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