle [18]. Most investigators have defined an ASA as an excursion of at least 10 or 15 mm. The aneurysm may either bulge persistently into the right or left atrium or exhibit striking oscillations from right atrium to left atrium during respiration, in response to fluctuating pressure gradients between the atria [18-20]. ASA is most commonly an incidental finding. However, some patients with ASA present with systemic thromboembolism and some present with symptoms and signs of significant intracardiac shunting via one or more associated ASDs. (See "Clinical manifestations and diagnosis of atrial septal defects in adults".) The diagnosis of ASA can sometimes be established by TTE7 ( movie 6), but TEE is more sensitive since the interatrial septum is visualized more consistently ( movie 7). In the review of 195 cases cited above, 47 percent were missed with TTE [21]. The prevalence of ASA varies with the method of identification and the population studied. ASAs have been found in 1 percent of necropsies [22] and 0.2 to 2 percent of patients undergoing TTE [23,24]. With TEE, ASAs were detected in 2.2 percent of population controls [25], 4 percent of patients referred for TEE for a reason other than detection of a source of embolic stroke [18], and 4.9 percent of patients undergoing cardiac surgery [26]. There is an increased prevalence of ASAs among patients with cerebral ischemic events [18,25,27]. As an example, ASA was observed in 7.9 to 15 percent of patients with a possible embolic stroke [18,25] and 28 percent of those with a cerebral ischemic event and normal carotid arteries [27]. Two mechanisms have been proposed to explain the association between ASA and cryptogenic stroke. Since ASA is commonly associated with PFO and ASD, paradoxical https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 4/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate embolism may occur via the septal defect. In patients with ASA without an intracardiac shunt, it has been hypothesized that fibrin-platelet particles adhere to the left atrial side of the aneurysm and are dislodged by oscillations of the aneurysm, causing systemic embolism. An intracardiac shunt has been reported in up to 78 percent of patients with an ASA [18- 21,25,27]. Most patients (54 to 84 percent) with cerebral ischemic events and an ASA also have an interatrial shunt, usually via a PFO [3,21,25,27]. In a multicenter review of 195 cases in which ASA was detected by TEE, ASA was the only defect in 32 percent and was associated with an interatrial shunt in 54 percent, most often a PFO (33 percent) or ASD (19 percent) [21]. Some ASAs are associated with multiple atrial septal fenestrations (perforations) [28]. Left-sided sources A common source of cerebral emboli originating in the systemic arterial circulation in patients with atrial septal abnormalities is the left atrium (particularly left atrial appendage), especially in those with atrial fibrillation. Patients with a hemodynamically significant ASD causing volume overload of the atria and right ventricle are at risk for atrial fibrillation, especially after age 50 years. Although evidence is more limited, patients with PFO or ASA may also be predisposed to atrial fibrillation [23,29]. However, whereas ASD can cause volume overload of the right heart chambers, an isolated PFO is not associated with volume overload of any cardiac chamber. Other potential sources of emboli are left-sided tumors, such as atrial myxoma and papillary fibroelastoma, left-sided prosthetic valve thrombosis, and vegetations caused by infective endocarditis or other disorders. (See "Complications and outcome of infective endocarditis", section on 'Metastatic infection'.) RISK OF EMBOLIC STROKE Approximately 25 to 40 percent of ischemic strokes are cryptogenic, including embolic stroke of undetermined source (ESUS; defined as a brain infarct without an identified cardioembolic or large vessel source and with a distribution that is not consistent with small vessel disease). The causes of cryptogenic stroke are likely heterogeneous with embolism a dominant etiology. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) There is an increased prevalence of PFO and ASA in patients who have an embolic-appearing ischemic stroke and no other evident source of stroke, suggesting that paradoxical embolism and/or other mechanisms related to PFO and ASA are the cause of some ischemic strokes. However, the detection of an atrial septal abnormality in a patient with an embolic stroke does not prove a cause-and-effect relationship given how common they are in the general population and the likelihood of other potential source when properly investigated. As an example, in a https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 5/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate report of 134 patients with cerebral embolic events, an ASA was found in 45, but 41 of these 45 patients had other potential sources for embolization [30]. PFO may be a risk factor for perioperative stroke, but the quality of the evidence is low [31]. One study found that a preoperative diagnosis of PFO was associated with an increased risk of perioperative ischemic stroke within 30 days after noncardiac surgery [32], and meta-analyses of observational studies have also found an association of PFO with an increased risk of stroke at 30 days after noncardiac surgery [31,33]. The strength of these findings is limited by the largely retrospective nature of the data, since patients with prior cardiac disease, including coronary artery disease and atrial fibrillation, were more likely to have a PFO identified. Nevertheless, patients, especially those 60 years of age, with an embolic-appearing ischemic stroke in the setting of a PFO with a right-to-left interatrial shunt and no other source of stroke despite a comprehensive evaluation are now recognized as most likely having a PFO-associated stroke [34]. Data on the risk of stroke in patients with PFO and pulmonary embolism is discussed separately. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Early'.) Prevalence of PFO in cryptogenic stroke A number of case-control and population-based studies have reported an increased prevalence of PFO and/or ASA in patients who have had a cryptogenic stroke [18,19,21,25,35-39]. A 2007 prospective case-control study examined 503 consecutive patients with ischemic stroke using transesophageal echocardiography (TEE), and compared 227 patients who had cryptogenic stroke (classified before TEE was performed) with 276 control patients who had stroke of known cause [38]. The prevalence of PFO was significantly higher among those with cryptogenic stroke compared with those with known cause of stroke in both the younger (<55 years of age; 43.9 versus 14.3 percent) and older ( 55 years of age; 28.3 versus 11.9 percent) groups. In multivariate analysis, the presence of a PFO was independently associated with cryptogenic stroke in both the younger (odds ratio [OR] 3.7, 95% CI 1.42-9.65) and older age groups (OR 3.0, 95% CI 1.73-5.23). Similarly, a 2018 prospective population-based study found that the prevalence of right-to-left shunt (RLS, which is known to be caused mainly by PFO) identified by contrast-enhanced transcranial Doppler (TCD) was significantly higher among patients with cryptogenic events (transient ischemic attack [TIA] or ischemic stroke) compared with those who had a known cause of stroke, both in the overall population (OR 1.93, 95% CI 1.32-2.82) and in those >60 years of age (OR 2.06, 95% CI 1.32-3.23) [39]. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 6/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate In a meta-analysis that included 9 studies (including both of the above prospective studies) of PFO prevalence (as assessed by TEE, transthoracic echocardiography [TTE], or TCD), a significant association between PFO and cryptogenic events was identified for all three screening modalities [39]. A significant association between PFO and cryptogenic events was also identified among older patients (patients greater than 40 to 60 years old in various studies) for each of the three screening modalities, although the results of the TEE studies were heterogeneous. Even in a patient with a cryptogenic stroke, the presence of an atrial septal abnormality does not establish the stroke etiology. A 2009 meta-analysis of case-control studies evaluating the prevalence of PFO in patients with cryptogenic stroke suggested that approximately one-third of PFOs detected in such patients are incidental findings [40]. In a 2021 meta-analysis of individual patient data from six randomized controlled trials of PFO closure for patients with PFO- associated stroke, the risk reduction for recurrent stroke with PFO closure varied among subgroups with different probabilities that the stroke was causally related to the PFO, as determined by the Risk of Paradoxical Embolism (RoPE) score ( table 1A) and a modified PFO- associated stroke causal likelihood (PASCAL) classification ( table 2) [41]. The RoPE score and PASCAL classification are discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'RoPE score' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification'.) Risk factors In patients with PFO, some retrospective analyses have suggested that certain factors may increase the likelihood of initial and recurrent stroke [42]. These include a history of Valsalva maneuver (eg, straining) preceding the cerebral embolic event, a history of multiple strokes in different vascular distributions, and possibly a transient or chronic hypercoagulable state [17,43-45]. By contrast, one study found that these factors were not associated with radiologic markers of stroke recurrence [46]. The association of an ASD with cerebral embolic events has been less well studied [4,21]. In one series of 103 patients (mean age 52 years) with a presumed paradoxical embolism and an atrial septal abnormality undergoing percutaneous closure, a PFO alone was present in 81, an ASD alone in 12, and both a PFO and ASD in 10 [4]. PFO characteristics PFO characteristics possibly associated with an increased risk of recurrent stroke include large PFO, large right-to-left shunt, spontaneous right-to-left shunt, greater PFO flap mobility, prominent Eustachian valve or Chiari network, and the presence of an ASA [41,42,47-53]. However, characteristics such as concurrent ASA or shunt size were not associated with increased recurrent stroke risk in some studies [54-57]. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 7/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate An analysis of individual patient data on 898 patients with recent PFO-associated stroke from two prospective observational studies and the medical arms of two randomized trials (CLOSE and DEFENSE-PFO) assessed risk factors for recurrent stroke with medical therapy [53]. During a median follow-up of 3.8 years, 47 patients (5 percent) experienced a recurrent stroke. In a multivariate model incorporating age, hypertension, antithrombotic therapy and PFO anatomy, presence of an ASA was associated with recurrent stroke (adjusted HR 3.27; 95% CI 1.82-5.86), whereas large PFO was not (adjusted HR 1.43; 95% CI 0.50-4.03). Prospective studies Prospective observational and therapeutic studies of the risk of cryptogenic stroke with PFO and ASA have yielded variable results [3,26,38,49,54,55,58]. However, there is good evidence that PFO as a sole risk factor for stroke is associated with a low risk of recurrent stroke. The Risk of Paradoxical Embolism (RoPE) study performed a patient level meta-analysis of 12 cryptogenic stroke cohorts [59,60]. The following observations were noted: Among 3023 patients with cryptogenic stroke, the prevalence of PFO, and the likelihood that PFO was the cause of the stroke (the PFO-attributable fraction), correlated with the absence of vascular risk factors (ie, hypertension, diabetes, smoking, prior stroke or TIA, older age) and the presence of a cortical (as opposed to subcortical) cryptogenic infarct on imaging [59]. Using multivariate modeling, the investigators devised the RoPE score [( table 1A) and (calculator 1)], which estimates the probability that a PFO is incidental or pathogenic in a patient with cryptogenic stroke [59]. High RoPE scores, as found in younger patients who lack vascular risk factors and have a cortical infarct on neuroimaging, suggest pathogenic PFOs, while low RoPE scores, as found in older patients with vascular risk factors, suggest incidental PFOs. For each RoPE score stratum, the corresponding PFO prevalence was used to estimate the PFO-attributable fraction ( table 1B) (ie, the probability that the index event was related to the PFO). Patients with the highest PFO-attributable fraction (ie, those whose PFO was most likely to have caused the cryptogenic stroke) were at the lowest risk for stroke recurrence. As an example, a patient less than 30 years of age with none of the vascular risk factors noted above had a PFO-attributable fraction of 88 percent and an estimated two-year stroke recurrence rate of 1 percent (95% CI 0-2 percent), while a patient 70 years of age or older with all of the vascular risk factors noted above had a PFO-attributable fraction of 0 percent and an estimated two-year stroke recurrence rate of 16 percent (95% CI 9- 24 percent). https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 8/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate In a subsequent analysis, stroke recurrence was associated with the following three variables only in the high RoPE score group: a history of stroke or TIA (hazard ratio [HR] 3.79, 95% CI 1.43-10.09), a hypermobile interatrial septum (HR 2.31, 95% CI 1.05-5.05), and a small shunt (HR 3.26, 95% CI 1.59-6.67) [60]. In a meta-analysis of 14 prospective studies reporting recurrent cerebrovascular events in 4241 medically treated patients, patients with a PFO had no increased risk of recurrent cryptogenic stroke compared with those without a PFO (annual rate 2.0 versus 2.4 percent, risk ratio 0.85, 95% CI 0.59-1.22) [61]. Furthermore, PFO size was not associated with the risk of recurrent stroke or TIA. Among several of the cryptogenic stroke cohorts included in the RoPE analysis cited above, the presence of PFO together with an ASA was a significant predictor of an increased risk of recurrent stroke, but this was not the case in PICSS, the German Stroke Study, or CODICIA studies [54,55,62]. Population-based studies Two prospective population-based cohort studies [56,63] and one population-based case-control study [57] suggest that PFO and large PFO are not independent risk factors for ischemic stroke in patients without prior stroke. These results could be due to study populations composed largely of older adults and therefore a low average RoPE score (ie, a low PFO-attributable fraction of stroke). In the NOMAS study of 1100 stroke-free subjects 40 years of age or older (mean age 69 years), PFO was not associated with a statistically significant increase in stroke risk (HR 1.64, 95% CI 0.87-3.09), nor was the coexistence of PFO and ASA (HR 1.25, 95% CI 0.17-9.24) or the presence of an isolated ASA (HR 3.66, 95% CI 0.88-15.3), although the confidence intervals for these HRs do not exclude clinically important associations [56]. In the SPARC study of 585 randomly sampled subjects 45 years of age or older, PFO was not a significant independent predictor of cerebrovascular events after adjustment for age and comorbid conditions (HR 1.46; 95% CI 0.74-2.88) [63]. Furthermore, there was no association of large PFO size with risk of cerebrovascular events. ASA was associated with a nearly fourfold increase in the risk of cerebrovascular events, but this risk did not achieve statistical significance (HR 3.72; 95% CI 0.88-15.71), possibly because ASA was present in only 11 subjects, of whom only two had cerebrovascular events. In a population-based, case-control study, PFO and large PFO were not independent risk factors for cryptogenic stroke in the entire study population, which was generally older than age 65 [57]. The small number of patients younger than age 55 led to wide confidence intervals in the analysis of that subgroup, and the study does not refute the contention https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 9/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate that PFO is associated with an increased ischemic stroke risk in children or young adults [64]. Conclusions The true risk of primary or recurrent ischemic stroke associated with PFO and ASA remains uncertain. However, available data can be summarized as follows (see 'Prevalence of PFO in cryptogenic stroke' above and 'Prospective studies' above and 'Population-based studies' above): Multiple case-control trials have reported an increased prevalence of PFO in younger patients who have had a cryptogenic stroke, suggesting that PFO is frequent cause of cryptogenic stroke. By contrast, population-based cohort studies, which enrolled predominantly older subjects, have found no statistically significant association between the risk of first ischemic stroke and presence of a PFO. The PFO-attributable fraction of stroke varies widely and decreases with age and the presence of vascular risk factors. Differences in the PFO-attributable fraction of stroke likely explain, at least in part, the discrepant findings of the case-control and population-based studies. Subjects with cryptogenic stroke are generally younger and more likely to have a higher PFO-attributable fraction of stroke than the older subjects enrolled in the population-based studies. Additionally, it is possible that patients with PFO-associated stroke have other risk factors that may predispose to paradoxical embolism, such as a hypercoagulable condition [65]. For patients with cryptogenic stroke and PFO, the risk of stroke recurrence is inversely related to the likelihood that the PFO was responsible for the index stroke. Large-shunt PFO and the presence of an ASA with a PFO are probably risk factors for recurrent PFO-associated stroke. DIAGNOSIS The diagnosis of ischemic stroke or transient ischemic attack (TIA) due to paradoxical embolism through a PFO (ie, a PFO-associated stroke) or ASD is usually one of exclusion. A PFO or ASD should be considered as a potential cause of embolic stroke or TIA in patients with no other identifiable cause, particularly in younger patients (eg, 60 years of age). When evaluating whether an ischemic stroke is related to PFO or to another mechanism, the assessment should look for features that increase the probability that a PFO is the cause of the https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 10/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate stroke. These include [34]: Factors that increase right-to-left shunt flow (eg, large PFO size, chronic right atrial hypertension, or a Valsalva maneuver) Presence of embolic stroke Presence of associated ASA Risk for current or prior venous thrombosis Absence of atherosclerotic risk factors or other likely causes of ischemic stroke, including atrial fibrillation The diagnostic evaluation and treatment of PFO-associated stroke is discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) TREATMENT Therapeutic options for secondary prevention of PFO-associated stroke include medical therapy with antithrombotic agents or percutaneous closure of the defect. These options are discussed separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) No specific treatment is needed for incidentally discovered PFO, small ASD and/or ASA in asymptomatic patients. The available evidence from population-based studies suggests that PFO and large PFO are not independent risk factors for ischemic stroke in otherwise asymptomatic individuals. However, given the potential risk of paradoxical embolism in patients with PFO or small ASD, it is reasonable to educate the patient on how to prevent deep venous thrombosis by avoiding prolonged period of immobilization and dehydration. (See 'Population-based studies' above.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 11/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Patent foramen ovale (The Basics)") SUMMARY Embolic sources Emboli leading to stroke or to transient ischemic attack (TIA) can originate in either the systemic venous circulation (paradoxical emboli) or in the systemic arterial circulation. Some patients with an embolic-appearing ischemic stroke and no other evident source of stroke have a patent foramen ovale (PFO), an atrial septal defect (ASD), and/or an atrial septal aneurysm (ASA) that can be best identified by transesophageal echocardiography (TEE). These structures have been implicated in the pathogenesis of embolic events. However, identification of one or more of these atrial septal abnormalities in a patient with an ischemic event does not prove a causal relationship since other sources or conduits of embolism may also be present. (See 'Sources of emboli' above.) Cryptogenic stroke Approximately 25 to 40 percent of ischemic strokes are cryptogenic (ie, without an identified cardioembolic or large vessel source and with a distribution that is not consistent with small vessel disease). The causes of cryptogenic stroke are likely heterogeneous, with embolism a dominant etiology. (See 'Risk of embolic stroke' above and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) Risk of stroke from a PFO The true risk of primary or recurrent ischemic stroke associated with PFO and ASA remains uncertain. However, available data can be summarized as follows (see 'Conclusions' above): Multiple case-control trials have reported an increased prevalence of PFO in patients who have had a cryptogenic stroke, suggesting that PFO is frequent cause of cryptogenic stroke. By contrast, population-based cohort studies, which enrolled predominantly older subjects, have found no statistically significant association between the risk of first https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 12/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate ischemic stroke and presence of a PFO. The PFO-attributable fraction of stroke varies widely and decreases with age and the presence of vascular risk factors, as shown in the table ( table 1A-B) and calculator (calculator 1) for the RoPE score. Differences in the PFO-attributable fraction of stroke probably explain the discrepant findings of the case-control and population-based studies. Subjects with an embolic-appearing cryptogenic stroke are generally younger and more likely to have a higher PFO-attributable fraction of stroke than the older subjects enrolled in the population-based studies. For patients with cryptogenic stroke, the risk of stroke recurrence is inversely related to the likelihood that the PFO was responsible for the index stroke. Large-shunt PFO and the presence of an ASA with a PFO are probably a risk factors for recurrent PFO-associated stroke. PFO-associated stroke Patients with an embolic-appearing ischemic stroke in the setting of a PFO with a right-to-left interatrial shunt and no other source of stroke or other risk factors for stroke despite a comprehensive evaluation are now recognized as having a PFO- associated stroke. Select patients with PFO-associated stroke may benefit from PFO closure. (See 'Risk of embolic stroke' above and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Stroke associated with patent foramen ovale (PFO): Management".) ACKNOWLEDGMENTS The editorial staff at UpToDate, Inc. acknowledge Joseph K Perloff, MD (deceased), Thomas Graham Jr, MD and Robert S Schwartz, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Cardiogenic brain embolism. Cerebral Embolism Task Force. Arch Neurol 1986; 43:71. 2. CORRIN B. PARADOXICAL EMBOLISM. Br Heart J 1964; 26:549. 3. Lamy C, Giannesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA Study. Atrial Septal Aneurysm. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 13/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate Stroke 2002; 33:706. 4. Khositseth A, Cabalka AK, Sweeney JP, et al. Transcatheter Amplatzer device closure of atrial septal defect and patent foramen ovale in patients with presumed paradoxical embolism. Mayo Clin Proc 2004; 79:35. 5. Kerut EK, Norfleet WT, Plotnick GD, Giles TD. Patent foramen ovale: a review of associated conditions and the impact of physiological size. J Am Coll Cardiol 2001; 38:613. 6. Harvey JR, Teague SM, Anderson JL, et al. Clinically silent atrial septal defects with evidence for cerebral embolization. Ann Intern Med 1986; 105:695. 7. Caes FL, Van Belleghem YV, Missault LH, et al. Surgical treatment of impending paradoxical embolism through patent foramen ovale. Ann Thorac Surg 1995; 59:1559. 8. Falk V, Walther T, Krankenberg H, Mohr FW. Trapped thrombus in a patent foramen ovale. Thorac Cardiovasc Surg 1997; 45:90. 9. Meacham RR 3rd, Headley AS, Bronze MS, et al. Impending paradoxical embolism. Arch Intern Med 1998; 158:438. 10. d'audiffret A, Pillai L, Dryjski M. Paradoxical emboli: the relationship between patent foramen ovale, deep vein thrombosis and ischaemic stroke. Eur J Vasc Endovasc Surg 1999; 17:468. 11. Yan C, Li H. Preliminary Investigation of In situ Thrombus Within Patent Foramen Ovale in Patients With and Without Stroke. JAMA 2021; 325:2116. 12. Supple GE, Ren JF, Zado ES, Marchlinski FE. Mobile thrombus on device leads in patients undergoing ablation: identification, incidence, location, and association with increased pulmonary artery systolic pressure. Circulation 2011; 124:772. 13. DeSimone CV, DeSimone DC, Patel NA, et al. Implantable cardiac devices with patent foramen ovale a risk factor for cardioembolic stroke? J Interv Card Electrophysiol 2012; 35:159. 14. DeSimone CV, DeSimone DC, Hagler DJ, et al. Cardioembolic stroke in patients with patent foramen ovale and implanted cardiac leads. Pacing Clin Electrophysiol 2013; 36:50. 15. DeSimone CV, Friedman PA, Noheria A, et al. Stroke or transient ischemic attack in patients with transvenous pacemaker or defibrillator and echocardiographically detected patent foramen ovale. Circulation 2013; 128:1433. 16. Langholz D, Louie EK, Konstadt SN, et al. Transesophageal echocardiographic demonstration of distinct mechanisms for right to left shunting across a patent foramen ovale in the absence of pulmonary hypertension. J Am Coll Cardiol 1991; 18:1112. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 14/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate 17. Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc 1999; 74:862. 18. Pearson AC, Nagelhout D, Castello R, et al. Atrial septal aneurysm and stroke: a transesophageal echocardiographic study. J Am Coll Cardiol 1991; 18:1223. 19. Cabanes L, Mas JL, Cohen A, et al. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using
medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Patent foramen ovale (The Basics)") SUMMARY Embolic sources Emboli leading to stroke or to transient ischemic attack (TIA) can originate in either the systemic venous circulation (paradoxical emboli) or in the systemic arterial circulation. Some patients with an embolic-appearing ischemic stroke and no other evident source of stroke have a patent foramen ovale (PFO), an atrial septal defect (ASD), and/or an atrial septal aneurysm (ASA) that can be best identified by transesophageal echocardiography (TEE). These structures have been implicated in the pathogenesis of embolic events. However, identification of one or more of these atrial septal abnormalities in a patient with an ischemic event does not prove a causal relationship since other sources or conduits of embolism may also be present. (See 'Sources of emboli' above.) Cryptogenic stroke Approximately 25 to 40 percent of ischemic strokes are cryptogenic (ie, without an identified cardioembolic or large vessel source and with a distribution that is not consistent with small vessel disease). The causes of cryptogenic stroke are likely heterogeneous, with embolism a dominant etiology. (See 'Risk of embolic stroke' above and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) Risk of stroke from a PFO The true risk of primary or recurrent ischemic stroke associated with PFO and ASA remains uncertain. However, available data can be summarized as follows (see 'Conclusions' above): Multiple case-control trials have reported an increased prevalence of PFO in patients who have had a cryptogenic stroke, suggesting that PFO is frequent cause of cryptogenic stroke. By contrast, population-based cohort studies, which enrolled predominantly older subjects, have found no statistically significant association between the risk of first https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 12/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate ischemic stroke and presence of a PFO. The PFO-attributable fraction of stroke varies widely and decreases with age and the presence of vascular risk factors, as shown in the table ( table 1A-B) and calculator (calculator 1) for the RoPE score. Differences in the PFO-attributable fraction of stroke probably explain the discrepant findings of the case-control and population-based studies. Subjects with an embolic-appearing cryptogenic stroke are generally younger and more likely to have a higher PFO-attributable fraction of stroke than the older subjects enrolled in the population-based studies. For patients with cryptogenic stroke, the risk of stroke recurrence is inversely related to the likelihood that the PFO was responsible for the index stroke. Large-shunt PFO and the presence of an ASA with a PFO are probably a risk factors for recurrent PFO-associated stroke. PFO-associated stroke Patients with an embolic-appearing ischemic stroke in the setting of a PFO with a right-to-left interatrial shunt and no other source of stroke or other risk factors for stroke despite a comprehensive evaluation are now recognized as having a PFO- associated stroke. Select patients with PFO-associated stroke may benefit from PFO closure. (See 'Risk of embolic stroke' above and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Stroke associated with patent foramen ovale (PFO): Management".) ACKNOWLEDGMENTS The editorial staff at UpToDate, Inc. acknowledge Joseph K Perloff, MD (deceased), Thomas Graham Jr, MD and Robert S Schwartz, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Cardiogenic brain embolism. Cerebral Embolism Task Force. Arch Neurol 1986; 43:71. 2. CORRIN B. PARADOXICAL EMBOLISM. Br Heart J 1964; 26:549. 3. Lamy C, Giannesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA Study. Atrial Septal Aneurysm. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 13/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate Stroke 2002; 33:706. 4. Khositseth A, Cabalka AK, Sweeney JP, et al. Transcatheter Amplatzer device closure of atrial septal defect and patent foramen ovale in patients with presumed paradoxical embolism. Mayo Clin Proc 2004; 79:35. 5. Kerut EK, Norfleet WT, Plotnick GD, Giles TD. Patent foramen ovale: a review of associated conditions and the impact of physiological size. J Am Coll Cardiol 2001; 38:613. 6. Harvey JR, Teague SM, Anderson JL, et al. Clinically silent atrial septal defects with evidence for cerebral embolization. Ann Intern Med 1986; 105:695. 7. Caes FL, Van Belleghem YV, Missault LH, et al. Surgical treatment of impending paradoxical embolism through patent foramen ovale. Ann Thorac Surg 1995; 59:1559. 8. Falk V, Walther T, Krankenberg H, Mohr FW. Trapped thrombus in a patent foramen ovale. Thorac Cardiovasc Surg 1997; 45:90. 9. Meacham RR 3rd, Headley AS, Bronze MS, et al. Impending paradoxical embolism. Arch Intern Med 1998; 158:438. 10. d'audiffret A, Pillai L, Dryjski M. Paradoxical emboli: the relationship between patent foramen ovale, deep vein thrombosis and ischaemic stroke. Eur J Vasc Endovasc Surg 1999; 17:468. 11. Yan C, Li H. Preliminary Investigation of In situ Thrombus Within Patent Foramen Ovale in Patients With and Without Stroke. JAMA 2021; 325:2116. 12. Supple GE, Ren JF, Zado ES, Marchlinski FE. Mobile thrombus on device leads in patients undergoing ablation: identification, incidence, location, and association with increased pulmonary artery systolic pressure. Circulation 2011; 124:772. 13. DeSimone CV, DeSimone DC, Patel NA, et al. Implantable cardiac devices with patent foramen ovale a risk factor for cardioembolic stroke? J Interv Card Electrophysiol 2012; 35:159. 14. DeSimone CV, DeSimone DC, Hagler DJ, et al. Cardioembolic stroke in patients with patent foramen ovale and implanted cardiac leads. Pacing Clin Electrophysiol 2013; 36:50. 15. DeSimone CV, Friedman PA, Noheria A, et al. Stroke or transient ischemic attack in patients with transvenous pacemaker or defibrillator and echocardiographically detected patent foramen ovale. Circulation 2013; 128:1433. 16. Langholz D, Louie EK, Konstadt SN, et al. Transesophageal echocardiographic demonstration of distinct mechanisms for right to left shunting across a patent foramen ovale in the absence of pulmonary hypertension. J Am Coll Cardiol 1991; 18:1112. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 14/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate 17. Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc 1999; 74:862. 18. Pearson AC, Nagelhout D, Castello R, et al. Atrial septal aneurysm and stroke: a transesophageal echocardiographic study. J Am Coll Cardiol 1991; 18:1223. 19. Cabanes L, Mas JL, Cohen A, et al. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography. Stroke 1993; 24:1865. 20. Belkin RN, Kisslo J. Atrial septal aneurysm: recognition and clinical relevance. Am Heart J 1990; 120:948. 21. M gge A, Daniel WG, Angermann C, et al. Atrial septal aneurysm in adult patients. A multicenter study using transthoracic and transesophageal echocardiography. Circulation 1995; 91:2785. 22. Silver MD, Dorsey JS. Aneurysms of the septum primum in adults. Arch Pathol Lab Med 1978; 102:62. 23. Hanley PC, Tajik AJ, Hynes JK, et al. Diagnosis and classification of atrial septal aneurysm by two-dimensional echocardiography: report of 80 consecutive cases. J Am Coll Cardiol 1985; 6:1370. 24. Olivares-Reyes A, Chan S, Lazar EJ, et al. Atrial septal aneurysm: a new classification in two hundred five adults. J Am Soc Echocardiogr 1997; 10:644. 25. Agmon Y, Khandheria BK, Meissner I, et al. Frequency of atrial septal aneurysms in patients with cerebral ischemic events. Circulation 1999; 99:1942. 26. Burger AJ, Sherman HB, Charlamb MJ. Low incidence of embolic strokes with atrial septal aneurysms: A prospective, long-term study. Am Heart J 2000; 139:149. 27. Mattioli AV, Aquilina M, Oldani A, et al. Atrial septal aneurysm as a cardioembolic source in adult patients with stroke and normal carotid arteries. A multicentre study. Eur Heart J 2001; 22:261. 28. Ewert P, Berger F, Vogel M, et al. Morphology of perforated atrial septal aneurysm suitable for closure by transcatheter device placement. Heart 2000; 84:327. 29. Djaiani G, Phillips-Bute B, Podgoreanu M, et al. The association of patent foramen ovale and atrial fibrillation after coronary artery bypass graft surgery. Anesth Analg 2004; 98:585. 30. Ilercil A, Meisner JS, Vijayaraman P, et al. Clinical significance of fossa ovalis membrane aneurysm in adults with cardioembolic cerebral ischemia. Am J Cardiol 1997; 80:96. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 15/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate 31. Hobbes B, Akseer S, Pikula A, et al. Risk of Perioperative Stroke in Patients With Patent Foramen Ovale: A Systematic Review and Meta-analysis. Can J Cardiol 2022; 38:1189. 32. Ng PY, Ng AK, Subramaniam B, et al. Association of Preoperatively Diagnosed Patent Foramen Ovale With Perioperative Ischemic Stroke. JAMA 2018; 319:452. 33. Rais G, Vassallo P, Schorer R, et al. Patent foramen ovale and perioperative stroke in noncardiac surgery: a systematic review and meta-analysis. Br J Anaesth 2022; 129:898. 34. Elgendy AY, Saver JL, Amin Z, et al. Proposal for Updated Nomenclature and Classification of Potential Causative Mechanism in Patent Foramen Ovale-Associated Stroke. JAMA Neurol 2020; 77:878. 35. Webster MW, Chancellor AM, Smith HJ, et al. Patent foramen ovale in young stroke patients. Lancet 1988; 2:11. 36. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318:1148. 37. Di Tullio M, Sacco RL, Gopal A, et al. Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med 1992; 117:461. 38. Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med 2007; 357:2262. 39. Mazzucco S, Li L, Binney L, et al. Prevalence of patent foramen ovale in cryptogenic transient ischaemic attack and non-disabling stroke at older ages: a population-based study, systematic review, and meta-analysis. Lancet Neurol 2018; 17:609. 40. Alsheikh-Ali AA, Thaler DE, Kent DM. Patent foramen ovale in cryptogenic stroke: incidental or pathogenic? Stroke 2009; 40:2349. 41. Kent DM, Saver JL, Kasner SE, et al. Heterogeneity of Treatment Effects in an Analysis of Pooled Individual Patient Data From Randomized Trials of Device Closure of Patent Foramen Ovale After Stroke. JAMA 2021; 326:2277. 42. Wu LA, Malouf JF, Dearani JA, et al. Patent foramen ovale in cryptogenic stroke: current understanding and management options. Arch Intern Med 2004; 164:950. 43. Dearani JA, Ugurlu BS, Danielson GK, et al. Surgical patent foramen ovale closure for prevention of paradoxical embolism-related cerebrovascular ischemic events. Circulation 1999; 100:II171. 44. Bogousslavsky J, Garazi S, Jeanrenaud X, et al. Stroke recurrence in patients with patent foramen ovale: the Lausanne Study. Lausanne Stroke with Paradoxal Embolism Study Group. Neurology 1996; 46:1301. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 16/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate 45. Pezzini A, Grassi M, Zotto ED, et al. Do common prothrombotic mutations influence the risk of cerebral ischaemia in patients with patent foramen ovale? Systematic review and meta- analysis. Thromb Haemost 2009; 101:813. 46. Kitsios GD, Lasker A, Singh J, Thaler DE. Recurrent stroke on imaging and presumed paradoxical embolism: a cross-sectional analysis. Neurology 2012; 78:993. 47. Schuchlenz HW, Weihs W, Horner S, Quehenberger F. The association between the diameter of a patent foramen ovale and the risk of embolic cerebrovascular events. Am J Med 2000; 109:456. 48. Homma S, Di Tullio MR, Sacco RL, et al. Characteristics of patent foramen ovale associated with cryptogenic stroke. A biplane transesophageal echocardiographic study. Stroke 1994; 25:582. 49. De Castro S, Cartoni D, Fiorelli M, et al. Morphological and functional characteristics of patent foramen ovale and their embolic implications. Stroke 2000; 31:2407. 50. Stone DA, Godard J, Corretti MC, et al. Patent foramen ovale: association between the degree of shunt by contrast transesophageal echocardiography and the risk of future ischemic neurologic events. Am Heart J 1996; 131:158. 51. Hanna JP, Sun JP, Furlan AJ, et al. Patent foramen ovale and brain infarct. Echocardiographic predictors, recurrence, and prevention. Stroke 1994; 25:782. 52. Rigatelli G, Dell'avvocata F, Braggion G, et al. Persistent venous valves correlate with increased shunt and multiple preceding cryptogenic embolic events in patients with patent foramen ovale: an intracardiac echocardiographic study. Catheter Cardiovasc Interv 2008; 72:973. 53. Turc G, Lee JY, Brochet E, et al. Atrial Septal Aneurysm, Shunt Size, and Recurrent Stroke Risk in Patients With Patent Foramen Ovale. J Am Coll Cardiol 2020; 75:2312. 54. Serena J, Marti-F bregas J, Santamarina E, et al. Recurrent stroke and massive right-to-left shunt: results from the prospective Spanish multicenter (CODICIA) study. Stroke 2008; 39:3131. 55. Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002; 105:2625. 56. Di Tullio MR, Sacco RL, Sciacca RR, et al. Patent foramen ovale and the risk of ischemic stroke in a multiethnic population. J Am Coll Cardiol 2007; 49:797. 57. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between patent foramen ovale and cerebrovascular ischemic events. Mayo Clin Proc 2006; https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 17/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate 81:602. 58. Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001; 345:1740. 59. Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. 60. Thaler DE, Ruthazer R, Weimar C, et al. Recurrent stroke predictors differ in medically treated patients with pathogenic vs. other PFOs. Neurology 2014; 83:221. 61. Katsanos AH, Spence JD, Bogiatzi C, et al. Recurrent stroke and patent foramen ovale: a systematic review and meta-analysis. Stroke 2014; 45:3352. 62. Weimar C, Holle DN, Benemann J, et al. Current management and risk of recurrent stroke in cerebrovascular patients with right-to-left cardiac shunt. Cerebrovasc Dis 2009; 28:349. 63. Meissner I, Khandheria BK, Heit JA, et al. Patent foramen ovale: innocent or guilty? Evidence from a prospective population-based study. J Am Coll Cardiol 2006; 47:440. 64. Adams HP Jr. Cardiac disease and stroke: will history repeat itself? Mayo Clin Proc 2006; 81:597. 65. Chiasakul T, De Jesus E, Tong J, et al. Inherited Thrombophilia and the Risk of Arterial Ischemic Stroke: A Systematic Review and Meta-Analysis. J Am Heart Assoc 2019; 8:e012877. Topic 1092 Version 30.0 https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 18/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate GRAPHICS Risk of Paradoxical Embolism (RoPE) score RoPE score Characteristic Points No history of hypertension 1 No history of diabetes 1 No history of stroke or TIA 1 Nonsmoker 1 Cortical infarct on imaging 1 Age, years 18 to 29 5 30 to 39 4 40 to 49 3 50 to 59 2 60 to 69 1 70 0 Total score (sum of individual points) Maximum score (a patient <30 years with no hypertension, no 10 diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct) Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct) 0 TIA: transient ischemic attack. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97895 Version 5.0 https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 19/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism Probable Highly probable or deep venous thrombosis preceding an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal aneurysm or (2) a large-shunt PFO Possible Probable Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 20/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate PFO prevalence, attributable fraction, and estimated two-year risk of stroke/TIA CS patients with PFO (n = Cryptogenic stroke (n = 3023) 1324) Estimated two-year stroke/TIA Prevalence of PFO- RoPE patients with a PFO, attributable fraction, Number of CS patients with score Number of patients recurrence rate (Kaplan- percent (95% CI)* percent (95% CI)* PFO* Meier), percent (95% CI) 0 to 3 613 23 (19 to 26) 0 (0 to 4) 108 20 (12 to 28) 4 511 35 (31 to 39) 38 (25 to 48) 148 12 (6 to 18) 5 516 34 (30 to 38) 34 (21 to 45) 186 7 (3 to 11) 6 482 47 (42 to 51) 62 (54 to 68) 236 8 (4 to 12) 7 434 54 (49 to 59) 72 (66 to 76) 263 6 (2 to 10) 8 287 67 (62 to 73) 84 (79 to 87) 233 6 (2 to 10) 9 to 10 180 73 (66 to 79) 88 (83 to 91) 150 2 (0 to 4) CI: confidence interval; CS: cryptogenic stroke; PFO: patent foramen ovale; RoPE: Risk of Paradoxical Embolism; TIA: transient ischemic attack. NOTE: 95% CI for PFO prevalence and attributable fraction based on normal approximation to the binomial distribution. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97896 Version 5.0 https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 21/22 7/5/23, 12:34 PM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate Contributor Disclosures Steven R Mess , MD Equity Ownership/Stock Options: Neuralert Technologies [Stroke monitoring]. Grant/Research/Clinical Trial Support: Biogen [Hemispheric ischemic stroke]; Mallinkrodt, Inc [Nitric oxide and cerebral perfusion]; Novartis [Intracerebral hemorrhage]; WL Gore & Associates [PFO closure for secondary stroke prevention, neurologic outcomes from proximal aortic repair]. Consultant/Advisory Boards: Boston Scientific [steering committee for PROTECTED-TAVR trial of embolic protection during TAVR]; EmStop [embolic protection during TAVR]; WL Gore [DSMB for post marketing study of PFO closure for secondary stroke prevention]. Other Financial Interest: Novo Nordisk [ONWARDS trial event adjudication committee]; Terumo [Patient selection committee, Relay Branch trial]. All of the relevant financial relationships listed have been mitigated. Naser M Ammash, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Heidi M Connolly, MD, FACC, FASE No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 22/22
7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cerebral and cervical artery dissection: Treatment and prognosis : David S Liebeskind, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 22, 2022. INTRODUCTION Arterial dissections are a common cause of stroke in the young but may occur at any age. Dissection occurs when structural integrity of the arterial wall is compromised, allowing blood to collect between layers as an intramural hematoma. Dissections that occur without overt trauma are often labeled as "spontaneous" even though there is often a triggering event or underlying predisposition contributing to the pathogenesis. The optimal treatment of dissection remains a challenge due to limitations in rapidly establishing a definitive diagnosis, the overall low incidence, low recurrence rate, and marked variation in patient characteristics [1]. This topic will review the treatment and prognosis of cerebral and cervical artery dissection. Other aspects of this disorder are reviewed separately. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis".) ACUTE ISCHEMIC STROKE OR TIA DUE TO DISSECTION General management For patients with cervicocephalic dissection who present with transient ischemic attack (TIA) or acute ischemic stroke, standard approaches to management should be rigorously followed including blood pressure regulation, fluid administration, control of hyperglycemia and other metabolic derangements, and airway management. These issues are discussed in detail separately. (See "Initial assessment and management of acute stroke" https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 1/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy (see 'Reperfusion therapy for eligible patients' below). Reperfusion therapy for eligible patients The immediate goal of reperfusion therapy for acute ischemic stroke is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. The long-term goal is to improve outcome by reducing stroke-related disability and mortality. Options for reperfusion therapy that are proven effective include intravenous thrombolysis with alteplase or tenecteplase, and mechanical thrombectomy. Since the ischemic stroke mechanism is often unknown or unconfirmed at the time of decision-making for intravenous thrombolysis, and since cervical or cerebral artery dissection is not a contraindication, patients with suspected cervical or intracranial dissection should receive intravenous thrombolysis if otherwise eligible. Intravenous thrombolysis Intravenous thrombolysis with alteplase (tPA) or tenecteplase is indicated for eligible patients ( table 1) with acute ischemic stroke, including those with isolated extracranial or intracranial cervical artery dissection. Extension of aortic dissection, however, is a known complication of thrombolysis. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) The major randomized trials of intravenous thrombolysis for acute ischemic stroke did not exclude patients with cervicocephalic arterial dissection. While thrombolysis in the setting of dissection may theoretically cause enlargement of the intramural hematoma, accumulating evidence suggests that the effectiveness and safety of thrombolysis for patients with ischemic stroke related to cervical artery dissection are similar to its effectiveness and safety for patients with ischemic stroke from other causes [2-7]. Perhaps the strongest evidence, although indirect, comes from a 2011 meta-analysis of individual patient data from 14 retrospective series and 22 case reports involving 180 patients with cervical artery dissection who were treated with thrombolysis and followed for a median of three months [4]. When these patients were compared with matched historic controls from the observational SITS-ISTR registry of patients treated with intravenous alteplase for acute ischemic stroke, there were no major differences between groups for rates of symptomatic intracranial hemorrhage, mortality, excellent outcome, or favorable outcome. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 2/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate There is controversy regarding the use of thrombolysis for ischemic symptoms in patients with isolated intracranial dissection alone or intracranial extension of extracranial dissection because of a presumed increased risk of subarachnoid or symptomatic intracranial hemorrhage. Limited observational data suggest this risk is minimal, but efficacy and safety are still uncertain [8]. Mechanical thrombectomy For select patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion in the anterior circulation, early treatment with mechanical thrombectomy is indicated when performed at stroke centers with appropriate expertise, whether or not the patient received treatment with intravenous thrombolysis. This includes patients with extracranial carotid dissection who have a tandem proximal intracranial artery occlusion amenable to mechanical thrombectomy [9-13]. The efficacy of mechanical thrombectomy for vertebral and basilar artery occlusions is unproven. (See "Mechanical thrombectomy for acute ischemic stroke".) Emergency stenting In addition to mechanical thrombectomy, angioplasty and stenting of arterial dissection may be treatment options for acute stroke at expert centers [14-17]. Choosing between antiplatelet and anticoagulation therapy Antithrombotic therapy is often used for the prevention of new or recurrent ischemic symptoms caused by arterial dissection, but the approach may differ for extracranial versus intracranial dissection. Extracranial dissection For patients with extracranial carotid or vertebral artery dissection, antithrombotic treatment using either antiplatelet or anticoagulation therapy is generally recommended [18-24]. However, there is no clear consensus about which of these is optimal. Some experts, including the author, prefer anticoagulation rather than antiplatelet therapy [25], while other experts advise antiplatelet therapy rather than anticoagulation. The choice between antiplatelet and anticoagulant therapy should be guided by the clinical experience of the treating physician and by shared decision making that incorporates patient values and preferences, comorbid conditions, and tolerance of these agents. The limited available evidence suggests, but does not establish, that there is no difference in efficacy between anticoagulation and antiplatelet treatment for preventing ischemic stroke in patients with extracranial dissection. In an open-label, assessor-blind pilot trial (CADISS), 250 subjects with extracranial carotid and vertebral dissection were randomly assigned to antiplatelet or anticoagulant treatment for three months [26]. At the end of this period, there was no significant difference between the two treatment groups; ipsilateral ischemic stroke occurred in 3 of 126 (2 percent) in the antiplatelet group and 1 of 124 (1 percent) in the anticoagulant group (odds https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 3/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate ratio 0.34, 95% CI 0.01-4.23). There were no deaths in either group. There was one major bleeding event, a subarachnoid hemorrhage, in a patient assigned to the anticoagulation group who had a vertebral artery dissection with intracranial extension. At 12 months of follow-up, the rate of recurrent stroke remained low (approximately 2.5 percent) in both treatment groups with no difference between groups for any outcome, including no difference in the angiographic recanalization rate among patients with confirmed dissection [27]. Because of the low stroke rate and rarity of outcome events, the CADISS trial was unable to establish which treatment is superior or safer when used to treat cervical artery dissection [1]. The investigators estimated that a definitive trial would require approximately 10,000 participants, making such a trial unfeasible given the slow enrollment rate of the CADISS trial. However, it is highly likely that anticoagulation is associated with a higher risk of hemorrhagic events, since anticoagulation is a known risk factor for bleeding. (See "Risks and prevention of bleeding with oral anticoagulants".) The subsequent TREAT-CAD trial was an open-label, assessor-blind trial that enrolled 194 adult patients who presented with symptomatic extracranial dissection within two weeks of enrollment and were randomly assigned to aspirin monotherapy (300 mg daily) or to anticoagulation with a vitamin K antagonist (target INR 2.0 to 3.0) for 90 days [28]. The trial was designed to test the noninferiority of aspirin compared with vitamin K antagonist anticoagulants. The trialists chose a composite primary endpoint of clinical events (stroke, major hemorrhage, or death) and magnetic resonance imaging findings (new silent ischemic or hemorrhagic brain lesions) in order to achieve sufficient power, and performed a per-protocol analysis of 173 patients who received the allocated treatment and completed the assessment period. The composite endpoint occurred more often in the aspirin group compared with the vitamin K antagonist group (23 versus 15 percent, absolute difference 8 percent, 95% CI -4 to 21 percent); while the difference was not statistically significant, aspirin failed to meet noninferiority criteria because the upper limit of the 95% CI (21 percent) exceeded the predefined noninferiority margin of 12 percent. Ischemic stroke was also more frequent in the aspirin group (8 versus 0 percent), and all ischemic stroke occurred within seven days of trial enrollment. There were no deaths in either group. There was one major extracranial hemorrhage (a gastrointestinal bleed) in a patient from the vitamin K antagonist group and none in the aspirin group. The risk of ischemic stroke in the TREAT-CAD aspirin group (8 percent) was greater than that in the CADISS antiplatelet group (2 percent); one possible explanation for the difference is that TREAT-CAD used aspirin monotherapy, whereas CADISS permitted the use of other antiplatelet agents and dual antiplatelet therapy [29]. However, this is speculative, https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 4/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate as indirect cross-trial comparisons may be confounded by various issues and lead to erroneous conclusions. A 2012 meta-analysis of nonrandomized studies with over 1600 patients with cervical artery dissection reported no significant difference in recurrent stroke risk or mortality comparing anticoagulation with antiplatelet agents [30]. Similarly, a 2015 meta-analysis of nonrandomized studies with over 1300 patients who had acute carotid artery dissection found no differences in outcome or complication rates comparing anticoagulation with antiplatelet therapy [31]. Intracranial dissection For patients who have ischemic neurologic symptoms caused by intracranial arterial dissection, we suggest antiplatelet therapy rather than anticoagulation [24]. Anticoagulation is generally avoided in the setting of intracranial dissection due to the risk of subarachnoid hemorrhage, although limited evidence suggests that anticoagulation can be used safely for some patients who have intracranial dissection without subarachnoid hemorrhage [32]. Starting antiplatelet therapy For patients selected for antiplatelet therapy (rather than anticoagulation), initiation should be delayed for 24 hours after infusion of intravenous thrombolytic therapy. Otherwise, antiplatelet agents should be started as soon as possible after the diagnosis of TIA or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Treatment on presentation'.) 2 For patients with a low-risk TIA, defined by an ABCD score <4 ( table 2), or moderate to major ischemic stroke, defined by a National Institutes of Health Stroke Scale (NIHSS) score >5 ( table 3), we start treatment with aspirin (162 to 325 mg daily) alone. 2 For patients with a high-risk TIA, defined by an ABCD score 4 ( table 2), or minor ischemic stroke, defined by a NIHSS score 5 ( table 3), we begin with dual antiplatelet therapy (DAPT) for 21 days using aspirin (160 to 325 mg loading dose, followed by 50 to 100 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily) rather than aspirin alone. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.) Most reports of antiplatelet therapy for acute cervical artery dissection have employed daily aspirin at various doses; there are few data regarding other antiplatelet agents such as clopidogrel, dipyridamole, or combinations of these agents. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 5/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Starting anticoagulation therapy For patients selected for anticoagulation rather than antiplatelet therapy, the initiation of therapy is affected by a number of factors. For medically stable patients with a small- or moderate-sized infarct, anticoagulation using heparin or low molecular weight heparin (as a bridge to warfarin) can be started as soon as 24 hours after symptom onset, or at least 24 hours after infusion of thrombolytic therapy, with minimal risk of transformation to hemorrhagic stroke; anticoagulation with a direct oral anticoagulant (DOAC) can be started as soon as 48 hours after stroke onset, as DOACs have a more rapid anticoagulant effect. However, the role of DOACs for treating dissection is uncertain and data are limited [21]. For patients with large infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension, withholding oral anticoagulation for one to two weeks is generally recommended. In such cases, we start aspirin if there are no significant bleeding complications; anticoagulation can be started (and aspirin stopped) after one to two weeks if the patient is stable. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Timing of long-term anticoagulation'.) Anticoagulation can be started immediately for patients with a TIA due to dissection. Acute anticoagulation may be achieved with either subcutaneous low molecular weight heparin such as enoxaparin (1 mg/kg twice daily) or dalteparin (100 units/kg twice daily) or with intravenous unfractionated heparin (dose-adjusted to achieve a goal activated partial thromboplastin time of 1.5 to 2 times control). Transition to warfarin (dose adjusted for a goal international normalized ratio [INR] of 2.5 with an acceptable range of 2 to 3) can be pursued in the subacute period for clinically stable patients. Vessel monitoring and repeat imaging After three to six months from symptom onset or diagnosis of dissection, repeat neurovascular imaging is suggested to assess the status of artery or arteries affected by dissection and guide the need for ongoing treatment, particularly if the patient is being treated with anticoagulation. We use transcranial Doppler, carotid duplex, computed tomography angiography (CTA), and/or magnetic resonance angiography (MRA) to help us decide the status of the arterial system prior to discontinuing anticoagulation therapy. Further treatment is tailored to imaging findings. (See 'Duration of antithrombotic therapy' below.) In most cases, arteries with stenosis or luminal irregularities caused by dissection undergo recanalization and healing in the first months after the initial event. In a report of 61 patients with acute vertebral artery dissection who presented with symptoms of vertebrobasilar territory ischemia, complete recanalization of the vertebral artery was observed at six months in 62 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 6/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate percent [33]. In another study that followed 76 patients with cervical artery dissection involving 105 vessels with a mean follow-up of 58 months, complete recanalization was noted in 51 percent of vessels, nearly all occurring within the first nine months, and hemodynamically significant recanalization in 20 percent [34]. Data from the prospective CADISS study suggest that dissecting aneurysms are inconstant and can either resolve or develop for the first time in the months following the clinical diagnosis of extracranial cervical artery dissection [35]. Residual headache may indicate persistent vascular abnormalities [36]. Duration of antithrombotic therapy For patients treated with anticoagulation in the acute phase, it is reasonable to stop warfarin and start long-term antiplatelet therapy after six months of anticoagulation, as long as symptoms are not recurrent and the arterial lesion is thrombosed or healed on repeat imaging at three to six months. For patients with persistent vascular luminal stenosis, irregularity, or dissecting aneurysm, it is reasonable to continue anticoagulation. For patients treated with antiplatelet therapy in the acute phase, long-term antiplatelet therapy is recommended using aspirin, clopidogrel, aspirin-extended-release dipyridamole, or cilostazol for secondary prevention of stroke. However, there are no concrete data regarding optimal duration of antithrombotic therapy. The time course of healing of the vessel wall or resolution of vascular abnormalities may be used to guide duration of initial treatment. Most arterial abnormalities stabilize in appearance or resolve by three months, and vessels that fail to reconstitute a normal lumen by six months are highly unlikely to recover at later time points [37]. Recurrent ischemia Recurrence of TIA or ischemic stroke may be due to dissection or another stroke mechanism (eg, large artery atherosclerosis, cardiac embolism, small vessel disease, or other determined etiology) and should be thoroughly evaluated for all causes with a history and examination, brain and vessel imaging, and cardiac and laboratory testing. (See "Initial assessment and management of acute stroke" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke" and "Neuroimaging of acute stroke".) Due to dissection In various reports, the rate of recurrent ischemic symptoms (stroke and transient ischemic attack) after dissection ranges from 0 to 13 percent [38,39], but it is likely that the actual rate of recurrent ischemic stroke caused by dissection is at the lower end of this range. The prospective CADISS trial found that the rate of recurrent ischemic stroke at three months was approximately 2 percent, and all recurrences were within 10 days of randomization, suggesting that the risk beyond the first two weeks is extremely low https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 7/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate [26]. Prospective data from the CADISS study also suggest that extracranial cervical dissecting aneurysms have a benign prognosis, with a low rate (1 of 48, or approximately 2 percent) of ischemic stroke during 12 months of follow-up, similar to the rate observed in dissections without aneurysm formation [35]. Another study evaluated 432 surviving patients with carotid or vertebral dissection who were followed for a mean time of 31 months [40]. Recurrent ischemic stroke due to initial or recurrent dissection was observed in four patients (0.9 percent), giving an annual incidence of 0.3 percent. Transient ischemic attack was observed in eight patients (1.8 percent), for an annual incidence of 0.6 percent. Endovascular and surgical repair for dissection Endovascular techniques or surgical repair have been used to treat dissection, mainly for patients who have recurrent ischemia despite antithrombotic therapy [23]. Endovascular techniques for the treatment of dissection and dissecting aneurysm include angioplasty, stent placement, embolization with various materials, and combinations of such approaches [23,41]. Angioplasty and stenting may occlude the false lumen and restore true arterial lumen patency. However, data regarding endovascular treatment of dissection is limited to case reports and case series [41-48]. There are no randomized trial data comparing endovascular techniques with medical therapies, and the long-term safety and durability of these methods are unknown. In isolated cases, accessible lesions may be treated by surgical vessel reconstruction or bypass around a dissecting aneurysm [49,50]. Other surgical revascularization procedures include extracranial-intracranial bypass, endarterectomy, thrombectomy, and proximal vessel ligation. SUBARACHNOID HEMORRHAGE DUE TO INTRACRANIAL DISSECTION Subarachnoid hemorrhage is an uncommon complication of intracranial dissection. (See "Nonaneurysmal subarachnoid hemorrhage", section on 'Intracranial arterial dissection'.) It is managed according to the same principles as subarachnoid hemorrhage caused by rupture of a saccular aneurysm (see "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis"), with the exception that the surgical or endovascular treatment of dissecting aneurysm itself may differ from that of a saccular aneurysm because of morphologic differences between the two types of aneurysms. The risk of rebleeding from an intracranial dissecting https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 8/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate aneurysm is as high as 40 percent in the first week or so after the event [51-54]. Thus, early repair is typically recommended [51]. The morphology of most dissecting aneurysms limits standard surgical clipping. Management is individualized according to location and other anatomic features, and can include proximal occlusion of the artery, trapping or wrapping of the pseudoaneurysm, bypass, embolization, or stenting [52,54]. These are complicated procedures that can incur additional morbidity. NONISCHEMIC LOCAL SYMPTOMS For patients with nonischemic symptoms caused by extracranial or intracranial carotid or vertebral artery dissection, we suggest antiplatelet therapy for prevention of ischemic stroke. Headache and neck pain associated with dissection can usually be managed with simple analgesics such as acetaminophen. Anecdotally, gabapentin may be helpful. Nonsteroidal antiinflammatory drugs (NSAIDs; eg, naproxen sodium, ibuprofen) are generally avoided in patients receiving anticoagulation because of the increased risk of bleeding. There is no specific treatment for other local symptoms of dissection such as Horner syndrome, lower cranial nerve palsy, audible bruit, or tinnitus, but these may improve with time and vessel healing. MEASURES TO REDUCE RISK OF DISSECTION There are no proven methods that reduce the risk of recurrent cervicocephalic arterial dissection. Nevertheless, some experts suggest that patients with dissection should avoid contact sports, chiropractic neck manipulation, and any activity that involves abrupt rotation and flexion-extension of the neck [55,56]. In addition, estrogen-containing compounds should be discontinued, as estrogen may induce proliferation of intimal and fibromuscular arterial tissue. All vascular risk factors including hypertension should be addressed. (See "Overview of secondary prevention of ischemic stroke".) PROGNOSIS Neurologic outcome The prognosis of cerebral and cervical artery dissection is related primarily to the severity of associated ischemic stroke or subarachnoid hemorrhage. Morbidity and mortality of acute cervicocephalic arterial dissection varies according to the specific arteries involved and location of the lesion. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 9/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate In the CADISP study of 982 patients with extracranial cervical artery dissection, an unfavorable outcome at three months among patients with ischemic stroke, defined as a modified Rankin Scale ( table 4) score >2, was more likely with stroke due to internal carotid artery dissection compared with stroke due to vertebral artery dissection (25 versus 8 percent) [57]. This result was largely driven by stroke severity at onset, which was greater for patients with internal carotid dissection compared with those who had vertebral dissection by mean National Institutes of Health Stroke Scale (NIHSS) score on admission (8 versus 3). Only limited systematic data are available regarding long-term outcomes of dissection. Complete or excellent recovery occurs in 70 to 85 percent of patients with extracranial dissection, with major disabling deficits in 10 to 25 percent, and death in 5 to 10 percent of cases [38,58]. In observational studies, factors associated with poor functional outcome after cervical artery dissection include a high NIHSS score at onset, arterial occlusion, and older age [58-61]. Quality of life may be impaired in almost half of long-term survivors after dissection [62]. Recurrence of dissection The recurrence rate of cervical and intracranial artery dissection, with or without symptoms, is uncertain, and available data are inconsistent. In the CADISP study, which retrospectively and prospectively recruited 982 patients with cervical artery dissection, the recurrence rate for extracranial cervical dissection at three months was 2 percent [57]. Even higher rates were reported by a single-center study of 232 patients with cervical artery dissection who were followed clinically and with serial imaging for at least one year. Over the course of the study, there were 46 new dissections affecting 39 patients (16 percent). Recurrent dissection was detected within one month of the initial event in 9 percent, and beyond one month until up to eight years after the initial event in another 7 percent [63]. Most initial dissections were linked to ischemic stroke, but the majority of recurrent dissections were either asymptomatic or associated with purely local symptoms. Recurrent dissection may affect several vessels at once, even when preceded by initial dissection isolated to one artery [63,64]. Although data are limited, rare patients with familial dissection tend to be young (mean age 36 years) and are probably at high risk for recurrent or multiple dissection [65]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 10/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Acute management of TIA or ischemic stroke For patients with cervicocephalic dissection who present with transient ischemic attack (TIA) or acute ischemic stroke, standard approaches to stroke management should be rigorously followed. All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy. (See 'General management' above and 'Reperfusion therapy for eligible patients' above and "Approach to reperfusion therapy for acute ischemic stroke".) Choice of antithrombotic therapy for secondary ischemic stroke prevention Beyond the hyperacute period of acute stroke, antithrombotic therapy with either anticoagulation or antiplatelet drugs is accepted treatment for prevention of new or recurrent ischemic symptoms due to extracranial artery dissection, although there is controversy regarding the choice between the two. (See 'Choosing between antiplatelet and anticoagulation therapy' above.) Ischemia due to extracranial dissection For patients with acute ischemic stroke or TIA caused by extracranial carotid or vertebral artery dissection, antithrombotic treatment using either antiplatelet or anticoagulation therapy is generally recommended. Some experts, including the author, prefer anticoagulation rather than antiplatelet therapy, while other experts advise antiplatelet therapy rather than anticoagulation. The choice between antiplatelet and anticoagulant therapy should be guided by the clinical experience of the treating physician and by patient values and preferences, comorbid conditions, and tolerance of these agents. The limited available evidence suggests (but does not establish) that there no difference in efficacy between anticoagulation and antiplatelet treatment for preventing ischemic stroke in patients with extracranial dissection, although it is likely that anticoagulation is associated with a higher risk of hemorrhagic events. (See 'Extracranial dissection' above.) Nonischemic local symptoms due to extracranial dissection For patients with nonischemic local symptoms caused by extracranial cervical dissection, we suggest antiplatelet therapy for prevention of ischemic stroke (Grade 2C). (See 'Nonischemic local symptoms' above.) Ischemia due to intracranial dissection For patients who have ischemic stroke or TIA caused by intracranial dissection, we suggest antiplatelet therapy rather than https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 11/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate anticoagulation (Grade 2C). (See 'Intracranial dissection' above.) Initiating therapy The timing and suggested dosing for starting antiplatelet or anticoagulant therapy is detailed in the sections above. (See 'Starting antiplatelet therapy' above and 'Starting anticoagulation therapy' above.) Vessel monitoring and duration of antithrombotic therapy Repeat neurovascular imaging is suggested after three to six months from symptom onset or diagnosis of dissection to assess the status of the artery or arteries affected by dissection. For patients treated with anticoagulation in the acute phase, it is reasonable to stop warfarin and start long-term antiplatelet therapy after six months of anticoagulation, as long as symptoms are not recurrent and the arterial lesion is thrombosed or healed. (See 'Vessel monitoring and repeat imaging' above and 'Duration of antithrombotic therapy' above.) Recurrent ischemia requires evaluation for all causes Recurrence of TIA or ischemic stroke may be due to dissection or another stroke mechanism (eg, large artery atherosclerosis, cardiac embolism, small vessel disease, or other determined etiology) and should be thoroughly evaluated for all causes. (See 'Recurrent ischemia' above.) Subarachnoid hemorrhage due to intracranial dissection Subarachnoid hemorrhage is an uncommon complication of intracranial dissection and has a high risk of early rebleeding. Early repair is typically recommended. (See 'Subarachnoid hemorrhage due to intracranial dissection' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Jeffrey Saver, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kasner SE. CADISS: a feasibility trial that answered its question. Lancet Neurol 2015; 14:342. 2. Engelter ST, Rutgers MP, Hatz F, et al. Intravenous thrombolysis in stroke attributable to cervical artery dissection. Stroke 2009; 40:3772. 3. Georgiadis D, Baumgartner RW. Thrombolysis in cervical artery dissection. Front Neurol Neurosci 2005; 20:140. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 12/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 4. Zinkstok SM, Vergouwen MD, Engelter ST, et al. Safety and functional outcome of thrombolysis in dissection-related ischemic stroke: a meta-analysis of individual patient data. Stroke 2011; 42:2515. 5. Qureshi AI, Chaudhry SA, Hassan AE, et al. Thrombolytic treatment of patients with acute ischemic stroke related to underlying arterial dissection in the United States. Arch Neurol 2011; 68:1536. 6. Engelter ST, Dallongeville J, Kloss M, et al. Thrombolysis in cervical artery dissection data from the Cervical Artery Dissection and Ischaemic Stroke Patients (CADISP) database. Eur J Neurol 2012; 19:1199. 7. Tsivgoulis G, Zand R, Katsanos AH, et al. Safety and outcomes of intravenous thrombolysis in dissection-related ischemic stroke: an international multicenter study and comprehensive meta-analysis of reported case series. J Neurol 2015; 262:2135. 8. Bernardo F, Nannoni S, Strambo D, et al. Intravenous thrombolysis in acute ischemic stroke due to intracranial artery dissection: a single-center case series and a review of literature. J Thromb Thrombolysis 2019; 48:679. 9. Hoving JW, Marquering HA, Majoie CBLM. Endovascular treatment in patients with carotid artery dissection and intracranial occlusion: a systematic review. Neuroradiology 2017; 59:641. 10. Blassiau A, Gawlitza M, Manceau PF, et al. Mechanical Thrombectomy for Tandem Occlusions of the Internal Carotid Artery-Results of a Conservative Approach for the Extracranial Lesion. Front Neurol 2018; 9:928. 11. Gory B, Piotin M, Haussen DC, et al. Thrombectomy in Acute Stroke With Tandem Occlusions From Dissection Versus Atherosclerotic Cause. Stroke 2017; 48:3145. 12. Marnat G, Mourand I, Eker O, et al. Endovascular Management of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection Using a Distal to Proximal Approach: Insight from the RECOST Study. AJNR Am J Neuroradiol 2016; 37:1281. 13. Li S, Zi W, Chen J, et al. Feasibility of Thrombectomy in Treating Acute Ischemic Stroke Because of Cervical Artery Dissection. Stroke 2018; 49:3075. 14. Fields JD, Lutsep HL, Rymer MR, et al. Endovascular mechanical thrombectomy for the treatment of acute ischemic stroke due to arterial dissection. Interv Neuroradiol 2012; 18:74. 15. Farouk M, Sato K, Matsumoto Y, Tominaga T. Endovascular Treatment of Internal Carotid Artery Dissection Presenting with Acute Ischemic Stroke. J Stroke Cerebrovasc Dis 2020; 29:104592. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 13/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 16. Labeyrie MA, Civelli V, Reiner P, et al. Prevalence and treatment of spontaneous intracranial artery dissections in patients with acute stroke due to intracranial large vessel occlusion. J Neurointerv Surg 2018; 10:761. 17. Marnat G, Lapergue B, Sibon I, et al. Safety and Outcome of Carotid Dissection Stenting During the Treatment of Tandem Occlusions: A Pooled Analysis of TITAN and ETIS. Stroke 2020; 51:3713. 18. Wein T, Lindsay MP, C t R, et al. Canadian stroke best practice recommendations: Secondary prevention of stroke, sixth edition practice guidelines, update 2017. Int J Stroke 2018; 13:420. 19. National Institute for Health and Care Excellence (NICE). Stroke and transient ischaemic atta ck in over 16s: diagnosis and initial management. NICE guideline NG128. Available at: http s://www.nice.org.uk/guidance/ng128/chapter/Recommendations (Accessed on August 25, 2 020). 20. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 21. Serkin Z, Le S, Sila C. Treatment of Extracranial Arterial Dissection: the Roles of Antiplatelet Agents, Anticoagulants, and Stenting. Curr Treat Options Neurol 2019; 21:48. 22. Biller J, Sacco RL, Albuquerque FC, et al. Cervical arterial dissections and association with cervical manipulative therapy: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2014; 45:3155. 23. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 24. Debette S, Mazighi M, Bijlenga P, et al. ESO guideline for the management of extracranial and intracranial artery dissection. Eur Stroke J 2021; 6:XXXIX. 25. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/ SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 14/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Vasc Med 2011; 16:35. 26. CADISS trial investigators, Markus HS, Hayter E, et al. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol 2015; 14:361.
Vessel monitoring and duration of antithrombotic therapy Repeat neurovascular imaging is suggested after three to six months from symptom onset or diagnosis of dissection to assess the status of the artery or arteries affected by dissection. For patients treated with anticoagulation in the acute phase, it is reasonable to stop warfarin and start long-term antiplatelet therapy after six months of anticoagulation, as long as symptoms are not recurrent and the arterial lesion is thrombosed or healed. (See 'Vessel monitoring and repeat imaging' above and 'Duration of antithrombotic therapy' above.) Recurrent ischemia requires evaluation for all causes Recurrence of TIA or ischemic stroke may be due to dissection or another stroke mechanism (eg, large artery atherosclerosis, cardiac embolism, small vessel disease, or other determined etiology) and should be thoroughly evaluated for all causes. (See 'Recurrent ischemia' above.) Subarachnoid hemorrhage due to intracranial dissection Subarachnoid hemorrhage is an uncommon complication of intracranial dissection and has a high risk of early rebleeding. Early repair is typically recommended. (See 'Subarachnoid hemorrhage due to intracranial dissection' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Jeffrey Saver, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kasner SE. CADISS: a feasibility trial that answered its question. Lancet Neurol 2015; 14:342. 2. Engelter ST, Rutgers MP, Hatz F, et al. Intravenous thrombolysis in stroke attributable to cervical artery dissection. Stroke 2009; 40:3772. 3. Georgiadis D, Baumgartner RW. Thrombolysis in cervical artery dissection. Front Neurol Neurosci 2005; 20:140. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 12/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 4. Zinkstok SM, Vergouwen MD, Engelter ST, et al. Safety and functional outcome of thrombolysis in dissection-related ischemic stroke: a meta-analysis of individual patient data. Stroke 2011; 42:2515. 5. Qureshi AI, Chaudhry SA, Hassan AE, et al. Thrombolytic treatment of patients with acute ischemic stroke related to underlying arterial dissection in the United States. Arch Neurol 2011; 68:1536. 6. Engelter ST, Dallongeville J, Kloss M, et al. Thrombolysis in cervical artery dissection data from the Cervical Artery Dissection and Ischaemic Stroke Patients (CADISP) database. Eur J Neurol 2012; 19:1199. 7. Tsivgoulis G, Zand R, Katsanos AH, et al. Safety and outcomes of intravenous thrombolysis in dissection-related ischemic stroke: an international multicenter study and comprehensive meta-analysis of reported case series. J Neurol 2015; 262:2135. 8. Bernardo F, Nannoni S, Strambo D, et al. Intravenous thrombolysis in acute ischemic stroke due to intracranial artery dissection: a single-center case series and a review of literature. J Thromb Thrombolysis 2019; 48:679. 9. Hoving JW, Marquering HA, Majoie CBLM. Endovascular treatment in patients with carotid artery dissection and intracranial occlusion: a systematic review. Neuroradiology 2017; 59:641. 10. Blassiau A, Gawlitza M, Manceau PF, et al. Mechanical Thrombectomy for Tandem Occlusions of the Internal Carotid Artery-Results of a Conservative Approach for the Extracranial Lesion. Front Neurol 2018; 9:928. 11. Gory B, Piotin M, Haussen DC, et al. Thrombectomy in Acute Stroke With Tandem Occlusions From Dissection Versus Atherosclerotic Cause. Stroke 2017; 48:3145. 12. Marnat G, Mourand I, Eker O, et al. Endovascular Management of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection Using a Distal to Proximal Approach: Insight from the RECOST Study. AJNR Am J Neuroradiol 2016; 37:1281. 13. Li S, Zi W, Chen J, et al. Feasibility of Thrombectomy in Treating Acute Ischemic Stroke Because of Cervical Artery Dissection. Stroke 2018; 49:3075. 14. Fields JD, Lutsep HL, Rymer MR, et al. Endovascular mechanical thrombectomy for the treatment of acute ischemic stroke due to arterial dissection. Interv Neuroradiol 2012; 18:74. 15. Farouk M, Sato K, Matsumoto Y, Tominaga T. Endovascular Treatment of Internal Carotid Artery Dissection Presenting with Acute Ischemic Stroke. J Stroke Cerebrovasc Dis 2020; 29:104592. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 13/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 16. Labeyrie MA, Civelli V, Reiner P, et al. Prevalence and treatment of spontaneous intracranial artery dissections in patients with acute stroke due to intracranial large vessel occlusion. J Neurointerv Surg 2018; 10:761. 17. Marnat G, Lapergue B, Sibon I, et al. Safety and Outcome of Carotid Dissection Stenting During the Treatment of Tandem Occlusions: A Pooled Analysis of TITAN and ETIS. Stroke 2020; 51:3713. 18. Wein T, Lindsay MP, C t R, et al. Canadian stroke best practice recommendations: Secondary prevention of stroke, sixth edition practice guidelines, update 2017. Int J Stroke 2018; 13:420. 19. National Institute for Health and Care Excellence (NICE). Stroke and transient ischaemic atta ck in over 16s: diagnosis and initial management. NICE guideline NG128. Available at: http s://www.nice.org.uk/guidance/ng128/chapter/Recommendations (Accessed on August 25, 2 020). 20. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 21. Serkin Z, Le S, Sila C. Treatment of Extracranial Arterial Dissection: the Roles of Antiplatelet Agents, Anticoagulants, and Stenting. Curr Treat Options Neurol 2019; 21:48. 22. Biller J, Sacco RL, Albuquerque FC, et al. Cervical arterial dissections and association with cervical manipulative therapy: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2014; 45:3155. 23. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 24. Debette S, Mazighi M, Bijlenga P, et al. ESO guideline for the management of extracranial and intracranial artery dissection. Eur Stroke J 2021; 6:XXXIX. 25. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/ SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 14/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Vasc Med 2011; 16:35. 26. CADISS trial investigators, Markus HS, Hayter E, et al. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol 2015; 14:361. 27. Markus HS, Levi C, King A, et al. Antiplatelet Therapy vs Anticoagulation Therapy in Cervical Artery Dissection: The Cervical Artery Dissection in Stroke Study (CADISS) Randomized Clinical Trial Final Results. JAMA Neurol 2019; 76:657. 28. Engelter ST, Traenka C, Gensicke H, et al. Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial. Lancet Neurol 2021; 20:341. 29. Kasner SE. Antithrombotic therapy for cervical arterial dissection. Lancet Neurol 2021; 20:328. 30. Kennedy F, Lanfranconi S, Hicks C, et al. Antiplatelets vs anticoagulation for dissection: CADISS nonrandomized arm and meta-analysis. Neurology 2012; 79:686. 31. Chowdhury MM, Sabbagh CN, Jackson D, et al. Antithrombotic treatment for acute extracranial carotid artery dissections: a meta-analysis. Eur J Vasc Endovasc Surg 2015; 50:148. 32. Metso TM, Metso AJ, Helenius J, et al. Prognosis and safety of anticoagulation in intracranial artery dissections in adults. Stroke 2007; 38:1837. 33. Arauz A, M rquez JM, Artigas C, et al. Recanalization of vertebral artery dissection. Stroke 2010; 41:717. 34. Baracchini C, Tonello S, Meneghetti G, Ballotta E. Neurosonographic monitoring of 105 spontaneous cervical artery dissections: a prospective study. Neurology 2010; 75:1864. 35. Larsson SC, King A, Madigan J, et al. Prognosis of carotid dissecting aneurysms: Results from CADISS and a systematic review. Neurology 2017; 88:646. 36. Manabe H, Yonezawa K, Kato T, et al. Incidence of intracranial arterial dissection in non- emergency outpatients complaining of headache: preliminary investigation with MRI/MRA examinations. Acta Neurochir Suppl 2010; 107:41. 37. Nedeltchev K, Bickel S, Arnold M, et al. R2-recanalization of spontaneous carotid artery dissection. Stroke 2009; 40:499. 38. Debette S, Leys D. Cervical-artery dissections: predisposing factors, diagnosis, and outcome. Lancet Neurol 2009; 8:668. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 15/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 39. Arauz A, Hoyos L, Espinoza C, et al. Dissection of cervical arteries: Long-term follow-up study of 130 consecutive cases. Cerebrovasc Dis 2006; 22:150. 40. Touz E, Gauvrit JY, Moulin T, et al. Risk of stroke and recurrent dissection after a cervical artery dissection: a multicenter study. Neurology 2003; 61:1347. 41. Donas KP, Mayer D, Guber I, et al. Endovascular repair of extracranial carotid artery dissection: current status and level of evidence. J Vasc Interv Radiol 2008; 19:1693. 42. Ansari SA, Thompson BG, Gemmete JJ, Gandhi D. Endovascular treatment of distal cervical and intracranial dissections with the neuroform stent. Neurosurgery 2008; 62:636. 43. Ecker RD, Levy EI, Hopkins LN. Acute neuroform stenting of a symptomatic petrous dissection. J Invasive Cardiol 2007; 19:E137. 44. Cohen JE, Leker RR, Gotkine M, et al. Emergent stenting to treat patients with carotid artery dissection: clinically and radiologically directed therapeutic decision making. Stroke 2003; 34:e254. 45. Biondi A, Katz JM, Vallabh J, et al. Progressive symptomatic carotid dissection treated with multiple stents. Stroke 2005; 36:e80. 46. Kadkhodayan Y, Jeck DT, Moran CJ, et al. Angioplasty and stenting in carotid dissection with or without associated pseudoaneurysm. AJNR Am J Neuroradiol 2005; 26:2328. 47. Edgell RC, Abou-Chebl A, Yadav JS. Endovascular management of spontaneous carotid artery dissection. J Vasc Surg 2005; 42:854. 48. Kim BM, Shin YS, Kim SH, et al. Incidence and risk factors of recurrence after endovascular treatment of intracranial vertebrobasilar dissecting aneurysms. Stroke 2011; 42:2425. 49. M ller BT, Luther B, Hort W, et al. Surgical treatment of 50 carotid dissections: indications and results. J Vasc Surg 2000; 31:980. 50. Chiche L, Praquin B, Koskas F, Kieffer E. Spontaneous dissection of the extracranial vertebral artery: indications and long-term outcome of surgical treatment. Ann Vasc Surg 2005; 19:5. 51. Ono H, Nakatomi H, Tsutsumi K, et al. Symptomatic recurrence of intracranial arterial dissections: follow-up study of 143 consecutive cases and pathological investigation. Stroke 2013; 44:126. 52. Debette S, Compter A, Labeyrie MA, et al. Epidemiology, pathophysiology, diagnosis, and management of intracranial artery dissection. Lancet Neurol 2015; 14:640. 53. Mizutani T, Aruga T, Kirino T, et al. Recurrent subarachnoid hemorrhage from untreated ruptured vertebrobasilar dissecting aneurysms. Neurosurgery 1995; 36:905. 54. Bond KM, Krings T, Lanzino G, Brinjikji W. Intracranial dissections: A pictorial review of pathophysiology, imaging features, and natural history. J Neuroradiol 2021; 48:176. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 16/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 55. Paciaroni M, Bogousslavsky J. Cerebrovascular complications of neck manipulation. Eur Neurol 2009; 61:112. 56. Reuter U, H mling M, Kavuk I, et al. Vertebral artery dissections after chiropractic neck manipulation in Germany over three years. J Neurol 2006; 253:724. 57. Debette S, Grond-Ginsbach C, Bodenant M, et al. Differential features of carotid and vertebral artery dissections: the CADISP study. Neurology 2011; 77:1174. 58. Arnold M, Bousser MG, Fahrni G, et al. Vertebral artery dissection: presenting findings and predictors of outcome. Stroke 2006; 37:2499. 59. Milhaud D, de Freitas GR, van Melle G, Bogousslavsky J. Occlusion due to carotid artery dissection: a more severe disease than previously suggested. Arch Neurol 2002; 59:557. 60. Dziewas R, Konrad C, Dr ger B, et al. Cervical artery dissection clinical features, risk factors, therapy and outcome in 126 patients. J Neurol 2003; 250:1179. 61. Traenka C, Grond-Ginsbach C, Goeggel Simonetti B, et al. Artery occlusion independently predicts unfavorable outcome in cervical artery dissection. Neurology 2020; 94:e170. 62. Fischer U, Ledermann I, Nedeltchev K, et al. Quality of life in survivors after cervical artery dissection. J Neurol 2009; 256:443. 63. Kloss M, Grond-Ginsbach C, Ringleb P, et al. Recurrence of cervical artery dissection: An underestimated risk. Neurology 2018; 90:e1372. 64. Dittrich R, Nassenstein I, Bachmann R, et al. Polyarterial clustered recurrence of cervical artery dissection seems to be the rule. Neurology 2007; 69:180. 65. Martin JJ, Hausser I, Lyrer P, et al. Familial cervical artery dissections: clinical, morphologic, and genetic studies. Stroke 2006; 37:2924. Topic 16649 Version 30.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 17/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate GRAPHICS Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 18/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 19/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 20/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 2 ABCD score 2 The ABCD score can be used to estimate the risk of ischemic stroke in the first two days after TIA. The score is tallied as follows: Age: 60 years 1 point <60 years 0 points Blood pressure elevation when first assessed after TIA: Systolic 140 mmHg or diastolic 90 mmHg 1 point Systolic <140 mmHg and diastolic <90 mmHg 0 points Clinical features: Unilateral weakness 2 points Isolated speech disturbance 1 point Other 0 points Duration of TIA symptoms: 60 minutes 2 points 10 to 59 minutes 1 point <10 minutes 0 points Diabetes: Present 1 point Absent 0 points Data from: Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and re nement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:283. Graphic 62381 Version 3.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 21/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The investigator must choose a response if a full evaluation is prevented by such obstacles as an endotracheal tube, language barrier, orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement 0 = Alert; keenly responsive. 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. 2 = Not alert; requires repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). _____ (other than reflexive posturing) in response to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend 0 = Answers both questions correctly. 1 = Answers one question correctly. 2 = Answers neither question correctly. the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial _____ answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The patient is asked to open and close the eyes and then to grip and release the non-paretic hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is 0 = Performs both tasks correctly. _____ 1 = Performs one task correctly. 2 = Performs neither task correctly. made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 22/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or total gaze paresis is not present. 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. maneuver. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower 0 = No visual loss. quadrants) are tested by confrontation, using finger counting or visual threat, as 1 = Partial hemianopia. 2 = Complete hemianopia. appropriate. Patients may be encouraged, but if they look at the side of the moving fingers appropriately, this can be scored as 3 = Bilateral hemianopia (blind including cortical blindness). normal. If there is unilateral blindness or enucleation, visual fields in the remaining _____ eye are scored. Score 1 only if a clear-cut asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to 0 = Normal symmetrical movements. _____ encourage - the patient to show teeth or raise eyebrows and close eyes. Score 1 = Minor paralysis (flattened nasolabial fold, asymmetry on smiling). symmetry of grimace in response to noxious 2 = Partial paralysis (total or near-total stimuli in the poorly responsive or non- comprehending patient. If facial paralysis of lower face). trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 23/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not hit bed or other support. falls before 10 seconds. The aphasic patient is encouraged using urgency in the voice 2 = Some effort against gravity; limb and pantomime, but not noxious cannot get to or maintain (if cued) 90 (or 45) stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in degrees, drifts down to bed, but has some effort against gravity. _____ the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 0 = No drift; leg holds 30-degree position for full 5 seconds. degrees (always tested supine). Drift is 1 = Drift; leg falls by the end of the 5-second scored if the leg falls before 5 seconds. The aphasic patient is encouraged using urgency period but does not hit bed. 2 = Some effort against gravity; leg falls to in the voice and pantomime, but not noxious stimulation. Each limb is tested in bed by 5 seconds, but has some effort against gravity. turn, beginning with the non-paretic leg. Only in the case of amputation or joint _____ 3 = No effort against gravity; leg falls to fusion at the hip, the examiner should bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. 0 = Absent. _____ 1 = Present in one limb. Test with eyes open. In case of visual defect, ensure testing is done in intact visual field. 2 = Present in two limbs. The finger-nose-finger and heel-shin tests are performed on both sides, and ataxia is UN = Amputation or joint fusion, explain:________________ scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 24/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of should test as many body areas (arms [not being touched. hands], legs, trunk, face) as needed to accurately check for hemisensory loss. A 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, score of 2, "severe or total sensory loss," should only be given when a severe or total and leg. _____ loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of information about comprehension will be 0 = No aphasia; normal. _____ 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of obtained during the preceding sections of the examination. For this scale item, the comprehension, without significant limitation on ideas expressed or form of patient is asked to describe what is happening in the attached picture, to name expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. Comprehension is judged from responses conversation about provided materials difficult or impossible. For example, in conversation about provided materials, here, as well as to all of the commands in the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the 2 = Severe aphasia; all communication is hand, repeat, and produce speech. The through fragmentary expression; great need intubated patient should be asked to write. The patient in a coma (item 1a=3) will for inference, questioning, and guessing by the listener. Range of information that can automatically score 3 on this item. The examiner must choose a score for the be exchanged is limited; listener carries burden of communication. Examiner cannot patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 25/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be 0 = Normal. normal, an adequate sample of speech must be obtained by asking patient to read or 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of 2 = Severe dysarthria; patient's speech is so articulation of spontaneous speech can be _____ slurred as to be unintelligible in the absence rated. Only if the patient is intubated or has other physical barriers to producing speech, of or out of proportion to any dysphasia, or is mute/anarthric. the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the explain:________________ patient why he or she is being tested. 11. Extinction and inattention (formerly 0 = No abnormality. neglect): Sufficient information to identify 1 = Visual, tactile, auditory, spatial, or neglect may be obtained during the prior testing. If the patient has a severe visual loss personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. preventing visual double simultaneous stimulation, and the cutaneous stimuli are 2 = Profound hemi-inattention or normal, the score is normal. If the patient _____ extinction to more than one modality; does not recognize own hand or orients to has aphasia but does appear to attend to both sides, the score is normal. The only one side of space. presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 26/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 27/28 7/5/23, 12:34 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Contributor Disclosures David S Liebeskind, MD Consultant/Advisory Boards: Cerenovus [Stroke]; Genentech [Stroke]; Medtronic [Stroke]; Stryker [Stroke]. Speaker's Bureau: Astra-Zeneca [Stroke]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 28/28
7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) : Martin Dichgans, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Apr 18, 2023. INTRODUCTION Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited angiopathy caused by pathogenic variants in the NOTCH3 gene on chromosome 19 [1]. CADASIL is now recognized as an important cause of stroke in the young [2,3]. Stroke and vascular cognitive impairment remain the main causes of morbidity and mortality in patients with CADASIL. Previous descriptions of families with "hereditary multi-infarct dementia," "chronic familial vascular encephalopathy," and "familial subcortical dementia" represent early reports of the same condition. PATHOPHYSIOLOGY CADASIL is caused by cysteine-altering pathogenic variants in the NOTCH3 gene, which lead to vasculopathic changes predominantly involving small penetrating arteries, arterioles, and brain capillaries [3]. The underlying vascular lesion is a specific nonatherosclerotic, amyloid-negative angiopathy involving small arteries (100 to 400 microns in diameter) and capillaries, primarily in the brain but also in other organs [4]. Genetics The NOTCH3 gene on chromosome 19p13.2-p13.1 is one of four mammalian homologs of the Drosophila NOTCH gene [5]. NOTCH genes code for large transmembrane https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 1/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate receptors involved in cell fate decisions during embryonic development [6]. The protein product Notch3 is critical for vascular smooth muscle cell (VSMC) differentiation and vascular development [7]. In adults, expression of NOTCH3 is largely restricted to VSMCs and capillary pericytes. More than 200 different pathogenic variants in NOTCH3 have been reported in patients with CADASIL from all over the world [8,9]. All described pathogenic variants are located in the extracellular region of the Notch3 transmembrane receptor within epidermal growth factor (EGF)-like repeat domains. The spectrum includes missense variants, splice site variants, and small in-frame deletions [10,11]. Approximately 95 percent of patients have pathogenic missense variants. Some of these variants are particularly prevalent, but many families have private pathogenic variants. Pathogenic variants show a highly stereotyped nature since all involve cysteine residues. The usual number of six cysteine residues within wild type EGF-like repeat domains is changed toward an odd number. There have been reports of atypical "mutations" not involving cysteine residues [12,13]. However, there is no experimental evidence to demonstrate the pathogenicity of these sequence variants, which may represent rare polymorphisms. CADASIL pathogenic variants are strongly clustered at the N-terminus; approximately 60 percent are located in exon 4 and approximately 85 percent in exons 2 to 6, thereby enabling targeted screening strategies [10]. (See 'Genetic analysis' below.) Molecular mechanisms Like all Notch receptors, the Notch3 receptor is proteolytically processed in the trans-Golgi network as it traffics from the endoplasmic reticulum to the plasma membrane. Proteolytic cleavage results in a large extracellular fragment and a small intracellular fragment that contains the transmembrane region. In CADASIL, the extracellular domain of the Notch3 receptor accumulates within blood vessels. Accumulation takes place at the cytoplasmic membrane of VSMCs and pericytes in close vicinity to the granular osmiophilic material (GOM) that characterize the disease [14]. Notch3 recruits other proteins into the extracellular deposits, among them vitronectin and tissue inhibitor of metalloproteinase-3 (TIMP3), which may be relevant for disease pathogenesis [15]. Evidence from transgenic mice suggests that Notch3 accumulation in cerebral pericytes leads to a significant reduction in pericyte number, a progressive loss of astrocytic end-foot process contact with capillaries, disruption of the blood-brain barrier, and functional impairment of microvessels [16]. https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 2/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate Apart from its role in vessel development, the Notch3 receptor seems to be involved in vascular remodeling following injury [17,18]. An interesting observation potentially relating to the frequent occurrence of migraine with aura in CADASIL is that transgenic mice expressing a CADASIL-typical NOTCH3 pathogenic variant show an enhanced susceptibility to experimentally induced cortical spreading depression [19]. Vascular complications in the brain Although CADASIL is a generalized angiopathy, the vascular complications are largely limited to the brain. This discrepancy might, in part, be related to the predominant involvement of leptomeningeal and long penetrating arteries of the brain [20]. Morphometric studies have revealed a significant reduction of the internal diameter of small penetrating arteries and an increased thickness of the arteriolar wall in both the gray and white matter of the brain. Another potential factor contributing to the preferential involvement of the brain is the specific anatomy of the blood-brain barrier [4,21]. Normally, brain endothelial cells are connected via tight junctions that typically prevent the bidirectional exchange of hydrophilic substances between the blood and the brain. Also, brain microvessels are covered by astrocytic end-feet, which contribute to integrity of the blood-brain barrier and relay energy demand from neurons to the vasculature. As mentioned above, experimental studies in CADASIL transgenic mice have shown profound alterations of cerebral microvessels, with detachment of astrocytic end-feet from microvessels, leakage of plasma proteins, and reduced microvascular reactivity [16]. Pathology Most autopsy studies have been carried out in patients with advanced disease. Macroscopic examination of the brain reveals rarefaction of the subcortical white matter with periventricular preference [4]. Another consistent finding is lacunar infarcts predominantly within the basal ganglia, thalamus, and brainstem, particularly in the pons. (See "Lacunar infarcts".) Histologically, various degrees of demyelination, axonal loss, enlargement of the extracellular space, and mild astrocytic gliosis are found; these findings are compatible with chronic ischemia [4]. In a neuropathologic study of four patients who died from complications of CADASIL, neuronal apoptosis was seen in layers 3 and 5 of the cerebral cortex [22]. Genotype-phenotype correlations There are several reports on associations between specific NOTCH3 pathogenic variants and particular disease manifestations or accelerated disease progression [2,23-26]. While the association with specific disease manifestations is still disputed, there is reasonably strong evidence that pathogenic variants in the first six epidermal growth factor-like repeat domains (EGFRs 1 to 6) of the Notch3 protein are associated with an earlier age of stroke onset, a more severe clinical phenotype, increased white matter https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 3/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate hyperintensity volume, and lower survival compared with pathogenic variants in EGFRs 7 to 34 [27-30]. Within the latter group, limited data based on small patient numbers suggest that variants in EGFRs 7 to 9 and EGFRs 18 to 34 are also associated with more severe disease [30]; further studies are needed to confirm these correlations. EPIDEMIOLOGY Although most studies come from Europe, CADASIL has been reported worldwide [31]. Based upon data from single referral centers and regional databases, the estimated prevalence of individuals harboring pathogenic variants in NOTCH3 from earlier studies was 0.8 to 5 per 100,000 individuals [32-35]. Subsequent reports suggest that the prevalence of NOTCH3 cysteine- altering pathogenic variants is substantially higher, and may be as high as 1 in 300 worldwide [27,36-38]. In one report, cysteine-altering NOTCH3 variants were associated with an increased risk of vascular dementia and stroke, and increased white matter hyperintensity volume, particularly involving the anterior temporal lobes [38]. Hence, the phenotypic spectrum of NOTCH3 cysteine-altering pathogenic variants is very broad and includes classic CADASIL, mild small vessel disease, and nonpenetrance [31,37-39]. Pathogenic variants in single genes, including those in NOTCH3, are thought to be rare cause of lacunar stroke [40]. CLINICAL FEATURES Patients with CADASIL usually present with one or more of the following manifestations [3,41- 43]: Migraine with aura Acute reversible encephalopathy Ischemic episodes Cognitive impairment and dementia Psychiatric disturbances Onset The onset of symptomatic disease in patients with CADASIL typically occurs in adulthood [3,44]. However, there are case reports of children and adolescents with genetically confirmed CADASIL [45-49]. One of the earliest onset cases of symptomatic CADASIL involved a three-year-old boy who presented with global developmental delay [46]. Brain MRI showed multiple foci of increased T2 signal on brain MRI and genetic sequencing identified a NOTCH3 pathogenic variant. https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 4/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate Migraine with aura Migraine with aura occurs in nearly one-half of CADASIL cases and is often the initial manifestation of the disease [42,50,51]. In a minority, migraine with aura is the sole symptom of CADASIL [51]. The average age at onset of migraine with aura is approximately 30 years [52,53]. Aura symptoms tend to involve the visual and sensory system. However, one- half or more of patients have at least one atypical aura with manifestations such as motor symptoms (hemiplegic migraine), confusion, altered consciousness, hallucinations, or basilar symptoms (migraine with brainstem aura), acute onset aura, or long-lasting aura [51]. These may be difficult to differentiate from ischemic episodes [41,52]. Isolated migraine aura (ie, never accompanied by headache) affects approximately 20 percent of patients with CADASIL [51]. The frequency of migraine attacks seems to decrease after the first stroke [41]. At younger ages ( 50 years), migraine with aura in patients with CADASIL may be more prevalent in women than in men [54]. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine aura' and "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine subtypes'.) Acute reversible encephalopathy Acute reversible encephalopathy (also known as CADASIL encephalopathy or "CADASIL coma") occurs in up to 10 percent of cases [43,55-57]. Manifestations may include altered consciousness, visual hallucinations, seizures, and focal neurologic deficits including unilateral weakness or sensory deficits, dysarthria, aphasia, neglect and inattention, apraxia, or visual agnosia. In one report of 33 patients with 50 episodes of encephalopathy, the encephalopathic event was the first major symptom that led to the diagnosis of CADASIL in 94 percent; complete recovery occurred within one month in 74 percent and within three months in 96 percent of episodes [43]. A majority of affected patients had a history of migraine or migraine aura directly preceding the encephalopathy. The underlying mechanisms are not fully understood. Some experts consider CADASIL encephalopathy to be a severe form of migraine, as the episodes often begin with a migraine headache accompanied by nausea, vomiting, seizures, fever, and/or hallucinations [58,59]. Ischemic stroke and transient ischemic attacks Ischemic stroke and transient ischemic attacks are frequent manifestations of CADASIL, occurring in approximately 85 percent of symptomatic individuals [41,42]. In a large retrospective study, the age at onset for ischemic stroke ranged from 19 to 67 years, and the median age for ischemic stroke onset in men and women was 51 and 53 years, respectively [2]. At younger ages ( 50 years), ischemic stroke in patients with CADASIL may be more prevalent in men than in women [54]. In one prospective report of over 200 subjects with CADASIL who were followed for a mean of 3.4 years, incident https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 5/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate lacunes developed in approximately 25 percent and were predicted by the number of prevalent lacunes and systolic blood pressure at baseline [60]. In many cases, ischemic episodes present as a classic lacunar syndrome (pure motor stroke, ataxic-hemiparesis, dysarthria-clumsy hand syndrome, pure sensory stroke, sensorimotor stroke), but other lacunar syndromes (brainstem or hemispheric) are also observed. Strokes are often recurrent, leading to motor and cognitive decline, and sometimes to severe disability with gait disturbance, urinary incontinence, and pseudobulbar palsy. (See "Lacunar infarcts".) Cortical infarcts involving the territory of a large artery are atypical but occasionally have been reported [61], and a study that evaluated 13 patients from Korea with CADASIL found angiographic large artery stenosis in five (38 percent) [62]. However, these observations may be coincidental. The presence of conventional stroke risk factors may exacerbate disease severity in CADASIL. In a study of 200 patients with CADASIL, the risk of stroke was significantly higher in those with hypertension (odds ratio [OR] 2.57, 95% CI 1.29-5.14) [57]. In addition, the risk of stroke increased with pack-years of smoking (OR 1.07, 95% CI 1.03-1.11). Cognitive impairment and dementia Cognitive deficits are the second most frequent feature of CADASIL. In a report of 176 patients with genetically confirmed CADASIL and a mean age of 51 years, vascular cognitive impairment was observed in approximately 50 percent [63]. Approximately 75 percent eventually develop dementia [2,41]. In different studies, history of stroke, lacunar lesion volume, lacune count, global brain atrophy on brain MRI (see 'Magnetic resonance imaging' below), and older age have been identified as predictors of cognitive impairment [63-65]. Another important aspect is lesion location, particularly involvement of frontal-subcortical circuits [66]. The cognitive syndrome in CADASIL is characterized by deficits in multiple domains [67]. Early impairment of executive function is followed by deterioration in other cognitive domains with aging [68,69]. In most cases, cognitive decline is slowly progressive with additional stepwise deterioration [70]. Neuropsychologic testing usually shows pronounced deficits in executive function, cognitive processing speed, and verbal fluency [71]. Neuropsychiatric symptoms Mood disorders occur in approximately 25 to 30 percent of patients with CADASIL [41,42,72]. Many patients develop adjustment disorder or moderate depression, but major depression is also seen. Other manifestations include bipolar disorder, panic disorder, hallucinatory syndrome, and delusional episodes. Rarely, CADASIL presents with a picture of schizophrenia [73]. https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 6/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate Apathy is another common problem in CADASIL [74], and appears to be more common in men than women with the disorder [54]. Apathy has been defined as a primary loss of motivation, characterized by diminished speech, motor activity, and emotional expression. This definition of apathy is similar to that of abulia, defined as a loss of the impulse, will, or motivation to think, speak, and act. Diminished motivation is the key concept in both apathy and abulia. Although apathy frequently occurs with depression, apathy can develop in the absence of depression. In a prospective cohort study of 132 patients with CADASIL, apathy was present in 54 (41 percent), similar to the frequencies of depression, disturbed sleep, and irritability (46, 45, and 43 percent, respectively) [74]. Seizures Seizures occur in 5 to 10 percent of patients with CADASIL [35,41,75,76]; seizures may accompany episodes of acute reversible encephalopathy [43]. (See 'Acute reversible encephalopathy' above.) Other manifestations Less common manifestations include the following: Spinal cord involvement or infarction has been noted in case reports [77-81]. Intracerebral hemorrhage has been rarely described in patients with CADASIL [82-84]. However, an exception is a case series of 20 consecutive symptomatic patients with CADASIL from Korea [85]. Intracerebral hemorrhage was the presenting sign in two patients (10 percent), while high susceptibility brain MRI sequences (T2-weighted images) detected seven intracerebral hemorrhages in five patients (25 percent). Hemorrhages were located in the basal ganglia, thalamus, cerebellum, and parietal lobe; their largest diameters ranged from 1.2 to 2.8 cm. Complications with pregnancy Affected women with CADASIL may develop complications during pregnancy, but data regarding pregnancy in women with CADASIL are limited and inconsistent. In a retrospective analysis, 12 of 25 mothers (48 percent) developed neurologic symptoms in 40 percent of their pregnancies [86]. Complications included transient ischemic episodes, migraine, and preeclampsia-like symptoms. In most cases, these complications were the initial disease manifestation. However, another retrospective report of 93 pregnancies involving 56 women with CADASIL reported that none had disease onset or ischemic events during pregnancy [87]. There were 16 miscarriages (17 percent), a rate that is within the range of miscarriage observed in the general population. The investigators concluded that CADASIL did not appear to be associated with an unfavorable outcome for the mother or the fetus. EVALUATION https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 7/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate When to suspect the diagnosis CADASIL is usually suspected when patients present with typical clinical signs (eg, TIA, stroke, migraine, cognitive impairment, psychiatric symptoms, seizures), particularly when there is a positive family history for stroke or dementia, or when there are typical findings on brain magnetic resonance imaging (MRI). However, the diagnosis is not excluded by the apparent lack of a family history [31]. Because the individual clinical features of CADASIL are nonspecific, patients may come to attention from stroke services, memory clinics, headache clinics, psychiatry services, or others. In many cases, suspicion for CADASIL is first raised by findings from brain MRI that is ordered for the evaluation of stroke, cognitive decline, or other indications. (See 'Clinical features' above and 'Neuroimaging' below.) History and examination In addition to a history of the presenting illness and past medical history, it is important to obtain a thorough family history focused on stroke, migraine, mood disorders, seizures, and dementia. A detailed neurologic examination includes an assessment for manifestations of CADASIL including cognitive impairment and focal neurologic deficits. Neuroimaging We obtain brain MRI for all patients with suspected CADASIL. Brain MRI is the most useful imaging method to demonstrate the radiologic features of CADASIL, including recent lacunar infarctions, chronic lacunes, and white matter hyperintensities. Head computed tomography (CT) may show lacunar infarctions and leukoaraiosis (reflecting white matter changes) but is less sensitive than MRI. Magnetic resonance imaging MRI of the brain ( image 1) shows two major types of abnormalities [88,89]: Small, circumscribed regions that are isointense to cerebrospinal fluid (CSF) on T1- and T2- weighted images. Most of these lesions are consistent with lacunes in terms of their size, shape, and location. Less well demarcated T2 hyperintensities of variable size that may show different degrees of hypointensity on T1-weighted images but are clearly distinct from CSF. The majority of these lesions are located in the subcortical white matter ( image 2), but similar lesions may be seen in other brain regions, including the brainstem and subcortical gray matter [88,89]. While the brain lesions of CADASIL are characteristically bilateral, at least one atypical case of unilateral leukoencephalopathy has been reported [90]. The onset of MRI-visible lesions and the rate of lesion progression are variable [42,91,92], but by age 35 years all carriers of NOTCH3 pathogenic variants have developed MRI lesions [42]. Small irregular T2 hyperintensities involving the periventricular and deep white matter are usually the first sign in younger individuals. https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 8/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate The following MRI signs may help to identify patients with CADASIL: Temporal lobe and external capsule hyperintensities Anterior temporal lobe (temporal pole) white matter hyperintensities seen on T2-weighted sequences ( image 3) are found in approximately 90 percent of patients with CADASIL, whereas such lesions are uncommon in sporadic small vessel disease [89,93]. External capsule and corpus callosum hyperintensities seen on T2-weighted sequences are also characteristic findings [93]. Subcortical lacunar lesions Subcortical lacunar lesions are linearly arranged groups of rounded circumscribed lesions that are just below the cortex at the gray-white matter junction with a signal intensity identical to CSF [94]. These lacunar lesions are very small and are best differentiated from surrounding white matter hyperintensity with fluid- attenuated inversion recovery (FLAIR) sequences [95]. Cerebral microbleeds Cerebral microbleeds (also known as microhemorrhages) have been reported in 31 to 69 percent of patients [23,96-98]. Microbleeds are small, 2 mm to 5 mm focal or multifocal areas of hemosiderin deposition and are the remnants of subclinical leaks of blood. They are best detected as small, rounded dark lesions on gradient echo or T2-weighted MRI images that are sensitive to iron ( image 1). Microbleeds are not specific for CADASIL since they are also found in patients with other types of small vessel disease. In a multicenter cohort study that evaluated 147 patients with CADASIL, the presence of cerebral microbleeds was independently associated with increased blood pressure, glycated hemoglobin (A1C) levels, lacunar infarct volume, and the extent of white matter hyperintensities [97]. In addition, the number of cerebral microbleeds was independently associated with poor functional outcome. In a later study, cerebral microbleeds were detected in 36 percent of 369 patients with CADASIL and were independently associated with an increased risk of incident ischemic stroke [98]. These findings suggest that cerebral microbleeds are a marker for a subgroup of patients with CADASIL who have a more severe or advanced form of the disease [97,98]. Brain atrophy Brain atrophy as measured on MRI is another important feature of CADASIL. Brain atrophy may be due in part to secondary neurodegeneration of cortical regions caused by ischemic lesions in subcortical regions that disrupt connecting fibers [99]. In a prospective longitudinal cohort study of 76 patients with CADASIL, brain atrophy was significantly correlated with measures of disability and cognitive impairment both at baseline and follow-up [65]. Age and male sex were independent risk factors for brain https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 9/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate atrophy at baseline, while age and systolic blood pressure predicted change (loss) in brain volume over time. In contrast to the loss of overall brain volume, brain lesion volume on T2-weighted MRI did not correlate with changes in clinical measures over time [65,100]. Other imaging studies Perfusion MRI, Doppler sonography, and nuclear medicine techniques may show reductions of cerebral blood flow, mean flow velocity, cerebral blood volume, and cerebral metabolism, but are less helpful in establishing the diagnosis [101-103]. Postmortem high-field MRI at 7 Tesla has revealed small intracortical infarcts in a patient with CADASIL [104]. Cortical involvement also has been reported in other patients with sporadic small vessel disease and may be clinically important. Conventional angiography is not contributory and potentially harmful, as patients with CADASIL appear to have a high risk of developing angiographic complications [105]. Lumbar puncture Lumbar puncture with cerebrospinal fluid analysis (CSF) is not required for the evaluation of CADASIL, but may be helpful when multiple sclerosis is a consideration in the differential diagnosis (see 'Differential diagnosis' below). In a report of 87 patients with CADASIL who had lumbar puncture with CSF examination, none had a pleocytosis, and oligoclonal bands were detected in only 1 percent [21]. A mildly elevated protein level was present in 29 percent; the mean protein level was 40 mg/dL (range 10.2 to 75 mg/dL). By contrast, most patients with multiple sclerosis have CSF oligoclonal bands and a mild CSF pleocytosis. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'CSF analysis and oligoclonal bands'.) DIAGNOSIS Confirming the diagnosis In order to firmly establish a diagnosis of CADASIL, one of the following is required: Documentation of a pathogenic variant in the NOTCH3 gene by genetic analysis Documentation of characteristic ultrastructural deposits within small blood vessels by skin biopsy if genetic analysis is not definitive There have been efforts to define screening scales for CADASIL [106]. However, the utility of these scales remains to be confirmed in other populations. https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 10/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate Genetic analysis Molecular genetic testing establishes the diagnosis of CADASIL by identifying a heterozygous pathogenic variant in NOTCH3 [31]. The approach may involve single- gene testing (sequence analysis of NOTCH3 and gene-targeted deletion/duplication analysis) or a multigene panel (where available) that includes NOTCH3 and other genes of interest associated with stroke risk. Apart from establishing the diagnosis, identification of the pathogenic variant is critical for genetic counseling and testing of relatives at risk. (See 'Screening asymptomatic family members' below.) Genetic testing does not detect all patients with CADASIL. In up to 4 percent of patients, sequencing of all exons encoding EGF-like domains fails to identify a pathogenic variant [10]. As a result, skin biopsy is indicated if genetic testing is negative (or unavailable) when there is a high index of clinical suspicion for the diagnosis of CADASIL. Skin biopsy The angiopathy in CADASIL is characterized by two main features, which are highly specific for this condition: Granular osmiophilic material (GOM) within the vascular basal lamina of arteries, arterioles, and precapillaries on electron microscopy [107-110]. The deposits are typically located at the surface of vascular smooth muscle cells. Deposition of the extracellular domain of the Notch3 receptor in the vascular media of arteries and arterioles [111]. These changes are present in all organs, enabling a firm diagnosis by biopsy. The sensitivity and specificity of skin biopsy with subsequent ultrastructural examination has not been formally addressed. According to the author's experience, the specificity of typical GOM deposits is 100 percent. The sensitivity is less than 100 percent and largely depends upon the quality of the sample and the number of available arterioles and arteries. We usually request investigation of three arteries or arterioles before claiming a biopsy "negative." The diagnostic value of Notch3 immunostaining is less clear [111,112]. In one series, the sensitivity was less than 90 percent with incomplete specificity [112]. In addition, the respective antibody has not been approved for diagnostic purposes. DIFFERENTIAL DIAGNOSIS The differential diagnosis of CADASIL includes the following conditions: https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 11/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate Acquired disorders: Sporadic small vessel disease with or without hypertension as the main risk factor Multiple sclerosis Primary angiitis of the central nervous system (PACNS) Inherited disorders: Fabry disease, caused by pathogenic variants in the GAL gene Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) and other forms of familial symptomatic small vessel disease due to pathogenic variants in the HTRA1 gene Some forms of leukodystrophy These disorders have clinical features that may overlap with CADASIL, including focal, multifocal, or global symptoms and signs of cerebral dysfunction, a clinical course that can be marked by variable intervals of deterioration, stabilization, or seeming improvement, and evidence of focal, multifocal, or coalescent white matter lesions on neuroimaging. Unlike CADASIL, the acquired disorders are not characterized by a family history of stroke or dementia. Other clinical features may also help to distinguish them from CADASIL: Clues that point to multiple sclerosis rather than CADASIL include the presence of optic nerve or spinal cord involvement (usually spared in CADASIL) and the pattern of lesions on magnetic resonance imaging (MRI), which are hyperintense on proton density and T2- weighted studies and hypointense if visible at all on T1-weighted images, typically occur in the periventricular region with an ovoid appearance, are arranged at right angles to the corpus callosum (Dawson fingers), and spare the temporal pole white matter (often involved in CADASIL). Another indication suggestive of multiple sclerosis is the detection of oligoclonal bands in the cerebrospinal fluid. (See "Evaluation and diagnosis of multiple sclerosis in adults" and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis".) Features suggestive of sporadic forms of small vessel ischemic and lacunar infarction (see "Lacunar infarcts") include the presence of hypertension (the main risk factor for sporadic small vessel disease) and the absence of anterior temporal lobe white matter hyperintensities on T2-weighted MRI sequences ( image 3), which are found in approximately 90 percent of patients with CADASIL and are uncommon in sporadic small vessel disease. https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 12/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate PACNS may cause ischemia and infarction in any part of the central nervous system, often manifesting as multifocal infarcts in different vascular territories (see "Primary angiitis of the central nervous system in adults"). By contrast, the ischemic lesions in CADASIL are typically restricted to the white matter. In most cases, the clinical features and mode of inheritance help to distinguish other inherited disorders in the differential diagnosis from CADASIL: Fabry disease is an X-linked glycolipid storage disorder associated with an increased risk of ischemic stroke and white matter disease, particularly in affected adult males. Other characteristic features include a peripheral neuropathy with severe paroxysmal pain the hands and feet, telangiectasias and angiokeratomas, renal insufficiency, and cardiovascular manifestations such as left ventricular hypertrophy. (See "Fabry disease: Clinical features and diagnosis" and "Fabry disease: Neurologic manifestations" and "Fabry disease: Cardiovascular disease".) CARASIL is a rare disorder suggested by autosomal recessive inheritance, early onset of white matter and external capsule lesions on neuroimaging, and other associated features including alopecia and spondylosis with disk degeneration, osteophyte formation, and episodes of acute low back pain [113]. The diagnosis is made by the detection of causative pathogenic variants in the HTRA1 gene. Heterozygous pathogenic variants in the HTRA1 gene are now recognized as an important cause of familial small vessel disease [114,115]. The clinical and MRI phenotype as well as age of onset very much resemble sporadic small vessel disease. MANAGEMENT There is no specific disease-modifying treatment for CADASIL, and only limited information is available regarding management of the major manifestations of the disorder. Ischemic manifestations Acute stroke and TIA Acute transient ischemic attack and acute stroke in patients with CADASIL are managed following the general principles of stroke medicine. There is no evidence to suggest that systemic intravenous thrombolysis improves outcome after a stroke caused by small vessel occlusion in CADASIL patients. However, if a patient with known or suspected CADASIL has an acute ischemic stroke in the territory of a thromboembolic large vessel occlusion, it is likely unrelated to CADASIL, and the benefit of https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 13/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate thrombolysis and/or mechanical thrombectomy probably outweighs the potential risk of intracerebral hemorrhage. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke" and "Initial assessment and management of acute stroke".) Secondary prevention For secondary stroke prevention, patients with CADASIL should be treated with all available risk reduction strategies, including control of hypertension, statin therapy for hyperlipidemia, glucose control, and antiplatelet therapy, although specific evidence that these measures are effective for CADASIL is lacking. Smoking cessation may be particularly important, since there is evidence that active smoking increases the risk of stroke and dementia in patients with CADASIL [116]. Lifestyle modifications that may reduce risk include limited alcohol consumption, weight control, regular aerobic physical activity, and a Mediterranean diet that is rich in fruits, vegetables, and low-fat dairy products. (See "Overview of secondary prevention of ischemic stroke", section on 'Lifestyle modification'.) Antithrombotic therapy Long-term management includes low-dose aspirin (81 mg daily) in patients who have experienced an ischemic attack and who tolerate the drug. There are no data to support the use of oral anticoagulants, which may put patients at an unnecessarily high risk of developing complications [23,82,96]. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Antihypertensive therapy Although there are no studies of blood pressure control in CADASIL, hypertension may be a risk factor for ischemic stroke, progression of brain atrophy, and the presence of cerebral microbleeds (see 'Magnetic resonance imaging' above). Thus, treatment of hypertension may have an additional benefit in patients with CADASIL. We suggest measures to control blood pressure for all patients with CADASIL who have elevated systolic blood pressure. Treatment of hypertension for secondary stroke prevention is discussed separately. (See "Antihypertensive therapy for secondary stroke prevention".) Glucose control Similarly, although there is no evidence that strict glucose control can slow CADASIL progression, elevated glycated hemoglobin (A1C) levels may be a risk factor for the presence of cerebral microbleeds (see 'Magnetic resonance imaging' above). Thus, glucose control may also have an additional benefit in patients with CADASIL, and we suggest measures to normalize glycemia and A1C levels in patients with elevated A1C levels. The target A1C value should be 7.0 percent or lower for most patients. The goal should be set somewhat higher for older patients and those with a limited life expectancy in whom the risk of hypoglycemia may outweigh the potential https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 14/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate benefit. (See "Glycemic control and vascular complications in type 1 diabetes mellitus" and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus".)
