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Cryptogenic stroke and embolic stroke of undetermined source (ESUS)

Cryptogenic stroke and embolic stroke of undetermined source (ESUS)
Literature review current through: May 2024.
This topic last updated: Mar 20, 2024.

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 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)

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).

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 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 [24-29]. Imaging features of substenotic (<50 percent) carotid disease that have been 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 [30]. 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) [31]. 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 [32]. (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:

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 [33-41]. 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.

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 [42].

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) [35].

Other stroke registries found lower rates (23 to 34 percent) in younger age groups, which were similar to those in older age groups [43-45].

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 [46]. 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 [47]. 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 [48]. 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 [46,49].

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 [38].

Several studies have documented that hypertension is less common in cryptogenic stroke compared with other stroke subtypes [35,36,38,39,47,50]. However, patients with cryptogenic stroke may have an increased prevalence of hypertension compared with stroke-free controls, and one case-control study found that hypertension was associated with cryptogenic stroke (odds ratio 4.5, 95% CI 1.5-13.2) [51].

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 [33].

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 [52-55]. 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 [56]. Lacunar syndromes are rare, accounting for usually less than 5 percent [57,58]. The severity of the initial presentation varies but, on average, tends to be milder than cardioembolic strokes and worse than lacunar strokes [39,56,58-60].

Superficial hemispheric infarction is present in 62 to 84 percent of patients [57,58]. Forty percent of cryptogenic strokes in the Stroke Data Bank were found to have cortical infarcts [57]. Among 314 patients with cryptogenic stroke in the PFO-ASA study, 56 percent had superficial infarcts [56]. 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 [39]. 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) [61]. 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 atheromas [62,63]. The timing of transesophageal echocardiography (<72 hours versus >72 hours) in relation to the index stroke does not appear to alter sensitivity [64]. 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 (algorithm 1 and table 4). 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 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 [4,65]:

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 [4,66].

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. Where available, vessel wall imaging (VWI) using advanced MRI techniques to directly visualize the arterial wall can be helpful in detecting nonstenotic vascular lesions that may be missed on luminal imaging with conventional MRA and CTA [67,68].

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'.)

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 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 [69]. 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 [70].

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 [71]. 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 5) 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 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.

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 [72]. 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) [73,74].

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 (algorithm 1 and table 4). However, there is no consensus or strong evidence base regarding the use of more advanced or specialized investigations for rare causes of ischemic stroke [75].

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 [76-79]:

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'.)

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 [65,80]. (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 [81-86]. (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 [87]. 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) [88-92]. However, high-resolution MRI has limited availability and requires further study to establish reliability and to determine how well imaging findings correlate with vessel pathology [87].

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 [93]. (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 [94-96]. (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 (algorithm 1 and table 4) [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 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".)

Antiplatelet therapy — Antiplatelet therapy is recommended for most patients with noncardioembolic stroke, including cryptogenic TIA and stroke, as outlined in the algorithms (algorithm 2 and algorithm 3) [97,98]. 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 [97,98].

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, dabigatran, and apixaban 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 [99]. 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. 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) [100]. Lastly, the ARCADIA trial of over 1000 patients with ESUS and evidence of atrial cardiopathy was stopped early for futility; there was no benefit of apixaban compared with aspirin for reducing the rate of recurrent stroke (4.4 percent in both groups) [101].

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) [102]. 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.

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 [103]. 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 [104]. 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 [105]. 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 CHA2DS2-VASc score (table 7), the presence of cortical or large 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 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 [98]. 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 [72]. 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 [39,59,60,106]. 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 percent at three months [107]. In the NINDS Stroke Data Bank, 3 percent of patients with cryptogenic stroke had recurrent events at one month [108]. In the NOMASS study at three months, the risk of recurrence for the cryptogenic group was 3.7 percent [109], slightly lower than those found in the Oxford meta-analysis [107].

At two years, recurrence risk ranges from 14 to 20 percent [34,103,106]. In the Stroke Data Bank, cryptogenic stroke had the lowest two-year recurrence risk and was an independent predictor of low recurrence risk [110]. At five years, the long-term recurrence risk was 33.2 percent in Rochester, not significantly different from the other subtypes [106].

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.)

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 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.

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