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. 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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