variable intervals of deterioration, stabilization, or seeming improvement, and evidence of focal, multifocal, or coalescent white matter lesions on neuroimaging. Unlike CADASIL, the acquired disorders are not characterized by a family history of stroke or dementia. Other clinical features may also help to distinguish them from CADASIL: Clues that point to multiple sclerosis rather than CADASIL include the presence of optic nerve or spinal cord involvement (usually spared in CADASIL) and the pattern of lesions on magnetic resonance imaging (MRI), which are hyperintense on proton density and T2- weighted studies and hypointense if visible at all on T1-weighted images, typically occur in the periventricular region with an ovoid appearance, are arranged at right angles to the corpus callosum (Dawson fingers), and spare the temporal pole white matter (often involved in CADASIL). Another indication suggestive of multiple sclerosis is the detection of oligoclonal bands in the cerebrospinal fluid. (See "Evaluation and diagnosis of multiple sclerosis in adults" and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis".) Features suggestive of sporadic forms of small vessel ischemic and lacunar infarction (see "Lacunar infarcts") include the presence of hypertension (the main risk factor for sporadic small vessel disease) and the absence of anterior temporal lobe white matter hyperintensities on T2-weighted MRI sequences ( image 3), which are found in approximately 90 percent of patients with CADASIL and are uncommon in sporadic small vessel disease. https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 12/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate PACNS may cause ischemia and infarction in any part of the central nervous system, often manifesting as multifocal infarcts in different vascular territories (see "Primary angiitis of the central nervous system in adults"). By contrast, the ischemic lesions in CADASIL are typically restricted to the white matter. In most cases, the clinical features and mode of inheritance help to distinguish other inherited disorders in the differential diagnosis from CADASIL: Fabry disease is an X-linked glycolipid storage disorder associated with an increased risk of ischemic stroke and white matter disease, particularly in affected adult males. Other characteristic features include a peripheral neuropathy with severe paroxysmal pain the hands and feet, telangiectasias and angiokeratomas, renal insufficiency, and cardiovascular manifestations such as left ventricular hypertrophy. (See "Fabry disease: Clinical features and diagnosis" and "Fabry disease: Neurologic manifestations" and "Fabry disease: Cardiovascular disease".) CARASIL is a rare disorder suggested by autosomal recessive inheritance, early onset of white matter and external capsule lesions on neuroimaging, and other associated features including alopecia and spondylosis with disk degeneration, osteophyte formation, and episodes of acute low back pain [113]. The diagnosis is made by the detection of causative pathogenic variants in the HTRA1 gene. Heterozygous pathogenic variants in the HTRA1 gene are now recognized as an important cause of familial small vessel disease [114,115]. The clinical and MRI phenotype as well as age of onset very much resemble sporadic small vessel disease. MANAGEMENT There is no specific disease-modifying treatment for CADASIL, and only limited information is available regarding management of the major manifestations of the disorder. Ischemic manifestations Acute stroke and TIA Acute transient ischemic attack and acute stroke in patients with CADASIL are managed following the general principles of stroke medicine. There is no evidence to suggest that systemic intravenous thrombolysis improves outcome after a stroke caused by small vessel occlusion in CADASIL patients. However, if a patient with known or suspected CADASIL has an acute ischemic stroke in the territory of a thromboembolic large vessel occlusion, it is likely unrelated to CADASIL, and the benefit of https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 13/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate thrombolysis and/or mechanical thrombectomy probably outweighs the potential risk of intracerebral hemorrhage. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke" and "Initial assessment and management of acute stroke".) Secondary prevention For secondary stroke prevention, patients with CADASIL should be treated with all available risk reduction strategies, including control of hypertension, statin therapy for hyperlipidemia, glucose control, and antiplatelet therapy, although specific evidence that these measures are effective for CADASIL is lacking. Smoking cessation may be particularly important, since there is evidence that active smoking increases the risk of stroke and dementia in patients with CADASIL [116]. Lifestyle modifications that may reduce risk include limited alcohol consumption, weight control, regular aerobic physical activity, and a Mediterranean diet that is rich in fruits, vegetables, and low-fat dairy products. (See "Overview of secondary prevention of ischemic stroke", section on 'Lifestyle modification'.) Antithrombotic therapy Long-term management includes low-dose aspirin (81 mg daily) in patients who have experienced an ischemic attack and who tolerate the drug. There are no data to support the use of oral anticoagulants, which may put patients at an unnecessarily high risk of developing complications [23,82,96]. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Antihypertensive therapy Although there are no studies of blood pressure control in CADASIL, hypertension may be a risk factor for ischemic stroke, progression of brain atrophy, and the presence of cerebral microbleeds (see 'Magnetic resonance imaging' above). Thus, treatment of hypertension may have an additional benefit in patients with CADASIL. We suggest measures to control blood pressure for all patients with CADASIL who have elevated systolic blood pressure. Treatment of hypertension for secondary stroke prevention is discussed separately. (See "Antihypertensive therapy for secondary stroke prevention".) Glucose control Similarly, although there is no evidence that strict glucose control can slow CADASIL progression, elevated glycated hemoglobin (A1C) levels may be a risk factor for the presence of cerebral microbleeds (see 'Magnetic resonance imaging' above). Thus, glucose control may also have an additional benefit in patients with CADASIL, and we suggest measures to normalize glycemia and A1C levels in patients with elevated A1C levels. The target A1C value should be 7.0 percent or lower for most patients. The goal should be set somewhat higher for older patients and those with a limited life expectancy in whom the risk of hypoglycemia may outweigh the potential https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 14/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate benefit. (See "Glycemic control and vascular complications in type 1 diabetes mellitus" and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus".) Statin therapy In patients with elevated lipids, the use of statin therapy is suggested because of the beneficial effects for patients with atherosclerotic arterial disease, and because of experimental evidence suggesting they have neuroprotective effects [3,117]. The treatment of dyslipidemia for secondary stroke prevention is reviewed elsewhere. (See "Overview of secondary prevention of ischemic stroke", section on 'Dyslipidemia'.) Symptomatic therapy The specific management of CADASIL focuses on the control of symptoms such as headache, depression, and urinary incontinence. (See "Unipolar major depression in adults: Choosing initial treatment" and "Female urinary incontinence: Treatment" and "Unipolar depression in adults: Choosing treatment for resistant depression".) Cognitive impairment and dementia We offer donepezil to patients with prominent deficits in executive dysfunction and slowed processing speed [118]. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia" and "Treatment of vascular cognitive impairment and dementia".) Pseudobulbar palsy Pseudobulbar palsy is caused by bilateral corticobulbar tract degeneration from lacunar infarcts and rarefaction of the subcortical white matter. Emotional lability (pseudobulbar affect) with pathologic crying and laughing may respond to selective serotonin reuptake inhibitors (eg, a single evening dose of 100 mg fluvoxamine) [119]. When oral hydration and feeding become insufficient, the patient should receive additional tube feeding. (See "Oropharyngeal dysphagia: Clinical features, diagnosis, and management".) Migraine Migraine attacks can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Triptans are relatively contraindicated in patients with CADASIL based upon the theoretical concern of increased stroke risk due to vasospasm. (See "Acute treatment of migraine in adults".) Since the attack frequency of migraine with aura is low in most patients with CADASIL, few require prophylactic treatment [3]. For those who do, anecdotal evidence suggests that acetazolamide (250 mg per day) may be beneficial [120,121]. Standard prophylactic regimens for migraine can also be used. These are discussed separately. (See "Preventive treatment of episodic migraine in adults".) https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 15/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate CLINICAL COURSE AND PROGNOSIS Clinical progression in CADASIL tends to occur with the sequential development of migraine with aura around age 30 years, transient ischemic attacks, ischemic strokes and mood disorders between 40 and 60 years, dementia between 50 and 60 years, and gait difficulty at approximately 60 years [3,41,42,52]. However, the overall course of CADASIL is highly variable even within affected families. Some patients remain asymptomatic until their seventies [2]. Onset of symptomatic disease in childhood has been reported. (See 'Onset' above.) Early onset does not necessarily predict rapid progression. In a review of 102 patients from 29 families, the duration from onset to death varied from 3 to 43 years, with a mean of 23 years [41]. While individual progression varies, a substantial proportion of adults with CADASIL experience clinical deterioration over a period of three years. This observation emerged from a prospective study of 290 adults (mean age approximately 51 years) with CADASIL who were recruited from two major referral centers in Europe [116]. The major clinical manifestations of the cohort at baseline were the following: Asymptomatic, 4 percent Transient ischemic attack or stroke, 66 percent Migraine with aura, 39 percent Gait disturbance, 30 percent Moderate or severe disability, 18 percent Dementia, 14 percent Mean number of lacunes, 5 At three-year follow-up, with complete information available for 265 patients, the composite outcome of incident stroke, incident dementia, moderate or severe disability, or death occurred in 124 (47 percent) [116]. The proportion affected by individual end points was as follows: New stroke, 20 percent; of these, most (approximately 80 percent) strokes occurred in patients with a history of stroke Development of dementia in subjects without dementia at baseline, 21 percent Progression to moderate or severe disability in subjects with no or mild disability at baseline, 9 percent Death, 5 percent https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 16/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate Baseline factors independently associated with the composite endpoint in different multivariable models included gait disturbance, active smoking, a history of stroke, and more than three lacunar strokes or presence of brain atrophy on magnetic resonance imaging (MRI) [116]. In a retrospective analysis of 411 patients with CADASIL, the median age at death was 65 years in men and 71 years in women [2]. SCREENING ASYMPTOMATIC FAMILY MEMBERS Asymptomatic family members should receive genetic counseling prior to any procedures, such as brain magnetic resonance imaging (MRI), which might detect subclinical signs of CADASIL. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.) Predictive genetic testing should be carried out according to published guidelines dealing with ethical, legal, and psychosocial issues in other late-onset neurologic conditions for which no disease-modifying treatment is available. Asymptomatic children should not be tested, while adults at risk should be referred to a genetic counselor for an educational meeting. Pre- and post-test counseling should be performed irrespective of the result of the test. (See "Genetic testing".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited angiopathy caused by pathogenic variants in the NOTCH3 gene. The underlying vascular lesion in CADASIL is a nonatherosclerotic angiopathy involving small arteries and capillaries, primarily in the brain, characterized by the presence of electron-dense granular osmiophilic material (GOM) within the arterial media surrounding the smooth muscle cells. (See 'Pathophysiology' above.) The major clinical manifestations of CADASIL are transient ischemic attack and ischemic stroke predominately involving small vessels, cognitive deficits with early executive dysfunction, migraine with aura, and neuropsychiatric disturbances. Stroke and vascular https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 17/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate cognitive impairment are the main causes of morbidity and mortality. (See 'Clinical features' above.) Brain magnetic resonance imaging (MRI) ( image 1) shows lacunar infarcts and less well demarcated T2 hyperintensities primarily located in the subcortical white matter, but also in the brainstem and subcortical gray matter. White matter T2 hyperintensities in the anterior temporal lobe and external capsule are additional features suggestive of CADASIL. (See 'Magnetic resonance imaging' above.) The diagnosis of CADASIL is suspected based upon a combination of suggestive clinical and neuroimaging features, particularly when there is a positive family history for stroke or dementia. The diagnosis of CADASIL is established by genetic analysis with documentation of a typical NOTCH3 pathogenic variant, or by skin biopsy showing granular osmiophilic material (GOM) within small blood vessels. Skin biopsy is indicated if genetic testing is negative. (See 'Evaluation' above.) There is no specific disease-modifying treatment for CADASIL. For patients with CADASIL who are symptomatic with ischemic stroke or transient ischemic attack, we suggest antiplatelet therapy (aspirin 81 mg daily) for secondary stroke prevention (Grade 2C). However, there are no data establishing that antiplatelet therapy is effective for preventing stroke related to CADASIL. (See 'Management' above and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Although specific evidence of benefit for patients with CADASIL is lacking, we employ all available risk reduction strategies for secondary stroke prevention, including low-dose aspirin (81 mg daily), control of hypertension, statin therapy for dyslipidemia, and strict control blood glucose. (See 'Ischemic manifestations' above.) The management of CADASIL otherwise focuses on the control of symptoms related to progressive dementia, migraine, depression, and urinary incontinence. (See 'Symptomatic therapy' above.) Clinical progression in CADASIL tends to occur with the sequential development of migraine with aura around age 30 years, transient ischemic attacks, ischemic strokes and mood disorders between 40 and 60 years, dementia between 50 and 60 years, and gait difficulty at approximately 60 years. However, the clinical course of CADASIL is highly variable even within affected families. (See 'Clinical course and prognosis' above.) 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Rinnoci V, Nannucci S, Valenti R, et al. Cerebral hemorrhages in CADASIL: report of four cases and a brief review. J Neurol Sci 2013; 330:45. 84. Liao YC, Hsiao CT, Fuh JL, et al. Characterization of CADASIL among the Han Chinese in Taiwan: Distinct Genotypic and Phenotypic Profiles. PLoS One 2015; 10:e0136501. 85. Choi JC, Kang SY, Kang JH, Park JK. Intracerebral hemorrhages in CADASIL. Neurology 2006; 67:2042. 86. Roine S, P yh nen M, Timonen S, et al. Neurologic symptoms are common during gestation and puerperium in CADASIL. Neurology 2005; 64:1441. 87. Donnini I, Rinnoci V, Nannucci S, et al. Pregnancy in CADASIL. Acta Neurol Scand 2017; 136:668. 88. Chabriat H, Levy C, Taillia H, et al. Patterns of MRI lesions in CADASIL. Neurology 1998; 51:452. 89. Auer DP, P tz B, G ssl C, et al. Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology 2001; 218:443. https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 24/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate 90. Gollion C, Morel H, Bonneville F. Unilateral Leukoencephalopathy Revealing Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. Ann Neurol 2022; 91:889. 91. Dichgans M, Filippi M, Br ning R, et al. Quantitative MRI in CADASIL: correlation with disability and cognitive performance. Neurology 1999; 52:1361. 92. Liem MK, Lesnik Oberstein SA, Haan J, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: progression of MR abnormalities in prospective 7-year follow-up study. Radiology 2008; 249:964. 93. O'Sullivan M, Jarosz JM, Martin RJ, et al. MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology 2001; 56:628. 94. van den Boom R, Lesnik Oberstein SA, Ferrari MD, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR imaging findings at different ages 3rd-6th decades. Radiology 2003; 229:683. 95. van Den Boom R, Lesnik Oberstein SA, van Duinen SG, et al. Subcortical lacunar lesions: an MR imaging finding in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Radiology 2002; 224:791. 96. Dichgans M, Holtmannsp tter M, Herzog J, et al. Cerebral microbleeds in CADASIL: a gradient-echo magnetic resonance imaging and autopsy study. Stroke 2002; 33:67. 97. Viswanathan A, Guichard JP, Gschwendtner A, et al. Blood pressure and haemoglobin A1c are associated with microhaemorrhage in CADASIL: a two-centre cohort study. Brain 2006; 129:2375. 98. Puy L, De Guio F, Godin O, et al. Cerebral Microbleeds and the Risk of Incident Ischemic Stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy). Stroke 2017; 48:2699. 99. Duering M, Righart R, Csanadi E, et al. Incident subcortical infarcts induce focal thinning in connected cortical regions. Neurology 2012; 79:2025. 100. Holtmannsp tter M, Peters N, Opherk C, et al. Diffusion magnetic resonance histograms as a surrogate marker and predictor of disease progression in CADASIL: a two-year follow-up study. Stroke 2005; 36:2559. 101. Chabriat H, Pappata S, Ostergaard L, et al. Cerebral hemodynamics in CADASIL before and after acetazolamide challenge assessed with MRI bolus tracking. Stroke 2000; 31:1904. 102. Tatsch K, Koch W, Linke R, et al. Cortical hypometabolism and crossed cerebellar diaschisis suggest subcortically induced disconnection in CADASIL: an 18F-FDG PET study. J Nucl Med 2003; 44:862. https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 25/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate 103. Tuominen S, Miao Q, Kurki T, et al. Positron emission tomography examination of cerebral blood flow and glucose metabolism in young CADASIL patients. Stroke 2004; 35:1063. 104. Jouvent E, Poupon C, Gray F, et al. Intracortical infarcts in small vessel disease: a combined 7-T postmortem MRI and neuropathological case study in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 2011; 42:e27. 105. Dichgans M, Petersen D. Angiographic complications in CADASIL. Lancet 1997; 349:776. 106. Pescini F, Nannucci S, Bertaccini B, et al. The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale: a screening tool to select patients for NOTCH3 gene analysis. Stroke 2012; 43:2871. 107. Ruchoux MM, Chabriat H, Bousser MG, et al. Presence of ultrastructural arterial lesions in muscle and skin vessels of patients with CADASIL. Stroke 1994; 25:2291. 108. Mayer M, Straube A, Bruening R, et al. Muscle and skin biopsies are a sensitive diagnostic tool in the diagnosis of CADASIL. J Neurol 1999; 246:526. 109. Ebke M, Dichgans M, Bergmann M, et al. CADASIL: skin biopsy allows diagnosis in early stages. Acta Neurol Scand 1997; 95:351. 110. Smith BW, Henneberry J, Connolly T. Skin biopsy findings in CADASIL. Neurology 2002; 59:961. 111. Joutel A, Favrole P, Labauge P, et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet 2001; 358:2049. 112. Lesnik Oberstein SA, van Duinen SG, van den Boom R, et al. Evaluation of diagnostic NOTCH3 immunostaining in CADASIL. Acta Neuropathol 2003; 106:107. 113. Onodera O, Nozaki H, Fukutake T. CARASIL. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK 32533/ (Accessed on June 30, 2016). 114. Verdura E, Herv D, Scharrer E, et al. Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. Brain 2015; 138:2347. 115. Hara K, Shiga A, Fukutake T, et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med 2009; 360:1729. 116. Chabriat H, Herv D, Duering M, et al. Predictors of Clinical Worsening in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Prospective Cohort Study. Stroke 2016; 47:4. 117. Wang Q, Yan J, Chen X, et al. Statins: multiple neuroprotective mechanisms in neurodegenerative diseases. Exp Neurol 2011; 230:27. 118. Dichgans M, Markus HS, Salloway S, et al. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurol 2008; https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 26/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate 7:310. 119. Iannaccone S, Ferini-Strambi L. Pharmacologic treatment of emotional lability. Clin Neuropharmacol 1996; 19:532. 120. Weller M, Dichgans J, Klockgether T. Acetazolamide-responsive migraine in CADASIL. Neurology 1998; 50:1505. 121. Forteza AM, Brozman B, Rabinstein AA, et al. Acetazolamide for the treatment of migraine with aura in CADASIL. Neurology 2001; 57:2144. Topic 1091 Version 27.0 https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 27/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate GRAPHICS Main MRI changes in CADASIL (A) Lacunar infarcts shown on T1-weighted imaging are mainly located in the brainstem (pons), thalamus, an lentiform nuclei in a 61-year-old man with a history of stroke, gait difficulties, and executive dysfunction with memory deficits. (B) Small deep infarcts are shown on fluid-attenuated inversion recovery images in association with diffuse a confluent white-matter hyperintensities involving the anterior part of the temporal lobes. (C) Microbleeds are visible on T2 or gradient-echo images as small hypointense foci in the thalamus and brainstem. CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 28/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate Reproduced from: Chabriat H, Joutel A, Dichgans M, et al. Cadasil. Lancet Neurol 2009; 8:643. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 113184 Version 1.0 https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 29/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate Brain MRI in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Axial images of the brain with fluid-attenuated inversion-recovery (FLAIR) MRI in representative patients with biopsy-proved CADASIL show a typical pattern of brain lesions. Note the symmetry of the lesions and their extension into the superficial white matter (arrows). MRI: magnetic resonance imaging. Reprinted with permission from: Auer, D, Putz, B, Gossl, C, et al. Di erential Lesion Patterns in CADASIL and Sporadic Subcortical Arteriosclerotic Encephalopathy: MR Imaging Study with Statistical Parametric Group Comparison. Radiology 2001; 218:443. Copyright 2001 Radiological Society of North America. Graphic 60844 Version 3.0 https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 30/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate Anterior temporal lobe involvement in CADASIL Brain MRI of a 46-year-old male with CADASIL and skin biopsy positive for granular osmiophilic material. There is hyperintensity in the periventricular and subcortical white matter on T2-weighted (A) and FLAIR (B) sequences, a nonspecific pattern that may be seen with other small vessel ischemic disease processes. In addition, there is increased signal intensity in the anterior temporal lobe white matter on T2-weighted (D) and FLAIR (E) sequences, a finding that may be more specific for CADASIL. Additional findings include a right periventricular lacunar infarction of CSF signal intensity (A, B, C) and involvement of the pons (D, E). CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery. Images courtesy of Eric Schwartz, MD. Graphic 81669 Version 3.0 https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 31/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate Contributor Disclosures Martin Dichgans, MD Grant/Research/Clinical Trial Support: Bayern Innovativ, Gesellschaft f r Innovation und Wissenstransfer mbH [Stroke]; DFG/DLR [Stroke]; DZNE [Stroke]; European Union, Horizon 2020 [Stroke and dementia]; Foundation Leducq [Small vessel disease]; Intramural Funds Ludwig-Maximilians University [Stroke and dementia]; Josef-Hackl-Foundation [Clinical biomarkers for stroke]; National Institutes of Health [Early-onset stroke]; Vascular Dementia Research Foundation [Dementia]. Consultant/Advisory Boards: Ever Pharma [Stroke]. Speaker's Bureau: Bayer [Stroke]; Pfizer [Stroke]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 32/32
7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cerebral venous thrombosis: Treatment and prognosis : Jos M Ferro, MD, PhD, Patr cia Canh o, MD, PhD : Scott E Kasner, MD, Douglas R Nordli, Jr, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 05, 2022. INTRODUCTION Cerebral venous thrombosis (CVT) is an uncommon but serious disorder. Clinical manifestations can include headache, papilledema, visual loss, focal or generalized seizures, focal neurologic deficits, confusion, altered consciousness, and coma. Many cases have been linked to inherited and acquired thrombophilias, pregnancy, puerperium, infection, and malignancy. Infarctions due to CVT are often hemorrhagic and associated with vasogenic edema. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) Treatment, which is started as soon as the diagnosis is confirmed, consists of reversing the underlying cause when known, control of seizures and intracranial hypertension, and antithrombotic therapy. Anticoagulation is the mainstay of acute and subacute treatment for CVT. This topic will review the prognosis and treatment of CVT. Other aspects of this disorder are discussed separately. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) ACUTE ANTITHROMBOTIC MANAGEMENT While the overall aim of treatment for CVT is to improve outcome, the immediate goals treatment for CVT are [1-4]: https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 1/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate To recanalize the occluded sinus/vein To prevent the propagation of the thrombus, namely to the bridging cerebral veins To treat the underlying prothrombotic state, in order to prevent venous thrombosis in other parts of the body, particularly pulmonary embolism, and to prevent the recurrence of CVT The main treatment option to achieve these goals is anticoagulation, most commonly using either heparin or low molecular weight heparin (LMWH), as discussed in the next section. Initial anticoagulation Management for most patients For most patients with CVT, we recommend anticoagulation with subcutaneous LMWH or intravenous heparin for adults with symptomatic CVT who have no contraindication. The presence of hemorrhagic venous infarction, intracerebral hemorrhage, or isolated subarachnoid hemorrhage are not contraindications for anticoagulant treatment in CVT. The evidence summarized below (see 'Efficacy' below) suggests that subcutaneous LMWH is more effective than unfractionated heparin (UFH) and is at least as safe. Therefore, we prefer subcutaneous LMWH unless the patient is clinically unstable or invasive interventions such as lumbar puncture or surgery are planned or there is a contraindication to LMWH, such as kidney failure. Treatment for children during the acute phase of CVT is similar to that for adults, but the evidence is weaker since there are no large randomized trials in this age group [5]. Treatment regimens for patients with CVT and heparin-induced thrombocytopenia (HIT) are discussed separately. (See "Management of heparin-induced thrombocytopenia".) The duration of antithrombotic treatment is reviewed below. (See 'Long-term anticoagulation' below.) Management for patients with COVID-19 vaccine-associated thrombosis Case series have described instances of CVT associated with thrombocytopenia in patients who are between 5 and 30 days post-vaccination with an adenovirus-vector ChAdOx1 nCov-19 (AstraZeneca COVID-19) or Ad26.COV2.S (Janssen COVID-19) vaccine [6-11]. These events are due to vaccine-induced autoantibodies against a PF4 platelet antigen, similar to those found in patients with HIT [7]. Treatment for most patients includes anticoagulation (eg, a direct oral anticoagulant, fondaparinux, argatroban) and intravenous immune globulin [12]. Platelet transfusions are typically reserved for cases of clinical relevant bleeding or https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 2/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate preoperatively for procedures associated with a high bleeding risk (eg, neurosurgery) [13,14]. (See "COVID-19: Vaccines", section on 'Thrombosis with thrombocytopenia' and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)", section on 'Management'.) Efficacy Although definitive evidence of effectiveness is lacking, there is a general consensus that anticoagulation with UFH or LMWH is appropriate treatment for acute CVT, based on available data on efficacy as well as rapid onset of effect and reversibility [3]. As an example, more than 80 percent of the patients in the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) were treated with anticoagulation [15]. Two randomized controlled trials of anticoagulation in acute CVT ( table 1) have been published [1,16]. Both have methodologic problems, most importantly their modest sample size. The Berlin trial of intravenous heparin versus placebo was stopped prematurely because of excess mortality in the placebo arm [16]. Patients randomized to the heparin arm had significantly better outcomes on a nonvalidated composite CVT severity scale than those in the placebo group. The average length from onset of symptoms to anticoagulation treatment, four weeks, was exceptionally long. The Dutch trial of subcutaneous nadroparin versus placebo enrolled 60 patients but excluded those who needed lumbar punctures for the relief of increased intracranial pressure [1]. More patients treated with LMWH followed by oral anticoagulation had a favorable outcome than controls, but the difference between the groups was not statistically significant ( table 1). Despite randomization, an imbalance at baseline may have favored the placebo group, as there were more cases with isolated intracranial hypertension in the placebo group and more patients with infarcts in the nadroparin group. A meta-analysis of these two trials found that anticoagulant treatment compared with placebo was associated with a pooled relative risk of death of 0.33 (95% CI 0.08-1.21) and a risk of death or dependency of 0.46 (95% CI 0.16-1.31) [17]. While these data suggest that anticoagulant treatment for CVT may be associated with a reduced risk of death or dependency, the results did not achieve statistical significance. Limited data suggest that LMWH is more effective than UFH and at least as safe for the treatment of CVT: In an open-label trial, 66 adults with CVT were randomly assigned to treatment with LMWH or UFH [18]. In-hospital mortality was significantly lower in the LMWH group (0 versus 19 percent). At three months, the proportion of patients with complete recovery was greater https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 3/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate for the LMWH group (88 versus 63 percent), but the difference was not statistically significant. Small numbers limit the strength of these findings. In a nonrandomized case-control study, a greater proportion of adult patients treated with LMWH (n = 119) compared with UFH (n = 302) were independent at six months (92 versus 84 percent; adjusted odds ratio 2.4, 95% CI 1.0-5.7) [19]. Treatment with LMWH was also associated with slightly lower rates of mortality (6 versus 8 percent) and new intracranial hemorrhage (10 versus 16 percent), but these outcomes were not statistically significant. In a single-center double-blind trial conducted in Iran, 52 cases of CVT were randomly assigned to treatment with LMWH or UFH. There was no difference between the treatment groups in neurological deficits, disability, and mortality [20]. Risk of new intracranial hemorrhage Anticoagulants appear to be safe to use in adult patients with CVT who have associated intracranial hemorrhage, either intracerebral (such as hemorrhagic venous infarction) or subarachnoid [21]. In the Berlin and Dutch trials, 34 of 79 patients (43 percent) had an intracerebral hemorrhage at baseline [1,16]. None of the patients randomized to heparin developed a new intracerebral hemorrhage. In contrast, a new intracerebral hemorrhage developed in three patients randomized to placebo. Case series have also reported relatively low risks of intracranial hemorrhage (<5 percent) and systemic hemorrhage (<2 percent), and such hemorrhages did not influence outcome [22-25]. These findings are in accordance with the hypothesis that hemorrhage in CVT is caused by the probable mechanism of venous outflow blockage and very high intradural and intravenous pressure, leading to both rupture of venules and to hemorrhagic transformation of venous infarctions. Similarly, observational data from case series and subgroup analyses of controlled trials suggest that anticoagulant therapy is safe in children with CVT [5,26-32]. Endovascular treatment For selected adults and children with CVT who develop progressive neurologic worsening despite adequate anticoagulation with subcutaneous LMWH or intravenous heparin, endovascular thrombolysis or mechanical thrombectomy may be a treatment option at centers experienced with these methods. The potential utility of endovascular treatment was described in a 2015 systematic review that identified 42 studies and 185 patients with CVT who were treated with mechanical thrombectomy [33]. Many of the patients were severely ill; pretreatment intracerebral hemorrhage was present in 60 percent and stupor or coma in 47 percent. A variety of devices were used, including the AngioJet rheolytic catheter, balloon angioplasty, stents, and microsnares; concurrent local thrombolysis was used in 71 percent. Overall, a good outcome https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 4/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate was reported for 84 percent of patients; mortality was 12 percent. New or worsened intracerebral hemorrhage affected 10 percent. A high recanalization rate (95 percent; 21 percent partial) was achieved. However, a randomized controlled trial (TO-ACT) [34] failed to show benefit of endovascular treatment (thrombectomy with or without chemical thrombolysis) over anticoagulation in patients with acute CVT and at least one risk factor for clinical deterioration (coma, mental status disturbance, CVT involving the deep venous system, intracerebral hemorrhage). However, as the trial had a modest sample size and was prematurely stopped for futility, the possibility of a small treatment effect in some patients cannot be excluded. Among nearly 50,000 patients with CVT from the United States Nationwide Inpatient Sample 2004 to 2014, mortality was higher for patients with CVT treated with endovascular approaches than medical therapy with anticoagulation, even after adjusting for age, severity of symptoms, and the burden of complications (eg, intracranial hemorrhage, venous infarction, and cerebral edema; odds ratio 1.96, 95% CI 1.6-3.3) [35]. In addition, a 2010 systematic review of 15 studies including 156 patients revealed that despite endovascular treatment, there is a death rate of 9 percent and that local thrombolysis is complicated by a non-negligible rate of major bleeding (10 percent), including 8 percent intracranial hemorrhages, 58 percent of which were fatal [36]. Guideline recommendations Consensus guidelines support the use of anticoagulation for the acute treatment of CVT in adults and children. Guidelines for acute treatment in adults include: The 2017 European Stroke Organization guidelines for the diagnosis and treatment of cerebral venous thrombosis, endorsed by the European Academy of Neurology, recommend heparin at therapeutic dosage to treat adult patients with acute CVT, including those with an intracerebral hemorrhage at baseline [37]. The guidelines suggest using LMWH instead of UFH. No recommendation is made regarding thrombolysis for acute CVT, except that patients who have a pretreatment low risk of poor outcome (eg, absence of coma, mental status disturbance, thrombosis of the deep venous system, intracranial hemorrhage, and malignancy) should not be exposed to aggressive treatments such as thrombolysis. The 2014 American Heart Association (AHA)/American Stroke Association (ASA) guidelines for the prevention of stroke state that anticoagulation is reasonable for patients with acute CVT, even in selected patients with intracranial hemorrhage [38]. The 2011 AHA/ASA guidelines for the diagnosis and management of CVT conclude that initial anticoagulation with adjusted-dose UFH or weight-based LMWH in full anticoagulant doses is reasonable, https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 5/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate followed by vitamin K antagonists, regardless of the presence of intracerebral hemorrhage [39]. Guidelines for acute treatment in children include: The 2012 American Academy of Chest Physicians (ACCP) guidelines recommends initial anticoagulation with UFH or LMWH, followed by LMWH or vitamin K antagonist treatment (ie, warfarin) for a minimum of three months for children with CVT but without significant intracerebral hemorrhage [40]. Anticoagulation for an additional three months is suggested if there is still cerebral sinovenous occlusion or ongoing symptoms (the latter presumably meaning new venous infarcts or increased intracranial pressure) after three months of therapy. For children with CVT who have significant intracerebral hemorrhage, the ACCP suggests either initial anticoagulation as for children without hemorrhage or radiologic monitoring of the thrombosis at five to seven days and anticoagulation if thrombus extension is noted at that time [40]. The ACCP suggests thrombolysis, thrombectomy, or surgical decompression only in children with severe CVT in whom there is no improvement with initial anticoagulation therapy. The 2019 AHA/ASA scientific statement for the management of stroke in neonates and children endorses anticoagulation for children with CVT [41]. Antithrombotic selection should be individualized, guided by patient circumstances, and informed by a multidisciplinary consensus approach particularly when CVT is associated with hemorrhagic infarction, otitis media/mastoiditis, head trauma, or cranial surgery. Surveillance vascular neuroimaging is recommended to guide the duration of anticoagulation. Endovascular intervention is an option for rare circumstances when there is sudden clinical deterioration or a high risk of mortality. For neonatal patients with CVT, anticoagulation with LMWH or heparin may be considered, particularly those with clinical deterioration or evidence of thrombus extension on serial imaging [41]. Serial imaging at five to seven days should be considered to exclude propagation when a decision is made not to be anticoagulated. OTHER ACUTE MANAGEMENT ISSUES Major problems that may require intervention in the acute phase of CVT include elevated intracranial pressure, brain swelling, and seizures. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 6/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Elevated intracranial pressure and herniation In the acute phase, elevated intracranial pressure (ICP) may arise from single or multiple large hemorrhagic lesions, infarcts, or brain edema. Elevated ICP or space-occupying lesions may cause transtentorial herniation and death. General recommendations to control acutely elevated ICP should be followed, including elevating the head of the bed, intensive care unit admission, mild sedation as needed, administering osmotic therapy (mannitol or hypertonic saline), hyperventilation to a target partial pressure of carbon dioxide (PaCO ) of 30 to 35 mmHg, and ICP monitoring [21,42]. 2 (See "Evaluation and management of elevated intracranial pressure in adults" and "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis".) In patients with impending herniation due to unilateral hemispheric lesion, hemicraniectomy can be lifesaving. Retrospective data from a registry and systematic reviews suggest that death can be prevented and a good functional outcome can be achieved [43,44]. There is no good evidence to support ventricular shunting as a treatment for acute hydrocephalus or impending brain herniation in the acute phase of CVT [45]. In patients with sustained ICP elevation, successful treatment of intracranial hypertension can prevent visual failure and resolve headache. A prospective study in 59 patients with CVT presenting with isolated intracranial hypertension noted a complete recovery in over 90 percent [46]; patients had a variety of interventions, and most had a therapeutic lumbar puncture (LP). However, there are no studies specifically evaluating therapeutic LP for elevated ICP or isolated intracranial hypertension in patients with CVT. Data from the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) did not show differences in the outcomes in patients who had diagnostic LP [15]. European guidelines state that therapeutic LP may be considered in patients with CVT and signs of intracranial hypertension, because of a potential beneficial effect on visual loss and/or headache, whenever its safety profile is acceptable [37]. Although glucocorticoids, in particular intravenous dexamethasone, are prescribed in many centers, they are not recommended for treating CVT in the absence of an underlying inflammatory disorder such as Beh et disease or systemic lupus erythematosus [37,47-49]. No randomized clinical trials have been performed to evaluate their efficacy for CVT, but available evidence suggests they are ineffective. This conclusion is supported by a study that analyzed data from the observational ISCVT cohort of 642 patients with CVT (including 150 patients treated with glucocorticoids) using case-control methods that failed to demonstrate any benefit of glucocorticoids, even for patients with parenchymal lesions [50]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 7/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Seizures For patients with CVT who have both seizures and focal cerebral supratentorial lesions such as edema or infarction on admission head computed tomography (CT) or brain magnetic resonance imaging (MRI) lesions, we recommend seizure prophylaxis with antiseizure medication. In patients with CVT, recurrent seizures are more likely to develop in those who present with seizures and in those with supratentorial brain lesions (focal edema or ischemic or hemorrhagic infarcts) on admission brain imaging [51]. The risk of developing seizures after CVT diagnosis is very low in patients who do not have these risk factors. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Seizures'.) Data are limited regarding the effectiveness of seizure prophylaxis with antiseizure medications in patients with CVT [21,52]. In the ISCVT cohort, early seizures (those occurring within two weeks after CVT diagnosis) were observed in the following patient subgroups, comparing those not treated with antiseizure medication versus those treated with antiseizure medication [51]: In patients with no supratentorial lesion and no seizure at presentation, early seizure occurred in 5 of 197 (2.5 percent) not on antiseizure medications versus 0 of 11 (0 percent) on antiseizure medications. In those with no supratentorial lesion who presented with seizure, early seizures occurred in 1 of 14 (7 percent) not on antiseizure medications and 0 of 35 (0 percent) on antiseizure medications. In patients with a supratentorial lesion but no seizure at presentation, early seizures occurred in 11 of 134 (8 percent) not on antiseizure medications and 1 of 35 (3 percent) on antiseizure medications (odds ratio [OR] 0.3, 95% CI 0.04-2.6). In patients with a supratentorial lesion who presented with seizure, early seizures occurred in 24 of 47 (51 percent) not on antiseizure medications and 1 of 148 (<1 percent) on antiseizure medications (OR 0.006, 95% CI 0.001-0.05). Thus, antiseizure medications prophylaxis appears to be associated with a reduced risk of early seizures in patients with CVT. The risk reduction was statistically significant for patients in the highest risk group (those with a supratentorial lesion and seizure at presentation) [51]. The strength of this study is limited by its observational and retrospective design, but it represents the largest experience in the literature. Based upon these data, we recommend seizure prophylaxis only for patients with both seizures at presentation and supratentorial lesions such as edema, infarction, or hemorrhage on admission head CT or brain MRI. Prophylaxis is not clearly required for a single early https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 8/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate symptomatic seizure with CVT in the absence of supratentorial lesion, as there is often no seizure recurrence. Furthermore, seizure prophylaxis is not recommended for patients who have focal cerebral lesions without seizures [37,39]. When antiseizure medication prophylaxis is used, valproate or levetiracetam is preferable to phenytoin because they have fewer pharmacologic interactions with oral vitamin K antagonist anticoagulants (eg, warfarin) [53]. General recommendations for the selection of antiseizure medications are discussed separately. (See "Overview of the management of epilepsy in adults", section on 'Antiseizure medication therapy' and "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Selection of an antiseizure medication'.) The duration of antiseizure medication therapy is discussed separately (See 'Seizure prevention' below.) Infection and inflammation Antibiotic treatment is mandatory whenever there is meningitis or other intracranial infection or an infection of a neighboring structure, such as otitis or mastoiditis. For associated inflammatory diseases such as Beh et disease, lupus, or vasculitis, treatment with glucocorticoids may be necessary. MANAGEMENT AFTER THE ACUTE PHASE The subacute phase of CVT often involves decisions regarding the duration of anticoagulation and antiseizure medication use. In addition, there may be long-term complications including headaches, visual loss, cognitive impairment, and psychiatric disturbances. Long-term anticoagulation The aim of continuing anticoagulation after the acute phase is to prevent CVT recurrence, which affects 2 to 7 percent of patients, and to prevent extracerebral venous thrombosis, which occurs in up to 5 percent of patients with CVT, mainly from deep venous thrombosis of the limbs or pelvis, and/or pulmonary embolism [15]. (See 'Recurrence' below.) Selection of anticoagulant For most adults with CVT, we suggest anticoagulation with warfarin or a direct oral anticoagulant after the acute phase. Direct oral anticoagulants may be preferable for most patients, based upon the lower burden of blood monitoring and dose adjustments, fewer drug interactions, and lack of dietary restrictions when compared with warfarin. When warfarin is used, the dose should be adjusted to an international normalized ratio (INR) target of 2.5 (acceptable range: 2 to 3). https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 9/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Although high-quality evidence is limited, either warfarin or a direct oral anticoagulant appears to be safe and effective to prevent recurrent CVT and other forms of venous thromboembolism (VTE) in patients with CVT. A systematic review of 19 studies that included nearly 2000 patients with CVT found rates of recurrent thromboembolism and intracranial hemorrhage were similar for patients treated with vitamin K antagonists or direct oral anticoagulants [54]. However, certainty of the data is limited by the observational nature of many of the included studies, risk of selection and treatment biases, as well as varied outcome parameters. In the open-label RE- SPECT CVT trial, 120 patients with CVT of mild to moderate severity were randomly assigned to dabigatran (150 mg twice daily) or warfarin (titrated to a target INR of 2 to 3) for a period of 24 weeks [55]. Patients with coma, major trauma, central nervous system infections, or active cancer were excluded. During the study period, there were no recurrent venous thromboembolic events in either treatment group. Major bleeding was limited to intestinal bleeding in one patient assigned to dabigatran and subdural hemorrhages in two patients assigned to warfarin. European guidelines, which were published in 2017 prior to the RE-SPECT CVT trial, do not recommend using direct oral anticoagulants for the prevention of recurrent venous thrombosis after CVT [37]. In the retrospective ACTION-CVT observational study that included 845 anticoagulated patients with CVT of mild to moderate severity, clinical and radiographic outcomes were assessed at a median follow-up of 345 days for patients treated with warfarin (52 percent), a direct oral anticoagulant (33 percent), or both at different times (15 percent) [56]. Patients with CVT associated with pregnancy, antiphospholipid syndrome, and cancer were excluded. Compared with warfarin, treatment with a direct oral anticoagulant was associated with similar risks of recurrent venous thrombosis and death, as well as similar rates of recanalization on follow-up imaging. In addition, treatment with a direct oral anticoagulant was associated with a lower risk of major hemorrhage (adjusted hazard ratio 0.35, 95% CI 0.15-0.82). Special populations of patients with CVT require a different approach: Malignancy For patients with malignancy who require long-term anticoagulation and who do not have chronic kidney failure (creatinine clearance <30 mL/minute), low molecular weight heparin (LMWH) is generally preferred rather than warfarin or direct oral anticoagulants, but oral anticoagulation is preferred over no therapy. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".) Antiphospholipid syndrome For patients with an antiphospholipid antibody syndrome and CVT, clinical efficacy and safety data suggest warfarin is preferred over direct oral anticoagulants. (See "Management of antiphospholipid syndrome".) https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 10/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Kidney failure Patients with severe chronic kidney failure should not receive direct oral anticoagulants; vitamin K antagonists (eg, warfarin) are preferred for oral therapy. Pregnancy For most patients who require long-term anticoagulation during pregnancy (with the exception of patients with mechanical heart valves), heparins are safer than other anticoagulants. Warfarin and direct oral anticoagulants are contraindicated. (See "Use of anticoagulants during pregnancy and postpartum".) Children Several anticoagulants have been used for children with CVT including vitamin K antagonists, unfractionated heparin, or LMWH [5]. Rivaroxaban or dabigatran can also be used to prevent recurrent venous thrombotic events after acute CVT, depending on patient and parent preferences and drug and dietary interactions. Rivaroxaban was compared with standard anticoagulation (LMWH or vitamin K antagonist) in children with CVT in an exploratory substudy [57] of the open-label EINSTEIN-Jr trial [58], which assigned patients with VTE to bodyweight-adjusted rivaroxaban 20 mg equivalent dose or standard anticoagulation for a period of three months. Partial or complete recanalization rates were similar in both groups and occurred in roughly 75 percent. There was one recurrent VTE (in a child assigned to standard anticoagulation). One subdural hematoma occurred among children assigned to standard anticoagulation (n = 41) and five clinically relevant (nonmajor extracranial) bleeding events in those who received rivaroxaban (n = 73). A subgroup analysis of the EINSTEIN-Jr trial, including children with CVT and an associated head or neck infection administered therapeutic anticoagulants, showed that generally they had low risks of bleeding and thrombotic complications, including those who had surgical interventions with delay or interruption of anticoagulation [59]. In a subgroup analysis of the DIVERSITY trial, a single-arm trial of dabigatran in children with VTE, few children with CVT developed recurrent VTE or experienced major or clinically relevant nonmajor bleeding when receiving prophylaxis with dabigatran [60]. Duration of anticoagulation After the acute phase of CVT, we suggest continuing anticoagulation for a minimum period of three months and up to 12 months. However, there is no definitive evidence regarding the optimal duration of anticoagulant therapy specifically for reducing the risk of recurrent CVT [37]. A reasonable approach may be to stratify the duration of anticoagulant therapy according to the individual prothrombotic risk as follows [39,61]: For patients with a provoked CVT associated with a transient risk factor ( table 2), anticoagulation is continued for three to six months. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 11/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate For patients with an unprovoked CVT, anticoagulation is continued for 6 to 12 months. For patients with recurrent CVT, VTE after CVT, or a first CVT with a severe thrombophilia (ie, homozygous prothrombin gene G20210A variant, homozygous factor V Leiden genetic variant, deficiencies of protein C, protein S, or antithrombin, combined thrombophilia defects, or antiphospholipid syndrome), anticoagulation may be continued indefinitely. Aspirin We generally do not use aspirin or other antiplatelet medications for long-term management of patients after CVT, unless a separate indication for therapy is present. The benefit of aspirin or other antiplatelet agents after CVT has not been established in controlled trials or observational studies, and current guidelines make no recommendation about aspirin in this setting [37,39]. Seizure prevention Patients who experience a seizure after a hemispheric CVT are typically started on antiseizure medication treatment, while patients who do not are generally not started on antiseizure medication prophylaxis. (See 'Seizures' above.) The optimal duration of antiseizure medication treatment after CVT is unknown. For patients with CVT and associated parenchymal brain lesions who present with one or more seizures in the acute phase, antiseizure medications should be continued until seizure-free for a defined duration (eg, one year). The risk of epilepsy after CVT ranges from 5 to 11 percent of patients [15,62-64]. The risk is higher in those with seizures in the acute phase, with hemorrhagic parenchymal lesions, and who survived a decompressive hemicraniectomy [63,64]. Late-onset seizures indicate an even higher risk of epilepsy. In one study of 123 CVT patients with late seizures (occurring more than seven days after CVT diagnosis), 70 percent had a recurrent seizure during a mean two-year follow-up [64]. General recommendations for the selection and withdrawal of antiseizure medications are discussed separately. (See "Overview of the management of epilepsy in adults", section on 'Antiseizure medication therapy' and "Overview of the management of epilepsy in adults", section on 'Discontinuing antiseizure medication therapy' and "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Selection of an antiseizure medication'.) Headaches Chronic headaches have been reported to occur in more than half of patients with prior CVT [65]. Headaches severe enough to require bed rest or hospital admission afflict 14 percent of patients with CVT [15]. Repeated brain MRI and magnetic resonance venography (MRV) are necessary to exclude the rare case of recurrent CVT. MRV may depict stenosis of a previously occluded sinus [66,67]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 12/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Lumbar puncture may be necessary to exclude chronically elevated intracranial pressure (ICP) if headache persists and brain MRI and MRV are normal. In such cases, therapeutic options to treat elevated ICP include acetazolamide (500 mg twice daily) or topiramate (for patients who cannot tolerate acetazolamide), but efficacy is unproven [39]. Additional options if severe headache associated with increased intracranial hypertension persists include repeated lumbar punctures, a lumboperitoneal shunt, or stenting of sinus stenosis [68-70], but efficacy after CVT is also unproven. Visual loss Severe visual loss due to CVT is fortunately a rare event [71-73]. Nevertheless, elevated intracranial pressure must be rapidly ruled out and managed accordingly if visual acuity decreases during follow-up and is not explained by ocular causes. Fenestration of the optic nerve sheath has also been used to relieve pressure and prevent optic nerve atrophy, but efficacy is not established [39,74]. Because of the potential for visual loss caused by severe or long-standing elevation of intracranial pressure, serial assessment of visual fields and visual acuity is recommended for children with CVT during follow-up, particularly during the first year [39,42]. It is reasonable to do the same for adults with visual complaints, chronic headaches, or papilledema. Cognitive and psychiatric complications Despite the apparent general good recovery in most patients with CVT, approximately one-half of the survivors feel depressed or anxious, and minor cognitive or language deficits may preclude them from resuming their previous jobs [75,76]. Patients should be reassured of the very low level of risk of recurrence of CVT and be encouraged to return to previous occupations and hobbies. In some cases, antidepressants may be necessary. Subsequent pregnancy We suggest prophylaxis with LMWH during pregnancy and puerperium for those with a previous history of CVT to reduce the risk of recurrent CVT and other venous thromboembolic events, in accord with guidelines from the European Stroke Organization and the American Heart Association/American Stroke Association [37,39,77]. For pregnant patients with a history of CVT, we suggest temporary prophylactic anticoagulation with subcutaneous LMWH throughout pregnancy and continuing up to eight weeks postpartum. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention".) Pregnancy and the puerperium are known risk factors for CVT (see "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Risk factors and associated conditions'). The absolute risk of complications during subsequent pregnancy among those who have a history of CVT appears to be low, although the relative risks of recurrent CVT and noncerebral VTE are quite elevated compared with the general population. Supporting evidence comes from https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 13/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate a 2016 systematic review of 13 observational studies evaluating the frequency of CVT or noncerebral VTE associated with pregnancy and the puerperium in those with a history of previous CVT [78]. The following observations were reported: Recurrent CVT occurred in 2 of 217 pregnancies (9 per 1000 pregnancies, 95% CI 3-33 per 1000), a rate that was more than 80-fold higher than the previously reported incidence in the general population. Noncerebral VTE occurred in 5 of 186 pregnancies (27 per 1000, 95% CI 12-61 per 1000), a rate that was approximately 16-fold higher than the incidence previously described in the general population. Spontaneous abortion occurred in 33 of 186 pregnancies (18 percent, 95% CI 13-24 percent), a rate similar to the estimated rate in the general population. (See "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology", section on 'Incidence'.) There was no significant difference in the rate of spontaneous abortion for patients treated or not treated with antithrombotic therapy (11 versus 19 percent). Thus, based upon the available evidence, a history of CVT, including pregnancy- or puerperium- related CVT, is not a contraindication for future pregnancy. Patients should be advised not to become pregnant while on warfarin because of its teratogenic effects and increased risk of fetal bleeding. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Already taking warfarin'.) Oral contraceptives Because it is a risk factor for CVT, female patients with prior CVT should be informed about the risks of combined estrogen-progestin hormonal contraception and advised against its use [37,42]. Risk is associated with the dose of ethinyl estradiol (less risk with doses <50 mcg). The type of progestin is also associated with VTE risk; in general, the lowest risk is seen with combined oral contraceptives that contain a second-generation progestin such as levonorgestrel. These risks are discussed in greater detail separately. (See "Combined estrogen- progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism'.) PROGNOSIS CVT can result in death or permanent disability but usually has a favorable prognosis. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 14/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Early deterioration and death Approximately 5 percent of patients die in the acute phase of the disorder [79,80]. Most of the early deaths are a consequence of CVT. A systematic review found that mortality rates among patients with CVT declined since the 1960s; increased detection of less severe cases with advances in neuroimaging along with improved hospital care may have accounted for some or all of the decreased mortality [81]. In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) that evaluated 624 patients (age >15 years) with CVT, 27 patients (4.3 percent) died during hospitalization for
with CVT and associated parenchymal brain lesions who present with one or more seizures in the acute phase, antiseizure medications should be continued until seizure-free for a defined duration (eg, one year). The risk of epilepsy after CVT ranges from 5 to 11 percent of patients [15,62-64]. The risk is higher in those with seizures in the acute phase, with hemorrhagic parenchymal lesions, and who survived a decompressive hemicraniectomy [63,64]. Late-onset seizures indicate an even higher risk of epilepsy. In one study of 123 CVT patients with late seizures (occurring more than seven days after CVT diagnosis), 70 percent had a recurrent seizure during a mean two-year follow-up [64]. General recommendations for the selection and withdrawal of antiseizure medications are discussed separately. (See "Overview of the management of epilepsy in adults", section on 'Antiseizure medication therapy' and "Overview of the management of epilepsy in adults", section on 'Discontinuing antiseizure medication therapy' and "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Selection of an antiseizure medication'.) Headaches Chronic headaches have been reported to occur in more than half of patients with prior CVT [65]. Headaches severe enough to require bed rest or hospital admission afflict 14 percent of patients with CVT [15]. Repeated brain MRI and magnetic resonance venography (MRV) are necessary to exclude the rare case of recurrent CVT. MRV may depict stenosis of a previously occluded sinus [66,67]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 12/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Lumbar puncture may be necessary to exclude chronically elevated intracranial pressure (ICP) if headache persists and brain MRI and MRV are normal. In such cases, therapeutic options to treat elevated ICP include acetazolamide (500 mg twice daily) or topiramate (for patients who cannot tolerate acetazolamide), but efficacy is unproven [39]. Additional options if severe headache associated with increased intracranial hypertension persists include repeated lumbar punctures, a lumboperitoneal shunt, or stenting of sinus stenosis [68-70], but efficacy after CVT is also unproven. Visual loss Severe visual loss due to CVT is fortunately a rare event [71-73]. Nevertheless, elevated intracranial pressure must be rapidly ruled out and managed accordingly if visual acuity decreases during follow-up and is not explained by ocular causes. Fenestration of the optic nerve sheath has also been used to relieve pressure and prevent optic nerve atrophy, but efficacy is not established [39,74]. Because of the potential for visual loss caused by severe or long-standing elevation of intracranial pressure, serial assessment of visual fields and visual acuity is recommended for children with CVT during follow-up, particularly during the first year [39,42]. It is reasonable to do the same for adults with visual complaints, chronic headaches, or papilledema. Cognitive and psychiatric complications Despite the apparent general good recovery in most patients with CVT, approximately one-half of the survivors feel depressed or anxious, and minor cognitive or language deficits may preclude them from resuming their previous jobs [75,76]. Patients should be reassured of the very low level of risk of recurrence of CVT and be encouraged to return to previous occupations and hobbies. In some cases, antidepressants may be necessary. Subsequent pregnancy We suggest prophylaxis with LMWH during pregnancy and puerperium for those with a previous history of CVT to reduce the risk of recurrent CVT and other venous thromboembolic events, in accord with guidelines from the European Stroke Organization and the American Heart Association/American Stroke Association [37,39,77]. For pregnant patients with a history of CVT, we suggest temporary prophylactic anticoagulation with subcutaneous LMWH throughout pregnancy and continuing up to eight weeks postpartum. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention".) Pregnancy and the puerperium are known risk factors for CVT (see "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Risk factors and associated conditions'). The absolute risk of complications during subsequent pregnancy among those who have a history of CVT appears to be low, although the relative risks of recurrent CVT and noncerebral VTE are quite elevated compared with the general population. Supporting evidence comes from https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 13/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate a 2016 systematic review of 13 observational studies evaluating the frequency of CVT or noncerebral VTE associated with pregnancy and the puerperium in those with a history of previous CVT [78]. The following observations were reported: Recurrent CVT occurred in 2 of 217 pregnancies (9 per 1000 pregnancies, 95% CI 3-33 per 1000), a rate that was more than 80-fold higher than the previously reported incidence in the general population. Noncerebral VTE occurred in 5 of 186 pregnancies (27 per 1000, 95% CI 12-61 per 1000), a rate that was approximately 16-fold higher than the incidence previously described in the general population. Spontaneous abortion occurred in 33 of 186 pregnancies (18 percent, 95% CI 13-24 percent), a rate similar to the estimated rate in the general population. (See "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology", section on 'Incidence'.) There was no significant difference in the rate of spontaneous abortion for patients treated or not treated with antithrombotic therapy (11 versus 19 percent). Thus, based upon the available evidence, a history of CVT, including pregnancy- or puerperium- related CVT, is not a contraindication for future pregnancy. Patients should be advised not to become pregnant while on warfarin because of its teratogenic effects and increased risk of fetal bleeding. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Already taking warfarin'.) Oral contraceptives Because it is a risk factor for CVT, female patients with prior CVT should be informed about the risks of combined estrogen-progestin hormonal contraception and advised against its use [37,42]. Risk is associated with the dose of ethinyl estradiol (less risk with doses <50 mcg). The type of progestin is also associated with VTE risk; in general, the lowest risk is seen with combined oral contraceptives that contain a second-generation progestin such as levonorgestrel. These risks are discussed in greater detail separately. (See "Combined estrogen- progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism'.) PROGNOSIS CVT can result in death or permanent disability but usually has a favorable prognosis. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 14/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Early deterioration and death Approximately 5 percent of patients die in the acute phase of the disorder [79,80]. Most of the early deaths are a consequence of CVT. A systematic review found that mortality rates among patients with CVT declined since the 1960s; increased detection of less severe cases with advances in neuroimaging along with improved hospital care may have accounted for some or all of the decreased mortality [81]. In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) that evaluated 624 patients (age >15 years) with CVT, 27 patients (4.3 percent) died during hospitalization for the acute phase, including 21 patients (3.4 percent) who died within 30 days from symptom onset [79]. Predictors of mortality at 30 days in the ISCVT were as follows [79]: Depressed consciousness Altered mental status Thrombosis of the deep venous system Right hemisphere hemorrhage Posterior fossa lesions Early mortality in children with CVT is similar to that in adults. In a European cohort of 396 children with CVT (median age 5.2 years), death in the first two weeks after presentation occurred in 12 patients (3 percent) [82]. The main cause of acute death with CVT is transtentorial herniation secondary to a large hemorrhagic lesion [79]. Other causes of early death include herniation due to multiple lesions or to diffuse brain edema, status epilepticus, medical complications, and pulmonary embolism [2]. Long-term outcome Mortality after the acute phase of CVT is predominantly related to underlying conditions. The main ISCVT report [15] performed a meta-analysis of seven prospective series and found that acute CVT was associated with a 15 percent overall death or dependency rate at the end of follow-up, which varied from 3 to 78 months. In the ISCVT study, complete recovery at the end of follow-up (median 16 months) was noted in 79 percent of the entire cohort of patients, while death was the outcome in 8 percent [15]. Predictors of poor long-term prognosis in the ISCVT were as follows [15]: Central nervous system infection Any malignancy Thrombosis of the deep venous system https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 15/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Hemorrhage on head CT or MRI Glasgow coma scale score <9 on admission ( table 3) Mental status abnormality Age >37 years Male sex The CVT risk score was designed to estimate the functional prognosis at six months after CVT onset; the score was derived using data from the original ISCVT cohort of 624 patients and validated in two smaller cohorts [83]. The score is tallied as follows: Presence of malignancy 2 points Coma on admission 2 points Thrombosis involving the deep venous system 2 points Mental status disturbance on admission 1 point Male sex 1 point Intracranial hemorrhage on admission 1 point A CVT risk score 3 was associated with a poor outcome, defined as a modified Rankin Scale ( table 4) score of >2 (dependency or death), with a high sensitivity but poor specificity (96 and 14 percent, respectively) [83]. In the ISCVT, complete recovery at six months was significantly more common for female than male patients (81 versus 71 percent), while dependency or death was less likely for females than males (12 versus 20 percent) [84]. These differences were driven entirely by the more favorable outcome for the subgroup of females who had sex-specific risk factors (mainly oral contraceptives, pregnancy, or puerperium) for CVT. Females without sex-specific risk factors had outcomes similar to males. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Epidemiology'.) Intracerebral hemorrhage present at the time of CVT diagnosis was identified in 245 patients (39 percent) of the ISCVT cohort [85]. In this subgroup with early intracerebral hemorrhage, predictors of poor prognosis at six months were older age, male sex, thrombosis of the deep cerebral venous system or of the right lateral sinus, and a motor deficit [85]. By contrast, several studies have found that a good outcome after CVT is predicted when symptoms of intracranial hypertension are the only manifestations of CVT at the time of diagnosis [46,86]. In patients with CVT presenting with isolated intracranial hypertension, a subgroup analysis of the ISCVT cohort found that poor outcome was associated with a longer diagnostic delay [87]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 16/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Recurrence The risk of recurrent CVT is approximately 2 to 4 percent, while the risk of recurrent venous thromboembolism (VTE) in other locations after CVT ranges from 4 to 7 percent. In the ISCVT study, which evaluated 624 patients with CVT over a median 16 months of follow-up, 14 (2 percent) had a recurrent CVT and 27 (4 percent) had other thrombotic events during follow-up [15]. The risks of recurrent CVT or any venous thrombosis were 1.5 and 4.1 per 100 person-years, respectively [88]. Observational data also suggest longer-term CVT recurrence rates appear to be lower than rates of recurrent VTE. In a retrospective cohort study of 706 patients with a first CVT who were followed for 6 to 297 months (median 40 months), CVT recurred in 31 patients (4 percent), and VTE in a different site occurred in 46 patients (7 percent) [89]. In another study that prospectively followed 145 patients with CVT for a median of six years after discontinuation of anticoagulant therapy, a recurrent CVT developed in five patients (3 percent), and other types of VTE developed in another 10 patients (6 percent) [90]. The risks of recurrent CVT or other types of VTE were 0.5 and 2.0 per 100 person-years, respectively. Risk factors for CVT recurrence in adults include the following [88-91]: History of prior VTE Polycythemia/thrombocythemia Clinical history or laboratory evidence of thrombophilia Male sex Black race Data on CVT recurrence and risk factors in children are limited. In the European cohort of 396 children with CVT (median age five years) followed for a median of 36 months, recurrent venous thrombosis occurred in 22 children at a median of six months, including CVT in 13 children (3 percent) [82]. There were no recurrences of CVT among children younger than 25 months. Factors independently associated with recurrent cerebral and systemic venous thrombosis in children were nonadministration of anticoagulant therapy before relapse (hazard ratio [HR] 11.2, 95% CI 3.4-37.0), persistent occlusion on repeat venous imaging (HR 4.1, 95% CI 1.1-14.8), and heterozygosity for the prothrombin (factor II) G20210A variant (HR 4.3, 95% CI 1.1-16.2) [82]. Recanalization Most patients with CVT achieve some degree of cerebral vein and sinus recanalization. A 2018 systematic review and meta-analysis identified 19 studies, mostly retrospective, that reported recanalization rates for adult patients with CVT who were treated with anticoagulation [92]. The overall recanalization rate was 85 percent among 818 patients who received follow-up imaging, with partial recanalization achieved by 35 percent and complete recanalization by 49 percent of patients. In the few studies with available data, the https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 17/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate recanalization rate increased with time, and approximately three-quarters of patients had achieved recanalization at three months. Positive predictors of recanalization were thrombosis of the superior sagittal sinus and female sex; negative predictors of recanalization were multiple thromboses, hormonal therapy, older age, and lack of identified risk factors for CVT. The meta-analysis also found that recanalization was associated with functional recovery [92]. A favorable outcome, defined as a modified Rankin Scale score ( table 4) of 0 (no symptoms) or 1 (no significant disability despite symptoms), was achieved in 319 of 357 (89 percent) patients with recanalization and in 42 of 59 (71 percent) patients without recanalization; the pooled odds ratio for a favorable outcome with recanalization was 3.3 (95% CI 1.2-8.9). In subsequent prospective cohort study of 68 patients with newly diagnosed CVT treated with anticoagulation and followed with MRI and magnetic resonance venography, early venous recanalization (confirmed by imaging on day 8 after starting anticoagulation) was associated with both regression and a reduced risk of enlargement of nonhemorrhagic lesions, including those with venous infarction [93]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Acute anticoagulation For adults with symptomatic cerebral venous thrombosis (CVT), with or without hemorrhagic venous infarction, we recommend initial anticoagulation therapy with subcutaneous low molecular weight heparin (LMWH) or intravenous heparin (Grade 1C). For children with CVT, with or without significant secondary hemorrhage, we suggest initial anticoagulation therapy with subcutaneous LMWH or intravenous heparin (Grade 2C). (See 'Initial anticoagulation' above.) Management of acute complications Complications that require intervention during the acute phase of CVT include elevated intracranial pressure, brain swelling, seizures, and infection. (See 'Other acute management issues' above.) Measures to control acutely increased intracranial pressure and impending herniation, including decompressive surgery, may be required in patients with CVT. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 18/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate For patients with CVT who have both seizures at presentation and focal cerebral supratentorial lesions (eg, edema, infarction, or hemorrhage on admission computed tomography or magnetic resonance imaging), we recommend seizure prophylaxis with an antiseizure medication (Grade 1B). For patients with a single early symptomatic seizure due to CVT in the absence of a supratentorial cerebral lesion, the benefit of seizure prophylaxis is uncertain due to low likelihood of recurrence. Seizure prophylaxis is avoided for those who have focal cerebral lesions without seizures. (See 'Seizures' above.) Antibiotic treatment is mandatory whenever there is meningitis or other intracranial infection or an infection of a neighboring structure, such as otitis or mastoiditis. Selection and duration of anticoagulation After the acute phase of CVT, we suggest anticoagulation for most patients with either a direct oral anticoagulant or warfarin for 3 to 12 months (Grade 2C). Exceptions include patients with comorbid malignancy (for whom LMWH is preferred), antiphospholipid syndrome or chronic kidney disease (for whom warfarin is preferred), and those who are pregnant (for whom heparins are preferred). (See 'Long-term anticoagulation' above and 'Selection of anticoagulant' above.) It is reasonable to continue anticoagulation for three to 6 months for patients with a provoked CVT associated with a transient risk factor ( table 2) and for 6 to 12 months for patients with an unprovoked CVT. Indefinite oral anticoagulation is reserved for patients with recurrent CVT, extracerebral venous thromboembolism after CVT, or those with an associated severe thrombophilia. (See 'Duration of anticoagulation' above.) Managing the risk of recurrence For pregnant patients with a history of CVT, we suggest temporary prophylactic anticoagulation with subcutaneous LMWH throughout pregnancy and continuing up to eight weeks postpartum (Grade 2C). For adolescent and adult females with a history of CVT, we advise not using combined oral contraceptives. Prognosis CVT is associated with a good outcome in close to 80 percent of patients. Approximately 5 percent of patients die in the acute phase of the disorder, and longer-term mortality is nearly 10 percent. The main cause of acute death with CVT is neurologic, most often from brain herniation. After the acute phase, most deaths are related to underlying disorders such as cancer. (See 'Prognosis' above.) 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Topic 1109 Version 45.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 26/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate GRAPHICS Placebo-controlled randomized trials of anticoagulants in acute cerebral venous thrombosis Einh upl et al 1991, intravenous heparin versus placebo Heparin versus placebo Outcome at three months Heparin group (n = 10) Total recovery 8 patients Residual motor deficit 2 patients Placebo group (n = 10) Total recovery 1 patient Minor residual deficit 6 patients Deaths 3 patients De Bruijn and Stam 1999, subcutaneous nadroparin versus placebo Outcome difference Nadroparin (n = 30) Placebo (n = 29) Risk difference At three weeks Deaths 2 4 BI score <15 4 3 Death or BI <15 6 (20 percent) 7 (24 percent) 4 percent (95% CI, 25 to 17 percent) At 12 weeks Deaths 2 4 Dependent (OHS 2 2 3 to 5) Death or dependent 4 (13 percent) 6 (21 percent) 7 percent (95% CI, 26 to 12 percent) BI: Barthel Index; OHS: Oxford Handicap Score. Data from: 1. Einh upl KM, Villringer A, Meister W, et al. Heparin treatment in sinus venous thrombosis. Lancet 1991; 338:597. 2. de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 1999; 30:484. Graphic 69484 Version 7.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 27/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Systemic and local conditions increasing the risk of cerebral venous thrombosis Transient risk factors Infection Central nervous system Ear, sinus, mouth, face, and neck Systemic infectious disease Pregnancy and puerperium Dehydration Mechanical precipitants Head injury Lumbar puncture Neurosurgical procedures Jugular catheter occlusion Drugs Oral contraceptives Hormone replacement therapy Androgens Asparaginase Tamoxifen Glucocorticoids Permanent risk factors Inflammatory diseases Systemic lupus erythematosus Beh et disease Granulomatosis with polyangiitis Thromboangiitis obliterans Inflammatory bowel disease Sarcoidosis Malignancy Central nervous system
61. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 62. Preter M, Tzourio C, Ameri A, Bousser MG. Long-term prognosis in cerebral venous thrombosis. Follow-up of 77 patients. Stroke 1996; 27:243. 63. Ferro JM, Correia M, Rosas MJ, et al. Seizures in cerebral vein and dural sinus thrombosis. Cerebrovasc Dis 2003; 15:78. 64. S nchez van Kammen M, Lindgren E, Silvis SM, et al. Late seizures in cerebral venous thrombosis. Neurology 2020; 95:e1716. 65. Bossoni AS, Peres MFP, Leite CDC, et al. Headache at the chronic stage of cerebral venous thrombosis. Cephalalgia 2022; 42:1476. 66. Farb RI, Vanek I, Scott JN, et al. Idiopathic intracranial hypertension: the prevalence and morphology of sinovenous stenosis. Neurology 2003; 60:1418. 67. Higgins JN, Gillard JH, Owler BK, et al. MR venography in idiopathic intracranial hypertension: unappreciated and misunderstood. J Neurol Neurosurg Psychiatry 2004; 75:621. 68. Higgins JN, Owler BK, Cousins C, Pickard JD. Venous sinus stenting for refractory benign intracranial hypertension. Lancet 2002; 359:228. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 24/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate 69. Owler BK, Parker G, Halmagyi GM, et al. Pseudotumor cerebri syndrome: venous sinus obstruction and its treatment with stent placement. J Neurosurg 2003; 98:1045. 70. Tsumoto T, Miyamoto T, Shimizu M, et al. Restenosis of the sigmoid sinus after stenting for treatment of intracranial venous hypertension: case report. Neuroradiology 2003; 45:911. 71. Ferro JM, Lopes MG, Rosas MJ, et al. Long-term prognosis of cerebral vein and dural sinus thrombosis. results of the VENOPORT study. Cerebrovasc Dis 2002; 13:272. 72. Ferro JM, Canh o P, Bousser MG, et al. Cerebral vein and dural sinus thrombosis in elderly patients. Stroke 2005; 36:1927. 73. Purvin VA, Trobe JD, Kosmorsky G. Neuro-ophthalmic features of cerebral venous obstruction. Arch Neurol 1995; 52:880. 74. Acheson JF. Optic nerve disorders: role of canal and nerve sheath decompression surgery. Eye (Lond) 2004; 18:1169. 75. de Bruijn SF, Budde M, Teunisse S, et al. Long-term outcome of cognition and functional health after cerebral venous sinus thrombosis. Neurology 2000; 54:1687. 76. Hiltunen S, Putaala J, Haapaniemi E, Tatlisumak T. Long-term outcome after cerebral venous thrombosis: analysis of functional and vocational outcome, residual symptoms, and adverse events in 161 patients. J Neurol 2016; 263:477. 77. Bushnell C, McCullough LD, Awad IA, et al. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45:1545. 78. Aguiar de Sousa D, Canh o P, Ferro JM. Safety of Pregnancy After Cerebral Venous Thrombosis: A Systematic Review. Stroke 2016; 47:713. 79. Canh o P, Ferro JM, Lindgren AG, et al. Causes and predictors of death in cerebral venous thrombosis. Stroke 2005; 36:1720. 80. Borhani Haghighi A, Edgell RC, Cruz-Flores S, et al. Mortality of cerebral venous-sinus thrombosis in a large national sample. Stroke 2012; 43:262. 81. Coutinho JM, Zuurbier SM, Stam J. Declining mortality in cerebral venous thrombosis: a systematic review. Stroke 2014; 45:1338. 82. Kenet G, Kirkham F, Niederstadt T, et al. Risk factors for recurrent venous thromboembolism in the European collaborative paediatric database on cerebral venous thrombosis: a multicentre cohort study. Lancet Neurol 2007; 6:595. 83. Ferro JM, Bacelar-Nicolau H, Rodrigues T, et al. Risk score to predict the outcome of patients with cerebral vein and dural sinus thrombosis. Cerebrovasc Dis 2009; 28:39. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 25/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate 84. Coutinho JM, Ferro JM, Canh o P, et al. Cerebral venous and sinus thrombosis in women. Stroke 2009; 40:2356. 85. Girot M, Ferro JM, Canh o P, et al. Predictors of outcome in patients with cerebral venous thrombosis and intracerebral hemorrhage. Stroke 2007; 38:337. 86. Gameiro J, Ferro JM, Canh o P, et al. Prognosis of cerebral vein thrombosis presenting as isolated headache: early vs. late diagnosis. Cephalalgia 2012; 32:407. 87. Ferro JM, Canh o P, Stam J, et al. Delay in the diagnosis of cerebral vein and dural sinus thrombosis: influence on outcome. Stroke 2009; 40:3133. 88. Miranda B, Ferro JM, Canh o P, et al. Venous thromboembolic events after cerebral vein thrombosis. Stroke 2010; 41:1901. 89. Dentali F, Poli D, Scoditti U, et al. Long-term outcomes of patients with cerebral vein thrombosis: a multicenter study. J Thromb Haemost 2012; 10:1297. 90. Martinelli I, Bucciarelli P, Passamonti SM, et al. Long-term evaluation of the risk of recurrence after cerebral sinus-venous thrombosis. Circulation 2010; 121:2740. 91. Shu L, Bakradze E, Omran SS, et al. Predictors of Recurrent Venous Thrombosis After Cerebral Venous Thrombosis: Analysis of the ACTION-CVT Study. Neurology 2022; 99:e2368. 92. Aguiar de Sousa D, Lucas Neto L, Canh o P, Ferro JM. Recanalization in Cerebral Venous Thrombosis. Stroke 2018; 49:1828. 93. Aguiar de Sousa D, Lucas Neto L, Arauz A, et al. Early Recanalization in Patients With Cerebral Venous Thrombosis Treated With Anticoagulation. Stroke 2020; 51:1174. Topic 1109 Version 45.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 26/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate GRAPHICS Placebo-controlled randomized trials of anticoagulants in acute cerebral venous thrombosis Einh upl et al 1991, intravenous heparin versus placebo Heparin versus placebo Outcome at three months Heparin group (n = 10) Total recovery 8 patients Residual motor deficit 2 patients Placebo group (n = 10) Total recovery 1 patient Minor residual deficit 6 patients Deaths 3 patients De Bruijn and Stam 1999, subcutaneous nadroparin versus placebo Outcome difference Nadroparin (n = 30) Placebo (n = 29) Risk difference At three weeks Deaths 2 4 BI score <15 4 3 Death or BI <15 6 (20 percent) 7 (24 percent) 4 percent (95% CI, 25 to 17 percent) At 12 weeks Deaths 2 4 Dependent (OHS 2 2 3 to 5) Death or dependent 4 (13 percent) 6 (21 percent) 7 percent (95% CI, 26 to 12 percent) BI: Barthel Index; OHS: Oxford Handicap Score. Data from: 1. Einh upl KM, Villringer A, Meister W, et al. Heparin treatment in sinus venous thrombosis. Lancet 1991; 338:597. 2. de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 1999; 30:484. Graphic 69484 Version 7.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 27/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Systemic and local conditions increasing the risk of cerebral venous thrombosis Transient risk factors Infection Central nervous system Ear, sinus, mouth, face, and neck Systemic infectious disease Pregnancy and puerperium Dehydration Mechanical precipitants Head injury Lumbar puncture Neurosurgical procedures Jugular catheter occlusion Drugs Oral contraceptives Hormone replacement therapy Androgens Asparaginase Tamoxifen Glucocorticoids Permanent risk factors Inflammatory diseases Systemic lupus erythematosus Beh et disease Granulomatosis with polyangiitis Thromboangiitis obliterans Inflammatory bowel disease Sarcoidosis Malignancy Central nervous system https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 28/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Solid tumour outside central nervous system Hematologic Hematologic condition Prothrombotic states, genetic or acquired Protein C deficiency Protein S deficiency Antithrombin deficiency Factor V Leiden mutation G20210A prothrombin gene mutation Antiphospholipid syndrome Myeloproliferative neoplasms Nephrotic syndrome Paroxysmal nocturnal hemoglobinuria Hyperhomocysteinemia Polycythemia, thrombocythemia Severe anemia, including paroxysmal nocturnal hemoglobinuria Central nervous system disorders Dural fistulae Other disorders Congenital heart disease Thyroid disease Graphic 65303 Version 10.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 29/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Glasgow Coma Scale and Pediatric Glasgow Coma Scale Glasgow Coma [2] Sign Pediatric Glasgow Coma Scale Score [1] Scale Eye opening Spontaneous Spontaneous 4 To command To sound 3 To pain To pain 2 None None 1 Verbal Oriented Age-appropriate vocalization, smile, or orientation to 5 response sound; interacts (coos, babbles); follows objects Confused, disoriented Cries, irritable 4 Inappropriate words Cries to pain 3 Incomprehensible sounds Moans to pain 2 None None 1 Motor Obeys commands Spontaneous movements (obeys verbal command) 6 response Localizes pain Withdraws to touch (localizes pain) 5 Withdraws Withdraws to pain 4 Abnormal flexion to Abnormal flexion to pain (decorticate posture) 3 pain Abnormal extension to pain Abnormal extension to pain (decerebrate posture) 2 None None 1 Best total score 15 The Glasgow Coma Scale (GCS) is scored between 3 and 15, with 3 being the worst and 15 the best. It is composed of 3 parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. The Pediatric Glasgow Coma Scale (PGCS) was validated in children 2 years of age or younger. Data from: 1. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974; 2:81. 2. Holmes JF, Palchak MJ, MacFarlane T, Kuppermann N. Performance of the pediatric Glasgow coma scale in children with blunt head trauma. Acad Emerg Med 2005; 12:814. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 30/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Graphic 59662 Version 14.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 31/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 32/33 7/5/23, 12:35 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Contributor Disclosures Jos M Ferro, MD, PhD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Daiichi-Sankyo [Stroke]. All of the relevant financial relationships listed have been mitigated. Patr cia Canh o, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Douglas R Nordli, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 33/33
7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cryptogenic stroke and embolic stroke of undetermined source (ESUS) : Shyam Prabhakaran, MD, MS, Chinwe Ibeh, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 19, 2023. INTRODUCTION The majority of ischemic strokes are due to cardioembolism, large vessel atherothromboembolism, small vessel occlusive disease, or other unusual mechanisms. However, many ischemic strokes occur without a well-defined etiology and are labeled as cryptogenic. This topic will provide an overview of cryptogenic stroke. A discussion of stroke classification and the clinical diagnosis of stroke subtypes is found separately. (See "Stroke: Etiology, classification, and epidemiology" and "Clinical diagnosis of stroke subtypes".) CLASSIFICATION Cryptogenic stroke The cryptogenic stroke category was devised first, for research purposes, in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Data Bank [1,2] and later modified in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) trial [3]. Classification along these lines has become increasingly used in clinical practice, as optimal management relates to the underlying mechanism. (See "Stroke: Etiology, classification, and epidemiology", section on 'TOAST classification'.) By the TOAST classification ( table 1), which is the one most commonly used in clinical practice, cryptogenic stroke (or stroke of undetermined etiology in TOAST terminology) is defined as brain https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 1/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate infarction that is not attributable to a source of definite cardioembolism, large artery atherosclerosis, or small artery disease despite a standard vascular, cardiac, and serologic evaluation. The category of stroke of undetermined etiology in the TOAST classification includes patients with less well-established potential causes of cardiac embolism, such as patent foramen ovale (PFO), aortic arch atheroma, and mitral valve strands. A limitation of the TOAST classification, however, is that stroke of undetermined etiology also includes patients with two or more equally plausible identified causes of stroke and patients in whom a diagnostic evaluation has not been performed [3]. In its most useful clinical sense, the term cryptogenic stroke designates the category of ischemic stroke for which no probable cause is found despite a thorough diagnostic evaluation [4]. In addition to TOAST, there are several other ischemic stroke classification systems that include a category for stroke of undetermined cause, as discussed in detail separately (see "Stroke: Etiology, classification, and epidemiology", section on 'SSS-TOAST and CCS classification'). Among these, the Causative Classification System (CCS) was designed to determine the most likely cause of stroke even when multiple possible mechanisms are present ( table 2) [5,6]. Embolic stroke of undetermined source Embolic stroke of undetermined source (ESUS) represents a subset of cryptogenic stroke and emphasizes the likelihood that most strokes of unexplained etiology are probably embolic from an unestablished source [4,7,8]. ESUS is defined as a nonlacunar brain infarct without proximal arterial stenosis or cardioembolic sources [7]. The concept of ESUS, moreover, implies that a full standard evaluation was done, whereas the TOAST equivalent of cryptogenic stroke did not require a full evaluation, as noted above. The criteria for ESUS are: Stroke detected by computed tomography (CT) or magnetic resonance imaging (MRI) that is not lacunar (lacunar is defined as a subcortical infarct in the distribution of the small, penetrating cerebral arteries whose largest dimension is 1.5 cm on CT or 2.0 cm on MRI diffusion images) Absence of extracranial or intracranial atherosclerosis causing 50 percent luminal stenosis of the artery supplying the area of ischemia No major-risk cardioembolic source of embolism (ie, no permanent or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumors, mitral stenosis, recent (within four weeks) myocardial infarction, left ventricular ejection fraction <30 percent, valvular vegetations, or infective endocarditis) https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 2/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate No other specific cause of stroke identified (eg, arteritis, dissection, migraine, vasospasm, drug abuse) POSSIBLE MECHANISMS Numerous mechanisms for cryptogenic stroke have been proposed. Details regarding the various mechanisms of embolic stroke of undetermined source (ESUS) are described below and broadly include: Cardiac embolism secondary to occult paroxysmal atrial fibrillation (AF), aortic atheromatous disease, or other cardiac sources Paradoxical embolism, which originates in the systemic venous circulation and enters the systemic arterial circulation through a patent foramen ovale (PFO), atrial septal defect, ventricular septal defect, or extracardiac communication such as a pulmonary arteriovenous malformation Undefined thrombophilia (ie, hypercoagulable states including those related to antiphospholipid antibodies or to occult cancer with hypercoagulability of malignancy) Substenotic cerebrovascular disease (ie, intracranial and extracranial atherosclerotic disease causing less than 50 percent stenosis) and other vasculopathies (eg, dissection) In a single-center analysis using a machine-learning classifier to distinguish between cardioembolic and noncardioembolic subtypes of stroke, the classifier predicted that 44 percent of ESUS was due to occult cardioembolic sources [9]. In an analysis of the NAVIGATE-ESUS trial, which enrolled 7213 patients, the most commonly identified potential sources of embolism were atrial cardiopathy (37 percent), left ventricular disease (36 percent), and arterial atherosclerotic disease (29 percent) [10]. In studies of thrombi extracted from cerebral vessels in the setting of large vessel occlusions, the histologic composition of thrombi from patients with cryptogenic stroke is similar to that of those with cardioembolic stroke, providing further indirect evidence that most cryptogenic strokes are due to emboli from undetermined cardiac causes [11]. It is also likely that important but unidentified mechanisms exist, awaiting discovery. Embolism from occult sources in the heart or aorta The embolic appearance of most cryptogenic strokes implies that the cause is embolism from an occult source in the heart, aorta, or large artery. Cardioaortic conditions with a low or uncertain risk for embolic stroke include difficult to diagnose ("occult") or subclinical atrial fibrillation and related atrial cardiopathies, atrial septal abnormalities, complex aortic atheroma, and others listed in the table ( table 3). https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 3/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Occult atrial fibrillation Occult paroxysmal AF refers to asymptomatic paroxysmal AF in a patient without a prior history of AF, which is detected only by monitoring techniques. Evidence linking occult AF and cryptogenic stroke comes from the prospective ASSERT study of 2580 subjects, age 65 years, with hypertension and no history of AF who had recent implantation of a pacemaker or defibrillator [12]. At three months, subclinical atrial tachyarrhythmias detected by the implanted devices had occurred in 10 percent of patients and were associated with an increased risk (at a mean of 2.5 years) for clinical AF (hazard ratio [HR] 5.6, 95% CI 3.8-8.2) and for the combined endpoint of ischemic stroke or systemic embolism (HR 2.5, 95% CI 1.3-4.9). Among subjects with at least three months of continuous monitoring who experienced ischemic stroke or systemic embolism (n = 51), subclinical AF was detected overall in 26 (51 percent) [13]. However, subclinical AF occurring 30 days before ischemic stroke or systemic embolism was detected in only 4 subjects (8 percent). Thus, while subclinical AF was associated with an increased risk of embolic events, there was no definite temporal relationship of subclinical AF with stroke in most subjects. Atrial septal abnormalities Atrial septal abnormalities, including PFO, atrial septal aneurysm, and atrial septal defect, have been associated with cryptogenic stroke. There is an increased prevalence of PFO and atrial septal aneurysm in patients who have had an otherwise unexplained stroke. In addition, there is high-quality evidence that PFO closure reduces the risk of recurrence in patients age 60 years with an embolic-appearing ischemic stroke who have a medium- to high-risk PFO and no other evident source of stroke despite a comprehensive evaluation. In this setting. it is reasonable to conclude that paradoxical embolism through a PFO is the most likely stroke mechanism. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Risk of embolic stroke' and "Stroke associated with patent foramen ovale (PFO): Evaluation".) Atrial cardiopathies Structural and functional changes in the atria may increase the risk of thrombus formation and embolization. Markers of left atrial cardiopathy include left atrial enlargement, atrial fibrosis, elevated pro-brain natriuretic peptide (proBNP), increased P wave terminal force velocity in lead V1 (PWTFV1), and atrial fibrillation. Even in the absence of diagnosed atrial fibrillation, biomarkers of atrial dysfunction are associated with an increased risk of ischemic stroke [14-16]. For example, serum troponin and proBNP are associated with both AF and stroke. Similarly, PWTFV1, a measure of atrial contraction that can be measured on the electrocardiogram, is associated with stroke risk even in the absence of AF [17]. Although cardioembolism is presumed to be the most likely mechanism of stroke in patients with elevated proBNP or PWTFV1, it is difficult to establish a cause-and-effect relationship between these elevated cardiac biomarkers and occult cardioembolism; the association is confounded because https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 4/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate cardiac disease and elevated cardiac biomarkers are also markers of systemic atherosclerosis. In addition, these biomarkers are not widely available in clinical practice and their utility for management is still uncertain. However, biomarkers have the advantage of being measurable at the time of stroke without the need for long-term monitoring, and thus provide the potential to detect a high risk of cardioembolism. Further prospective study, including clinical trials, is needed to confirm that any of these biomarkers reliably predict a cardioembolic stroke mechanism and response to anticoagulant therapy in secondary stroke prevention. Aortic embolism Thoracic aortic atherosclerotic plaques are an important potential source of systemic emboli, leading to stroke, transient ischemic attack, and embolization to other arterial beds. The risk of thromboembolism in patients with aortic atherosclerosis is increased when there is complex plaque, which is defined as thickness >4 mm or ulceration. (See "Thromboembolism from aortic plaque", section on 'Complex aortic plaque'.) Besides proximal aortic atheromas, distal aortic sources of embolism have been proposed as a potential cause for cryptogenic stroke. One study using cardiac MRI suggested that complex atheromas in the descending aortic arch could lead to stroke via retrograde flow [18]. During diastole, retrograde flow in the descending aorta reached the great vessels supplying the brain in up to 24 percent of patients with cryptogenic stroke. This finding suggests that embolic material in the descending aortic arch could enter the cerebral vasculature during retrograde flow and cause ischemic stroke. Other potential causes of stroke include coarctation of the aorta and aortic dissection. The relationship of aortic embolism and stroke is reviewed in detail separately. (See "Stroke: Etiology, classification, and epidemiology", section on 'Aortic atherosclerosis' and "Thromboembolism from aortic plaque".) Pulmonary shunts Based on limited evidence, intrapulmonary right-to-left shunts due to pulmonary arteriovenous malformations or arteriovenous fistulas have been associated with cryptogenic stroke in several small studies [19-23]. This association does not prove causation; further studies are needed to define the relationship between intrapulmonary shunt and cryptogenic stroke. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults", section on 'Neurologic'.) Substenotic atherosclerotic disease Some cases of cryptogenic stroke may be caused by undetected large vessel disease, including occult atherosclerosis and nonstenosing, unstable plaques [24-28]. Imaging features of substenotic (<50 percent) carotid disease that have been https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 5/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate associated with increased stroke risk include plaque ulceration, plaque thickness >3 mm, intraplaque hemorrhage, fibrous cap rupture, lipid-rich core, and plaque echolucency [26]. In a Canadian cohort of 138 patients with ESUS, nonstenotic carotid plaques (<50 percent stenosis) were present in 39 percent of patients and were more frequently ipsilateral to the side of the stroke compared with contralateral (61 versus 39 percent, adjusted odds ratio 1.83, 95% CI 1.05-3.18) [27]. In another report of 579 patients who had anterior circulation stroke and were studied with brain magnetic resonance imaging (MRI) and neck magnetic resonance angiography (MRA) intraplaque hemorrhage on neck MRA was more common ipsilateral to brain infarction in cryptogenic stroke compared with contralateral (relative risk 2.1, 95% CI 1.4-3.1) [25]. Among 197 patients with ESUS, the presence of intraplaque hemorrhage ipsilateral to brain infarction allowed 41 patients (21 percent) to be reclassified from ESUS to large artery atherosclerosis. Data from autopsy studies suggest that ischemic stroke can be associated with lesser degrees of extracranial and intracranial large vessel stenosis (eg, 30 to 70 percent) or with vulnerable plaques without appreciable luminal compromise. In a case-control study that included 259 patients with fatal ischemic stroke, intracranial atherosclerotic plaques (with or without stenosis) were noted in 62 percent [29]. Furthermore, plaques with superimposed thrombi and stenosis of 30 to 70 percent were considered responsible for infarcts in four cases (1.5 percent), a group that would have been classified as cryptogenic in nonautopsy studies. In a subsequent study from the same investigators, plaques and stenoses involving the origin or proximal vertebral artery were present in more than twice as many patients with infarcts in posterior circulation as compared with anterior circulation infarcts (adjusted odds ratio 2.10, 95% CI 1.01-4.38) [30]. These lesions may be responsible for a larger proportion of strokes in the brainstem and posterior circulation than previously appreciated. Other causes Infection and associated thrombophilia may be a cause of unexplained stroke in young, otherwise healthy patients. As an example, coronavirus disease 2019 (COVID-19) may be a cause of otherwise unexplained strokes. In addition to traditional stroke mechanisms, potential mechanisms of ischemic stroke related to COVID-19 include thromboinflammation, severe inflammation, renin-angiotensin-aldosterone system dysfunction, cardiac dysfunction, and the consequences of severe respiratory illness [31]. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Cerebrovascular disease'.) Furthermore, subtle or undetected abnormalities of the large arteries, coagulation system, and genetic factors may be missed during the initial evaluation. These conditions include: https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 6/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Nonatherosclerotic vasculopathies, such as dissection, fibromuscular dysplasia, reversible cerebral vasoconstriction syndromes (RCVS), and vasculitis. Occult hypercoagulable states, such as the antiphospholipid syndrome, genetic thrombophilia, and hypercoagulable state associated with malignancy. Rare genetic conditions may present with stroke in the young; monogenic syndromes associated with an increased risk of ischemic stroke include Fabry disease, cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), sickle cell disease, and hereditary thrombotic thrombocytopenic purpura (TTP). However, detection of any of the above conditions would generally alter the diagnostic classification of stroke from cryptogenic stroke to stroke of other determined cause. In practice, an initial diagnosis of cryptogenic stroke may thus yield over time to a later diagnosis of a specific cause. Therefore, a diagnosis of cryptogenic stroke can be regarded as provisional until diagnostic testing is completed. EPIDEMIOLOGY AND RISK FACTORS Large epidemiologic studies have consistently reported that cryptogenic stroke accounts for 25 to 40 percent of ischemic stroke [32-40]. The incidence and prevalence of stroke subtypes among these studies may vary based upon the demographics of the study population, diagnostic definitions, extent of diagnostic evaluation, and methodology. Thus, it is conceivable that some strokes of other determined cause (eg, migraine, dissection, vasculitis) were misclassified in the undetermined category (ie, as cryptogenic) due to inadequate work-up or the limitations of diagnostic detection. However, given the rarity of these other causes in most registries (usually representing less than 5 percent of all strokes), this would not account for all cryptogenic strokes. Demographic factors The risk of cryptogenic stroke may vary by demographics, with higher incidence rates in Black and Hispanic populations compared with White populations, but no clear association has been found for age or sex. With the exception of the strokes classified in TOAST as "other determined etiology" (which includes dissection), all stroke subtypes are rare in the young, and incidence rates rise dramatically with increasing age. A few studies have reported that cryptogenic stroke disproportionately affects younger individuals, but the evidence is inconsistent. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 7/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate In the Northern Manhattan Stroke Study (NOMASS, 1993 to 1996), 55 percent of strokes in the young (age <45 years) were cryptogenic versus 42 percent in the older (age >45 years) group [41]. In a 2003 meta-analysis, young age (defined as <50 years) was inversely associated with cryptogenic stroke with a total odds ratio of 0.6 (95% CI 0.4-1.0, p = 0.05) [34]. Other stroke registries found lower rates (23 to 34 percent) in younger age groups, which were similar to those in older age groups [42-44]. The incidence of cryptogenic stroke may be higher in Black Americans and Hispanic Americans than in White Americans. In NOMASS, incidence rates of all ischemic stroke subtypes, including cryptogenic stroke, were higher in Black Americans and Hispanic Americans than in White Americans [45]. In the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS), Black Americans had twice the annual incidence rate of cryptogenic stroke as White Americans (125 versus 65 per 100,000 persons), a result not confounded by differential testing patterns among Black American versus White American patients [46]. In San Diego, an increased prevalence (nearly 46 percent) of cryptogenic stroke was seen in Mexican American patients, a statistic again that was not explained by differences in diagnostic testing [47]. The higher rates of cryptogenic stroke in Black and Hispanic Americans may be due to several dynamics affecting these populations, including higher rates of all ischemic stroke subtypes, possible underdetection of cardioembolic and large vessel stroke, and/or other unidentified factors [45,48]. Other risk factors Although risk factors often help unravel stroke mechanisms and may overlap with mechanisms, stroke risk factors and mechanisms are conceptually distinct. Thus, the presence of hypertension (ie, a risk factor) does not preclude the etiologic classification (ie, mechanism) of cryptogenic stroke. While it is possible to compare risk factors for cryptogenic stroke versus other stroke subtypes, the comparison is hindered in large part by definitional constraints. As an example, atrial fibrillation will be rare in cryptogenic stroke because of the way in which the subtypes are defined. In addition, risk factors that are associated with large artery ischemic stroke (eg, hypertension, hyperlipidemia, peripheral vascular disease, and diabetes mellitus) and cardioembolic stroke (eg, acute coronary events) are underrepresented in patients with cryptogenic stroke [37]. Several studies have documented that hypertension is less common in cryptogenic stroke compared with other stroke subtypes [34,35,37,38,46,49]. However, patients with cryptogenic stroke may have an increased prevalence of hypertension compared with stroke-free controls, https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 8/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate and one case-control study found that hypertension was associated with cryptogenic stroke (odds ratio 4.5, 95% CI 1.5-13.2) [50]. The prevalence of cardiac disease among patients with cryptogenic stroke varies from 10 to 30 percent. In Rochester, coronary artery disease was less common in the undetermined (ie, cryptogenic) subtype than in the large artery atherosclerosis subtype [32]. Studies assessing the prevalence of prothrombotic states and genetic polymorphisms predisposing individuals to thrombosis have not yielded convincing evidence that these are more common in patients with cryptogenic stroke than nonstroke controls [51-54]. Nevertheless, the available reports are small and not definitive. CLINICAL FEATURES Like patients with embolic stroke, patients with cryptogenic stroke typically present with sudden onset of focal neurologic deficits; most will have a superficial hemispheric ("embolic") infarct topography on brain imaging. They may also present with syndromes indicative of cortical involvement, such as aphasia, or faciobrachial motor syndromes rather than syndromes involving the entire hemibody. In one study of patients with cryptogenic stroke, cortical signs were present in 27 percent, and abrupt onset occurred in 59 percent [55]. Lacunar syndromes are rare, accounting for usually less than 5 percent [56,57]. The severity of the initial presentation varies but, on average, tends to be milder than cardioembolic strokes and worse than lacunar strokes [38,55,57-59]. Superficial hemispheric infarction is present in 62 to 84 percent of patients [56,57]. Forty percent of cryptogenic strokes in the Stroke Data Bank were found to have cortical infarcts [56]. Among 314 patients with cryptogenic stroke in the PFO-ASA study, 56 percent had superficial infarcts [55]. The German Stroke Study found that parenchymal hemorrhagic transformation occurred in approximately 2 percent of patients with stroke of unknown etiology in the first seven days, comparable to the percentage among cardioembolic stroke, suggesting an embolic mechanism [38]. Large subcortical strokes (>15 mm) also tend to be either cryptogenic or cardioembolic in origin. In a nationwide study of registry data from the United States, patients with cryptogenic stroke had milder presentations based on the National Institutes of Health Stroke Scale (NIHSS) score than patients with cardioembolic stroke (median NIHSS 3 versus 5) [60]. While cryptogenic stroke is often associated with cortical syndromes and milder deficits, stroke subtypes cannot be distinguished on the basis of clinical symptoms alone. In patients with cryptogenic stroke, the most frequently found abnormalities with echocardiography are patent foramen ovale (PFO), atrial septal aneurysm (ASA), and aortic https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 9/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate atheromas [61,62]. The timing of transesophageal echocardiography (<72 hours versus >72 hours) in relation to the index stroke does not appear to alter sensitivity [63]. The clinical significance of many of these findings is still unclear, with conflicting studies on the relative risks and appropriate management. EVALUATION AND DIAGNOSIS In its most useful clinical role, cryptogenic stroke is a diagnosis of exclusion based upon a thorough investigation for potential stroke etiologies. The diagnosis of cryptogenic stroke is made when a standard evaluation (see 'Standard evaluation' below) reveals no probable cause; there is no definite evidence of cardioembolism, large artery atherosclerosis (stenosis >50 percent) in the vessel supplying the area of infarction, small artery disease, or other determined etiology, and no evidence of atrial fibrillation on a 12-lead electrocardiogram (ECG) or on 24-hour cardiac monitoring. Patient age influences the relative likelihood of possible ischemic stroke mechanisms [4]. Cervicocephalic artery dissection is the most common cause in young adults (variably defined as <45 years of age); other considerations include congenital cardiac defects, recent pregnancy, hypercoagulable states, illicit drug use, metabolic disorders, and migraine. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Etiologies and risk factors in young adults'.) Premature atherosclerosis and acquired cardiac disease are increasingly prevalent in adults older than 30 years of age, and occult atrial fibrillation is increasingly discovered in patients older than 60 years of age [4]. Standard evaluation The standard evaluation of patients with acute ischemic stroke includes a history and physical examination, brain imaging to determine the location and topography of the lesion, and vessel imaging and a cardiac evaluation to help determine the most likely cause. Laboratory testing typically includes a complete blood count, cardiac enzymes and troponin, prothrombin time, international normalized ratio (INR), and activated partial thromboplastin time. Additional studies can be pursued if the standard evaluation fails to determine the probable cause. (See "Initial assessment and management of acute stroke" and "Overview of the evaluation of stroke".) Brain imaging Urgent brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is mandatory in all patients with sudden neurologic deterioration or https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 10/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate acute stroke (see "Neuroimaging of acute stroke"). Brain MRI with diffusion-weighted imaging is superior to noncontrast CT for the detection of acute ischemia, small infarcts, and infarcts located in the brainstem. The localization, topography, and distribution of ischemic brain lesions on MRI and CT can suggest a specific stroke mechanism [4,64]: Isolated superficial cerebral or cerebellar infarction suggests an embolic mechanism from a large artery, heart, or aorta Cortical or large subcortical infarcts in multiple vascular territories suggest a proximal source of embolism from the heart or aorta Infarcts of varying age in a single vascular territory suggest a large artery source of embolism Infarcts along the boundary regions between the major cerebral arteries (ie, border zone or watershed regions) suggest the stroke mechanism is low flow (hypoperfusion) or multiple small emboli Small subcortical infarcts suggest lacunar infarction from small vessel disease The diagnosis of small vessel disease as the cause of ischemic stroke is generally confirmed by neuroimaging when the location of a small noncortical infarct on CT or MRI correlates with the clinical features of a lacunar stroke syndrome. However, a small deep infarct may be considered cryptogenic when found in a patient <50 years of age with no standard vascular risk factors and no white matter hyperintensities or prior small deep infarcts [4,65]. Vessel imaging Vessel imaging to identify the lesion (eg, atherosclerotic stenosis or occlusion, dissection) responsible for stroke can be done with magnetic resonance angiography (MRA), computed tomography angiography (CTA), carotid duplex ultrasonography and transcranial Doppler ultrasonography, or conventional angiography (see "Neuroimaging of acute stroke"). Neurovascular imaging should assess the extracranial (internal carotid and vertebral) and intracranial (internal carotid, vertebral, basilar, and Circle of Willis) large vessels. Noninvasive methods are generally used unless urgent endovascular therapy is planned. MRA or CTA is preferred, while the combination of ultrasound methods (duplex and transcranial Doppler) can be used if CTA and MRA are unavailable or contraindicated. Availability and expertise at individual centers are major factors in the choice of the initial noninvasive neurovascular studies. Various neuroimaging modalities may be used to confirm a diagnosis of dissection, but fat- saturated T1 MRI is capable of revealing the intramural hematoma caused by dissection in vessels that otherwise have a normal appearance on MRA and CTA. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Choice of neuroimaging study'.) https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 11/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Conventional angiography is usually reserved for situations where acute intraarterial intervention is being considered and for follow-up when noninvasive studies are inconclusive. Cardiac and aortic evaluation The basic cardiac evaluation of acute ischemic stroke includes an electrocardiogram, cardiac monitoring for at least the first 24 hours after stroke onset to look for occult atrial fibrillation (AF), and echocardiography. (See "Overview of the evaluation of stroke", section on 'Cardiac evaluation'.) Both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) are effective diagnostic tests for the evaluation of suspected cardioaortic source of embolism. In most patients, TEE yields higher quality images and has a greater sensitivity and specificity than TTE, but a few conditions (eg, left ventricular thrombus) are better seen on TTE. However, TEE is an uncomfortable invasive procedure that may not be tolerated by very ill patients. Because it is less invasive and readily available in most institutions, TTE is often reasonable as the initial test of choice (see "Echocardiography in detection of cardiac and aortic sources of systemic embolism"). TTE is the preferred initial test for the majority of patients with a suspected cardiac or aortic source of emboli, including: Patients 45 years Patients with a high suspicion of left ventricular thrombus Patients in whom TEE is contraindicated (eg, esophageal stricture, unstable hemodynamic status) or who refuse TEE TEE may be especially helpful to localize the source of embolism in the following circumstances: Patients <45 years without known cardiovascular disease (ie, absence of myocardial infarction or valvular disease history) Patients with a high pretest probability of a cardiac embolic source in whom a negative TTE would be likely to be falsely negative Patients with atrial fibrillation and suspected left atrial or left atrial appendage thrombus, especially in the absence of therapeutic anticoagulation, but only if the TEE would impact management Patients with a mechanical or bioprosthetic heart valve or suspected infectious or marantic endocarditis Patients with suspected aortic pathology For patients 60 years of age with an embolic-appearing cryptogenic stroke or TIA, particularly those who lack cardiovascular risk factors, we suggest TEE when TTE is nondiagnostic. The TEE https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 12/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate should be performed with color Doppler study and agitated saline contrast injection at rest, with cough, and Valsalva maneuver. Although data are limited, a prospective study of 61 patients with embolic stroke of undetermined source (ESUS) found that abnormalities on TEE changed the therapeutic strategy in 16 percent [66]. Another prospective study enrolled patients with ischemic stroke, TIA, or retinal infarction of undetermined cause prior to cardiac imaging (and therefore not selected by criteria for ESUS); for 453 patients evaluated with both TTE and TEE, the treatment was changed after TEE in approximately 3 percent, and the classification of the cause of stroke was changed in 11.5 percent [67]. Transcranial Doppler with agitated saline may also be used to identify patent foramen ovale (PFO), atrial septal defect, and intrapulmonary shunting, and appears to be more sensitive than echocardiography to identify and quantify right-to-left intracardiac shunting [68]. TEE may provide greater morphological detail of the atrial septal wall, however. (See "Patent foramen ovale", section on 'Diagnosis and evaluation' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PFO assessment'.) Evaluation for PFO-associated stroke The diagnosis of stroke or TIA due to paradoxical embolism through a PFO or atrial septal defect has traditionally been one of exclusion; a PFO or atrial septal defect has been considered a potential cause of cryptogenic embolic stroke or TIA in patients who are 60 years of age with no other identifiable cause. However, it is now recognized that patients with an embolic stroke who have a medium- or high-risk PFO and who have no other identified stroke etiology should be recognized as having a PFO-associated stroke. Stroke risk classification of PFO is based on anatomic and clinical factors including shunt size, presence or absence of atrial septal aneurysm, and/or venous thromboembolism and is discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PFO assessment'.) A relatively simple scoring system incorporating age of the patient, traditional stroke risk factors, and prior history of stroke can be used to estimate the likelihood that an otherwise unexplained stroke could be attributed to a PFO. The Risk of Paradoxical Embolism (RoPE) score ( table 4) estimates the probability that a PFO is incidental or pathogenic in a patient with an otherwise-cryptogenic stroke. The PFO-attributable fraction of stroke derived from the RoPE score ( table 5) varies widely and decreases with age and the presence of vascular risk factors. High RoPE scores, as found in younger patients who lack vascular risk factors and have a cortical infarct on neuroimaging, suggest pathogenic, higher risk PFOs. By contrast, low RoPE scores, as found in older patients with vascular risk factors, suggest incidental, lower-risk PFOs. The score can thus be used to help neurologists and cardiologists decide which patients should undergo PFO closure. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 13/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate The PFO-associated stroke causal likelihood (PASCAL) classification system estimates the probability that stroke is associated with a PFO in patients with embolic infarct topography and without other major sources of ischemic stroke [69]. The classification uses the RoPE score combined with anatomic and clinical factors and categorizes the likelihood that the stroke is caused by a PFO as unlikely, possible, probable, highly probable, or definite, as shown in the table ( table 6). (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification'.) In presence of a PFO or atrial septal defect, it is reasonable to search for a source of thrombus in the leg veins with Doppler of the lower extremities as standard test and obtain a hypercoagulable panel in those <45 years of age. Pelvic magnetic resonance venography is of limited utility but could be used in specific scenarios (eg, recent pelvic surgery or mass) [70,71]. Advanced evaluation Additional testing, particularly further cardiac monitoring for atrial fibrillation, is warranted for patients with ischemic stroke when the cause is undetermined despite a standard evaluation described above. However, there is no consensus or strong evidence base regarding the use of more advanced or specialized investigations for rare causes of ischemic stroke [72]. Prolonged cardiac monitoring We suggest ambulatory cardiac monitoring for several weeks (eg, 30 days) for adult patients with a cryptogenic ischemic stroke or cryptogenic TIA (ie, no atrial fibrillation on initial monitoring) who have any of the following [73-76]: Age 50 years or older Abnormal P wave morphology on ECG Frequent ectopy or paroxysmal tachycardia on ECG or short-term monitoring/telemetry Atrial enlargement by echocardiography Elevated cardiac biomarkers such as N-terminal pro-brain natriuretic peptide (NT- proBNP) or troponin T Family history of atrial fibrillation The rationale is that paroxysmal atrial fibrillation, if transient, infrequent, and largely asymptomatic, may be undetected on standard cardiac monitoring such as continuous
Cardiac and aortic evaluation The basic cardiac evaluation of acute ischemic stroke includes an electrocardiogram, cardiac monitoring for at least the first 24 hours after stroke onset to look for occult atrial fibrillation (AF), and echocardiography. (See "Overview of the evaluation of stroke", section on 'Cardiac evaluation'.) Both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) are effective diagnostic tests for the evaluation of suspected cardioaortic source of embolism. In most patients, TEE yields higher quality images and has a greater sensitivity and specificity than TTE, but a few conditions (eg, left ventricular thrombus) are better seen on TTE. However, TEE is an uncomfortable invasive procedure that may not be tolerated by very ill patients. Because it is less invasive and readily available in most institutions, TTE is often reasonable as the initial test of choice (see "Echocardiography in detection of cardiac and aortic sources of systemic embolism"). TTE is the preferred initial test for the majority of patients with a suspected cardiac or aortic source of emboli, including: Patients 45 years Patients with a high suspicion of left ventricular thrombus Patients in whom TEE is contraindicated (eg, esophageal stricture, unstable hemodynamic status) or who refuse TEE TEE may be especially helpful to localize the source of embolism in the following circumstances: Patients <45 years without known cardiovascular disease (ie, absence of myocardial infarction or valvular disease history) Patients with a high pretest probability of a cardiac embolic source in whom a negative TTE would be likely to be falsely negative Patients with atrial fibrillation and suspected left atrial or left atrial appendage thrombus, especially in the absence of therapeutic anticoagulation, but only if the TEE would impact management Patients with a mechanical or bioprosthetic heart valve or suspected infectious or marantic endocarditis Patients with suspected aortic pathology For patients 60 years of age with an embolic-appearing cryptogenic stroke or TIA, particularly those who lack cardiovascular risk factors, we suggest TEE when TTE is nondiagnostic. The TEE https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 12/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate should be performed with color Doppler study and agitated saline contrast injection at rest, with cough, and Valsalva maneuver. Although data are limited, a prospective study of 61 patients with embolic stroke of undetermined source (ESUS) found that abnormalities on TEE changed the therapeutic strategy in 16 percent [66]. Another prospective study enrolled patients with ischemic stroke, TIA, or retinal infarction of undetermined cause prior to cardiac imaging (and therefore not selected by criteria for ESUS); for 453 patients evaluated with both TTE and TEE, the treatment was changed after TEE in approximately 3 percent, and the classification of the cause of stroke was changed in 11.5 percent [67]. Transcranial Doppler with agitated saline may also be used to identify patent foramen ovale (PFO), atrial septal defect, and intrapulmonary shunting, and appears to be more sensitive than echocardiography to identify and quantify right-to-left intracardiac shunting [68]. TEE may provide greater morphological detail of the atrial septal wall, however. (See "Patent foramen ovale", section on 'Diagnosis and evaluation' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PFO assessment'.) Evaluation for PFO-associated stroke The diagnosis of stroke or TIA due to paradoxical embolism through a PFO or atrial septal defect has traditionally been one of exclusion; a PFO or atrial septal defect has been considered a potential cause of cryptogenic embolic stroke or TIA in patients who are 60 years of age with no other identifiable cause. However, it is now recognized that patients with an embolic stroke who have a medium- or high-risk PFO and who have no other identified stroke etiology should be recognized as having a PFO-associated stroke. Stroke risk classification of PFO is based on anatomic and clinical factors including shunt size, presence or absence of atrial septal aneurysm, and/or venous thromboembolism and is discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PFO assessment'.) A relatively simple scoring system incorporating age of the patient, traditional stroke risk factors, and prior history of stroke can be used to estimate the likelihood that an otherwise unexplained stroke could be attributed to a PFO. The Risk of Paradoxical Embolism (RoPE) score ( table 4) estimates the probability that a PFO is incidental or pathogenic in a patient with an otherwise-cryptogenic stroke. The PFO-attributable fraction of stroke derived from the RoPE score ( table 5) varies widely and decreases with age and the presence of vascular risk factors. High RoPE scores, as found in younger patients who lack vascular risk factors and have a cortical infarct on neuroimaging, suggest pathogenic, higher risk PFOs. By contrast, low RoPE scores, as found in older patients with vascular risk factors, suggest incidental, lower-risk PFOs. The score can thus be used to help neurologists and cardiologists decide which patients should undergo PFO closure. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 13/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate The PFO-associated stroke causal likelihood (PASCAL) classification system estimates the probability that stroke is associated with a PFO in patients with embolic infarct topography and without other major sources of ischemic stroke [69]. The classification uses the RoPE score combined with anatomic and clinical factors and categorizes the likelihood that the stroke is caused by a PFO as unlikely, possible, probable, highly probable, or definite, as shown in the table ( table 6). (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification'.) In presence of a PFO or atrial septal defect, it is reasonable to search for a source of thrombus in the leg veins with Doppler of the lower extremities as standard test and obtain a hypercoagulable panel in those <45 years of age. Pelvic magnetic resonance venography is of limited utility but could be used in specific scenarios (eg, recent pelvic surgery or mass) [70,71]. Advanced evaluation Additional testing, particularly further cardiac monitoring for atrial fibrillation, is warranted for patients with ischemic stroke when the cause is undetermined despite a standard evaluation described above. However, there is no consensus or strong evidence base regarding the use of more advanced or specialized investigations for rare causes of ischemic stroke [72]. Prolonged cardiac monitoring We suggest ambulatory cardiac monitoring for several weeks (eg, 30 days) for adult patients with a cryptogenic ischemic stroke or cryptogenic TIA (ie, no atrial fibrillation on initial monitoring) who have any of the following [73-76]: Age 50 years or older Abnormal P wave morphology on ECG Frequent ectopy or paroxysmal tachycardia on ECG or short-term monitoring/telemetry Atrial enlargement by echocardiography Elevated cardiac biomarkers such as N-terminal pro-brain natriuretic peptide (NT- proBNP) or troponin T Family history of atrial fibrillation The rationale is that paroxysmal atrial fibrillation, if transient, infrequent, and largely asymptomatic, may be undetected on standard cardiac monitoring such as continuous telemetry and 24- or 48-hour Holter monitors. The optimal monitoring method (ie, continuous telemetry, ambulatory electrocardiography, serial ECG, transtelephonic ECG monitoring, or insertable cardiac monitor, also sometimes referred to as implantable cardiac monitor or implantable loop recorder) is uncertain, though longer durations of monitoring are likely to obtain the highest diagnostic yield. (See "Overview of the evaluation of stroke", section on 'Monitoring for subclinical atrial fibrillation'.) https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 14/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Advanced cardiac imaging Cardiac structural imaging with MRI can be helpful for identifying potential sources of embolism that may be missed by echocardiography, including left ventricular thrombi, isolated left ventricular noncompaction, and complex aortic atheroma [64,77]. (See "Clinical utility of cardiovascular magnetic resonance imaging" and "Isolated left ventricular noncompaction in adults: Clinical manifestations and diagnosis" and "Thromboembolism from aortic plaque".) Cardiac CT and CT angiography may also be useful for the detection of cardiac thrombi and to assess left ventricular morphology [78-83]. (See "Cardiac imaging with computed tomography and magnetic resonance in the adult".) Vascular studies Advanced vascular imaging can be useful for demonstrating lesions that escape detection on standard MRA and CTA. These are considered in specific scenarios such as small vessel vasculitis or vasculopathy (eg, catheter angiography) or subclinical atherosclerotic plaques (eg, high-resolution MRA). Conventional angiography is superior to standard noninvasive methods (MRA, CTA, and ultrasonography) for visualizing small and medium sized arteries. Digital subtraction angiography, the most widely used method of conventional catheter-based angiography, remains the gold standard for determining the degree of arterial stenosis and for identifying some nonatherosclerotic vasculopathies (see "Neuroimaging of acute stroke", section on 'Digital subtraction angiography'). The yield of catheter angiography may be highest in the first hours after stroke onset, since vascular abnormalities may resolve in the acute phase [4]. Monitoring with transcranial Doppler (TCD) ultrasonography for 30 to 60 minutes may be useful to detect asymptomatic microemboli arising from the heart, aorta, or large arteries, and thereby point to the possible embolic source of the cryptogenic stroke. (See "Management of asymptomatic extracranial carotid atherosclerotic disease", section on 'Asymptomatic embolism'.) Advanced, high-resolution MRI techniques allow direct visualization of the vessel wall, rather than just luminal narrowing as detected by conventional imaging [84]. These methods show promise for the evaluation of intracranial arterial pathology, such as differentiating atherosclerotic, vasospastic, and inflammatory vasculopathies, demonstrating nonstenotic plaques that occlude penetrating arteries, and identifying features that suggest plaque vulnerability, including in substenotic plaques (see 'Substenotic atherosclerotic disease' above) [85-89]. However, high-resolution MRI has https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 15/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate limited availability and requires further study to establish reliability and to determine how well imaging findings correlate with vessel pathology [84]. Hematologic testing Hematologic testing for arterial hypercoagulable states (eg, antiphospholipid syndrome and hyperhomocysteinemia) is indicated for many patients with cryptogenic stroke, particularly for patients who are young, have a history of lupus or symptoms compatible with lupus, or have features suggestive of antiphospholipid syndrome such as unexplained venous or arterial thrombotic events, miscarriages, or unexplained thrombocytopenia [90]. (See "Clinical manifestations of antiphospholipid syndrome" and "Overview of homocysteine", section on 'Vascular disease'.) In addition to testing for the antiphospholipid syndrome, additional testing for hypercoagulable states associated with venous thrombosis (eg, Factor V Leiden mutation, prothrombin gene mutation, protein S deficiency, protein C deficiency, and antithrombin deficiency) is suggested by some experts for patients with evidence of a cardiac or pulmonary right-to-left shunt [4]. For patients with cryptogenic stroke and systemic or constitutional symptoms suggestive of vasculitis, screening tests include erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum cryoglobulins, antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), and complement levels. (See "Overview of and approach to the vasculitides in adults".) Another consideration is testing ADAMTS13 activity, particularly in patients with low platelet counts; in rare cases, ischemic stroke may be the presenting finding or occur during remission in individuals with thrombotic thrombocytopenic purpura (TTP), which is caused by deficient activity of the ADAMTS13 protease [91-93]. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'TTP pathogenesis'.) Specialized evaluation In some patients with recurrent cryptogenic stroke in whom standard and advanced evaluations are nondiagnostic, a search for other rare causes may be indicated [4]. Specialized testing may include the following investigations: Testing for occult malignancy with mammography, stool Hemoccult, and CT of the chest, abdomen, and pelvis. A lumbar puncture with cerebrospinal fluid analysis for patients with symptoms suggestive of primary angiitis of the central nervous system (PACNS), such as unexplained TIA or https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 16/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate stroke (often multiple strokes in different vascular territories), headache, spinal cord dysfunction, or cognitive impairment. (See "Primary angiitis of the central nervous system in adults".) A brain biopsy, which is required to diagnose patients with suspected vasculitis, intravascular lymphoma, or certain infectious causes. Studies to detect a pulmonary arteriovenous malformation, a rare cause of ischemic stroke, which may be suspected in patients who have features such as a nodule on chest radiography, stigmata of a right-to-left shunt (eg, cyanosis, clubbing, history of ischemic stroke or brain abscess), unexplained hemoptysis, hypoxemia or dyspnea, and patients with suspected or known hereditary hemorrhagic telangiectasia. A delayed right-to-left shunt is often detected on transthoracic echocardiography with contrast (ie, bubble study) and the diagnosis can be confirmed with chest CT or pulmonary angiography. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults".) TREATMENT Acute therapy for patients with cryptogenic stroke is no different from other types of ischemic stroke (see 'Acute therapy' below). The choice of antithrombotic therapy for secondary prevention is challenging because no clear treatment target can be identified. (See 'Secondary prevention' below.) Acute therapy Intravenous thrombolysis with tPA (alteplase) is beneficial for eligible patients with ischemic stroke who can be treated within 4.5 hours of stroke onset, and mechanical thrombectomy using a second-generation stent retriever device is beneficial for patients with ischemic stroke caused by a large artery occlusion in the proximal anterior circulation. Acute management for patients with cryptogenic stroke who are not eligible for these interventions is also similar to patients with other ischemic stroke subtypes. (See "Initial assessment and management of acute stroke" and "Approach to reperfusion therapy for acute ischemic stroke" and "Mechanical thrombectomy for acute ischemic stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) Secondary prevention For secondary prevention, most patients with an ischemic stroke or transient ischemic attack (TIA) should be treated with all available risk reduction strategies. Currently viable strategies include blood pressure reduction, antithrombotic therapy, statin therapy, and lifestyle modification. (See "Overview of secondary prevention of ischemic stroke".) https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 17/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Antiplatelet therapy Antiplatelet therapy is recommended for most patients with noncardioembolic stroke, including cryptogenic TIA and stroke, as outlined in the algorithms ( algorithm 1 and algorithm 2) [94,95]. However, the choice of antithrombotic therapy for secondary stroke prevention after cryptogenic TIA or stroke is challenging because no clear treatment target can be identified, with the exception of a patent foramen ovale (PFO) with right- to-left shunt (see 'Presence of a PFO' below). (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) There is a high degree of uncertainty regarding the optimal management of patients with cryptogenic stroke who have an isolated atrial septal aneurysm (ASA), or atheromatous aortic disease. The optimal management of specific coagulation disorders is also unclear at the moment. Therefore, antiplatelet therapy is usually recommended for patients with cryptogenic stroke who have these conditions [94,95]. Lack of benefit with anticoagulation There is no proven benefit of anticoagulation compared with antiplatelet therapy for preventing recurrent ischemic stroke in patients with cryptogenic stroke, including those with embolic stroke of undetermined source (ESUS). Direct oral anticoagulants (DOACs) such as rivaroxaban and dabigatran should not be used as empiric treatment for patients with cryptogenic stroke, including ESUS. The NAVIGATE- ESUS trial randomly assigned over 7200 patients with ESUS to treatment with rivaroxaban or aspirin [96]. The trial was stopped early for futility after an interim analysis showed no benefit of rivaroxaban on the rate of stroke or systemic embolism but an increase in major bleeding in the rivaroxaban arm. Likewise, the RE-SPECT ESUS trial, with over 5300 patients with ESUS, found that rate of stroke (of any type) at 19 months was similar in the groups assigned to dabigatran or aspirin (4.1 and 4.8 percent per year, respectively) [97]. In the multicenter, double-blind COMPASS trial, over 27,000 patients with stable atherosclerotic vascular disease were randomly assigned to rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban (5 mg twice a day), or aspirin (100 mg once a day). A secondary analysis of ischemic stroke subtypes identified 291 patients who had an ischemic stroke during follow-up; among this group, criteria for ESUS were met in 42 (14 percent) [98]. ESUS was less likely in the rivaroxaban-plus-aspirin group compared with the aspirin-only group (HR 0.30, 95% CI 0.12-0.74). In addition to inherent limitations as a secondary analysis, this trial was not conducted among those with history of cryptogenic stroke and so cannot be used to determine optimal therapy for those with cryptogenic stroke. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 18/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate The Warfarin-Aspirin Recurrent Stroke Study (WARSS) compared aspirin with warfarin in the prevention of recurrent ischemic stroke among noncardioembolic stroke patients and found no superiority of warfarin over aspirin [99]. Among patients with cryptogenic stroke, the event rate (recurrent stroke or death) at two years was not significantly different for the warfarin-treated group compared with the aspirin-treated group (15.0 versus 16.5 percent, respectively). A post hoc analysis of WARSS data showed that warfarin therapy was associated with significantly fewer recurrent strokes or deaths at two years compared with aspirin in selected subgroups of patients with cryptogenic stroke: those with mild stroke severity (National Institutes of Health Stroke Scale score 5), those with posterior circulation infarcts sparing the brainstem, and those with no hypertension at baseline [100]. In the subgroup of patients with cryptogenic stroke who had an infarct topography consistent with an embolic mechanism, the event rate was lower with warfarin compared with aspirin (12 versus 18 percent, HR 0.66, 95% CI 0.37-1.15), but this difference did not achieve statistical significance. In another post-hoc analysis of WARSS data, there was a significant reduction in the composite end point of stroke or death favoring warfarin over aspirin treatment among patients with highly elevated levels of N-terminal pro-brain natriuretic peptide (NT- proBNP), a marker associated with atrial fibrillation and cardiac dysfunction [101]. Since these results come from post-hoc analyses based on relatively small numbers of patients, they must be interpreted with great caution, and further prospective studies are needed to determine if warfarin is beneficial in specific subgroups of patients with cryptogenic stroke. Pending long-term cardiac monitoring As above, we recommend antiplatelet therapy while awaiting the results of long-term cardiac monitoring to detect atrial fibrillation in patients with a first cryptogenic stroke and continuing antiplatelet therapy if no atrial fibrillation is detected on long-term monitoring. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Some stroke experts use anticoagulation when there is a high suspicion for a cardiac source of embolism despite the lack of evidence from randomized trials to support such an approach. For example, while awaiting the results of long-term cardiac monitoring, some experts would start empiric oral anticoagulation at hospital discharge for patients with acute embolic stroke that is cryptogenic after standard evaluation if there are multiple risk factors for occult atrial fibrillation [4]. These include higher CHA DS -VASc score ( table 7), the presence of cortical or large 2 2 subcortical infarcts in multiple vascular territories, and evidence of left atrial cardiopathy (eg, left atrial dilatation, strain, reduced emptying fraction, left atrial appendage size and single lobe morphology, increased P wave dispersion on electrocardiogram [ECG], and frequent premature atrial complex [PAC; also referred to a premature atrial beat, premature supraventricular https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 19/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate complex, or premature supraventricular beat]) [4]. Further antithrombotic treatment is directed by the presence or absence of atrial fibrillation detected on 30-day cardiac monitoring. Occult or subclinical atrial fibrillation on monitoring We suggest anticoagulant therapy with warfarin or a direct oral anticoagulant (DOAC) for patients initially diagnosed with cryptogenic stroke who have atrial fibrillation of any duration detected on long-term monitoring, even if detected remotely from the incident stroke. Most experts agree that occult or subclinical atrial fibrillation found on long-term monitoring should be treated with anticoagulants [95]. However, there is no consensus regarding the use of anticoagulant treatment for patients when monitoring detects only very brief (eg, 30 seconds) or rare episodes of paroxysmal atrial fibrillation. Presence of a PFO Patients with an embolic stroke who have a medium- or high-risk PFO are now classified as having a PFO-associated stroke [69]. Percutaneous PFO closure in addition to antiplatelet therapy is suggested for most patients age 60 years with an embolic-appearing ischemic stroke who have a PFO, no other evident source of stroke despite a comprehensive evaluation, and a possible, probable, or definite likelihood by the PASCAL classification ( table 6) that the PFO was causally associated with the stroke. PFO closure is reviewed in greater detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) Recurrent cryptogenic stroke For patients on antiplatelet therapy who have a recurrent cryptogenic stroke and no atrial fibrillation on re-evaluation with long-term cardiac monitoring, options include continuing the same antiplatelet agent or switching to another antiplatelet agent; for patients with recurrent embolic stroke of undetermined source (see 'Embolic stroke of undetermined source' above), switching to empiric anticoagulant therapy is also a reasonable option. PROGNOSIS Compared with other stroke subtypes, cryptogenic stroke tends to have a better prognosis at three months, six months, and one year. Approximately 50 to 60 percent of patients score <2 on the modified Rankin Scale ( table 8) at follow-up [38,58,59,102]. Mortality rates are lower than those for cardioembolic stroke but higher than those for small artery disease. Overall, the short-term risk of recurrent stroke after cryptogenic stroke is intermediate between the high early risk after large artery atherosclerosis stroke and low risk after small artery disease stroke. In the Oxford meta-analysis of four large population-based studies, the risk of recurrent stroke after cryptogenic stroke was 1.6 percent at seven days, 4.2 percent at one month, and 5.6 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 20/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate percent at three months [103]. In the NINDS Stroke Data Bank, 3 percent of patients with cryptogenic stroke had recurrent events at one month [104]. In the NOMASS study at three months, the risk of recurrence for the cryptogenic group was 3.7 percent [105], slightly lower than those found in the Oxford meta-analysis [103]. At two years, recurrence risk ranges from 14 to 20 percent [33,99,102]. In the Stroke Data Bank, cryptogenic stroke had the lowest two-year recurrence risk and was an independent predictor of low recurrence risk [106]. At five years, the long-term recurrence risk was 33.2 percent in Rochester, not significantly different from the other subtypes [102]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Classification Cryptogenic stroke is defined as brain infarction that is not attributable to a source of definite cardioembolism, large artery atherosclerosis, or small artery disease despite a thorough vascular, cardiac, and serologic evaluation. Embolic stroke of undetermined source (ESUS) is defined as a nonlacunar brain infarct without proximal arterial stenosis or cardioembolic sources. ESUS represents a subset of cryptogenic stroke. (See 'Classification' above.) Cause The pathophysiology of cryptogenic stroke is likely heterogeneous. Proposed mechanisms include cardiac embolism secondary to occult paroxysmal atrial fibrillation, aortic atheromatous disease or other cardiac sources, paradoxical embolism from atrial septal abnormalities such as patent foramen ovale (PFO), hypercoagulable states, and preclinical or subclinical cerebrovascular disease. (See 'Possible mechanisms' above.) Epidemiology Cryptogenic stroke accounts for 25 to 40 percent of ischemic stroke. (See 'Epidemiology and risk factors' above.) Presentation Cryptogenic stroke presents with superficial hemispheric infarction in the majority of patients, and a significant proportion of cryptogenic strokes adhere to embolic infarct topography on brain imaging. (See 'Clinical features' above.) https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 21/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Diagnosis Cryptogenic stroke is a diagnosis of exclusion. The diagnosis is made when a standard evaluation reveals no definite evidence of cardioembolism, large artery atherosclerosis, small artery disease, or other determined etiology, and no evidence of atrial fibrillation on a 12-lead electrocardiogram (ECG) and on 24-hour cardiac monitoring. Additional studies can be pursued if the standard evaluation fails to determine the probable cause. We suggest prolonged (eg, 30 days) ambulatory cardiac monitoring for select patients with a cryptogenic ischemic stroke or cryptogenic transient ischemic stroke (TIA) who are age 50 years or have abnormal P wave morphology, ectopy, paroxysmal tachycardia, atrial enlargement, elevated cardiac biomarkers, or a family history of atrial fibrillation. (See 'Evaluation and diagnosis' above.) Management The acute management of cryptogenic stroke is similar to that of other ischemic stroke subtypes. For secondary prevention, most patients with an ischemic stroke or TIA should be treated with blood pressure reduction, antithrombotic therapy, statin therapy, and lifestyle modification. However, the optimal antithrombotic therapy of patients with cryptogenic stroke who have atrial septal aneurysm, atheromatous aortic disease, or coagulation disorders is uncertain. (See 'Treatment' above.) For patients with a first cryptogenic stroke, we recommend antiplatelet therapy rather than anticoagulant therapy while awaiting the results of long-term cardiac monitoring (Grade 1B). (See 'Pending long-term cardiac monitoring' above.) For patients initially diagnosed with cryptogenic stroke who have atrial fibrillation of any duration detected on long-term monitoring, even if detected remotely from the incident stroke, we suggest anticoagulant therapy with warfarin or a direct oral anticoagulant (DOAC) rather than antiplatelet therapy (Grade 2C). (See 'Occult or subclinical atrial fibrillation on monitoring' above.) Percutaneous PFO closure in addition to antiplatelet therapy is suggested for most patients age 60 years with an embolic-appearing ischemic stroke who have a PFO, no other evident source of stroke despite a comprehensive evaluation, and a possible, probable, or definite likelihood by the PASCAL classification ( table 6) that the PFO was causally associated with the stroke. PFO closure is reviewed in greater detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) For patients on antiplatelet therapy who have a recurrent cryptogenic stroke and no atrial fibrillation on re-evaluation with long-term cardiac monitoring, options include continuing the same antiplatelet agent or switching to another antiplatelet agent; for https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 22/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate patients with recurrent ESUS, switching to empiric anticoagulant therapy is also a reasonable option. (See 'Recurrent cryptogenic stroke' above.) Outcomes Compared with other stroke subtypes, cryptogenic stroke tends to have a better prognosis and lower long-term risk of recurrence. (See 'Prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Mitchell SV Elkind, MD, MS, FAAN, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kunitz SC, Gross CR, Heyman A, et al. The pilot Stroke Data Bank: definition, design, and data. Stroke 1984; 15:740. 2. Foulkes MA, Wolf PA, Price TR, et al. The Stroke Data Bank: design, methods, and baseline characteristics. Stroke 1988; 19:547. 3. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24:35. 4. Saver JL. CLINICAL PRACTICE. Cryptogenic Stroke. N Engl J Med 2016; 374:2065. 5. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. 6. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke 2007; 38:2979. 7. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13:429. 8. Kamel H, Merkler AE, Iadecola C, et al. Tailoring the Approach to Embolic Stroke of Undetermined Source: A Review. JAMA Neurol 2019; 76:855. 9. Kamel H, Navi BB, Parikh NS, et al. Machine Learning Prediction of Stroke Mechanism in Embolic Strokes of Undetermined Source. Stroke 2020; 51:e203. 10. Ntaios G, Pearce LA, Veltkamp R, et al. Potential Embolic Sources and Outcomes in Embolic Stroke of Undetermined Source in the NAVIGATE-ESUS Trial. Stroke 2020; 51:1797. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 23/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 11. Boeckh-Behrens T, Kleine JF, Zimmer C, et al. Thrombus Histology Suggests Cardioembolic Cause in Cryptogenic Stroke. Stroke 2016; 47:1864. 12. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366:120. 13. Brambatti M, Connolly SJ, Gold MR, et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation 2014; 129:2094. 14. Kamel H, Bartz TM, Elkind MSV, et al. Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). Stroke 2018; 49:980. 15. Fonseca AC, Alves P, In cio N, et al. Patients With Undetermined Stroke Have Increased Atrial Fibrosis: A Cardiac Magnetic Resonance Imaging Study. Stroke 2018; 49:734. 16. Kamel H, Okin PM, Longstreth WT Jr, et al. Atrial cardiopathy: a broadened concept of left atrial thromboembolism beyond atrial fibrillation. Future Cardiol 2015; 11:323. 17. He J, Tse G, Korantzopoulos P, et al. P-Wave Indices and Risk of Ischemic Stroke: A Systematic Review and Meta-Analysis. Stroke 2017; 48:2066. 18. Harloff A, Simon J, Brendecke S, et al. Complex plaques in the proximal descending aorta: an underestimated embolic source of stroke. Stroke 2010; 41:1145. 19. Abushora MY, Bhatia N, Alnabki Z, et al. Intrapulmonary shunt is a potentially unrecognized cause of ischemic stroke and transient ischemic attack. J Am Soc Echocardiogr 2013; 26:683. 20. Ahn KT, Choi JH, Park SW. Pulmonary arteriovenous fistula in a patient with cryptogenic stroke. Heart 2011; 97:2093. 21. Alhazzaa M, Sharma M, Stotts G. A case report of an isolated pulmonary arteriovenous malformation causing stroke. Can J Neurol Sci 2011; 38:158. 22. Shovlin CL, Jackson JE, Bamford KB, et al. Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax 2008; 63:259. 23. Cottin V, Chinet T, Lavol A, et al. Pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: a series of 126 patients. Medicine (Baltimore) 2007; 86:1. 24. Komatsu T, Iguchi Y, Arai A, et al. Large but Nonstenotic Carotid Artery Plaque in Patients With a History of Embolic Stroke of Undetermined Source. Stroke 2018; 49:3054. 25. Kamel H, Navi BB, Merkler AE, et al. Reclassification of Ischemic Stroke Etiological Subtypes on the Basis of High-Risk Nonstenosing Carotid Plaque. Stroke 2020; 51:504. 26. Goyal M, Singh N, Marko M, et al. Embolic Stroke of Undetermined Source and Symptomatic Nonstenotic Carotid Disease. Stroke 2020; 51:1321. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 24/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 27. Ospel JM, Singh N, Marko M, et al. Prevalence of Ipsilateral Nonstenotic Carotid Plaques on Computed Tomography Angiography in Embolic Stroke of Undetermined Source. Stroke 2020; 51:1743. 28. Fakih R, Roa JA, Bathla G, et al. Detection and Quantification of Symptomatic Atherosclerotic Plaques With High-Resolution Imaging in Cryptogenic Stroke. Stroke 2020; 51:3623. 29. Mazighi M, Labreuche J, Gongora-Rivera F, et al. Autopsy prevalence of intracranial atherosclerosis in patients with fatal stroke. Stroke 2008; 39:1142. 30. Mazighi M, Labreuche J, Gongora-Rivera F, et al. Autopsy prevalence of proximal extracranial atherosclerosis in patients with fatal stroke. Stroke 2009; 40:713. 31. Bonaventura A, Vecchi A, Dagna L, et al. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol 2021; 21:319. 32. Petty GW, Brown RD Jr, Whisnant JP, et al. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke 1999; 30:2513. 33. Kolominsky-Rabas PL, Weber M, Gefeller O, et al. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 2001; 32:2735. 34. Schulz UG, Rothwell PM. Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of population-based studies. Stroke 2003; 34:2050. 35. Schneider AT, Kissela B, Woo D, et al. Ischemic stroke subtypes: a population-based study of incidence rates among blacks and whites. Stroke 2004; 35:1552. 36. Lee BI, Nam HS, Heo JH, et al. Yonsei Stroke Registry. Analysis of 1,000 patients with acute cerebral infarctions. Cerebrovasc Dis 2001; 12:145. 37. Li L, Yiin GS, Geraghty OC, et al. Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet Neurol 2015; 14:903. 38. Grau AJ, Weimar C, Buggle F, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke 2001; 32:2559. 39. Putaala J, Metso AJ, Metso TM, et al. Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke: the Helsinki young stroke registry. Stroke 2009; 40:1195. 40. Ornello R, Degan D, Tiseo C, et al. Distribution and Temporal Trends From 1993 to 2015 of Ischemic Stroke Subtypes: A Systematic Review and Meta-Analysis. Stroke 2018; 49:814. 41. Jacobs BS, Boden-Albala B, Lin IF, Sacco RL. Stroke in the young in the northern Manhattan stroke study. Stroke 2002; 33:2789. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 25/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 42. Adams HP Jr, Kappelle LJ, Biller J, et al. Ischemic stroke in young adults. Experience in 329
reasonable option. (See 'Recurrent cryptogenic stroke' above.) Outcomes Compared with other stroke subtypes, cryptogenic stroke tends to have a better prognosis and lower long-term risk of recurrence. (See 'Prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Mitchell SV Elkind, MD, MS, FAAN, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kunitz SC, Gross CR, Heyman A, et al. The pilot Stroke Data Bank: definition, design, and data. Stroke 1984; 15:740. 2. Foulkes MA, Wolf PA, Price TR, et al. The Stroke Data Bank: design, methods, and baseline characteristics. Stroke 1988; 19:547. 3. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24:35. 4. Saver JL. CLINICAL PRACTICE. Cryptogenic Stroke. N Engl J Med 2016; 374:2065. 5. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. 6. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke 2007; 38:2979. 7. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13:429. 8. Kamel H, Merkler AE, Iadecola C, et al. Tailoring the Approach to Embolic Stroke of Undetermined Source: A Review. JAMA Neurol 2019; 76:855. 9. Kamel H, Navi BB, Parikh NS, et al. Machine Learning Prediction of Stroke Mechanism in Embolic Strokes of Undetermined Source. Stroke 2020; 51:e203. 10. Ntaios G, Pearce LA, Veltkamp R, et al. Potential Embolic Sources and Outcomes in Embolic Stroke of Undetermined Source in the NAVIGATE-ESUS Trial. Stroke 2020; 51:1797. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 23/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 11. Boeckh-Behrens T, Kleine JF, Zimmer C, et al. Thrombus Histology Suggests Cardioembolic Cause in Cryptogenic Stroke. Stroke 2016; 47:1864. 12. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366:120. 13. Brambatti M, Connolly SJ, Gold MR, et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation 2014; 129:2094. 14. Kamel H, Bartz TM, Elkind MSV, et al. Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). Stroke 2018; 49:980. 15. Fonseca AC, Alves P, In cio N, et al. Patients With Undetermined Stroke Have Increased Atrial Fibrosis: A Cardiac Magnetic Resonance Imaging Study. Stroke 2018; 49:734. 16. Kamel H, Okin PM, Longstreth WT Jr, et al. Atrial cardiopathy: a broadened concept of left atrial thromboembolism beyond atrial fibrillation. Future Cardiol 2015; 11:323. 17. He J, Tse G, Korantzopoulos P, et al. P-Wave Indices and Risk of Ischemic Stroke: A Systematic Review and Meta-Analysis. Stroke 2017; 48:2066. 18. Harloff A, Simon J, Brendecke S, et al. Complex plaques in the proximal descending aorta: an underestimated embolic source of stroke. Stroke 2010; 41:1145. 19. Abushora MY, Bhatia N, Alnabki Z, et al. Intrapulmonary shunt is a potentially unrecognized cause of ischemic stroke and transient ischemic attack. J Am Soc Echocardiogr 2013; 26:683. 20. Ahn KT, Choi JH, Park SW. Pulmonary arteriovenous fistula in a patient with cryptogenic stroke. Heart 2011; 97:2093. 21. Alhazzaa M, Sharma M, Stotts G. A case report of an isolated pulmonary arteriovenous malformation causing stroke. Can J Neurol Sci 2011; 38:158. 22. Shovlin CL, Jackson JE, Bamford KB, et al. Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax 2008; 63:259. 23. Cottin V, Chinet T, Lavol A, et al. Pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: a series of 126 patients. Medicine (Baltimore) 2007; 86:1. 24. Komatsu T, Iguchi Y, Arai A, et al. Large but Nonstenotic Carotid Artery Plaque in Patients With a History of Embolic Stroke of Undetermined Source. Stroke 2018; 49:3054. 25. Kamel H, Navi BB, Merkler AE, et al. Reclassification of Ischemic Stroke Etiological Subtypes on the Basis of High-Risk Nonstenosing Carotid Plaque. Stroke 2020; 51:504. 26. Goyal M, Singh N, Marko M, et al. Embolic Stroke of Undetermined Source and Symptomatic Nonstenotic Carotid Disease. Stroke 2020; 51:1321. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 24/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 27. Ospel JM, Singh N, Marko M, et al. Prevalence of Ipsilateral Nonstenotic Carotid Plaques on Computed Tomography Angiography in Embolic Stroke of Undetermined Source. Stroke 2020; 51:1743. 28. Fakih R, Roa JA, Bathla G, et al. Detection and Quantification of Symptomatic Atherosclerotic Plaques With High-Resolution Imaging in Cryptogenic Stroke. Stroke 2020; 51:3623. 29. Mazighi M, Labreuche J, Gongora-Rivera F, et al. Autopsy prevalence of intracranial atherosclerosis in patients with fatal stroke. Stroke 2008; 39:1142. 30. Mazighi M, Labreuche J, Gongora-Rivera F, et al. Autopsy prevalence of proximal extracranial atherosclerosis in patients with fatal stroke. Stroke 2009; 40:713. 31. Bonaventura A, Vecchi A, Dagna L, et al. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol 2021; 21:319. 32. Petty GW, Brown RD Jr, Whisnant JP, et al. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke 1999; 30:2513. 33. Kolominsky-Rabas PL, Weber M, Gefeller O, et al. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 2001; 32:2735. 34. Schulz UG, Rothwell PM. Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of population-based studies. Stroke 2003; 34:2050. 35. Schneider AT, Kissela B, Woo D, et al. Ischemic stroke subtypes: a population-based study of incidence rates among blacks and whites. Stroke 2004; 35:1552. 36. Lee BI, Nam HS, Heo JH, et al. Yonsei Stroke Registry. Analysis of 1,000 patients with acute cerebral infarctions. Cerebrovasc Dis 2001; 12:145. 37. Li L, Yiin GS, Geraghty OC, et al. Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet Neurol 2015; 14:903. 38. Grau AJ, Weimar C, Buggle F, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke 2001; 32:2559. 39. Putaala J, Metso AJ, Metso TM, et al. Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke: the Helsinki young stroke registry. Stroke 2009; 40:1195. 40. Ornello R, Degan D, Tiseo C, et al. Distribution and Temporal Trends From 1993 to 2015 of Ischemic Stroke Subtypes: A Systematic Review and Meta-Analysis. Stroke 2018; 49:814. 41. Jacobs BS, Boden-Albala B, Lin IF, Sacco RL. Stroke in the young in the northern Manhattan stroke study. 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Groeneveld NS, Guglielmi V, Leeflang MMG, et al. CT angiography vs echocardiography for detection of cardiac thrombi in ischemic stroke: a systematic review and meta-analysis. J Neurol 2020; 267:1793. 82. Aimo A, Kollia E, Ntritsos G, et al. Echocardiography versus computed tomography and cardiac magnetic resonance for the detection of left heart thrombosis: a systematic review and meta-analysis. Clin Res Cardiol 2021; 110:1697. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 28/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 83. Kauw F, Velthuis BK, Takx RAP, et al. Detection of Cardioembolic Sources With Nongated Cardiac Computed Tomography Angiography in Acute Stroke: Results From the ENCLOSE Study. Stroke 2023; 54:821. 84. Bodle JD, Feldmann E, Swartz RH, et al. High-resolution magnetic resonance imaging: an emerging tool for evaluating intracranial arterial disease. 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Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 96. Hart RG, Sharma M, Mundl H, et al. Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source. N Engl J Med 2018; 378:2191. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 29/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 97. Diener HC, Sacco RL, Easton JD, et al. Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source. N Engl J Med 2019; 380:1906. 98. Perera KS, Ng KKH, Nayar S, et al. Association Between Low-Dose Rivaroxaban With or Without Aspirin and Ischemic Stroke Subtypes: A Secondary Analysis of the COMPASS Trial. JAMA Neurol 2020; 77:43. 99. Mohr JP, Thompson JL, Lazar RM, et al. 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Topic 1090 Version 45.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 30/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate GRAPHICS TOAST classification of subtypes of acute ischemic stroke Large-artery atherosclerosis Cardioembolism Small-vessel occlusion Stroke of other determined etiology Stroke of undetermined etiology Two or more causes identified Negative evaluation Incomplete evaluation Graphic 62571 Version 1.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 31/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Causative Classification System (CCS) of ischemic stroke etiology Stroke Level of Criteria mechanism confidence 1. Either occlusive or stenotic ( 50 percent diameter reduction or <50 percent diameter reduction with plaque ulceration or thrombosis) vascular disease judged to be caused by Large artery Evident atherosclerosis atherosclerosis in the clinically relevant extracranial or intracranial arteries, and 2. The absence of acute infarction in vascular territories other than the stenotic or occluded artery 1. History of 1 transient monocular blindness (TMB), TIA, or stroke from the territory of index artery affected by atherosclerosis within the last month, or Probable 2. Evidence of near-occlusive stenosis or nonchronic complete occlusion judged to be caused by atherosclerosis in the clinically relevant extracranial or intracranial arteries (except for the vertebral arteries), or 3. The presence of ipsilateral and unilateral internal watershed infarctions or multiple, temporally separate, infarctions exclusively within the territory of the affected artery Possible 1. The presence of an atherosclerotic plaque protruding into the lumen and causing mild stenosis (<50 percent) in the absence of any detectable plaque ulceration or thrombosis in a clinically relevant extracranial or intracranial artery and history of 2 TMB, TIA, or stroke from the territory of index artery affected by atherosclerosis, at least one event within the last month, or 2. Evidence for evident large artery atherosclerosis in the absence of complete diagnostic investigation for other mechanisms https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 32/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Cardio-aortic embolism Evident The presence of a high-risk cardiac source of cerebral embolism Probable 1. Evidence of systemic embolism, or 2. The presence of multiple acute infarctions that have occurred closely related in time within both right and left anterior or both anterior and posterior circulations in the absence of occlusion or near-occlusive stenosis of all relevant vessels. Other diseases that can cause multifocal ischemic brain injury such as vasculitides, vasculopathies, and hemostatic or hemodynamic disturbances must not be present. Possible 1. The presence of a cardiac condition with low or uncertain primary risk of cerebral embolism, or 2. Evidence for evident cardio-aortic embolism in the absence of complete diagnostic investigation for other mechanisms Small artery occlusion Evident Imaging evidence of a single and clinically relevant acute infarction <20 mm in greatest diameter within the territory of basal or brainstem penetrating arteries in the absence of any other pathology in the parent artery at the site of the origin of the penetrating artery (focal atheroma, parent vessel dissection, vasculitis, vasospasm, etc) Probable 1. The presence of stereotypic lacunar transient ischemic attacks within the past week, or 2. The presence of a classical lacunar syndrome Possible 1. Presenting with a classical lacunar syndrome in the absence of imaging that is sensitive enough to detect small infarctions, or 2. Evidence for evident small artery occlusion in the absence of complete diagnostic investigation for other mechanisms Other causes Evident The presence of a specific disease process that involves clinically appropriate brain arteries Probable A specific disease process that has occurred in clear and close temporal or spatial relationship to the onset of brain infarction such as arterial dissection, cardiac or arterial surgery, and cardiovascular interventions Possible Evidence for an evident other cause in the absence of complete diagnostic investigation for mechanisms listed above https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 33/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Undetermined causes Unknown (no evident, Cryptogenic embolism: 1. Angiographic evidence of abrupt cut-off consistent with a blood clot within otherwise angiographically normal looking intracranial probable, or possible arteries, or criteria for the causes 2. Imaging evidence of complete recanalization of previously occluded artery, or above) 3. The presence of multiple acute infarctions that have occurred closely related in time without detectable abnormality in the relevant vessels Other cryptogenic: Those not fulfilling the criteria for cryptogenic embolism Incomplete evaluation: The absence of diagnostic tests that, under the examiner's judgment, would have been essential to uncover the underlying etiology Unclassified The presence of >1 evident mechanism in which there is either probable evidence for each, or no probable evidence to be able to establish a single cause Reproduced with permission from: Ay H, Benner T, Arsava EM. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. Graphic 57732 Version 4.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 34/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Cardioaortic sources of cerebral embolism Sources with high primary risk for Sources with low or uncertain primary ischemic stroke risk for ischemic stroke Atrial fibrillation Cardiac sources of embolism: Paroxysmal atrial fibrillation Mitral annular calcification Left atrial thrombus Patent foramen ovale Left ventricular thrombus Atrial septal aneurysm Sick sinus syndrome Atrial septal aneurysm and patent foramen ovale Atrial flutter Left ventricular aneurysm without thrombus Recent myocardial infarction (within one month prior to stroke) Left atrial spontaneous echo contrast ("smoke") Mitral stenosis or rheumatic valve disease Congestive heart failure with ejection fraction <30% Mechanical heart valves Bioprosthetic heart valves Chronic myocardial infarction together with low Apical akinesia ejection fraction (<28%) Dilated cardiomyopathy (prior established diagnosis or left ventricular dilatation with an ejection fraction of <40% or fractional shortening of <25%) Wall motion abnormalities (hypokinesia, akinesia, dyskinesia) other than apical akinesia Nonbacterial thrombotic endocarditis Hypertrophic cardiomyopathy Infective endocarditis Left ventricular hypertrophy Papillary fibroelastoma Left ventricular hypertrabeculation/non- compaction Left atrial myxoma Recent aortic valve replacement or coronary artery bypass graft surgery Presence of left ventricular assist device Paroxysmal supraventricular tachycardia Aortic sources of embolism: Complex atheroma in the ascending aorta or proximal arch (protruding with >4 mm thickness, or mobile debris, or plaque ulceration) The high- and low-risk cardioaortic sources in this table are separated using an arbitrary 2% annual https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 35/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate or one-time primary stroke risk threshold. Data from: 1. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. 2. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. 3. Arsava EM, Ballabio E, Benner T, et al. The Causative Classi cation of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. 4. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 2013; 44:1550. 5. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017; 36:1080. Reproduced and modi ed with permission from: Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. Copyright 2005 American Neurological Association. Graphic 60843 Version 11.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 36/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Risk of Paradoxical Embolism (RoPE) score RoPE Characteristic Points score No history of hypertension 1 No history of diabetes 1 No history of stroke or TIA 1 Nonsmoker 1 Cortical infarct on imaging 1 Age, years 18 to 29 5 30 to 39 4 40 to 49 3 50 to 59 2 60 to 69 1 70 0 Total score (sum of individual points) Maximum score (a patient <30 years with no hypertension, no 10 diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct) Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct) 0 TIA: transient ischemic attack. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97895 Version 5.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 37/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate PFO prevalence, attributable fraction, and estimated two-year risk of stroke/TIA CS patients with PFO (n = Cryptogenic stroke (n = 3023) 1324) Estimated two-year stroke/TIA Prevalence of PFO- RoPE patients with a PFO, attributable fraction, Number of CS patients with score Number of patients recurrence rate (Kaplan- percent (95% CI)* percent (95% CI)* PFO* Meier), percent (95% CI) 0 to 3 613 23 (19 to 26) 0 (0 to 4) 108 20 (12 to 28) 4 511 35 (31 to 39) 38 (25 to 48) 148 12 (6 to 18) 5 516 34 (30 to 38) 34 (21 to 45) 186 7 (3 to 11) 6 482 47 (42 to 51) 62 (54 to 68) 236 8 (4 to 12) 7 434 54 (49 to 59) 72 (66 to 76) 263 6 (2 to 10) 8 287 67 (62 to 73) 84 (79 to 87) 233 6 (2 to 10) 9 to 10 180 73 (66 to 79) 88 (83 to 91) 150 2 (0 to 4) CI: confidence interval; CS: cryptogenic stroke; PFO: patent foramen ovale; RoPE: Risk of Paradoxical Embolism; TIA: transient ischemic attack. NOTE: 95% CI for PFO prevalence and attributable fraction based on normal approximation to the binomial distribution. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97896 Version 5.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 38/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism Probable Highly probable or deep venous thrombosis preceding an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal Possible Probable aneurysm or (2) a large-shunt PFO Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 39/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Antithrombotic therapy according to cause of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of antithrombotic therapy based on mechanism for patients with a TIA. For further details, including suggested dosing regimens of antithrombot agents, refer to the relevant UpToDate topic reviews. ICA: internal carotid artery; CEA: carotid endarterectomy; CAS: carotid artery stenting; DAPT: dual antiplatelet 2 therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h valve, and treatment of venous thromboembolism. Some experts prefer DAPT based upon observational evidence. Long-term single-agent antiplatelet therapy using aspirin, clopidogrel, or aspirin-extended-release dipyrida Graphic 131695 Version 3.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 40/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 41/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 42/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted [1] CHADS acronym Score CHADS acronym ischemic stroke rate (% per year) 2 2 Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc acronym 2 2 [2] CHA DS -VASc acronym Score 2 2 (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. 2 2 2 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 43/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results
150 2 (0 to 4) CI: confidence interval; CS: cryptogenic stroke; PFO: patent foramen ovale; RoPE: Risk of Paradoxical Embolism; TIA: transient ischemic attack. NOTE: 95% CI for PFO prevalence and attributable fraction based on normal approximation to the binomial distribution. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97896 Version 5.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 38/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism Probable Highly probable or deep venous thrombosis preceding an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal Possible Probable aneurysm or (2) a large-shunt PFO Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 39/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Antithrombotic therapy according to cause of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of antithrombotic therapy based on mechanism for patients with a TIA. For further details, including suggested dosing regimens of antithrombot agents, refer to the relevant UpToDate topic reviews. ICA: internal carotid artery; CEA: carotid endarterectomy; CAS: carotid artery stenting; DAPT: dual antiplatelet 2 therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h valve, and treatment of venous thromboembolism. Some experts prefer DAPT based upon observational evidence. Long-term single-agent antiplatelet therapy using aspirin, clopidogrel, or aspirin-extended-release dipyrida Graphic 131695 Version 3.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 40/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 41/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 42/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted [1] CHADS acronym Score CHADS acronym ischemic stroke rate (% per year) 2 2 Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc acronym 2 2 [2] CHA DS -VASc acronym Score 2 2 (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. 2 2 2 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 43/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 44/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 45/46 7/5/23, 12:37 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Contributor Disclosures Shyam Prabhakaran, MD, MS Grant/Research/Clinical Trial Support: Agency for Healthcare Research and Quality [Diagnostic error, prehospital care]; National Institutes of Health (NIH) [Stroke]. All of the relevant financial relationships listed have been mitigated. Chinwe Ibeh, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 46/46
7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Definition, etiology, and clinical manifestations of transient ischemic attack : Natalia S Rost, MD, MPH, Erica Camargo Faye, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 23, 2022. INTRODUCTION Stroke and transient ischemic attack (TIA) are caused by one of several pathophysiologic processes involving the blood flow of the brain: The process may be intrinsic to the vessel, as in atherosclerosis, lipohyalinosis, inflammation, amyloid deposition, arterial dissection, developmental malformation, aneurysmal dilation, or venous thrombosis. The process may originate remotely, as occurs when an embolus from the heart or extracranial circulation lodges in an intracranial vessel. The process may result from inadequate cerebral blood flow due to decreased perfusion pressure or increased blood viscosity. The process may result from rupture of a vessel in the subarachnoid space or intracerebral tissue. The first three processes can lead to transient cerebral ischemia (transient cerebral ischemic attack or TIA) or permanent cerebral infarction (ischemic stroke), while the fourth results in either subarachnoid hemorrhage or an intracerebral hemorrhage (primary hemorrhagic stroke). This topic will discuss the definition, etiology, and clinical manifestations of TIA. The clinical diagnosis, evaluation, and treatment of TIA are discussed separately. (See "Initial evaluation and https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 1/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate management of transient ischemic attack and minor ischemic stroke" and "Differential diagnosis of transient ischemic attack and acute stroke" and "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) DEFINITION OF TIA Traditional time-based definition of TIA TIA was originally defined as a sudden onset of a focal neurologic symptom and/or sign lasting less than 24 hours, brought on by a transient decrease in blood flow, which renders the brain ischemic in the area producing the symptom. The time limit was intended to separate ischemia without infarction from infarction. However, this classic, time-based definition of TIA is inadequate for several reasons. Most notably, there is risk of permanent tissue injury (ie, infarction) even when focal transient neurologic symptoms last less than one hour. Tissue-based definition of TIA In the tissue-based definition, TIA is a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction [1]. In keeping with this definition of TIA, ischemic stroke is defined as an infarction of central nervous system tissue (brain, spinal cord, or retinal cells) attributable to ischemia, based on neuropathologic, neuroimaging, and/or clinical evidence (ie, persistence of symptoms or findings) of permanent tissue injury [2]. Thus, the benign connotation of "TIA" has been replaced by an understanding that even relatively brief ischemia can cause permanent neurologic or retinal injury. (See 'Symptom duration and infarction' below.) The advantages of tissue-based definitions of TIA and stroke include the following [1,3]: The end point is biologic (tissue injury, as confirmed or excluded by neuroimaging) rather than arbitrary (24 hours) The definition encourages use of neurodiagnostic tests to identify brain injury and its cause, which furthers earlier therapeutic interventions The presence or absence of ischemic brain is more accurately reflected The shortcomings of tissue-based definitions of TIA/stroke include the following: Dependency on the sensitivity and availability of neuroimaging Infarctions associated with classically-defined TIA are often very small; most are less than 1 mL in volume [4]. Imaging methods that have low sensitivity for small infarcts, such as computed tomography (CT) or conventional magnetic resonance imaging (MRI), would result in some https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 2/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate transient events being inappropriately classified as TIA without acute infarction. Conversely, imaging with diffusion-weighted MRI (DWI), with its higher sensitivity for acute infarction, would increase the proportion of transient events classified as ischemic stroke [5]. High variance in practice for imaging in patients with suspected TIA would reduce the ability to compare studies from different institutions as well as from different time periods. Dependency on population and case-mix The diagnosis of TIA without acute infarction depends not only on the sensitivity of imaging but also on clinical judgment as to whether the signs and symptoms are consistent with an ischemic syndrome and therefore warrant an imaging study. Hence, the prevalence of TIA without acute infarction depends on the population characteristics and the case mix, particularly the mixture of typical and atypical transient spells (see 'Typical TIA' below and 'Atypical TIA' below). There is a high variance in the prevalence of brain infarcts for TIA defined by time (ie, transient symptoms lasting <24 hours), with infarct rates ranging from 4 to 34 percent by CT and 21 to 67 percent by diffusion-weighted MRI [6]. Symptom duration and infarction The duration of ischemic symptoms does not reliably distinguish whether a symptomatic ischemic event will result in ischemic infarction [1]. A classically defined TIA with symptoms lasting for as little as a few minutes can be associated with infarction on DWI, whereas a spell lasting for many hours may show no signs of infarction on DWI. In patients with prolonged symptoms without development of infarction, concern for a nonischemic etiology of the spell should be raised [7]. Some reports suggest that increased duration of classically defined TIA (<24 hours in duration) is associated with a higher probability of infarction on DWI, but the association is not absolute [4,8- 11]. A systematic analysis of patients with classically defined TIA found that symptom duration was not a reliable predictor for the presence of infarction ( figure 1), even though the mean duration tended to be significantly longer in patients with infarction than in those without infarction [4]. One potential caveat is that abnormalities on initial imaging, such as DWI obtained during or soon after symptoms, may actually be reversible injuries. However, most patients with TIA seek medical attention after their symptoms fully resolve; a low proportion ( 7 percent) of patients with classically defined TIA are admitted and scanned at the height of their symptoms [8-10,12]. Therefore, infarcts observed in patients with classically defined TIA most likely represent permanent brain injury, as the probability of DWI reversibility decreases as the time from symptom onset to imaging increases. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 3/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate EPIDEMIOLOGY TIA is a common neurologic problem [13]. In a population-based cohort study from 1948 to 2017 of over 14,000 predominantly White participants from the Framingham Heart Study, the estimated overall incidence of TIA was 1.19 per 1000 person-years [14]. The incidence increased with age; for the age group 45 to 54 years, the incidence was 0.22 per 1000 person-years, while for the age group 85 to 94 years, the incidence was 4.88 per 1000 person-years. In a community-based registry study from Italy, the annual incidence of TIA from 2007 to 2009 was 0.52 per 1000 population [15]. In the Cincinnati and Northern Kentucky region of the United States, where the ethnic and socioeconomic demographics are similar to that of the United States as a whole, another population-based study found that the adjusted annual incidence rate for TIA from 1993 to 1994 was 0.83 per 1000 population, and that Black individuals and men had significantly higher rates of TIA than White individuals and women [16]. From these data, it was estimated that 240,000 TIAs occurred in the United States in 2002. The estimated overall prevalence of TIA among adults in the United States is approximately 2 percent [17]. This number is felt to under-represent the true prevalence of TIA. Poor awareness by lay-persons of the signs and symptoms of cerebral or ocular ischemia and the risk of subsequent stroke, combined with a high rate of failure to seek medical attention after a TIA, may account for this finding [18]. Use of the tissue-based definition of TIA in epidemiologic studies is likely to modestly alter the incidence and prevalence rates of TIA and stroke, but these changes are encouraged because they should reflect more accurate diagnosis [1]. Data from several reports suggest that defining TIA by the absence of infarction on imaging will decrease the annual rate of TIA by approximately 30 percent and increase the annual incidence of stroke by 7 percent [19-21]. MECHANISMS AND CLINICAL MANIFESTATIONS A TIA should be considered a syndrome. The symptoms of a TIA depend in part upon the pathophysiologic subtype, which are divided into three main mechanisms: Embolic TIA, which may be artery-to-artery, or due to a cardioaortic or unknown source Lacunar or small penetrating vessel TIA Large artery, low-flow TIA Embolic TIA Embolic TIAs are characterized by discrete, usually single (and not stereotyped if multiple), more prolonged episodes of focal neurologic symptoms. The embolus may arise from https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 4/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate a pathologic process in an artery, usually extracranial, or from the heart (eg, atrial fibrillation or left ventricular thrombus) or aorta. A diligent search for a potential embolic source is necessary in all cases of TIA. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) Embolic TIAs may last hours rather than minutes as in low-flow TIAs. As an example, in one study that divided patients with TIAs into those with symptoms of short duration (less than 60 minutes) or long duration (60 minutes or greater), the latter group was more likely to have an embolic source (86 versus 46 percent) [22]. Embolic TIAs also may less likely be repetitive compared with low-flow TIAs since they are the result of emboli from a specific source (eg, a one-, two-, or three-time phenomenon). When the source of the embolus is in a proximal vessel, recurrent emboli can lodge in different branches of the parent vessel giving different symptoms. Emboli are subject to natural thrombolysis and migration since they typically break off of fresh thrombus. They may produce transient ischemia on many occasions, but an element of silent infarction remains. Embolic TIAs are best divided into those in the anterior cerebral circulation (carotid, anterior cerebral artery, middle cerebral artery territory) and those in the posterior cerebral circulation (vertebrobasilar, posterior cerebral artery territory). Symptoms in both circulations depend upon the size of the embolic fragment in relation to the size of the artery occluded. Anterior circulation embolic TIAs Embolic TIAs in the anterior circulation may be large enough to occlude the middle cerebral artery stem, producing a contralateral hemiplegia secondary to ischemia in the deep white matter and basal ganglion/internal capsule lenticulostriate territory ( figure 2). In addition, they may produce cortical surface symptoms. These include aphasic and dysexecutive syndromes in the dominant hemisphere and anosognosia or neglect in the nondominant hemisphere. Smaller emboli that occlude branches of the middle cerebral artery stem result in more focal symptoms, including hand alone or arm and hand numbness, weakness, and/or heaviness induced by ischemia to the frontal area of the contralateral frontal lobe motor system ( figure 3). Rarely, the symptoms also may be as specific as thumb or hand numbness or a swollen feeling, suggesting focal ischemia in the hand area of the sensory strip or parietal association cortex. Isolated upper limb weakness may implicate cervical carotid atherosclerosis as the cause of cerebral ischemic symptoms [23]. Transient monocular visual loss often signifies atherothrombotic disease in the internal carotid artery proximal to the ophthalmic artery origin (see "Amaurosis fugax (transient monocular or binocular visual loss)"). Atherothrombotic disease is most often responsible https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 5/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate for these syndromes, although carotid dissection and embolism from the aorta, heart, or an unknown source also should be considered. In a report of 129 patients with monocular visual loss of presumed ischemic origin, diffusion-weighted MRI of the brain revealed concurrent acute brain infarcts in 24 percent [24]. These infarcts were typically small, often multiple, frequently ipsilateral to the involved eye, and usually asymptomatic. The finding of concurrent acute brain infarction in a patient with transient monocular visual loss suggests a proximal source of embolic particles that travel to both the retinal and hemispheric circulations. Posterior circulation embolic TIAs Posterior circulation territory embolic TIAs are generally produced by emboli arising from atherothrombotic disease at the origin or distal segment of one of the vertebral arteries or of the proximal basilar artery. Emboli arising from the aortic arch, the heart, an unknown source, or from a dissecting lesion in the vertebral artery should also be considered. Symptoms vary according to the vertebral or basilar artery branch in which the embolus lodges ( figure 4). Emboli can produce transient ataxia, dizziness, diplopia, dysarthria, quadrantanopsia, hemianopsia, numbness, crossed face and body numbness, and unilateral hearing loss. When the top of the basilar artery is embolized, sudden, overwhelming stupor or coma may ensue due to bilateral medial thalamic, subthalamus, and medial rostral midbrain reticular activating system ischemia. Emboli in the more distal branches of the posterior cerebral artery may result in a homonymous field defect or in memory loss (inferior medial temporal lobe ischemia). Lacunar or small vessel TIA Lacunar or penetrating or small vessel TIAs are due to transient cerebral ischemia induced by stenosis of one of the intracerebral penetrating vessels arising from the middle cerebral artery stem, the basilar artery, the vertebral artery ( figure 5), or the circle of Willis ( figure 6 and figure 7). Occasionally, recurrent stereotyped TIAs occur; in this setting, the term lacunar or small vessel TIAs seems appropriate. Most often, lacunar or small vessel TIAs are thought to be caused either by atherothrombotic obstructive lesions at the origin of the penetrating vessel or by lipohyalinosis distally within the penetrating vessel. Less commonly, embolism may cause lacunar or small vessel TIAs. (See "Lacunar infarcts", section on 'Etiology'.) These small vessel TIAs cause symptoms similar to the lacunar strokes that are likely to follow. Thus, face, arm, and leg weakness or numbness due to ischemia in the internal capsule, pons, or thalamus may occur, similar to the symptoms due to ischemia from embolism or large vessel https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 6/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate atherothrombotic disease or dissection. As a result, serious disease in the parent vessel must be excluded before the diagnosis of lacunar or small vessel TIA can be established with confidence. Lacunar infarcts may be preceded by lacunar TIAs consisting of brief repetitive stereotyped clinical symptoms and signs, and lacunar stroke onset may be stepwise and progressive rather than abrupt [25-27]. Such a pattern of TIAs, or non-sudden onset in association with a lacunar syndrome, is highly suggestive of small vessel lipohyalinotic etiology [28]. (See "Lacunar infarcts".) Low-flow TIA Large artery low-flow TIAs are often associated with a tightly stenotic atherosclerotic lesion at the internal carotid artery origin or in the intracranial portion of the internal carotid artery (siphon) when collateral flow from the circle of Willis to the ipsilateral middle or anterior cerebral artery is impaired ( figure 6 and figure 7). Other important causes include atherosclerotic stenotic lesions in the middle cerebral artery stem ( figure 3) or at the junction of the vertebral and basilar artery. Any obstructive vascular process in the extracranial or intracranial arteries can cause a low-flow TIA syndrome if collateral flow to the potentially ischemic brain also is diminished. Low-flow TIAs usually are brief (minutes) and often recurrent. They may occur as little as several times per year but typically occur more often (once per week or up to several times per day). Anterior circulation low-flow TIAs Low-flow TIAs are generally stereotyped, especially when they are due to hemodynamically significant stenotic lesions at the origin of the internal carotid artery, at the siphon portion of the internal carotid artery where collateral flow to the circle of Willis is inadequate, or in the middle cerebral artery stem. Symptoms due to ischemia from these lesions often include weakness or numbness of the hand, arm, leg, face, tongue, and/or cheek. Recurrent aphasic syndromes appear when there is focal ischemia in the dominant hemisphere, and recurrent neglect occurs in the presence of focal ischemia in the nondominant hemisphere ischemia. Limb-shaking TIAs are a rare, but classic, hypoperfusion syndrome of repetitive jerking movements of the arm or leg due to a severe stenosis or occlusion of the contralateral internal carotid or middle cerebral artery [29-31]. Posterior circulation low-flow TIAs In contrast, recurrent symptoms are often not stereotyped when the stenotic lesion that obstructs flow involves the vertebrobasilar junction or the basilar artery. The many closely packed neuronal structures in the brainstem preclude consistent manifestations of recurrent focal ischemia in this area. Nevertheless, certain generalizations about recurrent low-flow TIA symptoms in the posterior circulation can be made. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 7/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Obstructive lesions in the distal vertebral artery or at the vertebrobasilar junction usually cause dizziness that may or may not include spinning or vertigo. The patient may complain that the room is tilting or that the floor is coming up at them, rather than spinning dizziness. Patients may use the word dizziness to describe a myriad of symptoms, not necessarily spinning. Other symptoms can include numbness of one side of the body or face, dysarthria, or diplopia. Ischemia in the pons from stenotic lesions in the proximal to mid-basilar artery can cause bilateral leg and arm weakness or numbness and a feeling of heaviness in addition to dizziness. Ischemia in the territory of the top of the basilar artery or proximal posterior cerebral artery may present with all of the above recurrent symptoms as well as overwhelming drowsiness, vertical diplopia, eyelid drooping, and an inability to look up. Transient ischemia at the top of the basilar artery is usually due to embolism rather than low-flow TIA. URGENCY OF EVALUATION TIA is a neurologic emergency ( table 1). Patients with TIA and minor, nondisabling stroke have a high early risk of recurrent stroke (see 'Risk of recurrent stroke' below). Recognition of TIAs can identify patients who may benefit from preventive therapy. Therefore, the initial management of suspected TIA and minor ischemic stroke includes immediate antiplatelet treatment and urgent evaluation ( algorithm 1). This is reviewed in detail separately. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) DIAGNOSIS The diagnosis of TIA is based upon the clinical features of the transient attack and the neuroimaging findings [6]. Since few patients with suspected TIA present when fully symptomatic [32], determining the likelihood of ischemia as the cause of the event often depends upon the history as reported by the patient and witnesses. Typical TIA Typical TIAs are characterized by transient, focal neurologic symptoms, generally with sudden onset, that can be localized to a single vascular territory within the brain, including one or more of the following: Transient monocular blindness (amaurosis fugax) https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 8/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Aphasia or dysarthria Hemianopia Hemiparesis and/or hemisensory loss In such cases, the likelihood of ischemia is relatively high. However, events consistent with typical TIA may sometimes occur due to nonischemic mechanisms such as seizure, migraine, intracerebral hemorrhage, and others. (See "Differential diagnosis of transient ischemic attack and acute stroke".) A key problem with the diagnosis of TIA is how to determine if symptoms are caused by ischemia when brain imaging is normal. Although clinical features are not definitive for etiology, an ischemic insult is the most likely cause when the attack is consistent with a typical TIA (ie, one with transient, focal neurologic symptoms localizing to a single vascular territory). Atypical TIA The clinical characteristics of transient symptoms considered to be atypical of an ischemic attack include the following [33-35]: Gradual build-up of symptoms (more than five minutes) March of symptoms from one body part to another (without passing the midline) Progression of symptoms from one type to another Isolated disturbance of vision in both eyes characterized by the occurrence of positive phenomena (eg, flashing lights) Isolated sensory symptoms with remarkably focal distribution, such as in a finger, chin, or tongue Very brief spells (less than 30 seconds) Identical spells occurring over a period of more than one year Isolated brainstem symptoms, such as dysarthria, diplopia, or hearing loss Amnesia, confusion Incoordination of limbs With atypical attacks as defined above, the likelihood of an ischemic cause may be relatively low. In several reports, the proportion of patients with atypical attacks who had acute brain infarction on diffusion weighted magnetic resonance imaging (MRI) was approximately 10 percent, suggesting that a minority of atypical spells have an ischemic cause and are therefore TIAs [6,36,37]. Alternatively, it may be the case that the sensitivity of MRI is not sufficient to reveal the ischemic lesions associated with atypical spells. One report that evaluated 275 patients with definite vertebrobasilar territory infarction found that preceding transient isolated brainstem symptoms occurred in 16 percent, suggesting that isolated brainstem symptoms can sometimes signify an ischemic attack [38]. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 9/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate However, there is evidence that patients with atypical TIAs characterized by negative focal symptoms (where "negative" indicates a loss of some neurologic function) have similar short- and long-term risks of subsequent ischemic stroke as do patients with typical TIAs and should therefore be investigated and treated as true TIAs. A population-based longitudinal cohort study from the United Kingdom prospectively evaluated patients with minor ischemic stroke (n = 1287), classic TIA (n = 1021), or nonconsensus TIA (n = 570), the latter defined by isolated vertigo, isolated ataxia, isolated diplopia, isolated speech disturbance (slurred speech) without aphasia, isolated bilateral decreased vision, or isolated unilateral sensory loss involving only one body part (face, arm, hand, or leg) [37]. All patients were treated according to secondary prevention guidelines; the median follow-up was 5.2 years. At baseline, the prevalence of stroke risk factors including atrial fibrillation, arterial stenoses, and patent foramen ovale was similar for nonconsensus and classic TIA. Furthermore, the 90-day stroke risk after the index event was similar for nonconsensus TIA (10.6 percent [95% CI 7.8-12.9]) and classic TIA (11.6 percent [95% CI 9.6-13.6]), as was the 10-year risk of major vascular events (27.1 versus 30.9 percent). Differential diagnosis The differential diagnosis of TIA ( table 1) is discussed in detail separately. (See "Differential diagnosis of transient ischemic attack and acute stroke".) RISK OF RECURRENT STROKE TIA is a neurologic emergency because patients with time-based TIA and minor, nondisabling stroke are at increased risk of recurrent stroke, especially in the days following the event. Factors that affect stroke risk The risk of stroke after TIA appears to vary according to several factors, including time after the index event, presence of vascular pathologies, and the presence of acute infarction on MRI scan. The first days after the event The risk of stroke is highest in the first days after a TIA, ranging from 1.5 to 3.5 percent in the first 48 hours after TIA, making up approximately 40 percent of the 90-day stroke risk [39-42]. The urgency associated with TIA derives also from the observation that TIAs are most likely to occur in the hours and days immediately preceding ischemic stroke. As an example, a study that analyzed four cohorts of patients who had recent ischemic stroke found that TIAs occurred most often in the 48 hours prior to the stroke [43]. Another study found that the risk of ischemic stroke occurring within 24 hours of a probable or definite TIA was approximately 5 percent [42]. Of all ischemic strokes during the 30 days after a first TIA, 42 percent occurred within the first 24 hours. This may be an overestimate related to the difficulty distinguishing a single ischemic event (stroke) with fluctuating symptoms from separate events (TIA followed by stroke) within a https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 10/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate short period of time. Nevertheless, these observations underscore the high early risk of developing a permanent deficit after transient ischemic symptoms and the importance of urgent assessment, risk stratification, and treatment. Given this short time window and high risk of stroke (1.5 to 3.5 percent in the first 48 hours after TIA [39,40]) neurologic evaluation of and intervention for TIA should occur urgently. Recognition and urgent evaluation of TIAs can identify patients who may benefit from preventive therapy or from revascularization of large vessels such as the carotid artery. Premonitory carotid territory TIAs occur in approximately 50 to 75 percent of patients with ischemic stroke from extracranial carotid disease [44-46], and vertebrobasilar TIAs are associated with a risk of subsequent stroke or death that is similar to or possibly higher than that seen with carotid TIAs [47]. Higher risk with vascular pathologies TIA caused by vascular pathologies (ie, large artery atherosclerosis and small vessel disease) appears to confer a higher risk of subsequent stroke than cardiac and other nonvascular subtypes of TIA. A study from the prospective TIAregistry.org project, with over 4700 patients, found that large artery atherosclerosis was an independent risk factor for recurrent stroke [39]. Another prospective population-based study of 1000 patients from the United Kingdom reported that TIA due to small vessel vasculopathy was associated with a higher risk of early stroke than TIA due to other causes [48]. The stroke risk was particularly elevated after multiple stereotyped small vessel TIAs occurring in a brief period of time and characterized by motor symptoms but no cortical signs, the so-called "capsular warning syndrome" [27] or "stuttering lacunar syndrome." Although data are limited, the risk of early (within seven days) stroke after such events may be as high as 40 percent or more [27,48]. Higher risk with infarction There is accumulating evidence suggesting that the findings of acute infarction on diffusion-weighted MRI (DWI) [32,49-52] or acute or chronic ischemic lesions on computed tomography (CT) [53] after a transient ischemic event are important predictors of stroke. As an example, in a pooled analysis of 3206 patients with TIA who were evaluated with DWI, the risk of stroke at seven days was much lower in patients with no infarction compared with those with infarction (0.4 versus 7.1 percent) [20]. In patients with an imaging-positive transient event, the 90-day risk of stroke appears to be as high as 14 percent [32,49,50,54]. In contrast, after an imaging-negative transient event, the corresponding risk is <1 percent. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 11/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Is the stroke risk after TIA declining over time? In a 2016 report from the TIAregistry.org project, a prospective multinational registry of over 4700 patients with TIA or minor stroke (defined by a modified Rankin scale score of 0 or 1 when first evaluated), the estimated risks of stroke at 2, 30, 90, and 365 days after the index event were 1.5, 2.8, 3.7, and 5.1 percent, respectively [39]. In a 2018 follow-up study, the estimated cumulative risk of stroke at five years after the index event was 9.5 percent [55]. These rates are lower than those previously reported [40,56,57], possibly due to the more rapid implementation of newer and more effective strategies for the secondary prevention of ischemic stroke; the registry included only sites with dedicated systems for the urgent evaluation of TIA, and most patients were seen by a stroke specialist within 24 hours of symptom onset. Independent risk factors for recurrent stroke were multiple infarctions on brain imaging, 2 large artery atherosclerosis, and an ABCD score of 6 or 7. (See 'Stroke risk stratification' below.) A systematic review and meta-analysis of 68 studies published from 1971 to March 2019 that included over 200,000 patients found that the risk of stroke after TIA was 2.4 percent within two days, 3.8 percent within seven days, 4.1 percent within 30 days, and 4.7 percent within 90 days [41]. The incidence of stroke was lower among study populations enrolled after 1999. Similarly, in a longitudinal population-based cohort study from the Framingham Heart Study that included over 14,000 participants from 1948 to 2017 with no history of TIA or stroke at baseline, the risk of stroke after TIA was lower in the epoch of 2000 to 2017 compared with 1948 to 1985 [14]. High-risk lesions There are four pathologic processes that give rise to embolic TIAs or low- flow TIAs and that can produce sudden devastating stroke if not recognized and treated. Internal carotid artery atherosclerosis An atherothrombotic stenotic lesion at the origin of the internal carotid artery that is narrowed to more than 70 percent of its normal lumen diameter poses a threat of embolic or low-flow TIA or stroke [58-61]. Even a 50 percent stenosis may be important when considering carotid endarterectomy for prevention of a secondary stroke or of a primary stroke when a TIA has occurred. In this setting, embolism is more common than low flow as a cause of TIA or stroke. (See "Management of symptomatic carotid atherosclerotic disease".) Prospective natural history studies of asymptomatic atherothrombotic disease at the origin of the internal carotid artery (mostly asymptomatic carotid artery bruits) suggest that the rate of ipsilateral stroke increases dramatically when the residual lumen diameter narrows to greater than 70 percent stenosis ( figure 8 and figure 9) [62-64]. In one series of 500 patients with asymptomatic cervical bruits, the incidence of stroke was 1.7 percent per https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 12/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate year overall but 5.5 percent per year in those with more than a 75 percent carotid artery stenosis [63]. This degree of stenosis corresponds to a residual lumen diameter of 1.5 mm, the precise point at which pressure drops across the stenotic lesion [65,66]. When the pressure drops, flow to the ipsilateral middle cerebral artery stem is in part supplied by collateral circulation from the circle of Willis and from the external carotid to ophthalmic to distal internal carotid artery system ( figure 6 and figure 7). Less flow is provided by the internal carotid artery as the lesion further narrows. We believe that this provides a milieu for thrombus formation at the site of the stenosis and subsequent embolism. When the circle of Willis is compromised, low-flow TIA ensues. Intracranial atherothrombotic disease Intracranial atherothrombotic disease that produces low-flow or embolic TIA most commonly occurs at the distal vertebral artery/vertebrobasilar junction/proximal basilar artery site. The potential of this lesion to precipitate a disastrous stroke by thrombosis, thrombus propagation, and embolism is extremely important. The other two most important, but less common, sites include the siphon portion of the internal carotid artery and the middle cerebral artery stem. The common carotid artery origin and the vertebral artery origin are much less problematic since they only rarely give rise to artery-to-artery emboli. The ability to noninvasively diagnose and follow these intracranial arterial lesions with precision through MRI angiography, CT angiography, duplex Doppler, and transcranial Doppler flow assessment allows for important preventive therapeutic considerations. (See "Intracranial large artery atherosclerosis: Treatment and prognosis" and "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) Arterial, aortic, or cardiac sources of emboli Emboli at the top of the basilar artery or the middle cerebral artery stem that come from a source below arterial, aortic, or cardiac are extremely important to recognize since they may produce fluctuating symptoms or TIAs prior to a devastating stroke. Transient focal symptoms due to an embolus at these sites occur because blood flow reestablishes itself around the embolus. The symptoms may return in abundance and produce a stroke when the embolus itself causes a thrombus that further occludes the artery. This can occur hours or even days after the embolus has lodged at the site because it did not migrate or lyse. Dissection lesions Dissection lesions at the origin of the petrous portion of the internal carotid artery or at the C1-2 level of the vertebral artery as it enters the foramen transversarium cause symptoms of cerebral ischemia due to low flow or embolism, which https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 13/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate occur within minutes, hours, or even days prior to a devastating stroke. Modern neurovascular imaging technology can establish the diagnosis noninvasively. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis" and "Cerebral and cervical artery dissection: Treatment and prognosis".) Stroke risk stratification Methods that can reliably assess the risk of stroke after TIA in individual patients would be useful for triaging patients. The discussion that follows applies to the traditional time-based definition of TIA, which is characterized clinically by the temporary nature (<24 hours) of the associated neurologic symptoms. 2 ABCD2 score A simple but suboptimal assessment called the ABCD score (ie, ABCD squared, for Age, Blood pressure, Clinical features, Duration of symptoms, and Diabetes) was designed to identify patients at high risk of ischemic stroke in the first seven days after TIA ( table 2) [67]. 2 Despite the score's simplicity, it is often miscalculated [68]. The ABCD score is tallied as follows (calculator 1): Age ( 60 years = 1 point) Blood pressure elevation when first assessed after TIA (systolic 140 mmHg or diastolic 90 mmHg = 1 point) Clinical features (unilateral weakness = 2 points; isolated speech disturbance = 1 point; other = 0 points) Duration of TIA symptoms ( 60 minutes = 2 points; 10 to 59 minutes = 1 point; <10 minutes = 0 points) Diabetes (present = 1 point) 2 Estimated two-day stroke risks determined by the ABCD score in the combined derivation and validation cohorts were as follows [67]: Score 6 to 7: High two-day stroke risk (8 percent) Score 4 to 5: Moderate two-day stroke risk (4 percent) Score 0 to 3: Low two-day stroke risk (1 percent) 2 The ABCD score was designed to be used in primary care settings to stratify patients according to stroke risk and thus identify those who required emergency assessment by specialists. However, its predictive performance is not satisfactory. A systematic review and meta-analysis of 2 29 studies that included over 13,700 patients with TIA found that the ABCD score did not reliably distinguish those with a low and high risk of recurrent stroke, or those with TIAs and TIA mimics [69]. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 14/41 7/5/23, 12:37 PM
registry included only sites with dedicated systems for the urgent evaluation of TIA, and most patients were seen by a stroke specialist within 24 hours of symptom onset. Independent risk factors for recurrent stroke were multiple infarctions on brain imaging, 2 large artery atherosclerosis, and an ABCD score of 6 or 7. (See 'Stroke risk stratification' below.) A systematic review and meta-analysis of 68 studies published from 1971 to March 2019 that included over 200,000 patients found that the risk of stroke after TIA was 2.4 percent within two days, 3.8 percent within seven days, 4.1 percent within 30 days, and 4.7 percent within 90 days [41]. The incidence of stroke was lower among study populations enrolled after 1999. Similarly, in a longitudinal population-based cohort study from the Framingham Heart Study that included over 14,000 participants from 1948 to 2017 with no history of TIA or stroke at baseline, the risk of stroke after TIA was lower in the epoch of 2000 to 2017 compared with 1948 to 1985 [14]. High-risk lesions There are four pathologic processes that give rise to embolic TIAs or low- flow TIAs and that can produce sudden devastating stroke if not recognized and treated. Internal carotid artery atherosclerosis An atherothrombotic stenotic lesion at the origin of the internal carotid artery that is narrowed to more than 70 percent of its normal lumen diameter poses a threat of embolic or low-flow TIA or stroke [58-61]. Even a 50 percent stenosis may be important when considering carotid endarterectomy for prevention of a secondary stroke or of a primary stroke when a TIA has occurred. In this setting, embolism is more common than low flow as a cause of TIA or stroke. (See "Management of symptomatic carotid atherosclerotic disease".) Prospective natural history studies of asymptomatic atherothrombotic disease at the origin of the internal carotid artery (mostly asymptomatic carotid artery bruits) suggest that the rate of ipsilateral stroke increases dramatically when the residual lumen diameter narrows to greater than 70 percent stenosis ( figure 8 and figure 9) [62-64]. In one series of 500 patients with asymptomatic cervical bruits, the incidence of stroke was 1.7 percent per https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 12/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate year overall but 5.5 percent per year in those with more than a 75 percent carotid artery stenosis [63]. This degree of stenosis corresponds to a residual lumen diameter of 1.5 mm, the precise point at which pressure drops across the stenotic lesion [65,66]. When the pressure drops, flow to the ipsilateral middle cerebral artery stem is in part supplied by collateral circulation from the circle of Willis and from the external carotid to ophthalmic to distal internal carotid artery system ( figure 6 and figure 7). Less flow is provided by the internal carotid artery as the lesion further narrows. We believe that this provides a milieu for thrombus formation at the site of the stenosis and subsequent embolism. When the circle of Willis is compromised, low-flow TIA ensues. Intracranial atherothrombotic disease Intracranial atherothrombotic disease that produces low-flow or embolic TIA most commonly occurs at the distal vertebral artery/vertebrobasilar junction/proximal basilar artery site. The potential of this lesion to precipitate a disastrous stroke by thrombosis, thrombus propagation, and embolism is extremely important. The other two most important, but less common, sites include the siphon portion of the internal carotid artery and the middle cerebral artery stem. The common carotid artery origin and the vertebral artery origin are much less problematic since they only rarely give rise to artery-to-artery emboli. The ability to noninvasively diagnose and follow these intracranial arterial lesions with precision through MRI angiography, CT angiography, duplex Doppler, and transcranial Doppler flow assessment allows for important preventive therapeutic considerations. (See "Intracranial large artery atherosclerosis: Treatment and prognosis" and "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) Arterial, aortic, or cardiac sources of emboli Emboli at the top of the basilar artery or the middle cerebral artery stem that come from a source below arterial, aortic, or cardiac are extremely important to recognize since they may produce fluctuating symptoms or TIAs prior to a devastating stroke. Transient focal symptoms due to an embolus at these sites occur because blood flow reestablishes itself around the embolus. The symptoms may return in abundance and produce a stroke when the embolus itself causes a thrombus that further occludes the artery. This can occur hours or even days after the embolus has lodged at the site because it did not migrate or lyse. Dissection lesions Dissection lesions at the origin of the petrous portion of the internal carotid artery or at the C1-2 level of the vertebral artery as it enters the foramen transversarium cause symptoms of cerebral ischemia due to low flow or embolism, which https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 13/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate occur within minutes, hours, or even days prior to a devastating stroke. Modern neurovascular imaging technology can establish the diagnosis noninvasively. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis" and "Cerebral and cervical artery dissection: Treatment and prognosis".) Stroke risk stratification Methods that can reliably assess the risk of stroke after TIA in individual patients would be useful for triaging patients. The discussion that follows applies to the traditional time-based definition of TIA, which is characterized clinically by the temporary nature (<24 hours) of the associated neurologic symptoms. 2 ABCD2 score A simple but suboptimal assessment called the ABCD score (ie, ABCD squared, for Age, Blood pressure, Clinical features, Duration of symptoms, and Diabetes) was designed to identify patients at high risk of ischemic stroke in the first seven days after TIA ( table 2) [67]. 2 Despite the score's simplicity, it is often miscalculated [68]. The ABCD score is tallied as follows (calculator 1): Age ( 60 years = 1 point) Blood pressure elevation when first assessed after TIA (systolic 140 mmHg or diastolic 90 mmHg = 1 point) Clinical features (unilateral weakness = 2 points; isolated speech disturbance = 1 point; other = 0 points) Duration of TIA symptoms ( 60 minutes = 2 points; 10 to 59 minutes = 1 point; <10 minutes = 0 points) Diabetes (present = 1 point) 2 Estimated two-day stroke risks determined by the ABCD score in the combined derivation and validation cohorts were as follows [67]: Score 6 to 7: High two-day stroke risk (8 percent) Score 4 to 5: Moderate two-day stroke risk (4 percent) Score 0 to 3: Low two-day stroke risk (1 percent) 2 The ABCD score was designed to be used in primary care settings to stratify patients according to stroke risk and thus identify those who required emergency assessment by specialists. However, its predictive performance is not satisfactory. A systematic review and meta-analysis of 2 29 studies that included over 13,700 patients with TIA found that the ABCD score did not reliably distinguish those with a low and high risk of recurrent stroke, or those with TIAs and TIA mimics [69]. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 14/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate An earlier meta-analysis found that the score performance was poor in settings of low baseline risk and in TIA diagnosed by nonspecialists [70]. 2 The predictive power of the ABCD score is generally lower in hospital settings compared with population-based settings, thus limiting its utility for high-risk populations [67,71,72]. Other risk models Risk models that combine information from acute DWI, noninvasive angiography, and presumed TIA etiology improve the accuracy of stroke risk prediction after TIA [20,32,49,73-77]. There are a number of examples: 2 Several scores are based upon the conventional ABCD score: The Clinical- and Imaging-based Prediction (CIP) model incorporates diffusion-weighted 2 MRI findings with a dichotomized ABCD score [32]. 2 The ABCD -I score adds information about brain infarction on diffusion-weighted MRI or CT [20]. 3 The ABCD -I score assigns points for an earlier TIA within seven days of the index event and further incorporates data from initial diagnostic brain and carotid imaging [73]. The Canadian TIA Score ( table 3) estimates the probability of stroke within seven days of a TIA and is based upon nine items from the history and examination and four items from investigations that were correlated with having an impending stroke [78]. The total score ranges from -3 to 23. In the derivation study, scores 5 were associated with a low risk ( 0.5 percent) of subsequent stroke, while scores from 6 to 9 were associated with an intermediate risk (approximately 1 to 3 percent), and scores 10 were associated with a high risk ( 5 percent). In a prospective cohort study of over 7000 patients with TIA, the 2 2 Canadian TIA Score was more accurate compared with the ABCD or the ABCD -I for predicting subsequent stroke or carotid artery revascularization [79]. The Recurrence Risk Estimator (RRE) score combines clinical (recent history of stroke or TIA plus admission stroke subtype) and imaging information (location, multiplicity, distribution, and age of brain infarcts) [74] for predicting recurrent stroke following TIA with infarction [80,81]. As mentioned above, time-based TIA associated with acute brain infarction is a high-risk condition, and the RRE is the only predictive score that can be used to further stratify the risk in this particular population. The score identifies subsets of patients with a seven-day stroke risk that is as low as 1 percent and as high as 40 percent. The RRE score was externally validated in a multicenter cohort of over 1400 patients with acute ischemic stroke [82]. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 15/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Additional research and validation of these models is needed to determine whether these stroke risk stratification models have any utility for clinical practice. The requirement for MRI limits the widespread applicability of advanced risk prediction models. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Transient ischemic attack (The Basics)") Beyond the Basics topic (see "Patient education: Transient ischemic attack (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Time-based definition The classic, time-based definition of transient ischemic attack (TIA) is a sudden onset of a focal neurologic symptom and/or sign lasting less than 24 hours, caused by a transient decrease in blood supply to the brain, spinal cord, or retina. Although still widely used, this classic definition is inadequate because even relatively brief ischemia can cause permanent neurologic or retinal injury. A substantial proportion of patients with a classically defined TIA (<24 hours in duration) have corresponding ischemic lesions on diffusion-weighted or perfusion-weighted magnetic resonance imaging (MRI) https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 16/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate that could explain the transient clinical manifestations. The associated infarctions are often very small. (See 'Traditional time-based definition of TIA' above.) Tissue-based definition The tissue-based definition of TIA is defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. Defining TIA by the absence of infarction means that the end point is biological (tissue injury) rather than arbitrary (24 hours). In addition, this tissue- based definition encourages the use of neurodiagnostic tests to identify brain injury and its cause. (See 'Tissue-based definition of TIA' above.) Mechanisms The symptoms of a TIA depend in part upon the pathophysiologic subtype, which are divided into three main mechanisms (see 'Mechanisms and clinical manifestations' above): Embolic TIA, which may be artery-to-artery, or due to a cardioaortic or unknown source. (See 'Embolic TIA' above.) Lacunar or small penetrating vessel TIA. (See 'Lacunar or small vessel TIA' above.) Large artery, low-flow TIA. (See 'Low-flow TIA' above.) Neurologic emergency TIA is a neurologic emergency. Therefore, the initial evaluation of suspected TIA and minor ischemic stroke requires urgent evaluation ( algorithm 1). (See 'Urgency of evaluation' above and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke", section on 'Urgent investigations'.) Clinical features and diagnosis The diagnosis of TIA is based upon the clinical features of the transient attack and the neuroimaging findings. (See 'Diagnosis' above.) Typical TIAs Typical TIAs are characterized by transient, focal neurologic symptoms that can be localized to a single vascular territory within the brain, including one or more of the following (see 'Typical TIA' above): - - - Transient monocular blindness (amaurosis fugax) Aphasia or dysarthria Hemianopia Hemiparesis and/or hemisensory loss Atypical TIAs Atypical spells suggestive of TIA ( table 1) may be less likely to have an ischemic cause, but atypical TIAs characterized by negative focal symptoms (where "negative" indicates a loss of some neurologic function) have similar short- and long- term risks of subsequent ischemic stroke, as do patients with typical TIAs, and should therefore be investigated and treated as true TIAs. (See 'Atypical TIA' above.) https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 17/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Differential diagnosis The differential diagnosis of TIA is summarized in the table ( table 1) and discussed in detail separately. (See "Differential diagnosis of transient ischemic attack and acute stroke".) Risk of stroke Both traditionally defined TIA (ie, time-based, lasting <24 hours) and minor ischemic stroke are associated with a high early risk of recurrent stroke. The stroke risk in 2 the first two days after TIA is approximately 1.5 to 3.5 percent. The ABCD score ( table 2) was designed to identify patients at high risk of ischemic stroke in this time period, but its predictive performance is not optimal. Risk stratification models that combine information from brain imaging, vascular imaging, and presumed TIA etiology in addition to the clinical 2 ABCD score may improve the accuracy of stroke risk prediction after TIA. (See 'Risk of recurrent stroke' above.) ACKNOWLEDGMENTS The UpToDate editorial staff acknowledges J Philip Kistler, MD, Hakan Ay, MD, and Karen L Furie, MD, MPH, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. 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BMJ 2021; 372:n49. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 23/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 80. Arsava EM, Furie KL, Schwamm LH, et al. Prediction of early stroke risk in transient symptoms with infarction: relevance to the new tissue-based definition. Stroke 2011; 42:2186. 81. Maier IL, Bauerle M, Kermer P, et al. Risk prediction of very early recurrence, death and progression after acute ischaemic stroke. Eur J Neurol 2013; 20:599. 82. Arsava EM, Kim GM, Oliveira-Filho J, et al. Prediction of Early Recurrence After Acute Ischemic Stroke. JAMA Neurol 2016; 73:396. Topic 1088 Version 24.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 24/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate GRAPHICS Temporal behavior of symptoms in patients with transient ischemic attack (TIA) The probability density function curve of symptom duration for transient symptoms associated with infarction (TSI) indicates the absence of continuity within the first 24 hours. The probability density function is the probability that the variable takes a value in a given interval and is equal to 1 over its entire range of values. The area under curve is almost equal to 1 at around 200 minutes. Also note that the curves for TIA with or without infarction overlap (p = 0.82). The distribution of duration of symptoms as seen here suggests that symptom duration is not a reliable feature to be used for predicting whether a transient neurological spell is associated with infarction. DWI: diffusion-weighted magnetic resonance imaging. Reproduced with permission from: Ay, H, Koroshetz, WJ, Benner, T, et al. Transient ischemic attack with infarction: a unique syndrome. Ann Neurol 2005; 57:679. Copyright 2005 John Wiley & Sons. Graphic 82729 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 25/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Anterior cerebral artery distribution and signs and symptoms of occlusion Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 60945 Version 3.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 26/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Middle cerebral artery distribution and signs and symptoms of occlusion Reproduced with permission from Kistler JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 81813 Version 2.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 27/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Posterior cerebral artery distribution and signs and symptoms of occlusion Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 60416 Version 2.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 28/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Superior pontine syndrome Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 53412 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 29/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Anatomy of the cerebral arterial circulation Frontal view of the carotid arteries, vertebral arteries, and intracranial vessels and their communication with each other via the circle of Willis. Reproduced with permission from: U acker R. Atlas Of Vascular Anatomy: An Angiographic Approach, Second Edition. Philadelphia: Lippincott Williams & Wilkins, 2006. Copyright 2006 Lippincott Williams & Wilkins. Graphic 51410 Version 6.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 30/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Major cerebral vascular territories Representation of the territories of the major cerebral vessels shown in a coronal section of the brain. Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases. Harrison's Principles of Internal Medicine, 13th ed, McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 65199 Version 2.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 31/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Transient ischemic attack (TIA) and minor ischemic stroke: Rapid overview of emergency management Clinical features Typical TIAs are characterized by transient, focal neurologic symptoms that can be localized to a single vascular territory within the brain, including one or more of the following: Transient monocular blindness (amaurosis fugax) Aphasia or dysarthria Hemianopia Hemiparesis and/or hemisensory loss (complete or partial) Atypical TIAs may present with transient isolated neurologic symptoms: Isolated vertigo Isolated ataxia Isolated diplopia Isolated speech disturbance (slurred speech) without aphasia Isolated bilateral decreased vision Isolated unilateral sensory loss involving only one body part Differential diagnosis Seizure Migraine aura Syncope Transient global amnesia Central nervous system demyelinating disorder (eg, multiple sclerosis) Peripheral vestibulopathy Metabolic disorder (eg, hypoglycemia) Myasthenia gravis Cranial/peripheral neuropathy Cerebral amyloid angiopathy Subdural hematoma Subarachnoid or intracerebral hemorrhage Transient neurologic attack not otherwise specified Immediate treatment while evaluating the ischemic mechanism For patients with TIA or minor, nondisabling acute ischemic stroke (and thus not eligible for thrombolytic therapy or mechanical thrombectomy), start antiplatelet therapy immediately while the evaluation is in progress: Start DAPT (aspirin plus clopidogrel, or aspirin plus ticagrelor) for patients with one of the following: 2 High-risk TIA, defined by an ABCD score 4 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 32/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Time-based TIA with a relevant large artery stenosis or DWI lesion on MRI (if imaging available at this stage) Minor, nondisabling ischemic stroke, defined by an NIHSS score 5 Start aspirin monotherapy for patients who do not meet the above criteria (ie, TIA with an 2 ABCD score <4 and no relevant large artery stenosis or DWI lesion on MRI [if imaging available at this stage])
attack: multicentre prospective cohort study. BMJ 2021; 372:n49. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 23/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 80. Arsava EM, Furie KL, Schwamm LH, et al. Prediction of early stroke risk in transient symptoms with infarction: relevance to the new tissue-based definition. Stroke 2011; 42:2186. 81. Maier IL, Bauerle M, Kermer P, et al. Risk prediction of very early recurrence, death and progression after acute ischaemic stroke. Eur J Neurol 2013; 20:599. 82. Arsava EM, Kim GM, Oliveira-Filho J, et al. Prediction of Early Recurrence After Acute Ischemic Stroke. JAMA Neurol 2016; 73:396. Topic 1088 Version 24.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 24/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate GRAPHICS Temporal behavior of symptoms in patients with transient ischemic attack (TIA) The probability density function curve of symptom duration for transient symptoms associated with infarction (TSI) indicates the absence of continuity within the first 24 hours. The probability density function is the probability that the variable takes a value in a given interval and is equal to 1 over its entire range of values. The area under curve is almost equal to 1 at around 200 minutes. Also note that the curves for TIA with or without infarction overlap (p = 0.82). The distribution of duration of symptoms as seen here suggests that symptom duration is not a reliable feature to be used for predicting whether a transient neurological spell is associated with infarction. DWI: diffusion-weighted magnetic resonance imaging. Reproduced with permission from: Ay, H, Koroshetz, WJ, Benner, T, et al. Transient ischemic attack with infarction: a unique syndrome. Ann Neurol 2005; 57:679. Copyright 2005 John Wiley & Sons. Graphic 82729 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 25/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Anterior cerebral artery distribution and signs and symptoms of occlusion Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 60945 Version 3.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 26/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Middle cerebral artery distribution and signs and symptoms of occlusion Reproduced with permission from Kistler JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 81813 Version 2.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 27/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Posterior cerebral artery distribution and signs and symptoms of occlusion Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 60416 Version 2.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 28/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Superior pontine syndrome Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 53412 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 29/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Anatomy of the cerebral arterial circulation Frontal view of the carotid arteries, vertebral arteries, and intracranial vessels and their communication with each other via the circle of Willis. Reproduced with permission from: U acker R. Atlas Of Vascular Anatomy: An Angiographic Approach, Second Edition. Philadelphia: Lippincott Williams & Wilkins, 2006. Copyright 2006 Lippincott Williams & Wilkins. Graphic 51410 Version 6.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 30/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Major cerebral vascular territories Representation of the territories of the major cerebral vessels shown in a coronal section of the brain. Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases. Harrison's Principles of Internal Medicine, 13th ed, McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 65199 Version 2.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 31/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Transient ischemic attack (TIA) and minor ischemic stroke: Rapid overview of emergency management Clinical features Typical TIAs are characterized by transient, focal neurologic symptoms that can be localized to a single vascular territory within the brain, including one or more of the following: Transient monocular blindness (amaurosis fugax) Aphasia or dysarthria Hemianopia Hemiparesis and/or hemisensory loss (complete or partial) Atypical TIAs may present with transient isolated neurologic symptoms: Isolated vertigo Isolated ataxia Isolated diplopia Isolated speech disturbance (slurred speech) without aphasia Isolated bilateral decreased vision Isolated unilateral sensory loss involving only one body part Differential diagnosis Seizure Migraine aura Syncope Transient global amnesia Central nervous system demyelinating disorder (eg, multiple sclerosis) Peripheral vestibulopathy Metabolic disorder (eg, hypoglycemia) Myasthenia gravis Cranial/peripheral neuropathy Cerebral amyloid angiopathy Subdural hematoma Subarachnoid or intracerebral hemorrhage Transient neurologic attack not otherwise specified Immediate treatment while evaluating the ischemic mechanism For patients with TIA or minor, nondisabling acute ischemic stroke (and thus not eligible for thrombolytic therapy or mechanical thrombectomy), start antiplatelet therapy immediately while the evaluation is in progress: Start DAPT (aspirin plus clopidogrel, or aspirin plus ticagrelor) for patients with one of the following: 2 High-risk TIA, defined by an ABCD score 4 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 32/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Time-based TIA with a relevant large artery stenosis or DWI lesion on MRI (if imaging available at this stage) Minor, nondisabling ischemic stroke, defined by an NIHSS score 5 Start aspirin monotherapy for patients who do not meet the above criteria (ie, TIA with an 2 ABCD score <4 and no relevant large artery stenosis or DWI lesion on MRI [if imaging available at this stage]) Once the ischemic mechanism is determined, antithrombotic therapy can be modified as necessary Urgent evaluation Brain imaging with diffusion-weighted MRI (preferred) or CT to identify infarction and rule out nonischemic causes Vascular imaging of extracranial and intracranial large arteries with MRA or CTA to identify large artery cause Cardiac evaluation (ECG, cardiac monitoring, echocardiography) to identify atrial fibrillation or other cardioembolic source Laboratories: CBC, PT and PTT, serum electrolytes, creatinine, fasting blood glucose or HbA1c, lipids, and (as indicated for selected patients) ESR and CRP Targeted treatment by mechanism for secondary prevention Cardiogenic embolism due to atrial fibrillation: Stop antiplatelet agents and start long-term anticoagulation Symptomatic internal carotid artery stenosis: Carotid revascularization with CEA or CAS and long-term antiplatelet therapy Intracranial large artery atherosclerosis with 70 to 99% stenosis: Continue DAPT for 21 to 90 days, then switch to long-term single-agent antiplatelet therapy Small vessel disease, extracranial vertebral artery stenosis, intracranial large artery atherosclerosis with 50 to 69% stenosis, or cryptogenic: Continue DAPT for 21 days, then switch to long-term single-agent antiplatelet therapy for: 2 High-risk TIA (ABCD score 4), or TIA with a relevant DWI lesion on MRI, or extracranial stenosis not amenable to revascularization Minor ischemic stroke (NIHSS 5) 2 Continue long-term single-agent antiplatelet therapy for low-risk TIA (ABCD score <4), and TIA without a relevant large artery stenosis or DWI lesion on MRI Intensive risk factor management Antihypertensive therapy for patients with known or newly established hypertension LDL-cholesterol lowering with high-intensity statin therapy Glucose control to near normoglycemic levels for patients with diabetes Lifestyle modification as appropriate: Moderate to vigorous exercise most days of the week for those capable Smoking cessation for recent or current tobacco users Mediterranean diet https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 33/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Weight reduction for patients with obesity Reduced alcohol consumption for heavy drinkers This rapid overview presents a general approach to the management of TIA and minor stroke. Please refer to UpToDate content for details, including descriptions and calculators for the NIHSS and 2 ABCD scores. 2 DAPT: dual antiplatelet therapy; ABCD : Age, Blood pressure, Clinical features, Duration of symptoms, and Diabetes; NIHSS: National Institutes of Health Stroke Scale; DWI: diffusion-weighted imaging; MRI: magnetic resonance imaging; CT: computed tomography; MRA: magnetic resonance angiography; CTA: computed tomographic angiography; ECG: electrocardiography; CBC: complete blood count; PT: prothrombin time; PTT: partial thromboplastin time; HbA1c: glycated hemoglobin; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; CEA: carotid endarterectomy; CAS: carotid artery stenting; LDL: low density lipoprotein; ICAS: intracranial larger artery atherosclerosis. Graphic 131201 Version 4.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 34/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Evaluation of patient presenting with acute symptoms of possible TIA or minor ischemic stroke This algorithm should be used in conjunction with UpToDate topics on the initial evaluation and management of TIA and ischemic stroke. CDUS: carotid duplex ultrasonography; CNS: central nervous system; CT: computed tomography; CTA: computed tomography angiography; ECG: electrocardiography; IV: intravenous; MRA: magnetic resonance angiography; MRI: magnetic resonance imaging; TIA: transient ischemic attack; TCD: transcranial Doppler. Patients who present within the appropriate time window after ischemic symptom onset and have a persistent neurologic deficit that is potentially disabling, despite https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 35/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate improvement of any degree, should be treated with intravenous thrombolysis and/or mechanical thrombectomy in the absence of other contraindications. Further management of these patients is similar to that of other patients with a potentially disabling stroke. Can begin aspirin and statin therapy while awaiting results of remaining diagnostic studies if imaging is negative for hemorrhage and other nonischemic cause of symptoms. Viable strategies include antihypertensive therapy, antithrombotic therapy, statin therapy, and lifestyle modification; select patients with symptomatic cervical internal carotid artery disease may benefit from carotid revascularization. Graphic 107065 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 36/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Severity of carotid stenosis predicts stroke risk Relation between the degree of carotid artery stenosis and the annual risk of stroke. Data from Barnett, HJ, Eliasziw, M, Meldrum, HE, Taylor, DW, Neurology 1996; 46:603. Graphic 60048 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 37/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Cerebral ischemia events with asymptomatic carotid artery bruits Incidence of ischemic events in 500 patients with asymptomatic carotid artery bruits according to the severity of carotid artery stenosis on initial Doppler ultrasonography. Patients with 75 percent stenosis were at significantly increased risk (P <0.0001). Data from Chambers BR, Norris JW. Outcome in patients with asymptomatic neck bruits. N Engl J Med 1986; 315:860. Graphic 66153 Version 3.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 38/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 2 ABCD score 2 The ABCD score can be used to estimate the risk of ischemic stroke in the first two days after TIA. The score is tallied as follows: Age: 60 years 1 point <60 years 0 points Blood pressure elevation when first assessed after TIA: Systolic 140 mmHg or diastolic 90 mmHg 1 point Systolic <140 mmHg and diastolic <90 mmHg 0 points Clinical features: Unilateral weakness 2 points Isolated speech disturbance 1 point Other 0 points Duration of TIA symptoms: 60 minutes 2 points 10 to 59 minutes 1 point <10 minutes 0 points Diabetes: Present 1 point Absent 0 points Data from: Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and re nement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:283. Graphic 62381 Version 3.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 39/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Canadian TIA score Items Points Clinical findings First TIA (in lifetime) 2 Symptoms 10 min 2 History of carotid stenosis 2 Already on antiplatelet therapy 3 History of gait disturbance 1 History of unilateral weakness 1 History of vertigo 3 Initial triage diastolic blood pressure 110 mm Hg 3 Dysarthria or aphasia (history or examination) 1 Investigations in emergency department Atrial fibrillation on ECG 2 Infarction (new or old) on CT 1 9 Platelet count 400 10 /L 2 Glucose 15 mmol/L 3 Total score (-3 to 23) TIA: transient ischemic attack; ECG: electrocardiography; CT: computed tomography. From: Perry JJ, Sharma M, Sivilotti ML, et al. A prospective cohort study of patients with transient ischemic attack to identify high-risk clinical characteristics. Stroke 2014; 45:92. DOI: 10.1161/STROKEAHA.113.003085. Copyright American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 134718 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 40/41 7/5/23, 12:37 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Contributor Disclosures Natalia S Rost, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Erica Camargo Faye, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 41/41
7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Differential diagnosis of transient ischemic attack and acute stroke : Louis R Caplan, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 30, 2021. INTRODUCTION The symptoms of brain ischemia may be transient, lasting seconds to minutes, or can persist for longer periods of time. Symptoms and signs remain indefinitely if the brain becomes irreversibly damaged and infarction occurs. Unfortunately, the presence of neurologic symptoms does not accurately reflect the presence or absence of infarction, and the tempo of the symptoms is not diagnostic for the cause of the ischemia [1,2]. This is a critical issue because treatment depends upon accurately identifying the cause of symptoms, and the nature, location, and severity of causative cardiac, hematologic, and cerebrovascular abnormalities. The differential diagnosis of transient ischemic attack and stroke will be reviewed here. The evaluation of stroke and transient cerebral ischemia are discussed separately. (See "Overview of the evaluation of stroke" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) PERSISTENT NEUROLOGIC DEFICITS WITH ABRUPT ONSET Ischemic strokes are characterized by the abrupt or at least very acute onset of focal neurologic symptoms and signs that leave persistent neurologic deficits. Other disorders that have acute onset and cause persistent focal signs should be considered in the differential diagnosis. https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 1/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Intracerebral hemorrhages usually develop during minutes and cause gradually increasing focal signs. Patients with large hemorrhages often develop headache, vomiting, and reduced consciousness; these findings are typically absent in patients with small hemorrhages. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) Brain tumors can cause an abrupt onset or worsening of symptoms; hemorrhage into a tumor is one mechanism for such a change. In addition, some tumors which are outside the brain (eg, meningiomas) reach a critical mass and can cause abrupt displacement of brain tissue with the sudden onset of symptoms. (See "Overview of the clinical features and diagnosis of brain tumors in adults".) Brain abscesses cause focal neurologic symptoms and signs which can begin abruptly; fever, headache, and seizures are common accompanying signs. (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess".) Nonketotic hyperglycemic stupor is often associated with focal neurologic signs; there may be a focal region of brain edema on brain imaging tests. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis".) Attacks of multiple sclerosis can begin abruptly and may have paroxysmal transient manifestations (see 'Other causes' below). Most often however, MS attacks develop over 5 to 21 days, a longer period than strokes. MS is most common in the third to fifth decades of life, while the frequency of stroke peaks later. A history of prior attacks is very important in making the diagnosis. (See "Manifestations of multiple sclerosis in adults".) Demyelination can occur around veins after various viral infections which result in the abrupt onset of multifocal signs that develop over days. This disorder is often called acute disseminated encephalomyelitis (ADEM). Other viral infections, particularly cytomegalovirus, can cause focal brain lesions associated with focal neurologic signs. TRANSIENT ISCHEMIC ATTACK Transient ischemic attack (TIA) is defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. In keeping with this definition of TIA, ischemic stroke is defined as an infarction of central nervous system tissue. (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Definition of TIA'.) https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 2/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate The term "transient ischemic attack" was first introduced in the early 1950s based upon the recognition that a transient focal loss of neurologic function often preceded strokes [3]. In the years after this initial description in patients with carotid artery disease, various groups and committees arbitrarily defined TIAs as lasting less than 24 hours [2]. However, this classic definition of TIA was inadequate for several reasons. Most notably, there is risk of permanent tissue injury (ie, infarction) even when focal transient neurologic symptoms last less than one hour. Subsequent data showed that ischemic attacks that last longer than one hour are most often associated with brain infarction [4,5]. Most TIAs last less than one hour [2]. Thus, the benign connotation of TIA has been replaced by an understanding that even relatively brief ischemia can cause permanent brain injury. When strokes develop after a TIA, they almost always have the same cause as the TIA. Strokes occur most often within days or weeks after the TIA. Symptoms of TIA Transient ischemic attacks are caused by decreased blood flow to a local portion of the brain. Decreased perfusion can be due to blockage of blood flow to a brain region from an in-situ occlusion of a supply artery, or from embolism to that artery. Symptoms are focal, suggesting that they relate to dysfunction of a localized area of the brain. Symptoms are also transient when the arterial blockage passes (eg, following dissolution or distal passage of an embolus) or when collateral circulation is able to restore adequate perfusion to the region of ischemia. The symptoms and signs may fluctuate depending upon the adequacy of perfusion, which is in turn related to systemic factors (eg, blood volume, cardiac output, blood pressure, blood viscosity) and local factors (eg, propagation and embolization of clot, development of collateral circulation). The symptoms of TIAs depend upon the underlying vascular cause ( table 1) [6]. When ischemia is caused by penetrating artery disease, for example, the symptoms are usually stereotyped (eg, numbness of the face, arm, and leg on one side of the body, or hemiparesis). In contrast, attacks due to large artery occlusive disease have different symptoms in different attacks: When the carotid artery is narrowed or occluded, patients may have monocular blindness on the side of the occlusive lesion, weakness of the contralateral hand, or aphasia [3]. Occlusive lesions of the internal carotid artery in the neck or head, or of its major intracranial branches, the middle and anterior cerebral arteries, cause loss of cerebral hemisphere functions. Occlusive lesions of the vertebral arteries in the head and neck and of the basilar artery cause brainstem and cerebellar symptoms and deficits. https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 3/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Occlusive disease of the posterior cerebral arteries (PCAs) causes visual and somatosensory symptoms due to loss of function in the lateral thalamus and occipital lobe regions supplied by the PCAs. Thus, some TIAs, such as those causing transient monocular blindness, diplopia, and aphasia, are very specific for one vascular territory, while others, such as limb weakness or numbness, are compatible with a number of different territories. The occurrence of a TIA is not helpful in predicting the presence of brain damage, the cause and mechanism of the ischemia, or the prognosis [1,2]. Transient brain ischemia can be caused by a variety of different conditions (see "Definition, etiology, and clinical manifestations of transient ischemic attack"): Brain embolism arising from the heart, aorta, or proximal arterial vessels. Occlusive lesions of either large extracranial or intracranial arteries. These large artery lesions are associated with intermittent hypoperfusion of the symptomatic regions of the brain, or with embolization of fibrin-platelet (white thrombi) or erythrocyte-fibrin (red thrombi) clots into the distal brain circulation. Emboli often break up or pass through the vasculature, explaining the transiency of the neurologic symptoms. Occlusive lesions (either lipohyalinosis or atheromatous branch disease) of small microscopic-sized intracranial arteries and arterioles. Hypercoagulability and diseases that cause thrombosis of small vessels (eg, thrombotic thrombocytopenic purpura). TRANSIENT NEUROLOGIC EVENTS The differential diagnosis of TIAs includes all other causes of transient "spells." The Australians often use the nonspecific word "turns" for such transient episodes of neurologic dysfunction. In addition to TIAs, the most important and frequent causes of discrete self-limited attacks include ( table 2): Seizure Migraine aura Syncope Some disorders mentioned above cause focal abnormalities of brain function, while others cause dysfunction that is either widespread or difficult to localize to any one anatomic region https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 4/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate ( table 3). Certain disorders may also cause both focal and nonfocal attacks. Seizures, for example, can begin and remain focal or can be generalized. Similarly, patients with hypoglycemia usually have global deficits in alertness and cognition, but on occasion can have focal symptoms such as hemiplegia [7]. The term "transient neurological attack" (TNA) has been proposed to describe sudden neurologic symptoms that completely resolve within 24 hours, with no clear evidence to support a diagnosis of migraine, epilepsy, M ni re disease, hyperventilation, cardiac syncope, hypoglycemia, or orthostatic hypotension [8]. The symptoms of TNAs can be focal, nonfocal, or mixed. In this classification, focal TNAs represent TIAs, while TNAs with nonfocal or mixed symptoms are heterogeneous in terms of etiology. Like TIAs, both nonfocal and mixed TNAs appear to be associated with an increased risk of stroke [8]. In addition, some patients diagnosed with TNAs by experienced stroke neurologists have evidence of acute ischemic brain lesions on diffusion-weighted MRI [9]. This finding suggests that clinical features alone do not always distinguish TIA from TNA. Seizure An epileptic seizure refers to a transient occurrence of signs and/or symptoms due to abnormally excessive neuronal activity of the brain. Seizures, especially repeated focal seizures, can be followed by postictal paralysis or loss of other functions. (See "Evaluation and management of the first seizure in adults", section on 'Postictal period'.) Nonepileptic seizures are characterized by sudden changes in behavior that resemble epileptic seizures but are not associated with the typical neurophysiological changes that characterize epileptic seizures. (See "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis".) The symptoms of seizures and nonepileptic paroxysmal events are diverse. These are discussed in detail separately. (See "Evaluation and management of the first seizure in adults", section on 'Initial evaluation' and "Nonepileptic paroxysmal disorders in adolescents and adults".) Migraine aura Migraine aura is the complex of neurologic symptoms that often accompanies migraine headache. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine aura'.) An aura presents as a progressive neurologic deficit or disturbance with subsequent complete recovery. Auras are thought to be caused by cortical spreading depression occurring in regions of the cortex that correspond to the clinical manifestations of the aura. Patients often have a history of migraine or migraine with auras that dates back years, sometimes beginning in childhood and adolescence. This contrasts with TIAs, which seldom recur over more than a few months. https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 5/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Auras typically occur before the onset of migraine headache, and the headache usually begins simultaneously with or just after the end of the aura phase. However, headache onset can rarely occur an hour or more after the end of the aura phase. Although atypical, an aura can develop during or after the onset of headache, and many patients have migraine aura with only a minimal or no headache. Most migraine auras resolve in 20 to 30 minutes and seldom last more than one hour. Typical auras may involve one or more of visual disturbances, sensory symptoms, motor weakness, or speech disturbances. Visual disturbances are the most common type of aura. Visual auras usually begin with seeing a small formed object or objects. The objects vary; stars, circles, squares, zig-zags, pointed lines, fire-flies, lightning bolts, heat waves, pinwheels, rods, beads are a few of the names given by patients. At times, the forms are linear and have angles and straight edges. The resemblance of the edges and lines to forts led to frequent use of the term "fortifications" and fortification spectra to describe this visual experience. Often the forms are bright and may be colored, especially red, green, blue, extra white, or purple. Migraineurs usually describe some type of motion, both in place and across the visual field. In-place motion is often described as flickering, shimmering, rotating, oscillating, or like a kaleidoscope. A key feature of the visual symptoms is buildup of the visual forms. The forms often become brighter, larger, and more objects may appear with time. Characteristically, the forms often move slowly across the visual field leaving a void or darkness (ie, a scotoma) in their wake. Often, as the forms move, the scotoma enlarges. In some patients, the predominant symptom is loss of vision without illusory forms. This can take the form of a black spot, but, more often, the visual loss is that of a hemianopia. Altitudinal or quadrantic visual field defects occur occasionally but are not common. The visual field loss is usually binocular and very similar in the two eyes. It may begin abruptly or progress over a few minutes. Total obscuration of vision with dimness or blackness also occurs. In most patients, the visual symptoms are the only aura symptom. In some patients, the visual symptoms are followed by paresthesias or other sensory phenomena. Less often, the attacks begin or consist solely of somatosensory symptoms. Somatosensory symptoms are the second most common type of migraine aura. Tingling, prickling, pins-and-needles, and numbness are the most common descriptions used to describe sensory phenomena. They may begin anywhere but probably favor the face and hand (cheiro-oral). A march, spread, or buildup of the somatosensory symptoms is https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 6/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate characteristic. At times, the paresthesia spread from one finger to the next, gradually spreading up the hand to the wrist, then to the arm, and then to the shoulder. Most often the initial symptoms are "positive," that is, paresthesia and other spontaneous abnormal sensations rather than a loss of feeling. When the paresthesia move up a limb, they often leave a numbness and loss of feeling in their wake. The parallel between the visual and somatosensory symptoms is clear. A spread or march of positive phenomena (eg, scintillations, sparkles, paresthesias) followed in the wake of the slow spread by negative phenomena (eg, loss of vision, scotomas, and numbness). Like the visual scintillations, the march of paresthesias is relatively slow, much slower than in a seizure, in which the sensory march usually takes seconds. Some patients only note numbness and have no paresthetic symptoms. When visual symptoms precede sensory symptoms, the visual symptoms usually, but not always, clear before the sensory symptoms begin. The march of symptoms includes not only gradual spread within each modality, such as vision and sensation, but also a gradual changeover from one modality to another. Late-life migraine accompaniments are symptoms related to the onset of migraine aura without headache in patients who are 50 years of age or older. The most common symptoms are visual auras, followed by sensory auras (paresthesia), speech disturbances, and motor auras (weakness or paralysis). (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Late-life migraine accompaniments'.) The relationship between migraine and ischemic stroke is discussed in detail separately. (See "Migraine-associated stroke: risk factors, diagnosis, and prevention".) Syncope Syncope is the abrupt and transient loss of consciousness associated with absence of postural tone, followed by a rapid and usually complete recovery. Syncope is caused by an interruption of energy sources to the brain, usually because of a sudden reduction of cerebral perfusion. Common types of syncope include: Neurocardiogenic (vasovagal) syncope Situational syncope (during or immediately after urination, defecation, cough, or swallowing) Orthostatic syncope (associated with orthostatic hypotension) Syncope related to cardiac ischemia or cardiac arrhythmia https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 7/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate These are reviewed in detail elsewhere. (See "Syncope in adults: Clinical manifestations and initial diagnostic evaluation" and "Syncope in adults: Epidemiology, pathogenesis, and etiologies" and "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation".) Transient global amnesia Transient global amnesia (TGA) is reviewed here briefly and discussed in detail separately. (See "Transient global amnesia".) Briefly, TGA is a syndrome characterized by the acute onset of severe anterograde amnesia accompanied by retrograde amnesia, without other cognitive or focal neurologic impairment. The amnesia resolves within 24 hours. Most patients are middle aged or older adults. Episodes are usually not recurrent, but some patients have infrequent attacks that recur over several years. The etiology of TGA is uncertain. Most TGA episodes are probably related to vasoconstriction, but some may be caused by transient ischemia or complex partial seizures. TGA can be associated with small focal abnormalities on diffusion-weighted MRI, but the significance of these remains unclear. Other causes Less frequent causes of transient neurologic events include the following: Metabolic perturbations, such as hypoglycemia, can be associated with focal neurologic deficits. Multiple sclerosis occasionally can cause paroxysmal attacks, particularly of ataxia and dysarthria. (See "Manifestations of multiple sclerosis in adults", section on 'Paroxysmal symptoms'.) Brain tumors can occasionally result in transient neurologic symptoms; the mechanism in these cases is thought to involve mechanical changes that result in pressure on structures adjacent to the tumor. (See "Overview of the clinical features and diagnosis of brain tumors in adults".) Subdural hematomas may cause attacks of transient neurologic dysfunction, again due to mechanical changes that result in pressure on structures adjacent to the hematoma. (See "Subdural hematoma in adults: Etiology, clinical features, and diagnosis".) Intracerebral hemorrhage can rarely present with rapidly resolving symptoms and signs that resemble transient ischemic attacks [10]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 8/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Cerebral amyloid angiopathy, better known as a cause of intracerebral hemorrhage, may also cause transient neurologic symptoms. Affected patients complain of recurrent, brief (minutes), often stereotyped spells of weakness, numbness, paresthesias, or other cortical symptoms that can spread smoothly over contiguous body parts. (See "Cerebral amyloid angiopathy", section on 'Transient focal neurologic episodes'.) Hepatic, renal, and pulmonary encephalopathies can produce temporary aberrations in alertness, behavior and movement. Compressive myelopathy [11] and spinal dural arteriovenous fistulas [12,13] may occasionally present with sudden transient sensory changes and motor deficits, especially in the bilateral lower limbs. Pressure- or position-related peripheral nerve or nerve root compression can cause transient paresthesias and numbness. Peripheral vestibulopathies can cause transient episodic dizziness. (See "Approach to the patient with dizziness" and "Evaluation of the patient with vertigo".) Hysteria and other psychiatric disorders may underlie attacks that include swoons, falls, and episodic blindness, deafness, and paralysis, which can be confused with organic loss of function. DISTINGUISHING TRANSIENT ATTACKS The history is important in distinguishing the various causes of transient attacks. Useful historical features include ( table 2): The focal or nonfocal nature of attacks The nature of the symptoms and their progression The duration and timing of symptoms Associated symptoms during and after the attacks The evaluation of a patient presenting with acute symptoms suggestive of TIA or ischemic stroke is outlined in the algorithm ( algorithm 1) and discussed in detail separately. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) Nature of symptoms Symptoms can be categorized using Jacksonian terminology as either "positive" or "negative." https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 9/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Positive symptoms indicate active discharge from central nervous system neurons. Typical positive symptoms can be visual (eg, bright lines, shapes, objects), auditory (eg, tinnitus, noises, music), somatosensory (eg, burning, pain, paresthesia), or motor (eg, jerking or repetitive rhythmic movements). Negative symptoms indicate an absence or loss of function, such as loss of vision, hearing, feeling, or ability to move a part of the body. Seizures and migraine auras characteristically (but not always) begin with positive symptoms, while TIAs invariably are characterized by negative symptoms. Seizures occasionally cause paralytic attacks but, on close observation, there are usually features of the history and physical examination that suggest the presence of a seizure disorder such as minor twitching of a finger or toe or a tingling sensation in the affected limb [14]. Progression and course The progression and course of the symptoms are also helpful in the differential diagnosis. Migraine aura often progresses slowly within one modality. As an example, scintillations or bright objects tend to move slowly across the visual field. Paresthesia may gradually progress from one finger, to all the digits, to the wrist, forearm, shoulder, trunk, and then the face and leg. This progression normally occurs over minutes. After the positive symptoms move, they are often followed by loss of function. The moving train of visual scintillations may end in a scotoma or visual field defect. Similarly, as paresthesia travel centripetally, they may leave the initial areas of skin numb and devoid of feeling. Migrainous aura typically progresses from one modality to another; after the visual symptoms clear, paresthesia begins. When paresthesia clear, aphasia or other cortical function abnormalities may develop [15-17]. In contrast to migraine: Seizures usually consist of positive phenomena in one modality which progress very quickly over seconds. TIA symptoms are negative; when more than one modality or function is involved, all are affected at about the same time. Loss of consciousness is very common in seizures and syncope, which usually produce relatively stereotyped attacks; in comparison, loss of consciousness is rare in TIAs, and symptoms can be stereotyped or different in various TIAs. Duration and tempo The duration and tempo of attacks also are useful in predicting the cause: https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 10/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Migrainous auras characteristically last 20 to 30 minutes, although they may persist for hours TIAs are usually fleeting, usually lasting less than one hour Seizures last on average about 30 seconds to 3 minutes; some seizures, including absence attacks, atonic seizures and myoclonic jerks, are shorter in duration Syncope is very brief (seconds) unless the patient is artificially propped up or otherwise cannot obtain a supine position Seizures occur sporadically over the years but sometimes appear in flurries. In comparison, TIAs usually cluster during a finite period of time and can occur as frequent "shotgun"-like attacks, and syncopal attacks are scattered over years. Attacks that are scattered over many years are almost always either faints, migraines, or seizures; TIAs almost never continue over this time span. Precipitating factors Precipitants often give clues to the cause of attacks. Activation of seizures may occur in some patients after stroboscopic stimulation, hyperventilation, stopping antiseizure medications, fever, and alcohol or drug withdrawal. In some patients, TIAs occur when blood pressure is reduced, or upon sudden standing or bending. Dizziness and vertigo in patients with peripheral vestibulopathies are often triggered by sudden movements and positional changes. The "classical" or "typical" presentation of vasovagal syncope refers to syncope triggered by emotional or orthostatic stress, painful or noxious stimuli, fear of bodily injury, prolonged standing, heat exposure, or after physical exertion. As examples, vasovagal syncope commonly occurs when patients see blood, have or are about to have phlebotomy or other medical procedures, see an electric saw poised to remove a plaster cast on their arm or leg, stand up for a long time in church, or when a dental drill is aimed directly at their open mouth by a dentist. Hypovolemia also frequently precipitates syncope. Associated symptoms Non-neurologic associated symptoms can be characteristic of certain disorders. Headache is common after migraine aura and following a seizure. Headache can also occur during a TIA, but rarely at the same time or directly after neurologic symptoms. A bitten tongue, incontinence, and muscle aches are frequently associated with seizure. Vomiting is common after migraine and occasionally follows syncope, but is rare after or during https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 11/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate TIA and rare in relation to seizure. In the latter circumstance, vomiting may develop after the patient has lost consciousness; patients do not recall vomiting unless they see the vomitus when they awaken. Nausea and a need to urinate or defecate often precede or follow syncope; sweating and pallor are other common features of syncope. Age and sex of patient Demographic information may be helpful but there is substantial overlap ( table 2). Seizures occur at any age, while TIAs are not very common in young individuals, particularly those who do not have prominent risk factors for vascular disease (eg, hypertension, diabetes, smoking, cardiac disease, sickle cell disease, etc). In otherwise healthy women who are pregnant, transient focal neurologic symptoms are often related to migraine with aura, and usually have a benign outcome [18]. Syncope has little predilection for age, but is more common in women. TIAs and strokes are somewhat more common in men, although after menopause the frequencies are nearly equal in the two sexes. Seizures have no strong sex predilection. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Transient ischemic attack (Beyond the Basics)" and "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 12/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate SUMMARY Ischemic stroke is characterized by the abrupt or at least very acute onset of focal neurologic symptoms and signs that leave persistent neurologic deficits. Other disorders that have acute onset and cause persistent focal signs should be considered in the differential diagnosis, including intracerebral hemorrhage, brain tumor, brain abscess, nonketotic hyperglycemic stupor, attacks of multiple sclerosis, and acute disseminated encephalomyelitis (ADEM). (See 'Persistent neurologic deficits with abrupt onset' above.) Transient ischemic attack (TIA) is defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. Ischemic stroke is defined as an infarction of central nervous system tissue. The symptoms of TIAs are typically focal and depend upon the underlying vascular cause ( table 1). (See 'Transient ischemic attack' above.) In addition to TIA, the most important and frequent causes of discrete self-limited attacks include seizure, migraine aura, and syncope ( table 2). Transient global amnesia or TGA is an uncommon syndrome characterized by the acute onset of temporary but severe anterograde amnesia accompanied by retrograde amnesia, without other cognitive or focal neurologic impairment. (See 'Transient neurologic events' above.) Other less frequent causes of transient neurologic events include hypoglycemia, multiple sclerosis, brain tumor, subdural hematoma, cerebral amyloid angiopathy, various toxic or metabolic encephalopathies, compressive myelopathy, nerve root compression, peripheral vestibulopathies, and psychogenic etiologies. (See 'Other causes' above.) Useful features for distinguishing the various causes of transient attacks include the focal or nonfocal nature of attacks, the nature of the symptoms and their progression, the duration and timing of symptoms, and associated symptoms during and after the attacks ( table 2). Some disorders cause focal abnormalities of brain function, while others cause dysfunction that is either widespread or difficult to localize to any one anatomic region ( table 3). Certain disorders may cause both focal and nonfocal attacks. (See 'Distinguishing transient attacks' above.) The evaluation of a patient presenting with acute symptoms suggestive of TIA or ischemic stroke is outlined in the algorithm ( algorithm 1) and discussed in detail separately. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 13/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Caplan LR. TIAs: we need to return to the question, 'What is wrong with Mr. Jones?'. Neurology 1988; 38:791. 2. Caplan LR. Transient ischemic attack: definition and natural history. Curr Atheroscler Rep 2006; 8:276. 3. FISHER M. Occlusion of the internal carotid artery. AMA Arch Neurol Psychiatry 1951; 65:346. 4. Albers GW, Caplan LR, Easton JD, et al. Transient ischemic attack proposal for a new definition. N Engl J Med 2002; 347:1713. 5. Caplan LR. Transient ischemic attack with abnormal diffusion-weighted imaging results: what's in a name? Arch Neurol 2007; 64:1080. 6. Kumar S, Caplan LR. Clinical syndromes - brain. In: Transient ischemic attacks, 1st ed, Chatur vedi S, Levine SR (Eds), Blackwell Publishing, Malden 2004. p.73. 7. MONTGOMERY BM, PINNER CA. TRANSIENT HYPOGLYCEMIC HEMIPLEGIA. Arch Intern Med 1964; 114:680. 8. Bos MJ, van Rijn MJ, Witteman JC, et al. Incidence and prognosis of transient neurological attacks. JAMA 2007; 298:2877. 9. van Rooij FG, Vermeer SE, G raj BM, et al. Diffusion-weighted imaging in transient neurological attacks. Ann Neurol 2015; 78:1005. 10. Kumar S, Selim M, Marchina S, Caplan LR. Transient Neurological Symptoms in Patients With Intracerebral Hemorrhage. JAMA Neurol 2016; 73:316. 11. Cochrane T, Schmahmann JD. Compressive myelopathy presenting as cervical cord neurapraxia: a differential diagnosis of TIA. Neurology 2005; 65:1140. 12. Muraszko KM, Oldfield EH. Vascular malformations of the spinal cord and dura. Neurosurg Clin N Am 1990; 1:631. 13. Krings T, Geibprasert S. Spinal dural arteriovenous fistulas. AJNR Am J Neuroradiol 2009; 30:639. 14. Villani F, D'Amico D, Pincherle A, et al. Prolonged focal negative motor seizures: a video-EEG study. Epilepsia 2006; 47:1949. 15. Fisher CM. Transient paralytic attacks of obscure nature: the question of non-convulsive seizure paralysis. Can J Neurol Sci 1978; 5:267. https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 14/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate 16. Fisher CM. Migraine accompaniments versus arteriosclerotic ischemia. Trans Am Neurol Assoc 1968; 93:211. 17. Caplan LR. Nonatherosclerotic vasculopathies. In: Caplan's Stroke: A Clinical Approach, 4th e d, Saunders, Philadelphia 2009. p.389. 18. Liberman A, Karussis D, Ben-Hur T, et al. Natural course and pathogenesis of transient focal neurologic symptoms during pregnancy. Arch Neurol 2008; 65:218. Topic 1137 Version 19.0 https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 15/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate GRAPHICS Symptoms of transient ischemic attacks and the vascular territories involved ICA/MCA VA/BA PCA SVD Visual abnormalities Transient ++++ monocular blindness Hemianopia + +++ Blindness ++ ++ Motor abnormalities Hemiparesis + + ++ Quadriparesis ++++ Single part weakness Face + ++ + Arm/hand +++ + Thigh/leg/foot ++ + + Crossed weakness* ++++ Limb ataxia/weakness ++ ++ Gait ataxia +++ + Sensory abnormalities Hemisensory + ++ ++ Single part sensory Face + ++ + ++ Arm/hand ++ ++ + Thigh/leg/foot + + + + Crossed sensory* ++++ Cognitive abnormalities Aphasia ++++ + https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 16/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Amnesia + +++ Alexia +++ +++ Abulia ++ + + Brainstem and cranial nerve symptoms Dizziness/vertigo + +++ Diplopia ++++ Dysarthria + ++ ++ Dysphagia ++ ++ Tinnitus/hearing loss ++++ ICA: internal carotid arteries; MCA: middle cerebral arteries; VA: vertebral arteries; BA: basilar artery; PCA: posterior cerebral arteries; SVD: small vessel disease. Crossed weakness or crossed sensory refers to one side of the cranial structures and the opposite side limbs and trunk. Graphic 71676 Version 5.0 https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 17/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Clinical features of seizures, syncope, and other paroxysmal neurologic events in adults Clinical Recall of the Diagnostic Duration features event tools Focal seizure Initial symptoms depend on location in brain; Usually <2 minutes; can be difficult to Variable depending on whether EEG may show interictal spikes (poor sensitivity); motor and visual symptoms usually "positive" (eg, shaking, jerking, flashing lights, or visual distortion); distinguish ictal from postictal phase consciousness is impaired ambulatory EEG if episodes are frequent enough; MRI may show structural lesion may have anatomic "march" over seconds; some progress rapidly to GTC Generalized seizure Sudden alteration or loss of <5 minutes (for GTC); <1 minute Complete amnesia; patient EEG may show generalized spike- consciousness without warning; some have myoclonic jerks or staring; tongue- biting and urinary incontinence may for absence may recall initial focal symptoms and-wave characteristic of specific syndrome; MRI usually normal for generalized epilepsy occur (for GTC) syndromes, may show structural lesion if focal onset Psychogenic nonepileptic seizure Fluctuating, asynchronous motor activity, Rarely <1 minute; often prolonged (>30 minutes)
Transient ischemic attack (TIA) is defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. Ischemic stroke is defined as an infarction of central nervous system tissue. The symptoms of TIAs are typically focal and depend upon the underlying vascular cause ( table 1). (See 'Transient ischemic attack' above.) In addition to TIA, the most important and frequent causes of discrete self-limited attacks include seizure, migraine aura, and syncope ( table 2). Transient global amnesia or TGA is an uncommon syndrome characterized by the acute onset of temporary but severe anterograde amnesia accompanied by retrograde amnesia, without other cognitive or focal neurologic impairment. (See 'Transient neurologic events' above.) Other less frequent causes of transient neurologic events include hypoglycemia, multiple sclerosis, brain tumor, subdural hematoma, cerebral amyloid angiopathy, various toxic or metabolic encephalopathies, compressive myelopathy, nerve root compression, peripheral vestibulopathies, and psychogenic etiologies. (See 'Other causes' above.) Useful features for distinguishing the various causes of transient attacks include the focal or nonfocal nature of attacks, the nature of the symptoms and their progression, the duration and timing of symptoms, and associated symptoms during and after the attacks ( table 2). Some disorders cause focal abnormalities of brain function, while others cause dysfunction that is either widespread or difficult to localize to any one anatomic region ( table 3). Certain disorders may cause both focal and nonfocal attacks. (See 'Distinguishing transient attacks' above.) The evaluation of a patient presenting with acute symptoms suggestive of TIA or ischemic stroke is outlined in the algorithm ( algorithm 1) and discussed in detail separately. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 13/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Caplan LR. TIAs: we need to return to the question, 'What is wrong with Mr. Jones?'. Neurology 1988; 38:791. 2. Caplan LR. Transient ischemic attack: definition and natural history. Curr Atheroscler Rep 2006; 8:276. 3. FISHER M. Occlusion of the internal carotid artery. AMA Arch Neurol Psychiatry 1951; 65:346. 4. Albers GW, Caplan LR, Easton JD, et al. Transient ischemic attack proposal for a new definition. N Engl J Med 2002; 347:1713. 5. Caplan LR. Transient ischemic attack with abnormal diffusion-weighted imaging results: what's in a name? Arch Neurol 2007; 64:1080. 6. Kumar S, Caplan LR. Clinical syndromes - brain. In: Transient ischemic attacks, 1st ed, Chatur vedi S, Levine SR (Eds), Blackwell Publishing, Malden 2004. p.73. 7. MONTGOMERY BM, PINNER CA. TRANSIENT HYPOGLYCEMIC HEMIPLEGIA. Arch Intern Med 1964; 114:680. 8. Bos MJ, van Rijn MJ, Witteman JC, et al. Incidence and prognosis of transient neurological attacks. JAMA 2007; 298:2877. 9. van Rooij FG, Vermeer SE, G raj BM, et al. Diffusion-weighted imaging in transient neurological attacks. Ann Neurol 2015; 78:1005. 10. Kumar S, Selim M, Marchina S, Caplan LR. Transient Neurological Symptoms in Patients With Intracerebral Hemorrhage. JAMA Neurol 2016; 73:316. 11. Cochrane T, Schmahmann JD. Compressive myelopathy presenting as cervical cord neurapraxia: a differential diagnosis of TIA. Neurology 2005; 65:1140. 12. Muraszko KM, Oldfield EH. Vascular malformations of the spinal cord and dura. Neurosurg Clin N Am 1990; 1:631. 13. Krings T, Geibprasert S. Spinal dural arteriovenous fistulas. AJNR Am J Neuroradiol 2009; 30:639. 14. Villani F, D'Amico D, Pincherle A, et al. Prolonged focal negative motor seizures: a video-EEG study. Epilepsia 2006; 47:1949. 15. Fisher CM. Transient paralytic attacks of obscure nature: the question of non-convulsive seizure paralysis. Can J Neurol Sci 1978; 5:267. https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 14/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate 16. Fisher CM. Migraine accompaniments versus arteriosclerotic ischemia. Trans Am Neurol Assoc 1968; 93:211. 17. Caplan LR. Nonatherosclerotic vasculopathies. In: Caplan's Stroke: A Clinical Approach, 4th e d, Saunders, Philadelphia 2009. p.389. 18. Liberman A, Karussis D, Ben-Hur T, et al. Natural course and pathogenesis of transient focal neurologic symptoms during pregnancy. Arch Neurol 2008; 65:218. Topic 1137 Version 19.0 https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 15/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate GRAPHICS Symptoms of transient ischemic attacks and the vascular territories involved ICA/MCA VA/BA PCA SVD Visual abnormalities Transient ++++ monocular blindness Hemianopia + +++ Blindness ++ ++ Motor abnormalities Hemiparesis + + ++ Quadriparesis ++++ Single part weakness Face + ++ + Arm/hand +++ + Thigh/leg/foot ++ + + Crossed weakness* ++++ Limb ataxia/weakness ++ ++ Gait ataxia +++ + Sensory abnormalities Hemisensory + ++ ++ Single part sensory Face + ++ + ++ Arm/hand ++ ++ + Thigh/leg/foot + + + + Crossed sensory* ++++ Cognitive abnormalities Aphasia ++++ + https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 16/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Amnesia + +++ Alexia +++ +++ Abulia ++ + + Brainstem and cranial nerve symptoms Dizziness/vertigo + +++ Diplopia ++++ Dysarthria + ++ ++ Dysphagia ++ ++ Tinnitus/hearing loss ++++ ICA: internal carotid arteries; MCA: middle cerebral arteries; VA: vertebral arteries; BA: basilar artery; PCA: posterior cerebral arteries; SVD: small vessel disease. Crossed weakness or crossed sensory refers to one side of the cranial structures and the opposite side limbs and trunk. Graphic 71676 Version 5.0 https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 17/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Clinical features of seizures, syncope, and other paroxysmal neurologic events in adults Clinical Recall of the Diagnostic Duration features event tools Focal seizure Initial symptoms depend on location in brain; Usually <2 minutes; can be difficult to Variable depending on whether EEG may show interictal spikes (poor sensitivity); motor and visual symptoms usually "positive" (eg, shaking, jerking, flashing lights, or visual distortion); distinguish ictal from postictal phase consciousness is impaired ambulatory EEG if episodes are frequent enough; MRI may show structural lesion may have anatomic "march" over seconds; some progress rapidly to GTC Generalized seizure Sudden alteration or loss of <5 minutes (for GTC); <1 minute Complete amnesia; patient EEG may show generalized spike- consciousness without warning; some have myoclonic jerks or staring; tongue- biting and urinary incontinence may for absence may recall initial focal symptoms and-wave characteristic of specific syndrome; MRI usually normal for generalized epilepsy occur (for GTC) syndromes, may show structural lesion if focal onset Psychogenic nonepileptic seizure Fluctuating, asynchronous motor activity, Rarely <1 minute; often prolonged (>30 minutes) Variable Video-EEG monitoring often with eye closure, side-to- side head or body movements, pelvic thrusting; most occur in front of a witness; fully or partially https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 18/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate alert despite bilateral motor activity; tongue- biting is rare Syncope Transient loss of 1 to 2 minutes Patient can recall ECG; consciousness resulting in loss of postural tone; prodrome of lightheadedness, warm or cold prodromal symptoms, if present; lack of warning may suggest cardiac source echocardiography if structural cardiac disease is suspected; ambulatory ECG monitoring if feeing, sweating, palpitations, pallor; myoclonic jerks or tonic posturing may occur, especially if arrhythmia is suspected; orthostatic blood pressure measurements patient is kept upright; no or minimal post- event confusion Transient ischemic attack (TIA) Rapid loss of neurologic function due to interrupted blood flow; symptoms Several minutes to a few hours Usually complete unless language areas involved MRI/MRA, CTA, vascular risk factors depend on vascular territory but are typically "negative" (eg, weakness, numbness, aphasia, visual loss); intensity is usually maximal at onset; consciousness usually preserved Migraine aura Positive and/or negative Up to 1 hour Complete Personal or family history of neurologic symptoms, most often visual and sensory, evolving gradually over 5 migraine https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 19/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate minutes (slower onset than TIA or focal seizure); slow spread of positive followed by negative symptoms, if present, is very characteristic; usually followed by headache Panic attack Palpitations, dyspnea, chest pain, Minutes to hours Complete History of anxiety or depressive symptoms, lightheadedness, sense of impending doom; associated hyperventilation may result in triggering events or stressors perioral and distal limb paresthesias Transient global amnesia Prominent anterograde amnesia (inability to form new memories) and variable 1 to 10 hours (mean 6 hours) Complete amnesia for the main episode; retrograde amnesia resolves within 24 hours Clinical diagnosis; negative MRI and toxicology screens retrograde amnesia; patient is disoriented in time, asking repetitive questions; other cognitive and motor functions spared; rare in adults younger than 50 years GTC: generalized tonic-clonic; EEG: electroencephalography; MRI: magnetic resonance imaging; ECG: electrocardiogram; MRA: magnetic resonance angiography; CTA: computed tomography angiography. Graphic 111740 Version 3.0 https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 20/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Focal or nonfocal symptoms of transient neurologic attacks Focal symptoms Nonfocal symptoms Common disorders Seizure +++ ++ Transient ischemic attack ++++ + Migraine aura ++++ + Syncope 0 ++++ Less common disorders Vestibulopathy ++ ++ Metabolic + +++ "Tumor attacks" +++ + Multiple sclerosis ++++ + Psychiatric ++ ++ Nerve and nerve root ++++ 0 Transient global amnesia ++++ 0 Graphic 62326 Version 5.0 https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 21/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Evaluation of patient presenting with acute symptoms of possible TIA or minor ischemic stroke This algorithm should be used in conjunction with UpToDate topics on the initial evaluation and management of TIA and ischemic stroke. CDUS: carotid duplex ultrasonography; CNS: central nervous system; CT: computed tomography; CTA: computed tomography angiography; ECG: electrocardiography; IV: intravenous; MRA: magnetic resonance angiography; MRI: magnetic resonance imaging; TIA: transient ischemic attack; TCD: transcranial Doppler. Patients who present within the appropriate time window after ischemic symptom onset and have a persistent neurologic deficit that is potentially disabling, despite https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 22/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate improvement of any degree, should be treated with intravenous thrombolysis and/or mechanical thrombectomy in the absence of other contraindications. Further management of these patients is similar to that of other patients with a potentially disabling stroke. Can begin aspirin and statin therapy while awaiting results of remaining diagnostic studies if imaging is negative for hemorrhage and other nonischemic cause of symptoms. Viable strategies include antihypertensive therapy, antithrombotic therapy, statin therapy, and lifestyle modification; select patients with symptomatic cervical internal carotid artery disease may benefit from carotid revascularization. Graphic 107065 Version 1.0 https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 23/24 7/5/23, 12:38 PM Differential diagnosis of transient ischemic attack and acute stroke - UpToDate Contributor Disclosures Louis R Caplan, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/differential-diagnosis-of-transient-ischemic-attack-and-acute-stroke/print 24/24
7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis : As'ad Ehtisham, MD, MBBS, FAHA, Tanya N Turan, MD, MSCR : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 27, 2023. INTRODUCTION Atherosclerotic stenosis of the major intracranial arteries, also known as intracranial atherosclerosis (ICAS) or cerebral atherosclerosis, is an important cause of ischemic stroke. This topic focuses on the epidemiology, clinical manifestations, and diagnosis of ICAS. The treatment and prognosis of ICAS is reviewed separately. (See "Intracranial large artery atherosclerosis: Treatment and prognosis".) Other ischemic stroke subtypes are discussed elsewhere. (See "Stroke: Etiology, classification, and epidemiology" and "Clinical diagnosis of stroke subtypes" and "Lacunar infarcts" and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) PATHOPHYSIOLOGY Atherosclerosis is a pathologic process that causes disease of the aorta, coronary, cerebral, and peripheral arteries. Multiple factors contribute to the pathogenesis of atherosclerosis, including endothelial dysfunction, inflammatory and immunologic factors, plaque rupture, and the traditional risk factors of hypertension, diabetes, dyslipidemia, and smoking. The first stage of atherosclerosis begins in childhood with the development of fatty streaks, followed by progression involving the development of fibrous plaques, fibrous caps, and advanced atheromatous lesions. (See "Pathogenesis of atherosclerosis".) https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 1/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Atherosclerosis is the most common cause of in situ local disease within the large extracranial and intracranial arteries that supply the brain ( picture 1 and image 1). An intracranial artery stenosis is considered symptomatic when the degree of stenosis is at least 50 percent and the stroke or transient ischemic attack (TIA) symptoms are localized to the region of the brain supplied by the artery. ICAS can lead to ischemic stroke or TIA by a variety of mechanisms ( image 2), which include [1-5]: In situ thromboembolism leading most often to artery-to-artery embolism, and less often to hemodynamic insufficiency or to a combination of embolism and hemodynamic insufficiency Progression of luminal stenosis resulting in hemodynamic insufficiency Atheroma encroaching on the orifice of small penetrating vessels ("branch atheromatous disease") causing small vessel occlusion Subtypes and mechanisms of ischemic stroke are discussed in greater detail elsewhere. (See "Pathophysiology of ischemic stroke" and "Stroke: Etiology, classification, and epidemiology" and "Clinical diagnosis of stroke subtypes".) EPIDEMIOLOGY Frequency of stroke due to intracranial atherosclerosis ICAS is an important cause of ischemic stroke, particularly among Asian and Black populations worldwide, and among Hispanic populations originating in Latin America [1,6-9]. In the United States, ICAS accounts for approximately 8 to 10 percent of ischemic stroke, and may account for 30 to 50 percent of ischemic stroke in Asian populations [10-12]. Racial and ethnic differences Several studies have found that ICAS is more prevalent in Asian, Black, and Hispanic populations compared with White populations [1,13-16]. As an example, one population-based study found that the adjusted annual incidence of intracranial atherosclerotic stroke among Black, Hispanic, and White patients was 15, 13, and 3 per 100,000, respectively [15]. The explanation for the variance in the distribution of ICAS in different races is uncertain. One hypothesis is that Black, Hispanic, and Asian populations have a genetic susceptibility to intracranial large artery disease [17,18]. An alternative hypothesis is that racial and ethnic differences in lifestyle and risk factor profiles (eg, higher rates of diabetes and hypercholesterolemia in some populations) play a more important role in determining the distribution of atherosclerosis [11,19,20]. Based on the ethnic make-up of the world population, ICAS may be the most common cause of stroke worldwide [21]. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 2/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Risk factors Risk factors associated with symptomatic ICAS include the following [1,2,7,22,23]: Age Hypertension Hyperlipidemia/dyslipidemia Smoking Diabetes A post hoc analysis of data from the WASID study of patients with TIA or stroke due to 50 to 99 percent intracranial large artery atherosclerosis showed that risk factors were more prevalent than reported for other stroke subtypes and that a history of a lipid disorder was independently associated with severe (70 to 99 percent) intracranial stenosis (odds ratio 1.62, 95% CI 1.09-2.42) [24]. Risk factors also differed by location of stenosis, with basilar artery stenoses associated with older age and hyperlipidemia, middle cerebral artery stenoses more common in women and Black individuals, and intracranial carotid artery stenoses associated with diabetes. Similar associations between risk factors and location of stenosis were reported in a post hoc analysis of data from the SAMMPRIS trial, which included patients with 70 to 99 percent intracranial stenosis [25]. CLINICAL MANIFESTATIONS The manifestations of ischemia due to intracranial large artery atherosclerosis are not specific, as the same stroke syndromes may arise from other sources of ischemia, including cardiac embolism, artery-to-artery embolism from extracranial large artery stenosis, and small vessel disease. Anterior circulation In the anterior circulation, ICAS most often involves the middle cerebral artery (MCA); the intracranial internal carotid artery (ICA) is also commonly affected. In situ thrombotic occlusion of the MCA or artery-to-artery embolism of an ICA or MCA thrombus can lead to a cortical infarction with symptoms that may include aphasia, neglect, and/or contralateral hemiparesis. MCA atherosclerosis may also cause subcortical infarction via branch atheromatous disease, resulting in a clinical presentation similar to lacunar infarction with motor, sensory, or sensorimotor symptoms affecting the contralateral hemibody. Less commonly, low flow or hypoperfusion through a stenotic ICA or MCA can be the result of hypotension or positional changes. Such symptoms may be transient and improve with increased intravascular volume, or may result in watershed (borderzone) or hypoperfusion https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 3/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate infarcts. Limb-shaking transient ischemic attack (TIA) is a rare, but classic, hypoperfusion syndrome of repetitive jerking movements of the arm or leg due to a contralateral ICA stenosis or occlusion [26]. Posterior circulation In the posterior circulation, ischemic symptoms and signs may include dizziness, nausea or vomiting, unilateral limb weakness or ataxia, gait ataxia, dysarthria, diplopia, nystagmus, altered level of consciousness, and visual field loss. This section provides a brief overview; a more complete discussion is found separately. (See "Posterior circulation cerebrovascular syndromes".) ICAS of the distal vertebral arteries presents in a variety of ways. Infarction may involve the medulla (eg, lateral medullary infarction) or cerebellum in the territory of the posterior inferior cerebellar artery via branch atheromatous occlusion. Artery-to-artery embolization of a vertebral artery thrombus may cause TIA or infarction in the territory of the basilar artery or its branches. Basilar artery atherosclerosis most often presents as ischemia in the pons due to branch atheromatous occlusion; the predominant symptoms and signs are motor and oculomotor. Although less common, ischemic infarction of the ventral pons due to basilar artery embolism or thrombosis can cause locked-in syndrome; infarction of the bilateral medial pontine tegmentum can cause a reduced level of consciousness or coma. Occlusion of the rostral portion of the basilar artery (the "top of the basilar") can cause ischemia of the midbrain, thalami, and temporal and occipital lobe hemispheral territories supplied by the posterior cerebral artery branches of the basilar artery. The major abnormalities associated with rostral brainstem infarction involve alertness, behavior, memory, and oculomotor and pupillary functions. Most infarcts in the territory of the posterior cerebral artery (PCA) are due to embolism from a more proximal source, such as the vertebral or basilar arteries. The most frequent neurologic deficit with PCA territory infarction involving the occipital lobe is visual loss (eg, a hemianopia or quadrantanopia), sometimes accompanied by visual neglect. Infarction due to in situ atherosclerosis of the PCAs is less common but can cause thalamic or midbrain infarction through branch occlusion. Lateral thalamic infarction typically leads to somatosensory symptoms and signs. DIAGNOSTIC EVALUATION The standard evaluation of patients with acute ischemic stroke or transient ischemic stroke (TIA) includes a history and physical examination, brain imaging to determine the location and https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 4/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate topography of the ischemic lesion, and vessel imaging and a cardiac evaluation to help determine the most likely cause. Laboratory testing typically includes a complete blood count, cardiac enzymes and troponin, prothrombin time, international normalized ratio (INR), and activated partial thromboplastin time. (See "Initial assessment and management of acute stroke" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) Brain and vascular imaging All patients with acute ischemic stroke or TIA should have brain and neurovascular imaging. The brain imaging study can be done with either computed tomography (CT) or magnetic resonance imaging (MRI), while large vessel imaging can be obtained with either computed tomography angiography (CTA) or magnetic resonance angiography (MRA); additional methods include duplex ultrasound (DUS) and transcranial Doppler ultrasound (TCD), which assess the patency of the extracranial and intracranial large arteries, respectively. The brain and neurovascular imaging studies should not be considered in isolation, but rather as one part of the acute stroke evaluation. However, the approach to imaging may differ according to individual patient characteristics (eg, time from stroke onset, potential candidate for reperfusion therapies) and local availability of stroke expertise and imaging capabilities. (See "Neuroimaging of acute stroke".) Choice of vascular imaging We use CTA or MRA to evaluate the extracranial arteries (internal carotid and vertebral) and intracranial arteries (internal carotid, middle cerebral, anterior cerebral, vertebral, basilar, posterior cerebral) that supply blood to the brain. Noninvasive methods (MRA, CTA, or TCD) are preferred because they are more easily obtained, less invasive, safer, and less expensive compared with gold-standard conventional contrast angiography (eg, digital subtraction angiography [DSA]). (See 'Accuracy of noninvasive vascular imaging' below.) Conventional contrast angiography is usually reserved for situations in which noninvasive studies are inconclusive. (See 'Role of catheter angiography' below.) Need for urgent imaging Patients with acute ischemic stroke who are potential candidates for reperfusion therapies should be rapidly screened for treatment with intravenous thrombolysis ( table 1) and/or mechanical thrombectomy ( algorithm 1). Diagnostic neuroimaging is essential before considering these interventions. Reperfusion therapy for patients with acute ischemic stroke is reviewed in detail elsewhere. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 5/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke".) Accuracy of noninvasive vascular imaging Noninvasive imaging methods (mainly MRA and CTA) are useful for excluding moderate to severe (50 to 99 percent) stenosis of large proximal intracranial arteries and are usually sufficient to identify intracranial arteries with moderate to severe stenosis. However, MRA and CTA have certain limitations related to accuracy and sensitivity when compared with the gold standard of catheter angiography. As examples, noninvasive methods may not be sufficiently accurate to differentiate an occlusion from pseudo- occlusion with critical stenosis or to confirm the severity of a clinically significant stenosis. In addition, they tend to overestimate the severity of stenosis. In the prospective multicenter SONIA trial of patients with TIA or ischemic stroke who were suspected of having intracranial large artery stenosis, both TCD ultrasonography and MRA had high negative predictive values (86 and 91 percent) and low positive predictive values (36 and 59 percent) for the detection of intracranial stenosis in the MCA, intracranial ICA, vertebral, and basilar arteries compared with catheter angiography [27]. Similarly, a subsequent report from SONIA found that CTA had a good negative predictive value (73 percent) and a low positive predictive value (47 percent) [28]. Nevertheless, intensive medical therapy is indicated for patients with a first event related to symptomatic intracranial large artery stenosis detected by noninvasive imaging (see "Intracranial large artery atherosclerosis: Treatment and prognosis"); more precise characterization of the stenosis with catheter angiography would not affect the initial management in most cases. Role of catheter angiography Catheter angiography is unnecessary for the vast majority of cases with suspected intracranial large artery atherosclerosis since it will seldom alter clinical management. Angiography enables an accurate measurement of the degree of stenosis of the diseased artery [29], differentiation of arterial occlusion from a very severe stenosis, assessment of collateral flow patterns, and evaluation of other intracranial and extracranial arteries. Thus, conventional angiography may be needed in some cases to confirm the presence of intracranial stenosis when noninvasive imaging is inconclusive or to investigate an alternative etiology such as moyamoya disease, intracranial dissection, and vasculitis. The major drawback of angiography is the risk of stroke [30,31], which was as high as 1.2 percent in the Asymptomatic Carotid Atherosclerosis Study (ACAS) [30]. Among patients with ICAS in the WASID study, the risk of neurological events was 2 percent, but all of these events were transient. Identifying other causes of intracranial stenosis Neurovascular imaging plays a key role in identifying intracranial stenosis caused by other types of vasculopathy such as arterial https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 6/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate dissection, fibromuscular dysplasia, cerebral vasoconstriction, primary or secondary vasculitis, moyamoya disease, and other vasculopathies. These conditions are less common than atherosclerotic disease among adult populations with vascular risk factors; clinical or radiologic features can help to distinguish them from atherosclerosis: Dissection Dissection is suspected when vascular imaging demonstrates an arterial string sign, a tapered stenosis or occlusion, a flame-shaped occlusion, an intimal flap, a dissecting aneurysm, or a distal pouch. Fat-saturated MRI sequences may show an intramural hematoma. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Choice of neuroimaging study'.) Dissection of intracranial arteries is far less frequent than dissection of extracranial cervical arteries. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Epidemiology'.) Conditions characterized by segmental arterial narrowing The angiographic demonstration of alternating focal concentric narrowing resembling a "string of beads" in one or more intracranial vessels is a nonspecific finding that may be present due to atherosclerosis, infection, vasospasm or vasoconstriction, and fibromuscular dysplasia. The clinical setting is crucial to determining the most likely cause. Primary angiitis of the central nervous system Primary angiitis of the central nervous system is a rare disorder associated with headache, cognitive impairment, and TIA or stroke, with multiple infarcts in different vascular territories. The onset is typically subacute and insidious. The angiographic appearance of a "string of beads" predominantly involves the smaller distal intracranial vessels, not the proximal larger arteries, which are affected by atherosclerosis. (See "Primary angiitis of the central nervous system in adults", section on 'Neuroimaging' and "Primary angiitis of the central nervous system in adults", section on 'Alternative diagnoses'.) Reversible cerebral vasoconstriction syndrome Reversible cerebral vasoconstriction syndrome (RCVS) represents a group of conditions that show reversible multifocal narrowing of the cerebral arteries with clinical manifestations that typically include thunderclap headache and sometimes include neurologic deficits related to brain edema, stroke, or seizure. (See "Reversible cerebral vasoconstriction syndrome".) Fibromuscular dysplasia With fibromuscular dysplasia, the most frequently involved arteries are the renal and internal carotid and vertebral arteries. Less commonly, there is involvement of the external carotid artery and the larger intracranial arteries (the middle cerebral, anterior cerebral, basilar, and anterior communicating arteries). The https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 7/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate most common manifestations are hypertension, headache, dizziness, tinnitus, TIA, and stroke, but other manifestations may occur, depending upon the arterial segment involved and the severity of disease. (See "Clinical manifestations and diagnosis of fibromuscular dysplasia".) Moyamoya disease Moyamoya disease is diagnosed based upon the characteristic angiographic appearance of bilateral stenoses affecting the distal internal carotid arteries and proximal circle of Willis vessels, along with the presence of prominent basal collateral moyamoya vessels. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".) SUMMARY AND RECOMMENDATIONS Atherosclerotic stenosis of the major intracranial arteries (intracranial carotid artery, middle cerebral artery, vertebral artery, and basilar artery) is an important cause of ischemic stroke, especially in Asian, Black, and Hispanic populations. (See 'Epidemiology' above.) The symptoms of ischemic stroke or TIA attributed to large artery intracranial atherosclerosis (ICAS) depend upon the mechanism (eg, in situ thromboembolism, branch atheroma) and the size and location of the brain region affected by ischemia ( table 2). (See 'Clinical manifestations' above.) All patients with acute ischemic stroke or TIA should have brain and neurovascular imaging. Patients with acute ischemic stroke who are potential candidates for reperfusion therapies should be rapidly screened for treatment with intravenous thrombolysis ( table 1) and/or mechanical thrombectomy ( algorithm 1). Noninvasive imaging methods (mainly magnetic resonance angiography [MRA] and computed tomographic angiography [CTA]) are useful for excluding moderate to severe (50 to 99 percent) stenosis of large proximal intracranial arteries and are usually sufficient to identify intracranial vessels with moderate to severe stenosis. MRA and CTA have certain limitations related to https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 8/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate accuracy and sensitivity when compared with the gold standard of catheter angiography, but catheter angiography is unnecessary for the vast majority of cases with suspected intracranial large artery atherosclerosis since it will seldom alter clinical management. (See 'Diagnostic evaluation' above.) Neurovascular imaging plays a key role in identifying intracranial stenosis caused by other types of vasculopathy such as arterial dissection, fibromuscular dysplasia, cerebral vasoconstriction, primary or secondary vasculitis, moyamoya disease, and others. These conditions are less common than atherosclerotic disease among adult populations with vascular risk factors, and clinical or radiologic features can help to distinguish them from atherosclerosis. (See 'Identifying other causes of intracranial stenosis' above.) The treatment and prognosis of TIA and stroke attributed to intracranial large artery atherosclerosis is reviewed in detail separately. (See "Intracranial large artery atherosclerosis: Treatment and prognosis".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Qureshi AI, Caplan LR. Intracranial atherosclerosis. Lancet 2014; 383:984. 2. Holmstedt CA, Turan TN, Chimowitz MI. Atherosclerotic intracranial arterial stenosis: risk factors, diagnosis, and treatment. Lancet Neurol 2013; 12:1106. 3. Bang OY. Intracranial atherosclerosis: current understanding and perspectives. J Stroke 2014; 16:27. 4. Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol 1998; 55:1475. 5. Feng X, Chan KL, Lan L, et al. Stroke Mechanisms in Symptomatic Intracranial Atherosclerotic Disease: Classification and Clinical Implications. Stroke 2019; 50:2692. 6. Bos D, Portegies ML, van der Lugt A, et al. Intracranial carotid artery atherosclerosis and the risk of stroke in whites: the Rotterdam Study. JAMA Neurol 2014; 71:405. 7. Ritz K, Denswil NP, Stam OC, et al. Cause and mechanisms of intracranial atherosclerosis. Circulation 2014; 130:1407. 8. Banerjee C, Chimowitz MI. Stroke Caused by Atherosclerosis of the Major Intracranial Arteries. Circ Res 2017; 120:502. 9. Al Kasab S, Derdeyn CP, Guerrero WR, et al. Intracranial Large and Medium Artery https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 9/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Atherosclerotic Disease and Stroke. J Stroke Cerebrovasc Dis 2018; 27:1723. 10. Mattioni A, Cenciarelli S, Biessels G, et al. Prevalence of intracranial large artery stenosis and occlusion in patients with acute ischaemic stroke or TIA. Neurol Sci 2014; 35:349. 11. Sacco RL, Kargman DE, Gu Q, Zamanillo MC. Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction. The Northern Manhattan Stroke Study. Stroke 1995; 26:14. 12. Wong LK. Global burden of intracranial atherosclerosis. Int J Stroke 2006; 1:158. 13. Wong KS, Li H. Long-term mortality and recurrent stroke risk among Chinese stroke patients with predominant intracranial atherosclerosis. Stroke 2003; 34:2361. 14. De Silva DA, Woon FP, Lee MP, et al. South Asian patients with ischemic stroke: intracranial large arteries are the predominant site of disease. Stroke 2007; 38:2592. 15. White H, Boden-Albala B, Wang C, et al. Ischemic stroke subtype incidence among whites, blacks, and Hispanics: the Northern Manhattan Study. Circulation 2005; 111:1327. 16. Leng X, Hurford R, Feng X, et al. Intracranial arterial stenosis in Caucasian versus Chinese patients with TIA and minor stroke: two contemporaneous cohorts and a systematic review. J Neurol Neurosurg Psychiatry 2021. 17. Feldmann E, Daneault N, Kwan E, et al. Chinese-white differences in the distribution of occlusive cerebrovascular disease. Neurology 1990; 40:1541. 18. Gorelick PB, Caplan LR, Langenberg P, et al. Clinical and angiographic comparison of asymptomatic occlusive cerebrovascular disease. Neurology 1988; 38:852. 19. Williams AO, Resch JA, Loewenson RB. Cerebral atherosclerosis a comparative autopsy study between Nigerian Negroes and American Negroes and Caucasians. Neurology 1969; 19:205. 20. Arenillas JF, Molina CA, Chac n P, et al. High lipoprotein (a), diabetes, and the extent of symptomatic intracranial atherosclerosis. Neurology 2004; 63:27. 21. Gorelick PB, Wong KS, Bae HJ, Pandey DK. Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier. Stroke 2008; 39:2396. 22. Rincon F, Sacco RL, Kranwinkel G, et al. Incidence and risk factors of intracranial atherosclerotic stroke: the Northern Manhattan Stroke Study. Cerebrovasc Dis 2009; 28:65. 23. Sirimarco G, Deplanque D, Lavall e PC, et al. Atherogenic dyslipidemia in patients with transient ischemic attack. Stroke 2011; 42:2131. 24. Turan TN, Makki AA, Tsappidi S, et al. Risk factors associated with severity and location of intracranial arterial stenosis. Stroke 2010; 41:1636. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 10/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate 25. Almallouhi E, Al Kasab S, Yamada L, et al. Relationship Between Vascular Risk Factors and Location of Intracranial Atherosclerosis in the SAMMPRIS Trial. J Stroke Cerebrovasc Dis 2020; 29:104713. 26. Persoon S, Kappelle LJ, Klijn CJ. Limb-shaking transient ischaemic attacks in patients with internal carotid artery occlusion: a case-control study. Brain 2010; 133:915. 27. Feldmann E, Wilterdink JL, Kosinski A, et al. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial. Neurology 2007; 68:2099. 28. Liebeskind DS, Kosinski AS, Saver JL, et al. Computed Tomography Angiography in the Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) Study. Interv Neurol 2014; 2:153. 29. Samuels OB, Joseph GJ, Lynn MJ, et al. A standardized method for measuring intracranial arterial stenosis. AJNR Am J Neuroradiol 2000; 21:643. 30. Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995; 273:1421. 31. Dion JE, Gates PC, Fox AJ, et al. Clinical events following neuroangiography: a prospective study. Stroke 1987; 18:997. Topic 131456 Version 6.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 11/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate GRAPHICS Atherosclerotic lesions in the Circle of Willis of a 90-year-old patient Circle of Willis of a 90-year-old patient. Macroscopically, atherosclerotic lesions can be identified by the white whereas nondiseased arteries appear largely transparent. This case shows prominent atherosclerosis mainly internal carotid artery, vertebral artery, basilar artery, left middle cerebral artery, and posterior cerebral arter https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 12/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate From: Ritz K, Denswil NP, Stam OC, et al. Cause and mechanisms of intracranial atherosclerosis. Circulation 2014; 130:1407. DOI: 10.1161/CIRCULATIONAHA.114.011147. Copyright 2014 American Heart Association. Reproduced with permission from Wolters Kluw Unauthorized reproduction of this material is prohibited. Graphic 105011 Version 8.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 13/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Intracranial plaque and arterial wall imaging by high-resolution MRI Intracranial plaque and arterial wall imaging by high-resolution MRI. An intracranial atherosclerosis lesion located at proximal basilar artery with severe luminal stenosis was identified on time-of-flight magnetic resonance angiography (arrow, A). High-resolution MRI revealed an eccentric atherosclerotic plaque along the anterolateral and posterolateral walls of basilar artery (arrowhead, B through D). From: Leng X, Wong KS, Liebeskind DS. Evaluating intracranial atherosclerosis rather than intracranial stenosis. Stroke 2014; 45:645. DOI: 10.1161/STROKEAHA.113.002491. Copyright 2014 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 14/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Graphic 105006 Version 5.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 15/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Mechanisms of stroke in patients with intracranial atherosclerotic disease Mechanisms of stroke in patients with ICAD. (A) Thrombotic occlusion is a rare phenotype of ICAD. MRA shows in situ thrombotic occlusion at the site of st plaque. DWI shows territorial infarcts by severe hemodynamic compromise and embolic infarcts on the corte High-resolution MRI can show vulnerable plaque on intracranial vessels. (B) Artery-to-artery embolism is one of common phenotypes of ICAD. Artery-to-artery embolism is usually associated with a severe degree of intracranial stenosis, and transcranial Doppler ultrasonography can detec symptomatic or asymptomatic embolism during microembolic signal monitoring. DWI shows small, scattered cortical embolic infarcts. (C) Hemodynamic impairment is another phenotype of ICAD. This phenotype is usually associated with a seve stenosis and a marked hemodynamic compromise, as seen on a PWI. DWI typically shows borderzone-type in and infarct growth is common with clinical deterioration. (D) Branch occlusive disease is a common phenotype of ICAD. This phenotype is often misclassified as small a disease due to a mild degree of stenosis on MRA, small deep infarcts on DWI, and relatively small perfusion d High-resolution MRI can reveal plaque without stenosis near the orifices of penetrating arteries. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 16/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate ICAD: intracranial atherosclerotic disease; DWI: diffusion-weighted imaging; PWI: perfusion-weighted imagin MRA: time-of-flight magnetic resonance angiography. Reproduced with permission from: Bang OY. Intracranial atherosclerosis: current understanding and perspectives. J Stroke 2014; 16:27 Copyright 2014 Korean Stroke Academy. Graphic 105007 Version 1.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 17/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 18/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 19/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended.
15/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Mechanisms of stroke in patients with intracranial atherosclerotic disease Mechanisms of stroke in patients with ICAD. (A) Thrombotic occlusion is a rare phenotype of ICAD. MRA shows in situ thrombotic occlusion at the site of st plaque. DWI shows territorial infarcts by severe hemodynamic compromise and embolic infarcts on the corte High-resolution MRI can show vulnerable plaque on intracranial vessels. (B) Artery-to-artery embolism is one of common phenotypes of ICAD. Artery-to-artery embolism is usually associated with a severe degree of intracranial stenosis, and transcranial Doppler ultrasonography can detec symptomatic or asymptomatic embolism during microembolic signal monitoring. DWI shows small, scattered cortical embolic infarcts. (C) Hemodynamic impairment is another phenotype of ICAD. This phenotype is usually associated with a seve stenosis and a marked hemodynamic compromise, as seen on a PWI. DWI typically shows borderzone-type in and infarct growth is common with clinical deterioration. (D) Branch occlusive disease is a common phenotype of ICAD. This phenotype is often misclassified as small a disease due to a mild degree of stenosis on MRA, small deep infarcts on DWI, and relatively small perfusion d High-resolution MRI can reveal plaque without stenosis near the orifices of penetrating arteries. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 16/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate ICAD: intracranial atherosclerotic disease; DWI: diffusion-weighted imaging; PWI: perfusion-weighted imagin MRA: time-of-flight magnetic resonance angiography. Reproduced with permission from: Bang OY. Intracranial atherosclerosis: current understanding and perspectives. J Stroke 2014; 16:27 Copyright 2014 Korean Stroke Academy. Graphic 105007 Version 1.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 17/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 18/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 19/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 20/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Indications for mechanical thrombectomy to treat patients with acute ischemic IV: intravenous; tPA: tissue plasminogen activator (alteplase or tenecteplase); CTA: computed tomography an artery occlusion; MT: mechanical thrombectomy; ASPECTS: Alberta Stroke Program Early CT Score; NIHSS: Na tomography; MRI: magnetic resonance imaging; mRS: modified Rankin Scale; MCA: middle cerebral artery; IC recovery. Patients are not ordinarily eligible for IV tPA unless the time last known to be well is <4.5 hours. However, im that is diffusion positive and FLAIR negative) is an option at expert stroke centers to select patients with wake associated UpToDate topics for details. Usually assessed with MRA or CTA, less often with digital subtraction angiography. There is intracranial arterial occlusion of the distal ICA, middle cerebral (M1/M2), or anterior cerebral (A1/A2 MT may be a treatment option for patients with acute ischemic stroke caused by occlusion of the basilar ar stroke centers, but benefit is uncertain. [1] Based upon data from the Aurora study . Reference: https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 21/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate 1. Albers GW, Lansberg MG, Brown S, et al. Assessment of Optimal Patient Selection for Endovascular Thrombectomy Beyond 6 Hou Neurol 2021; 78:1064. Graphic 117086 Version 3.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 22/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Acute ischemic stroke syndromes according to vascular territory Artery involved Syndrome Anterior cerebral artery Motor and/or sensory deficit (leg > face, arm) Grasp, sucking reflexes Abulia, paratonic rigidity, gait apraxia Middle cerebral artery Dominant hemisphere: aphasia, motor and sensory deficit (face, arm > leg > foot), may be complete hemiplegia if internal capsule involved, homonymous hemianopia Non-dominant hemisphere: neglect, anosognosia, motor and sensory deficit (face, arm > leg > foot), homonymous hemianopia Posterior cerebral artery Homonymous hemianopia; alexia without agraphia (dominant hemisphere); visual hallucinations, visual perseverations (calcarine cortex); sensory loss, choreoathetosis, spontaneous pain (thalamus); III nerve palsy, paresis of vertical eye movement, motor deficit (cerebral peduncle, midbrain) Penetrating vessels Pure motor hemiparesis (classic lacunar syndromes) Pure sensory deficit Pure sensory-motor deficit Hemiparesis, homolateral ataxia Dysarthria/clumsy hand Vertebrobasilar Cranial nerve palsies Crossed sensory deficits Diplopia, dizziness, nausea, vomiting, dysarthria, dysphagia, hiccup Limb and gait ataxia Motor deficit Coma Bilateral signs suggest basilar artery disease Internal carotid artery Progressive or stuttering onset of MCA syndrome, occasionally ACA syndrome as well if insufficient collateral flow Graphic 75487 Version 7.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 23/24 7/6/23, 11:55 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Contributor Disclosures As'ad Ehtisham, MD, MBBS, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Tanya N Turan, MD, MSCR No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 24/24
7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Intracranial large artery atherosclerosis: Treatment and prognosis : Tanya N Turan, MD, MSCR, Jose Gutierrez, MD, MPH : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 06, 2022. INTRODUCTION Atherosclerotic stenosis of the major intracranial arteries, also known as intracranial atherosclerosis (ICAS) or cerebral atherosclerosis, is an important cause of ischemic stroke. This topic focuses on the treatment and prognosis of ICAS. The epidemiology, clinical manifestations, and diagnosis of ICAS are reviewed separately. (See "Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis".) Other ischemic stroke subtypes are discussed elsewhere. (See "Stroke: Etiology, classification, and epidemiology" and "Clinical diagnosis of stroke subtypes" and "Lacunar infarcts" and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) TREATMENT OF ACUTE STROKE OR TIA The initial treatment of acute stroke or transient ischemic attack (TIA) due to ICAS is similar to the treatment of acute ischemic stroke or TIA attributed to other mechanisms, as reviewed in detail separately. (See "Initial assessment and management of acute stroke".) Of utmost importance, timely restoration of blood flow using reperfusion therapies (intravenous thrombolysis and/or mechanical thrombectomy) is the most effective way to salvage ischemic brain tissue that is not already infarcted. There is a relatively narrow time window during which this can be accomplished, since the benefit of these interventions decreases over time. Thus, an https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 1/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate important aspect of the hyperacute phase of acute ischemic stroke management is the rapid determination of patients who are eligible for intravenous thrombolysis and mechanical thrombectomy. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke".) Antiplatelet therapy has an important role in the both the acute and chronic phase of ischemic stroke management, as discussed below. (See 'Antiplatelet therapy' below.) SECONDARY PREVENTION Our approach For patients with transient ischemic attack (TIA) or ischemic stroke attributed to ICAS, we employ intensive medical therapy that includes antiplatelet therapy and strict control of vascular risk factors including the use of antihypertensive agents; low density lipoprotein cholesterol (LDL-C) lowering therapy; and physical activity and other lifestyle modification (eg, smoking cessation, weight control, salt restriction, and a healthy diet) [1]. (See 'Antiplatelet therapy' below and 'Risk factor management' below.) Intensive medical therapy is superior to intracranial arterial stenting for patients with recent stroke or TIA attributed to severe ICAS. (See 'Stenting' below.) Antiplatelet therapy Aspirin and other antithrombotic agents should not be given for the first 24 hours following treatment with intravenous thrombolysis. Otherwise, antiplatelet therapy should be started for most patients without an indication for anticoagulation as soon as possible after the diagnosis of TIA or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete. This issue is reviewed in detail elsewhere. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Treatment on presentation'.) For patients without serious bleeding complications who are not on anticoagulation or antiplatelet therapy at baseline, we start antiplatelet therapy as soon as possible while evaluating the ischemic stroke mechanism, as follows: For patients with a recent (within 30 days) stroke or TIA attributed to atherosclerotic intracranial large artery stenosis of 70 to 99 percent, we suggest short-term (up to 90 days) dual antiplatelet therapy (DAPT) with aspirin (325 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily), rather than aspirin monotherapy, followed by long-term aspirin monotherapy [1-3]. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 2/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate For patients with a recent minor stroke (NIHSS score 5) or TIA attributed to atherosclerotic intracranial large artery stenosis of 50 to 69 percent, options for initial treatment include aspirin monotherapy or short-term (21-day) DAPT. For patients with brain ischemia attributed to atherosclerotic intracranial large artery stenosis of 50 to 69 percent who have 2 a low-risk TIA, defined by an ABCD score <4, or a moderate to major ischemic stroke, defined by a National Institutes of Health Stroke Scale (NIHSS) score >5, we start treatment 2 with aspirin (325 mg daily) alone. For patients with a high-risk TIA, defined by an ABCD score 4, or minor ischemic stroke, defined by a NIHSS score 5, we begin with dual antiplatelet therapy (DAPT) for 21 days using aspirin (160 to 325 mg loading dose, followed by 50 to 100 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily) rather than aspirin alone. For long-term stroke prevention (beyond the 21- or 90-day duration of DAPT), we recommend treatment with aspirin. Clopidogrel monotherapy or the combination drug aspirin-extended- release dipyridamole are reasonable alternatives to aspirin but have not been specifically studied in ICAS. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Exceptions may include patients with an indication for anticoagulation, as discussed separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Cardioembolic source' and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Treatment on presentation'.) Evidence supporting short-term DAPT Accumulating data suggest that short-term (up to 90 days) DAPT may be beneficial for patients with acute stroke or TIA attributed to high- grade ICAS. Short-term DAPT with aspirin and clopidogrel The multicenter SAMMPRIS trial enrolled patients with 70 to 99 percent stenosis of a major intracranial artery who had a TIA or ischemic stroke within 30 days prior to study entry; in the aggressive medical treatment arm of the trial, the short-term use of DAPT with aspirin and clopidogrel for the first 90 days after enrollment may have contributed to the relatively low rate of combined stroke and death at one year of 12.2 percent [4,5]. This contrasts with findings from a post hoc analysis of the WASID trial, which enrolled patients with a stroke or TIA attributed to a 50 to 99 percent intracranial stenosis; the subgroup of patients in WASID who would have met the SAMMPRIS trial entry criteria (ie, 70 to 99 percent intracranial large artery stenosis and TIA or stroke within 30 days prior to study entry) and who were treated with aspirin or warfarin had a combined stroke and death rate at one year of 23 percent [6]. Additional support for DAPT comes from a subgroup https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 3/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate analysis of patients with ICAS in the CHANCE trial, which reported that those treated with DAPT had a lower rate of early recurrent stroke than those on monotherapy, although the difference was not statistically significant [7]. Similarly, the CLAIR study showed that patients with middle cerebral artery (MCA) stenosis on DAPT had significantly lower rates of microemboli distal to the stenosis when compared with those on aspirin alone and a lower (nonsignificant) rate of recurrent stroke [8]. In summary, the lower rates of recurrent stroke in SAMMPRIS patients on DAPT compared with similar patients from WASID, combined with the supportive CHANCE and CLAIR data, make a compelling argument to continue DAPT up to 90 days in patients with severe ICAS. Most importantly, the high risk of recurrent stroke from ICAS that persists beyond the first month distinguishes these patients from other stroke subtypes and argues for longer DAPT treatment. Short-term DAPT with aspirin and ticagrelor The THALES trial compared ticagrelor (90 mg twice daily after 180 mg loading dose) plus aspirin (75 to 100 mg once daily after 300 to 325 mg loading dose) among patients with recent non-cardioembolic stroke with NIHSS 5 or high-risk TIA or symptomatic >30 percent intracranial or extracranial stenosis. A subgroup analysis of THALES patients with ICAS 30 percent ipsilateral to the qualifying ischemic event found lower rates of ischemic stroke in those on combination ticagrelor plus aspirin compared with those on aspirin alone at 30 days (9.5 versus 15.2 percent, hazard ratio [HR] 0.66, 95% CI 0.47 0.93) [9]. Unlike other ICAS trials wherein the stenosis was determined by the investigator to be symptomatic for study qualification, the stenosis in this THALES analysis may have been incidental (eg, a 40 percent cavernous carotid stenosis ipsilateral to a lenticulostriate stroke). Additionally, the treatment duration was limited to 30 days, as were the reported outcomes. Given that ICAS stroke risk remains high beyond 30 days and the bleeding risk with ticagrelor and aspirin reported in THALES, additional long-term and comparative data are needed to better understand the role of this combination compared with other DAPT options. Additional support for the use of short-term DAPT in the setting of acute minor ischemic stroke or high-risk TIA comes from several randomized trials and meta-analysis, as reviewed in detail separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.) Evidence supporting long-term antiplatelet therapy Aspirin, clopidogrel, and the combination aspirin-extended-release dipyridamole have been established as effective for prevention of recurrent ischemic stroke in the patients with a history of noncardioembolic ischemic stroke or TIA of atherothrombotic, lacunar (small vessel occlusive), or cryptogenic type. Since antiplatelet drugs are effective in this larger group of patients with different https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 4/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate types of noncardioembolic ischemic stroke, they are likely to be effective in patients with ICAS, a subgroup that appears to be at particularly high risk of recurrent ischemic stroke. However, antiplatelet drugs have not been compared with placebo or with each other in randomized controlled trials specifically for patients with stroke or TIA attributed to ICAS. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Cilostazol is a phosphodiesterase 3 inhibitor and antiplatelet agent with vasodilating and possible antiatherogenic effects [10]. Early randomized trials conducted in East Asia failed to show a benefit of cilostazol plus aspirin compared with aspirin alone or clopidogrel plus aspirin for reducing stroke risk due to ICAS [11,12]. Later randomized trials from East Asia of cilostazol in combination with aspirin or clopidogrel showed a benefit for stroke prevention in patients with ICAS, but the findings may not be generalizable to all populations [13,14]. The CATHARSIS trial compared cilostazol plus aspirin with aspirin alone in patients with symptomatic 50 to 99 percent ICAS [13]. At two years, rates of vascular events and silent brain infarcts were lower in those on dual therapy (10.7 versus 25 percent, HR 0.37, 95% CI 0.14-0.97) without an increased bleeding risk. Similarly, among ICAS patients in the CSPS.com trial, with 0.5- to 3.5-year follow-up, those randomly assigned to cilostazol plus aspirin or clopidogrel had a lower rate of ischemic stroke compared with patients randomly assigned to placebo plus aspirin or clopidogrel (4.5 versus 9.9 percent, HR 0.48, 95% CI 0.21-1.11) and no increased bleeding risk [14]. In addition, other randomized trials support the safety and efficacy of cilostazol for secondary ischemic stroke prevention in East Asian populations, as described elsewhere. (See "Long- term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Cilostazol'.) Other antiplatelet agents such as prasugrel and vorapaxar are not well studied in this population. No role for oral anticoagulation There is randomized trial evidence that oral anticoagulation with warfarin is harmful for patients with TIA or stroke due to ICAS. The WASID trial enrolled patients with TIA or nondisabling stroke caused by an angiographically verified 50 to 99 percent stenosis of a major intracranial artery; patients were randomly assigned to treatment with either warfarin (target international normalized ratio [INR] 2.0 to 3.0) or aspirin (1300 mg/day) [15]. The study was stopped prematurely because of safety concerns for patients in the warfarin arm after enrolling 569 patients with an average follow-up of 1.8 years. Aspirin treatment was associated with a significantly lower rate of death than warfarin (4.3 versus 9.7 percent, HR 0.46, 95% CI 0.23-0.90). The composite rate of ischemic stroke, brain hemorrhage, or death from vascular cause other than stroke was similar between aspirin and warfarin treatment (22.1 versus 21.8 percent, hazard ratio [HR] https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 5/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate 1.04, 95% CI 0.73-1.48). The rate of ischemic stroke recurrence in the territory of the stenotic intracranial artery was high for both aspirin and warfarin treatment (15.0 versus 12.1 percent, HR 1.26, 95% CI 0.81-1.97) and primarily occurred within the first year from the qualifying event, suggesting that neither aspirin alone nor warfarin was particularly effective for preventing early recurrent stroke. Of note, the WASID trial was performed before the era of intensive risk factor management that included statin therapy for aggressive LDL-lowering. The efficacy of direct (non-vitamin K) oral anticoagulants (DOACs) for prevention of stroke due to ICAS has not been systematically studied, but planning is underway for a trial that will randomize patients to aspirin plus either clopidogrel, ticagrelor or low-dose rivaroxaban. Risk factor management Management of risk factors including hypertension, hyperlipidemia, physical inactivity, obesity, diabetes, and smoking is a critical component of the treatment of patients with atherosclerotic cardiovascular disease, including those with ischemic stroke. Post hoc analyses from the WASID trial showed that patients with ICAS and poorly controlled blood pressure or elevated cholesterol during follow-up had a significantly higher rate of stroke, myocardial infarction, or vascular death compared with patients with good control of these risk factors [16,17]. In addition, post hoc analyses of patients in the aggressive medical management only arm of the SAMMPRIS trial (see 'Stenting' below) found that intensive treatment of blood pressure and LDL-C was important to prevent recurrent vascular events and that physical inactivity was the most important independent predictor of vascular events and stroke [18]. Given that risk factor control reduces the risk of vascular events and recurrent stroke in patients with heterogeneous causes of stroke (see "Overview of secondary prevention of ischemic stroke"), combined with the post hoc analyses described above [16-18], it is likely that patients with stroke due to ICAS have better outcomes with intensive risk factor control that includes antihypertensive therapy, LDL-C lowering therapy, and lifestyle modification. (See "Overview of secondary prevention of ischemic stroke".) Antihypertensive therapy We treat all patients with hypertension using nonpharmacologic therapy (ie, salt restriction, adequate potassium intake, weight control, healthy diet, limited alcohol intake, and exercise) and pharmacologic therapy. For patients with hypertension, we suggest targeting a systolic blood pressure (SBP) of <140 mmHg [1- 3]. In the absence of definitive data supporting lower SBP targets in patients with ICAS, we advise caution when pursuing lower targets of SBP (eg, SBP <130 or <120), especially in patients with ICAS and fluctuating neurological symptoms, a recent stroke, or documented https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 6/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate low flow on quantitative magnetic resonance angiography. More research is needed to establish an alternative blood pressure target for such patients. The optimal target blood pressure to reduce the risk of recurrent ischemic stroke in patients with stroke due to ICAS is informed largely by post hoc analyses and data from a randomized controlled trial. The WASID and SAMMPRIS clinical trials demonstrated that in the vast majority of stable patients with stroke due to ICAS, lowering SBP to <140 mmHg was safe and was associated with a reduced risk of recurrent stroke [16-19]. However, targets below 140 mmHg were not studied in those analyses, and emerging data suggests caution should be advised with lower targets. As an example, a randomized controlled trial from Korea of 132 patients with recent subacute stroke due to ICAS found the group assigned to aggressive blood pressure control (mean SBP 124.6 mmHg) had a tendency toward larger infarct volume and more fluid-attenuated inversion recovery lesions on magnetic resonance imaging (MRI) at follow-up compared with the group assigned to standard blood pressure control (mean SBP 132 mmHg) [20]. In the MYRIAD observational study of patients with symptomatic ICAS, a change in systolic blood pressure from baseline to six- to eight-week follow-up was an independent predictor of early recurrent stroke [21]. Another study found that patients with ICAS who had a low translesional pressure gradient (measured using computational fluid dynamics from computed tomographic angiography) and a mean SBP <130 mmHg during follow-up had an increased risk of recurrent stroke in the territory compared with patients who had a SBP of 130 to 150 mmHg during follow-up [22]. Similarly, a post hoc analysis of the VERiTAS study of patients with posterior circulation stenosis reported that patients with both low flow on quantitative MRI and a mean SBP <140 mmHg had a higher risk of stroke compared with patients lacking one or both of these factors [19]. Specific aspects of the pharmacologic and nonpharmacologic evaluation and management of hypertension are discussed in greater detail separately. (See "Overview of hypertension in adults" and "Salt intake, salt restriction, and primary (essential) hypertension" and "Potassium and hypertension" and "Diet in the treatment and prevention of hypertension" and "Overweight, obesity, and weight reduction in hypertension" and "Exercise in the treatment and prevention of hypertension".) LDL-C lowering therapy For patients with a history of ischemic stroke or TIA, independent of the baseline LDL-C level, we recommend lifelong high-intensity statin therapy (atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg); we prefer the highest approved dose in most cases. For patients who do not tolerate these doses, the maximally tolerated dose of a statin should be used. For patients whose LDL-C is 70 mg/dL (1.8 mmol/L) on high-intensity statin therapy, we recommend adding ezetimibe or a PCSK9 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 7/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate inhibitor to statin therapy. In most cases, this second drug will be ezetimibe for reasons of cost and convenience. For patients who do not tolerate any statin regimen, we start ezetimibe. For those patients whose LDL-C remains above 70 mg/dL (1.8 mmol/L), we consider adding a PCSK9 inhibitor. This approach is similar to that presented in many societal guidelines, including the 2022 American Academy of Neurology guidelines [1] and the 2019 multisociety American guidelines [23]; recommendations from the 2019 European Society of Cardiology are somewhat more aggressive for the highest-risk patients [24]. There is overwhelming evidence from randomized trials that LDL-C lowering reduces the risk of cardiovascular events including ischemic stroke. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Benefits of LDL-C lowering'.) Data specific to patients with ICAS has also emerged for the use of high-intensity statins and targeting LDL <70 mg/dL (1.8 mmol/L). A single-center randomized controlled trial of 120 patients from China with symptomatic MCA or basilar stenosis found a lower rate of recurrent cerebrovascular events during follow-up in those treated with high-intensity statins compared with low- and standard-intensity statins [25]. A post hoc analysis from the SAMMPRIS trial showed a lower risk of recurrent stroke and vascular events with lower LDL- C when analyzed as a continuous variable, but achieving the target LDL-C <70 mg/dL was associated with only a trend toward benefit [18]. However, the TST trial of over 2800 patients with recent ischemic stroke or TIA and atherosclerosis (including ICAS) found lower rates of recurrent vascular events, particularly stroke, in those assigned to the LDL target of <70 mg/dL compared with those assigned to a target range of 90 to 110 mg/dL [26]. (See "Overview of secondary prevention of ischemic stroke", section on 'LDL-C lowering therapy'.) Lifestyle modification A number of behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease [1]. These include smoking cessation, regular aerobic physical activity, limited alcohol consumption, weight control, salt restriction, and a Mediterranean diet. Physical activity, in particular, is strongly recommended for patients with ICAS since it was independently associated with lower rates of recurrent stroke, myocardial infarction, and vascular death in the medically treated patients in the SAMMPRIS trial (odds ratio [OR] 0.6, 95% CI 0.4 0.8), with higher rates of activity increasing the protective effect [18]. (See "Overview of secondary prevention of ischemic stroke", section on 'Lifestyle modification'.) https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 8/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Glycemic control Tight glucose control reduces microvascular complications. Diet, exercise, oral hypoglycemic drugs, and insulin are proven methods to achieve glycemic control. A reasonable goal of therapy for most patients with diabetes is a hemoglobin A1C value of 7 percent. However, the available evidence has not demonstrated a consistent beneficial effect of intensive glucose-lowering therapy or lifestyle modification for reducing macrovascular outcomes (eg, stroke and death) in patients with type 2 diabetes. (See "Overview of primary prevention of cardiovascular disease", section on 'Management of type 2 diabetes' and "Overview of secondary prevention of ischemic stroke", section on 'Glycemic control'.) Failure of medical therapy Although unproven, therapies of last resort for patients who have recurrent ischemic stroke due to ICAS despite maximal medical therapy include endovascular stenting (see 'Stenting' below) or submaximal angioplasty (see 'Submaximal angioplasty' below) as reviewed in the sections below. However, there are no comparative data from randomized trials demonstrating benefit of these treatments over medical therapy that can be used to guide management for patients with recurrent stroke in this setting. Intracranial arterial stenting and other interventional procedures are not recommended for patients with a first stroke or TIA attributable to severe intracranial artery stenosis [1-3], since results from the SAMMPRIS and VISSIT trials showed that medical management was superior to intracranial stenting (see 'Stenting' below). In the United States, the policy of the Centers for Medicare and Medicaid Services is not to reimburse for intracranial angioplasty with or without stenting outside the context of a clinical trial [27]. Other interventions are not routinely used because of lack of evidence or evidence of harm: Intracranial angioplasty without stenting has been studied only in small observational studies [28]. There are numerous drawbacks to intracranial angioplasty, including immediate elastic recoil of the artery, intimal damage, dissection, acute vessel closure, residual stenosis >50 percent following the procedure, and high restenosis rates [29-31]. A 2019 systematic review and meta-analysis of balloon angioplasty for ICAS including 25 studies and 674 patients showed a 30-day stroke and death rate of 16.3 percent in patients with severe stenosis [32]. Therefore, angioplasty alone has largely been replaced with submaximal angioplasty to minimize periprocedural complications. Extracranial-intracranial bypass, or direct bypass, was mostly abandoned for the treatment of ICAS after the extracranial-intracranial (EC-IC) bypass trial results were reported in 1985 [33]. In that study, 1377 patients with symptomatic extracranial carotid occlusion, distal carotid occlusive disease, or MCA stenosis were randomly assigned to either medical https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 9/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate therapy alone (usually aspirin) or to extracranial-intracranial anastomosis surgery (joining the superficial temporal artery and the middle cerebral artery) combined with medical therapy. The mean follow-up was 56 months. The results demonstrated that EC-IC bypass was ineffective for preventing stroke in these patients [33]. Subgroup analyses showed that EC-IC bypass was ineffective in patients with distal carotid stenosis, and was actually hazardous in patients with MCA stenosis [33,34]. In 109 patients with 70 percent MCA stenosis, stroke frequency was significantly higher for patients who had EC-IC compared with medically treated patients (44 versus 24 percent). Indirect bypass, also known as encephaloduroarteriosynangiosis (EDAS), is an investigational surgical procedure that showed some early promising results for stroke prevention in ICAS in a two-center prospective uncontrolled study [35]. However, evidence of efficacy from randomized trials is needed before the procedure is widely adopted to treat medically refractory ICAS. Stenting Several multicenter randomized trials, described below, found that patients with symptomatic ICAS treated with angioplasty and stenting had worse outcomes than those who received medical therapy or showed no benefit of stenting [4,36,37]. In addition, a systematic review that identified three randomized controlled trials (including SAMMPRIS [4,5], VISSIT [36], and a trial from China [38]) with 632 patients who had symptomatic intracranial atherosclerotic stenosis found that, compared with medical treatment alone, endovascular therapy plus medical treatment led to higher rate of death or stroke at 30 days (16 versus 5 percent, absolute risk increase 11 percent, risk ratio [RR] 3.07, 95% CI 1.80-5.24) and at one year (24 versus 14 percent, absolute risk increase 10 percent, RR 1.69, 95% CI 1.21-2.36) [39]. Given these data, we recommend against intracranial stenting for patients with recent stroke or TIA attributed to ICAS [1-3]. All patients should be treated with intensive medical therapy that includes antiplatelet therapy and strict control of vascular risk factors, as described above. (See 'Secondary prevention' above.) SAMMPRIS trial The multicenter SAMMPRIS trial enrolled patients with 70 to 99 percent stenosis of a major intracranial artery who had a TIA or ischemic stroke within 30 days prior to study entry [4,5]. Patients were randomly assigned to treatment with intracranial angioplasty and stenting using the Wingspan system plus aggressive medical management, or to treatment with aggressive medical management alone. Aggressive medical therapy consisted of aspirin 325 mg daily for the duration of follow-up, clopidogrel 75 mg daily for 90 days after enrollment, and intensive risk factor management with a target blood pressure of <140/90 mmHg (or <130/80 mmHg if diabetic) and an LDL-C target of <70 mg/dL (<1.81 mmol/L). https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 10/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Trial enrollment in SAMMPRIS was halted prematurely after recruitment of 451 of the planned 764 patients because the 30-day rate of stroke or death was higher for patients treated with angioplasty and stenting compared with those treated with medical therapy alone (14.7 versus 5.8 percent) [4]. The periprocedural rate of stroke was higher than expected for the stenting group, and the early stroke rate was lower than estimated for the medical management group. Of the 33 early symptomatic stroke events in the stenting group, 25 occurred within one day of the procedure, and the remaining 8 occurred within six days of the procedure [40]. Of the early strokes, symptomatic intracranial, subarachnoid, or intraventricular hemorrhage occurred in 10 patients (4.5 percent), resulting in death in 4 patients (1.8 percent). By contrast, there were 12 early strokes in the medical management group, and none were hemorrhagic. In the stenting group, the main cause of the early ischemic strokes was occlusion of perforating vessels. Of the early hemorrhagic strokes, approximately one-half involved predominantly subarachnoid bleeding that was evident immediately after the procedure, while the rest were intraparenchymal hemorrhages that were attributed to reperfusion. At study end, with a median follow-up of 32 months, the rate of stroke or death remained significantly higher for the angioplasty and stenting group compared with the medical management group (19.7 versus 12.6 percent at one year, and 23.9 versus 14.9 percent at three years) [5]. These long-term differences were driven largely by the 30-day outcomes, since the rates of stroke and death beyond 30 days were similar for the two groups, demonstrating no long-term benefit from stenting. VISSIT trial The VISSIT trial randomly assigned 112 patients with symptomatic ICAS to treatment with a balloon-expandable stent plus medical therapy or to medical therapy alone. It was terminated early by the sponsor due to the low likelihood of detecting superiority of stenting over medical therapy [36]. At 30 days, the rate of the primary safety outcome, a composite of any stroke, death, or intracranial hemorrhage, was significantly higher in the stent group compared with the medical group (24 versus 9 percent). At 12 months, the rate of the primary outcome measure, a composite of stroke and TIA in the same territory, was significantly higher in the stent group (36 versus 15 percent). CASSISS trial The CASSISS trial, conducted at eight sites in China, was an open-label, randomized trial of 358 patients with symptomatic ICAS enrolled at least three weeks after the index stroke that compared angioplasty and stenting with the Wingspan stenting system with medical therapy [37,41]. In contrast to SAMMPRIS and VISSIT, CASSISS excluded patients with perforator ischemic events in the basal ganglia, thalamus, and https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 11/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate brainstem and patients with MRI evidence of recent stroke by diffusion-weighted imaging (DWI) at the time of randomization in order to reduce the risk of periprocedural complications and symptomatic intracranial hemorrhage that was seen in earlier trials [41]. CASSISS reported a lower primary endpoint rate (a composite of any stroke or death within 30 days or stroke in territory within one year) than prior trials in both the stenting and medical groups (8 versus 7.2 percent, respectively), likely because of the lower-risk population enrolled and differences in event ascertainment during follow-up [37]. Nevertheless, the CASSISS trial found no benefit over medical therapy from angioplasty and stenting with the Wingspan stenting system for any of the primary or secondary outcome measures. Periprocedural brain hemorrhage affected four patients in the stenting group (two of which were fatal) versus none in the medical group. There was a trend toward higher three-year mortality in the stenting arm (4.4 versus 1.3 percent, 95% CI 0.77- 18.13). Although stenting for stroke prevention in patients with ICAS has been shown to be harmful in these randomized trials [39], some physicians treat with stenting as a last resort for patients with high-grade intracranial large artery stenosis who have multiple symptomatic ischemic events. Results from the WEAVE study, an open-label, single-arm postmarket surveillance study of the WINGSPAN stent, suggested that stenting appeared safe with a relatively low risk of recurrent stroke in highly-selected patients with symptomatic ICAS who are at least seven days from their most recent ischemic event and have had two or more recurrent ischemic events in the vascular territory of the stenotic intracranial large artery despite optimal medical management [42]. However, patients were only required to be followed for 72 hours or until discharge, and in some cases, assessments were done by phone if the patient was already discharged. Additionally, the stroke and death rate in WEAVE for patients with ICAS who did not meet strict US Food and Drug Administration criteria (eg, did not fail medical therapy, were less than seven days since last stroke, or more than two strokes) was approximately 24 percent [43,44]. Along those lines, another ICAS registry of patients treated with stenting or angioplasty who failed medical therapy or had with progressive stroke symptoms reported a 90-day ischemic stroke rate of 6.7 percent and 90-day mortality of 11.2 percent [45]. Given the high complication rates and low-quality evidence supporting safety in these uncontrolled studies, randomized controlled trials are needed before stenting is adopted as a rescue therapy even in those who have failed medical therapy. Analyses of the SAMMPRIS trial found no benefit for stenting for any subgroup of patients, including those patients with a prior ischemic stroke in the territory of the symptomatic intracranial artery and those who had their qualifying ischemic event on antithrombotic therapy [5,46,47]. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 12/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Submaximal angioplasty Submaximal angioplasty involves angioplasty alone with slow expansion of a balloon undersized to 50 to 70 percent of nominal vessel diameter to limit periprocedural complications. A 2020 meta-analysis identified nine studies (eight retrospective) with 395 patients who had 408 procedures with submaximal angioplasty [48]. The pooled periprocedural complication rate for stroke or death was approximately 5 percent, while the pooled rate beyond 30 days was approximately 4 percent. Technical success reported in six studies was achieved in approximately 96 percent of procedures. These results compare favorably with periprocedural event rates observed in the stenting and medical treatment arms of the SAMMPRIS and VISSIT trials described above. (See 'Stenting' above.) These limited data suggest that submaximal angioplasty may be a promising strategy for safe revascularization in the future, but more research is needed before it is widely used in practice. Recommendations of others The 2021 American Heart Association/American Stroke Association recommendations for intracranial stenosis are as follows [2]: For patients with a stroke or TIA attributable to a 50 to 99 percent stenosis of a major intracranial artery, aspirin 325 mg daily is recommended in preference to warfarin. For patients with recent stroke or TIA (within 30 days) attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, the addition of clopidogrel 75 mg daily to aspirin for up to 90 days is reasonable. For patients with a stroke or TIA attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, the addition of cilostazol 200 mg daily to aspirin or clopidogrel might be considered. For patients with recent (within 24 hours) minor stroke or high-risk TIA and concomitant ipsilateral >30 percent stenosis of a major intracranial artery, the addition of ticagrelor 90 mg twice daily to aspirin for up to 30 days might be considered. For patients with a stroke or TIA attributable to a 50 to 99 percent stenosis of a major intracranial artery, maintenance of SBP below 140 mm Hg, high-intensity statin therapy, and at least moderate physical activity are recommended. For patients with stroke or TIA attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, angioplasty or stenting should not be performed as initial treatment, even for patients who were taking an antithrombotic agent at the time of the stroke or TIA. In patients with severe stenosis (70 to 99 percent) of a major intracranial artery and actively progressing symptoms or recurrent TIA or stroke after institution of aspirin and clopidogrel https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 13/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate therapy, achievement of SBP <140 mmHg, and high-intensity statin therapy (so-called medical failures), the usefulness of angioplasty alone or stent placement to prevent
three years) [5]. These long-term differences were driven largely by the 30-day outcomes, since the rates of stroke and death beyond 30 days were similar for the two groups, demonstrating no long-term benefit from stenting. VISSIT trial The VISSIT trial randomly assigned 112 patients with symptomatic ICAS to treatment with a balloon-expandable stent plus medical therapy or to medical therapy alone. It was terminated early by the sponsor due to the low likelihood of detecting superiority of stenting over medical therapy [36]. At 30 days, the rate of the primary safety outcome, a composite of any stroke, death, or intracranial hemorrhage, was significantly higher in the stent group compared with the medical group (24 versus 9 percent). At 12 months, the rate of the primary outcome measure, a composite of stroke and TIA in the same territory, was significantly higher in the stent group (36 versus 15 percent). CASSISS trial The CASSISS trial, conducted at eight sites in China, was an open-label, randomized trial of 358 patients with symptomatic ICAS enrolled at least three weeks after the index stroke that compared angioplasty and stenting with the Wingspan stenting system with medical therapy [37,41]. In contrast to SAMMPRIS and VISSIT, CASSISS excluded patients with perforator ischemic events in the basal ganglia, thalamus, and https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 11/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate brainstem and patients with MRI evidence of recent stroke by diffusion-weighted imaging (DWI) at the time of randomization in order to reduce the risk of periprocedural complications and symptomatic intracranial hemorrhage that was seen in earlier trials [41]. CASSISS reported a lower primary endpoint rate (a composite of any stroke or death within 30 days or stroke in territory within one year) than prior trials in both the stenting and medical groups (8 versus 7.2 percent, respectively), likely because of the lower-risk population enrolled and differences in event ascertainment during follow-up [37]. Nevertheless, the CASSISS trial found no benefit over medical therapy from angioplasty and stenting with the Wingspan stenting system for any of the primary or secondary outcome measures. Periprocedural brain hemorrhage affected four patients in the stenting group (two of which were fatal) versus none in the medical group. There was a trend toward higher three-year mortality in the stenting arm (4.4 versus 1.3 percent, 95% CI 0.77- 18.13). Although stenting for stroke prevention in patients with ICAS has been shown to be harmful in these randomized trials [39], some physicians treat with stenting as a last resort for patients with high-grade intracranial large artery stenosis who have multiple symptomatic ischemic events. Results from the WEAVE study, an open-label, single-arm postmarket surveillance study of the WINGSPAN stent, suggested that stenting appeared safe with a relatively low risk of recurrent stroke in highly-selected patients with symptomatic ICAS who are at least seven days from their most recent ischemic event and have had two or more recurrent ischemic events in the vascular territory of the stenotic intracranial large artery despite optimal medical management [42]. However, patients were only required to be followed for 72 hours or until discharge, and in some cases, assessments were done by phone if the patient was already discharged. Additionally, the stroke and death rate in WEAVE for patients with ICAS who did not meet strict US Food and Drug Administration criteria (eg, did not fail medical therapy, were less than seven days since last stroke, or more than two strokes) was approximately 24 percent [43,44]. Along those lines, another ICAS registry of patients treated with stenting or angioplasty who failed medical therapy or had with progressive stroke symptoms reported a 90-day ischemic stroke rate of 6.7 percent and 90-day mortality of 11.2 percent [45]. Given the high complication rates and low-quality evidence supporting safety in these uncontrolled studies, randomized controlled trials are needed before stenting is adopted as a rescue therapy even in those who have failed medical therapy. Analyses of the SAMMPRIS trial found no benefit for stenting for any subgroup of patients, including those patients with a prior ischemic stroke in the territory of the symptomatic intracranial artery and those who had their qualifying ischemic event on antithrombotic therapy [5,46,47]. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 12/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Submaximal angioplasty Submaximal angioplasty involves angioplasty alone with slow expansion of a balloon undersized to 50 to 70 percent of nominal vessel diameter to limit periprocedural complications. A 2020 meta-analysis identified nine studies (eight retrospective) with 395 patients who had 408 procedures with submaximal angioplasty [48]. The pooled periprocedural complication rate for stroke or death was approximately 5 percent, while the pooled rate beyond 30 days was approximately 4 percent. Technical success reported in six studies was achieved in approximately 96 percent of procedures. These results compare favorably with periprocedural event rates observed in the stenting and medical treatment arms of the SAMMPRIS and VISSIT trials described above. (See 'Stenting' above.) These limited data suggest that submaximal angioplasty may be a promising strategy for safe revascularization in the future, but more research is needed before it is widely used in practice. Recommendations of others The 2021 American Heart Association/American Stroke Association recommendations for intracranial stenosis are as follows [2]: For patients with a stroke or TIA attributable to a 50 to 99 percent stenosis of a major intracranial artery, aspirin 325 mg daily is recommended in preference to warfarin. For patients with recent stroke or TIA (within 30 days) attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, the addition of clopidogrel 75 mg daily to aspirin for up to 90 days is reasonable. For patients with a stroke or TIA attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, the addition of cilostazol 200 mg daily to aspirin or clopidogrel might be considered. For patients with recent (within 24 hours) minor stroke or high-risk TIA and concomitant ipsilateral >30 percent stenosis of a major intracranial artery, the addition of ticagrelor 90 mg twice daily to aspirin for up to 30 days might be considered. For patients with a stroke or TIA attributable to a 50 to 99 percent stenosis of a major intracranial artery, maintenance of SBP below 140 mm Hg, high-intensity statin therapy, and at least moderate physical activity are recommended. For patients with stroke or TIA attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, angioplasty or stenting should not be performed as initial treatment, even for patients who were taking an antithrombotic agent at the time of the stroke or TIA. In patients with severe stenosis (70 to 99 percent) of a major intracranial artery and actively progressing symptoms or recurrent TIA or stroke after institution of aspirin and clopidogrel https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 13/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate therapy, achievement of SBP <140 mmHg, and high-intensity statin therapy (so-called medical failures), the usefulness of angioplasty alone or stent placement to prevent ischemic stroke in the territory of the stenotic artery is unknown. For patients with a stroke or TIA attributable to moderate stenosis (50 to 69 percent) of a major intracranial artery, angioplasty or stenting is associated with excess morbidity and mortality compared with medical management alone. Recommendations from the 2017 update to the Canadian stroke best practice recommendations for ICAS are as follows [49]: Intracranial stenting is not recommended for the treatment of recently symptomatic intracranial 70 to 99 percent stenosis. As in the medical management arm of the SAMMPRIS trial, dual antiplatelet therapy with aspirin and clopidogrel started within 30 days of stroke or TIA and treatment for up to 90 days should be considered for patients on an individual basis, along with aggressive management of all vascular risk factors including blood pressure, lipids, diabetes mellitus, and other at-risk lifestyle patterns. In patients managed with maximal medical therapy in the presence of intracranial stenosis who experience a recurrent stroke, there is lack of clear evidence to guide further management decisions; intracranial angioplasty (with or without stenting) may be reasonable in carefully selected patients. Recommendations from the UK National Institute for Health and Care Excellence (NICE) state that endovascular stent insertion for intracranial atherosclerotic disease should only be used in the context of research, noting that evidence shows a significant risk of periprocedural stroke and death [50]. PROGNOSIS Risk and location of recurrent stroke ICAS is associated with a high risk of recurrent stroke. As an example, a randomized controlled trial (WASID) published in 2005 that compared warfarin with aspirin in 569 patients with symptomatic stenosis (50 to 99 percent) of a major intracranial found that the ischemic stroke rate in the territory of the stenotic artery at one year was 11 to 12 percent in both treatment groups [15]. The risk of recurrent stroke is likely lower in the modern era with the advent of intensive medical therapy (ie, dual antiplatelet therapy for three months followed by long-term antiplatelet therapy, antihypertensive, and high-intensity LDL-C lowering https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 14/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate treatment), as suggested by stroke rates among medically treated patients in the SAMMPRIS and VISSIT trials. Patients in the medical arm of SAMMPRIS treated with dual-antiplatelet therapy and intensive risk factor control had a lower primary endpoint rate at six months compared with similar patients from WASID with severe stenosis treated with aspirin alone (approximately 9 versus 18 percent, respectively) [17]. (See 'Stenting' above.) Populations at high risk of recurrent stroke Available evidence suggests there may be subgroups of patients with ICAS who are at particularly high risk of stroke: Patients with severe intracranial large artery stenosis [51]. In the prospective WASID trial, severe stenosis ( 70 percent) was associated with a significantly higher risk of stroke in the same territory compared with stenosis <70 percent (hazard ratio [HR] 2.03, 95% CI 1.29- 3.22) ( figure 1) [52]. Patients with recent ischemic symptoms [51]. WASID also demonstrated that patients with symptoms within the prior 17 days were at significantly higher risk of stroke in the same territory compared with patients whose symptoms were more remote (HR 1.67, 95% CI 1.1- 2.9) [52]. Patients with borderzone infarcts and impaired collateral flow. In a post hoc analysis of a subgroup of SAMMPRIS patients with middle cerebral artery stenosis, patients with borderzone pattern of infarcts and those who had impaired collateral flow had the highest risk of recurrent stroke (37 percent) compared with those without impaired collaterals or other infarct patterns [53]. Patients with clinically significant hemodynamic intracranial stenosis, described below. (See 'Implications of hemodynamic stenosis' below.) Women. The WASID trial found that the frequency of the combined end point of stroke or vascular death in patients with symptomatic intracranial arterial stenosis was greater in women than in men (28.4 versus 16.6 percent, respectively; HR 1.58, 95% CI 1.01-2.48) [54]. In addition, women had a higher risk of recurrent ischemic stroke than men (HR 1.85, 95% CI 1.14-3.01). In the medical treatment arm of the SAMMPRIS trial, which enrolled patients with ischemic stroke or transient ischemic attack (TIA) attributed to severe (70 to 99 percent) stenosis of a major intracranial artery, high-risk features for recurrent stroke were the presence of an old infarct in the territory of the stenosis, presentation with stroke, and absence of statin use at trial entry [55]. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 15/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Implications of hemodynamic stenosis Intracranial stenosis considered "hemodynamically significant" purely on clinical grounds emerged as another potential risk factor for recurrent ischemic stroke in the GESICA study, a prospective observational report that enrolled 102 patients with 50 percent symptomatic intracranial large artery atherosclerotic stenosis [56]. Intracranial stenosis was classified as hemodynamic in GESICA if symptoms related to the stenosis occurred during a change in body position from supine to prone, during effort/exertion, or with the introduction or increase of antihypertensive medication. Patients with a hemodynamic stenosis had a higher frequency of recurrent ischemic stroke or TIA in the territory of the stenotic artery than those without a hemodynamic stenosis (61 versus 32 percent). By contrast, among patients in the SAMMPRIS trial with a 70 to 99 percent stenosis who had qualifying symptoms suggestive of hypoperfusion (same definition as above) and were assigned to the aggressive medical management group (n = 31), the two-year probability of an outcome event (ie, 30-day stroke and death and later strokes in the territory of the qualifying artery) was only 7 percent (95% CI 1.8-25.3) [47]. The observational VERITAS study analyzed hemodynamics for 72 patients with recent posterior circulation TIA or stroke and >50 percent atherosclerotic stenosis or occlusion of the vertebral and/or basilar arteries [57]. Low blood flow in these arteries, as determined by quantitative magnetic resonance angiography (QMRA), was associated with an increased risk for subsequent vertebrobasilar stroke (adjusted HR 11.55, 95% CI 1.88-71.00). By contrast, the MyRIAD observational cohort of 105 patients with 50 to 99 percent intracranial stenosis in either the anterior or posterior circulation did not show an association between low flow (as measured by QMRA and perfusion MRI) and recurrent infarcts [58]. Given that measures of hemodynamic stability (eg, clinical symptoms, perfusion or flow imaging) inconsistently predict ischemic risk, further research is needed to identify a more accurate biomarker that may be used to select patients at high risk due to hypoperfusion. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".) SUMMARY AND RECOMMENDATIONS https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 16/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate The initial treatment of acute stroke or transient ischemic attack (TIA) due to intracranial large artery atherosclerosis (ICAS) is similar to the treatment of acute ischemic stroke or TIA attributed to other mechanisms. An important aspect of the hyperacute phase of acute ischemic stroke management is the rapid determination of patients who are eligible for intravenous thrombolysis and mechanical thrombectomy. (See "Initial assessment and management of acute stroke" and "Approach to reperfusion therapy for acute ischemic stroke".) For patients with recent (within 30 days) stroke or TIA attributed to intracranial large artery stenosis of 70 to 99 percent, we recommend against intracranial stenting because there is evidence of harm with higher rates of stroke or death compared with medical therapy alone (Grade 1B). All patients with recent ischemic stroke or TIA attributed to an intracranial large artery stenosis should receive intensive medical therapy with antiplatelet therapy and strict control of vascular risk factors, including the use of antihypertensive agents, low density lipoprotein cholesterol (LDL-C) lowering therapy, physical activity, and other lifestyle modification (eg, smoking cessation, weight control, salt restriction, and a healthy diet). (See 'Our approach' above.) For patients with a recent (within 30 days) TIA or stroke attributed to atherosclerotic intracranial large artery stenosis of 70 to 99 percent, we suggest dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel (rather than aspirin monotherapy) for up to 90 days (Grade 2C). For patients with brain ischemia attributed to atherosclerotic intracranial large artery stenosis of 50 to 69 percent who have a low-risk TIA, defined by 2 an ABCD score <4, or a moderate to major ischemic stroke, defined by a National Institutes of Health Stroke Scale (NIHSS) score >5, we start treatment with aspirin alone. 2 For patients with a high-risk TIA, defined by an ABCD score 4, or minor ischemic stroke, defined by a NIHSS score 5, we begin with dual antiplatelet therapy (DAPT) for 21 days using aspirin plus clopidogrel rather than aspirin alone. For long-term stroke prevention (beyond the 21- or 90-day duration of DAPT), we treat with aspirin monotherapy. Clopidogrel monotherapy or the combination drug aspirin-extended- release dipyridamole are reasonable alternatives to aspirin but have not been specifically studied in ICAS. (See 'Antiplatelet therapy' above.) We treat all patients with hypertension with nonpharmacologic therapy (ie, salt restriction, adequate potassium intake, weight control, healthy diet, limited alcohol intake) and pharmacologic therapy. For patients with hypertension who have a stroke or TIA attributed to intracranial large artery stenosis of 50 to 99 percent, we suggest targeting a systolic blood pressure (SBP) of <140 mmHg rather than a lower target SBP (Grade 2C). (See 'Risk factor management' above.) https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 17/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate For patients with TIA or ischemic stroke of atherosclerotic origin, including those with symptomatic ICAS, we use high-intensity statin therapy with atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily; we prefer the highest approved dose in most cases. We also target treatment to achieve a low-density lipoprotein cholesterol (LDL-C) level <70 mg/dL. (See 'Risk factor management' above and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) Although unproven, therapies of last resort for patients who have recurrent ischemic stroke due to ICAS despite maximal medical therapy include indirect bypass, endovascular stenting, or submaximal angioplasty. However, there are no comparative data from randomized trials to suggest these treatments provide benefit over medical therapy. (See 'Failure of medical therapy' above.) ICAS is associated with a high risk of recurrent stroke. Subgroups that may be at particularly high risk of stroke in the territory of the affected vessel include patients with clinically significant hemodynamic intracranial stenosis, patients with borderzone infarct pattern and impaired collateral flow, patients with severe ( 70 percent) intracranial stenosis, patients with recent ischemic symptoms, and women. (See 'Prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Marc I Chimowitz, MD, and Cathy A Sila, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Turan TN, Zaidat OO, Gronseth GS, et al. 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Detailed analysis of periprocedural strokes in patients undergoing intracranial stenting in Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS). Stroke 2012; 43:2682. 41. Gao P, Zhao Z, Wang D, et al. China Angioplasty and Stenting for Symptomatic Intracranial Severe Stenosis (CASSISS): A new, prospective, multicenter, randomized controlled trial in China. Interv Neuroradiol 2015; 21:196. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 21/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate 42. Alexander MJ, Zauner A, Chaloupka JC, et al. WEAVE Trial: Final Results in 152 On-Label Patients. Stroke 2019; 50:889. 43. Use of the Stryker Wingspan Stent System outside of approved indications leads to an incre ased risk of stroke or death: FDA safety communication, April 25, 2019. 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Kasner SE, Chimowitz MI, Lynn MJ, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006; 113:555. 53. Wabnitz AM, Derdeyn CP, Fiorella DJ, et al. Hemodynamic Markers in the Anterior Circulation as Predictors of Recurrent Stroke in Patients With Intracranial Stenosis. Stroke 2018; :STROKEAHA118020840. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 22/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate 54. Williams JE, Chimowitz MI, Cotsonis GA, et al. Gender differences in outcomes among patients with symptomatic intracranial arterial stenosis. Stroke 2007; 38:2055. 55. Waters MF, Hoh BL, Lynn MJ, et al. Factors Associated With Recurrent Ischemic Stroke in the Medical Group of the SAMMPRIS Trial. JAMA Neurol 2016; 73:308. 56. Mazighi M, Tanasescu R, Ducrocq X, et al. Prospective study of symptomatic atherothrombotic intracranial stenoses: the GESICA study. Neurology 2006; 66:1187. 57. Amin-Hanjani S, Pandey DK, Rose-Finnell L, et al. Effect of Hemodynamics on Stroke Risk in Symptomatic Atherosclerotic Vertebrobasilar Occlusive Disease. JAMA Neurol 2016; 73:178. 58. Romano JG, Prabhakaran S, Nizam A, et al. Infarct Recurrence in Intracranial Atherosclerosis: Results from the MyRIAD Study. J Stroke Cerebrovasc Dis 2021; 30:105504. Topic 1101 Version 41.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 23/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate GRAPHICS Stroke probability by stenosis Product-limit estimate of the cumulative probability of an ischemic stroke in the territory of the stenotic artery versus years after randomization, according to percent stenosis ( 70 percent stenosis shown as red solid line, <70 percent stenosis as blue dashed line); log- rank test P 0.0010. Reproduced with permission from Kasner, SE, Chimowitz, MI, Lynn, MJ, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006; 113:555. Copyright 2006 Lippincott Williams & Wilkins. Graphic 73498 Version 1.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 24/25 7/6/23, 11:56 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Contributor Disclosures Tanya N Turan, MD, MSCR No relevant financial relationship(s) with ineligible companies to disclose. Jose Gutierrez, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 25/25
7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use : Jamary Oliveira-Filho, MD, MS, PhD, Owen B Samuels, MD : Jos Biller, MD, FACP, FAAN, FAHA, Alejandro A Rabinstein, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 30, 2023. INTRODUCTION The most important factor in successful reperfusion therapy of acute ischemic stroke is early treatment. Nonetheless, selection of appropriate candidates for reperfusion demands a neurologic evaluation and a neuroimaging study. In addition, reperfusion therapy for acute stroke requires a system that coordinates emergency services, stroke neurology, intensive care services, neuroimaging, and neurosurgery to provide optimal treatment. This topic will review the administration of intravenous thrombolytic therapy for patients with acute ischemic stroke. The approach to reperfusion therapy and selection of appropriate patients for treatment is discussed elsewhere. (See "Approach to reperfusion therapy for acute ischemic stroke".) Mechanical thrombectomy is reviewed in detail separately. (See "Mechanical thrombectomy for acute ischemic stroke".) Other aspects of acute ischemic stroke care are discussed elsewhere. (See "Initial assessment and management of acute stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and "Neuroimaging of acute stroke".) OVERVIEW OF THERAPY https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 1/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate The immediate goal of reperfusion therapy for acute ischemic stroke is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. The long-term goal is to improve outcome by reducing stroke-related disability and mortality. There are two options for reperfusion therapy that are proven effective: Intravenous thrombolytic therapy is the mainstay of treatment for acute ischemic stroke, provided that treatment is initiated within 4.5 hours of clearly defined symptom onset time or within 4.5 hours of the time the patient was last known to be well ( table 1). (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Benefit by time to treatment'.) For patients with wake-up stroke or unknown time last known well, imaging-based criteria to determine eligibility for intravenous thrombolysis (ie, an MRI showing an acute ischemic lesion that is diffusion positive and fluid-attenuated inversion recovery [FLAIR] negative) is an option at expert stroke centers to determine eligibility for IVT. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Benefit with imaging selection of patients'.) Because the benefit is time-dependent, it is critical to treat eligible patients as quickly as possible. Alteplase, a recombinant tissue plasminogen activator (tPA), initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converting entrapped plasminogen to plasmin. In turn, plasmin breaks up the thrombus. The pivotal randomized trials that established the efficacy of intravenous thrombolytic therapy for acute stroke used alteplase as the thrombolytic agent. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Alteplase'.) Tenecteplase is a thrombolytic agent that is more fibrin-specific and has a longer duration of action compared with alteplase. Although not licensed in the United States for intravenous thrombolysis in acute ischemic stroke treatment, there is evidence that intravenous tenecteplase has similar efficacy and safety outcomes compared with alteplase. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Tenecteplase'.) Mechanical thrombectomy is indicated for patients with acute ischemic stroke due to a large artery occlusion in the anterior circulation who can be treated within 24 hours of the time last known to be well (ie, at neurologic baseline), regardless of whether they receive intravenous thrombolysis for the same ischemic stroke event. (See "Mechanical thrombectomy for acute ischemic stroke".) https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 2/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Eligible patients should receive intravenous thrombolysis without delay even if mechanical thrombectomy is being considered [1]. ADMINISTRATION OF THROMBOLYTIC THERAPY "Time is brain." The sooner intravenous thrombolysis is initiated after ischemic stroke, the more likely it is to be beneficial. The benefits and risks of thrombolytic therapy with alteplase or tenecteplase are discussed in detail separately (see "Approach to reperfusion therapy for acute ischemic stroke"). The selection of appropriate patients for such therapy is summarized in the table ( table 1). Preparing for treatment Prior to treatment, all patients require confirmation of the following: The diagnosis is acute ischemic stroke Treatment is commencing within the required 4.5-hour time window after the onset of symptoms, defined as the time last seen normal or at baseline There is a persistent, measurable, disabling neurologic deficit Eligibility criteria are met ( table 1) Serum glucose must be checked to rule out hypoglycemia as a cause of neurologic deficit The noncontrast head computed tomography (CT) or brain magnetic resonance imaging (MRI) is without hemorrhage or other contraindication Blood pressure parameters are met (see 'Management of blood pressure' below) Two intravenous lines, preferably large bore, are in place Accurate body weight has been determined [2] Management of blood pressure Strict blood pressure control is critical prior to and during the first 24 hours after thrombolytic therapy. The blood pressure must be at or below 185 mmHg systolic and 110 mmHg diastolic before administering thrombolysis. Patients with blood pressure above this range should be treated with intravenous agents such as intravenous labetalol or nicardipine, or clevidipine ( table 2) [1]. Alternative agents include hydralazine and enalaprilat. If intravenous treatment does not bring the blood pressure into the acceptable range, the patient should not be treated with thrombolysis because the risk of intracerebral hemorrhage with thrombolytic therapy may be increased. Once thrombolytic therapy has been administered, the blood pressure must be maintained below 180/105 mmHg during and for 24 hours following thrombolytic therapy ( table 2). https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 3/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Intravenous labetalol, nicardipine, or clevidipine are suggested agents of first choice [1]. Frequent blood pressure monitoring is recommended to ensure that the blood pressure remains in the acceptable range. Current guidelines recommend monitoring every 15 minutes for the first 2 hours after starting thrombolytic treatment, then every 30 minutes for the next 6 hours, then every hour until 24 hours after starting treatment. The frequency of blood pressure monitoring should be increased if the systolic blood pressure is >180 mmHg or if the diastolic blood pressure is >105 mmHg. For patients with stroke caused by a known large artery occlusion (documented by computed tomography angiography [CTA] or magnetic resonance angiography [MRA]), we suggest keeping systolic blood pressure between 150 to 180 mmHg prior to reperfusion, and targeting systolic blood pressure to <140 mmHg once reperfusion is achieved with intravenous thrombolysis or mechanical thrombectomy (see "Mechanical thrombectomy for acute ischemic stroke", section on 'Blood pressure management'). These recommendations regarding blood pressure control are based on consensus, since there are no data supporting the use of any specific antihypertensive agent or regimen for patients with acute ischemic stroke treated with thrombolysis. The optimal lower end of the range of desired blood pressure is unclear in those requiring antihypertensive treatment for thrombolysis. Maintaining the blood pressure below 180/105 mmHg for at least the first 24 hours after administration of thrombolytic therapy is the only guideline recommendation [1]. In this situation, there is still a risk of worsening blood flow within the ischemic penumbra if blood pressure is driven too low. Therefore, it is important to avoid excessive blood pressure lowering when using intravenous antihypertensive treatment. Despite concerns about reducing perfusion, more intensive blood pressure reduction might reduce the risk of symptomatic intracerebral hemorrhage and thereby improve outcomes. The blood pressure control assessment arm of the open-label, international ENCHANTED trial tested this strategy and found that a target blood pressure of 130 to 140 mmHg with intravenous thrombolytic therapy did not appear to be beneficial or harmful. The ENCHANTED trial enrolled over 2200 alteplase-eligible patients with acute ischemic stroke and randomly assigned them to intensive blood pressure lowering (to a target systolic blood pressure of 130 to 140 mmHg within one hour) or guideline blood pressure lowering (target <180 mmHg) over 72 hours [3]. The mean systolic blood pressure over 24 hours in the intensive and guideline groups was 144.3 mmHg and 149.8 mmHg, respectively. At 90 days, there was no difference in functional status between groups. Intracranial hemorrhage was less frequent in the intensive group compared with the guideline group (14.8 versus 18.7 percent), but there was no significant difference between groups in rates of symptomatic intracerebral hemorrhage or serious adverse events. https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 4/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Dosing Alteplase dose A dedicated intravenous line is required for alteplase, and all patients should have at least one additional large bore intravenous line. The alteplase dose is calculated at 0.9 mg/kg of actual body weight, with a maximum dose of 90 mg Ten percent of the dose is given as an intravenous bolus over one minute and the remainder is infused over one hour It is advisable to remove any excess alteplase from the bottle prior to administration, in order to avoid overdosage if the intravenous pump is inaccurately calibrated. In Japan, the approved dose of alteplase for acute ischemic stroke is 0.6 mg/kg, based upon the results of a small open-label study suggesting that this dose was associated with a lower risk of intracerebral hemorrhage and similar efficacy compared with the standard alteplase dose of 0.9 mg/kg [4]. However, in the ENCHANTED trial, which enrolled over 3300 subjects (63 percent Asian) with acute ischemic stroke, low-dose alteplase (0.6 mg/kg) did not meet noninferiority criteria compared with standard-dose alteplase (0.9 mg/kg) for the outcome of death and disability at 90 days [5]. Tenecteplase dose The dose of tenecteplase is 0.25 mg/kg (maximum total dose 25 mg) given in a single intravenous bolus over 5 seconds, followed by a saline flush [6,7]. Monitoring All patients treated with intravenous thrombolysis for acute ischemic stroke should be admitted to an intensive care unit or dedicated stroke unit for at least 24 hours of close neurologic and cardiac monitoring [1]. Symptomatic intracerebral hemorrhage should be suspected in any patient who develops sudden neurologic deterioration, a decline in level of consciousness, new headache, nausea and vomiting, or a sudden rise in blood pressure after thrombolytic therapy is administered, especially within the first 24 hours of treatment. (See 'Management of symptomatic intracerebral hemorrhage' below.) Important measures during the first 24 hours of treatment with thrombolytic therapy include the following [1]: Vital signs and neurologic status should be checked every 15 minutes for two hours, then every 30 minutes for six hours, then every 60 minutes until 24 hours from the start of thrombolysis. Blood pressure must be maintained at or below 180/105 mmHg during the first 24 hours. (See 'Management of blood pressure' above.) https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 5/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Antithrombotic agents, such as heparin, warfarin, direct oral anticoagulants, or antiplatelet drugs, should not be administered for at least 24 hours after the alteplase infusion or tenecteplase bolus is completed, unless their administration is absolutely necessary. Placement of intra-arterial catheters, indwelling bladder catheters, and nasogastric tubes should be avoided for at least 24 hours if the patient can be safely managed without them. A follow-up noncontrast CT (or MRI) brain scan should be obtained 24 hours after thrombolysis is initiated before starting treatment with antiplatelet or anticoagulant agents [1]. COMPLICATIONS The most feared complication of thrombolytic therapy is symptomatic intracerebral hemorrhage. Asymptomatic intracerebral hemorrhage, systemic bleeding, and angioedema are additional complications that may arise. Intracerebral hemorrhage Treatment with intravenous (IV) thrombolysis within 4.5 hours of acute ischemic stroke onset is associated with an increased early risk of intracerebral hemorrhage, which was in the range of 5 to 7 percent; lower rates have been observed using stricter definitions of symptomatic intracerebral hemorrhage. This risk is offset by later benefit in the form of reduced disability. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Alteplase' and "Approach to reperfusion therapy for acute ischemic stroke", section on 'Risk of intracerebral hemorrhage'.) Management of symptomatic intracerebral hemorrhage Symptomatic intracerebral hemorrhage should be suspected in any patient who develops sudden neurologic deterioration, a decline in level of consciousness, new headache, nausea and vomiting, or a sudden rise in blood pressure after thrombolytic therapy is administered, especially within the first 24 hours of treatment. In patients with suspected intracerebral hemorrhage, the alteplase infusion should be discontinued and a stat noncontrast head computed tomography (CT) or magnetic resonance imaging (MRI) scan should be arranged ( table 3) [1]. Blood should be drawn for typing and cross matching, and measurement of prothrombin time, activated partial thromboplastin time, platelet count, and fibrinogen. Treatment options for intracerebral hemorrhage related to intravenous thrombolytic treatment are unproven but include the administration of agents to reverse the effects of thrombolytic therapy and antithrombotic therapy [1,8-13]: https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 6/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Cryoprecipitate, 10 units immediately (infused over 10 to 30 minutes) and more as needed to achieve a serum fibrinogen level of 150 to 200 mg/dL Antifibrinolytic agents: aminocaproic acid 4 to 5 g IV during first hour, followed by 1 g/hour for 8 hours until bleeding is controlled, or tranexamic acid 10 to 15 mg/kg IV over 10 to 20 minutes Prothrombin complex concentrate as adjunctive therapy to cryoprecipitate for patients on warfarin prior to thrombolytic treatment Fresh frozen plasma as adjunctive therapy to cryoprecipitate for patients on warfarin prior to thrombolytic treatment if prothrombin complex concentrate is not available Vitamin K as adjunctive therapy for patients on warfarin prior to thrombolytic treatment Six to eight units of platelets for patients with thrombocytopenia (platelet count <100,000/microL) In patients receiving unfractionated heparin (UFH) for any reason, it is reasonable to treat with 1 mg of protamine for every 100 units of UFH given in the preceding 4 hours Urgent neurosurgery and hematology consultations are indicated for patients with symptomatic intracranial hemorrhage associated with thrombolysis [1]. Supportive therapy includes management of blood pressure, intracranial pressure, cerebral perfusion pressure, and glucose control. The efficacy of neurosurgical evacuation in this setting is unproven. However, in a retrospective analysis of data from the GUSTO-I trial of thrombolysis for myocardial infarction, 30-day survival was significantly higher with neurosurgical hematoma evacuation than without (65 versus 35 percent), and there was a trend towards improved functional outcome due to a higher incidence of nondisabling stroke in those with evacuation compared with those without (20 versus 12 percent) [14]. However, no definitive conclusions can be drawn from this retrospective, nonrandomized study. Systemic bleeding Mild systemic bleeding usually occurs in the form of oozing from intravenous catheter sites, ecchymoses (especially under automated blood pressure cuffs), and gum bleeding; these complications do not require cessation of treatment. More serious bleeding, such as from the gastrointestinal or genitourinary system, may require discontinuation of alteplase depending on the severity. Rarely, patients who suffer stroke after a recent myocardial infarction can develop bleeding into the pericardium, resulting in life-threatening tamponade [15,16]. Consequently, patients who become hypotensive after thrombolytic therapy should be evaluated with urgent echocardiography. https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 7/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Angioedema Orolingual angioedema occurs in 1 to 8 percent of patients treated with alteplase or tenecteplase for ischemic stroke [17-20], and it is typically mild, transient, and contralateral to the ischemic hemisphere [18,21]. Patients taking angiotensin converting enzyme inhibitors and those with CT evidence of ischemia in the frontal and insular cortex may be at increased risk. Severe orolingual angioedema is rare but may cause partial airway obstruction and require emergent airway management [1,18,21,22]. CT of the tongue can distinguish hematoma from angioedema in this setting [23]. The patient with angioedema near or involving the tongue, uvula, soft palate, or larynx must be immediately assessed for signs of airway compromise. If intubation is necessary, the airway should be managed by the most experienced person available, because intubation in the presence of laryngeal angioedema can be difficult due to distortion of the normal anatomy. Angioedema of the lips or mouth sometimes spreads to involve the throat, and frequent monitoring of airway patency is critical throughout treatment. (See "An overview of angioedema: Clinical features, diagnosis, and management".) Treating centers should be aware of the potential need for stopping the drug infusion, administering antihistamines and glucocorticoids, and intubating patients who develop stridor. Specific management recommendations for orolingual angioedema include the following [1]: Maintain airway: Endotracheal intubation may not be necessary if edema is limited to anterior tongue and lips. Edema involving larynx, palate, floor of mouth, or oropharynx with rapid progression (within 30 minutes) poses higher risk of requiring intubation. Awake fiberoptic intubation is optimal. Nasotracheal intubation may be necessary but is associated with a risk of epistaxis after treatment with IV thrombolysis. Emergency cricothyrotomy is rarely needed and is also problematic after IV thrombolysis treatment, but in a life-threatening circumstance the need to establish an airway supersedes this concern. (See "Approach to the difficult airway in adults for emergency medicine and critical care" and "The difficult pediatric airway for emergency medicine".) Discontinue alteplase infusion and hold angiotensin converting enzyme inhibitor Give in rapid sequence: IV methylprednisolone 125 mg https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 8/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate IV diphenhydramine 50 mg IV famotidine 20 mg If there is further increase in angioedema, give epinephrine (0.1 percent) 0.3 mL subcutaneously or 0.5 mL by nebulizer, but note that epinephrine has a theoretical risk of blood pressure elevation and hemorrhage Additional treatment options for refractory angioedema include icatibant and plasma-derived C1 inhibitor concentrate, which have been used to treat hereditary angioedema and angiotensin converting enzyme inhibitor-related angioedema [1]. (See "ACE inhibitor-induced angioedema", section on 'Therapies of unproven efficacy'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Ischemic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 9/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Time is brain Intravenous thrombolysis is the mainstay of treatment for acute ischemic stroke, provided that treatment is initiated within 4.5 hours of clearly defined symptom onset. Because the benefit of is time-dependent, it is critical to treat patients as quickly as possible. (See 'Overview of therapy' above.) Patient selection Prior to treatment, eligibility should be confirmed ( table 1), two intravenous lines, preferably large bore, should be placed, and accurate body weight determined. (See 'Preparing for treatment' above.) Blood pressure management Strict blood pressure control is critical prior to and during the first 24 hours after thrombolytic therapy. The blood pressure must be at or below 185/110 mmHg before starting treatment. The blood pressure must be maintained at or below 180/105 mmHg for 24 hours following thrombolytic treatment ( table 2). (See 'Management of blood pressure' above.) Dosing The alteplase dose is calculated at 0.9 mg/kg of actual body weight, with a maximum dose of 90 mg. Ten percent of the dose is given as an intravenous bolus over one minute and the remainder is infused over one hour. In Japan, however, the approved dose of alteplase for acute ischemic stroke is 0.6 mg/kg. The tenecteplase dose is 0.25 mg/kg (maximum total dose 25 mg) given in a single intravenous bolus over 5 seconds, followed by a saline flush. (See 'Dosing' above.) No antithrombotics for 24 hours Treatment with anticoagulant or antiplatelet agents should not be started within the first 24 hours of thrombolytic therapy in patients with acute ischemic stroke. Antiplatelet therapy should be started for most patients 24 to 48 hours after thrombolytic therapy. (See 'Monitoring' above and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) Adverse effects The most feared complication of thrombolytic therapy is symptomatic intracerebral hemorrhage. Asymptomatic intracerebral hemorrhage, systemic bleeding, and angioedema are additional complications that may arise. (See 'Complications' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 10/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. 2. Michaels AD, Spinler SA, Leeper B, et al. Medication errors in acute cardiovascular and stroke patients: a scientific statement from the American Heart Association. Circulation 2010; 121:1664. 3. Anderson CS, Huang Y, Lindley RI, et al. Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial. Lancet 2019; 393:877. 4. Yamaguchi T, Mori E, Minematsu K, et al. Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT). Stroke 2006; 37:1810. 5. Anderson CS, Robinson T, Lindley RI, et al. Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. N Engl J Med 2016; 374:2313. 6. Campbell BCV, Mitchell PJ, Churilov L, et al. Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial. JAMA 2020; 323:1257. 7. Mitchell PJ, Yan B, Churilov L, et al. Endovascular thrombectomy versus standard bridging thrombolytic with endovascular thrombectomy within 4 5 h of stroke onset: an open-label, blinded-endpoint, randomised non-inferiority trial. Lancet 2022; 400:116. 8. Yaghi S, Eisenberger A, Willey JZ. Symptomatic intracerebral hemorrhage in acute ischemic stroke after thrombolysis with intravenous recombinant tissue plasminogen activator: a review of natural history and treatment. JAMA Neurol 2014; 71:1181. 9. Yaghi S, Boehme AK, Dibu J, et al. Treatment and Outcome of Thrombolysis-Related Hemorrhage: A Multicenter Retrospective Study. JAMA Neurol 2015; 72:1451. 10. French KF, White J, Hoesch RE. Treatment of intracerebral hemorrhage with tranexamic acid after thrombolysis with tissue plasminogen activator. Neurocrit Care 2012; 17:107. 11. Yaghi S, Willey JZ, Cucchiara B, et al. Treatment and Outcome of Hemorrhagic Transformation After Intravenous Alteplase in Acute Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2017; 48:e343. 12. Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 2016; 24:6. 13. O'Carroll CB, Aguilar MI. Management of Postthrombolysis Hemorrhagic and Orolingual Angioedema Complications. Neurohospitalist 2015; 5:133. https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 11/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate 14. Mahaffey KW, Granger CB, Sloan MA, et al. Neurosurgical evacuation of intracranial hemorrhage after thrombolytic therapy for acute myocardial infarction: experience from the GUSTO-I trial. Global Utilization of Streptokinase and tissue-plasminogen activator (tPA) for Occluded Coronary Arteries. Am Heart J 1999; 138:493. 15. Kasner SE, Villar-Cordova CE, Tong D, Grotta JC. Hemopericardium and cardiac tamponade after thrombolysis for acute ischemic stroke. Neurology 1998; 50:1857. 16. Marto JP, Kauppila LA, Jorge C, et al. Intravenous Thrombolysis for Acute Ischemic Stroke After Recent Myocardial Infarction: Case Series and Systematic Review. Stroke 2019; 50:2813. 17. Hill MD, Buchan AM, Canadian Alteplase for Stroke Effectiveness Study (CASES) Investigators. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study. CMAJ 2005; 172:1307. 18. Hurford R, Rezvani S, Kreimei M, et al. Incidence, predictors and clinical characteristics of orolingual angio-oedema complicating thrombolysis with tissue plasminogen activator for ischaemic stroke. J Neurol Neurosurg Psychiatry 2015; 86:520. 19. Myslimi F, Caparros F, Dequatre-Ponchelle N, et al. Orolingual Angioedema During or After Thrombolysis for Cerebral Ischemia. Stroke 2016; 47:1825. 20. Zhong CS, Beharry J, Salazar D, et al. Routine Use of Tenecteplase for Thrombolysis in Acute Ischemic Stroke. Stroke 2021; 52:1087. 21. Hill MD, Lye T, Moss H, et al. Hemi-orolingual angioedema and ACE inhibition after alteplase treatment of stroke. Neurology 2003; 60:1525. 22. Chodirker WB. Reactions to alteplase in patients with acute thrombotic stroke. CMAJ 2000; 163:387. 23. Engelter ST, Fluri F, Buitrago-T llez C, et al. Life-threatening orolingual angioedema during thrombolysis in acute ischemic stroke. J Neurol 2005; 252:1167. Topic 16134 Version 61.0 https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 12/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate GRAPHICS Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 13/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 14/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 15/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Options to treat hypertension before and during reperfusion therapy for acu te ischemic stroke Patient otherwise eligible for acute reperfusion therapy except that blood pressure is >185/110 mmHg* Labetalol 10 to 20 mg intravenously over 1 to 2 minutes, may repeat one time; or Nicardipine 5 mg/hour intravenously, titrate up by 2.5 mg/hour every 5 to 15 minutes, maximum 15 mg/hour; when desired blood pressure reached, adjust to maintain proper blood pressure limits; or Clevidipine 1 to 2 mg/hour intravenously, titrate by doubling the dose every 2 to 5 minutes, maximum 21 mg/hour, until desired blood pressure reached ; or
Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 13/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 14/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 15/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Options to treat hypertension before and during reperfusion therapy for acu te ischemic stroke Patient otherwise eligible for acute reperfusion therapy except that blood pressure is >185/110 mmHg* Labetalol 10 to 20 mg intravenously over 1 to 2 minutes, may repeat one time; or Nicardipine 5 mg/hour intravenously, titrate up by 2.5 mg/hour every 5 to 15 minutes, maximum 15 mg/hour; when desired blood pressure reached, adjust to maintain proper blood pressure limits; or Clevidipine 1 to 2 mg/hour intravenously, titrate by doubling the dose every 2 to 5 minutes, maximum 21 mg/hour, until desired blood pressure reached ; or Other agents (hydralazine, enalaprilat, etc) may also be considered If blood pressure is not maintained at or below 185/110 mmHg, do not administer alteplase Management to maintain blood pressure at or below 180/105 mmHg during and after acute reperfusion therapy* Monitor blood pressure every 15 minutes for 2 hours from the start of rtPA therapy, then every 30 minutes for 6 hours, and then every hour for 16 hours If systolic blood pressure is >180 to 230 mmHg or diastolic is >105 to 120 mmHg: Labetalol 10 mg intravenously followed by continuous infusion 2 to 8 mg/min; or Nicardipine 5 mg/hour intravenously, titrate up to desired effect by 2.5 mg/hour every 5 to 15 minutes, maximum 15 mg/hour; or Clevidipine 1 to 2 mg/hour intravenously, titrate by doubling the dose every 2 to 5 minutes, maximum 21 mg/hour, until desired blood pressure reached If blood pressure is not controlled or diastolic blood pressure >140 mmHg, consider intravenous sodium nitroprusside Different treatment options may be appropriate in patients who have comorbid conditions that may benefit from acute reductions in blood pressure, such as acute coronary event, acute heart failure, aortic dissection, or preeclampsia/eclampsia. Clevidipine has been included as part of the 2018 guidelines for the early management of patients with acute ischemic stroke [1] . Reference: 1. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2018; 49:e46. Adapted with permission. Stroke. 2013: 44:870-947. Copyright 2013 American Heart Association, Inc. https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 16/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Graphic 50725 Version 15.0 https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 17/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Management of intracerebral hemorrhage after thrombolysis for ischemic stroke 1. Consider bleeding the likely cause of neurologic worsening after use of a thrombolytic drug until a brain scan confirms or refutes hemorrhage 2. Immediately discontinue ongoing infusion of thrombolytic drug 3. Obtain stat noncontrast head CT or MRI 4. Obtain blood samples for type and cross match, complete blood count, platelet count, PT, INR, aPTT, and fibrinogen 5. If symptomatic intracerebral hemorrhage is confirmed by imaging: Give cryoprecipitate 10 units infused over 10 to 30 minutes and more as needed to achieve a serum fibrinogen level of 150 to 200 mg/dL Consider aminocaproic acid 4 to 5 g IV over one hour followed by 1 g/hour for 8 hours until bleeding is controlled, or tranexamic acid 10 to 15 mg/kg IV over 10 to 20 minutes For patients on warfarin therapy prior to alteplase treatment, consider vitamin K and PCC as adjunctive therapy to cryoprecipitate, or FFP if PCC is not available For patients with thrombocytopenia (platelet count <100,000/microL), give 6 to 8 units of platelets For patients receiving unfractionated heparin for any reason, give 1 mg of protamine for every 100 units of UFH received in the preceding four hours 6. Obtain neurosurgery and hematology consultations; consider evacuation of the hematoma CT: computed tomography; MRI: magnetic resonance imaging; PT: prothrombin time; INR: international normalized ratio; aPTT: activated partial thromboplastin time; IV: intravenous; PCC: prothrombin complex concentrate; FFP: fresh frozen plasma; UFH: unfractionated heparin. Graphic 68717 Version 7.0 https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 18/19 7/6/23, 11:59 AM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Contributor Disclosures Jamary Oliveira-Filho, MD, MS, PhD No relevant financial relationship(s) with ineligible companies to disclose. Owen B Samuels, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 19/19
7/6/23, 12:00 PM Lacunar infarcts - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Lacunar infarcts : Jamary Oliveira-Filho, MD, MS, PhD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 20, 2022. INTRODUCTION AND DEFINITION Lacunar infarcts are small (2 to 15 mm in diameter) noncortical infarcts caused by occlusion of a single penetrating branch of a large cerebral artery [1,2]. These branches arise at acute angles from the large arteries of the circle of Willis, stem of the middle cerebral artery (MCA), or the basilar artery. Although this definition implies that pathological confirmation is necessary, diagnosis in vivo may be made in the setting of appropriate clinical syndromes and radiological tests. Not all small deep infarcts are lacunar, and the diagnosis of lacunar infarction also requires the exclusion of other etiologies of ischemic stroke. Note that the pathology studies that defined lacunar infarcts were performed in the chronic phase of stroke [1]; some neuroimaging studies in the acute phase (<10 days from stroke onset) have used 20 mm as the upper size limit for lacunes, since some volume reduction is expected over time. (See 'Imaging confirmation' below.) HISTORY Dechambre first used the term "lacune" in 1838 to describe softenings in subcortical regions of the brain found on autopsy [3]. At the time, there was dispute regarding whether these lacunes were caused by encephalitis, a late phase of a small hemorrhage, or ischemic necrosis. Marie in 1901 first described a clinical syndrome associated with multiple lacunes, characterized by sudden hemiplegia with good recovery, a characteristic gait with small steps ("marche a petits pas de Dejerine"), pseudobulbar palsy, and dementia [4]. https://www.uptodate.com/contents/lacunar-infarcts/print 1/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate In the 1960s, careful clinicopathological correlations by Fisher generated the so-called "lacunar hypothesis," which suggested that lacunes are due to a chronic vasculopathy related to systemic hypertension, cause a variety of defined clinical syndromes, and imply a generally good prognosis [5]. The introduction of computed tomography (CT) and magnetic resonance imaging (MRI) has generated data that both supports and opposes the lacunar theory [6,7]. Some authors have suggested abandoning the concept altogether [8,9]. Detractors of the lacunar hypothesis note the lack of animal data or an animal model of lacunar infarction and the demonstration of embolic sources from the heart, aorta, or large arteries in a substantial percentage of lacunar strokes [10,11]. Proponents concede that some small number of lacunes may result from emboli, but they point out that the proportion of embolic sources found in association with lacunar syndromes is far lower than for other ischemic stroke types and that there are clear clinical and epidemiologic reasons to separate lacunes from other ischemic stroke subtypes [11,12]. One of the major difficulties in interpreting these data stems from the inability of imaging techniques to show that an infarct was due to occlusion of a single penetrating artery. Furthermore, various studies have used different sets of criteria to define "lacunar infarcts" and the many lacunar syndromes [13,14]. However, continuing publications on the subject have demonstrated that the term "lacune" is clinically useful and has gained wide acceptance in the literature. VASCULAR ANATOMY Most lacunes occur in the basal ganglia (putamen, globus pallidus, caudate), thalamus, subcortical white matter (internal capsule and corona radiata), and pons [5,15,16]. These locations correspond to vascular territories of the lenticulostriate branches from the anterior and middle cerebral arteries, the recurrent artery of Heubner from the anterior cerebral artery, the anterior choroidal artery from the distal internal carotid artery, thalamoperforant branches from the posterior cerebral artery, and paramedian branches from the basilar artery ( figure 1) [17,18]. These small branches originate directly from large arteries, making them particularly vulnerable to the effects of hypertension, probably explaining this peculiar distribution. A study using fluorescent and radiopaque dye injection techniques has demonstrated that penetrating vessels supply distinct microvascular territories of the basal ganglia, with minimal overlap and sparse anastomoses between the penetrating vessels [18]. The ultimately terminal https://www.uptodate.com/contents/lacunar-infarcts/print 2/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate rather than anastomotic nature of these vessels is another factor explaining the predisposition of this region to lacunar infarction. ETIOLOGY Several mechanisms for small vessel disease and lacunar infarction have been described, primarily hypertension-related microangiopathy, microatheroma of the origin of the penetrating arteries, embolism, and endothelial dysfunction with disruption of the associated blood-brain barrier [1,2,19-22]. The first two mechanisms are proven pathologically [1], and generally regarded as a consequence of systemic hypertension. A systematic review of 19 cohort studies involving 5864 patients with ischemic stroke found that those who had a lacunar infarct as the index event were more likely to have lacunar than nonlacunar stroke recurrence, lending some support to the notion that lacunar strokes represent a different form of arteriopathy than other ischemic stroke subtypes [23]. Other mechanisms have been proposed to account for lacunar infarcts, but none are pathologically proven. Hypertensive microangiopathy Hypertensive microangiopathy is considered the usual cause of lacunar infarcts. Uncontrolled hypertension leads to arteriolar wall thickening and narrowing of the lumen of the small penetrating arteries due to arteriolosclerosis and related pathologies including lipohyalinosis, fibrinoid necrosis, and segmental arterial disorganization, sometimes accompanied by microaneurysm formation [1,21,24]. The pathology of lacunar infarcts may be changing as the medical management of hypertension becomes more effective [25]. A decline in the number of lacunes per patient in comparable pathology series was attributed to the introduction of antihypertensive therapy [1]. A later neuropathology study in lacunar infarcts found only 69 percent of patients with evidence of systemic hypertension and rare cases of classic lipohyalinosis [25], further suggesting that modern antihypertensive therapy may have changed the natural history and/or pathophysiology of lacunes. Branch atheromatous disease Microatheroma of the origin of the penetrating arteries coming off the middle cerebral artery stem, circle of Willis, or distal basilar or vertebral arteries is another mechanism of lacunar infarction, and has been termed branch atheromatous disease [19]. This mechanism has been proven pathologically by serial section for the basilar artery [26]. In a retrospective study, lacunar infarcts in the territory of a single perforating branch artery of the middle cerebral artery (MCA) were found significantly more often in association with atherosclerotic MCA occlusive disease than with https://www.uptodate.com/contents/lacunar-infarcts/print 3/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate internal carotid occlusive disease or cardiac embolism [27]. This observation supports the hypothesis that some lacunar strokes are caused by parent artery (eg, MCA or basilar artery) atheroma that occludes the origin of the penetrating artery [28]. Embolism The potential for embolism to cause lacunar infarcts is supported both experimentally [29] and by case reports of lacunes in patients with high-risk cardiac sources for emboli [30] and reports of lacunar infarcts following cardiac and arch angiography [31]. Studies investigating possible stroke mechanisms in lacunar infarcts have found carotid stenosis in 13 to 23 percent [32,33] and cardiac sources in 18 to 24 percent [33,34] of patients with a radiologically-demonstrated lacunes. These rates are much lower than those of patients with cortical infarcts [32,35] and may be similar to asymptomatic elderly populations, making the argument of a causal relationship between the verified sources and the lacunes difficult to prove. It also appears that patients with lacunar infarcts more often have milder degrees of carotid stenosis than those with cortical infarcts [36]. On the other hand, ipsilateral carotid stenosis appears to be more common than contralateral stenosis, which supports a possible causal relationship [37]. In some reports, multiple acute to subacute subcortical or small cortical infarcts have been detected by diffusion-weighted magnetic resonance imaging (DWI), suggesting an embolic source. One study using DWI in patients presenting with a lacunar syndrome found that 16 percent had multiple infarcts detected as DWI-hyperintense lesions, implying that all lesions were acute to subacute ( image 1) [38]. This subgroup more frequently harbored a proximal embolic source than patients with single lesions (p <0.05). Endothelial dysfunction and disruption of the blood-brain barrier One alternate explanation is that failure of the arteriolar and capillary endothelium and the blood-brain barrier leads to small vessel disease, lacunar stroke, and white matter lesions [20,39-42]. This failure allows extravasation of blood components into the vessel wall, which results in perivascular edema and damage to the vessel wall, perivascular neurons, and glia [43,44]. This theory remains unconfirmed. One neuropathologic study found no compelling evidence of a specific cerebral endothelial response in patients with small vessel disease [45]. However, a preliminary study using 3 Tesla MRI identified focal clusters, thought to be disorganized small vessels, in the white matter of patients with severe small vessel disease [46]. These clusters were visualized on susceptibility-weighted imaging (SWI), which can identify deoxygenated blood; they corresponded to white matter hyperintensities in various stages of cavity formation seen on fluid-attenuated inversion recovery (FLAIR) MRI. The clusters were associated with the number of lacunes and higher white matter https://www.uptodate.com/contents/lacunar-infarcts/print 4/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate hyperintensity volume. The investigators proposed that the vessel clusters represent dysfunctional and dilated small vessels. EPIDEMIOLOGY Lacunar infarcts account for 15 to 26 percent of ischemic stroke [32,47-50]. Like other stroke subtypes, the prevalence of lacunar stroke increases with age. Limited data suggest that the incidence of lacunar strokes is higher in Black Americans compared with White Americans [49]. No significant differences by sex have been observed [51]. One group estimated that 18 percent of first ischemic strokes in the United States are lacunes [48]. This compares with 16 percent due to large vessel atherosclerosis with stenosis, 26 percent cardioembolic, 3 percent due to an uncommon mechanism, and 37 percent of unknown or no obvious cause. A population-based study from Japan suggests that the incidence of lacunar stroke has been steadily declining since the 1960s [52]. This finding was attributed to improved control of hypertension and decreased prevalence of smoking during subsequent years. RISK FACTORS AND ASSOCIATIONS The main risk factor and mechanism for lacunar stroke is related to a chronic vasculopathy associated with systemic hypertension. (See 'Etiology' above.) Other possible risk factors for lacunar infarction include diabetes mellitus, smoking, age, and low-density lipoprotein (LDL) cholesterol [53]. Hyperhomocysteinemia has been associated with an increased risk of ischemic stroke and lacunar infarction in several studies [54-56]. (See "Overview of homocysteine".) Hypertension and diabetes Hypertension and diabetes mellitus are associated with an increased risk of stroke in general. Whether they are more commonly associated with lacunar stroke and small vessel disease compared with other stroke subtypes (as many believe) is not clear, since the evidence is conflicting [48,57-61]. The answer may depend upon the population studied and the criteria used to define lacunar-type infarction. One explanation for the difference in lacunar stroke incidence rates between White and Black Americans cited above (see 'Epidemiology' above) is a higher incidence of risk factors such as diabetes and hypertension among Black Americans [49]. In the community-based study of Black https://www.uptodate.com/contents/lacunar-infarcts/print 5/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Americans in Cincinnati, Ohio, the odds ratios of first-ever lacunar infarct among patients with diabetes or hypertension were 4.4 and 5.0, respectively, compared with nondiabetic and normotensive individuals [49]. The attributable risk (proportion of cases that can be attributed to the risk factor) for these two diseases were 30 and 68 percent, respectively (hypertension has a greater impact than diabetes because of its higher overall prevalence in the population). The rates of hypertension and current smoking were found to be significantly increased in patients with lacunar infarcts compared with other stroke subtypes. Other studies have also found a difference in the incidence of risk factors between patients with lacunar stroke and those with other stroke subtypes. In the Stroke Data Bank, patients with lacunar stroke had fewer previous transient ischemic attacks (TIAs) and strokes than those with large vessel atherosclerotic infarction and, compared with patients who had cardioembolic strokes, those with lacunar infarcts more frequently had hypertension and diabetes [32]. These findings contrast with some other community-based studies [48,60]. As an example, in the Oxfordshire Community Stroke Project, a study of first-ever stroke, comparison between the risk factor profiles of patients with lacunar infarction and carotid artery distribution infarct involving the cortex found that the two groups did not differ in the prevalence of prestroke hypertension or markers of sustained hypertension, or in the prevalence of other risk factors for ischemic stroke such as diabetes mellitus, previous TIA, cervical bruit, peripheral vascular disease, or cigarette smoking [60]. Similarly, the Rochester, Minnesota study found no greater incidence of diabetes and hypertension among patients with lacunar infarcts and those with other stroke subtypes [48]. Genetic factors The heritability of small vessel ischemic stroke is estimated to be 16 to 25 percent [62,63]. A 2021 pooled analysis of individual patient data and genome-wide association studies reported 12 loci that were associated with lacunar stroke; five of these loci were directly associated with lacunar stroke, and seven were associated jointly with lacunar stroke and white matter hyperintensities, including two loci (COL4A2 and HTRA1) that are linked to monogenic small vessel stroke [64]. Further study is needed to identify and verify the genetic mechanisms related to lacunar stroke. Several rare conditions are characterized by hereditary cerebral small vessel arteriopathy [65]: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This is probably the most common monogenic cause of cerebral small vessel disease [51]. (See "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)".) https://www.uptodate.com/contents/lacunar-infarcts/print 6/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Familial cerebral amyloid angiopathy (CAA), an important cause of primary lobar intracerebral hemorrhage in older adults, characterized by the deposition of congophilic material in small to medium-sized blood vessels of the brain and leptomeninges. (See "Cerebral amyloid angiopathy".) Autosomal dominant retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), which is due to pathogenic variants in the TREX1 gene. The major clinical manifestations are retinopathy, focal neurological symptoms including ischemic events, and cognitive impairment. Other symptoms include liver disease, kidney disease, anemia, gastrointestinal bleeding, subclinical hypothyroidism, Raynaud phenomenon, migraine with and without aura, and hypertension. (See "Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S)".) Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) due to HTRA1 pathogenic variants [66,67]. Several heterozygous HTRA1 pathogenic variants also cause symptomatic small vessel disease, with a milder clinical course compared with CARASIL [68,69]. Cathepsin A related arteriopathy with strokes and leukoencephalopathy (CARASAL), an autosomal dominant, adult-onset disorder caused by a pathogenic variant in the CTSA gene [70]. Brain small vessel disease with hemorrhage [71-74]. While all of these conditions affect small vessels and may theoretically manifest as a classic lacunar syndrome, CADASIL is most likely to do so. (See "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)", section on 'Ischemic stroke and transient ischemic attacks'.) CLINICAL FEATURES Lacunar syndromes The five classic lacunar syndromes, which may present as transient ischemic attacks (TIAs) in addition to stroke, are named according to their clinical manifestations: Pure motor hemiparesis Pure sensory stroke Ataxic hemiparesis Sensorimotor stroke https://www.uptodate.com/contents/lacunar-infarcts/print 7/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Dysarthria-clumsy hand syndrome Other stroke syndromes that may be related to lacunar infarcts, sometimes referred to as atypical lacunar syndromes, are shown in the table ( table 1), but these have not been studied in large clinical series [75]. Absence of cortical signs Due to their subcortical location in the brain, lacunar syndromes generally lack cortical symptoms and signs, such as aphasia, hemianopia, agnosia, neglect, or apraxia. Infarcts in several different subcortical locations can cause the clinical manifestations associated with each of these classic lacunar syndromes, as shown in the table ( table 2). Time course Penetrating artery occlusions usually cause symptoms that develop over a short period of time, typically minutes to hours ( figure 2), in some cases preceded by TIAs with the same symptoms. With lacunar stroke, a stuttering course may ensue, as with large artery thrombosis, and symptoms sometimes evolve over several days. In fact, lacunar infarction is the main ischemic stroke subtype associated with worsening motor deficits after hospital admission [76]. The classic lacunar syndromes are reviewed in the sections that follow. The syndrome of multiple subcortical infarcts is also discussed since interest has arisen regarding whether this entity can cause dementia. Pure motor hemiparesis Pure motor hemiparesis is the most frequent syndrome in most clinical series, accounting for 45 to 57 percent of all lacunar syndromes [32,77-80]. It is characterized by weakness involving the face, arm, and leg on one side of the body in the absence of "cortical" signs (aphasia, agnosia, neglect, apraxia, or hemianopsia) or sensory deficit. The motor deficit may develop as a single event or, less frequently, be preceded by hemiplegic TIAs [1]. A series of the latter cases has been described as the "capsular warning syndrome," which was found to be predictive of an acute internal capsule infarct on head CT [81]. Some of these cases may arise due to penetrating branch ischemia from a diseased parent vessel (middle cerebral artery [MCA] stem or basilar) causing intermittent and fluctuating symptoms. Pure sensory stroke Pure sensory stroke is defined as numbness of the face, arm, and leg on one side of the body in the absence of motor deficit or cortical signs [82]. It is found in 7 to 18 percent of lacunar syndromes in case series [32,77,79,80], but its prevalence is probably underestimated because many cases present as TIA and were not included in the series. https://www.uptodate.com/contents/lacunar-infarcts/print 8/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Ataxic hemiparesis Ataxic hemiparesis is responsible for 3 to 18 percent of lacunar syndromes in case series [32,77,79,80,83]. Patients characteristically develop ipsilateral weakness and limb ataxia that is out of proportion to the motor deficit. Some patients may exhibit dysarthria, nystagmus, and gait deviation towards the affected side. As with other lacunar syndromes, the above-mentioned cortical signs are absent. Sensorimotor stroke Sensorimotor stroke is characterized by weakness and numbness of the face, arm, and leg on one side of the body in the absence of the aforementioned cortical signs [84]. It is responsible for 15 to 20 percent of lacunar syndromes [32,77,79,80]. Sensorimotor strokes arise from infarcts involving the posterolateral thalamus and posterior limb of the internal capsule. The exact vascular anatomy is debated. Theoretically, penetrating arteries from the posterior cerebral artery (PCA) supply the thalamus and the internal capsule is supplied from the lenticulostriate branches of the MCA. Occlusion of a single penetrating artery involving both arterial territories is difficult to implicate; the site of vascular occlusion was not identified in the original case description [84]. Dysarthria-clumsy hand syndrome Dysarthria-clumsy hand syndrome is the least common of all lacunar syndromes in most case series, accounting for 2 to 6 percent of lacunar syndromes [32,77,79,80,85]. Facial weakness, dysarthria, dysphagia, and slight weakness and clumsiness of one hand are characteristic. There are no sensory deficits or cortical signs. Multiple subcortical infarcts and dementia Patients with arteriolosclerotic cerebral small vessel disease may develop multiple lacunes and/or extensive, confluent white matter lesions. leading to vascular dementia. Vascular dementia is reviewed in detail elsewhere. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia".) EVALUATION AND DIAGNOSIS Acute identification of lacunar syndromes is important in choosing among treatment modalities and predicting clinical outcome. Rapid evaluation All adult patients with a suspected diagnosis of acute ischemic stroke should be screened for treatment with intravenous thrombolytic therapy. Simultaneously, patients with suspected acute ischemic stroke involving the anterior circulation should be rapidly screened for treatment with mechanical thrombectomy. Urgent neuroimaging is a critical component of the rapid evaluation for reperfusion thrombolysis and mechanical thrombectomy. Vascular imaging (with computed tomography angiography [CTA] or magnetic resonance angiography [MRA]) can be performed at the same time as brain imaging (with CT or MRI) to https://www.uptodate.com/contents/lacunar-infarcts/print 9/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate evaluate patients for these therapies, as discussed in detail separately. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Rapid evaluation'.) By definition, patients with confirmed lacunar infarction are not candidates for mechanical thrombectomy since they do not have an amenable large artery occlusion as the cause of the stroke. However, small deep infarcts are not always lacunar infarctions and, therefore, vascular imaging is warranted in the acute setting. Notably, some patients presenting with a small deep infarct have concomitant large artery occlusive disease on imaging; this has been particularly true for patients of Asian origin [86]. Standard evaluation We perform a standard evaluation of all patients with suspected acute stroke, since a minority of lacunar stroke cases will be associated with a potential cardiac or large artery source of embolism, which may require different management strategies. The standard evaluation (covering anything not already performed as part of a rapid evaluation) includes a complete history and physical examination, brain imaging with CT or MRI to determine the location and topography of the lesion, neurovascular imaging with CTA or MRA to evaluate for large artery source of stroke, and cardiac monitoring and echocardiography to look for potential cardiogenic source of embolism. More extensive investigation of potential embolic sources may be necessary in young patients with no cerebral risk factors. The evaluation of acute stroke mechanisms is discussed in more detail separately. (See "Initial assessment and management of acute stroke" and "Overview of the evaluation of stroke".) Clinical diagnosis The diagnosis of lacunar infarction is suspected in patients who present with a recognized lacunar syndrome (eg, pure motor hemiparesis, pure sensory stroke, ataxic hemiparesis, sensorimotor stroke, dysarthria-clumsy hand syndrome) or other acute stroke symptoms without cortical involvement ( table 2 and table 1). As a general rule, lacunar syndromes lack findings such as aphasia, agnosia, neglect, apraxia, or hemianopsia (so-called "cortical" signs). Monoplegia, stupor, coma, loss of consciousness, and seizures also are typically absent. (See 'Clinical features' above.) Lacunar syndrome recognition in the hyperacute setting may not reflect a final diagnosis of lacunar infarction. A study of patients admitted within six hours of stroke symptom onset reported only a 30 percent positive predictive value for lacunar infarction by CT scan [87]. Unlike our ability to visualize large vessel occlusion by vascular imaging with conventional angiography and CTA or MRA, there is no clinically available imaging method to visualize small vessel occlusion, as the penetrating vessels responsible for lacunar infarction are not large enough to be seen on angiography. Thus, the radiologic diagnosis of lacunar infarction relies upon finding a small noncortical infarct on CT or MRI whose location is consistent with the https://www.uptodate.com/contents/lacunar-infarcts/print 10/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate clinical lacunar syndrome defined by history and examination. In some cases, neuroimaging may not identify the culprit lacunar infarction, and the diagnosis is made on purely clinical grounds. Confirmation with neuroimaging is desirable, but the sensitivity of CT for acute lacunar infarction is suboptimal, and follow-up imaging with MRI may be needed to determine the presence of lacunar infarction. (See 'Imaging confirmation' below.) Imaging confirmation We obtain brain MRI with diffusion-weighted imaging (DWI) and conventional MRI when head CT is nondiagnostic for clinically diagnosed lacunar infarction. For most situations, brain MRI with clinical correlation adequately defines the infarct location and excludes a cortically-based infarct. Lacunar infarcts have traditionally been described as small (2 to 15 mm in diameter) noncortical lesions. However, some neuroimaging studies in the acute phase (<10 days from stroke onset) have defined the upper size limit for lacunes as 20 mm or even 25 mm on DWI [88,89], since some volume reduction is expected over time [90-92]. As already noted, not all small deep infarcts are lacunar, and the diagnosis of lacunar infarction requires the exclusion of other etiologies of ischemic stroke. (See 'Standard evaluation' above.) Computed tomography Noncontrast head CT is the initial imaging modality for most patients presenting with an acute stroke syndrome. However, in prospective studies, CT has low sensitivity for detecting small acute infarcts such as lacunes (30 to 44 percent) [15,93]. The sensitivity of CT for lacunes in the hyperacute phase (<6 hours) is likely to be even lower [87]. Thus, a lacune seen on CT in this time window is more frequently chronic and not related to the clinical symptoms. CT also is limited in identifying posterior fossa infarcts and in defining the degree of cortical extension in subcortical infarcts. Magnetic resonance imaging Standard brain MRI protocols that include conventional T1-weighted, T2-weighted, fluid-attenuated inversion recovery (FLAIR), and T2*-weighted gradient-recalled echo (GRE) sequences along with DWI can reliably diagnose both acute ischemic stroke and acute hemorrhagic stroke in emergency settings. Conventional MRI On conventional MRI, lacunar infarcts typically are visualized as focal lesions characterized by decreased T1-weighted and increased T2-weighted signal intensity ( image 1). Conventional MRI has a higher sensitivity and specificity than CT [93,94], and is better for defining the exact anatomical localization of acute infarcts. In one study, for example, MRI detected lacunar infarcts in 19 of 22 patients with compatible symptoms, compared with 11 found by CT [94]. A second report confirmed that MRI was superior to CT for detecting lacunes; the sensitivity of MRI was greatest for https://www.uptodate.com/contents/lacunar-infarcts/print 11/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate patients who presented with pure motor hemiparesis, detecting 85 percent of lesions [93]. MRI usually shows infarcts within eight hours of symptom onset. DWI Diffusion-weighted imaging (DWI) is a fast MRI technique that demonstrates a hyperintense signal whenever there is an area of restricted water diffusion, as occurs during acute ischemia. DWI has the advantages of a higher sensitivity for acute lesions than T2-weighted MRI or FLAIR, ability to differentiate between acute and chronic lacunar infarcts, and ability to identify multiple acute infarcts potentially linked to embolic sources [38,95,96]. In one study, 25 percent of DWI-hyperintense lacunar infarcts were either not seen or mistakenly called "chronic" on T2 or FLAIR imaging [96]. This finding suggests that patients require DWI to define the clinically appropriate infarct when multiple subcortical infarcts of various ages are present ( image 1). (See "Neuroimaging of acute stroke", section on 'Assessment of early infarct signs'.) The size of acute lacunar infarction is overestimated on DWI by approximately 40 percent when compared with final infarct size at 30 days or more after stroke onset on conventional MRI (T2 or FLAIR sequences) and CT [90]. Correlation of clinical lacunar syndromes with imaging findings Of the 20 lacunar syndromes described, the five classic syndromes have been validated as being predictive for the presence of lacunar infarction on brain imaging: Pure motor hemiparesis (see 'Pure motor hemiparesis' above) Pure sensory stroke (see 'Pure sensory stroke' above) Ataxic hemiparesis (see 'Ataxic hemiparesis' above) Sensorimotor stroke (see 'Sensorimotor stroke' above) Dysarthria-clumsy hand syndrome (see 'Dysarthria-clumsy hand syndrome' above) Predicted infarct locations in relation to clinical manifestations are shown in the table ( table 2). Earlier retrospective studies, mainly based on CT, found that the presence of these syndromes (as a group) had a positive predictive value as high as 87 to 90 percent for detecting a radiological lacune [77,97], although some clinical syndromes were more predictive than others [98-102]. Preceding TIAs and nonsudden onset increased the positive predictive value for these lacunar syndromes in another report [103]. Clinical presentation does not always predict actual stroke type Patients with lacunar syndromes identified clinically are sometimes found to have an acute nonlacunar infarct by imaging. In one report of 478 patients with lacunar syndromes nonlacunar infarcts were https://www.uptodate.com/contents/lacunar-infarcts/print 12/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate the cause in 21 percent [104]. Another study evaluated 73 patients presenting with lacunar syndromes; all underwent DWI as well as extensive neurovascular and cardiac evaluations for potential embolic sources [105]. DWI radiologic patterns suggestive of nonlacunar infarction (mainly embolism) were seen in a total of 30 patients (41 percent); of these, 16 had one large or multiple acute lesions within a single vascular territory, and another 14 had multiple infarcts in different vascular territories [105]. Patients with more than one infarct on DWI were significantly more likely to have a clinically proven embolic source, although no embolic source was found in nine patients with a DWI pattern suggestive of a nonlacunar/embolic stroke mechanism. Conversely, brain imaging may identify acute lacunar infarcts that were not classified as lacunar syndromes on initial clinical evaluation [88]. In addition, the false negative rate with CT scan (ie, acute lacunar syndrome but no acute stroke on CT) ranges from 35 to 50 percent [87,106,107]. An inherent difficulty of both CT and conventional MRI, but not DWI, is the ability to differentiate between acute and chronic lesions. In one study, 16 percent of patients presenting with a lacunar syndrome had at least two lesions on conventional MRI that correlated with clinical symptoms [15]. Furthermore, in patients presenting with a lacunar syndrome, multiple chronic subcortical lesions are not rare, occurring in approximately 42 to 75 percent of cases [5,93]. For these reasons, knowledge of possible lesion locations based upon neurologic findings is necessary before implicating a particular lesion found on head CT or conventional MRI as responsible for the clinical symptoms ( table 2). Other studies Genetic screening for pathogenic variants in NOTCH3 is appropriate if there is suspicion for CADASIL, as suggested by a family history of stroke and dementia, absence of hypertension or known vascular risk factors, and clinical features including TIA and ischemic stroke predominately involving small vessels, cognitive deficits with early executive dysfunction, migraine with aura, neuropsychiatric disturbances, and brain MRI with white matter hyperintensities on T2 imaging in the anterior temporal lobes and external capsule. (See "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)".) ACUTE TREATMENT All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy. Screening https://www.uptodate.com/contents/lacunar-infarcts/print 13/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate patients with acute stroke for reperfusion therapies begins immediately upon presentation, even before the diagnosis is confirmed. (See 'Rapid evaluation' above.) Aspirin and other antithrombotic agents should not be given alone or in combination for the first 24 hours following treatment with intravenous thrombolysis. Otherwise, in the absence of contraindications, antiplatelet agents should be started as soon as possible after the diagnosis of transient ischemic attack (TIA) or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete. Reperfusion therapy Randomized controlled trials have shown that intravenous alteplase (recombinant tissue-type plasminogen activator or tPA) improves functional outcome from ischemic stroke and that benefits outweigh the risks for eligible patients who receive treatment within 4.5 hours of symptom onset (or within 4.5 hours of when the patient was last seen normal in cases when onset time is unknown). Intravenous thrombolysis may also be beneficial for select patients who wake-up with stroke more than 4.5 hours after they were last known well or those who have unknown time of symptom onset, if they have an acute ischemic brain lesion detected on diffusion MRI but no corresponding hyperintensity on fluid-attenuated inversion recovery (FLAIR) MRI. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Alteplase'.) Most clinical trials investigating stroke treatment and prevention have failed to adequately study the lacunar infarct subpopulation. Nevertheless, subgroup analysis of trial data suggest that the benefit with thrombolysis is sustained in patients with lacunar stroke [108]. However, stroke subtype was classified mainly by clinical impression in the thrombolysis trials since vascular studies usually were not performed before treatment initiation. Thus, some patients with a large vessel or cardioembolic stroke mechanism (eg, those with proximal middle cerebral artery occlusion, good leptomeningeal collaterals, and recanalization after thrombolysis) may have been incorrectly classified as having a small vessel etiology. Nonetheless, until better data are available, we recommend that patients with lacunar syndromes be selected for thrombolysis according to current guidelines in the same way as patients with other subtypes of ischemic stroke ( table 3). (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) Thrombolytic therapy is associated with a 6 percent risk of symptomatic brain hemorrhage. This treatment option should be discussed with the patient and family in each individual case. Antiplatelet therapy Most patients with acute ischemic stroke should be treated with early antiplatelet therapy, and short-term dual antiplatelet therapy may be appropriate for https://www.uptodate.com/contents/lacunar-infarcts/print 14/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate select patients with high-risk TIA or minor ischemic stroke. This topic is discussed separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) SECONDARY PREVENTION Most patients with ischemic stroke or transient ischemic attack (TIA) should be treated with intensive medical intervention and risk factor management, including blood pressure control, antiplatelet and statin therapy, and lifestyle modification. These interventions for secondary prevention apply both to patients who present with stroke or TIA and to patients who have no history of symptomatic stroke but have imaging evidence of lacunar infarction (ie, silent stroke). However, the risk/benefit of antiplatelet therapy has not been adequately studied for patients with silent lacunar infarcts. (See "Overview of secondary prevention of ischemic stroke".) After the acute phase of stroke (when permissive hypertension is often employed) antihypertensive therapy should be resumed in previously treated, neurologically stable patients with known hypertension for prevention of recurrent stroke and other vascular events. In addition, antihypertensive therapy should be started in previously untreated, neurologically stable patients with any type of stroke or TIA who have an established blood pressure that is above goal. (See "Antihypertensive therapy for secondary stroke prevention".) Beyond the acute phase of TIA and ischemic stroke (ie, >21 days), and in the absence of an
syndromes (as a group) had a positive predictive value as high as 87 to 90 percent for detecting a radiological lacune [77,97], although some clinical syndromes were more predictive than others [98-102]. Preceding TIAs and nonsudden onset increased the positive predictive value for these lacunar syndromes in another report [103]. Clinical presentation does not always predict actual stroke type Patients with lacunar syndromes identified clinically are sometimes found to have an acute nonlacunar infarct by imaging. In one report of 478 patients with lacunar syndromes nonlacunar infarcts were https://www.uptodate.com/contents/lacunar-infarcts/print 12/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate the cause in 21 percent [104]. Another study evaluated 73 patients presenting with lacunar syndromes; all underwent DWI as well as extensive neurovascular and cardiac evaluations for potential embolic sources [105]. DWI radiologic patterns suggestive of nonlacunar infarction (mainly embolism) were seen in a total of 30 patients (41 percent); of these, 16 had one large or multiple acute lesions within a single vascular territory, and another 14 had multiple infarcts in different vascular territories [105]. Patients with more than one infarct on DWI were significantly more likely to have a clinically proven embolic source, although no embolic source was found in nine patients with a DWI pattern suggestive of a nonlacunar/embolic stroke mechanism. Conversely, brain imaging may identify acute lacunar infarcts that were not classified as lacunar syndromes on initial clinical evaluation [88]. In addition, the false negative rate with CT scan (ie, acute lacunar syndrome but no acute stroke on CT) ranges from 35 to 50 percent [87,106,107]. An inherent difficulty of both CT and conventional MRI, but not DWI, is the ability to differentiate between acute and chronic lesions. In one study, 16 percent of patients presenting with a lacunar syndrome had at least two lesions on conventional MRI that correlated with clinical symptoms [15]. Furthermore, in patients presenting with a lacunar syndrome, multiple chronic subcortical lesions are not rare, occurring in approximately 42 to 75 percent of cases [5,93]. For these reasons, knowledge of possible lesion locations based upon neurologic findings is necessary before implicating a particular lesion found on head CT or conventional MRI as responsible for the clinical symptoms ( table 2). Other studies Genetic screening for pathogenic variants in NOTCH3 is appropriate if there is suspicion for CADASIL, as suggested by a family history of stroke and dementia, absence of hypertension or known vascular risk factors, and clinical features including TIA and ischemic stroke predominately involving small vessels, cognitive deficits with early executive dysfunction, migraine with aura, neuropsychiatric disturbances, and brain MRI with white matter hyperintensities on T2 imaging in the anterior temporal lobes and external capsule. (See "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)".) ACUTE TREATMENT All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy. Screening https://www.uptodate.com/contents/lacunar-infarcts/print 13/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate patients with acute stroke for reperfusion therapies begins immediately upon presentation, even before the diagnosis is confirmed. (See 'Rapid evaluation' above.) Aspirin and other antithrombotic agents should not be given alone or in combination for the first 24 hours following treatment with intravenous thrombolysis. Otherwise, in the absence of contraindications, antiplatelet agents should be started as soon as possible after the diagnosis of transient ischemic attack (TIA) or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete. Reperfusion therapy Randomized controlled trials have shown that intravenous alteplase (recombinant tissue-type plasminogen activator or tPA) improves functional outcome from ischemic stroke and that benefits outweigh the risks for eligible patients who receive treatment within 4.5 hours of symptom onset (or within 4.5 hours of when the patient was last seen normal in cases when onset time is unknown). Intravenous thrombolysis may also be beneficial for select patients who wake-up with stroke more than 4.5 hours after they were last known well or those who have unknown time of symptom onset, if they have an acute ischemic brain lesion detected on diffusion MRI but no corresponding hyperintensity on fluid-attenuated inversion recovery (FLAIR) MRI. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Alteplase'.) Most clinical trials investigating stroke treatment and prevention have failed to adequately study the lacunar infarct subpopulation. Nevertheless, subgroup analysis of trial data suggest that the benefit with thrombolysis is sustained in patients with lacunar stroke [108]. However, stroke subtype was classified mainly by clinical impression in the thrombolysis trials since vascular studies usually were not performed before treatment initiation. Thus, some patients with a large vessel or cardioembolic stroke mechanism (eg, those with proximal middle cerebral artery occlusion, good leptomeningeal collaterals, and recanalization after thrombolysis) may have been incorrectly classified as having a small vessel etiology. Nonetheless, until better data are available, we recommend that patients with lacunar syndromes be selected for thrombolysis according to current guidelines in the same way as patients with other subtypes of ischemic stroke ( table 3). (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) Thrombolytic therapy is associated with a 6 percent risk of symptomatic brain hemorrhage. This treatment option should be discussed with the patient and family in each individual case. Antiplatelet therapy Most patients with acute ischemic stroke should be treated with early antiplatelet therapy, and short-term dual antiplatelet therapy may be appropriate for https://www.uptodate.com/contents/lacunar-infarcts/print 14/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate select patients with high-risk TIA or minor ischemic stroke. This topic is discussed separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) SECONDARY PREVENTION Most patients with ischemic stroke or transient ischemic attack (TIA) should be treated with intensive medical intervention and risk factor management, including blood pressure control, antiplatelet and statin therapy, and lifestyle modification. These interventions for secondary prevention apply both to patients who present with stroke or TIA and to patients who have no history of symptomatic stroke but have imaging evidence of lacunar infarction (ie, silent stroke). However, the risk/benefit of antiplatelet therapy has not been adequately studied for patients with silent lacunar infarcts. (See "Overview of secondary prevention of ischemic stroke".) After the acute phase of stroke (when permissive hypertension is often employed) antihypertensive therapy should be resumed in previously treated, neurologically stable patients with known hypertension for prevention of recurrent stroke and other vascular events. In addition, antihypertensive therapy should be started in previously untreated, neurologically stable patients with any type of stroke or TIA who have an established blood pressure that is above goal. (See "Antihypertensive therapy for secondary stroke prevention".) Beyond the acute phase of TIA and ischemic stroke (ie, >21 days), and in the absence of an indication for oral anticoagulation, long-term single-agent antiplatelet therapy for secondary stroke prevention should be continued with aspirin, clopidogrel, or aspirin- extended-release dipyridamole. Long-term dual antiplatelet therapy with aspirin and clopidogrel is not recommended. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Patients with ischemic stroke, all of whom are at high risk for recurrent cerebrovascular and cardiovascular events, should receive high-intensity statin therapy. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) Recommended lifestyle modifications to reduce the risk of stroke include smoking cessation, limited alcohol consumption, weight control, regular aerobic physical activity, salt restriction, and a Mediterranean diet. (See "Overview of secondary prevention of ischemic stroke", section on 'Lifestyle modification'.) https://www.uptodate.com/contents/lacunar-infarcts/print 15/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate The efficacy of aspirin and other antiplatelet agents for preventing second strokes and mortality has been illustrated for patients with noncardioembolic ischemic stroke in general (see "Long- term antithrombotic therapy for the secondary prevention of ischemic stroke"). A 2015 meta- analysis identified two trials that evaluated antiplatelets versus placebo and reported outcomes in the subgroup of patients with lacunar stroke; in the pooled analysis, treatment with any single antiplatelet agent was associated with a significant reduction in ischemic stroke recurrence (relative risk 0.48, 95% CI 0.30-0.78) [109]. Despite early enthusiasm, results from the SPS3 trial suggest that the long-term use of combined antiplatelet therapy with aspirin plus clopidogrel is harmful for patients with lacunar stroke because it leads to an increased risk of hemorrhage and death but does not reduce the risk of recurrent stroke [110]. Therefore, it should not be employed for secondary prevention in this population in the absence of proven indications. The use of aspirin plus clopidogrel for prevention of different subtypes of ischemic stroke is discussed separately in detail. (See "Long- term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Aspirin plus clopidogrel'.) PROGNOSIS Short-term outcomes Lacunar infarcts have a better short-term prognosis than infarcts due to other stroke mechanisms, at least up to one year after onset. As examples, 91 percent of patients with lacunar stroke from the placebo arm of a controlled clinical trial had a favorable outcome at three months, as defined by moderate to good recovery on the Glasgow Outcome Scale [111]. This contrasts with strokes due to large vessel atherosclerosis; only 55 percent of these patients had a favorable outcome at three months. In a later prospective study of 1425 ischemic stroke survivors, patients with lacunar stroke (n = 234) were more likely to have further neurologic improvement between three months and one year compared with patients with nonlacunar stroke [112]. Long-term outcomes The long-term prognosis after lacunar stroke may not differ greatly from nonlacunar stroke. This observation comes from a systematic review of 19 cohort studies involving 2402 patients with lacunar and 3462 patients with nonlacunar ischemic stroke [23]. The odds of death were significantly greater following nonlacunar than lacunar infarction at one month, 1 to 12 months, and one to five years (odds ratio [OR] 3.81, 2.32 and 1.77, respectively), although the difference gradually decreased. However, the odds of recurrent stroke were significantly greater for nonlacunar infarction only at one month (OR 2.11), and the difference in stroke recurrence between nonlacunar and lacunar groups was nonsignificant at 1 to 12 months and one to five years. https://www.uptodate.com/contents/lacunar-infarcts/print 16/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Analogous findings were reported in a population-based study from Italy [47]. Patients with lacunar stroke (n = 491) had better five-year survival than patients with nonlacunar stroke (n = 2153), mainly due to lower mortality within the first year of follow-up for the lacunar stroke group. The lacunar group also had a lower average annual stroke recurrence rate within the first year. However, stroke recurrence and mortality rates were similar in the two groups from the second year through study completion at five years. Outcome predictors Among patients with recent lacunar stroke, factors associated with an increased risk of ischemic stroke recurrence include a prior lacunar stroke or transient ischemic attack (TIA), diabetes, being from a Black population, and male sex [113]. In addition, the risk of stroke recurrence is increased in the presence of cerebral microbleeds [114]. Patients with lacunar infarction and more severe initial motor deficits have worse functional outcome [108,115]. What is not known is whether patients with a lacunar infarct due to embolism or large vessel atherosclerosis obstructing the ostium of a penetrator branch have a different prognosis and response to therapy. As long as this question remains, investigation of the operating stroke mechanism remains important. (See 'Etiology' above.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Description and location Lacunar infarcts are small (0.2 to 15 mm in diameter) noncortical infarcts caused by occlusion of a single penetrating branch of a large cerebral artery. These branches arise at acute angles from the large arteries of the circle of Willis, stem of the middle cerebral artery, and the basilar artery ( figure 1). Most lacunes occur in the basal ganglia (putamen, globus pallidus, caudate), thalamus, subcortical white matter (internal capsule and corona radiata), and pons. (See 'Introduction and definition' above and 'History' above and 'Vascular anatomy' above.) Etiology Several mechanisms for occlusion of small penetrator branches have been described (see 'Etiology' above): https://www.uptodate.com/contents/lacunar-infarcts/print 17/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Hypertensive microangiopathy Branch atheromatous disease Embolism from cardiac or large artery sources Endothelial dysfunction and associated blood-brain barrier disruption Epidemiology Lacunes account for 15 to 26 percent of ischemic strokes. (See 'Epidemiology' above.) Risk factors The main risk factor and mechanism for lacunar stroke is related to a chronic vasculopathy associated with systemic hypertension. Other likely risk factors include diabetes mellitus and possibly smoking. (See 'Risk factors and associations' above.) Clinical features Lacunar syndromes More than 20 lacunar syndromes have been described. The five classic lacunar syndromes ( table 2), which may present as transient ischemic attacks (TIAs) in addition to stroke, are named according to their clinical features: - - - - Pure motor hemiparesis (see 'Pure motor hemiparesis' above) Pure sensory stroke (see 'Pure sensory stroke' above) Ataxic hemiparesis (see 'Ataxic hemiparesis' above) Sensorimotor stroke (see 'Sensorimotor stroke' above) Dysarthria-clumsy hand syndrome (see 'Dysarthria-clumsy hand syndrome' above) A large number of atypical lacunar syndromes are also recognized ( table 1). Absence of cortical signs As a general rule, lacunar syndromes lack findings such as aphasia, agnosia, neglect, apraxia, or hemianopsia (so-called "cortical" signs). Monoplegia, stupor, coma, loss of consciousness, and seizures also are typically absent. (See 'Clinical features' above.) Acute stroke evaluation All patients presenting with acute ischemic stroke, including those with suspected lacunar stroke, should be screened for treatment with intravenous thrombolysis and mechanical thrombectomy and be evaluated with a standard stroke evaluation that includes brain and neurovascular imaging, cardiac monitoring, and echocardiography. (See 'Rapid evaluation' above and 'Standard evaluation' above.) Diagnosis Lacunar infarction is suspected in patients who present with a recognized lacunar syndrome (eg, pure motor hemiparesis, pure sensory stroke, ataxic hemiparesis, sensorimotor stroke, dysarthria-clumsy hand syndrome) or other acute stroke symptoms without cortical involvement. The radiologic diagnosis of lacunar infarction relies upon https://www.uptodate.com/contents/lacunar-infarcts/print 18/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate finding a small noncortical infarct on CT or MRI whose location is consistent with the clinical lacunar syndrome defined by history and examination ( image 1). We obtain brain MRI with diffusion-weighted imaging (DWI) and conventional MRI when head CT is nondiagnostic for clinically diagnosed lacunar infarction. (See 'Clinical diagnosis' above and 'Imaging confirmation' above.) Acute treatment Intravenous thrombolysis improves outcomes for eligible patients with ischemic stroke. Aspirin and other antithrombotic agents should not be given alone or in combination for the first 24 hours following treatment with intravenous thrombolysis. Otherwise, in the absence of contraindications, antiplatelet agents should be started as soon as possible after the diagnosis of TIA or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete. (See 'Acute treatment' above.) Secondary prevention For secondary prevention, most patients with ischemic stroke or TIA should be treated with intensive medical intervention and risk factor management, including blood pressure control, antiplatelet and statin therapy, and lifestyle modification. (See 'Secondary prevention' above.) Prognosis Lacunar infarcts usually have a better short-term prognosis than infarcts due to other stroke mechanisms, at least up to one year after onset. However, the long-term prognosis after lacunar stroke may not differ greatly from nonlacunar stroke. (See 'Prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges J Philip Kistler, MD, who contributed to an earlier version of this topic review. 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The natural history of lacunar infarction: the Oxfordshire Community Stroke Project. Stroke 1987; 18:545. 80. Schonewille WJ, Tuhrim S, Singer MB, Atlas SW. Diffusion-weighted MRI in acute lacunar syndromes. A clinical-radiological correlation study. Stroke 1999; 30:2066. 81. Donnan GA, O'Malley HM, Quang L, et al. The capsular warning syndrome: pathogenesis and clinical features. Neurology 1993; 43:957. 82. FISHER CM. PURE SENSORY STROKE INVOLVING FACE, ARM, AND LEG. Neurology 1965; 15:76. 83. FISHER CM, COLE M. HOMOLATERAL ATAXIA AND CRURAL PARESIS: A VASCULAR SYNDROME. J Neurol Neurosurg Psychiatry 1965; 28:48. 84. Mohr JP, Kase CS, Meckler RJ, Fisher CM. Sensorimotor stroke due to thalamocapsular ischemia. Arch Neurol 1977; 34:739. 85. Fisher CM. A lacunar stroke. The dysarthria-clumsy hand syndrome. Neurology 1967; 17:614. 86. Gerraty RP, Parsons MW, Barber PA, et al. Examining the lacunar hypothesis with diffusion and perfusion magnetic resonance imaging. Stroke 2002; 33:2019. 87. Toni D, Iweins F, von Kummer R, et al. Identification of lacunar infarcts before thrombolysis in the ECASS I study. Neurology 2000; 54:684. 88. Arba F, Mair G, Phillips S, et al. Improving Clinical Detection of Acute Lacunar Stroke: https://www.uptodate.com/contents/lacunar-infarcts/print 24/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Analysis From the IST-3. Stroke 2020; 51:1411. 89. Cho AH, Kang DW, Kwon SU, Kim JS. Is 15 mm size criterion for lacunar infarction still valid? A study on strictly subcortical middle cerebral artery territory infarction using diffusion- weighted MRI. Cerebrovasc Dis 2007; 23:14. 90. Koch S, McClendon MS, Bhatia R. Imaging evolution of acute lacunar infarction: leukoariosis or lacune? Neurology 2011; 77:1091. 91. Lee KJ, Jung H, Oh YS, et al. The Fate of Acute Lacunar Lesions in Terms of Shape and Size. J Stroke Cerebrovasc Dis 2017; 26:1254. 92. Kwon HS, Cho AH, Lee MH, et al. Evolution of acute lacunar lesions in terms of size and shape: a PICASSO sub-study. J Neurol 2019; 266:766. 93. Arboix A, Mart -Vilalta JL, Pujol J, Sanz M. Lacunar cerebral infarct and nuclear magnetic resonance. A review of sixty cases. Eur Neurol 1990; 30:47. 94. Brown JJ, Hesselink JR, Rothrock JF. MR and CT of lacunar infarcts. AJR Am J Roentgenol 1988; 151:367. 95. Singer MB, Chong J, Lu D, et al. Diffusion-weighted MRI in acute subcortical infarction. Stroke 1998; 29:133. 96. Oliveira-Filho J, Ay H, Schaefer PW, et al. Diffusion-weighted magnetic resonance imaging identifies the "clinically relevant" small-penetrator infarcts. Arch Neurol 2000; 57:1009. 97. Boiten J, Lodder J. Lacunar infarcts. Pathogenesis and validity of the clinical syndromes. Stroke 1991; 22:1374. 98. Gorman MJ, Dafer R, Levine SR. Ataxic hemiparesis: critical appraisal of a lacunar syndrome. Stroke 1998; 29:2549. 99. Melo TP, Bogousslavsky J, van Melle G, Regli F. Pure motor stroke: a reappraisal. Neurology 1992; 42:789. 100. Toni D, Del Duca R, Fiorelli M, et al. Pure motor hemiparesis and sensorimotor stroke. Accuracy of very early clinical diagnosis of lacunar strokes. Stroke 1994; 25:92. 101. Moulin T, Bogousslavsky J, Chopard JL, et al. Vascular ataxic hemiparesis: a re-evaluation. J Neurol Neurosurg Psychiatry 1995; 58:422. 102. Kim JS. Pure sensory stroke. Clinical-radiological correlates of 21 cases. Stroke 1992; 23:983. 103. Herv D, Gautier-Bertrand M, Labreuche J, et al. Predictive values of lacunar transient ischemic attacks. Stroke 2004; 35:1430. 104. Giacomozzi S, Caso V, Agnelli G, et al. Lacunar stroke syndromes as predictors of lacunar and non-lacunar infarcts on neuroimaging: a hospital-based study. Intern Emerg Med 2020; 15:429. https://www.uptodate.com/contents/lacunar-infarcts/print 25/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate 105. Wessels T, R ttger C, Jauss M, et al. Identification of embolic stroke patterns by diffusion- weighted MRI in clinically defined lacunar stroke syndromes. Stroke 2005; 36:757. 106. Mead GE, Lewis SC, Wardlaw JM, et al. How well does the Oxfordshire community stroke project classification predict the site and size of the infarct on brain imaging? J Neurol Neurosurg Psychiatry 2000; 68:558. 107. Stapf C, Hofmeister C, Hartmann A, et al. Predictive value of clinical lacunar syndromes for lacunar infarcts on magnetic resonance brain imaging. Acta Neurol Scand 2000; 101:13. 108. Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke 1997; 28:2119. 109. Kwok CS, Shoamanesh A, Copley HC, et al. Efficacy of antiplatelet therapy in secondary prevention following lacunar stroke: pooled analysis of randomized trials. Stroke 2015; 46:1014. 110. SPS3 Investigators, Benavente OR, Hart RG, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012; 367:817. 111. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. JAMA 1998; 279:1265. 112. Ganesh A, Gutnikov SA, Rothwell PM, Oxford Vascular Study. Late functional improvement after lacunar stroke: a population-based study. J Neurol Neurosurg Psychiatry 2018; 89:1301. 113. Hart RG, Pearce LA, Bakheet MF, et al. Predictors of stroke recurrence in patients with recent lacunar stroke and response to interventions according to risk status: secondary prevention of small subcortical strokes trial. J Stroke Cerebrovasc Dis 2014; 23:618. 114. Shoamanesh A, Pearce LA, Bazan C, et al. Microbleeds in the Secondary Prevention of Small Subcortical Strokes Trial: Stroke, mortality, and treatment interactions. Ann Neurol 2017; 82:196. 115. Samuelsson M, S derfeldt B, Olsson GB. Functional outcome in patients with lacunar infarction. Stroke 1996; 27:842. Topic 1136 Version 42.0 https://www.uptodate.com/contents/lacunar-infarcts/print 26/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate GRAPHICS [1-5] Vascular anatomy of lacunar strokes Anatomic location of lenticulostriate, thalamoperforating, and paramedian pontine branches. References: 1. Thieme Atlas of Anatomy: Head and Neuroanatomy, 3rd ed, Ross LM, Lamperti ED, Taub E (Eds), Thieme, Stuttgart 2010. 2. Qureshi AI, Tuhrim S, Broderick JP, et al. Spontaneous intracerebral hemorrhage. N Engl J Med 2001; 344:1450. 3. Kistler, JP, et al, Cerebrovascular diseases, Harrison's Principles of Internal Medicine, 13th ed, McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. 4. Nervous System, Part 1: Anatomy and Physiology (Ciba Collection of Medical Illustrations, Volume 1), Netter FH (Ed), Ciba-Geigy Corporation 1991. 5. Caplan's Stroke: A Clinical Approach, 4th ed, Caplan L, Saunders 2009. Graphic 73027 Version 2.0 https://www.uptodate.com/contents/lacunar-infarcts/print 27/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Acute lacunar infarction on brain MRI Brain MRI of a 71-year-old woman with a two-day history of left-sided ataxic hemiparesis. Left panels: Diffusion-weighted MRI sequences show two acute lesions, one in the cerebellum (top panel) and one in the thalamocapsular region (bottom panel). T2-weighted (middle panels) and FLAIR (right panels) MRI sequences correctly identify the lesions (arrows), but neither could be called "acute" without diffusion imaging. A high-risk cardiac source (an akinetic left ventricular segment) was found on echocardiogram. MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery. Courtesy of Jamary Oliveira-Filho, MD. Graphic 54402 Version 4.0 https://www.uptodate.com/contents/lacunar-infarcts/print 28/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Other lacunar stroke syndromes Modified pure motor hemiparesis with motor aphasia Pure motor hemiparesis sparing face Mesencephalo-thalamic syndrome Thalamic dementia Pure motor hemiparesis with horizontal gaze palsy Pure motor hemiparesis with crossed third-nerve palsy (Weber syndrome) Pure motor hemiparesis with crossed sixth-nerve palsy Pure motor hemiparesis with confusion Cerebellar ataxia with crossed third-nerve palsy (Claude syndrome) Hemiballismus Lower basilar branch syndrome dizziness, diplopia, gaze palsy, dysarthria, cerebellar ataxia, trigeminal numbness Lateral medullary syndrome Lateral pontomedullary syndrome Locked-in syndrome (bilateral pure motor hemiparesis) Pure dysarthria Acute dystonia of thalamic origin Lacunar state Adapted from: Fisher CM, Neurology 1982; 32:871. Graphic 57474 Version 4.0 https://www.uptodate.com/contents/lacunar-infarcts/print 29/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Classic lacunar stroke syndromes Positive predictive value Lacunar syndrome Location Clinical findings Pure motor hemiparesis Internal capsule, corona radiata, basal Unilateral paralysis of face, arm and leg, no 52-85 percent pons, medial medulla sensory signs, dysarthria and dysphagia may be present Pure sensory syndrome Thalamus, pontine tegmentum, corona Unilateral numbness of face, arm and leg 95-100 percent radiata without motor deficit Ataxic hemiparesis Internal capsule- corona radiata, basal Unilateral weakness and limb ataxia 59-95 percent pons, thalamus Sensorimotor syndrome Thalamocapsular, maybe basal pons or Hemiparesis or hemiplegia of face, arm 51-87 percent lateral medulla and leg with ipsilateral sensory impairment Dysarthria-clumsy Basal pons, internal Unilateral facial About 96 percent hand syndrome capsule, corona radiata weakness, dysarthria and dysphagia, with mild hand weakness and clumsiness Graphic 67341 Version 4.0
Stroke Cerebrovasc Dis 2017; 26:1254. 92. Kwon HS, Cho AH, Lee MH, et al. Evolution of acute lacunar lesions in terms of size and shape: a PICASSO sub-study. J Neurol 2019; 266:766. 93. Arboix A, Mart -Vilalta JL, Pujol J, Sanz M. Lacunar cerebral infarct and nuclear magnetic resonance. A review of sixty cases. Eur Neurol 1990; 30:47. 94. Brown JJ, Hesselink JR, Rothrock JF. MR and CT of lacunar infarcts. AJR Am J Roentgenol 1988; 151:367. 95. Singer MB, Chong J, Lu D, et al. Diffusion-weighted MRI in acute subcortical infarction. Stroke 1998; 29:133. 96. Oliveira-Filho J, Ay H, Schaefer PW, et al. Diffusion-weighted magnetic resonance imaging identifies the "clinically relevant" small-penetrator infarcts. Arch Neurol 2000; 57:1009. 97. Boiten J, Lodder J. Lacunar infarcts. Pathogenesis and validity of the clinical syndromes. Stroke 1991; 22:1374. 98. Gorman MJ, Dafer R, Levine SR. Ataxic hemiparesis: critical appraisal of a lacunar syndrome. Stroke 1998; 29:2549. 99. Melo TP, Bogousslavsky J, van Melle G, Regli F. Pure motor stroke: a reappraisal. Neurology 1992; 42:789. 100. Toni D, Del Duca R, Fiorelli M, et al. Pure motor hemiparesis and sensorimotor stroke. Accuracy of very early clinical diagnosis of lacunar strokes. Stroke 1994; 25:92. 101. Moulin T, Bogousslavsky J, Chopard JL, et al. Vascular ataxic hemiparesis: a re-evaluation. J Neurol Neurosurg Psychiatry 1995; 58:422. 102. Kim JS. Pure sensory stroke. Clinical-radiological correlates of 21 cases. Stroke 1992; 23:983. 103. Herv D, Gautier-Bertrand M, Labreuche J, et al. Predictive values of lacunar transient ischemic attacks. Stroke 2004; 35:1430. 104. Giacomozzi S, Caso V, Agnelli G, et al. Lacunar stroke syndromes as predictors of lacunar and non-lacunar infarcts on neuroimaging: a hospital-based study. Intern Emerg Med 2020; 15:429. https://www.uptodate.com/contents/lacunar-infarcts/print 25/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate 105. Wessels T, R ttger C, Jauss M, et al. Identification of embolic stroke patterns by diffusion- weighted MRI in clinically defined lacunar stroke syndromes. Stroke 2005; 36:757. 106. Mead GE, Lewis SC, Wardlaw JM, et al. How well does the Oxfordshire community stroke project classification predict the site and size of the infarct on brain imaging? J Neurol Neurosurg Psychiatry 2000; 68:558. 107. Stapf C, Hofmeister C, Hartmann A, et al. Predictive value of clinical lacunar syndromes for lacunar infarcts on magnetic resonance brain imaging. Acta Neurol Scand 2000; 101:13. 108. Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke 1997; 28:2119. 109. Kwok CS, Shoamanesh A, Copley HC, et al. Efficacy of antiplatelet therapy in secondary prevention following lacunar stroke: pooled analysis of randomized trials. Stroke 2015; 46:1014. 110. SPS3 Investigators, Benavente OR, Hart RG, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012; 367:817. 111. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. JAMA 1998; 279:1265. 112. Ganesh A, Gutnikov SA, Rothwell PM, Oxford Vascular Study. Late functional improvement after lacunar stroke: a population-based study. J Neurol Neurosurg Psychiatry 2018; 89:1301. 113. Hart RG, Pearce LA, Bakheet MF, et al. Predictors of stroke recurrence in patients with recent lacunar stroke and response to interventions according to risk status: secondary prevention of small subcortical strokes trial. J Stroke Cerebrovasc Dis 2014; 23:618. 114. Shoamanesh A, Pearce LA, Bazan C, et al. Microbleeds in the Secondary Prevention of Small Subcortical Strokes Trial: Stroke, mortality, and treatment interactions. Ann Neurol 2017; 82:196. 115. Samuelsson M, S derfeldt B, Olsson GB. Functional outcome in patients with lacunar infarction. Stroke 1996; 27:842. Topic 1136 Version 42.0 https://www.uptodate.com/contents/lacunar-infarcts/print 26/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate GRAPHICS [1-5] Vascular anatomy of lacunar strokes Anatomic location of lenticulostriate, thalamoperforating, and paramedian pontine branches. References: 1. Thieme Atlas of Anatomy: Head and Neuroanatomy, 3rd ed, Ross LM, Lamperti ED, Taub E (Eds), Thieme, Stuttgart 2010. 2. Qureshi AI, Tuhrim S, Broderick JP, et al. Spontaneous intracerebral hemorrhage. N Engl J Med 2001; 344:1450. 3. Kistler, JP, et al, Cerebrovascular diseases, Harrison's Principles of Internal Medicine, 13th ed, McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. 4. Nervous System, Part 1: Anatomy and Physiology (Ciba Collection of Medical Illustrations, Volume 1), Netter FH (Ed), Ciba-Geigy Corporation 1991. 5. Caplan's Stroke: A Clinical Approach, 4th ed, Caplan L, Saunders 2009. Graphic 73027 Version 2.0 https://www.uptodate.com/contents/lacunar-infarcts/print 27/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Acute lacunar infarction on brain MRI Brain MRI of a 71-year-old woman with a two-day history of left-sided ataxic hemiparesis. Left panels: Diffusion-weighted MRI sequences show two acute lesions, one in the cerebellum (top panel) and one in the thalamocapsular region (bottom panel). T2-weighted (middle panels) and FLAIR (right panels) MRI sequences correctly identify the lesions (arrows), but neither could be called "acute" without diffusion imaging. A high-risk cardiac source (an akinetic left ventricular segment) was found on echocardiogram. MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery. Courtesy of Jamary Oliveira-Filho, MD. Graphic 54402 Version 4.0 https://www.uptodate.com/contents/lacunar-infarcts/print 28/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Other lacunar stroke syndromes Modified pure motor hemiparesis with motor aphasia Pure motor hemiparesis sparing face Mesencephalo-thalamic syndrome Thalamic dementia Pure motor hemiparesis with horizontal gaze palsy Pure motor hemiparesis with crossed third-nerve palsy (Weber syndrome) Pure motor hemiparesis with crossed sixth-nerve palsy Pure motor hemiparesis with confusion Cerebellar ataxia with crossed third-nerve palsy (Claude syndrome) Hemiballismus Lower basilar branch syndrome dizziness, diplopia, gaze palsy, dysarthria, cerebellar ataxia, trigeminal numbness Lateral medullary syndrome Lateral pontomedullary syndrome Locked-in syndrome (bilateral pure motor hemiparesis) Pure dysarthria Acute dystonia of thalamic origin Lacunar state Adapted from: Fisher CM, Neurology 1982; 32:871. Graphic 57474 Version 4.0 https://www.uptodate.com/contents/lacunar-infarcts/print 29/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Classic lacunar stroke syndromes Positive predictive value Lacunar syndrome Location Clinical findings Pure motor hemiparesis Internal capsule, corona radiata, basal Unilateral paralysis of face, arm and leg, no 52-85 percent pons, medial medulla sensory signs, dysarthria and dysphagia may be present Pure sensory syndrome Thalamus, pontine tegmentum, corona Unilateral numbness of face, arm and leg 95-100 percent radiata without motor deficit Ataxic hemiparesis Internal capsule- corona radiata, basal Unilateral weakness and limb ataxia 59-95 percent pons, thalamus Sensorimotor syndrome Thalamocapsular, maybe basal pons or Hemiparesis or hemiplegia of face, arm 51-87 percent lateral medulla and leg with ipsilateral sensory impairment Dysarthria-clumsy Basal pons, internal Unilateral facial About 96 percent hand syndrome capsule, corona radiata weakness, dysarthria and dysphagia, with mild hand weakness and clumsiness Graphic 67341 Version 4.0 https://www.uptodate.com/contents/lacunar-infarcts/print 30/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Time course of lacunar infarction Penetrating artery occlusions usually cause symptoms that develop over a short period of time, hours or at most a few days, compared to large artery-related brain ischemia which can evolve over a longer period. A stuttering course may ensue, as with large artery thrombosis. This patient had a pure motor hemiparesis. Graphic 52246 Version 1.0 https://www.uptodate.com/contents/lacunar-infarcts/print 31/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage https://www.uptodate.com/contents/lacunar-infarcts/print 32/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or https://www.uptodate.com/contents/lacunar-infarcts/print 33/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/lacunar-infarcts/print 34/35 7/6/23, 12:00 PM Lacunar infarcts - UpToDate Contributor Disclosures Jamary Oliveira-Filho, MD, MS, PhD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/lacunar-infarcts/print 35/35
7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Malignant cerebral hemispheric infarction with swelling and risk of herniation : David Roh, MD, Rishi Gupta, MD : Scott E Kasner, MD, Alejandro A Rabinstein, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 17, 2023. INTRODUCTION This topic will review the clinical features and management of life threatening malignant (ie, massive) hemispheric infarction. The acute treatment of hemispheric infarction in the first few hours after stroke onset (prior to the development of severe brain swelling) is similar to other types of acute ischemic stroke, as discussed in detail elsewhere. (See "Initial assessment and management of acute stroke".) MALIGNANT HEMISPHERIC INFARCTION Description Less than 10 percent of ischemic strokes are classified as malignant or massive, which is characterized by the development of space-occupying cerebral edema that is severe enough to produce brain tissue shifts and herniation [1,2]. The development of this malignant ischemic stroke syndrome is seen primarily following large hemispheric infarctions from cardioembolic or thrombotic etiologies. These hemispheric infarcts commonly result from occlusions of the internal carotid artery or the proximal segment (stem or M1 segment) of the middle cerebral artery (MCA). By one accepted definition, a large hemispheric infarction affects the total or subtotal territory of the MCA and at least partially affects the basal ganglia, with or without involvement of adjacent territories [3]. https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 1/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Patients with this syndrome can have a mortality rate as high as 78 percent due to local mass effect and herniation of the temporal lobe onto the brainstem, as well as major systemic complications [4]. This very high mortality rate may also be explained at least in part by withdrawal of life support measures because of the expected poor quality of life for these patients were they to survive. Presentation and progression On presentation, patients with a large hemispheric infarction at risk for swelling and herniation typically have severe neurologic deficits with forced gaze deviation, visual field deficits, hemiplegia, and aphasia or neglect, depending on the hemisphere involved. This combination of neurologic findings yields a National Institutes of Health Stroke Scale (NIHSS) score >15 for a right hemisphere infarction and >20 for a left hemisphere infarction; see table ( table 1) and calculator (calculator 1) for determination of the NIHSS score. Neuroimaging with head computed tomography (CT) or magnetic resonance imaging (MRI) should be obtained immediately upon presentation and repeated urgently if there is neurologic worsening. Neurologic deterioration in these patients is often due to new or worsening cerebral edema, sometimes accompanied by hemorrhagic transformation of the ischemic infarction. Hemorrhagic transformation is less frequently the primary cause of neurologic decline. Cerebral edema The development of space-occupying cerebral edema due to large infarction leads to neurologic deterioration with signs that typically include impairments of consciousness, pupillary changes, and worsening of motor responses [5]. These neurologic signs can indicate the need to intervene urgently with measures to treat brain swelling, including hemicraniectomy for patients who want aggressive treatment (see 'Care considerations' below). Cerebral edema with mass effect and neurologic deterioration may develop with a rapid and fulminant course over 24 to 36 hours from stroke onset but can also follow a more gradual course over several days to a week [4-8]. Hemorrhagic transformation Hemorrhagic transformation of a cerebral infarction occurs when blood extravasates from vessels that are damaged by ischemia [9]. The risk of hemorrhagic transformation is thought to increase with increasing size of the infarction, such that patients with malignant hemispheric infarction are at particularly high risk. The clinical impacts of hemorrhagic transformation occur across a spectrum of severity [10]; hemorrhagic infarction with heterogenous or confluent hemorrhage within an infarct region generally does not cause mass effect and is asymptomatic, while confluent parenchymal hematoma with mass effect occurring outside of the infarct region causes symptoms ranging from minimal worsening to precipitous neurologic decline. https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 2/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Clinical predictors of progression A systematic review of 38 studies and over 3200 patients found that malignant edema after ischemic stroke was associated with younger age, higher NIHSS scores on admission, and parenchymal hypoattenuation of more than 50 percent of the MCA territory on initial head CT [11]. Additionally, in this study, revascularization within 24 hours after stroke onset was associated with a reduced risk of malignant edema. The early development of decreased consciousness in patients with malignant hemispheric infarction who are awake at initial presentation is predictive of poor outcome. Supporting evidence comes from an analysis of prospective data from a randomized trial that included 564 placebo-treated patients with major anterior circulation ischemic stroke who did not have impairment in level of consciousness at baseline; the trial enrolled patients up to 12 hours after symptom onset [12]. Decreased level of consciousness at three hours after enrollment and maximum score on a level of consciousness scale (indicating no reaction to pain) in the first 24 hours were both significantly associated with increased mortality. In a prospective study of 140 patients with occlusion of the MCA diagnosed by magnetic resonance angiography (MRA) within six hours of stroke onset, malignant MCA infarction developed in 27 (19 percent) [13]. The severity of neurologic deficit on admission as measured by the NIHSS score was an independent predictor for the development of malignant MCA infarction (per point, odds ratio 1.18, 95% CI 1.01-1.38). However, an NIHSS score >18 predicted the development of malignant MCA infarction with only low to moderate sensitivity and specificity (70 and 63 percent). The association of malignant MCA infarction with younger age has been identified in other studies as well [14-16], and may be explained by a protective effect afforded by cerebral atrophy that accommodates brain swelling in older patients [4,14]. Radiologic predictors of progression Large infarct volume, typically defined by early infarction involving >50 percent of the MCA territory on initial head CT, is the most important predictor of malignant edema, herniation, and death [3]. Extracranial and intracranial carotid occlusion as well as poor collateral circulation (eg, due to an incomplete ipsilateral circle of Willis) are also plausible factors contributing to malignant infarction [17,18]. Because CT findings consistent with infarction may lag behind physiologic tissue infarction, other radiographic methods that are more sensitive to evolving infarction and edema may be more sensitive in predicting patients at risk of herniation in the first few hours after stroke onset. These methods include perfusion CT, diffusion and perfusion MRI, and several techniques that measure cerebral blood flow, including positron emission tomography (PET), xenon CT, and https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 3/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate single photon emission computed tomography (SPECT). However, PET, xenon CT, and SPECT are not widely used for this indication in clinical practice. CT Head CT is the most widely available neuroimaging study in acute stroke. The detection of a large area of early ischemic change (ie, involving >50 percent of the MCA territory) on CT is useful for predicting the subsequent development of malignant brain swelling ( image 1) [3,14,19,20]. Additional CT findings that may be predictive of malignant edema include midline shift of the septum pellucidum >5 mm, infarction of additional vascular territories (eg, anterior cerebral artery territory plus MCA, or posterior cerebral artery territory plus MCA in patients with fetal origin of the posterior cerebral artery) [21], and low a ASPECTS (Alberta stroke program early CT score). ASPECTS is a method of assessing early ischemic changes in the MCA territory on head CT scan, as described separately (see "Neuroimaging of acute stroke", section on 'ASPECTS method'). The score divides the MCA territory into 10 regions of interest that are evaluated on two axial CT cuts ( figure 1). When rating the ASPECTS, one point is subtracted for each identified area of early ischemic change from a total of 10 defined regions. Therefore, a normal CT scan has an ASPECTS value of 10 points, while diffuse ischemic change throughout the MCA territory gives a value of 0. In one retrospective report of 121 patients with large hemispheric infarction, an ASPECTS of 7 at baseline was independently associated with the development of malignant brain edema [22]. Several reports have found that perfusion CT can be used to predict malignant MCA infarction [2,23,24]. As an example, one study used perfusion CT to calculate infarct volume and routine CT to calculate intracranial cerebrospinal fluid volume, a measure of intracranial volume reserve [2]. The ratio of infarct volume to cerebrospinal fluid volume was a better predictor of a malignant course than other measures such as ischemic lesion volume or clinical characteristics. MRI Similar to head CT, a large volume of infarction on MRI ( image 2), as measured by restricted diffusion on diffusion-weighted imaging (DWI) and correspondingly low apparent diffusion coefficient, may predict a malignant course in MCA territory stroke that is characterized by cerebral edema. Risk of massive edema is particularly high in patients 3 with DWI lesions >145 cm in volume [13,25]. The predictive utility of both CT and MRI are higher the later the scan is acquired (given the known growth of infarct over time). However, within critical acute time periods where these scans would provide the highest benefit for early risk detection, MRI may provide higher sensitivities/specificities compared with CT scans for developing malignant hemispheric infarct. https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 4/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Cerebral blood flow studies Although rarely applied to patients with malignant MCA territory infarction in clinical practice, small studies suggest that quantifying cerebral blood flow with CT angiography (CTA), xenon CT, SPECT, or PET may be predictive of cerebral swelling [18,26-30]. CARE CONSIDERATIONS Level of care Most patients with acute hemispheric infarction should be monitored and managed in an intensive care unit or dedicated stroke unit in a center with available expertise in neurology, neurosurgery, neuroradiology, and critical care. If such services are not available locally, these patients should be transferred to a higher-level facility. Exceptions include those with advanced directives to withhold resuscitation and life support measures. Within hours or days of stroke onset, patients with large hemispheric infarction may deteriorate from mass effect caused by cerebral edema. Thus, it is important to quickly establish goals of care with patients, families, caregivers, or other relevant medical decision makers to clarify clinical care options and potential outcome expectations. In the acute phase, patients may require intubation and mechanical ventilation, blood pressure control, and pharmacologic interventions for cerebral edema with mass effect (see 'Medical management' below). Surgical decompressive hemicraniectomy may improve outcomes in selected patients, as discussed below. Surgical decompression or medical care only? Decompressive hemicraniectomy is a surgical technique used to remove the skull overlying the infarcted tissue in order to reverse mass effect and relieve brain tissue shifts (see 'Decompressive hemicraniectomy' below). There is evidence that hemicraniectomy for malignant hemispheric infarction substantially reduces mortality. However, many surviving patients are left with major disability. Thus, the dilemma for patients and families is that surgery may leave patients alive with severe disability [31], while medical management alone most often results in death. (See 'Efficacy' below.) Given the dire prognosis for survival associated with medical treatment, we suggest decompressive hemicraniectomy within 48 hours of stroke onset for patients age 60 years with an indisputable diagnosis of large hemispheric infarction (with >50 percent infarction of middle cerebral artery [MCA] territory by head computed tomography [CT] or magnetic resonance imaging [MRI]) who are at high risk of developing malignant edema and who value survival despite the substantial likelihood of survival with severe disability. This surgery may also be offered on a case-by-case basis for otherwise healthy patients older than 60 years of age and beyond 48 hours after stroke onset. https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 5/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate The choice between surgical decompression and medical management ultimately depends upon the values and preferences of patients, families, caregivers, or health care proxy [32]. Hemicraniectomy is clearly an aggressive therapy and may not be appropriate for many patients, particularly for older patients or those who do not wish to survive with severe disability. Hemicraniectomy should proceed only after a thorough discussion with the patient (if cognizant), family, or other relevant medical decision-makers; they should understand that hemicraniectomy increases the odds of survival, but most patients who survive are left with severe to very severe disability. Hemicraniectomy may increase the chance of surviving with only moderate disability in younger patients, but not in those older than 60 years. (See 'Efficacy' below.) Alternative treatment options for malignant hemispheric infarction include medical management of increased intracranial pressure and cerebral edema, and supportive medical care or withdrawal of medical care for those who do not desire aggressive therapy. Standard medical therapy for large hemispheric infarctions, regardless of surgical decision, involves close monitoring for neurologic deterioration secondary to developing or evolving mass effect; management of cerebral edema with measures such as elevation of the head of the bed, osmotic therapy (mannitol or hypertonic saline), and brief periods of hyperventilation as needed; blood pressure, temperature, and glycemic management; and prevention of secondary complications such as aspiration and deep venous thrombosis. (See 'Medical management' below and 'Palliative care' below.) Other aspects that may influence the choice between aggressive medical treatment and surgery include the following: Quality of life In addition to mortality and function, patient-centered outcomes are crucial considerations. However, there are few data about quality of life after hemicraniectomy; evidence from the three major clinical trials is limited by small patient numbers and the early stopping of some of these trials [33-37]. Perspectives may differ before and after the procedure The perspective of patients, families, and caregivers who have survived the hemicraniectomy procedure may differ from the perspective of those contemplating the procedure beforehand. A priori, many may feel that survival with severe disability (ie, unable to walk without assistance and requiring assistance to attend to bodily needs) after stroke is an unacceptable outcome tantamount to or worse than death [38]. By contrast, limited data from observational studies and trials suggest that most patients who survive after hemicraniectomy have favorable responses to the procedure and, in retrospect, would consent to having the procedure again [39]. As an example, among 64 survivors of hemicraniectomy after https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 6/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate infarction in six separate observational reports, 44 patients and families (69 percent) reported that they would favor undergoing decompressive surgery if in the same situation [40]. However, the opinions of survivors of hemicraniectomy may reflect bias since the group is self-selected for the procedure. Survivors may have adapted to a degree of disability that they previously would have considered unacceptable, and their views may be altered by reduced cognitive capacity [31]. Side of infarction and expected deficits There has been controversy about offering hemicraniectomy for large dominant hemisphere infarcts, since survival may be accompanied by poor quality of life due to severe aphasia [41]. However, nondominant hemisphere strokes can lead to severe and disabling deficits related to behavioral change, depression, abulia, inattention, or neglect. These problems may interfere with rehabilitation efforts as much as or more than aphasia. Assessments of patients at risk of stroke have indicated that hemiplegia is sometimes viewed as worse than aphasia or death [38]. Thus, the side of infarction should not influence the decision regarding whether to proceed with hemicraniectomy. However, communication of these expected deficits with the patient, family, or other medical decision-makers are needed to help guide shared decision-making for treatments to follow. In a 2004 systematic review, there was a bias toward surgery of the nondominant hemisphere [40]. Among the 27 patients who had decompression of the dominant hemisphere, functional outcome was no worse than among the 111 patients who had nondominant infarcts. These data must be interpreted cautiously, but it is possible that language deficits may be of less consequence in patients severely disabled by hemiplegia. Additionally, some patients may recover significantly from aphasia after decompressive hemicraniectomy, especially those who are younger. Support for this notion comes from a study that followed 14 patients with left MCA territory infarction who had surgical decompression; a significant improvement in different aspects of aphasia was observed in 13 patients (93 percent) [42]. Palliative care Hemispheric infarction is a devastating event that should prompt discussion about the goals of care and life-sustaining treatment. Faced with a poor prognosis for a good functional recovery and a high probability of death with best medical treatment or severe disability following surgical treatment, some patients and families or caregivers may choose supportive medical care or withdrawal of medical care. However, prognosis for individual patients with acute ischemic stroke cannot be estimated precisely. Therefore, it is reasonable to implement full aggressive medical care for most patients while postponing consideration of limitations to care until at least the second full day of hospitalization after stroke onset. This approach avoids the self-fulfilling prophecy of poor outcomes caused by clinical nihilism. This https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 7/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate recommendation does not apply to patients with preexisting advanced directive orders limiting care, nor to patients who present with minimal brainstem function in whom the possibility of clinical recovery is thought to be negligible. (See "Neuropalliative care of stroke".) MEDICAL MANAGEMENT Immediate interventions As noted above, patients with large or "malignant" hemispheric infarction should be managed in an intensive care unit or stroke unit (with the exception of patients with advanced directives to withhold resuscitation and life support measures and patients who present with catastrophic hemispheric infarction and minimal brainstem function). Basic supportive measures include the following [3,5]: Intubation and mechanical ventilation are indicated for patients who want aggressive care and have diminished level of consciousness, respiratory insufficiency, or neurologic deterioration. (See "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure".) Analgesia and sedation should be used cautiously as needed to treat pain or agitation and to enable procedures. However, these measures should be minimized and stopped as soon as possible because they depress the neurologic status, making it difficult to accurately assess for neurologic deterioration secondary to stroke progression. Analgesia and sedation may also result in hypoventilation in nonventilated patients, leading to additive intracranial pressure burden from vasodilation. Specific blood pressure targets are undefined, but general guidelines for patients with ischemic stroke apply; hypertension with systolic blood pressure >220 mmHg or diastolic >105 mmHg may increase the risk of hemorrhagic transformation and should be treated. Conversely, hypotension should be avoided. (See "Initial assessment and management of acute stroke", section on 'Blood pressure goals in ischemic stroke'.) Low serum glucose (<60 mg/dL [3.3 mmol/L]) should be corrected rapidly. It is reasonable to treat hyperglycemia if the glucose level is >180 mg/dL (>10 mmol/L) with a goal of keeping serum glucose levels within a range of 140 to 180 mg/dL (7.8 to 10 mmol/L). (See "Initial assessment and management of acute stroke", section on 'Hypoglycemia' and "Initial assessment and management of acute stroke", section on 'Hyperglycemia'.) Initially, isotonic saline should be used for fluid maintenance; hypotonic/hypo-osmolar fluids should be strictly avoided. (See "Evaluation and management of elevated intracranial https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 8/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate pressure in adults", section on 'Fluid management'.) Elevation of the head of bed to 30 degrees is suggested for patients at risk for cerebral edema and elevated intracranial pressure. (See "Initial assessment and management of acute stroke", section on 'Head and body position'.) Therapeutic anticoagulation, if previously or currently clinically indicated, should be held following large hemispheric infarctions given the hemorrhagic transformation risk and the potential decompressive hemicraniectomy surgical indication/need. It is reasonable to avoid antiplatelets for the first 48 hours, until the absence of major hemorrhagic conversion is confirmed and once it is clear whether the patient will undergo decompressive hemicraniectomy. Venous thromboembolism prophylaxis is indicated for all patients with stroke who have restricted mobility using intermittent pneumatic compression plus prophylactic low-dose anticoagulation with subcutaneous low molecular weight heparin or unfractionated heparin. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke", section on 'Approach in acute ischemic stroke'.) Dysphagia is common after stroke and is a major risk factor for developing aspiration pneumonia. Prevention of aspiration includes initial nulla per os (NPO) status (including medications) until swallowing function can be evaluated. (See "Complications of stroke: An overview", section on 'Dysphagia'.) Prophylactic osmotic therapy is not recommended prior to the development of brain edema or tissue shifts. However, osmotic therapy with mannitol and/or hypertonic saline is reasonable for patients who develop neurologic deterioration from cerebral edema. (See 'Osmotic and salvage therapies' below.) Fever should be treated if present, with the goal of achieving a normal temperature [3]. Fever is associated with unfavorable outcomes in patients with acute stroke, but pharmacologic treatment to lower temperature has not been proven to be beneficial. Therapeutic hypothermia may lower intracranial pressure but has not been demonstrated to be effective for treating malignant hemispheric infarction [5]. A randomized trial of moderate hypothermia after hemicraniectomy for large hemispheric infarction was stopped early, after only 50 patients were randomized, due to higher rate of serious adverse events among the patients treated with hypothermia without any evidence of improved functional outcomes [43]. (See "Initial assessment and management of acute stroke", section on 'Fever'.) https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 9/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Frequent monitoring Patients with large hemispheric infarction are at high risk for neurologic deterioration associated with the development of cerebral edema and herniation. Frequent monitoring (eg, hourly) for level of consciousness, ipsilateral pupillary dilation, and onset or progression of other neurologic deficits (including early signs such as new development of ipsilateral Babinski sign or cerebral ptosis [ie, inability to open the eyes despite preserved consciousness]) is recommended to identify patients who might benefit from timely urgent interventions (ie, osmotic and salvage therapies, decompressive hemicraniectomy) that might prevent an irreversible decline and fatal outcome [5]. Hourly neurologic checks are indicated in these patients for at least the first 48 hours following stroke onset. Routine intracranial pressure (ICP) monitoring is not recommended; a number of studies suggest ICP monitoring has limited or no value for predicting herniation or improving clinical outcome in this setting [5,7,44,45]. Osmotic and salvage therapies Acute cerebral edema with life-threatening mass effect can be treated, at least temporarily, with hypertonic saline, mannitol, or hyperventilation. These interventions are most effective when used as a bridging therapy to decompressive hemicraniectomy [3], and are not intended for prolonged use. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Osmotic therapy and diuresis'.) Intravenous mannitol quickly and effectively lowers intracranial pressure. Mannitol regimens vary between institutions and regions. It is most common to start with a bolus of 1 to 1.5 g/kg of mannitol 20 percent. Subsequent doses may be scheduled (eg, 0.5 g/kg every 6 hours) or given as needed for signs of clinical decline or radiologic progression. Patients receiving repeated doses of mannitol should have their serum osmolality and osmolar gap monitored to avoid nephrotoxicity; the risk is high when serum osmolality increases above 320 milliosmoles/kg and when the osmolar gap is greater than 20. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Osmotic therapy and diuresis' and "Complications of mannitol therapy".) Hypertonic saline is an effective hyperosmolar agent for lowering intracranial pressure. Bolus doses of various concentrations (from 3 to 23.4 percent) and volumes (most commonly 50 mL of 14 percent or 30 mL of 23.4 percent sodium chloride) can be administered. (See "Management of acute moderate and severe traumatic brain injury", section on 'Osmotic therapy'.) Hyperventilation causes a rapid lowering of intracranial pressure by inducing cerebral vasoconstriction, but the effect is short-lived. Brief hyperventilation may be used as a https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 10/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate bridge to more definitive therapy for deteriorating patients with signs of brainstem herniation [3,46]. A partial pressure of carbon dioxide (PaCO ) goal of 30 to 35 mmHg is 2 suggested. More aggressive (ie, a PaCO goal of 26 to 30 mmHg) or prolonged 2 hyperventilation may result in brain ischemia and worse outcomes. DECOMPRESSIVE HEMICRANIECTOMY Description and goals of surgery Decompressive hemicraniectomy (DHC) with durotomy is a surgical technique used to relieve the increased intracranial pressure and brain tissue shifts that occur in the setting of large cerebral hemisphere mass or space-occupying lesions ( image 3). The main goal of hemicraniectomy for malignant hemispheric infarction is to prevent further brain injury by reversing mass effect, reducing brain tissue shifts, decreasing intracranial pressure, and improving cerebral perfusion pressure [47]. DHC should be considered as an adjunct to optimal medical care, and never a substitute for it. In general, the technique involves removal of bone tissue (skull) and incision of the restrictive dura mater covering the brain, allowing swollen brain tissue to herniate upwards through the surgical defect rather than downwards to compress the brainstem ( image 4 and image 5). Bone resection should be extensive (ideally 12 cm or greater) to allow adequate brain pressure alleviation and avoid brain tissue injury around the borders of the intact skull. Efficacy Evidence from several small randomized controlled trials demonstrates that DHC for massive middle cerebral artery (MCA) territory infarction increases survival, compared with standard medical therapy, but most patients who survive are left with moderately severe to severe disability (ie, a modified Rankin Scale (mRS) ( table 2) score of 4 or 5). However, several of the trials were stopped early, which could lead to an overestimation of effect size [48]. In particular, the individual trial risk estimates for achieving a mRS score of 3 (moderate disability or less) are of low to moderate certainty. Additionally, these separate trials differed in the upper age limit of included patients and the time window within which surgical decompression was performed. A 2021 meta-analysis of seven trials, with patient-level data for 488 patients (including unpublished data from one trial), found that a favorable outcome (defined as a mRS 3) at one year was more likely with DHC compared with medical treatment alone (37 versus 15 percent, absolute difference, 22 percent, adjusted odds ratio [OR] 2.95, 99% CI 1.55-5.60) [49]. In addition, DHC reduced the risk of death at one year (29 versus 71 percent, absolute difference 42 percent, adjusted OR 0.16, 95% CI 0.10-0.24). The favorable outcome benefits of decompressive surgery were consistent across subgroups defined by age (<60 versus >60 years), sex, presence of https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 11/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate aphasia, baseline NIH Stroke Scale score, time to randomization (<24, 24 to 48 and >48 hours), and extent of infarction by vascular territory. However, among patients >60 years old, the proportion who achieved a favorable outcome varied markedly across studies, from 0 to 66 percent, and the authors concluded that the evidence of benefit in older patients remained uncertain. Similarly, too few patients were treated beyond 48 hours to draw reliable conclusions about late treatment. And parallel to the individual trial data, it was again seen that DHC led to increased numbers of patients with moderately severe or severe disability (mRS 4 or 5), although these disability outcomes were not individually analyzed. Thus, as demonstrated by meta-analyses of randomized controlled trials, the primary benefit of DHC across age groups is increased survival. Though DHC increases the number of survivors with moderate or severe disability as illustrated in the figure ( figure 2), it also increases the chances of more favorable outcomes, particularly in patients less than 60 years of age [49-51]. Although these studies assessed clinical efficacy using mRS as the neurological outcome assessment, they did not assess other metrics of outcome such as quality of life or cognitive outcomes. While DHC confers survival benefit in patients older than 60, it is less clear whether DHC improve clinical outcomes in these patients given that they generally do not achieve good neurological outcomes (ie, moderate or slight disability) regardless of treatment. The available data also suggest that DHC within 48 hours is more likely to be beneficial than later hemicraniectomy, as noted in earlier meta-analyses [48,52]. Less robust data suggest but do not establish that later surgery (ie, from 48 to 96 hours) may be beneficial [49,53]. Selection of patients General eligibility criteria for DHC are listed in the table ( table 3). Timing of surgery Some investigators have advocated early (within 24 hours of onset), prophylactic surgical decompression for large hemispheric infarction, before the appearance of signs of herniation. This approach has intuitive appeal since it is logical that early decompressive surgery (before the development of life-threatening herniation with secondary brain injury) should result in the best clinical outcomes [47]. There is also experimental evidence that early surgery is more likely to be beneficial [54,55]. Furthermore, there is clinical evidence that aggressive medical reversal of a single episode of transtentorial herniation in the absence of radiographic evidence of midbrain injury may permit good long-term outcome [56]. These findings suggest that herniation alone does not preclude benefit from surgical decompression and that medical management may be an appropriate initial therapeutic option to a bridge to DHC. https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 12/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate However, the data are limited and conflicting regarding the utility of selecting patients for surgical decompression based upon time since symptom onset to treatment. Timing of surgery has been analyzed for <24 hours, 24 to 48 hours, and 48 to 96 hours. In subgroup analyses of pooled data from three randomized controlled trials, there was no difference in outcome between patients assigned to early (<24 hours after stroke onset, n = 45) or later (24 to 48 hours, n = 38) decompressive surgery [52]. In the HAMLET trial, which evaluated DHC up to 96 hours after stroke onset, there was no benefit on any outcome measure for patients assigned to surgery after 48 hours (n = 25) [35]. However, small numbers of patients treated beyond 48 hours in the meta-analysis [52], HAMLET [35], and HeADDFIRST [57] preclude definitive conclusions about of the possible efficacy of surgical decompression after 48 hours. In a 2004 systematic review of 12 studies with over 100 patients who were treated with hemicraniectomy for malignant MCA territory infarction, the time to treatment, clinical signs of herniation, sex, and side of infarction did not predict outcome with decompressive surgery [40]. Other reports have not found time to treatment to be a predictive factor for outcome, although this may be confounded by variables such as age [58]. A retrospective study from the United States analyzed 1301 patients from the Nationwide Inpatient Sample (2002-2011) who had decompressive craniectomy for stroke [59]. Of these, 726 had surgery within 48 hours. When time was evaluated as a continuous variable, later surgery was associated with increased risk of discharge to institutional care (OR 1.17, 95% CI 1.05-1.31) and poor outcome (OR 1.12, 95% CI 1.02-1.23). Procedure The surgical technique of DHC and durotomy varies in the literature. In general, a large question mark-shaped incision is made in the scalp, starting from the midline, that includes the frontal, parietal, and temporal lobes. A large incision is essential to the success of the procedure to avoid both incomplete release of pressure and further injury to the brain where it is forced against the edges of the craniotomy. A diameter of 12 cm or larger is recommended [3]. The protocol for one pilot trial defined required margins of the skull defect as follows [57]: Anterior: from the floor of the anterior cranial fossa at the mid-pupillary line Posterior: to 4 cm posterior to the external auditory canal Superior: to 1 cm lateral to the superior sagittal sinus Inferior: to the floor of the middle cranial fossa https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 13/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Bone is removed and can be stored in a frozen tissue bank or sewn into the peritoneal cavity of the patient if this is to be reused for later cranioplasty (replacement of skull). The dura is opened with a cruciate incision to allow the brain to swell outwards. In some reports, infarcted tissue is resected ("strokectomy") [60,61]. Other surgeons advocate against tissue resection, as the removal of islands of normal functioning tissue not apparent at the time of surgery may worsen outcome. However, removal of large areas of infarcted tissue may be required in certain cases to ensure adequate decompression and reduce the risk of herniation. Complications Possible complications of craniectomy include hydrocephalus, external brain tamponade, infections, seizures, and paradoxical herniation [62]. The "sinking skin flap" syndrome (SSFS), also termed "syndrome of the trephined," is a delayed complication of craniectomy that can occur when atmospheric pressure exceeds intracranial pressure [62]. The major clinical features are the sunken appearance of the skin over the skull defect and severe
unpublished data from one trial), found that a favorable outcome (defined as a mRS 3) at one year was more likely with DHC compared with medical treatment alone (37 versus 15 percent, absolute difference, 22 percent, adjusted odds ratio [OR] 2.95, 99% CI 1.55-5.60) [49]. In addition, DHC reduced the risk of death at one year (29 versus 71 percent, absolute difference 42 percent, adjusted OR 0.16, 95% CI 0.10-0.24). The favorable outcome benefits of decompressive surgery were consistent across subgroups defined by age (<60 versus >60 years), sex, presence of https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 11/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate aphasia, baseline NIH Stroke Scale score, time to randomization (<24, 24 to 48 and >48 hours), and extent of infarction by vascular territory. However, among patients >60 years old, the proportion who achieved a favorable outcome varied markedly across studies, from 0 to 66 percent, and the authors concluded that the evidence of benefit in older patients remained uncertain. Similarly, too few patients were treated beyond 48 hours to draw reliable conclusions about late treatment. And parallel to the individual trial data, it was again seen that DHC led to increased numbers of patients with moderately severe or severe disability (mRS 4 or 5), although these disability outcomes were not individually analyzed. Thus, as demonstrated by meta-analyses of randomized controlled trials, the primary benefit of DHC across age groups is increased survival. Though DHC increases the number of survivors with moderate or severe disability as illustrated in the figure ( figure 2), it also increases the chances of more favorable outcomes, particularly in patients less than 60 years of age [49-51]. Although these studies assessed clinical efficacy using mRS as the neurological outcome assessment, they did not assess other metrics of outcome such as quality of life or cognitive outcomes. While DHC confers survival benefit in patients older than 60, it is less clear whether DHC improve clinical outcomes in these patients given that they generally do not achieve good neurological outcomes (ie, moderate or slight disability) regardless of treatment. The available data also suggest that DHC within 48 hours is more likely to be beneficial than later hemicraniectomy, as noted in earlier meta-analyses [48,52]. Less robust data suggest but do not establish that later surgery (ie, from 48 to 96 hours) may be beneficial [49,53]. Selection of patients General eligibility criteria for DHC are listed in the table ( table 3). Timing of surgery Some investigators have advocated early (within 24 hours of onset), prophylactic surgical decompression for large hemispheric infarction, before the appearance of signs of herniation. This approach has intuitive appeal since it is logical that early decompressive surgery (before the development of life-threatening herniation with secondary brain injury) should result in the best clinical outcomes [47]. There is also experimental evidence that early surgery is more likely to be beneficial [54,55]. Furthermore, there is clinical evidence that aggressive medical reversal of a single episode of transtentorial herniation in the absence of radiographic evidence of midbrain injury may permit good long-term outcome [56]. These findings suggest that herniation alone does not preclude benefit from surgical decompression and that medical management may be an appropriate initial therapeutic option to a bridge to DHC. https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 12/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate However, the data are limited and conflicting regarding the utility of selecting patients for surgical decompression based upon time since symptom onset to treatment. Timing of surgery has been analyzed for <24 hours, 24 to 48 hours, and 48 to 96 hours. In subgroup analyses of pooled data from three randomized controlled trials, there was no difference in outcome between patients assigned to early (<24 hours after stroke onset, n = 45) or later (24 to 48 hours, n = 38) decompressive surgery [52]. In the HAMLET trial, which evaluated DHC up to 96 hours after stroke onset, there was no benefit on any outcome measure for patients assigned to surgery after 48 hours (n = 25) [35]. However, small numbers of patients treated beyond 48 hours in the meta-analysis [52], HAMLET [35], and HeADDFIRST [57] preclude definitive conclusions about of the possible efficacy of surgical decompression after 48 hours. In a 2004 systematic review of 12 studies with over 100 patients who were treated with hemicraniectomy for malignant MCA territory infarction, the time to treatment, clinical signs of herniation, sex, and side of infarction did not predict outcome with decompressive surgery [40]. Other reports have not found time to treatment to be a predictive factor for outcome, although this may be confounded by variables such as age [58]. A retrospective study from the United States analyzed 1301 patients from the Nationwide Inpatient Sample (2002-2011) who had decompressive craniectomy for stroke [59]. Of these, 726 had surgery within 48 hours. When time was evaluated as a continuous variable, later surgery was associated with increased risk of discharge to institutional care (OR 1.17, 95% CI 1.05-1.31) and poor outcome (OR 1.12, 95% CI 1.02-1.23). Procedure The surgical technique of DHC and durotomy varies in the literature. In general, a large question mark-shaped incision is made in the scalp, starting from the midline, that includes the frontal, parietal, and temporal lobes. A large incision is essential to the success of the procedure to avoid both incomplete release of pressure and further injury to the brain where it is forced against the edges of the craniotomy. A diameter of 12 cm or larger is recommended [3]. The protocol for one pilot trial defined required margins of the skull defect as follows [57]: Anterior: from the floor of the anterior cranial fossa at the mid-pupillary line Posterior: to 4 cm posterior to the external auditory canal Superior: to 1 cm lateral to the superior sagittal sinus Inferior: to the floor of the middle cranial fossa https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 13/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Bone is removed and can be stored in a frozen tissue bank or sewn into the peritoneal cavity of the patient if this is to be reused for later cranioplasty (replacement of skull). The dura is opened with a cruciate incision to allow the brain to swell outwards. In some reports, infarcted tissue is resected ("strokectomy") [60,61]. Other surgeons advocate against tissue resection, as the removal of islands of normal functioning tissue not apparent at the time of surgery may worsen outcome. However, removal of large areas of infarcted tissue may be required in certain cases to ensure adequate decompression and reduce the risk of herniation. Complications Possible complications of craniectomy include hydrocephalus, external brain tamponade, infections, seizures, and paradoxical herniation [62]. The "sinking skin flap" syndrome (SSFS), also termed "syndrome of the trephined," is a delayed complication of craniectomy that can occur when atmospheric pressure exceeds intracranial pressure [62]. The major clinical features are the sunken appearance of the skin over the skull defect and severe orthostatic headache. Associated symptoms may include focal neurologic deficits, seizures, and altered mental status. Unchecked, SSFS may progress to paradoxical brain herniation, coma, and death. In the DECIMAL trial, with follow-up data available from 27 patients, SSFS developed at three to five months after hemicraniectomy in three patients (11 percent) [63]. Radiologic SSFS developed in another four patients (15 percent) and was generally asymptomatic except for partial seizures affecting one patient. Management of SSFS and paradoxical herniation, which is a neurocritical care emergency, requires measures that increase intracranial pressure, such as Trendelenburg position, intravenous hydration, clamping of cerebrospinal fluid drainage, and discontinuation of hyperosmolar measures [62]. In the absence of paradoxical herniation, SSFS may respond to intravenous fluid administration and supine position with head turned down to the side of the craniectomy [63]. Cranioplasty is the definitive treatment for this syndrome. Independent of SSFS, cranioplasty is a necessary second-phase procedure for stroke survivors with hemicraniectomies. While the timing of cranioplasties varies, there is evidence that earlier cranioplasty (potentially within same hospitalization) is associated with enhanced neurologic recovery [64], potentially attributable to restoration of cerebral hemo- and hydrodynamics. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 14/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate SUMMARY AND RECOMMENDATIONS Malignant hemispheric infarction This type of stroke is characterized by the development of space-occupying cerebral edema that is severe enough to produce brain tissue shifts and herniation. Clinical features typically include forced gaze deviation, visual field deficit, hemiplegia, and aphasia or neglect, depending on the hemisphere involved. The most common etiology is cardioembolic or thrombotic occlusion of the internal carotid artery or the proximal segment (stem or M1 segment) of the middle cerebral artery (MCA). The mortality is as high as 78 percent due to herniation of the temporal lobe on to the brainstem. (See 'Description' above and 'Presentation and progression' above.) Predictors of malignant edema Markers that may predict the development of malignant edema after a large hemispheric infarction include the early onset of decreased consciousness, younger age, higher National Institutes of Health Stroke Scale (NIHSS) scores on admission, and evidence of early infarction involving >50 percent of the MCA on initial head computed tomography (CT) or magnetic resonance imaging (MRI). (See 'Clinical predictors of progression' above and 'Radiologic predictors of progression' above.) Medical treatment options These include management of increased intracranial pressure and cerebral edema, and supportive medical care or withdrawal of medical care for those who do not desire aggressive therapy. Standard medical therapy for large hemispheric infarctions involves close monitoring for neurologic complications, such as depressed mental status and herniation; management of intracerebral pressure, with measures such as elevation of the head of the bed, osmotic therapy, and brief periods of hyperventilation as needed; and prevention of secondary complications such as aspiration and deep venous thrombosis. (See 'Medical management' above and 'Palliative care' above.) Outcomes with hemicraniectomy Decompressive hemicraniectomy (DHC) for malignant hemispheric infarction substantially reduces mortality. However, most surviving patients are left with major disability. Thus, the dilemma for patients, families, and medical decision- makers is that surgery may leave patients alive with severe disability, while medical management alone most often results in death. Among patients older than 60 years of age with malignant hemispheric infarction, DHC can increase survival, yet it is less clear whether DHC will confer clinical benefit in these patients, and most who survive are left with severe to very severe disability. (See 'Surgical decompression or medical care only?' above and 'Efficacy' above.) https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 15/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Possible complications of DHC include hydrocephalus, infections, seizures, intracranial hemorrhage and fluid collections, sinking skin flap syndrome, and paradoxical herniation. (See 'Complications' above.) Our approach For patients age 60 years or younger with infarction involving >50 percent of the MCA territory associated with a decreased level of consciousness, who are thus at high risk of developing malignant edema, we suggest decompressive hemicraniectomy (DHC) if surgery can be initiated within 48 hours of stroke onset (Grade 2B). Hemicraniectomy should occur only after a thorough discussion with the patient (if cognizant), family, or appropriate medical decision-makers (eg, health care proxy); they should understand that hemicraniectomy increases the odds of survival and may increase the chance of surviving with only moderate disability, but most patients who survive are left with severe to very severe disability. The alternative treatment of aggressive medical therapy for malignant edema may be considered if surgery is deferred. (See 'Surgical decompression or medical care only?' above and 'Decompressive hemicraniectomy' above and 'Medical management' above.) 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Rahme R, Zuccarello M, Kleindorfer D, et al. Decompressive hemicraniectomy for malignant middle cerebral artery territory infarction: is life worth living? J Neurosurg 2012; 117:749. 40. Gupta R, Connolly ES, Mayer S, Elkind MS. Hemicraniectomy for massive middle cerebral artery territory infarction: a systematic review. Stroke 2004; 35:539. 41. Carter BS, Ogilvy CS, Candia GJ, et al. One-year outcome after decompressive surgery for massive nondominant hemispheric infarction. Neurosurgery 1997; 40:1168. 42. Kastrau F, Wolter M, Huber W, Block F. Recovery from aphasia after hemicraniectomy for infarction of the speech-dominant hemisphere. Stroke 2005; 36:825. 43. Neugebauer H, Schneider H, B sel J, et al. Outcomes of Hypothermia in Addition to Decompressive Hemicraniectomy in Treatment of Malignant Middle Cerebral Artery Stroke: A Randomized Clinical Trial. JAMA Neurol 2019; 76:571. 44. Bardutzky J, Schwab S. Antiedema therapy in ischemic stroke. Stroke 2007; 38:3084. 45. Poca MA, Benejam B, Sahuquillo J, et al. Monitoring intracranial pressure in patients with malignant middle cerebral artery infarction: is it useful? J Neurosurg 2010; 112:648. 46. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. 47. Wijman CA. Editorial comment Can we predict massive space-occupying edema in large hemispheric infarctions? Stroke 2003; 34:1899. 48. Cruz-Flores S, Berge E, Whittle IR. Surgical decompression for cerebral oedema in acute ischaemic stroke. Cochrane Database Syst Rev 2012; 1:CD003435. https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 19/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate 49. Reinink H, J ttler E, Hacke W, et al. Surgical Decompression for Space-Occupying Hemispheric Infarction: A Systematic Review and Individual Patient Meta-analysis of Randomized Clinical Trials. JAMA Neurol 2021; 78:208. 50. Alexander P, Heels-Ansdell D, Siemieniuk R, et al. Hemicraniectomy versus medical treatment with large MCA infarct: a review and meta-analysis. BMJ Open 2016; 6:e014390. 51. Back L, Nagaraja V, Kapur A, Eslick GD. Role of decompressive hemicraniectomy in extensive middle cerebral artery strokes: a meta-analysis of randomised trials. Intern Med J 2015; 45:711. 52. Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 2007; 6:215. 53. Dower A, Mulcahy M, Maharaj M, et al. Surgical decompression for malignant cerebral oedema after ischaemic stroke. Cochrane Database Syst Rev 2022; 11:CD014989. 54. Forsting M, Reith W, Sch bitz WR, et al. Decompressive craniectomy for cerebral infarction. An experimental study in rats. Stroke 1995; 26:259. 55. Doerfler A, Engelhorn T, Heiland S, et al. Perfusion- and diffusion-weighted magnetic resonance imaging for monitoring decompressive craniectomy in animals with experimental hemispheric stroke. J Neurosurg 2002; 96:933. 56. Qureshi AI, Geocadin RG, Suarez JI, Ulatowski JA. Long-term outcome after medical reversal of transtentorial herniation in patients with supratentorial mass lesions. Crit Care Med 2000; 28:1556. 57. Frank JI, Schumm LP, Wroblewski K, et al. Hemicraniectomy and durotomy upon deterioration from infarction-related swelling trial: randomized pilot clinical trial. Stroke 2014; 45:781. 58. Curry WT Jr, Sethi MK, Ogilvy CS, Carter BS. Factors associated with outcome after hemicraniectomy for large middle cerebral artery territory infarction. Neurosurgery 2005; 56:681. 59. Dasenbrock HH, Robertson FC, Vaitkevicius H, et al. Timing of Decompressive Hemicraniectomy for Stroke: A Nationwide Inpatient Sample Analysis. Stroke 2017; 48:704. 60. Kalia KK, Yonas H. An aggressive approach to massive middle cerebral artery infarction. Arch Neurol 1993; 50:1293. 61. Moughal S, Trippier S, Al-Mousa A, et al. Strokectomy for malignant middle cerebral artery infarction: experience and meta-analysis of current evidence. J Neurol 2022; 269:149. https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 20/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate 62. Akins PT, Guppy KH. Sinking skin flaps, paradoxical herniation, and external brain tamponade: a review of decompressive craniectomy management. Neurocrit Care 2008; 9:269. 63. Sarov M, Guichard JP, Chibarro S, et al. Sinking skin flap syndrome and paradoxical herniation after hemicraniectomy for malignant hemispheric infarction. Stroke 2010; 41:560. 64. Malcolm JG, Rindler RS, Chu JK, et al. Early Cranioplasty is Associated with Greater Neurological Improvement: A Systematic Review and Meta-Analysis. Neurosurgery 2018; 82:278. Topic 1096 Version 27.0 https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 21/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate GRAPHICS National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The investigator must choose a response if a full 0 = Alert; keenly responsive. 1 = Not alert; but arousable by minor evaluation is prevented by such obstacles as stimulation to obey, answer, or respond. an endotracheal tube, language barrier, orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement (other than reflexive posturing) in response to noxious stimulation. 2 = Not alert; requires repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). _____ 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The patient is asked the month and his/her age. The answer must be correct - there is no 0 = Answers both questions correctly. 1 = Answers one question correctly. 2 = Answers neither question correctly. partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The 0 = Performs both tasks correctly. _____ patient is asked to open and close the eyes 1 = Performs one task correctly. and then to grip and release the non-paretic hand. Substitute another one step 2 = Performs neither task correctly. command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 22/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate the task should be demonstrated to him or her (pantomime), and the result scored (ie, follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye 0 = Normal. movements will be tested. Voluntary or reflexive (oculocephalic) eye movements will 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or total gaze paresis is not present. be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- _____ existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, 0 = No visual loss. 1 = Partial hemianopia. using finger counting or visual threat, as appropriate. Patients may be encouraged, but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or 2 = Complete hemianopia. 3 = Bilateral hemianopia (blind including cortical blindness). enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score fold, asymmetry on smiling). symmetry of grimace in response to noxious stimuli in the poorly responsive or non- https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 23/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate comprehending patient. If facial 2 = Partial paralysis (total or near-total trauma/bandages, orotracheal tube, tape or paralysis of lower face). other physical barriers obscure the face, these should be removed to the extent 3 = Complete paralysis of one or both sides (absence of facial movement in the upper and lower face). possible. 5. Motor arm: The limb is placed in the 0 = No drift; limb holds 90 (or 45) degrees appropriate position: extend the arms for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not falls before 10 seconds. The aphasic patient is encouraged using urgency in the voice hit bed or other support. 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) and pantomime, but not noxious stimulation. Each limb is tested in turn, degrees, drifts down to bed, but has some effort against gravity. beginning with the non-paretic arm. Only in _____ the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The aphasic patient is encouraged using urgency in the voice and pantomime, but not 0 = No drift; leg holds 30-degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. Only in the case of amputation or joint _____ 3 = No effort against gravity; leg falls to fusion at the hip, the examiner should record the score as untestable (UN), and bed immediately. 4 = No movement. clearly write the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. 0 = Absent. _____ 1 = Present in one limb. Test with eyes open. In case of visual defect, 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 24/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate are performed on both sides, and ataxia is UN = Amputation or joint fusion, scored only if present out of proportion to explain:________________ weakness. Ataxia is absent in the patient who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick when tested, or withdrawal from noxious 0 = Normal; no sensory loss. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the stimulus in the obtunded or aphasic patient. Only sensory loss attributed to stroke is affected side; or there is a loss of superficial scored as abnormal and the examiner pain with pinprick, but patient is aware of being touched. should test as many body areas (arms [not hands], legs, trunk, face) as needed to accurately check for hemisensory loss. A 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, and leg. score of 2, "severe or total sensory loss," should only be given when a severe or total loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If _____ the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of information about comprehension will be obtained during the preceding sections of 0 = No aphasia; normal. _____ 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant the examination. For this scale item, the patient is asked to describe what is limitation on ideas expressed or form of happening in the attached picture, to name the items on the attached naming sheet and expression. Reduction of speech and/or comprehension, however, makes to read from the attached list of sentences. conversation about provided materials difficult or impossible. For example, in Comprehension is judged from responses here, as well as to all of the commands in conversation about provided materials, examiner can identify picture or naming the preceding general neurological exam. If visual loss interferes with the tests, ask the card content from patient's response. patient to identify objects placed in the hand, repeat, and produce speech. The 2 = Severe aphasia; all communication is through fragmentary expression; great need for inference, questioning, and guessing by intubated patient should be asked to write. The patient in a coma (item 1a=3) will automatically score 3 on this item. The the listener. Range of information that can https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 25/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate examiner must choose a score for the be exchanged is limited; listener carries patient with stupor or limited cooperation, burden of communication. Examiner cannot but a score of 3 should be used only if the patient is mute and follows no one-step identify materials provided from patient response. commands. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be 0 = Normal. normal, an adequate sample of speech must be obtained by asking patient to read or 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can repeat words from the attached list. If the patient has severe aphasia, the clarity of be understood with some difficulty. 2 = Severe dysarthria; patient's speech is so slurred as to be unintelligible in the absence articulation of spontaneous speech can be rated. Only if the patient is intubated or has _____ of or out of proportion to any dysphasia, or is mute/anarthric. other physical barriers to producing speech, the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explain:________________ explanation for this choice. Do not tell the patient why he or she is being tested.
performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score fold, asymmetry on smiling). symmetry of grimace in response to noxious stimuli in the poorly responsive or non- https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 23/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate comprehending patient. If facial 2 = Partial paralysis (total or near-total trauma/bandages, orotracheal tube, tape or paralysis of lower face). other physical barriers obscure the face, these should be removed to the extent 3 = Complete paralysis of one or both sides (absence of facial movement in the upper and lower face). possible. 5. Motor arm: The limb is placed in the 0 = No drift; limb holds 90 (or 45) degrees appropriate position: extend the arms for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not falls before 10 seconds. The aphasic patient is encouraged using urgency in the voice hit bed or other support. 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) and pantomime, but not noxious stimulation. Each limb is tested in turn, degrees, drifts down to bed, but has some effort against gravity. beginning with the non-paretic arm. Only in _____ the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The aphasic patient is encouraged using urgency in the voice and pantomime, but not 0 = No drift; leg holds 30-degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. Only in the case of amputation or joint _____ 3 = No effort against gravity; leg falls to fusion at the hip, the examiner should record the score as untestable (UN), and bed immediately. 4 = No movement. clearly write the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. 0 = Absent. _____ 1 = Present in one limb. Test with eyes open. In case of visual defect, 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 24/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate are performed on both sides, and ataxia is UN = Amputation or joint fusion, scored only if present out of proportion to explain:________________ weakness. Ataxia is absent in the patient who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick when tested, or withdrawal from noxious 0 = Normal; no sensory loss. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the stimulus in the obtunded or aphasic patient. Only sensory loss attributed to stroke is affected side; or there is a loss of superficial scored as abnormal and the examiner pain with pinprick, but patient is aware of being touched. should test as many body areas (arms [not hands], legs, trunk, face) as needed to accurately check for hemisensory loss. A 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, and leg. score of 2, "severe or total sensory loss," should only be given when a severe or total loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If _____ the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of information about comprehension will be obtained during the preceding sections of 0 = No aphasia; normal. _____ 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant the examination. For this scale item, the patient is asked to describe what is limitation on ideas expressed or form of happening in the attached picture, to name the items on the attached naming sheet and expression. Reduction of speech and/or comprehension, however, makes to read from the attached list of sentences. conversation about provided materials difficult or impossible. For example, in Comprehension is judged from responses here, as well as to all of the commands in conversation about provided materials, examiner can identify picture or naming the preceding general neurological exam. If visual loss interferes with the tests, ask the card content from patient's response. patient to identify objects placed in the hand, repeat, and produce speech. The 2 = Severe aphasia; all communication is through fragmentary expression; great need for inference, questioning, and guessing by intubated patient should be asked to write. The patient in a coma (item 1a=3) will automatically score 3 on this item. The the listener. Range of information that can https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 25/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate examiner must choose a score for the be exchanged is limited; listener carries patient with stupor or limited cooperation, burden of communication. Examiner cannot but a score of 3 should be used only if the patient is mute and follows no one-step identify materials provided from patient response. commands. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be 0 = Normal. normal, an adequate sample of speech must be obtained by asking patient to read or 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can repeat words from the attached list. If the patient has severe aphasia, the clarity of be understood with some difficulty. 2 = Severe dysarthria; patient's speech is so slurred as to be unintelligible in the absence articulation of spontaneous speech can be rated. Only if the patient is intubated or has _____ of or out of proportion to any dysphasia, or is mute/anarthric. other physical barriers to producing speech, the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explain:________________ explanation for this choice. Do not tell the patient why he or she is being tested. 11. Extinction and inattention (formerly neglect): Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are 0 = No abnormality. 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. 2 = Profound hemi-inattention or extinction to more than one modality; normal, the score is normal. If the patient has aphasia but does appear to attend to both sides, the score is normal. The presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ does not recognize own hand or orients to only one side of space. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 26/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate CT large right hemispheric infarction Head CT showing a large acute right middle cerebral artery territory infarction. CT: computed tomography. Image courtesy of Alejandro Rabinstein, MD. Graphic 120602 Version 1.0 https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 27/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate ASPECTS study form The ASPECTS value is calculated from two standard axial CT cuts: one at the level of the thalamus and basal ganglia (left), and one just rostral to the basal ganglia (right). A: anterior circulation; P: posterior circulation; C: caudate; L: lentiform; IC: internal capsule; I: insular ribbon; MCA: middle cerebral artery; M1: anterior MCA cortex; M2: MCA cortex lateral to insular ribbon; M3: posterior MCA cortex; M4, M5, and M6 are anterior, lateral, and posterior MCA territories immediately superior to M1, M2, and M3, rostral to basal ganglia Reproduced with permission from: Barber, PA, Demchuk, AM, Zhang, J, Buchan, AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000; 355:1670. Copyright 2000 The Lancet. Graphic 72190 Version 1.0 https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 28/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate MRI large left hemispheric infarction Brain MRI showing a large acute left hemisphere infarction on diffusion-weighted imaging. MRI: magnetic resonance imaging. Reproduced with permission. Copyright 2014 American Heart Association, Inc. Graphic 120601 Version 10.0 https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 29/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Brain imaging findings before and after hemicraniectomy in malignant MCA infarction (A) Axial cranial CT seven hours after stroke onset. Arrows indicate the margins of the infarction. (B) Axial diffusion-weighted MRI in the acute phase of malignant MCA infarction. (C) and (D) Axial CT on day two after symptom onset after hemicraniectomy. Note that despite decompressive surgery, a compression of the ventricular system with slight midline shifting (C; axial CT at the level of the basal ganglia) and a beginning outward swelling (D; axial CT at the supraventricular level) of the ischemic brain tissue is evident. https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 30/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate CT: computed tomography; MCA: middle cerebral artery; MRI: magnetic resonance imaging. Reproduced from: Huttner HB, Schwab S. Malignant middle cerebral artery infarction: clinical characteristics, treatment strategies, and future perspectives. Lancet Neurol 2009; 8:949. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 120610 Version 1.0 https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 31/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Decompressive hemicraniectomy for malignant right MCA infarction (Panel A) Head CT scan of a large right MCA infarction before hemicraniectomy. (Panel B) Head CT scan after decompressive hemicraniectomy. MCA: middle cerebral artery; CT: computed tomography. Images courtesy of Alejandro Rabinstein, MD. Graphic 120612 Version 1.0 https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 32/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Decompressive hemicraniectomy for malignant left MCA infarction (Panel A) Head CT scan of a large left MCA infarction before hemicraniectomy. (Panel B) Head CT scan after decompressive hemicraniectomy. MCA: middle cerebral artery; CT: computed tomography. Images courtesy of Alejandro Rabinstein, MD. Graphic 120611 Version 1.0 https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 33/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 34/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Functional outcome after decompressive hemicraniectomy for malignant midd cerebral artery territory infarction (A) Functional outcome after hemicraniectomy and after medical (conservative) treatment according to the mRS score. (B) Functional outcome after hemicraniectomy and after medical (conservative) treatment according to the mRS score (six months data, five trials). mRS: modified Rankin Scale. https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 35/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate From: Alexander P, Heels-Ansdell D, Siemieniuk R, et al. Hemicraniectomy versus medical treatment with large MCA infarct: a review and meta-analysis. BMJ Open 2016; 6:e014390. Reproduced with permission from BMJ Publishing Group Ltd. Copyright 2016. Graphic 111928 Version 1.0 https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 36/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate General eligibility criteria for three major trials (DECIMAL, DESTINY, HAMLET) evaluating decompressive hemicraniectomy for malignant middle cerebral artery territory infarction Inclusion criteria: Age 18 to 60 years* Clinical deficits suggestive of infarction in the territory of the MCA with a NIHSS score 16 Decrease in the level of consciousness to a score of 1 on item 1a of the NIHSS Signs on brain CT of an infarct of 50 percent of the MCA territory, with or without additional infarction in the territory of the ipsilateral anterior or posterior cerebral artery, or infarct volume 3 >145 cm on diffusion-weighted brain MRI Time from symptom onset to start of surgical decompression <48 hours Written informed consent by the patient or a legal representative Exclusion criteria: Prestroke mRS score 2 Both pupils fixed and dilated Contralateral ischemia or other brain lesion that could affect outcome Space-occupying hemorrhagic transformation of the infarct Life expectancy <3 years Other serious illness that could affect outcome Known coagulopathy or systemic bleeding disorder Contraindication for anesthesia mRS: modified Rankin Scale; MCA: middle cerebral artery; NIHSS: National Institutes of Health Stroke Scale. Four other trials included patients over age 60. Data from: 1. Vahedi K, Vicaut E, Mateo J, et al. Sequential-design, multicenter, randomized, controlled trial of early decompressive craniectomy in malignant middle cerebral artery infarction (DECIMAL Trial). Stroke 2007; 38:2506. 2. J ttler E, Schwab S, Schmiedek P, et al. Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY): a randomized, controlled trial. Stroke 2007; 38:2518. 3. Hofmeijer J, Kappelle LJ, Algra A, et al. Surgical decompression for space-occupying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]): a multicentre, https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 37/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate open, randomised trial. Lancet Neurol 2009; 8:326. 4. Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 2007; 6:215. Graphic 108328 Version 2.0 https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 38/39 7/6/23, 12:02 PM Malignant cerebral hemispheric infarction with swelling and risk of herniation - UpToDate Contributor Disclosures David Roh, MD Grant/Research/Clinical Trial Support: Biogen [Large hemispheric ischemic stroke]. All of the relevant financial relationships listed have been mitigated. Rishi Gupta, MD Grant/Research/Clinical Trial Support: Rapid Medical [Endovascular stroke therapy]; Stryker Neurovascular [Endovascular stroke therapy]; ZOLL Medical Corporation [Stroke]. Consultant/Advisory Boards: Cerenovous [Stroke]; Rapid Medical [Endovascular stroke therapy]; Stryker Neurovascular [Endovascular stroke therapy]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator-initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/malignant-cerebral-hemispheric-infarction-with-swelling-and-risk-of-herniation/print 39/39
7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Mechanical thrombectomy for acute ischemic stroke : Jamary Oliveira-Filho, MD, MS, PhD, Owen B Samuels, MD : Jos Biller, MD, FACP, FAAN, FAHA, Alejandro A Rabinstein, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 30, 2023. INTRODUCTION Timely restoration of cerebral blood flow using reperfusion therapy is the most effective maneuver for salvaging ischemic brain tissue that is not already infarcted. There is a narrow window during which this can be accomplished since the benefit of reperfusion decreases over time. This topic will review the use of mechanical thrombectomy (MT) for acute ischemic stroke. The approach to reperfusion therapy for acute ischemic stroke, including the use of intravenous thrombolytic therapy (recombinant tissue plasminogen activator or tPA), is reviewed elsewhere. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) OVERVIEW OF REPERFUSION THERAPY For eligible patients with acute ischemic stroke, intravenous thrombolytic therapy with alteplase or tenecteplase is first-line therapy, provided that treatment is initiated within 4.5 hours since the time the patient was last known to be well ( table 1). Because the benefit is time dependent, it is critical to treat patients as quickly as possible; eligible patients should receive intravenous thrombolytic therapy without delay even if mechanical thrombectomy (MT) is being considered. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) MT is indicated for patients with acute ischemic stroke due to a large artery occlusion in the anterior circulation who can be treated within 24 hours of the time last known to be well (ie, at https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 1/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate neurologic baseline), regardless of whether they receive intravenous thrombolytic therapy for the same ischemic stroke event, as discussed in the sections that follow. Two issues may limit the widespread clinical use of MT. First, only an estimated 10 percent of patients with acute ischemic stroke have a proximal large artery occlusion in the anterior circulation and present early enough to qualify for MT within 6 hours [1-4], while approximately 9 percent of patients presenting in the 6- to 24-hour time window may qualify for MT [5]. Second, only a few stroke centers have sufficient resources and expertise to deliver this therapy [6]. However, eligible patients should receive standard treatment with intravenous thrombolysis if they present to hospitals where thrombectomy is not an option, and those with qualifying anterior circulation strokes from large artery occlusion should then be transferred, if at all possible, to tertiary stroke centers in which intra-arterial thrombectomy is available, a strategy called "drip and ship" [7]. PATIENT SELECTION Patients with ischemic stroke caused by a proximal large artery occlusion in the anterior circulation are candidates for intra-arterial mechanical thrombectomy (MT) if they present to, or can be transferred expeditiously to, a stroke center with expertise in the use of second- generation stent retrievers for acute ischemic stroke. Intra-arterial MT can be used in addition to treatment with intravenous thrombolysis using alteplase or tenecteplase. MT treatment should be started as quickly as possible and should not be delayed to assess the response to intravenous tissue plasminogen activator (tPA). Treatment with intravenous thrombolysis prior to MT is also known as bridging therapy. The potential efficacy of bridging therapy compared with MT alone is reviewed separately. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'IVT followed by MT'.) Who to treat For patients with acute ischemic stroke, we recommend treatment with intra- arterial MT, whether or not the patient received treatment with intravenous thrombolytic therapy, if the following conditions are met: Brain imaging using computed tomography (CT) without contrast or diffusion-weighted magnetic resonance imaging (DWI) excludes hemorrhage and is consistent with an Alberta Stroke Program Early CT Score (ASPECTS) 3. (See 'Role of ASPECTS method' below.) CT angiography (CTA) or MR angiography (MRA) demonstrates a proximal large vessel occlusion in the anterior circulation as the cause of the ischemic stroke. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 2/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate The patient has a persistent, potentially disabling neurologic deficit; some guidelines table 2) of 6 points require a National Institutes of Health Stroke Scale (NIHSS) score ( (calculator 1) [8]. Thrombectomy can be started within 24 hours of the time the patient was last known to be well. This recommendation applies when thrombectomy is performed at a stroke center with appropriate expertise in the use of endovascular therapy. Benefit may be most likely for patients who start treatment within 6 hours, or when imaging confirms the presence of salvageable brain tissue (eg, a mismatch by DAWN or DEFUSE 3 criteria) for patients who start treatment in the 6- to 24-hour time window. (See 'Benefit with a clinical or tissue mismatch defined by imaging' below.) Additional considerations Selection with CTP or DWI/PWI using automated infarct core analysis At stroke centers that have advanced imaging capability, using CT perfusion (CTP) imaging or DWI with perfusion-weighted magnetic resonance imaging (PWI), along with automated software imaging analysis to determine infarct volume, patients with acute anterior circulation ischemic stroke due to large vessel occlusion can be selected for MT if they have salvageable brain tissue, with a mismatch between a relatively larger area of ischemia (ie, hypoperfused brain tissue) and a smaller area of infarct core (ie, irreversibly injured brain tissue). The DAWN and DEFUSE 3 trials selected patients for treatment beyond 6 hours using these methods. Patients with little or no salvageable brain tissue were excluded from MT in these trials. (See 'Benefit with a clinical or tissue mismatch defined by imaging' below and "Neuroimaging of acute stroke", section on 'Mismatch and salvageable brain tissue'.) However, with increasing experience and evidence from clinical trials, the need for CTP or DWI/PWI to select patients for MT in the late time window (6 to 24 hours) is no longer considered essential [9]. Selection without automated infarct core analysis At stroke centers without CTP or automated infarct volume determination, patients with acute anterior circulation ischemic stroke due to large vessel occlusion can be selected for MT by several evidence-based methods: The presence of a large ischemic core (eg, defined by an ASPECTS 3 to 5 or a core volume 50 mL) (see 'Role of ASPECTS method' below and 'Benefit for large core infarcts' below) https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 3/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Preserved collateral flow by CTA in the ischemic territory (see 'Benefit with collateral flow' below and "Neuroimaging of acute stroke", section on 'Collateral blood flow') Comorbidities Patients with severe comorbidities prior to stroke onset (eg, pre-existing severe disability, life expectancy less than six months) are unlikely to benefit from MT, particularly if they have a large core infarct. However, findings from an observational study suggest that patients with slight or moderate prestroke disability, defined by a modified Rankin Scale (mRS) score ( table 3) of 2 or 3, have a similar likelihood of recovery to their prestroke level of function after treatment with MT compared with patients who are independent at baseline [10]. Prior intravenous thrombolysis Many patients who are eligible for MT will be treated with intravenous thrombolytic therapy using alteplase or tenecteplase prior to MT. Patients who are not candidates for intravenous thrombolytic therapy can still be treated with MT if otherwise eligible according to the criteria outlined here and above (see 'Who to treat' above). As an example, patients with infective endocarditis, which is a contraindication to intravenous thrombolysis, may still undergo MT if otherwise eligible [11]. Who not to treat While eligibility for MT has expanded since 2015 with trials showing benefit of MT in the 6- to 24-hour time window using several different selection criteria (see 'Benefit of later (6 to 24 hours) treatment' below), there are still scenarios where treatment may be futile if not dangerous. We would not treat patients with MT who have any of the following clinical and imaging findings: Presence of a large established hypodensity on head CT beyond the more subtle, early ischemic changes assessed by ASPECTS. (See 'Role of ASPECTS method' below.) No ischemic penumbra (ie, no mismatch suggesting no salvageable brain tissue) on CTP or DWI/PWI if these studies are performed, particularly if the infarct core is large. However, doing CTP or magnetic resonance imaging (MRI) before MT is not indispensable, even in patients with low ASPECTS on CT. Presence of a large core infarct (eg, defined by an ASPECTS 3 to 5 or imaging showing a core volume 50 mL) and severe prestroke comorbidities (eg, pre-existing severe disability such as mRS 4 to 5, or life expectancy less than six months). Individualized decisions The decision to employ MT needs to be carefully individualized for patients with anterior circulation stroke who do not precisely match all the inclusion or exclusion criteria as listed above. Examples include patients with imaging evidence of salvageable brain tissue who are beyond the 24-hour time window [12,13], with distal medium vessel occlusion https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 4/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate (eg, anterior cerebral artery beyond the A1 segment, middle cerebral artery beyond the proximal M2 segment) [14,15], or with minor stroke (NIHSS 5) [16]. The less severe the stroke deficits, the more difficult the treatment decision becomes because there is more to lose in case of a symptomatic hemorrhage. Role of ASPECTS method The ASPECTS was developed to provide a simple and reliable method of assessing ischemic changes on head CT scan in order to identify acute stroke patients unlikely to make an independent recovery despite thrombolytic treatment [17]. The ASPECTS method has also been adopted to assess the extent of ischemia on DWI; the ability to detect early ischemic changes by ASPECTS was similar on noncontrast CT and DWI [18]. Original (MCA territory) ASPECTS The ASPECTS value is calculated from two standard axial CT cuts; one at the level of the thalamus and basal ganglia, and one just rostral to the basal ganglia ( figure 1) [17,19]. The ASPECTS method divides the middle cerebral artery (MCA) territory into 10 regions of interest. Subcortical structures are allotted three points: one each for caudate, lentiform nucleus, and internal capsule. MCA cortex is allotted seven points: Four of these points come from the axial CT cut at the level of the basal ganglia, with one point for insular cortex and one point each for M1, M2, and M3 regions (anterior, lateral, and posterior MCA cortex). Three points come from the CT cut just rostral to the basal ganglia, with one point each for M4, M5, and M6 regions (anterior, lateral, and posterior MCA cortex). One point is subtracted for an area of early ischemic change, such as focal swelling or parenchymal hypoattenuation, for each of the defined regions. Therefore, a normal CT scan without ischemic change has an ASPECTS value of 10 points, while diffuse ischemic change throughout the MCA territory gives a value of 0. Posterior circulation ASPECTS The pc-ASPECTS subtracts one point for each ischemic lesion (right or left) of the thalamus, cerebellar hemisphere, or posterior cerebral artery territory, and two points for each lesion in the mesencephalon or pons [20,21]. A normal pc-ASPECTS has a value of 10 points; lower scores indicate greater extent of infarction. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 5/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate EFFICACY OF MECHANICAL THROMBECTOMY Early (within 24 hours) intra-arterial treatment with second-generation mechanical thrombectomy (MT) devices is safe and effective for reducing disability and is superior to standard treatment with intravenous thrombolysis alone for the treatment of acute ischemic stroke caused by a documented large artery occlusion in the proximal anterior circulation ( figure 2 and figure 3). Anterior circulation stroke Benefit of early (within 6 hours) treatment Landmark trials demonstrating benefit Five multicenter, open-label randomized controlled trials (MR CLEAN [22,23], ESCAPE [24], SWIFT PRIME [25], EXTEND-IA [26], and REVASCAT [27]) demonstrated that early intra-arterial treatment with second-generation MT devices is safe and effective for reducing disability and is superior to standard treatment with intravenous thrombolysis alone for ischemic stroke caused by a documented large artery occlusion in the proximal anterior circulation [1,28-34]. The number needed to treat (NNT) for one additional person to achieve functional independence in these trials ranged from approximately 3 to 7.5 [22-27,35]. When the positive results of the MR CLEAN trial were announced in late 2014 [22], the remaining trials (ESCAPE [24], SWIFT PRIME [25], EXTEND-IA [26], and REVASCAT [27]) were stopped early on the basis of positive interim efficacy analyses. All of these trials enrolled overlapping but not identical patient populations and had generally similar results. These trials included patients with a proximal large artery occlusion in the anterior circulation as the cause of the ischemic stroke who could start treatment (femoral puncture) within 6 hours of symptom onset. They excluded patients with large core infarcts, restricting eligibility to patients with an Alberta Stroke Program Early CT Score (ASPECTS) 6 or an infarct core volume <50 mL as determined by CT perfusion (CTP) or diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI). However, subsequent randomized trials have shown that MT also leads to better functional outcomes for patients with a large ischemic core. (See 'Benefit for large core infarcts' below.) HERMES meta-analysis In the HERMES meta-analysis of these trials, with pooled patient- level data for 1287 subjects, the rate of functional independence (ie, a 90-day modified Rankin Scale [mRS] score of 0 to 2) was significantly greater for the intervention group compared with the control group (46 versus 27 percent, odds ratio [OR] 2.35, 95% CI 1.85- https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 6/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate 2.98) [28]. Similarly, MT led to significantly reduced disability as indicated by an improvement of 1 point on the mRS at 90 days (adjusted OR 2.49, 95% CI 1.76-3.53). MT was beneficial across a wide range of patient subgroups, including age 80 years, high initial stroke severity, and those not treated with intravenous thrombolytic therapy. There was no significant difference between the MT and control groups for rates of symptomatic intracranial hemorrhage or 90-day mortality. Other trials demonstrating benefit Several additional trials (THERAPY [36], PISTE [37], EASI [38], and RESILIENT [39]) also had point estimates suggesting improved functional outcomes for patients treated with MT. The RESILIENT trial, conducted in 12 public hospitals in Brazil, showed that MT can be efficacious in a country with limited health care resources [39]. Earlier trials failed to show benefit Earlier trials (SYNTHESIS Expansion [40], IMS III [41], and MR RESCUE [42]) failed to show benefit for intra-arterial treatment of acute ischemic stroke, in part because they used older-generation thrombectomy devices, which were less likely to achieve reperfusion (see 'Devices' below), and because they did not require routine vessel imaging to confirm a large artery occlusion as the cause of the stroke [43]. Benefit of later (6 to 24 hours) treatment MT is also effective when used from 6 to 24 hours for patients selected by several different strategies. These strategies include imaging that confirms either the presence of salvageable brain tissue (eg, a tissue mismatch as defined by DAWN or DEFUSE 3 criteria), or demonstrates a large core infarct, or demonstrates collateral flow (by CTA [CT angiography]) ipsilateral to the ischemic hemisphere. Thus, selection of patients for MT in the late time window (6 to 24 hours) may be done using noncontrast CT alone as an alternative to advanced imaging with CTP or DWI/PWI [44-46]. Benefit with a clinical or tissue mismatch defined by imaging MT improves outcomes for patients with acute ischemic stroke due to occlusion of the intracranial carotid or proximal middle cerebral artery (MCA) who fulfill either the DAWN trial criteria for a clinical mismatch profile or the DEFUSE 3 trial criteria for a target perfusion mismatch profile [47]. DAWN trial The open-label DAWN trial enrolled 206 adults with acute ischemic stroke who were last known to be well 6 to 24 hours earlier; all had a stroke caused by occlusion of the intracranial internal carotid artery (ICA) or the proximal MCA and had a clinical mismatch between the severity of the neurologic deficit, as measured by the National Institutes of Health Stroke Scale (NIHSS; median score 17 at baseline), and the infarct volume, as measured by automated software analysis using DWI/PWI or CTP (median approximately 8 mL) [48]. Approximately 55 percent of the patients in the trial had a "wake- https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 7/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate up" stroke (ie, they were last known to be well before going to bed and stroke symptoms were first noted upon awakening). Patients were randomly assigned to thrombectomy plus standard care or to standard care alone (control). The trial was stopped early for efficacy at the first interim analysis. The following observations were noted: At 90 days, the rate of functional independence, as defined by a score of 0 to 2 on the mRS, was greater for the thrombectomy group compared with the control group (49 versus 13 percent, adjusted difference 33 percent, 95% CI 24-44). The NNT for one additional patient to achieve functional independence was 3. All other efficacy outcome measures also favored thrombectomy. There was no significant difference between the thrombectomy and control groups in the rate of symptomatic intracranial hemorrhage (6 and 3 percent) or mortality (19 and 18 percent). Eligibility criteria for the DAWN trial were as follows [48]: Treatment could be started (femoral puncture) within 6 to 24 hours of time last known to be well Failed or contraindicated for intravenous thrombolytic therapy with alteplase or tenecteplase table 2) of 10 points (calculator 1) A deficit on the NIHSS ( No significant prestroke disability: baseline mRS score 1 Baseline infarct involving less than one-third of the territory of the MCA on CT or MRI Intracranial arterial occlusion of the ICA or the M1 segment of the MCA A clinical-core mismatch according to age: - - Age 80 years: NIHSS 10 and an infarct volume <21 mL Age <80 years: NIHSS 10 to 19 and an infarct volume <31 mL Age <80 years: NIHSS 20 and an infarct volume <51 mL DEFUSE 3 trial The open-label DEFUSE 3 trial enrolled patients with ischemic stroke due to occlusion of the proximal MCA or ICA who were last known to be well 6 to 16 hours earlier [49]. Patients were required to have a target perfusion mismatch characterized by an infarct size of <70 mL and a ratio of ischemic tissue volume to infarct volume of 1.8, as measured by automated software processing of DWI/PWI or CTP imaging. The DEFUSE 3 trial was stopped early for efficacy after randomly assigning 182 patients to thrombectomy plus standard care or to standard care alone. Approximately one-half of the patients in the trial had a "wake-up" stroke. Patients assigned to thrombectomy were treated with stent retrievers or aspiration catheters. At 90 days, the percentage of patients who were https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 8/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate functionally independent, defined as an mRS score of 0 to 2, was higher with endovascular therapy compared with medical therapy alone (45 versus 17 percent, difference 28 percent), and therefore the NNT for one additional patient to achieve functional independence was 3.6. There was also a trend to lower mortality with endovascular therapy (14 versus 26 percent). There was no significant difference between groups in the rate of symptomatic intracranial hemorrhage (7 and 4 percent) or serious adverse events (43 and 53 percent). Eligibility criteria for DEFUSE 3 were as follows [49]: Treatment could be started (femoral puncture) within 6 to 24 hours of time last known to be well table 2) of 6 points (calculator 1) A deficit on the NIHSS ( Only slight or no prestroke disability: baseline mRS score 2 Arterial occlusion of the cervical or intracranial ICA (with or without tandem MCA lesions) or the M1 segment of the MCA demonstrated on MR angiography (MRA) or CTA A target mismatch profile on CTP or DWI/PWI defined as an ischemic core volume <70 mL, a mismatch ratio (the volume of the perfusion lesion divided by the volume of the ischemic core) >1.8, and a mismatch volume (volume of perfusion lesion minus the volume of the ischemic core) >15 mL Age 18 to 90 years AURORA study The AURORA study analyzed pooled patient-level data from 505 individuals from six randomized controlled trials of MT, including DAWN and DEFUSE 3, that included patients enrolled beyond 6 hours after they were last known to be well and who received treatment with a second-generation stent retriever [50]. At 90 days, MT led to higher rates of independence in activities of daily living, defined by an mRS of 0 to 2, compared with best medical therapy alone (45.9 versus 19.3 percent, adjusted relative risk [RR] 2.19, 95% CI 1.44-3.34, absolute risk reduction 26.6 percent). The NNT for one additional person to achieve functional independence in AURORA was approximately 4. The MT and best medical treatment groups had similar rates of mortality (16.5 versus 19.3 percent) and symptomatic intracerebral hemorrhage (5.3 versus 3.3 percent). The AURORA investigators also compared outcomes among three subgroups: first, patients (n = 295) who met criteria for a clinical mismatch profile as used in the DAWN trial; second, patients (n = 359) who met criteria for a target perfusion mismatch profile as used in the DEFUSE 3 trial; and third, patients (n = 132) with an undetermined mismatch profile due to the absence of an adequate CT or MRI perfusion study [51]. At 90 days, MT led to reduced disability for both the clinical mismatch subgroup (OR 3.57, 95% CI 2.29-5.57) and the https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 9/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate target perfusion mismatch subgroup (OR 3.13, 95% CI 2.10-4.66). Importantly, the benefit was significant in both subgroups for the entire 6- to 24-hour time window. There was a trend toward benefit for patients with an undetermined profile that did not reach statistical significance (OR 1.59, 95% CI 0.82-3.06). Limitations to these trials include stopping early, which can overestimate treatment effects. However, this drawback is at least partially offset by the relatively large effect size demonstrated in the trials and meta-analysis [48-50]. Although not definitive, evidence from a retrospective study of patients with anterior circulation large vessel occlusion presenting in the 6- to 24-hour time window who did not meet DAWN or DEFUSE 3 inclusion criteria found that treatment with MT (n = 102), performed at the discretion of the treating neurointerventionalist, was associated with higher odds of an improved functional outcome at three months compared with medical treatment alone (n = 88) as measured by a shift in the mRS score (adjusted common OR 1.46, 95% CI 1.02-2.10) [52]. Benefit for large core infarcts MT improves outcomes for patients with acute anterior circulation ischemic stroke due to large vessel occlusion who have a large ischemic core (eg, defined by an ASPECTS 3 to 5 or by a core volume 50 mL), as shown by randomized controlled trials including RESCUE-Japan LIMIT [53], SELECT2 [54], and ANGEL-ASPECT [55]. Despite differences in design, patient ethnicity, geographic location, and imaging criteria, all three trials showed benefit of thrombectomy for patients with large ischemic strokes treated within 24 hours from the time they were last known to be well [56]. Positive results from the RESCUE-Japan LIMIT trial prompted interim analyses that determined efficacy of the SELECT2 and ANGEL-ASPECT trials [53-55]. Both trials were then stopped early, which can result in overestimation of treatment effects. However, this concern is partially mitigated by the consistent benefit of thrombectomy shown in all three trials. In a 2023 meta- analysis of these three trials, functional independence (ie, an mRS score of 0 to 2) was more likely with thrombectomy compared with medical management alone (23.5 versus 9.0 percent, RR 2.59, 95% CI 1.89-3.57) [57]. The NNT for one additional person to achieve functional independence (ie, an mRS score of 0 to 2) was approximately 7. Note that all three trials enrolled patients who had very severe stroke deficits at baseline and enrolled very few octogenarians or excluded them entirely. Despite the benefit of MT, the majority of these patients were left with substantial disability; in the MT arms in SELECT2 and ANGEL-ASPECT at 90 days, the median mRS score was 4. Nevertheless, MT should now be considered the standard for patients with very disabling deficits, even if they have large ischemic core. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 10/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate RESCUE-Japan LIMIT trial The earlier requirement for a small infarct core as a criterion for MT eligibility was first challenged in 2022 by results from the RESCUE-Japan LIMIT trial, which enrolled 203 patients (18 years of age or older) with acute ischemic stroke due to a proximal MCA or ICA occlusion and a low ASPECTS of 3 to 5 on CT or DWI, consistent with a large infarct core (see 'Role of ASPECTS method' above) [53]. Patients were randomly assigned in a 1:1 ratio to endovascular therapy with medical care or medical care alone; enrolled patients were within 6 hours after the time last known to be well (n = 145) or within 6 to 24 hours after the time last known to be well if fluid-attenuated inversion recovery (FLAIR) MRI showed no signal change (n = 58), suggesting very recent infarction. At 90 days, more patients had a "good" outcome, defined by an mRS score of 0 to 3, in the endovascular therapy group compared with the medical care group (31.0 versus 12.7 percent, RR 2.43, 95% CI 1.35-4.37) [53]. For the outcome of an mRS of 0 to 2 (ie, functional independence), there was a trend towards benefit with endovascular therapy (14 versus 7.8 percent, RR 1.79, 95% CI 0.78-4.07). The endovascular group had a nonsignificantly higher rate of symptomatic intracranial hemorrhage (9 versus 4.9 percent, RR 1.84, 95% CI 0.64- 5.29) and a higher rate of any intracranial hemorrhage (58 versus 31.4 percent, RR 1.84, 95% CI 1.33-2.58). Limitations of this trial include concerns about generalizability beyond the Japanese population, and relatively small patient numbers in the 6- to 24-hour treatment subgroup [53]. SELECT2 trial This trial enrolled adult patients 18 to 85 years of age with a large ischemic core, defined by an ASPECTS of 3 to 5 or a core volume of 50 mL [54]. There were 31 participating sites across the United States, Canada, Europe, Australia, and New Zealand. Patients were randomly assigned to thrombectomy plus medical care (n = 178) or medical care only (n = 174) within 24 hours of the time last known to be well. The median age was 66.5 years, the median NIHSS was 19, and the median time to randomization was 9.3 hours. The trial was stopped early for efficacy. At 90 days, there was a shift in the distribution of the mRS scores toward better outcomes for the thrombectomy group (OR 1.51, 95% CI 1.20-1.89). Functional independence (ie, an mRS score of 0 to 2) was also more likely with thrombectomy (20 percent, versus 7 percent with medical care, RR 2.97, 95% CI 1.60-5.51). Mortality was similar for the thrombectomy and medical care groups (38.4 versus 41.5 percent). Symptomatic intracranial hemorrhage occurred in only one patient in the thrombectomy group and two in the medical care group. Early neurologic worsening was more frequent with thrombectomy (24.7 versus 15.5 percent) and was associated with larger baseline infarct size and worse outcomes. Procedural complications, including https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 11/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate dissection and cerebral vessel perforation, affected approximately 20 percent of patients in the thrombectomy group. ANGEL-ASPECT trial This trial enrolled patients 18 to 80 years of age with a large ischemic core, defined by an ASPECTS of 3 to 5 or an infarct core volume of 70 to 100 mL [55]. The trial was conducted at 46 stroke centers in China. Patients were randomly assigned to thrombectomy plus medical management (n = 231) or medical management alone (n = 225). The median age was 68 years, the median NIHSS was 16, and the median time to randomization was 7.6 hours. The trial was stopped early for efficacy. At 90 days, there was a shift in the distribution of the mRS scores toward better outcomes for the thrombectomy group (OR 1.37, 95% CI 1.11-1.69). Functional independence (ie, an mRS score of 0 to 2) was more likely for the thrombectomy group compared with the medical treatment group (30.0 versus 11.6 percent, OR 2.62, 95% CI 1.69-4.06). Mortality was similar for the thrombectomy and medical care groups (21.7 versus 20 percent). The thrombectomy group had a higher numerical rate of symptomatic intracranial hemorrhage (6.1 versus 2.7 percent, OR 2.07, 95% CI 0.79-5.41), but the difference was not statistically significant. Benefit with collateral flow MT improves outcomes for patients who have preserved collateral flow by CTA in the ischemic territory, as shown by the MR CLEAN-LATE trial [58]. The trial enrolled 535 adults presenting in the 6- to 24-hour time window with an acute anterior circulation stroke due to large vessel occlusion who had some degree of collateral flow in the MCA territory of the affected hemisphere by single-phase CTA or the arterial phase of multiphase CTA; patients eligible for MT by DAWN or DEFUSE 3 trials were excluded. Enrolled patients were randomly assigned in a 1:1 ratio to MT or no MT (control). The median age was 74 years, the median NIHSS score was 10, the median ASPECTS was 9 and 8 in the treatment and control groups, respectively, and the median time to randomization was approximately 11.5 hours. At 90 days, functional independence (an mRS score of 0 to 2) was achieved by more patients in the thrombectomy group compared with the control group (39 versus 34 percent), but the difference just missed statistical significance (OR 1.54, 95% CI 0.98-2.43). The thrombectomy group had improved outcomes compared with the control group by the median mRS (3 versus 4) and a shift in the distribution of the mRS scores favoring thrombectomy (OR 1.67, 95% CI 1.20-2.32). Mortality was lower in the thrombectomy group, but the difference was not statistically significant (24 versus 30 percent, OR 0.72, 95% CI 0.44-1.18), while symptomatic intracranial hemorrhage was more frequent in the thrombectomy group (7 versus 4 percent, OR 4.59, 95% CI 1.49-14.10). Earlier studies also suggested that moderate to good collateral flow status on CTA is useful for identifying patients who are likely to benefit from MT [8,24,59,60]. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 12/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Posterior circulation stroke Although the benefits are uncertain, MT may be a reasonable treatment option for patients with acute ischemic stroke caused by occlusion of the basilar artery, vertebral arteries, or posterior cerebral arteries when performed at centers with appropriate expertise [8,61-67]. Basilar artery occlusion There is moderate-quality evidence that MT is beneficial for patients of Chinese ancestry who can be treated within 24 hours of moderate to severe stroke (an NIHSS score 10) caused by a basilar artery occlusion if the posterior circulation ASPECTS (pc- ASPECTS) score is consistent with a limited extent of ischemia [68,69]. ATTENTION trial The ATTENTION trial evaluated patients from China with moderate to severe stroke (with an NIHSS 10) due to basilar artery occlusion who were within 12 hours of the estimated time of stroke onset and had a limited degree of early ischemic change, as quantified by the pc-ASPECTS [68]. Patients were randomly assigned in a 2:1 ratio to medical care plus endovascular thrombectomy or medical care alone (control). At baseline, the median NIHSS score was 24 in each group. Approximately one-third of patients in each group received intravenous thrombolysis. At 90 days, the rate of good functional status (ie, an mRS score of 0 to 3) was higher in the thrombectomy group compared with the control group (46 versus 23 percent, adjusted RR 2.06, 95% CI 1.46-2.91) and the mortality rate was lower in the thrombectomy group (37 versus 55 percent, RR 0.66, 95% CI 0.52-0.82). The rate of functional independence (ie, an mRS score of 0 to 2) was also higher in the thrombectomy group (33 versus 11 percent, RR 3.17, 95% CI 1.84-5.46), and results for most secondary outcomes favored thrombectomy. Symptomatic intracranial hemorrhage occurred in 5 percent of cases in the thrombectomy group versus none in the control group. MT was associated with procedural complications in 14 percent of patients, including one death caused by arterial perforation. BAOCHE trial The BAOCHE trial from China evaluated patients within 6 to 24 hours after stroke onset due to basilar artery occlusion [69]. Patients were randomly assigned in a 1:1 ratio to MT plus medical care with medical care alone. The trial was stopped early after an interim analysis suggested superiority of thrombectomy. At baseline, the median NIHSS was 20 for the thrombectomy group and 19 for the control group. The rate of intravenous thrombolysis was 14 percent in the thrombectomy group and 21 percent in the control group. At 90 days, the rate of good functional status (ie, an mRS score of 0 to 3) was higher in the thrombectomy group compared with the control group (46 versus 24 percent, RR 1.81, 95% CI 1.26-2.60), and the rate of functional independence (ie, an mRS score of 0 to 2) was also higher in the thrombectomy group (39 versus 14 percent, RR 2.64, 95% CI 1.54- 4.50). There was a trend for lower mortality at 90 days favoring the thrombectomy group (31 versus 42 percent, RR 0.75, 95% CI 0.54-1.04). Symptomatic intracranial hemorrhage https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 13/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate occurred more often in the thrombectomy group (6 versus 1 percent, RR 5.18, 95% CI 0.64- 42.18). Procedural complications occurred in 11 percent of the thrombectomy group. The ATTENTION and BAOCHE trial results are not generalizable to all patients with basilar artery stroke. The Chinese population has higher rates of large artery intracranial atherosclerotic disease relative to other populations, and many patients in the thrombectomy groups of both trials were also treated with angioplasty and/or stenting of the basilar artery. The low rates of treatment with intravenous thrombolysis in both trials may have reduced the rates of good outcomes particularly affecting the control groups and biased the results in favor of thrombectomy. Earlier trials were also limited by methodologic issues. A randomized trial (BEST) comparing endovascular treatment (MT) with standard medical care for patients with acute vertebrobasilar occlusion who could be treated within eight hours was stopped early for slow recruitment and high crossover rate after enrolling 131 patients [61]. Compared with standard medical care, patients assigned to endovascular therapy had similar rates of favorable outcome and 90-day mortality by intention-to-treat analysis. The BASICS trial of 300 patients with acute ischemic stroke attributed to basilar artery occlusion found no statistically significant difference in outcomes for endovascular therapy compared with medical therapy [63]. However, there was a nonsignificant trend of benefit with endovascular treatment in both trials [61,63]. Larger randomized controlled trials in more diverse populations are needed to assess the efficacy of endovascular therapy for posterior circulation stroke due to large artery occlusion. PROCEDURE Overview General anesthesia or conscious sedation may be used for the procedure, depending upon local preference and experience. (See 'Anesthesia' below.) Catheterization is commonly performed with femoral artery puncture. The catheter is guided to the internal carotid artery (ICA) and beyond to the site of the intracranial large artery occlusion. The stent retriever is then inserted through the catheter to reach the clot. The stent retriever is deployed and grabs the clot, which is removed as the device is pulled back. The initial goal is to achieve reperfusion, defined by a modified Thrombolysis in Cerebral Infarction (mTICI) perfusion grade 2b (anterograde reperfusion of more than half in the downstream target arterial territory)
thrombectomy group had a higher numerical rate of symptomatic intracranial hemorrhage (6.1 versus 2.7 percent, OR 2.07, 95% CI 0.79-5.41), but the difference was not statistically significant. Benefit with collateral flow MT improves outcomes for patients who have preserved collateral flow by CTA in the ischemic territory, as shown by the MR CLEAN-LATE trial [58]. The trial enrolled 535 adults presenting in the 6- to 24-hour time window with an acute anterior circulation stroke due to large vessel occlusion who had some degree of collateral flow in the MCA territory of the affected hemisphere by single-phase CTA or the arterial phase of multiphase CTA; patients eligible for MT by DAWN or DEFUSE 3 trials were excluded. Enrolled patients were randomly assigned in a 1:1 ratio to MT or no MT (control). The median age was 74 years, the median NIHSS score was 10, the median ASPECTS was 9 and 8 in the treatment and control groups, respectively, and the median time to randomization was approximately 11.5 hours. At 90 days, functional independence (an mRS score of 0 to 2) was achieved by more patients in the thrombectomy group compared with the control group (39 versus 34 percent), but the difference just missed statistical significance (OR 1.54, 95% CI 0.98-2.43). The thrombectomy group had improved outcomes compared with the control group by the median mRS (3 versus 4) and a shift in the distribution of the mRS scores favoring thrombectomy (OR 1.67, 95% CI 1.20-2.32). Mortality was lower in the thrombectomy group, but the difference was not statistically significant (24 versus 30 percent, OR 0.72, 95% CI 0.44-1.18), while symptomatic intracranial hemorrhage was more frequent in the thrombectomy group (7 versus 4 percent, OR 4.59, 95% CI 1.49-14.10). Earlier studies also suggested that moderate to good collateral flow status on CTA is useful for identifying patients who are likely to benefit from MT [8,24,59,60]. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 12/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Posterior circulation stroke Although the benefits are uncertain, MT may be a reasonable treatment option for patients with acute ischemic stroke caused by occlusion of the basilar artery, vertebral arteries, or posterior cerebral arteries when performed at centers with appropriate expertise [8,61-67]. Basilar artery occlusion There is moderate-quality evidence that MT is beneficial for patients of Chinese ancestry who can be treated within 24 hours of moderate to severe stroke (an NIHSS score 10) caused by a basilar artery occlusion if the posterior circulation ASPECTS (pc- ASPECTS) score is consistent with a limited extent of ischemia [68,69]. ATTENTION trial The ATTENTION trial evaluated patients from China with moderate to severe stroke (with an NIHSS 10) due to basilar artery occlusion who were within 12 hours of the estimated time of stroke onset and had a limited degree of early ischemic change, as quantified by the pc-ASPECTS [68]. Patients were randomly assigned in a 2:1 ratio to medical care plus endovascular thrombectomy or medical care alone (control). At baseline, the median NIHSS score was 24 in each group. Approximately one-third of patients in each group received intravenous thrombolysis. At 90 days, the rate of good functional status (ie, an mRS score of 0 to 3) was higher in the thrombectomy group compared with the control group (46 versus 23 percent, adjusted RR 2.06, 95% CI 1.46-2.91) and the mortality rate was lower in the thrombectomy group (37 versus 55 percent, RR 0.66, 95% CI 0.52-0.82). The rate of functional independence (ie, an mRS score of 0 to 2) was also higher in the thrombectomy group (33 versus 11 percent, RR 3.17, 95% CI 1.84-5.46), and results for most secondary outcomes favored thrombectomy. Symptomatic intracranial hemorrhage occurred in 5 percent of cases in the thrombectomy group versus none in the control group. MT was associated with procedural complications in 14 percent of patients, including one death caused by arterial perforation. BAOCHE trial The BAOCHE trial from China evaluated patients within 6 to 24 hours after stroke onset due to basilar artery occlusion [69]. Patients were randomly assigned in a 1:1 ratio to MT plus medical care with medical care alone. The trial was stopped early after an interim analysis suggested superiority of thrombectomy. At baseline, the median NIHSS was 20 for the thrombectomy group and 19 for the control group. The rate of intravenous thrombolysis was 14 percent in the thrombectomy group and 21 percent in the control group. At 90 days, the rate of good functional status (ie, an mRS score of 0 to 3) was higher in the thrombectomy group compared with the control group (46 versus 24 percent, RR 1.81, 95% CI 1.26-2.60), and the rate of functional independence (ie, an mRS score of 0 to 2) was also higher in the thrombectomy group (39 versus 14 percent, RR 2.64, 95% CI 1.54- 4.50). There was a trend for lower mortality at 90 days favoring the thrombectomy group (31 versus 42 percent, RR 0.75, 95% CI 0.54-1.04). Symptomatic intracranial hemorrhage https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 13/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate occurred more often in the thrombectomy group (6 versus 1 percent, RR 5.18, 95% CI 0.64- 42.18). Procedural complications occurred in 11 percent of the thrombectomy group. The ATTENTION and BAOCHE trial results are not generalizable to all patients with basilar artery stroke. The Chinese population has higher rates of large artery intracranial atherosclerotic disease relative to other populations, and many patients in the thrombectomy groups of both trials were also treated with angioplasty and/or stenting of the basilar artery. The low rates of treatment with intravenous thrombolysis in both trials may have reduced the rates of good outcomes particularly affecting the control groups and biased the results in favor of thrombectomy. Earlier trials were also limited by methodologic issues. A randomized trial (BEST) comparing endovascular treatment (MT) with standard medical care for patients with acute vertebrobasilar occlusion who could be treated within eight hours was stopped early for slow recruitment and high crossover rate after enrolling 131 patients [61]. Compared with standard medical care, patients assigned to endovascular therapy had similar rates of favorable outcome and 90-day mortality by intention-to-treat analysis. The BASICS trial of 300 patients with acute ischemic stroke attributed to basilar artery occlusion found no statistically significant difference in outcomes for endovascular therapy compared with medical therapy [63]. However, there was a nonsignificant trend of benefit with endovascular treatment in both trials [61,63]. Larger randomized controlled trials in more diverse populations are needed to assess the efficacy of endovascular therapy for posterior circulation stroke due to large artery occlusion. PROCEDURE Overview General anesthesia or conscious sedation may be used for the procedure, depending upon local preference and experience. (See 'Anesthesia' below.) Catheterization is commonly performed with femoral artery puncture. The catheter is guided to the internal carotid artery (ICA) and beyond to the site of the intracranial large artery occlusion. The stent retriever is then inserted through the catheter to reach the clot. The stent retriever is deployed and grabs the clot, which is removed as the device is pulled back. The initial goal is to achieve reperfusion, defined by a modified Thrombolysis in Cerebral Infarction (mTICI) perfusion grade 2b (anterograde reperfusion of more than half in the downstream target arterial territory) or grade 3 (complete anterograde reperfusion of the downstream target arterial territory) ( table 4), as early as possible [8,70]. In a meta-analysis of five trials that evaluated treatment within 6 hours of symptom onset, over 500 patients received mechanical thrombectomy (MT), https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 14/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate and substantial reperfusion (mTICI score of 2b or 3) was achieved in 71 percent of this group [34]. Following the procedure, most centers monitor patients in an intensive care unit setting until stable. Devices Both second-generation stent retrievers and catheter aspiration devices can be used for MT. The choice between them depends mainly upon local expertise and availability [71]. In some cases, treatment using stent retrievers and aspiration techniques in combination may be appropriate. Stent retrievers Several MT devices are approved in the United States and Europe for clot removal in patients with acute ischemic stroke due to large artery occlusion. These include the first-generation Merci Retriever and Penumbra System devices, the second- generation Solitaire Flow Restoration Device and Trevo Retriever, and the third-generation Tigertriever. The first-generation Merci and Penumbra devices may increase recanalization rates in carefully selected patients, but their clinical utility for improving outcomes after stroke is unproven [72-74]. When compared directly with the Merci retriever in small randomized trials, the second-generation Solitaire and Trevo neurothrombectomy devices achieved significantly higher reperfusion rates and better patient outcomes [75,76]. In a single-arm study, the Tigertriever device achieved higher reperfusion rates, improved patient outcomes, and had similar safety outcomes compared with historical controls from studies of the Solitaire and Trevo devices [77]. In light of these data and the positive thrombectomy trials discussed above [22,24-27], which preferentially used the second-generation devices, only the second-generation or later devices should be used to treat patients with acute ischemic stroke. Catheter aspiration devices Catheter aspiration devices are another option for MT. This method employs a catheter to aspirate the thrombus as the first approach to performing thrombectomy; if aspiration alone does not achieve reperfusion after one or more passes, a stent retriever can be inserted through the catheter to complete the thrombectomy. Mounting evidence suggests that catheter aspiration devices can attain rates of revascularization [36,78] and good functional outcome [79,80] that are similar to the rates achieved with second-generation stent retrievers. The open-label, multicenter COMPASS trial randomly assigned 270 patients within 6 hours of symptom onset to MT with either catheter aspiration as first-pass treatment or stent retriever first-line [79]. At 90 days, a good functional outcome (modified Rankin Scale [mRS] score of 0 to 2) was achieved by a similar number of patients in each treatment group (52 versus 50 percent for aspiration https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 15/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate first-pass and stent retriever first-line, respectively), indicating that aspiration first-pass was noninferior to stent retriever first-line treatment. In addition, secondary efficacy and angiographic outcome measures did not differ between treatment groups, and there were no significant differences in mortality, symptomatic intracranial hemorrhage, or other safety outcomes. One trial found a trend to higher rates of near-total or total reperfusion for combined stent retriever plus aspiration compared with stent retriever alone, but the difference did not achieve statistical significance (64.5 versus 57.9 percent, risk difference 6.6 percent, 95% CI -3.0 to 16.2) [81]. Anesthesia Either monitored anesthesia care (also called conscious sedation) or general anesthesia may be used for procedural sedation during MT. The anesthetic technique should be chosen based upon individual patient risk factors, preferences, and institutional experience [8]. (See "Anesthesia for endovascular therapy for acute ischemic stroke in adults", section on 'Choice of anesthetic technique: General anesthesia versus monitored anesthesia care'.) The type of anesthesia used for MT in patients with ischemic stroke may have some impact on short- and long-term outcomes, as reviewed in detail separately. (See "Anesthesia for endovascular therapy for acute ischemic stroke in adults", section on 'Literature comparing general anesthesia with monitored anesthesia care or conscious sedation'.) Risk of periprocedural antithrombotics There is no indication for the routine use of periprocedural antithrombotic agents. Based upon the results of the MR CLEAN-MED trial, the use of periprocedural aspirin or unfractionated heparin in patients undergoing endovascular therapy for acute ischemic stroke increases the risk of symptomatic hemorrhagic transformation and may increase the risk of worse outcomes [82]. However, antithrombotic agents may be indicated in specific instances (eg, if a stent gets deployed, or if there is distal embolism). Blood pressure management Admission systolic blood pressure (SBP) does not seem to impact the benefit of MT, as shown by the HERMES meta-analysis of seven trials with individual data from 1753 patients randomly assigned to MT or standard care (control) [83]. The meta- analysis found a nonlinear association between admission SBP and functional outcome measured by the mRS, with an inflection point at an SBP of 140 mmHg. Admission SBPs above 140 mmHg were associated with worse functional outcomes and higher mortality rates. However, there was no interaction between admission SBP and the effect of MT. At 90 days, the median mRS was lower (ie, functional outcome was better) with MT for both patients with an admission SBP <140 mmHg (median mRS 2, versus 3 for controls) and patients with an admission SBP 140 mmHg (median mRS 3, versus 4 for controls). The benefit of MT for a shift https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 16/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate towards a better functional outcome ordinal mRS was also similar for patients with admission SBP <140 mmHg (adjusted common OR 2.06, 95% CI 1.56-2.71) and patients with admission SBP 140 mmHg (OR 1.84, 95% CI 1.46-2.31). We suggest keeping SBP between 150 and 180 mmHg prior to reperfusion; SBP 150 mmHg may be useful for maintaining adequate collateral blood flow during the time the large artery remains occluded [8,24]. Some experts suggest no use of antihypertensives prior to reperfusion unless SBP exceeds 200 mmHg for patients not being treated with intravenous thrombolysis, or unless SBP exceeds 185 mmHg for patients who are candidates for intravenous thrombolysis [84]. However, the optimal blood pressure range with MT is not well defined, and there is no proven benefit of aggressive early blood pressure reduction after reperfusion [8,85-88]. Earlier evidence supported keeping SBP <160 to 170 mmHg for patients with successful reperfusion (ie, mTICI 2b or 3) and targeting SBP of 170 mmHg for patients with less successful reperfusion (ie, mTICI 0 to 2a) [84]. Other reports suggested targeting SBP to <140 mmHg after successful reperfusion [48,89]. More intensive blood pressure lowering (eg, targeting SBP <120 mmHg) may be harmful, particularly in Asian populations where the prevalence of large artery atherosclerosis is high [90,91]. Many patients undergoing MT will have been treated with intravenous thrombolytic therapy (recombinant tissue plasminogen activator or tPA) in the first hours after stroke symptom onset and should be managed accordingly, with systolic/diastolic blood pressure maintained at 180/105 mmHg during and for 24 hours following alteplase infusion or tenecteplase injection; a higher blood pressure may increase the risk of hemorrhage in ischemic brain regions even when thrombolytic agents are not used. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use", section on 'Management of blood pressure'.) Adverse effects In the MR CLEAN trial, clinical signs of a new ischemic stroke in a different vascular territory within 90 days of treatment were more common in the intra-arterial group compared with no endovascular therapy (5.6 versus 0.4 percent) [22]. Device-related serious adverse events are uncommon but include access site hematoma and pseudoaneurysm, arterial perforation, and arterial dissection [24-27]. Transient intraprocedural vasospasm is also uncommon but is sometimes treated. MT in general is not associated with increased rates of symptomatic intracranial hemorrhage (sICH) or mortality. In a meta-analysis of five trials, with pooled patient-level data for 1287 subjects, there was no significant difference between the intervention population and control population for 90-day sICH (4.4 versus 4.3 percent) or mortality (15 versus 19 percent) [28]. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 17/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Limited evidence suggests recent anticoagulation with an oral vitamin K antagonist (VKA), but not a direct oral anticoagulant (DOAC), may increase the risk of sICH or mortality for patients undergoing MT [92,93]. In a 2022 meta-analysis of 15 nonrandomized studies, VKA use compared with no oral anticoagulant use was associated with an increased risk of sICH (8.4 versus 6.5 percent, OR 1.49, 95% CI 1.10-2.02) and mortality (32.8 versus 24.2 percent, OR 1.67, 95% CI 1.35-2.06), whereas DOAC use compared with no oral anticoagulant use was associated with no increased risk of sICH (2.7 versus 5.9 percent, OR 0.80, 95% CI 0.45-1.44) or mortality (26.9 versus 23.0 percent, OR 1.27, 95% CI 0.96-1.70) [92]. Approach to tandem lesions Fifteen to 30 percent of patients eligible for MT present with tandem lesions characterized by extracranial carotid artery stenosis or occlusion and a downstream, ipsilateral intracranial large vessel occlusion [22,24,27,94]. MT is directed at revascularization of the intracranial occlusion, but the best approach to management of the extracranial carotid lesion is uncertain [94,95]. Options include acute treatment of the extracranial carotid lesion with stent placement (anterograde or retrograde), angioplasty alone, or thrombo-aspiration alone, versus deferred or no revascularization of the extracranial carotid artery lesion ( figure 4) [96]. Deferred revascularization options include eventual carotid endarterectomy or carotid artery stenting. (See "Management of symptomatic carotid atherosclerotic disease".) Available data from observational studies suggest that acute carotid stenting for patients with tandem lesions who are undergoing MT is associated with a higher rate of favorable outcomes at 90 days compared with no stenting [97,98]. A subgroup analysis from one study further suggests that stenting is associated with improved outcomes in patients with carotid lesions caused by atherosclerosis but not in patients with carotid lesions caused by dissection [98]. Rescue therapy for failed MT Approximately 8 to 30 percent of patients fail to achieve substantial reperfusion with MT, with failure defined by mTICI scores ( table 4) of 2a or less [28,99-101]. In such cases, urgent rescue therapy with intracranial angioplasty/stenting, intravenous glycoprotein IIb/IIIa inhibitors, or intravenous P2Y12 receptor inhibitors is sometimes attempted [99]. Limited observational data suggest that these interventions are safe [99,102], but prospective studies are lacking, and the optimal approach is uncertain. Intracranial stenting is the best-studied option [103-105]. The retrospective, multicenter SAINT study of patients who failed MT compared those who received acute rescue stenting (n = 107) with propensity-score matched patients who did not receive rescue stenting (n = 107) [103]. At 90 days, rescue stenting was associated with a shift to lower rates of disability in the overall mRS score distribution (adjusted OR 3.74, 95% CI 2.16-6.57), increased functional independence (34.6 versus 6.5 percent, OR 10.91, 95% CI 4.11-28.92), decreased mortality (29.9 versus 43.0 percent, https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 18/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate OR 0.49, 95% CI 0.25-0.94), and comparable rates of symptomatic intracranial hemorrhage (7.5 versus 11.2 percent, OR 0.87, 95% CI 0.31-2.42). These results are limited by retrospective design and wide confidence intervals, and further study is needed to determine the benefit of this intervention for failed MT. Adjunct intra-arterial thrombolysis Some patients have poor clinical outcomes after MT despite successful reperfusion (ie, a modified Thrombolysis in Cerebral Infarction [mTICI] 2b or 3) of the target large artery; one possible but controversial explanation is persisting impaired reperfusion of the microcirculation (the "no-reflow" phenomenon) [106,107]. The Chemical Optimization of Cerebral Embolectomy (CHOICE) trial investigated the use of adjunct intra- arterial thrombolysis with alteplase to treat hypothesized persistent thrombi in the microcirculation after angiographically successful MT [108]. At 90 days, more patients achieved an excellent neurologic outcome (an mRS score of 0 to 1) with intra-arterial alteplase compared with placebo (59 versus 40.4 percent, adjusted absolute risk reduction 18.4 percent, 95% CI 0.3- 36.4 percent). There was no increased risk of intracranial hemorrhage or mortality with intra- arterial alteplase. Limitations of the CHOICE trial include early stopping (due to slow recruitment and inability to obtain placebo), which can lead to overestimation of treatment effects, small patient numbers (and resulting wide confidence intervals with a lower limit of only 0.3 percent absolute risk reduction), and the protocol allowing premature stopping (and therefore potential underdosing) of intravenous alteplase infusion started before the onset of thrombectomy [108,109]. Thus, the benefit of this approach requires confirmation in larger trials. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Efficacy of mechanical thrombectomy Early intra-arterial treatment with mechanical thrombectomy (MT) is safe and effective for reducing disability and is superior to standard treatment with intravenous thrombolysis alone for ischemic stroke caused by a documented large artery occlusion in the proximal anterior circulation. (See 'Efficacy of mechanical thrombectomy' above.) Patient selection for anterior circulation stroke https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 19/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Who to treat For patients with acute ischemic stroke, we recommend treatment with intra-arterial MT, whether or not the patient received treatment with intravenous thrombolytic therapy, if the following conditions are met (Grade 1B): Brain imaging using CT without contrast or diffusion-weighted MRI (DWI) excludes hemorrhage and is consistent with an Alberta Stroke Program Early CT Score (ASPECTS) 3. (See 'Role of ASPECTS method' above.) CT angiography (CTA) or MR angiography (MRA) demonstrates a proximal large artery occlusion in the anterior circulation as the cause of the ischemic stroke. The patient has a persistent, potentially disabling neurologic deficit (eg, a National Institutes of Health Stroke Scale [NIHSS] score 6). The patient can start treatment (femoral puncture) within 24 hours of the time last known to be well. This recommendation applies when thrombectomy is performed at a stroke center with appropriate expertise in the use of endovascular therapy. Benefit may be most likely when imaging confirms the presence of salvageable brain tissue (eg, a mismatch by DAWN or DEFUSE 3 criteria). Who not to treat We would not treat with MT for patients who have any of the following findings (see 'Who not to treat' above): Presence of a large established hypodensity on head CT beyond the more subtle, early ischemic changes assessed by ASPECTS (see 'Role of ASPECTS method' above) No ischemic penumbra (ie, no mismatch suggesting no salvageable brain tissue) identified if CT perfusion (CTP) or DWI/PWI (perfusion-weighted MRI) is performed, particularly if the infarct core is large Presence of a large core infarct (eg, defined by an ASPECTS <6 or imaging showing a core volume 50 mL) and severe prestroke comorbidities (eg, pre-existing severe disability such as modified Rankin Scale [mRS] 4 to 5 or life expectancy less than six months) Individualized decisions The decision to employ MT needs to be carefully individualized for patients with anterior circulation stroke who do not precisely match the inclusion or exclusion criteria as listed above. Examples include patients with imaging evidence of salvageable brain tissue who are beyond the 24-hour time window, https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 20/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate medium vessel occlusion (eg, anterior cerebral artery beyond the A1 segment, middle cerebral artery [MCA] beyond the proximal M2 segment), or minor stroke (NIHSS 5). Use in posterior circulation stroke Although the benefits are uncertain, MT within 24 hours of the time last known to be well may be a reasonable treatment option for patients with acute ischemic stroke caused by occlusion of the basilar artery, vertebral arteries, or posterior cerebral arteries when performed at centers with appropriate expertise. Moderate-quality evidence supports the benefit of MT for patients of Chinese ancestry with basilar artery occlusion who have an NIHSS score 10, indicating a moderate to severe stroke; a posterior circulation ASPECTS (pc-ASPECTS) of 6, indicating a limited extent of ischemic change on brain imaging; and who can be treated within 24 hours of time last known to be well. (See 'Posterior circulation stroke' above.) Procedure Second-generation stent retriever devices or catheter aspiration devices should be used for MT. Other aspects of the MT procedure, including anesthesia, blood pressure management, and adverse events, are discussed above. (See 'Procedure' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Campbell BC, Donnan GA, Lees KR, et al. Endovascular stent thrombectomy: the new standard of care for large vessel ischaemic stroke. Lancet Neurol 2015; 14:846. 2. Furlan AJ. Endovascular therapy for stroke it's about time. N Engl J Med 2015; 372:2347. 3. 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Safety and efficacy of intensive blood pressure lowering after successful endovascular therapy in acute ischaemic stroke (BP-TARGET): a multicentre, open-label, randomised controlled trial. Lancet Neurol 2021; 20:265. 87. Mistry E, Hart K, Davis L, et al. Blood pressure after endovascular stroke treatment (BEST)-II: A randomized clinical trial. Presented at: 2023 International Stroke Conference; February 8-1 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 27/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate 0; Dallas, TX. LB18. 88. Morris NA, Jindal G, Chaturvedi S. Intensive Blood Pressure Control After Mechanical Thrombectomy for Acute Ischemic Stroke. Stroke 2023; 54:1457. 89. Anadani M, Arthur AS, Tsivgoulis G, et al. Blood Pressure Goals and Clinical Outcomes after Successful Endovascular Therapy: A Multicenter Study. Ann Neurol 2020; 87:830. 90. Yang P, Song L, Zhang Y, et al. Intensive blood pressure control after endovascular thrombectomy for acute ischaemic stroke (ENCHANTED2/MT): a multicentre, open-label, blinded-endpoint, randomised controlled trial. Lancet 2022; 400:1585. 91. Mistry EA, Nguyen TN. Blood pressure goals after mechanical thrombectomy: a moving target. Lancet 2022; 400:1558. 92. Chen JH, Hong CT, Chung CC, et al. Safety and efficacy of endovascular thrombectomy in acute ischemic stroke treated with anticoagulants: a systematic review and meta-analysis. Thromb J 2022; 20:35. 93. Mac Grory B, Holmes DN, Matsouaka RA, et al. Recent Vitamin K Antagonist Use and Intracranial Hemorrhage After Endovascular Thrombectomy for Acute Ischemic Stroke. JAMA 2023; 329:2038. 94. Jadhav AP, Zaidat OO, Liebeskind DS, et al. Emergent Management of Tandem Lesions in Acute Ischemic Stroke. Stroke 2019; 50:428. 95. Jacquin G, Poppe AY, Labrie M, et al. Lack of Consensus Among Stroke Experts on the Optimal Management of Patients With Acute Tandem Occlusion. Stroke 2019; 50:1254. 96. Poppe AY, Jacquin G, Roy D, et al. Tandem Carotid Lesions in Acute Ischemic Stroke: Mechanisms, Therapeutic Challenges, and Future Directions. AJNR Am J Neuroradiol 2020; 41:1142. 97. Dufort G, Chen BY, Jacquin G, et al. Acute carotid stenting in patients undergoing thrombectomy: a systematic review and meta-analysis. J Neurointerv Surg 2021; 13:141. 98. Anadani M, Marnat G, Consoli A, et al. Endovascular Therapy of Anterior Circulation Tandem Occlusions: Pooled Analysis From the TITAN and ETIS Registries. Stroke 2021; 52:3097. 99. Abdalla RN, Cantrell DR, Shaibani A, et al. Refractory Stroke Thrombectomy: Prevalence, Etiology, and Adjunctive Treatment in a North American Cohort. AJNR Am J Neuroradiol 2021; 42:1258. 100. Flottmann F, Leischner H, Broocks G, et al. Recanalization Rate per Retrieval Attempt in Mechanical Thrombectomy for Acute Ischemic Stroke. Stroke 2018; 49:2523. 101. Tsang COA, Cheung IHW, Lau KK, et al. Outcomes of Stent Retriever versus Aspiration-First Thrombectomy in Ischemic Stroke: A Systematic Review and Meta-Analysis. AJNR Am J https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 28/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Neuroradiol 2018; 39:2070. 102. Marnat G, Delvoye F, Finitsis S, et al. A Multicenter Preliminary Study of Cangrelor following Thrombectomy Failure for Refractory Proximal Intracranial Occlusions. AJNR Am J Neuroradiol 2021; 42:1452. 103. Mohammaden MH, Haussen DC, Al-Bayati AR, et al. Stenting and Angioplasty in Neurothrombectomy: Matched Analysis of Rescue Intracranial Stenting Versus Failed Thrombectomy. Stroke 2022; 53:2779. 104. Maingard J, Phan K, Lamanna A, et al. Rescue Intracranial Stenting After Failed Mechanical Thrombectomy for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis. World Neurosurg 2019; 132:e235. 105. Hassan AE, Ringheanu VM, Preston L, et al. Acute intracranial stenting with mechanical thrombectomy is safe and efficacious in patients diagnosed with underlying intracranial atherosclerotic disease. Interv Neuroradiol 2022; 28:419. 106. Ng FC, Churilov L, Yassi N, et al. Prevalence and Significance of Impaired Microvascular Tissue Reperfusion Despite Macrovascular Angiographic Reperfusion (No-Reflow). Neurology 2022; 98:e790. 107. Ter Schiphorst A, Charron S, Hassen WB, et al. Tissue no-reflow despite full recanalization following thrombectomy for anterior circulation stroke with proximal occlusion: A clinical study. J Cereb Blood Flow Metab 2021; 41:253. 108. Ren A, Mill n M, San Rom n L, et al. Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke: The CHOICE Randomized Clinical Trial. JAMA 2022; 327:826. 109. Khatri P. Intra-arterial Thrombolysis to Target Occlusions in Distal Arteries and the Microcirculation. JAMA 2022; 327:821. Topic 115663 Version 40.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 29/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate GRAPHICS Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 30/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 31/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 32/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The 0 = Alert; keenly responsive. investigator must choose a response if a full 1 = Not alert; but arousable by minor evaluation is prevented by such obstacles as an endotracheal tube, language barrier, stimulation to obey, answer, or respond. 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement to attend, or is obtunded and requires strong or painful stimulation to make _____ (other than reflexive posturing) in response to noxious stimulation. movements (not stereotyped). 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no 1 = Answers one question correctly. 2 = Answers neither question correctly. partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, _____ orotracheal trauma, severe dysarthria from any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The 0 = Performs both tasks correctly. _____ patient is asked to open and close the eyes 1 = Performs one task correctly. and then to grip and release the non-paretic hand. Substitute another one step 2 = Performs neither task correctly. command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 33/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If total gaze paresis is not present. the patient has a conjugate deviation of the eyes that can be overcome by voluntary or 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic reflexive activity, the score will be 1. If a maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower 0 = No visual loss. quadrants) are tested by confrontation, using finger counting or visual threat, as 1 = Partial hemianopia. 2 = Complete hemianopia. appropriate. Patients may be encouraged, but if they look at the side of the moving fingers appropriately, this can be scored as 3 = Bilateral hemianopia (blind including cortical blindness). normal. If there is unilateral blindness or enucleation, visual fields in the remaining _____ eye are scored. Score 1 only if a clear-cut asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to 0 = Normal symmetrical movements. _____ encourage - the patient to show teeth or 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score symmetry of grimace in response to noxious fold, asymmetry on smiling). 2 = Partial paralysis (total or near-total stimuli in the poorly responsive or non- comprehending patient. If facial paralysis of lower face). trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 34/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate other physical barriers obscure the face, these should be removed to the extent 3 = Complete paralysis of one or both sides (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not hit bed or other support. falls before 10 seconds. The aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in degrees, drifts down to bed, but has some effort against gravity. _____ the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 0 = No drift; leg holds 30-degree position for full 5 seconds. degrees (always tested supine). Drift is 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. scored if the leg falls before 5 seconds. The aphasic patient is encouraged using urgency 2 = Some effort against gravity; leg falls to in the voice and pantomime, but not noxious stimulation. Each limb is tested in bed by 5 seconds, but has some effort against gravity. turn, beginning with the non-paretic leg. _____ Only in the case of amputation or joint fusion at the hip, the examiner should 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. 0 = Absent. _____ 1 = Present in one limb. Test with eyes open. In case of visual defect, ensure testing is done in intact visual field. 2 = Present in two limbs. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 35/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner should test as many body areas (arms [not pain with pinprick, but patient is aware of being touched. hands], legs, trunk, face) as needed to accurately check for hemisensory loss. A 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, score of 2, "severe or total sensory loss," should only be given when a severe or total and leg. _____ loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of information about comprehension will be 0 = No aphasia; normal. _____ 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of obtained during the preceding sections of the examination. For this scale item, the comprehension, without significant limitation on ideas expressed or form of patient is asked to describe what is happening in the attached picture, to name the items on the attached naming sheet and expression. Reduction of speech and/or comprehension, however, makes conversation about provided materials to read from the attached list of sentences. Comprehension is judged from responses difficult or impossible. For example, in conversation about provided materials, here, as well as to all of the commands in the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the hand, repeat, and produce speech. The 2 = Severe aphasia; all communication is through fragmentary expression; great need intubated patient should be asked to write. The patient in a coma (item 1a=3) will for inference, questioning, and guessing by the listener. Range of information that can automatically score 3 on this item. The examiner must choose a score for the be exchanged is limited; listener carries burden of communication. Examiner cannot patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 36/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be 0 = Normal. normal, an adequate sample of speech must be obtained by asking patient to read or 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be 2 = Severe dysarthria; patient's speech is so _____ slurred as to be unintelligible in the absence rated. Only if the patient is intubated or has other physical barriers to producing speech, of or out of proportion to any dysphasia, or is mute/anarthric. the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the explain:________________ patient why he or she is being tested. 11. Extinction and inattention (formerly neglect): Sufficient information to identify 0 = No abnormality. 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to neglect may be obtained during the prior testing. If the patient has a severe visual loss bilateral simultaneous stimulation in one of the sensory modalities. preventing visual double simultaneous stimulation, and the cutaneous stimuli are 2 = Profound hemi-inattention or normal, the score is normal. If the patient _____ extinction to more than one modality; has aphasia but does appear to attend to both sides, the score is normal. The does not recognize own hand or orients to only one side of space. presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 37/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 38/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate ASPECTS study form The ASPECTS value is calculated from two standard axial CT cuts: one at the level of the thalamus and basal ganglia (left), and one just rostral to the basal ganglia (right). A: anterior circulation; P: posterior circulation; C:
in the voice and pantomime, but not noxious stimulation. Each limb is tested in bed by 5 seconds, but has some effort against gravity. turn, beginning with the non-paretic leg. _____ Only in the case of amputation or joint fusion at the hip, the examiner should 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. 0 = Absent. _____ 1 = Present in one limb. Test with eyes open. In case of visual defect, ensure testing is done in intact visual field. 2 = Present in two limbs. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 35/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner should test as many body areas (arms [not pain with pinprick, but patient is aware of being touched. hands], legs, trunk, face) as needed to accurately check for hemisensory loss. A 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, score of 2, "severe or total sensory loss," should only be given when a severe or total and leg. _____ loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of information about comprehension will be 0 = No aphasia; normal. _____ 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of obtained during the preceding sections of the examination. For this scale item, the comprehension, without significant limitation on ideas expressed or form of patient is asked to describe what is happening in the attached picture, to name the items on the attached naming sheet and expression. Reduction of speech and/or comprehension, however, makes conversation about provided materials to read from the attached list of sentences. Comprehension is judged from responses difficult or impossible. For example, in conversation about provided materials, here, as well as to all of the commands in the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the hand, repeat, and produce speech. The 2 = Severe aphasia; all communication is through fragmentary expression; great need intubated patient should be asked to write. The patient in a coma (item 1a=3) will for inference, questioning, and guessing by the listener. Range of information that can automatically score 3 on this item. The examiner must choose a score for the be exchanged is limited; listener carries burden of communication. Examiner cannot patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 36/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be 0 = Normal. normal, an adequate sample of speech must be obtained by asking patient to read or 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be 2 = Severe dysarthria; patient's speech is so _____ slurred as to be unintelligible in the absence rated. Only if the patient is intubated or has other physical barriers to producing speech, of or out of proportion to any dysphasia, or is mute/anarthric. the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the explain:________________ patient why he or she is being tested. 11. Extinction and inattention (formerly neglect): Sufficient information to identify 0 = No abnormality. 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to neglect may be obtained during the prior testing. If the patient has a severe visual loss bilateral simultaneous stimulation in one of the sensory modalities. preventing visual double simultaneous stimulation, and the cutaneous stimuli are 2 = Profound hemi-inattention or normal, the score is normal. If the patient _____ extinction to more than one modality; has aphasia but does appear to attend to both sides, the score is normal. The does not recognize own hand or orients to only one side of space. presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 37/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 38/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate ASPECTS study form The ASPECTS value is calculated from two standard axial CT cuts: one at the level of the thalamus and basal ganglia (left), and one just rostral to the basal ganglia (right). A: anterior circulation; P: posterior circulation; C: caudate; L: lentiform; IC: internal capsule; I: insular ribbon; MCA: middle cerebral artery; M1: anterior MCA cortex; M2: MCA cortex lateral to insular ribbon; M3: posterior MCA cortex; M4, M5, and M6 are anterior, lateral, and posterior MCA territories immediately superior to M1, M2, and M3, rostral to basal ganglia Reproduced with permission from: Barber, PA, Demchuk, AM, Zhang, J, Buchan, AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000; 355:1670. Copyright 2000 The Lancet. Graphic 72190 Version 1.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 39/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Visual decision aid depicting the benefits and risks of endovascular thrombectomy added to IV tPA versus IV tPA alone Choice consequence matrix type visual decision aid depicting the benefits and risks of endovascular thrombectomy added to IV tPA versus IV tPA alone. Dark green, attainment of excellent outcome (mRS, 0-1) as a result of thrombectomy; light green, improved disability outcome (other than excellent outcome) as a result of thrombectomy; light red, worse disability outcome (other than severely disabled/dead) as a result of thrombectomy; open rectangle, infarct in new territory as a result of thrombectomy. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 40/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate tPA: tissue-type plasminogen activator; IV: intravenous; mRS: modified Rankin scale; SICH: symptomatic intracranial hemorrhage. None were severely disabled or dead (mRS, 5-6) as a result of thrombectomy. No differences observed in the rate of SICH due to thrombectomy. From: Tokunboh I, Vales Montero M, Zopelaro Almeida MF, et al. Visual aids for patient, family, and physician decision making about endovascular thrombectomy for acute ischemic stroke. Stroke 2018; 49:90. DOI: 10.1161/STROKEAHA.117.018715. Copyright 2018 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 116247 Version 3.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 41/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Visual decision aid depicting the benefits and risks of endovascular thrombectomy for patients ineligible for IV tPA Choice consequence matrix type visual decision aid depicting the benefits and risks of endovascular thrombectomy among tPA-ineligible patients. Dark green, attainment of excellent outcome (mRS, 0-1) as a result of thrombectomy; light green, improved disability outcome (other than excellent outcome) as a result of thrombectomy; light red, worse disability outcome (other than severely disabled/dead) as a result of thrombectomy; open rectangle, infarct in new territory as a result of thrombectomy. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 42/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate tPA: tissue-type plasminogen activator; IV: intravenous; mRS: modified Rankin scale; SICH: symptomatic intracranial hemorrhage. None were severely disabled or dead (mRS, 5-6) due to thrombectomy. No differences observed in the rate of SICH due to thrombectomy. From: Tokunboh I, Vales Montero M, Zopelaro Almeida MF, et al. Visual aids for patient, family, and physician decision making about endovascular thrombectomy for acute ischemic stroke. Stroke 2018; 49:90. DOI: 10.1161/STROKEAHA.117.018715. Copyright 2018 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 116248 Version 3.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 43/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Modified Treatment In Cerebral Ischemia (TICI) scale 0 No reperfusion 1 Flow beyond occlusion without distal branch reperfusion 2a Reperfusion of less than half of the downstream target arterial territory 2b Reperfusion of more than half, yet incomplete, in the downstream target arterial territory 3 Complete reperfusion of the downstream target arterial territory, including distal branches with slow flow This relates to capillary-level reperfusion as measured on catheter angiography. From: Wintermark M, Albers GW, Broderick JP, et al. Acute Stroke Imaging Research Roadmap II. Stroke 2013; 44:2628. DOI: 10.1161/STROKEAHA.113.002015. Copyright 2013 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 116431 Version 3.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 44/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Main approaches to managing cervical carotid lesions in patients with tandem occlusions undergoing thrombectomy for acute stroke Schematic summarizing the main approaches to managing cervical carotid lesions in patients with tandem occlusions undergoing thrombectomy for acute stroke. ICA: internal carotid artery; CEA: carotid endarterectomy; CAS: carotid artery stenting; EVT: endovascular therapy. Reprinted with permission of the American Society of Neuroradiology, from: Poppe AY, Jacquin G, Roy D, et al. Tandem Carotid Lesions in Acute Ischemic Stroke: Mechanisms, Therapeutic Challenges, and Future Directions. AJNR Am J Neuroradiol 2020; 41:1142; permission conveyed through Copyright Clearance Center, Inc. Copyright 2020. Graphic 133185 Version 2.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 45/46 7/6/23, 12:04 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Contributor Disclosures Jamary Oliveira-Filho, MD, MS, PhD No relevant financial relationship(s) with ineligible companies to disclose. Owen B Samuels, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 46/46
7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis : Nijasri Charnnarong Suwanwela, MD : Jos Biller, MD, FACP, FAAN, FAHA, Douglas R Nordli, Jr, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 08, 2022. INTRODUCTION Moyamoya is an uncommon cerebrovascular condition characterized by progressive narrowing of large intracranial arteries and the secondary development of prominent small-vessel collaterals. These collateral vessels produce a characteristic smoky appearance on angiography, which was first called "moyamoya," a Japanese word meaning puffy, obscure, or hazy like a puff of smoke in the air. Moyamoya is a progressive disorder that may lead to ischemic stroke or intracranial hemorrhage in children and adults. This topic will review the etiologies, clinical features, and diagnosis of moyamoya. The prognosis and treatment of moyamoya are discussed separately. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis".) CLASSIFICATION AND TERMINOLOGY The term "moyamoya" describes the specific angiographic findings of unilateral or bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation ( image 1). https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 1/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no associated conditions. This may also be called primary or idiopathic moyamoya disease as well as the descriptive "spontaneous occlusion of the circle of Willis" [1,2]. Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition as described below. (See 'Associated conditions' below.) These secondary forms of the condition have been termed "moyamoya phenomenon," "angiographic moyamoya," or "quasi-moyamoya disease" [1,3-5]. ETIOLOGY AND PATHOGENESIS The etiology of MMD is unknown, but genetic associations have been identified. MMS has been associated with multiple conditions, which may implicate diverse pathophysiologic processes leading to the characteristic vascular abnormalities. Genetic associations The high incidence among the Japanese population, together with a familial occurrence of approximately 10 to 15 percent of cases, strongly suggests a genetic etiology. Accumulating evidence suggests that the RNF213 gene on chromosome 17q25.3 is an important susceptibility factor for MMD in populations in several East Asian countries [6-14]. Several reports have also linked familial MMD to chromosomes 3p24.2, p26, 6q25, 8q23, and 12p12 [15-17]. Although the mode of inheritance is not established, one study suggested that familial moyamoya is an autosomal dominant disease with incomplete penetrance [18]. The authors proposed that genomic imprinting and epigenetic modification may account for the predominantly maternal transmission and elevated female-to-male incidence ratio. (See 'Epidemiology' below and "Inheritance patterns of monogenic disorders (Mendelian and non- Mendelian)", section on 'Parent-of-origin effects (imprinting)'.) A later genome-wide association study confirmed the relationship of MMD and a previously reported locus on chromosome 17q25 [19]. The study also identified 10 novel risk loci, including the genes regulating homocysteine metabolism, loci related to large vessel disease, and loci that are highly expressed in the immune system. Associated conditions There are many conditions associated with MMS. They may be causative or syndromic. Some of the conditions reported to be associated with MMS include: Disease affecting arteries around the circle of Willis https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 2/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Atherosclerosis [20] Radiation therapy to the base of the brain [21] (see "Delayed complications of cranial irradiation", section on 'Cerebrovascular effects') Cranial trauma [22] Brain tumors [23-25] Meningitis [26] Other viral or bacterial infection (eg, Cutibacterium acnes, leptospirosis, human immunodeficiency virus [HIV]) [27-29] Hematologic conditions Sickle cell disease [30-32] Beta thalassemia [33] Fanconi anemia [34] Hereditary spherocytosis [35] Homocystinuria and hyperhomocysteinemia [36] Factor XII deficiency [37] Essential thrombocythemia [38] Protein S deficiency [39-41] Pyruvate kinase deficiency [42] Vasculitis and autoimmune and multisystem diseases Systemic lupus erythematosus [43] Polyarteritis nodosa and postinfectious vasculopathy [44] Graves disease and thyroiditis [45-48] Sneddon syndrome and the antiphospholipid antibody syndrome [49,50] Anti-Ro and anti-La antibodies [51] Type 1 diabetes mellitus [48] Pulmonary sarcoidosis [52,53] Genetic and developmental disorders Alagille syndrome [54,55] Down syndrome [56,57] Hypomelanosis of Ito [58] Marfan syndrome [59] Microcephalic osteodysplastic primordial dwarfism type 2 [60] Multisystem disorder with short stature, hypergonadotropic hypogonadism, and dysmorphism [61,62] https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 3/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Neurofibromatosis type 1 [63-66] Noonan syndrome [67-69] Phakomatosis pigmentovascularis type IIIb [70] Prader-Willi syndrome [71] Pseudoxanthoma elasticum [72] Sturge-Weber syndrome [73] Tuberous sclerosis [74] Turner syndrome [75] Williams syndrome [76] Morning glory optic disc anomaly ( image 2), usually in conjunction with other craniofacial abnormalities [77-79] (see "Congenital and acquired abnormalities of the optic nerve", section on 'Morning glory disc') Other vasculopathies and extracranial cardiovascular diseases Coarctation of the aorta [80] Congenital heart disease [81] Fibromuscular dysplasia [82] Renal artery stenosis [83] Metabolic diseases Type I glycogenosis [84,85] Hyperphosphatasia [86] Primary oxalosis [87] Renal disorders Polycystic kidney disease [88-90] Wilms tumor [83,91-103] Pathogenesis The pathophysiologic processes leading to arterial stenosis and small vessel collateralization involve vessel wall thickening and angiogenesis. A genetic susceptibility may be implicated in MMD, while underlying associated conditions trigger the development of MMS. Vascular changes in moyamoya may be related to impaired response to inflammation or defects in cellular repair mechanisms [104]. Such changes have been associated with evidence of increased angiogenesis-related factors, including endothelial colony-forming cells, various cytokines, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) [105-107]. High levels of fibroblast growth factor, which may stimulate arterial growth, have been found in the vascular intima, media, and smooth muscle as well as cerebrospinal fluid https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 4/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate among patients with moyamoya [108,109]. Transforming growth factor beta-1 (TGFB1), which mediates neovascularization, may also contribute to the pathogenesis [110,111]. High levels of hepatocyte growth factor (a strong inducer of angiogenesis) have been detected in the carotid fork and cerebrospinal fluid in patients with moyamoya [112]. Pathologic findings Tissue analysis in patients with moyamoya shows evidence of arterial vessel narrowing and secondary vascular proliferation characteristic of the disease as well as tissue damage related to the vascular abnormalities. Stroke Brain tissue of patients with moyamoya usually reveals evidence of prior ischemic or hemorrhagic stroke. Multiple areas of cerebral infarction and focal cortical atrophy are commonly found. Although large-vessel stenosis and occlusion are the hallmark of this disease, extensive territorial infarction is uncommon. The brain infarcts are generally small and located in the basal ganglia, internal capsule, thalamus, and subcortical regions [113]. However, the cause of death in most autopsy cases is intracerebral hemorrhage [93]. The hemorrhage is commonly found in the basal ganglia, thalamus, hypothalamus, midbrain, and/or periventricular region. Bleeding into the intraventricular space is frequently observed. Vascular stenosis Pathologic vascular lesions appear in the large vessels of the circle of Willis and in the small collateral vessels [94]. The terminal portions of the internal carotid arteries as well as the proximal middle and anterior cerebral arteries are most commonly involved [114]. Some patients may have unilateral stenosis at presentation, although progression to bilateral involvement may occur [115,116]. Less frequently, the posterior circulation is affected, especially the posterior cerebral artery. In the affected large arteries, variable stenosis or occlusion is associated with intimal fibrocellular thickening, tortuosity or duplication of the internal elastic lamina, and attenuation of the media [91,117-119]. Collateral vessels One of the hallmarks of moyamoya is the presence of a collateral meshwork of overgrown and dilated small arteries, the moyamoya vessels, that branch from the circle of Willis ( image 3). The pathology of the smaller perforating vessels in moyamoya is variable. Morphometric analysis suggests that some are dilated with relatively thin walls, while others are stenotic with thick walls [117]. Dilated vessels, more common in younger patients than in adults, tend to show fibrosis with attenuation of the media and microaneurysm formation. Histologic study from autopsy specimens of aneurysms showed disappearance of internal https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 5/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate elastic lamina and media [92]. These findings are similar to those of the berry aneurysms commonly observed in primary subarachnoid hemorrhage. Leptomeningeal vessels are another source of collaterals in moyamoya. As a result of intracranial internal carotid artery stenosis, leptomeningeal anastomoses may develop from the three main cerebral arteries (middle, anterior, and posterior). These collaterals result from dilatation of preexisting arteries and veins. In addition, transdural anastomoses, termed vault moyamoya, may develop from extracranial arteries such as the middle meningeal and superficial temporal arteries [95]. Aneurysms Cerebral aneurysms have been associated with moyamoya in a number of reports [96-100]. Aneurysms can develop at vessel branching points in the circle of Willis or along collateral vessels [101,120]. In a review of 111 moyamoya patients with cerebral aneurysm, most presented with intracranial hemorrhage and were found to have a single aneurysm in 86 percent of cases. Aneurysms along the circle of Willis were found in 56 percent, of which almost 60 percent were in the posterior circulation [120]. Aneurysms can also arise from the small collateral moyamoya vessels, choroidal arteries, or other peripheral collateral arteries [101]. These small-vessel aneurysms are the major cause of parenchymal (intracerebral) hemorrhage in moyamoya. Extracranial involvement In patients with moyamoya, stenosis due to fibrocellular intimal thickening may also affect the extracranial and systemic arteries, including the cervical carotid, renal, pulmonary, and coronary vessels [91,102]. Involvement of the renal arteries has been most frequently reported. In one study of 86 patients with MMD, six had renal artery stenosis, two had associated renovascular hypertension, and one had a renal artery aneurysm [83]. Similarly, in a later study of 73 consecutive patients with MMD, four had renal artery stenosis [121]. EPIDEMIOLOGY Incidence and prevalence The relative prevalence of MMD and MMS vary geographically. MMD is more common in East Asian countries than elsewhere, with the highest prevalence found in Japan, China, and Korea [114,122,123]. In epidemiologic surveys conducted in Japan, the following observations have been made [124- 127]: The annual incidence of moyamoya is 0.35 to 0.94 per 100,000 population. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 6/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate The prevalence of moyamoya is 3.2 to 10.5 per 100,000 population. There is a female predominance, with a female-to-male ratio of 1.9. A family history of MMD is present in 10 to 12 percent of patients. Using hospital admissions data, a United States study found an incidence of 0.57 per 100,000 persons/year [128]. Among ethnic groups in California, the moyamoya incidence rate for Asian Americans was 0.28 per 100,000, similar to that in Japan. The incidence rates were lower for African American, White American, and Hispanic populations (0.13, 0.06, and 0.03 per 100,000, respectively). The incidence of MMS in Japan is approximately 10 times lower than MMD [129,130]. Age distribution MMD and MMS both occur in children and adults; presentation in infancy is uncommon [131,132]. Data from a nationwide registry in Japan, with 2545 cases of MMD, showed a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second broader peak at approximately 40 years of age [127]. A cohort study of 802 patients with MMD from China also demonstrated a bimodal age distribution, with a major peak at five to nine years of age and another peak at 35 to 39 years of age [133]. CLINICAL PRESENTATIONS Moyamoya has varying clinical presentations; the expression of disease and the age at presentation are influenced by regional and ethnic differences. Ischemic stroke and transient ischemic attack The most common initial presentation of moyamoya is ischemic stroke [134-138]. Transient ischemic attack (TIA) is also a frequent initial presentation and may be recurrent [134,138]. In one retrospective series from the United States, 61 percent of 31 adults with MMD or MMS presented with ischemic symptoms; in those with stroke, the predominant pattern was a border- zone pattern of infarction [137]. In another retrospective study, 21 German patients with MMD all presented with ischemic events, including 16 who were adults at symptom onset [136]. In children, symptomatic episodes of ischemia in the anterior and middle cerebral artery vascular territories may commonly be triggered by exercise, crying, coughing, straining, fever, or hyperventilation [104,139,140]. In the International Pediatric Stroke Study involving 174 children with moyamoya, ischemic stroke was the initial presentation in 90 percent of children and TIA in 7.5 percent [134]. Ischemic symptoms of hemiparesis or speech impairment predominated, reflecting the predilection for stenosis of the anterior cerebral circulation (anterior and middle https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 7/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate cerebral artery territories). In this series, 20 percent of children had recurrent symptoms in the median 13-month follow-up interval. Multiple recurrent events are common in other studies as well, likely reflecting the fixed stenosis susceptible to recurrent hypoperfusion. In one study from Korea of 88 children and adults who were followed for 6 to 216 months, multiple cerebrovascular events occurred in 55 percent [141]. Recurrences were most commonly ischemic. Intracerebral, intraventricular, and subarachnoid hemorrhage While ischemic symptoms may be more common at presentation, hemorrhagic complications of moyamoya, mainly intracerebral hemorrhage (ICH), represent a significant clinical burden. ICH is more common in adults than children [138,142]. In the International Pediatric Stroke Study, ICH was the presenting syndrome in 2.5 percent [134], while, in a series of adult patients, 10 percent of patients presented with intracranial hematoma [137]. In a systematic review, intracerebral hemorrhage at initial presentation was more frequent for patients in China and Taiwan than in the United States [135]. Intraventricular hemorrhage with or without ICH was a common presentation of MMD, according to one report from Korea [143]. In adults who presented with ICH or intraventricular hemorrhage, small aneurysms in the periventricular area have been reported ( image 4). Patients may also present with subarachnoid hemorrhage [144]. Seizures Patients with moyamoya present infrequently with seizures, often secondary to ischemic damage [145]. The rate of epilepsy may be more frequent in children than in adults [142]. Other manifestations Headache Headache is common in patients with moyamoya [146]. Migraine is the most common headache phenotype, but tension-type headache and cluster headache have also been reported [147,148]. Other neurologic symptoms There are case reports of patients with moyamoya who develop dystonia, chorea, or dyskinesia, but these appear to be uncommon manifestations [149-151]. Asymptomatic disease Moyamoya can be found incidentally in asymptomatic patients undergoing screening imaging for other conditions or because of family history [152,153]. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 8/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate A nationwide study in Japan using a questionnaire in 1994 identified 33 asymptomatic cases (1.5 percent) out of a total of 2193 patients [154]. INITIAL TEST FINDINGS Because patients with MMD or MMS may present with signs and symptoms of acute cerebrovascular disease, initial testing typically includes neuroimaging. Electroencephalography is often performed in patients with seizures and sometimes in those with transient ischemic attack (TIA). Specific findings on these tests may suggest moyamoya. Neuroimaging Cerebral infarction may involve cortical and subcortical regions ( image 5). Ischemic injury distal to the stenotic or occluded moyamoya vessel is common in superficial and deep border-zone regions most susceptible to hypoperfusion [155]. Patterns of infarction may be suggestive of moyamoya, but these features are not specific for this condition. In a retrospective series of 32 adults with first-ever ischemic stroke, patients with early-stage MMD had ischemic lesions involving only deep subcortical structures, while those with advanced stage had predominantly cortical lesions [156]. In patients with intracerebral hemorrhage (ICH), bleeding occurs in deep structures such as the basal ganglia, thalamus, and/or ventricular system. Bleeding in the cortical and subcortical regions has been reported with lower frequency [157,158]. Asymptomatic cerebral microbleeds were present on T2*-weighted gradient-echo magnetic resonance imaging (MRI) in 30 percent or more of adult patients with MMD [159-161]. One study of 50 patients with moyamoya found that the presence of multiple microbleeds was an independent risk factor for subsequent intracerebral hemorrhage (hazard ratio [HR] 2.89, 95% CI 1.001-13.24) [160]. Additional MRI findings have been implicated in identifying vascular changes consistent with moyamoya: Dilated collateral vessels in the basal ganglia or thalamus can be demonstrated as multiple punctate flow voids, a finding that is considered virtually diagnostic of moyamoya ( image 6) [162]. The "ivy sign" refers to focal, tubular, or serpentine hyperintensities on fluid-attenuated inversion recovery (FLAIR) or contrast-enhanced T1 images in the subarachnoid spaces that represent slow, retrograde collateral flow through engorged pial vessels via leptomeningeal anastomoses ( image 7) [163-165]. Observational data of 48 patients with ischemic symptoms and MMD showed the extent of the ivy sign was associated with a reduction in cerebral vascular reserve assessed by single-photon emission computed https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 9/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate tomography (SPECT) [166]. This sign is not specific for MMS/MMD and has been reported in association with large-vessel stenosis or occlusions, where it is referred to as FLAIR vascular hyperintensities or the hyperintense vessel sign [167]. The "brush sign" refers to prominent hypointensity in medullary veins draining areas of impaired cerebral perfusion on susceptibility-weighted imaging (SWI), a high-spatial- resolution 3D gradient-echo MRI technique that accentuates paramagnetic properties of blood products such as deoxyhemoglobin. In a group of 33 patients, the brush sign was identified more often in moyamoya patients with TIA and infarction than in asymptomatic patients. This sign was also more prominent in those with impaired cerebrovascular reserve ( image 8) [168]. Like the ivy sign, the "brush sign" is not specific for moyamoya and has been identified in patients with subacute stroke from many causes [169]. Post-contrast enhancement within the arterial wall may be seen using high-resolution MRI [170]. One study of 24 patients with moyamoya who underwent high-resolution vessel wall imaging protocol with 3-tesla MRI showed that patients with MMD demonstrated concentric enhancement of the distal internal carotid arteries, whereas patients with intracranial atherosclerotic disease generally had focal and eccentric enhancement of the symptomatic arterial segment [171]. In addition, at six-month follow-up, vessel wall enhancement was found in eight of the nine patients (odds ratio [OR] 36.2, 95% CI 2.8- 475.0), while absence of enhancement was associated with nonprogressive stenosis. This technique may be helpful if angiographic findings on other more routine testing are not diagnostic but may not be readily available in many centers. Electroencephalographic findings Children with MMD often exhibit abnormalities on electroencephalography (EEG). Hyperventilation, performed as a part of EEG protocol, induces generalized high-voltage slow waves (the "build-up" phenomenon) that resolve after hyperventilation stops. The reappearance of generalized or localized high-voltage slow waves on EEG 20 to 60 seconds after the end of hyperventilation (the "rebuild-up" phenomenon) is considered pathognomonic for moyamoya and occurs in approximately two-thirds of affected children [172,173]. Asymmetric posterior alpha activity and centrotemporal slowing have also been described in children with moyamoya. Background abnormalities in children and adults with MMD include nonspecific generalized, asymmetric, or localized slow-wave activity [173,174]. Of note, hyperventilation should be minimized in patients with a diagnosis of moyamoya since it may induce reflex cerebral vasoconstriction [175]. While EEG with hyperventilation was reported https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 10/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate to be safe in one series of 127 children [173], rare reports link hyperventilation to limb-shaking TIA and episodes of chorea and dystonia [176-178]. DIAGNOSIS The diagnosis of moyamoya is made by identifying the characteristic angiographic appearance of bilateral stenoses affecting the distal internal carotid arteries (or other proximal circle of Willis vessels) along with the presence of prominent collateral vessels ( image 5). MMS is diagnosed by identifying characteristic angiographic features in the setting of an associated condition. MMD is diagnosed in patients with a genetic susceptibility or family history of moyamoya after associated conditions have been excluded. (See 'Associated conditions' above.) Indications for vascular imaging The possibility of MMD disease should be considered in: Children or young adults with repeated symptoms of ischemic attacks resulting from low perfusion in the same arterial territory. Patients who lack common factors for primary intracerebral hemorrhage (ICH) but present with intracerebral hemorrhage in brain regions supplied by small vessels that branch from the circle of Willis (eg, caudate, thalamus, or intraventricular hemorrhage within the lateral ventricles) ( image 9). Children or young adults with ischemic or hemorrhagic stroke who may lack common cerebrovascular risk factors. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Differential diagnosis'.) Patients who undergo MRI, particularly in the context of evaluation for cerebral ischemia, that shows associated findings such as dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," the "brush sign," or enhancement of the arterial wall. (See 'Neuroimaging' above.) Diagnostic criteria Definitive diagnosis of moyamoya requires neurovascular imaging. Diagnostic criteria proposed by a Japanese research committee include the following major requirements [4]: Stenosis or occlusion at the terminal portion of the internal carotid artery and at the proximal portion of the anterior and middle cerebral arteries. Abnormal vascular networks in the basal ganglia; these networks can also be diagnosed by the presence of multiple flow voids on brain MRI. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 11/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Angiographic findings are present bilaterally; cases with unilateral angiographic findings are considered probable. For the diagnosis of MMD, underlying associated conditions (suggestive instead of MMS) are excluded. (See 'Further evaluation' below.) Angiography Stenotic distal internal carotid or proximal circle of Willis arteries and prominent collateral vessels can be identified by angiogram, computed tomography angiogram (CTA), or magnetic resonance angiography (MRA). Conventional digital subtraction angiography (DSA) is the gold standard for the diagnosis of MMD. Additionally, DSA is typically required for treatment planning. Characteristic angiographic findings include stenosis or occlusion at the distal internal carotid artery and the origin of the anterior cerebral and middle cerebral arteries on both sides, as well as abnormal vascular networks at the basal ganglia or moyamoya vessels ( image 1). Noninvasive imaging (CTA and MRA) can demonstrate stenotic or occlusive lesions in the distal internal carotid arteries ( image 10) and the arteries around the circle of Willis [179-181]. Although less sensitive than DSA for smaller vessels, noninvasive testing can also visualize the collateral "moyamoya vessels" in the basal ganglia ( image 11). Nevertheless, due to its high diagnostic yield and noninvasive nature, CTA and MRA have supplanted conventional DSA in many centers as the initial imaging modality to evaluate moyamoya [162,181]. Because the vascular changes and associated risks of ischemia or hemorrhage sequelae in MMD and MMS are often progressive, characterizing the degree of vascular abnormality is important. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis", section on 'Neuroimaging'.) Angiographic severity staging systems can provide insight and guidance. Suzuki followed patients with MMD and classified the angiographic progression [182,183]. Further evaluation In the absence of a known genetic predisposition to MMD or known diagnosis associated with MMS (eg, sickle cell anemia), patients should be further evaluated for underlying conditions in order to institute the most appropriate secondary prevention strategy. Evaluation for vasculitis and other metabolic conditions may be indicated when suggestive features of clinical presentation are present. In general, work-up for atherosclerotic risk factors such as diabetes, dyslipidemia, hyperhomocysteinemia, and alternative sources to large-vessel vasculopathy should be performed. (See "Primary angiitis of the central nervous system in adults", section on 'When to suspect the diagnosis' and "Intracranial large artery atherosclerosis: https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 12/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Epidemiology, clinical manifestations, and diagnosis", section on 'Identifying other causes of intracranial stenosis'.) Hemodynamic studies are useful both pre- and postoperatively to help determine cerebrovascular reserve and to assess disease severity and risk of ischemic morbidity. These topics are discussed elsewhere. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis", section on 'Neuroimaging'.) SCREENING IMAGING In general, we do not screen asymptomatic individuals for moyamoya; however, screening with a noninvasive angiographic modality may be reasonable in those with a family history of MMD, particularly individuals from or with families from Eastern Asia. The 2008 American Heart Association Stroke Council guidelines state that there is insufficient evidence to justify screening studies in asymptomatic individuals or in relatives of patients with MMS in the absence of a strong family history of MMD or medical conditions that predispose to MMS [162]. Even in individuals with a strong family history of MMD or those with medical conditions that predispose to MMS, the utility of angiographic screening is unclear, particularly since available medical and surgical treatment of asymptomatic MMD is of uncertain benefit. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Classification and terminology Moyamoya describes chronic progressive cerebrovascular diseases typically characterized by bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation. (See 'Classification and terminology' above.) Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no underlying risk factors. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 13/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition. (See 'Classification and terminology' above and 'Associated conditions' above.) Epidemiology MMD and MMS are rare. MMD is more common in East Asian countries than elsewhere. There is a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second, broader peak at approximately 40 years of age. (See 'Incidence and prevalence' above.) Clinical presentations Ischemic stroke and transient ischemic attack (TIA) affecting the anterior circulation are the most common clinical presentations. (See 'Ischemic stroke and transient ischemic attack' above and 'Neuroimaging' above.) Intracranial hemorrhage is less common and is rare in children. Hemorrhage usually affects deep structures such as the basal ganglia or thalamus but may also be intraventricular or subarachnoid. (See 'Intracerebral, intraventricular, and subarachnoid hemorrhage' above and 'Neuroimaging' above.) Clinical and imaging findings suggestive of underlying moyamoya pathology MRI findings that suggest the diagnosis of moyamoya include dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," or the "brush sign." (See 'Neuroimaging' above.) The diagnosis of moyamoya is most often considered in those with suggestive MRI findings in the context of evaluation for ischemic stroke. Other settings in which the diagnosis should be considered include repeated episodes of ischemia in the same arterial territory, deep intracerebral hemorrhage in the absence of hypertension or other known cause, and ischemic or hemorrhagic stroke in children or young adults who lack cerebrovascular risk factors. (See 'Indications for vascular imaging' above.) Diagnosis The diagnosis of moyamoya is made by angiographic demonstration of bilateral stenoses affecting the distal internal carotid arteries or proximal circle of Willis vessels along with the presence of prominent basal collateral vessels. (See 'Diagnosis' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Smith ER, Scott RM. Spontaneous occlusion of the circle of Willis in children: pediatric moyamoya summary with proposed evidence-based practice guidelines. A review. J https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 14/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Neurosurg Pediatr 2012; 9:353. 2. Fukui M. Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis ('moyamoya' disease). Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) of the Ministry of Health and Welfare, Japan. Clin Neurol Neurosurg 1997; 99 Suppl 2:S238. 3. Arias EJ, Derdeyn CP, Dacey RG Jr, Zipfel GJ. Advances and surgical considerations in the treatment of moyamoya disease. Neurosurgery 2014; 74 Suppl 1:S116. 4. Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis, Health Labour Sciences Research Grant for Research on Measures for Infractable Diseases. Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo) 2012; 52:245. 5. Kim JS, Bang OY, Oh CW. Moyamoya disease. In: Uncommon Causes of Stroke, 3rd ed, Capla n L, Biller J (Eds), Cambridge University Press, New York, NY 2018. p.545. 6. Kamada F, Aoki Y, Narisawa A, et al. A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet 2011; 56:34. 7. Liu W, Morito D, Takashima S, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One 2011; 6:e22542. 8. Miyatake S, Miyake N, Touho H, et al. Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology 2012; 78:803. 9. Yamauchi T, Tada M, Houkin K, et al. Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke 2000; 31:930. 10. Mineharu Y, Liu W, Inoue K, et al. Autosomal dominant moyamoya disease maps to chromosome 17q25.3. Neurology 2008; 70:2357. 11. Miyawaki S, Imai H, Takayanagi S, et al. Identification of a genetic variant common to moyamoya disease and intracranial major artery stenosis/occlusion. Stroke 2012; 43:3371. 12. Wu Z, Jiang H, Zhang L, et al. Molecular analysis of RNF213 gene for moyamoya disease in the Chinese Han population. PLoS One 2012; 7:e48179. 13. Bang OY, Ryoo S, Kim SJ, et al. Adult Moyamoya Disease: A Burden of Intracranial Stenosis in East Asians? PLoS One 2015; 10:e0130663. 14. Wang Y, Zhang Z, Wei L, et al. Predictive role of heterozygous p.R4810K of RNF213 in the phenotype of Chinese moyamoya disease. Neurology 2020; 94:e678. 15. Ikeda H, Sasaki T, Yoshimoto T, et al. Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet 1999; 64:533. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 15/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 16. Inoue TK, Ikezaki K, Sasazuki T, et al. Linkage analysis of moyamoya disease on chromosome 6. J Child Neurol 2000; 15:179. 17. Sakurai K, Horiuchi Y, Ikeda H, et al. A novel susceptibility locus for moyamoya disease on chromosome 8q23. J Hum Genet 2004; 49:278. 18. Mineharu Y, Takenaka K, Yamakawa H, et al. Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting. J Neurol Neurosurg Psychiatry 2006; 77:1025. 19. Duan L, Wei L, Tian Y, et al. Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study. Stroke 2018; 49:11. 20. Lee SJ, Ahn JY. Stenosis of the proximal external carotid artery in an adult with moyamoya disease: moyamoya or atherosclerotic change? Neurol Med Chir (Tokyo) 2007; 47:356. 21. Ullrich NJ, Robertson R, Kinnamon DD, et al. Moyamoya following cranial irradiation for primary brain tumors in children. Neurology 2007; 68:932. 22. Fernandez-Alvarez E, Pineda M, Royo C, Manzanares R. "Moya-moya' disease caused by cranial trauma. Brain Dev 1979; 1:133. 23. Kitano S, Sakamoto H, Fujitani K, Kobayashi Y. Moyamoya disease associated with a brain stem glioma. Childs Nerv Syst 2000; 16:251. 24. Arita K, Uozumi T, Oki S, et al. Moyamoya disease associated with pituitary adenoma report of two cases. Neurol Med Chir (Tokyo) 1992; 32:753. 25. Tsuji N, Kuriyama T, Iwamoto M, Shizuki K. Moyamoya disease associated with craniopharyngioma. Surg Neurol 1984; 21:588. 26. Czartoski T, Hallam D, Lacy JM, et al. Postinfectious vasculopathy with evolution to moyamoya syndrome. J Neurol Neurosurg Psychiatry 2005; 76:256. 27. Yamada H, Deguchi K, Tanigawara T, et al. The relationship between moyamoya disease and bacterial infection. Clin Neurol Neurosurg 1997; 99 Suppl 2:S221. 28. Sharfstein SR, Ahmed S, Islam MQ, et al. Case of moyamoya disease in a patient with advanced acquired immunodeficiency syndrome. J Stroke Cerebrovasc Dis 2007; 16:268.
cerebrovascular diseases typically characterized by bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation. (See 'Classification and terminology' above.) Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no underlying risk factors. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 13/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition. (See 'Classification and terminology' above and 'Associated conditions' above.) Epidemiology MMD and MMS are rare. MMD is more common in East Asian countries than elsewhere. There is a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second, broader peak at approximately 40 years of age. (See 'Incidence and prevalence' above.) Clinical presentations Ischemic stroke and transient ischemic attack (TIA) affecting the anterior circulation are the most common clinical presentations. (See 'Ischemic stroke and transient ischemic attack' above and 'Neuroimaging' above.) Intracranial hemorrhage is less common and is rare in children. Hemorrhage usually affects deep structures such as the basal ganglia or thalamus but may also be intraventricular or subarachnoid. (See 'Intracerebral, intraventricular, and subarachnoid hemorrhage' above and 'Neuroimaging' above.) Clinical and imaging findings suggestive of underlying moyamoya pathology MRI findings that suggest the diagnosis of moyamoya include dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," or the "brush sign." (See 'Neuroimaging' above.) The diagnosis of moyamoya is most often considered in those with suggestive MRI findings in the context of evaluation for ischemic stroke. Other settings in which the diagnosis should be considered include repeated episodes of ischemia in the same arterial territory, deep intracerebral hemorrhage in the absence of hypertension or other known cause, and ischemic or hemorrhagic stroke in children or young adults who lack cerebrovascular risk factors. (See 'Indications for vascular imaging' above.) Diagnosis The diagnosis of moyamoya is made by angiographic demonstration of bilateral stenoses affecting the distal internal carotid arteries or proximal circle of Willis vessels along with the presence of prominent basal collateral vessels. (See 'Diagnosis' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Smith ER, Scott RM. Spontaneous occlusion of the circle of Willis in children: pediatric moyamoya summary with proposed evidence-based practice guidelines. A review. J https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 14/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Neurosurg Pediatr 2012; 9:353. 2. Fukui M. Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis ('moyamoya' disease). Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) of the Ministry of Health and Welfare, Japan. Clin Neurol Neurosurg 1997; 99 Suppl 2:S238. 3. Arias EJ, Derdeyn CP, Dacey RG Jr, Zipfel GJ. Advances and surgical considerations in the treatment of moyamoya disease. Neurosurgery 2014; 74 Suppl 1:S116. 4. Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis, Health Labour Sciences Research Grant for Research on Measures for Infractable Diseases. Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo) 2012; 52:245. 5. Kim JS, Bang OY, Oh CW. Moyamoya disease. In: Uncommon Causes of Stroke, 3rd ed, Capla n L, Biller J (Eds), Cambridge University Press, New York, NY 2018. p.545. 6. Kamada F, Aoki Y, Narisawa A, et al. A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet 2011; 56:34. 7. Liu W, Morito D, Takashima S, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One 2011; 6:e22542. 8. Miyatake S, Miyake N, Touho H, et al. Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology 2012; 78:803. 9. Yamauchi T, Tada M, Houkin K, et al. Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke 2000; 31:930. 10. Mineharu Y, Liu W, Inoue K, et al. Autosomal dominant moyamoya disease maps to chromosome 17q25.3. Neurology 2008; 70:2357. 11. Miyawaki S, Imai H, Takayanagi S, et al. Identification of a genetic variant common to moyamoya disease and intracranial major artery stenosis/occlusion. Stroke 2012; 43:3371. 12. Wu Z, Jiang H, Zhang L, et al. Molecular analysis of RNF213 gene for moyamoya disease in the Chinese Han population. PLoS One 2012; 7:e48179. 13. Bang OY, Ryoo S, Kim SJ, et al. Adult Moyamoya Disease: A Burden of Intracranial Stenosis in East Asians? PLoS One 2015; 10:e0130663. 14. Wang Y, Zhang Z, Wei L, et al. Predictive role of heterozygous p.R4810K of RNF213 in the phenotype of Chinese moyamoya disease. Neurology 2020; 94:e678. 15. Ikeda H, Sasaki T, Yoshimoto T, et al. Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet 1999; 64:533. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 15/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 16. Inoue TK, Ikezaki K, Sasazuki T, et al. Linkage analysis of moyamoya disease on chromosome 6. J Child Neurol 2000; 15:179. 17. Sakurai K, Horiuchi Y, Ikeda H, et al. A novel susceptibility locus for moyamoya disease on chromosome 8q23. J Hum Genet 2004; 49:278. 18. Mineharu Y, Takenaka K, Yamakawa H, et al. Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting. J Neurol Neurosurg Psychiatry 2006; 77:1025. 19. Duan L, Wei L, Tian Y, et al. Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study. Stroke 2018; 49:11. 20. Lee SJ, Ahn JY. Stenosis of the proximal external carotid artery in an adult with moyamoya disease: moyamoya or atherosclerotic change? Neurol Med Chir (Tokyo) 2007; 47:356. 21. Ullrich NJ, Robertson R, Kinnamon DD, et al. Moyamoya following cranial irradiation for primary brain tumors in children. Neurology 2007; 68:932. 22. Fernandez-Alvarez E, Pineda M, Royo C, Manzanares R. "Moya-moya' disease caused by cranial trauma. Brain Dev 1979; 1:133. 23. Kitano S, Sakamoto H, Fujitani K, Kobayashi Y. Moyamoya disease associated with a brain stem glioma. Childs Nerv Syst 2000; 16:251. 24. Arita K, Uozumi T, Oki S, et al. Moyamoya disease associated with pituitary adenoma report of two cases. Neurol Med Chir (Tokyo) 1992; 32:753. 25. Tsuji N, Kuriyama T, Iwamoto M, Shizuki K. Moyamoya disease associated with craniopharyngioma. Surg Neurol 1984; 21:588. 26. Czartoski T, Hallam D, Lacy JM, et al. Postinfectious vasculopathy with evolution to moyamoya syndrome. J Neurol Neurosurg Psychiatry 2005; 76:256. 27. Yamada H, Deguchi K, Tanigawara T, et al. The relationship between moyamoya disease and bacterial infection. Clin Neurol Neurosurg 1997; 99 Suppl 2:S221. 28. Sharfstein SR, Ahmed S, Islam MQ, et al. Case of moyamoya disease in a patient with advanced acquired immunodeficiency syndrome. J Stroke Cerebrovasc Dis 2007; 16:268. 29. Hammond CK, Shapson-Coe A, Govender R, et al. Moyamoya Syndrome in South African Children With HIV-1 Infection. J Child Neurol 2016; 31:1010. 30. Fryer RH, Anderson RC, Chiriboga CA, Feldstein NA. Sickle cell anemia with moyamoya disease: outcomes after EDAS procedure. Pediatr Neurol 2003; 29:124. 31. Dobson SR, Holden KR, Nietert PJ, et al. Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events. 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Topic 1131 Version 41.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 26/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate GRAPHICS 40-year-old with moyamoya disease Digital subtraction angiogram shows stenosis of right supraclinoid carotid, proximal middle cerebral artery a artery (oval), and lenticulostriate moyamoya collateral vessels (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129102 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 27/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Morning glory disc anomaly The disc is large and there is a central, white tuft of glial tissue. The retinal vessels proceed radially from the disc. Courtesy of Karl C Golnik, MD. Graphic 55325 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 28/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 9-year-old with unilateral moyamoya disease Digital subtraction angiogram shows stenosis of right supraclinoid and proximal middle cerebral arteries (cir lenticulostriate moyamoya collateral vessels (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129103 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 29/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Aneurysm in moyamoya disease Cerebral angiogram showing aneurysm (arrow) in patient with moyamoya disease. Courtesy of Nijasri Suwanwela, MD. Graphic 64850 Version 4.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 30/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 9-year-old male with moyamoya disease who presented with repeated episodes of transient left hemiparesis (A) Noncontrast head CT scan shows low-density area of infarction in the right basal ganglia (arrow). (B) MRI FLAIR image depicting a high-signal-intensity area in the right basal ganglia and multiple small hyperintense areas in both basal ganglia consistent with infarction. (C, D) Selective intra-arterial DSA (anteroposterior projection) shows severe stenoses of the distal right and left internal carotid arteries. Abnormal network of blood vessels (puff of smoke or moyamoya vessels) in the vicinity of the stenotic areas were noted (arrows). CT: computed tomography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DSA: digital subtraction angiogram. Courtesy of Nijasri Suwanwela, MD. Graphic 74421 Version 8.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 31/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 54-year-old with moyamoya disease T2-weighted sequence on magnetic resonance imaging shows lenticulostriate moyamoya collateral vessels on right (arrow). Courtesy of Glenn A Tung, MD, FACR. Graphic 129104 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 32/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 40-year-old with moyamoya disease "ivy sign" Fluid-attenuated inversion recovery sequence magnetic resonance imaging shows linear and curvilinear hyperintensities in the cerebral sulci consistent with "ivy sign" (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129105 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 33/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya disease "brush sign" The conspicuity of multiple deep medullary veins on susceptibility- weighted imaging sequence (oval) from reduced oxygen supply relative to tissue demand resulting in an increase in the concentration of deoxyhemoglobin in venous blood. Republished with permission of the American Society of Neuroradiology, from: Horie N, Morikawa M, Nozaki A, et al. "Brush sign" on susceptibility-weighted MR imaging indicates the severity of moyamoya disease. Am J Neurorad 2011; 32:1697; permission conveyed through Copyright Clearance Center, Inc. Copyright 2011. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 34/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Graphic 129106 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 35/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Intracerebral hemorrhage with intraventricular hemorrhage due to moyamoya syndrome
25/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 168. Horie N, Morikawa M, Nozaki A, et al. "Brush Sign" on susceptibility-weighted MR imaging indicates the severity of moyamoya disease. AJNR Am J Neuroradiol 2011; 32:1697. 169. Yu X, Yuan L, Jackson A, et al. Prominence of Medullary Veins on Susceptibility-Weighted Images Provides Prognostic Information in Patients with Subacute Stroke. AJNR Am J Neuroradiol 2016; 37:423. 170. Muraoka S, Araki Y, Taoka T, et al. Prediction of Intracranial Arterial Stenosis Progression in Patients with Moyamoya Vasculopathy: Contrast-Enhanced High-Resolution Magnetic Resonance Vessel Wall Imaging. World Neurosurg 2018; 116:e1114. 171. Ryoo S, Cha J, Kim SJ, et al. High-resolution magnetic resonance wall imaging findings of Moyamoya disease. Stroke 2014; 45:2457. 172. Kodama N, Aoki Y, Hiraga H, et al. Electroencephalographic findings in children with moyamoya disease. Arch Neurol 1979; 36:16. 173. Cho A, Chae JH, Kim HM, et al. Electroencephalography in pediatric moyamoya disease: reappraisal of clinical value. Childs Nerv Syst 2014; 30:449. 174. Frechette ES, Bell-Stephens TE, Steinberg GK, Fisher RS. Electroencephalographic features of moyamoya in adults. Clin Neurophysiol 2015; 126:481. 175. Smith ER. Moyamoya arteriopathy. Curr Treat Options Neurol 2012; 14:549. 176. Kim HY, Chung CS, Lee J, et al. Hyperventilation-induced limb shaking TIA in Moyamoya disease. Neurology 2003; 60:137. 177. Spengos K, Tsivgoulis G, Toulas P, et al. Hyperventilation-enhanced chorea as a transient ischaemic phenomenon in a patient with moyamoya disease. Eur Neurol 2004; 51:172. 178. Bakdash T, Cohen AR, Hempel JM, et al. Moyamoya, dystonia during hyperventilation, and antiphospholipid antibodies. Pediatr Neurol 2002; 26:157. 179. Tsuchiya K, Makita K, Furui S. Moyamoya disease: diagnosis with three-dimensional CT angiography. Neuroradiology 1994; 36:432. 180. Hasuo K, Mihara F, Matsushima T. MRI and MR angiography in moyamoya disease. J Magn Reson Imaging 1998; 8:762. 181. Yamada I, Nakagawa T, Matsushima Y, Shibuya H. High-resolution turbo magnetic resonance angiography for diagnosis of Moyamoya disease. Stroke 2001; 32:1825. 182. Suzuki J, Kodama N. Moyamoya disease a review. Stroke 1983; 14:104. 183. Suzuki J, Takaku A. Cerebrovascular "moyamoya" disease. Disease showing abnormal net- like vessels in base of brain. Arch Neurol 1969; 20:288. Topic 1131 Version 41.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 26/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate GRAPHICS 40-year-old with moyamoya disease Digital subtraction angiogram shows stenosis of right supraclinoid carotid, proximal middle cerebral artery a artery (oval), and lenticulostriate moyamoya collateral vessels (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129102 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 27/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Morning glory disc anomaly The disc is large and there is a central, white tuft of glial tissue. The retinal vessels proceed radially from the disc. Courtesy of Karl C Golnik, MD. Graphic 55325 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 28/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 9-year-old with unilateral moyamoya disease Digital subtraction angiogram shows stenosis of right supraclinoid and proximal middle cerebral arteries (cir lenticulostriate moyamoya collateral vessels (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129103 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 29/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Aneurysm in moyamoya disease Cerebral angiogram showing aneurysm (arrow) in patient with moyamoya disease. Courtesy of Nijasri Suwanwela, MD. Graphic 64850 Version 4.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 30/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 9-year-old male with moyamoya disease who presented with repeated episodes of transient left hemiparesis (A) Noncontrast head CT scan shows low-density area of infarction in the right basal ganglia (arrow). (B) MRI FLAIR image depicting a high-signal-intensity area in the right basal ganglia and multiple small hyperintense areas in both basal ganglia consistent with infarction. (C, D) Selective intra-arterial DSA (anteroposterior projection) shows severe stenoses of the distal right and left internal carotid arteries. Abnormal network of blood vessels (puff of smoke or moyamoya vessels) in the vicinity of the stenotic areas were noted (arrows). CT: computed tomography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DSA: digital subtraction angiogram. Courtesy of Nijasri Suwanwela, MD. Graphic 74421 Version 8.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 31/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 54-year-old with moyamoya disease T2-weighted sequence on magnetic resonance imaging shows lenticulostriate moyamoya collateral vessels on right (arrow). Courtesy of Glenn A Tung, MD, FACR. Graphic 129104 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 32/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 40-year-old with moyamoya disease "ivy sign" Fluid-attenuated inversion recovery sequence magnetic resonance imaging shows linear and curvilinear hyperintensities in the cerebral sulci consistent with "ivy sign" (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129105 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 33/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya disease "brush sign" The conspicuity of multiple deep medullary veins on susceptibility- weighted imaging sequence (oval) from reduced oxygen supply relative to tissue demand resulting in an increase in the concentration of deoxyhemoglobin in venous blood. Republished with permission of the American Society of Neuroradiology, from: Horie N, Morikawa M, Nozaki A, et al. "Brush sign" on susceptibility-weighted MR imaging indicates the severity of moyamoya disease. Am J Neurorad 2011; 32:1697; permission conveyed through Copyright Clearance Center, Inc. Copyright 2011. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 34/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Graphic 129106 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 35/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Intracerebral hemorrhage with intraventricular hemorrhage due to moyamoya syndrome Noncontrast head CT (A) showing hematoma in the right corpus striatum and lateral ventricles. Digital subtraction angiogram (B) showing critical stenosis of proximal right middle cerebral artery (arrow), prominent collateralization of both lenticulostriate vessels (circle), and branches of the anterior cerebral artery (thick arrows). CT: computed tomography. Courtesy of Glenn A Tung, MD, FACR. Graphic 132277 Version 1.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 36/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Magnetic resonance angiography (MRA) of a patient with moyamoya disease A) There is severe narrowing of the distal part of the both carotid arteries (arrows). In addition, there is markedly reduced flow in the left middle cerebral artery and absence of both anterior cerebral arteries. B) Lateral projection MRA demonstrates severe narrowing of the distal internal carotid artery (arrow). Courtesy of Nijasri Suwanwela, MD. Graphic 51947 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 37/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 12-year-old with moyamoya syndrome secondary to neurofibromatosis type 1 Magnetic resonance angiogram shows occlusion of left supraclinoid internal carotid artery (circles) and lentic collateral vessels (arrow). Courtesy of Glenn A Tung, MD, FACR. Graphic 129107 Version 3.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 38/39 7/6/23, 12:05 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Contributor Disclosures Nijasri Charnnarong Suwanwela, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Douglas R Nordli, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 39/39
7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Overview of ischemic stroke prognosis in adults : Matthew A Edwardson, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 07, 2023. INTRODUCTION Stroke is the third most common cause of disability and second most common cause of death worldwide (see "Stroke: Etiology, classification, and epidemiology", section on 'Epidemiology'). Clinicians are often asked to predict outcome after stroke by the patient, family, other healthcare workers, and insurance providers. A wide variety of factors influence stroke prognosis, including age, stroke severity, stroke mechanism, infarct location, comorbid conditions, clinical findings, and related complications. In addition, interventions such as thrombolysis, mechanical thrombectomy, stroke unit care, and rehabilitation can play a major role in the outcome of ischemic stroke. Knowledge of the important factors that affect prognosis is necessary for the clinician to make a reasonable prediction for individual patients, to provide a rational approach to patient management, and to help the patient and family understand the course of the disease. This topic will review the factors that affect stroke prognosis, with a focus on the acute phase of ischemic stroke. The major medical and neurologic complications of acute stroke are discussed elsewhere. (See "Complications of stroke: An overview".) The prognosis for different stroke subtypes is also discussed in the following topics: (See "Lacunar infarcts", section on 'Prognosis'.) (See "Intracranial large artery atherosclerosis: Treatment and prognosis", section on 'Prognosis'.) https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 1/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Prognosis'.) (See "Stroke after cardiac catheterization", section on 'Prognosis'.) (See "Ischemic stroke in children: Management and prognosis", section on 'Prognosis'.) (See "Stroke in the newborn: Management and prognosis", section on 'Prognosis'.) (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Early prognosis'.) (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Prognosis'.) MORBIDITY AND MORTALITY The estimated worldwide 30-day case fatality rate after first ischemic stroke ranges from 16 to 23 percent, though there is wide variation in reports from different countries [1,2]. A cohort study of adults 18 to 49 years of age who were 30-day survivors of first stroke found that, compared with the general population, mortality risk remained elevated up to 15 years after stroke [3]. Even minor ischemic strokes portend a diminished long-term prognosis. In a 10-year follow-up study of 322 patients with minor ischemic stroke, the cumulative mortality rate was 32 percent, almost twice that of the general population [4]. A population-based study from Australia and New Zealand found that the observed life expectancy for over 175,000 patients hospitalized with first ischemic stroke was 11.5 years, resulting in a five-year loss in life expectancy when compared with an expected life expectancy of 16.5 years for matched patients from the general population [5]. Intracerebral hemorrhage and subarachnoid hemorrhage are associated with higher morbidity and mortality than ischemic stroke [6-12]. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Early prognosis' and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Prognosis'.) In a community-based study from the United States that evaluated 220 ischemic stroke survivors (age 65 years), the following neurologic deficits were observed at six months after stroke [13]: Hemiparesis, 50 percent Cognitive deficits, 46 percent Hemianopia, 20 percent Aphasia, 19 percent Sensory deficits, 15 percent Disability measures at six months after stroke were as follows [13]: https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 2/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Depression symptoms, 35 percent Unable to walk unassisted, 31 percent Social disability, 30 percent Institutionalization, 26 percent Bladder incontinence, 22 percent A systematic review from 2009 identified only three studies that specifically evaluated work status after stroke and used appropriate analytic methods [14]. In these reports, the proportion of patients at 6 to 12 months after stroke who had returned to paid employment was just over 50 percent [15-17]. A subsequent report evaluated a hospital-based cohort of 694 working-age (18 to 50 years) patients with transient ischemic attack (TIA), ischemic stroke, or hemorrhagic stroke and found that the risk of unemployment after eight years of follow-up was two- to threefold higher compared with the general population of vocational age [18]. Outcome from ischemic stroke can be assessed with the modified Rankin Scale and the Barthel Index. The modified Rankin Scale ( table 1) measures functional independence on a seven- grade scale. The Barthel Index ( table 2) measures ten basic aspects of self-care and physical dependency. These indices are reviewed in greater detail elsewhere (see "Use and utility of stroke scales and grading systems", section on 'Modified Rankin Scale' and "Use and utility of stroke scales and grading systems", section on 'Barthel Index'). While the modified Rankin Scale and Barthel Index are helpful in assessing overall recovery and likelihood of return to independence, most rehabilitation experts prefer domain-specific recovery scales (eg, motor, speech, language, balance, cognition) [19]. (See "Use and utility of stroke scales and grading systems", section on 'Specific neurologic deficits'.) MAJOR PREDICTORS In the acute phase of stroke, the strongest predictors of outcome are stroke severity and patient age. Stroke severity can be judged clinically, based upon the degree of neurologic impairment (eg, altered mentation, language, behavior, visual field deficit, motor deficit) and the size and location of the infarction on neuroimaging with magnetic resonance imaging (MRI) or computed tomography (CT). Other important influences on stroke outcome include ischemic stroke mechanism, comorbid conditions, epidemiologic factors, and complications of stroke. Neurologic severity The severity of stroke on neurologic exam is probably the most important factor affecting short- and long-term outcome [6,20-32]. Generally, large strokes with severe initial clinical deficits have poor outcomes compared with smaller strokes. https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 3/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Neurologic impairment is measured quantitatively in many research studies, and increasingly in clinical practice, by use of the National Institutes of Health Stroke Scale (NIHSS), which measures neurologic impairment using a 15-item scale ( table 3) or less often by use of the Canadian Neurological Scale ( table 4). As an example, the combination of neurologic findings in patients with a large infarction involving the middle cerebral artery vascular territory typically includes forced gaze deviation, visual field deficit, hemiplegia, and aphasia or neglect, depending on the hemisphere involved, and yields a NIHSS score >15 for a right hemisphere infarction and >20 for a left hemisphere infarction. The NIHSS score is most often used when patients first present with stroke symptoms. Several studies have demonstrated that the NIHSS is a good predictor of stroke outcome [21,33-35]. One report analyzed NIHSS scores obtained within 24 hours of acute ischemic stroke symptom onset from over 1200 patients enrolled in a clinical trial [21]. Each additional point on the NIHSS decreased the odds of an excellent outcome at three months by 17 percent. At three months, the proportion of patients with excellent outcomes for NIHSS scores of 7 to 10 and 11 to 15 was approximately 46 and 23 percent, respectively. An NIHSS score of 6 predicted a good recovery (able to live independently, whether or not able to return to work or school), while a score 16 was associated with a high probability of death or severe disability. In many such studies, descriptors such as "good recovery" are based upon discharge location to home or independence in activities of daily living such as mobility. However, the NIHSS does not evaluate more complex goals such as return to prior level of employment, participation in leisure activities, or social participation. In general, recovery of these areas is less than those measured by the NIHSS. The relationship of NIHSS score with final outcome varies according to the time elapsed from stroke onset [27,33], in part because early stroke-related deficits tend to be unstable, and because many patients experience gradual recovery. Thus, the NIHSS score associated with a specific disability outcome shifts to lower values over time [27]. One study found that the best predictor of poor prognosis at 24 hours was an NIHSS of >22, and the best predictor at 7 to 10 days was an NIHSS score of >16 [33]. In addition, the correlation of the NIHSS score with final disability outcome increases with time [27]. The Canadian Neurological Scale (CNS) is also useful for predicting outcome after acute ischemic stroke. A CNS score of <6.5 on admission is associated with increased 30-day mortality and a poor outcome at six months [35,36]. Although comparative data are limited, the results of one study suggest that the NIHSS is more accurate than the CNS for predicting outcome at three months [34]. https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 4/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate An important limitation of both the NIHSS and the CNS scales is that they do not capture all stroke-related impairments. For example, a stroke can cause significant disability from impairment of hand function and fine motor coordination without any change to the NIHSS. Both scales may fail to capture significant cognitive dysfunction, and neither measures the patient's ability to balance. (See "Use and utility of stroke scales and grading systems", section on 'Stroke impairment and severity' and 'Global prognostic scales' below.) Patients with acute ischemic stroke who are treated with intravenous thrombolysis and/or mechanical thrombectomy according to recommended guidelines may have a dramatic reduction in neurologic impairment. A meta-analysis of mechanical thrombectomy trials found that, compared with controls, patients receiving the intervention were twice as likely to return to functional independence by 90 days after treatment [37]. Thus, impairment scales performed after the intervention are a more accurate gauge of prognosis than those performed at initial presentation [38]. Age Advancing age has a major negative impact on stroke morbidity, mortality, and long- term outcome [6,8,12,20,25,28,30,39-41]. The influence of age in stroke outcome is seen in both minor and major strokes. Older adults (over 65 years) have increased chance of dying in two months after stroke and being discharged to the skilled nursing facility if they survive [42,43]. Advancing age is used in several predictive models. (See 'Global prognostic scales' below.) Neuroimaging Findings on neuroimaging including stroke size and location are an important adjunct to the neurologic exam when gauging prognosis. Early after stroke, the neurologic exam alone can suggest a falsely grim or favorable prognosis. For example, a patient may have a small stroke on neuroimaging and present with stupor or coma caused by seizure or metabolic derangement that is reversible. Conversely, a patient presenting with mild stroke and a low NIHSS score on examination may have large vessel occlusion and a large perfusion deficit on neuroimaging, suggesting the possibility of stroke progression and worse outcome. Infarct volume The volume of acute infarction on neuroimaging studies may be used to estimate stroke outcome [44]. In one small study, the volume of ischemic tissue determined by diffusion-weighted MRI within 36 hours of stroke onset combined with the NIHSS score and time from stroke onset to imaging predicted the functional outcome at three months better than any of the individual factors alone [29]. A much larger study analyzed data from over 1800 patients who had CT or MRI within 72 hours of ischemic stroke onset and found that initial infarct volume was an independent predictor of stroke outcome at 90 days, along with age and NIHSS score [26]. In these and most other reports [26,29,44], the vast majority of infarcts analyzed were supratentorial (eg, anterior circulation, middle cerebral artery territory) and the results may not https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 5/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate apply to posterior circulation or infratentorial infarcts, in which an infarct of small volume can result in severe disability. Infarct location The prognosis for stroke recovery may vary by the affected vascular territory and site of ischemic brain injury. Acute occlusion of the cervical internal carotid artery [45,46], basilar artery [47], or a large intracranial artery is associated with an increased risk of poor outcome [48-50]. It follows that involvement of total anterior circulation or posterior circulation also portends poor prognosis [36,51-53]. Strokes in the insular region (supplied by the insular branch of the middle cerebral artery) have been associated with increased mortality, which is often attributed to autonomic dysregulation [54,55]. However, this association may be confounded by infarct size [56]. Insular infarcts may undergo early expansion due to associated large vessel occlusion and progression of infarction in surrounding areas of initially viable but ischemic brain tissue [57]. Anterior choroidal artery infarctions may be more likely to progress in the first few days after stroke than other subtypes [58,59]. In a prospective study of over 1300 patients with acute ischemic stroke, anterior choroidal territory infarcts had intermediate long-term prognosis between lacunar infarcts and large artery territory hemispheric infarcts [58]. A retrospective report of 75 survivors of ischemic stroke in the middle cerebral artery territory found that strokes located in the internal capsule demonstrated a worse prognosis for recovery of hand motor function at one year than strokes in the corona radiata or motor cortex after controlling for infarct size [60]. This is likely due to injury to the corticospinal tract. (See 'Predicting recovery' below.) There are limited and conflicting data regarding borderzone infarcts (ie, infarcts that occur along the boundaries of adjacent arterial territories, such as the middle cerebral and anterior cerebral artery territories) and outcome; some studies suggest a lower severity at onset and a good prognosis in most cases [61], while others describe severe impairment and poor recovery in a substantial proportion [62,63]. Other imaging findings In addition to stroke volume and location, there are other features identifiable on neuroimaging that may suggest poor prognosis: Diffusion-perfusion mismatch (ie, an ischemic brain lesion characterized by a core of infarcted tissue on MRI diffusion imaging that is embedded within a still viable but ischemic penumbral region on MRI perfusion imaging), which may be a risk factor for https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 6/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate lesion enlargement. (See "Neuroimaging of acute stroke", section on 'Mismatch and salvageable brain tissue'.) Poor collateral blood flow [64,65]. Development of cerebral edema in nonlacunar ischemic stroke [66]. Ischemic stroke mechanism The etiology or mechanism of ischemic stroke influences prognosis for recovery [67]. Patients with lacunar infarcts have a better prognosis up to one year after onset than those with infarcts due to other stroke mechanisms. However, the longer-term prognosis after lacunar stroke may not differ greatly from nonlacunar stroke. (See "Lacunar infarcts", section on 'Prognosis'.) Compared with other ischemic stroke subtypes, cryptogenic stroke, where no mechanism of stroke is identified, tends to have a better prognosis up to one year following onset. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Prognosis'.) Patients with strokes of cardioembolic or large artery etiology tend to have worse prognosis for recovery compared with other ischemic stroke subtypes [67-70]. Comorbidities A host of prestroke comorbid conditions are associated with an increased risk of poor outcome following ischemic stroke, including the following: Anemia [71,72] Atrial fibrillation [23,25,33,73,74] Cancer [23,73] Coronary artery disease [23] Dementia [23,28,75] Dependency [12,23,40,73] Diabetes mellitus [32,76,77] Hyperglycemia (eg, blood glucose >6.1 mmol/L [>110 mg/dL]) on admission [77,78] Heart failure [23,73] Myocardial infarction [79,80] Periventricular white matter disease or leukoaraiosis [81-83] Renal dysfunction or dialysis [23,84-88] Poor nutritional status [89] https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 7/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate The relationship between blood pressure in the acute phase of ischemic stroke and outcome is complex and is discussed separately. (See "Initial assessment and management of acute stroke", section on 'Blood pressure management'.) Body mass index appears to be inversely related to stroke prognosis, such that patients who are underweight or normal weight have paradoxically higher mortality rates and worse functional outcomes than patients who are overweight or obese [90-92]. Finally, ischemic stroke that occurs in the postoperative period has a high short-term morbidity [93]. Epidemiologic factors Differences in sex, race, and socioeconomic status may affect stroke recovery. Sex Most studies have found that women are more likely than men to have lower mortality but more disability after ischemic stroke [94-99]. However, the difference is mostly related to age, stroke severity, and pre-stroke dependency [100]. Racial, ethnic, and socioeconomic factors There are racial and ethnic differences in outcome after stroke. In studies from the United States, Black Americans and other groups have a higher risk for poor outcome compared with White Americans [81,101-103]. Lower levels of educational attainment [104,105], socioeconomic status [105-107], and lesser degrees of social support have been correlated with poor outcome following ischemic stroke, and a lower socioeconomic status has been associated with a worse health-related quality of life at five years [108,109]. However, it is unclear if these are independent prognostic factors, since lower socioeconomic status may also be associated with increased comorbidities and greater stroke severity [110,111]. In the United States, some studies found that Black race is associated with greater physical limitation after stroke, even after adjusting for level of education, socioeconomic status, and social support [103,112]. While these studies did not control for the amount of stroke rehabilitation, evidence suggests there are no differences in inpatient rehabilitation referral rates or the intensity of rehabilitation received between Black and White Americans [113]. COMPLICATIONS OF STROKE Medical complications of acute ischemic stroke are common and influence outcome after ischemic stroke. The most frequent serious medical complications include pneumonia, the need for intubation and mechanical ventilation, gastrointestinal bleeding, congestive heart failure, https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 8/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate cardiac arrest, deep vein thrombosis, pulmonary embolism, and urinary tract infection. (See "Complications of stroke: An overview".) Early neurologic deterioration during the acute phase of ischemic stroke affects a significant minority and is associated with an increased risk of morbidity and mortality. The mechanisms of early neurologic deterioration are heterogeneous (eg, cerebral edema, elevated intracranial pressure, hemorrhagic transformation), as reviewed separately. (See "Complications of stroke: An overview", section on 'Neurologic complications'.) Poststroke depression has a high prevalence and a negative impact on stroke outcome [75]. Stroke severity with subsequent disability and cognitive impairment are likely risk factors. (See "Complications of stroke: An overview", section on 'Depression'.) PREDICTING RECOVERY In the period from 12 hours to seven days after ischemic stroke onset, many patients who are without complications experience moderate but steady improvement in neurologic impairments [114]. The greatest proportion of recovery after stroke occurs in the first three to six months [22,24,115,116], though some patients experience further improvement up to 18 months [24]. In a prospective study that evaluated more than 1100 patients from Denmark with acute stroke, those who had mild disability tended to recover within two months and those who had moderate disability recovered within three months [22,116]. Patients with severe disability who recovered did so within four months, and those with the most severe disability within five months from onset ( figure 1). Other data suggest that functional outcome at three months after stroke predicts survival at four years [81], and functional status at six months predicts long- term survival [117]. Evidence suggests that the integrity of the ipsilesional corticospinal tract is necessary to allow for motor recovery and that excessive corticospinal tract injury predicts poor recovery [118-122]. The functional integrity of the corticospinal tract can be assessed by a variety of specialized techniques, including motor evoked potentials elicited by transcranial magnetic stimulation, and MRI techniques. These imaging techniques include overlaying the stroke lesion onto corticospinal tract masks [121,122] and measuring the loss of fractional anisotropy in the lesional corticospinal tract on diffusion tensor imaging [119,120]. Despite the emerging importance of corticospinal tract integrity for motor recovery, none of these measures are in widespread clinical use. https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 9/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Specific neurologic deficits Attempting to predict recovery from specific neurologic deficits is challenging and best provided by an experienced neurologist or physiatrist after careful clinical examination and review of pertinent neuroimaging. The time course and degree of improvement may vary for specific deficits, but as a general rule, mild deficits improve more rapidly and more completely than severe deficits [115]. Arm and hand impairment An early study found that in patients with hemiplegic stroke, the first voluntary movements were observed between 6 to 33 days after onset [123]. In a prospective report of patients with arm disability, the maximum degree of functional recovery was reached within three weeks from stroke onset by 80 percent of patients, and within nine weeks by 95 percent [124]. Complete functional arm recovery was achieved by patients with initial mild and severe arm paresis in 79 and 18 percent, respectively. The return of arm and hand function after stroke is particularly important to a good functional recovery. The flexor synergy seen after stroke limits the ability to isolate joint movements, so the ability to extend the fingers and release grasp is a significant component of a good motor outcome. Several studies have found that early active finger extension, grasp release, shoulder shrug, shoulder abduction, and active range of motion are associated with a favorable prognosis for arm and hand recovery at six months [125- 128]. As an example, in a prospective cohort study of 188 patients with monoparesis or hemiparesis from anterior circulation ischemic stroke, patients with some voluntary finger extension and shoulder abduction of the hemiplegic limb on day 2 after stroke onset had a high probability (0.98) to regain some dexterity by six months [129]. By contrast, the probability for patients without these voluntary movements at two and nine days was 0.25 and 0.14, respectively. Leg impairment and ambulation In a study of 154 patients who were unable to walk after first ischemic stroke, multivariate modeling showed that patients who could maintain sitting balance for 30 seconds and perform muscle contraction (with or without actual limb movement) in the paretic leg within the first 72 hours after stroke had a probability for ambulating independently at six months of 98 percent [130]. For those who did not reach either functional level within 72 hours, the probability for ambulating independently at six months was only 27 percent. In a meta-analysis of data from cohort studies with 2344 nonambulatory patients following stroke, factors measured within the first month after stroke onset that predicted independent walking at three months were independence in activities of daily living (odds ratio [OR] 10.5), an intact corticospinal tract (OR 8.3), good sitting (OR 7.9), good leg https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 10/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate strength (OR 5.0), no cognitive impairment (OR 3.5), younger age (OR 3.4), no neglect (OR 2.4), and continence (OR 2.3) [131]. Aphasia Patients with poststroke aphasia are likely to experience some improvement from the initial impairment. Not surprisingly, the prognosis for full recovery is greatest when patients have milder degrees of aphasia at onset. The time course for recovery from aphasia is similar to that of motor function. One prospective study included over 300 patients with aphasia at admission; the time to maximal language recovery in 95 percent of patients with initially mild, moderate, and severe aphasia was 2, 6, and 10 weeks, respectively [132]. (See "Aphasia: Prognosis and treatment".) Dysphagia Early after stroke, approximately 50 percent of patients have difficulty swallowing, placing them at risk for aspiration [133]. Swallowing impairments commonly improve over time. In a large cohort of patients with severe dysphagia on admission after stroke, 36 percent recovered swallowing ability by 7 days, and 70 percent by 30 days [134]. A large multicenter trial found no benefit to early enteral feeding via a percutaneous endoscopic gastrostomy (PEG) tube compared with no tube feeding [135]. Risk factors for more longstanding dysphagia eventually requiring PEG tube placement include high National Institutes of Health Stroke Scale (NIHSS) score and bihemispheric infarcts [136,137]. In a retrospective cohort study of 563 patients admitted for stroke rehabilitation, feeding tubes were placed in 6 percent [138]. Of these, approximately one-third of feeding tubes were discontinued before patients were discharged from rehabilitation, and almost all the rest were discontinued by one year. Persons with stroke lesions that were bilateral or in the posterior fossa were least likely to return to oral feeding. (See "Complications of stroke: An overview", section on 'Dysphagia'.) Sensory loss Sensory impairment is found in 65 to 94 percent of stroke survivors; the reported incidence depends greatly on the method of assessment, with formal quantitative testing being the most sensitive [139]. Sensory loss is also common on the apparently unaffected side. Sensory impairment is associated with reduced mobility and less independence in activities of daily living [140]. However, there are currently no reliable predictors of recovery from sensory loss. Patients with infarcts involving the spinothalamic or trigeminothalamic pathways sometimes develop a debilitating central poststroke pain syndrome [141]. (See "Approach to the patient with sensory loss", section on 'Thalamic lesions'.) Visuospatial neglect Limited data suggest that full recovery from visuospatial neglect occurs in 70 to 80 percent of affected patients within three months of stroke onset [142,143]. https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 11/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Hemianopia A study of 99 patients with acute stroke and homonymous hemianopia (HH) found that 17 percent of those with complete HH had full recovery at one month, whereas 72 percent with partial HH had full recovery [144]. It is important to counsel patients with hemianopia after stroke not to drive until they are cleared by an ophthalmologist or pass a formal driver rehabilitation program (offered at select rehabilitation centers). (See "Homonymous hemianopia", section on 'Driving'.) Global prognostic scales In stroke rehabilitation venues, the Orpington Prognostic Scale (OPS) [145,146] and the Reding three-factor approach [147] are in wide clinical use. The OPS ( table 5) includes assessments of arm motor function, proprioception, balance, and cognition, making it easier to perform than the NIHSS. The OPS is better at predicting return of function than NIHSS in those with mild to moderate stroke [145], possibly because balance is so critical to carrying out activities of daily living. The Reding three-factor approach provides a useful way to gauge the speed and degree of recovery for an individual patient [147]. Patients are divided into one of three groups: Motor deficit only Motor deficit plus somatic sensory deficit Motor deficit plus somatic sensory deficit plus homonymous visual field deficit Once the group is determined for the individual patient, their recovery can be compared with a cohort of similar patients ( figure 2) to estimate the probability of return to Barthel table 2) score of 60. This level of function is a useful benchmark, because most Index ( patients with a Barthel Index score 60 can walk with assistance and contribute to their activities of daily living; in addition, the likelihood of a supported discharge to the community rises substantially. With a Barthel Index score of 100, a discharge to the community at a level of independence becomes plausible but requires adequate cognitive function. Several other prognostic models may be useful for predicting global outcome from acute ischemic stroke; however, none of the current models is established as generally valid, and none is widely used in clinical practice. These models include the ASTRAL score [148,149], DRAGON score [150], iScore [151,152], PLAN score [73], and CoRisk score [153]. These stroke prognostic models are intended to be easy to calculate from data available on admission. However, they disregard information available from follow-up and testing, such as stroke etiology, treatment, and complications, that has an important impact on outcome [81,154]. The course of stroke often changes in the first days after onset, and assessment at later times (eg, from 1 to 10 days after stroke onset) is likely to provide a more reliable prognosis [27]. https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 12/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate INTERVENTIONS THAT IMPROVE OUTCOMES Interventions such as thrombolysis, mechanical thrombectomy, stroke unit care, and rehabilitation can play a major role in improving the outcome of ischemic stroke. The risk of stroke recurrence can be reduced by secondary prevention measures. Reperfusion therapy Reperfusion with intravenous thrombolysis and mechanical thrombectomy for acute ischemic stroke is discussed in detail separately. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke".) Stroke unit care The benefits of stroke unit care are reviewed elsewhere. (See "Initial assessment and management of acute stroke", section on 'Stroke unit care'.) Stroke rehabilitation The goals of stroke rehabilitation are to improve functional outcomes and to attain the highest level of independence that is possible despite persistent stroke-related neurologic deficits [155]. A variety of rehabilitation disciplines (eg, physical therapy, occupational therapy, speech and language therapy) employ exercises and compensatory and adaptive strategies to help patients improve function. Intense physical therapy (PT) and occupational therapy (OT) may be harmful if started very early (ie, in the first days after stroke) but they are generally considered beneficial at later time points [156,157]. Health care systems in most resource-rich countries offer inpatient rehabilitation services following acute hospitalization for patients with stroke who qualify. Inpatient rehabilitation typically starts around one week poststroke and may continue for two to six weeks or more depending on stroke severity. No large randomized clinical trials have demonstrated efficacy for inpatient rehabilitation therapy, but this remains difficult to study. Given the perceived value of inpatient rehabilitation by the public, health care providers, and policy makers alike, it would be considered unethical to conduct a study in which inpatient rehabilitation is withheld from a control group. While there is limited evidence to suggest early (started within three months poststroke) rehabilitation therapy is better [158], the few positive large rehabilitation trials were performed in the chronic phase (six months or more poststroke) [159,160]. Specifically, constraint-induced movement therapy in the chronic phase can improve motor impairment in the upper limb [159,161]. Vagus nerve stimulation paired with upper limb rehabilitation therapy is another promising approach for improving upper limb function in the chronic phase [162]. https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 13/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Speech and language therapy is recommended for patients with aphasia [163], but no particular technique is established as effective [164]. The optimal timing, dose, and duration of various rehabilitation methods remains to be determined [155,163,165]. Rehabilitation should be individualized according to specific patient needs and available resources. Secondary prevention Most patients with an ischemic stroke or transient ischemic attack (TIA) should be treated with all available risk reduction strategies, including antithrombotic therapy, blood pressure control, statin therapy, and lifestyle modification; select patients with symptomatic cervical internal carotid artery disease may benefit from revascularization. These issues are addressed in separate UpToDate topic reviews: (See "Overview of secondary prevention of ischemic stroke".) (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) (See "Stroke in patients with atrial fibrillation".) (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) (See "Antihypertensive therapy for secondary stroke prevention".) (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 14/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Basics topics (see "Patient education: Recovery after stroke (The Basics)") SUMMARY AND RECOMMENDATIONS Morbidity and mortality The estimated 30-day case fatality rate after first ischemic stroke ranges from 16 to 23 percent. Available data suggest that persistent neurologic deficits observed at six months after stroke include hemiparesis and cognitive deficits in 40 to 50 percent of patients, and hemianopia, aphasia, or sensory deficits in 15 to 20 percent. Disability outcomes at six months after stroke include depression, inability to walk unassisted, and social impairments in approximately 30 percent, and institutional care in approximately 25 percent. (See 'Morbidity and mortality' above.) Outcome predictors In the acute phase of stroke, the strongest predictors of outcome are stroke severity and patient age. Stroke severity can be judged clinically, based upon the degree of neurologic impairment (eg, altered mentation, language, behavior, visual field deficit, motor deficit), and the size and location of the infarction on neuroimaging with MRI or CT. Other important influences on stroke outcome include infarct location, ischemic stroke mechanism, comorbid conditions, epidemiologic factors, and complications of stroke. (See 'Major predictors' above.) Pace of recovery In the period from 12 hours to seven days after ischemic stroke onset, many patients who are without complications experience moderate but steady improvement in neurologic impairments. The greatest proportion of recovery occurs in the
function. Several other prognostic models may be useful for predicting global outcome from acute ischemic stroke; however, none of the current models is established as generally valid, and none is widely used in clinical practice. These models include the ASTRAL score [148,149], DRAGON score [150], iScore [151,152], PLAN score [73], and CoRisk score [153]. These stroke prognostic models are intended to be easy to calculate from data available on admission. However, they disregard information available from follow-up and testing, such as stroke etiology, treatment, and complications, that has an important impact on outcome [81,154]. The course of stroke often changes in the first days after onset, and assessment at later times (eg, from 1 to 10 days after stroke onset) is likely to provide a more reliable prognosis [27]. https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 12/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate INTERVENTIONS THAT IMPROVE OUTCOMES Interventions such as thrombolysis, mechanical thrombectomy, stroke unit care, and rehabilitation can play a major role in improving the outcome of ischemic stroke. The risk of stroke recurrence can be reduced by secondary prevention measures. Reperfusion therapy Reperfusion with intravenous thrombolysis and mechanical thrombectomy for acute ischemic stroke is discussed in detail separately. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke".) Stroke unit care The benefits of stroke unit care are reviewed elsewhere. (See "Initial assessment and management of acute stroke", section on 'Stroke unit care'.) Stroke rehabilitation The goals of stroke rehabilitation are to improve functional outcomes and to attain the highest level of independence that is possible despite persistent stroke-related neurologic deficits [155]. A variety of rehabilitation disciplines (eg, physical therapy, occupational therapy, speech and language therapy) employ exercises and compensatory and adaptive strategies to help patients improve function. Intense physical therapy (PT) and occupational therapy (OT) may be harmful if started very early (ie, in the first days after stroke) but they are generally considered beneficial at later time points [156,157]. Health care systems in most resource-rich countries offer inpatient rehabilitation services following acute hospitalization for patients with stroke who qualify. Inpatient rehabilitation typically starts around one week poststroke and may continue for two to six weeks or more depending on stroke severity. No large randomized clinical trials have demonstrated efficacy for inpatient rehabilitation therapy, but this remains difficult to study. Given the perceived value of inpatient rehabilitation by the public, health care providers, and policy makers alike, it would be considered unethical to conduct a study in which inpatient rehabilitation is withheld from a control group. While there is limited evidence to suggest early (started within three months poststroke) rehabilitation therapy is better [158], the few positive large rehabilitation trials were performed in the chronic phase (six months or more poststroke) [159,160]. Specifically, constraint-induced movement therapy in the chronic phase can improve motor impairment in the upper limb [159,161]. Vagus nerve stimulation paired with upper limb rehabilitation therapy is another promising approach for improving upper limb function in the chronic phase [162]. https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 13/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Speech and language therapy is recommended for patients with aphasia [163], but no particular technique is established as effective [164]. The optimal timing, dose, and duration of various rehabilitation methods remains to be determined [155,163,165]. Rehabilitation should be individualized according to specific patient needs and available resources. Secondary prevention Most patients with an ischemic stroke or transient ischemic attack (TIA) should be treated with all available risk reduction strategies, including antithrombotic therapy, blood pressure control, statin therapy, and lifestyle modification; select patients with symptomatic cervical internal carotid artery disease may benefit from revascularization. These issues are addressed in separate UpToDate topic reviews: (See "Overview of secondary prevention of ischemic stroke".) (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) (See "Stroke in patients with atrial fibrillation".) (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) (See "Antihypertensive therapy for secondary stroke prevention".) (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 14/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Basics topics (see "Patient education: Recovery after stroke (The Basics)") SUMMARY AND RECOMMENDATIONS Morbidity and mortality The estimated 30-day case fatality rate after first ischemic stroke ranges from 16 to 23 percent. Available data suggest that persistent neurologic deficits observed at six months after stroke include hemiparesis and cognitive deficits in 40 to 50 percent of patients, and hemianopia, aphasia, or sensory deficits in 15 to 20 percent. Disability outcomes at six months after stroke include depression, inability to walk unassisted, and social impairments in approximately 30 percent, and institutional care in approximately 25 percent. (See 'Morbidity and mortality' above.) Outcome predictors In the acute phase of stroke, the strongest predictors of outcome are stroke severity and patient age. Stroke severity can be judged clinically, based upon the degree of neurologic impairment (eg, altered mentation, language, behavior, visual field deficit, motor deficit), and the size and location of the infarction on neuroimaging with MRI or CT. Other important influences on stroke outcome include infarct location, ischemic stroke mechanism, comorbid conditions, epidemiologic factors, and complications of stroke. (See 'Major predictors' above.) Pace of recovery In the period from 12 hours to seven days after ischemic stroke onset, many patients who are without complications experience moderate but steady improvement in neurologic impairments. The greatest proportion of recovery occurs in the first three to six months after stroke, with lesser improvements thereafter. (See 'Predicting recovery' above.) Arm and hand function The return of arm and hand function after stroke is particularly important to a good functional recovery. Early active finger extension, grasp release, shoulder shrug, shoulder abduction, and active range of motion are associated with a favorable prognosis for arm and hand recovery at six months. (See 'Specific neurologic deficits' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Alexander Dromerick, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 15/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate REFERENCES 1. Grysiewicz RA, Thomas K, Pandey DK. Epidemiology of ischemic and hemorrhagic stroke: incidence, prevalence, mortality, and risk factors. Neurol Clin 2008; 26:871. 2. Feigin VL, Lawes CM, Bennett DA, Anderson CS. 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The influence of gender and age on disability following ischemic stroke: the Framingham study. J Stroke Cerebrovasc Dis 2003; 12:119. 14. Daniel K, Wolfe CD, Busch MA, McKevitt C. What are the social consequences of stroke for working-aged adults? A systematic review. Stroke 2009; 40:e431. 15. Glozier N, Hackett ML, Parag V, et al. The influence of psychiatric morbidity on return to paid work after stroke in younger adults: the Auckland Regional Community Stroke (ARCOS) https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 16/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Study, 2002 to 2003. Stroke 2008; 39:1526. 16. Wozniak MA, Kittner SJ, Price TR, et al. Stroke location is not associated with return to work after first ischemic stroke. Stroke 1999; 30:2568. 17. Saeki S, Ogata H, Okubo T, et al. Return to work after stroke. A follow-up study. Stroke 1995; 26:399. 18. Maaijwee NA, Rutten-Jacobs LC, Arntz RM, et al. 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The natural history of dysphagia following a stroke. Dysphagia 1997; 12:188. 134. Galovic M, Stauber AJ, Leisi N, et al. Development and Validation of a Prognostic Model of Swallowing Recovery and Enteral Tube Feeding After Ischemic Stroke. JAMA Neurol 2019; 76:561. 135. Dennis MS, Lewis SC, Warlow C, FOOD Trial Collaboration. Effect of timing and method of enteral tube feeding for dysphagic stroke patients (FOOD): a multicentre randomised controlled trial. Lancet 2005; 365:764. 136. Kumar S, Langmore S, Goddeau RP Jr, et al. Predictors of percutaneous endoscopic gastrostomy tube placement in patients with severe dysphagia from an acute-subacute hemispheric infarction. J Stroke Cerebrovasc Dis 2012; 21:114. 137. Okubo PC, F bio SR, Domenis DR, Takayanagui OM. Using the National Institute of Health Stroke Scale to predict dysphagia in acute ischemic stroke. Cerebrovasc Dis 2012; 33:501. 138. Teasell R, Foley N, McRae M, Finestone H. Use of percutaneous gastrojejunostomy feeding tubes in the rehabilitation of stroke patients. Arch Phys Med Rehabil 2001; 82:1412. 139. Doyle S, Bennett S, Fasoli SE, McKenna KT. Interventions for sensory impairment in the upper limb after stroke. Cochrane Database Syst Rev 2010; :CD006331. 140. Tyson SF, Hanley M, Chillala J, et al. Sensory loss in hospital-admitted people with stroke: characteristics, associated factors, and relationship with function. Neurorehabil Neural Repair 2008; 22:166. 141. Flaster M, Meresh E, Rao M, Biller J. Central poststroke pain: current diagnosis and treatment. Top Stroke Rehabil 2013; 20:116. 142. Cassidy TP, Lewis S, Gray CS. Recovery from visuospatial neglect in stroke patients. J Neurol Neurosurg Psychiatry 1998; 64:555. 143. Hier DB, Mondlock J, Caplan LR. Recovery of behavioral abnormalities after right hemisphere stroke. Neurology 1983; 33:345. 144. Gray CS, French JM, Bates D, et al. Recovery of visual fields in acute stroke: homonymous hemianopia associated with adverse prognosis. Age Ageing 1989; 18:419. https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 25/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate 145. Lai SM, Duncan PW, Keighley J. Prediction of functional outcome after stroke: comparison of the Orpington Prognostic Scale and the NIH Stroke Scale. Stroke 1998; 29:1838. 146. Kalra L, Crome P. The role of prognostic scores in targeting stroke rehabilitation in elderly patients. J Am Geriatr Soc 1993; 41:396. 147. Reding MJ, Potes E. Rehabilitation outcome following initial unilateral hemispheric stroke. Life table analysis approach. Stroke 1988; 19:1354. 148. Ntaios G, Faouzi M, Ferrari J, et al. An integer-based score to predict functional outcome in acute ischemic stroke: the ASTRAL score. Neurology 2012; 78:1916. 149. Papavasileiou V, Milionis H, Michel P, et al. ASTRAL score predicts 5-year dependence and mortality in acute ischemic stroke. Stroke 2013; 44:1616. 150. Strbian D, Meretoja A, Ahlhelm FJ, et al. Predicting outcome of IV thrombolysis-treated ischemic stroke patients: the DRAGON score. Neurology 2012; 78:427. 151. Saposnik G, Raptis S, Kapral MK, et al. The iScore predicts poor functional outcomes early after hospitalization for an acute ischemic stroke. Stroke 2011; 42:3421. 152. Saposnik G, Reeves MJ, Johnston SC, et al. Predicting clinical outcomes after thrombolysis using the iScore: results from the Virtual International Stroke Trials Archive. Stroke 2013; 44:2755. 153. De Marchis GM, Dankowski T, K nig IR, et al. A novel biomarker-based prognostic score in acute ischemic stroke: The CoRisk score. Neurology 2019; 92:e1517. 154. Caplan LR. Scores of scores. JAMA Neurol 2013; 70:252. 155. Belagaje SR. Stroke Rehabilitation. Continuum (Minneap Minn) 2017; 23:238. 156. AVERT Trial Collaboration group, Bernhardt J, Langhorne P, et al. Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trial. Lancet 2015; 386:46. 157. Dromerick AW, Lang CE, Birkenmeier RL, et al. Very Early Constraint-Induced Movement during Stroke Rehabilitation (VECTORS): A single-center RCT. Neurology 2009; 73:195. 158. Dromerick AW, Geed S, Barth J, et al. Critical Period After Stroke Study (CPASS): A phase II clinical trial testing an optimal time for motor recovery after stroke in humans. Proc Natl Acad Sci U S A 2021; 118. 159. Wolf SL, Winstein CJ, Miller JP, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial. JAMA 2006; 296:2095. 160. Lo AC, Guarino PD, Richards LG, et al. Robot-assisted therapy for long-term upper-limb impairment after stroke. N Engl J Med 2010; 362:1772. https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 26/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate 161. Etoom M, Hawamdeh M, Hawamdeh Z, et al. Constraint-induced movement therapy as a rehabilitation intervention for upper extremity in stroke patients: systematic review and meta-analysis. Int J Rehabil Res 2016; 39:197. 162. Dawson J, Liu CY, Francisco GE, et al. Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial. Lancet 2021; 397:1545. 163. Winstein CJ, Stein J, Arena R, et al. Guidelines for Adult Stroke Rehabilitation and Recovery: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2016; 47:e98. 164. Brady MC, Kelly H, Godwin J, Enderby P. Speech and language therapy for aphasia following stroke. Cochrane Database Syst Rev 2012; :CD000425. 165. Lang CE, Strube MJ, Bland MD, et al. Dose response of task-specific upper limb training in people at least 6 months poststroke: A phase II, single-blind, randomized, controlled trial. Ann Neurol 2016; 80:342. Topic 14086 Version 26.0 https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 27/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate GRAPHICS Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 28/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Barthel Index Activity Score Feeding 0 = Unable 5 = Needs help cutting, spreading butter, etc, or requires modified diet 10 = Independent Bathing 0 = Dependent 5 = Independent (or in shower) Grooming 0 = Needs to help with personal care 5 = Independent face/hair/teeth/shaving (implements provided) Dressing 0 = Dependent 5 = Needs help but can do about half unaided 10 = Independent (including buttons, zips, laces, etc) Bowels 0 = Incontinent (or needs to be given enemas) 5 = Occasional accident 10 = Continent Bladder 0 = Incontinent, or catheterized and unable to manage alone 5 = Occasional accident 10 = Continent Toilet use 0 = Dependent 5 = Needs some help, but can do something alone 10 = Independent (on and off, dressing, wiping) Transfers (bed to chair and back) https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 29/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate 0 = Unable, no sitting balance 5 = Major help (one or two people, physical), can sit 10 = Minor help (verbal or physical) 15 = Independent Mobility (on level surfaces) 0 = Immobile or <50 yards 5 = Wheelchair independent, including corners, >50 yards 10 = Walks with help of one person (verbal or physical) >50 yards 15 = Independent (but may use any aid; for example, stick) >50 yards Stairs 0 = Unable 5 = Needs help (verbal, physical, carrying aid) 10 = Independent Total (0-100): The Barthel ADL Index: Guidelines The index should be used as a record of what a patient does, not as a record of what a patient could do The main aim is to establish degree of independence from any help, physical or verbal, however minor and for whatever reason The need for supervision renders the patient not independent Patient performance should be established using the best available evidence provided by the patient, family, friends and caregivers; direct observation and common sense are also important, but direct testing is not needed Usually the patient's performance over the preceding 24 to 48 hours is important, but occasionally longer periods will be relevant Middle categories imply that the patient supplies over 50 percent of the effort Use of aids to be independent is allowed ADL: activities of daily living. References: 1. Mahoney FI, Barthel D. Functional evaluation: The Barthel Index. Maryland State Medical Journal 1965; 14:56. Used with permission. 2. Loewen SC, Anderson BA. Predictors of stroke outcome using objective measurement scales. Stroke 1990; 21:78. 3. Gresham GE, Phillips TF, Labi ML. ADL status in stroke: Relative merits of three standard indexes. Arch Phys Med Rehabil 1980; 61:355. 4. Collin C, Wade DT, Davies S, Horne V. The Barthel ADL Index: A reliability study. Int Disability Study 1988; 10:61. https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 30/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Graphic 77371 Version 3.0 https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 31/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The 0 = Alert; keenly responsive. investigator must choose a response if a full evaluation is prevented by such obstacles as 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. an endotracheal tube, language barrier, 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). _____ (other than reflexive posturing) in response to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from 1 = Answers one question correctly. 2 = Answers neither question correctly. _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The 0 = Performs both tasks correctly. _____ patient is asked to open and close the eyes and then to grip and release the non-paretic 1 = Performs one task correctly. 2 = Performs neither task correctly. hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 32/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in reflexive (oculocephalic) eye movements will one or both eyes, but forced deviation or total gaze paresis is not present. be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat, as appropriate. Patients may be encouraged, 0 = No visual loss. 1 = Partial hemianopia. 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut 3 = Bilateral hemianopia (blind including cortical blindness). _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score symmetry of grimace in response to noxious fold, asymmetry on smiling). 2 = Partial paralysis (total or near-total paralysis of lower face). stimuli in the poorly responsive or non- comprehending patient. If facial trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 33/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not falls before 10 seconds. The aphasic patient hit bed or other support. is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) degrees, drifts down to bed, but has some stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in _____ effort against gravity. the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The 0 = No drift; leg holds 30-degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. Only in the case of amputation or joint fusion at the hip, the examiner should 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. _____ 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding 0 = Absent. _____ evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, 1 = Present in one limb. 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 34/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of being touched. should test as many body areas (arms [not hands], legs, trunk, face) as needed to 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, accurately check for hemisensory loss. A score of 2, "severe or total sensory loss," should only be given when a severe or total loss of sensation can be clearly and leg. _____ demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of 0 = No aphasia; normal. _____ information about comprehension will be obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the attached picture, to name 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant limitation on ideas expressed or form of expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. conversation about provided materials Comprehension is judged from responses here, as well as to all of the commands in difficult or impossible. For example, in conversation about provided materials, the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the 2 = Severe aphasia; all communication is through fragmentary expression; great need hand, repeat, and produce speech. The intubated patient should be asked to write. for inference, questioning, and guessing by the listener. Range of information that can The patient in a coma (item 1a=3) will automatically score 3 on this item. The be exchanged is limited; listener carries burden of communication. Examiner cannot examiner must choose a score for the patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 35/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal, an adequate sample of speech must 0 = Normal. 1 = Mild-to-moderate dysarthria; patient be obtained by asking patient to read or slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of 2 = Severe dysarthria; patient's speech is so slurred as to be unintelligible in the absence articulation of spontaneous speech can be rated. Only if the patient is intubated or has _____ of or out of proportion to any dysphasia, or is mute/anarthric. other physical barriers to producing speech, the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the patient why he or she is being tested. explain:________________ 11. Extinction and inattention (formerly 0 = No abnormality. neglect): Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient has aphasia but does appear to attend to 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. 2 = Profound hemi-inattention or extinction to more than one modality; does not recognize own hand or orients to only one side of space. _____ both sides, the score is normal. The presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 36/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Canadian Neurological Scale Patient Name: Rater Name: Date: Time: Mentation Score Level consciousness Alert 3.0 Drowsy 1.5 Orientation Oriented 1.0 Disoriented/NA 0.0 Speech Normal 1.0 Expressive deficit 0.5 Receptive deficit 0.0 TOTAL: Motor functions (no comprehension deficit) Weakness Score Face None 0.5 Present 0.0 Arm: proximal None 1.5 Mild 1.0 Significant 0.5 Total 0 Arm: distal None 1.5 Mild 1.0 Significant 0.5 Total 0 Leg None 1.5 Mild 1.0 Significant 0.5 Total 0 TOTAL: Motor response (comprehension deficit) Score https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 37/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Face Symmetrical .5 Asymmetrical 0 Arms Equal 1.5 Unequal 0 Legs Equal 1.5 Unequal 0 TOTAL: Reproduced with permission from: C t R, Hachinski VC, Shurvell BL, et al. The Canadian Neurological Scale: a preliminary study in acute stroke. Stroke 1986; 17:731. Copyright 1986 Lippincott Williams & Wilkins. Graphic 55644 Version 9.0 https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 38/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Time course of neurologic recovery after stroke The time course of recovery in survivors shown as the cumulated rate of patients having reached their best neurological outcome. Rates are given for all patients, ; for patients with initial mild stroke severity, ; for patients with initial moderate stroke severity, ; for patients with initial severe stroke severity, *; for patients with initial very severe stroke severity, . The ANOVA test showed an overall difference in the time course of recovery between the groups, p<0.0001. Further analyses showed that the time course of recovery differed significantly between patients with initially mild strokes versus moderate strokes, p<0.0001, and between patients with moderate strokes versus severe strokes, p<0.03. No difference was found between patients with severe versus very severe strokes, p = 0.19. ANOVA: analysis of variance. Reproduced from: J rgensen HS1, Nakayama H, Raaschou HO, et al. Outcome and time course of recovery in stroke. Part II: Time course of recovery. The Copenhagen Stroke Study. Arch Phys Med Rehabil 1995; 76:406. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 96471 Version 4.0 https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 39/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Orpington Prognostic Scale A. Motor deficit in arm Lying supine, patient flexes shoulder to 90 and is given resistance. 0.0 = MRC grade 5 (normal power) 0.4 = MRC grade 4 (diminished power) 0.8 = MRC grade 3 (movement against gravity) 1.2 = MRC grade 1 to 2 (movement with gravity eliminated or trace) 1.6 = MRC grade 0 (no movement) B. Proprioception (eyes closed) Locates affected thumb: 0.0 = Accurately 0.4 = Slight difficulty 0.8 = Finds thumb via arm 1.2 = Unable to find thumb C. Balance 0.0 = Walks 10 feet without help 0.4 = Maintains standing position (unsupported for one minute) 0.8 = Maintains sitting position 1.2 = No sitting balance D. Cognition Hodkinson's Mental Test: Score one point for each correct answer. _____ 1. Age of patient _____ 2. Time (to the nearest hour) I am going to give you an address, please remember it and I will ask you later: 42 West Street. _____ 3. Name of hospital _____ 4. Year _____ 5. Date of birth of patient _____ 6. Month _____ 7. Years of the Second World War _____ 8. Name of the President https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 40/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate _____ 9. Count backwards (20 to 1) _____ 10. What is the address I asked you to remember: 42 West Street. 0.0 = Mental test score of 10 0.4 = Mental test score of 8 to 9 0.8 = Mental test score of 5 to 7 1.2 = Mental test score of 0 to 4 TOTAL SCORE: 1.6 + Motor + Proprioception + Balance + Cognition. MRC: Medical Research Council. From: Lai SM, Duncan PW, Keighley J. Prediction of functional outcome after stroke: comparison of the Orpington Prognostic Scale and the NIH Stroke Scale. Stroke 1998; 29:1838. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 1998 American Heart Association. Unauthorized reproduction of this material is prohibited. Graphic 98568 Version 5.0 https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 41/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Reding prognostic subgroups for outcome after stroke Life table curves for probability of reaching the goal of walking with assistance and assisted self-care function, defined as a Barthel Index score of 60. From: Reding MJ, Potes E. Rehabilitation outcome following initial unilateral hemispheric stroke. Life table analysis approach. Stroke 1988; 19:1354. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 1998 American Heart Association. Unauthorized reproduction of this material is prohibited. Graphic 98557 Version 4.0 https://www.uptodate.com/contents/overview-of-ischemic-stroke-prognosis-in-adults/print 42/43 7/6/23, 12:06 PM Overview of ischemic stroke prognosis in adults - UpToDate Contributor Disclosures Matthew A Edwardson, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. 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7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack : Natalia S Rost, MD, MPH, Shadi Yaghi, MD, FAHA : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 18, 2023. INTRODUCTION This topic will review the treatment of specific causes of transient ischemic attack (TIA) and ischemic stroke where the potential cause has been identified, emphasizing secondary prevention of recurrent cerebral ischemia and other vascular events. Risk factor management, which is appropriate for all patients with ischemic stroke or TIA, is reviewed in detail elsewhere. (See "Overview of secondary prevention of ischemic stroke".) The initial assessment of patients with cerebral ischemia and acute therapy for ischemic stroke are discussed separately. (See "Initial assessment and management of acute stroke" and "Approach to reperfusion therapy for acute ischemic stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) MEDICAL THERAPY Most patients with an ischemic stroke or TIA should be treated with all available risk reduction strategies, including antithrombotic therapy ( algorithm 1 and algorithm 2), blood pressure reduction, low-density lipoprotein lowering therapy, and lifestyle modification. These strategies are reviewed in detail separately: Overview of secondary prevention of ischemic stroke Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 1/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate Long-term antithrombotic therapy for the secondary prevention of ischemic stroke Antihypertensive therapy for secondary stroke prevention LARGE ARTERY DISEASE Options for the secondary prevention of ischemic stroke or TIA caused by large artery disease include revascularization for symptomatic internal carotid artery stenosis due to atherosclerosis, and multifactorial risk reduction including treatment with antiplatelet agents, blood pressure control, and low-density lipoprotein cholesterol (LDL-C) lowering therapy. The role of anticoagulation in this setting is quite limited. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Some specific situations are discussed below for atheromatous carotid, vertebral, and intracranial disease, and for nonatheromatous causes including carotid web, dissection, fibromuscular dysplasia, and moyamoya. Symptomatic carotid stenosis The treatment of symptomatic extracranial carotid atherosclerotic disease requires intensive medical management and may include carotid revascularization with carotid endarterectomy or carotid artery stenting. The importance of medical management, the identification of patients likely to benefit from revascularization, and the choice of revascularization procedure are discussed in detail separately. (See "Management of symptomatic carotid atherosclerotic disease".) Carotid occlusion Carotid artery occlusion may occur without clear symptoms, but it can be associated with TIA and stroke. Older data suggest that the subsequent yearly risk of a stroke ipsilateral to the occluded carotid artery is 2 to 5 percent [1,2]; later retrospective data suggest that the rate of early neurologic deterioration or recurrent stroke after symptomatic carotid occlusion ranges from 8 to 30 percent [3]. In most cases, medical management is the only practical option in the setting of chronic carotid occlusion. Data from small observational studies suggest that recanalization can be achieved by stenting of extracranial carotid artery occlusion [4], but clinical benefit is uncertain. Surgical revascularization is a viable option only when residual flow can be demonstrated in the internal carotid artery (ie, near occlusion), but efficacy is likewise unproven. (See "Management of symptomatic carotid atherosclerotic disease", section on 'Patients unlikely to benefit'.) With acute ischemic stroke related to extracranial internal carotid artery occlusion and a tandem intracranial large artery occlusion, treatment options include acute stenting and/or angioplasty of the extracranial carotid artery combined with mechanical thrombectomy of the intracranial https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 2/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate occlusion. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Approach to tandem lesions'.) For isolated acute symptomatic internal carotid artery occlusion, the optimal treatment is uncertain. Limited retrospective data from small observational studies suggest that urgent stenting results in a high revascularization rate, but benefit is unproven [5]. More data are needed to determine whether early secondary prevention with endovascular treatment improves outcomes compared with maximal medical therapy [3]. Historically, some experts used short-term (three to six months) anticoagulation for acute symptomatic occlusion; the rationale for this approach is based on limited evidence that emboli may form and propagate from the stump of the occluded artery after acute occlusion [6,7], but the risk and benefit of such an approach, particularly when compared with dual antiplatelet therapy, remains uncertain. An earlier randomized, controlled trial in patients with symptomatic carotid narrowing or occlusion found that surgical treatment using extracranial to intracranial bypass failed to reduce the risk of ischemic stroke [8], and the later Carotid Occlusion Surgery Study (COSS) trial in patients with symptomatic carotid occlusion and hemodynamic cerebral ischemia also found no benefit for extracranial to intracranial bypass surgery compared with medical therapy alone [9]. Carotid web Carotid web, considered a variant of fibromuscular dysplasia (see 'Fibromuscular dysplasia' below), is a shelf-like projection of intimal fibrous tissue of the internal carotid artery bulb that can be focal or multifocal [10]. It may appear as a filling defect on computed tomographic angiography, magnetic resonance angiography, or conventional contrast angiography (eg, digital subtraction angiography) [11,12]. Carotid web is rarely associated with severe stenosis. However, carotid web may alter hemodynamic flow and increase the risk of platelet aggregation leading to thromboembolism [13]. The optimal management of symptomatic carotid web is uncertain. The 2021 American Heart Association/American Stroke Association guidelines recommend antiplatelet therapy for secondary stroke prevention [14]. The guidelines also note that the risk of recurrent stroke in medically treated patients with symptomatic carotid web is high, and carotid stenting or endarterectomy may be considered to prevent recurrent events, particularly in patients who have a recurrent ischemic stroke despite medical treatment. Extracranial vertebral artery stenosis In most cases, prevention of ischemic stroke and TIA due to extracranial vertebral artery stenosis is managed by intensive medical treatment and multifactorial risk reduction, including the use of antiplatelet agents ( algorithm 1 and https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 3/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate algorithm 2), antihypertensive drugs, and LDL-C lowering therapy [14]. In addition, angioplasty and stenting is a treatment option [15-18], and surgical transposition of the vertebral artery to the common carotid artery is another alternative for vertebral origin stenosis. However, efficacy for these procedures is uncertain [14,18,19]. In an analysis that pooled individual patient data from three trials comparing stenting with medical treatment for the subgroup with symptomatic extracranial vertebral artery stenosis, there was no significant difference in the risk of any stroke in the stenting group compared with the medical treatment group (hazard ratio [HR] 0.63, 95% CI 0.27-1.46) [18]. Thus, extracranial vertebral artery revascularization is generally considered only when maximal medical therapy has failed to prevent embolism or low-flow recurrent ischemic events. Intracranial large artery atherosclerosis Atherosclerotic stenosis of the major intracranial arteries (carotid siphon, middle cerebral artery, vertebral artery, and basilar artery) is an important cause of ischemic stroke, particularly in Black, Asian, and Hispanic populations. Patients with TIA or ischemic stroke attributed to intracranial atherosclerosis should receive intensive medical management with antiplatelet therapy ( algorithm 1 and algorithm 2) and strict control of vascular risk factors, including the blood pressure control, LDL-C lowering therapy, and physical activity and other lifestyle modification (eg, smoking cessation, weight control, salt restriction, and a healthy diet). (See "Intracranial large artery atherosclerosis: Treatment and prognosis", section on 'Secondary prevention'.) Evidence from randomized controlled trials indicates that intensive medical management is superior to stenting for patients with recently symptomatic high-grade intracranial large artery stenosis [20]. (See "Intracranial large artery atherosclerosis: Treatment and prognosis", section on 'Stenting'.) Dissection Beyond the hyperacute period, antithrombotic therapy with either anticoagulation or antiplatelet drugs is an accepted treatment for ischemic stroke and TIA caused by dissection, although there is controversy regarding the choice between the two. The management of cerebral and cervical artery dissection is reviewed in detail separately. (See "Cerebral and cervical artery dissection: Treatment and prognosis".) Fibromuscular dysplasia Fibromuscular dysplasia (FMD) is a noninflammatory, nonatherosclerotic disorder that leads to arterial stenosis, occlusion, intraluminal thrombus, aneurysm, dissection, and arterial tortuosity [21]. The most frequently involved arteries are the renal and internal carotid arteries, followed by the vertebral, visceral, and external iliac arteries. Disease presentation may vary widely, depending upon the arterial segment involved and the severity of disease. TIA and ischemic stroke are potential manifestations of carotid or vertebral https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 4/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate artery FMD; hypertension is the most common presenting sign of renal artery FMD. (See "Clinical manifestations and diagnosis of fibromuscular dysplasia".) In patients with an ischemic stroke or TIA attributed to FMD, secondary prevention measures include antiplatelet therapy, blood pressure control, and lifestyle modification [14]. For patients with recurrent ischemic stroke or TIA attributed to carotid artery FMD, treatment using angioplasty with or without stenting is an option [14]. Moyamoya Moyamoya disease (MMD) is a unique cerebrovascular disorder characterized by progressive large intracranial artery narrowing and the development of prominent small vessel collaterals in patients who may have genetic susceptibilities but no underlying risk factors. Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Classification and terminology'.) Ischemic stroke and TIA affecting the anterior circulation are the most common clinical presentations. Hemorrhagic complications of moyamoya, mainly intracerebral hemorrhage, represent a significant clinical burden, particularly in adults. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Clinical presentations'.) Secondary stroke prevention for patients with symptomatic moyamoya is largely centered on surgical revascularization techniques. Antiplatelet therapy is reasonable [14], but evidence regarding clinical benefit is limited. In adults, hemorrhage may be the predominant manifestation of moyamoya, and anticoagulation is generally not recommended. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis".) For children and adults with asymptomatic or symptomatic ischemic MMD or MMS, some experts use long-term therapy with aspirin or cilostazol. This also applies to patients who undergo surgical revascularization. Rotational vertebral artery syndrome (bow hunter) Rotational vertebral artery syndrome is a rare cause of posterior circulation stroke due to vertebral artery compression by bony elements of the cervical spine (usually at C1 to C2) during physiologic head rotation. Antithrombotic therapy is reasonable in patients with ischemic stroke or TIA, and surgical interventions may be considered in patients who have recurrent ischemic symptoms while on antithrombotic treatment. (See "Posterior circulation cerebrovascular syndromes", section on 'Extracranial vertebral arteries' and "Causes of vertigo", section on 'Rotational vertebral artery syndrome'.) https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 5/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate SMALL ARTERY DISEASE Cerebral small artery disease, often referred to as small vessel disease, may cause a TIA or lacunar infarction due to the occlusion of a small penetrating branch of a large cerebral artery. (See "Lacunar infarcts".) Early antiplatelet therapy is indicated for most patients with TIA or acute ischemic stroke due to small artery disease who are not receiving oral anticoagulants, as shown in the algorithms ( algorithm 1 and algorithm 2). In the acute setting, most patients with a low-risk TIA or moderate to major ischemic stroke are treated with aspirin alone; patients with a high-risk TIA or minor ischemic stroke may benefit from dual antiplatelet therapy using aspirin and clopidogrel for 21 days rather than aspirin alone. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.) Beyond the acute phase of stroke, long-term antiplatelet therapy for secondary stroke prevention should be continued with either aspirin, clopidogrel, or the combination of aspirin- extended-release dipyridamole, although use of the latter has become increasingly rare in practice. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) In addition to antiplatelet therapy, attention to hypertension, serum lipids, blood glucose, and other modifiable risk factors is important for preventing lacunar strokes in patients with small artery disease. (See "Overview of secondary prevention of ischemic stroke".) CARDIOGENIC EMBOLISM Cardiogenic embolism is responsible for 14 to 30 percent of ischemic strokes [22]. In addition to atrial fibrillation, cardiac sources of embolism for which anticoagulation therapy may be indicated include left ventricular thrombus, cardiomyopathy, valvular disease, and congenital heart disease [14]. Minor potential sources of cardiogenic embolism include patent foramen ovale (PFO), left ventricular regional wall motion abnormalities, severe mitral annular calcification, mitral valve prolapse, mitral valve strands, and aortic valve disease ( table 1) [23]. The risk of stroke associated with these sources is low or uncertain, and except for PFO, the efficacy of and need for specific treatment is undefined [24]. Atrial fibrillation Atrial fibrillation is a major risk factor for ischemic stroke. Anticoagulation with one of the direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban, or https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 6/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate edoxaban) or warfarin is the most effective treatment to reduce stroke risk [14]. In most patients with atrial fibrillation, DOACs are preferred over warfarin due to convenience and lower risk of intracranial hemorrhage [25]. This subject is reviewed in greater detail elsewhere. (See "Stroke in patients with atrial fibrillation" and "Atrial fibrillation in adults: Use of oral anticoagulants".) For secondary stroke prevention, virtually all patients with atrial fibrillation who have a history of stroke or TIA of cardioembolic origin should be treated with lifelong anticoagulation in the absence of contraindications. (See "Stroke in patients with atrial fibrillation", section on 'Long- term anticoagulation'.) Placement of a left atrial appendage occlusion device may be an option for patients with nonvalvular atrial fibrillation who have a contraindication to long-term anticoagulation or strong preference to avoid long-term anticoagulation. (See "Atrial fibrillation: Left atrial appendage occlusion".) In rare cases when the patient is unwilling or unable to take anticoagulation despite careful consideration of the advantages of oral anticoagulation, or is not a candidate for left atrial appendage occlusion device placement, dual antiplatelet therapy is an alternative to therapy with aspirin alone. This issue is discussed in detail separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) Cardiac tumors Cardiac tumors, mainly left-sided myxoma and fibroelastoma, are rare causes of cardioembolic TIA or ischemic stroke. Surgical tumor resection via open heart surgery is the main treatment option to prevent recurrent stroke [14]. (See "Cardiac tumors".) Congenital heart disease Patients with cyanotic congenital heart disease are at increased risk for thromboembolism. The 2021 American Heart Association (AHA)/American Stroke Association (ASA) guidelines state that it is reasonable to treat patients with cardioembolic ischemic stroke or TIA attributed to congenital heart disease with warfarin anticoagulation [14]. (See "Medical management of cyanotic congenital heart disease in adults", section on 'Thromboembolism'.) The Fontan procedure is a palliative operation that diverts systemic venous return to the lungs in patients with an anatomic or functional single ventricle. For patients with Fontan circulation who have a history of thromboembolism, warfarin anticoagulation is advised [14]. (See "Overview of the management and prognosis of patients with Fontan circulation" and "Management of complications in patients with Fontan circulation", section on 'Thrombosis'.) Cardiomyopathy For patients in sinus rhythm with prior ischemic stroke or TIA who have either dilated cardiomyopathy (left ventricular ejection fraction 35 percent) or restrictive https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 7/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate cardiomyopathy, and without evidence of left atrial or left ventricular thrombus, the 2021 AHA/ASA guidelines note that the effectiveness of anticoagulation compared with antiplatelet therapy is uncertain, and the choice should be individualized [14]. The role of antithrombotic treatment for individuals with heart failure and prior thromboembolic events is reviewed in greater detail elsewhere. (See "Antithrombotic therapy in patients with heart failure".) Left ventricular thrombus Patients with left ventricular thrombus in the specific setting of an acute myocardial infarction have a significantly increased risk of embolic events. The 2021 American Heart Association/American Stroke Association guidelines state that patients with ischemic stroke or TIA in the setting of a left ventricular mural thrombus should be treated with warfarin (target international normalized ratio 2.5; range 2 to 3) for at least three months [14]. Despite very limited supporting evidence, some experts consider using a DOAC rather than warfarin due to convenience, as long as there is no specific indication for warfarin (eg, prosthetic heart valve). The issue of left ventricular thrombus and acute myocardial infarction is discussed in greater detail separately. (See "Left ventricular thrombus after acute myocardial infarction".) Patent foramen ovale Patent foramen ovale (PFO) device closure is more effective than medical therapy alone for select patients with a PFO-associated stroke (ie, a nonlacunar ischemic stroke in the setting of a PFO with a right-to-left interatrial shunt and no other source of stroke despite a comprehensive evaluation). Evaluation and treatment are discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) Valvular disease With atrial fibrillation Patients with atrial fibrillation and valvular heart disease should be treated with oral anticoagulation. The choice between warfarin and DOAC therapy depends upon the type of underlying valvular disease; warfarin is generally preferred for patients with atrial fibrillation and moderate to severe mitral stenosis or a mechanical heart valve, while a DOAC may be preferred for patients with atrial fibrillation and other types of valvular disease (eg, mild mitral stenosis, bioprosthetic valves, or native aortic, pulmonary, or tricuspid valve disease) [14]. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Patients with valvular heart disease' and "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Without atrial fibrillation For patients in sinus rhythm with ischemic stroke or TIA and native valvular disease or bioprosthetic heart valves, the 2021 AHA/ASA guidelines recommend antiplatelet therapy [14]. This includes patients with mitral annular calcification or mitral valve prolapse. https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 8/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate The 2021 AHA/ASA guidelines state that the role of oral anticoagulation has not been adequately studied for patients who have rheumatic mitral valve disease without atrial fibrillation and no other likely cause for ischemic stroke or TIA [14]. However, some experts consider a prior embolic event in patients with moderate to severe mitral stenosis as one of the indications for long-term oral anticoagulation with a vitamin K antagonist. (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Note that paroxysmal occult atrial fibrillation and infective endocarditis should be considered as potential causes when embolization occurs in patients with mitral stenosis who are in sinus rhythm. Mitral and aortic valvular disease is reviewed in greater detail elsewhere. (See "Clinical manifestations and diagnosis of mitral annular calcification" and "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Embolic events' and "Arrhythmic complications of mitral valve prolapse".) Mechanical heart valves All prosthetic heart valves require antithrombotic prophylaxis [14,26]. Antithrombotic therapy for mechanical and bioprosthetic heart valves is discussed in detail separately. (See "Antithrombotic therapy for mechanical heart valves" and "Overview of the management of patients with prosthetic heart valves", section on 'Antithrombotic therapy'.) Infective endocarditis Infective endocarditis is an important cause of embolic stroke and TIA for which anticoagulation is hazardous. Endocarditis must be excluded in any patient with a TIA or stroke and other suggestive findings such as fever and a heart murmur. Treatment consists of antibiotic therapy for the infection. Early valve surgery is indicated for patients with left-sided native valve infective endocarditis and one or more additional features, including symptoms or signs of heart failure, complicated infection, persistent infection, and/or recurrent embolic events. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Antimicrobial therapy of left-sided native valve endocarditis" and "Antithrombotic therapy in patients with infective endocarditis".). AORTIC ATHEROSCLEROSIS There are conflicting data regarding the stroke risk associated with aortic atherosclerosis. However, most reports evaluating secondary stroke risk have found that complex aortic https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 9/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate atherosclerosis is a risk factor for recurrent stroke, especially for aortic plaques 4 mm and mobile plaques. This issue is discussed separately. (See "Stroke: Etiology, classification, and epidemiology", section on 'Aortic atherosclerosis'.) The optimal treatment for patients with stroke or TIA attributed to aortic disease is not clear; the 2021 American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend antiplatelet therapy (including short-term dual antiplatelet therapy for minor stroke) and intensive lipid management to a low-density lipoprotein cholesterol target <70 mg/dL to prevent recurrent stroke [14]. Medical therapy for secondary prevention of aortic atheromatous disease is discussed in greater detail separately. (See "Thromboembolism from aortic plaque", section on 'Treatment'.) The open-label ARCH trial was terminated prematurely due to slow recruitment and is therefore inconclusive [27]. The ARCH trial enrolled 349 adults with ischemic stroke, TIA, or peripheral embolism who had thoracic aortic plaque 4 mm and no other identified embolic source; patients were randomly assigned to treatment with dual antiplatelet therapy (aspirin 75 to 150 mg daily in combination with clopidogrel 75 mg daily) or warfarin (target international normalized ratio 2.5). At a median follow-up of 3.4 years, the primary endpoint, a composite of cerebral infarction, myocardial infarction, peripheral embolism, vascular death, or intracranial hemorrhage, was lower in the antiplatelet group compared with the warfarin group (7.6 versus 11.3 percent, respectively), but the difference was not statistically significant (adjusted hazard ratio 0.76, 95% CI 0.36-1.61). SICKLE CELL DISEASE Stroke is a frequent complication of sickle cell disease (SCD), and the risk of recurrent stroke is high. Stroke risk can be reduced with chronic transfusion therapy. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease" and "Prevention of stroke (initial or recurrent) in sickle cell disease".) For patients with SCD and ischemic stroke or TIA, the 2014 American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend regular blood transfusions to reduce hemoglobin S to <30 percent of total hemoglobin [14]. In addition, the guidelines note that treatment with hydroxyurea is reasonable if transfusion therapy is not available or practical. General measures including traditional stroke risk factor identification and management as well as the use of antiplatelet agents (for prior ischemic stroke) are also reasonable. https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 10/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate The prevention of stroke in patients with SCD is discussed in greater detail separately. (See "Prevention of stroke (initial or recurrent) in sickle cell disease".) HYPERCOAGULABLE STATES Antiphospholipid syndrome The antiphospholipid syndrome (APS) is a hypercoagulable state characterized by recurrent arterial or venous thromboembolism, or pregnancy loss, in association with antibodies directed against plasma proteins that may be bound to anionic phospholipids. The presence of such antibodies may be detected as lupus anticoagulants, anticardiolipin antibodies, or anti-beta2 glycoprotein-I antibodies. (See "Diagnosis of antiphospholipid syndrome".) This disorder has been referred to as primary antiphospholipid syndrome when it occurs alone; however, it can also be seen in association with systemic lupus erythematosus, other rheumatic disorders, and autoimmune diseases. (See "Clinical manifestations of antiphospholipid syndrome".) Due to the high rate of recurrent thrombosis, long-term anticoagulation is the mainstay of therapy for patients with thrombotic APS. However, for patients with arterial thromboembolism, including ischemic stroke, data on the optimal therapeutic approach to prevent recurrent thromboembolism are limited. While experts agree that anticoagulation with warfarin (international normalized ratio range, 2 to 3) is the first-line therapy for patients with APS and arterial thromboembolism, some suggest adding low-dose aspirin for most patients with arterial events, particularly those with additional risk factors for atherosclerotic vascular disease. Direct oral anticoagulants (DOACs) may be less effective than warfarin for thrombosis prevention, particularly among patients with known or possible APL who are considered high risk and/or have a history of arterial thrombosis. (See "Management of antiphospholipid syndrome", section on 'Secondary thrombosis prevention'.) Inherited thrombophilias Inherited thrombophilias are hypercoagulable states that include a number of disorders: Protein C deficiency Protein S deficiency Antithrombin III deficiency Activated protein C resistance Factor V Leiden as a cause of activated protein C resistance Prothrombin G20210A mutation https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 11/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate These conditions are thought to be rare causes of ischemic stroke in adults, but may be more important causes of ischemic stroke in children. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Hematologic'.) The 2021 American Heart Association/American Stroke Association (AHA/ASA) guidelines note that it is uncertain whether testing for these hematologic traits is beneficial in the context of secondary stroke prevention [14]. Suspicion for hypercoagulable states as the cause of stroke may be heightened in younger patients with cryptogenic stroke, a history or family history of unprovoked thrombosis, prior spontaneous abortion, or concomitant systemic signs and symptoms suggestive of hypercoagulability. The same guidelines note that for patients with ischemic stroke or TIA of unknown source (despite a thorough diagnostic evaluation) who are found to have an inherited thrombophilia, antiplatelet treatment is reasonable to reduce the risk of recurrent stroke or TIA [14]. The evaluation and management of these conditions is discussed in greater detail separately. (See "Antithrombin deficiency" and "Protein C deficiency" and "Protein S deficiency" and "Factor V Leiden and activated protein C resistance" and "Prothrombin G20210A" and "Overview of homocysteine" and "Cerebral venous thrombosis: Treatment and prognosis".) Cancer-related hypercoagulable state Patients with cancer may be at increased risk for stroke due to hypercoagulability and other potential mechanisms, including compression or invasion of blood vessels, marantic endocarditis, infections, paraneoplastic disorders, and complications of cancer therapies [28,29]. (See "Cancer-associated hypercoagulable state: Causes and mechanisms".) For patients with TIA or ischemic stroke attributed to cancer hypercoagulability, optimal treatment for secondary stroke prevention is unknown, and data are limited [29]. Empiric treatment with low molecular weight heparin is often used, but the clinical risk and benefit compared with antiplatelets remains uncertain [30]. In patients with venous thromboembolism (VTE) and cancer, anticoagulant therapy is the mainstay of treatment. Low molecular weight heparin or DOACs are preferred in patients without renal insufficiency, whereas warfarin is the preferred treatment in patients with renal insufficiency (eg, creatinine clearance <30 mL/minute). (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".) The 2021 AHA/ASA guidelines note only that in the setting of atrial fibrillation and cancer, it is reasonable to consider anticoagulation with DOACs in preference to warfarin for stroke prevention [14]. https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 12/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate CRYPTOGENIC STROKE Cryptogenic stroke is variably defined and generally designates the category of brain infarction that is not attributed to an established source of cardioembolism, large artery atherosclerosis, small artery disease, or other determined cause of stroke. However, the term cryptogenic stroke has been applied to patients with an incomplete diagnostic evaluation, a complete but unrevealing evaluation, or an evaluation that identifies multiple potential causes of stroke. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Classification'.) Embolic stroke of undetermined source (ESUS) is a subcategory of cryptogenic stroke defined as a nonlacunar brain infarct without proximal arterial stenosis or cardioembolic sources; ESUS requires a full standardized stroke evaluation to exclude other causes. While the less well- defined term of cryptogenic stroke has been reported to account for approximately 25 to 40 percent of ischemic strokes, the more specific term of ESUS consistently accounts for approximately 20 percent of ischemic strokes. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Embolic stroke of undetermined source'.) For secondary prevention, most patients with a cryptogenic ischemic stroke or TIA should be treated with blood pressure control, low-density lipoprotein cholesterol lowering therapy, and lifestyle modification. Initial antiplatelet therapy is advised while awaiting the results of long- term cardiac monitoring. For patients initially diagnosed with cryptogenic stroke who have atrial fibrillation of any duration detected on long-term monitoring, even if detected remotely from the incident stroke, anticoagulant therapy with warfarin or a direct oral anticoagulant is advised rather than antiplatelet therapy. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Secondary prevention'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Fibromuscular dysplasia".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 13/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Transient ischemic attack (Beyond the Basics)" and "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Ischemic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Large artery disease Secondary prevention for ischemic stroke or transient ischemic attack (TIA) attributed to large artery disease may include the following measures: Symptomatic internal carotid stenosis In addition to medical management, revascularization is generally beneficial for patients with recently symptomatic internal carotid artery atherosclerotic stenosis with 50 to 99 percent luminal narrowing. In the setting of complete carotid occlusion, medical management is the only practical option. (See 'Symptomatic carotid stenosis' above.) Extracranial vertebral artery In most cases, ischemic stroke and TIA due to extracranial vertebral artery stenosis is managed by intensive medical treatment with multifactorial risk reduction. (See 'Extracranial vertebral artery stenosis' above.) Intracranial atherosclerosis Aggressive medical management is superior to stenting for patients with recently symptomatic high-grade intracranial large artery stenosis.