7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cryptogenic stroke and embolic stroke of undetermined source (ESUS) : Shyam Prabhakaran, MD, MS, Chinwe Ibeh, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 19, 2023. INTRODUCTION The majority of ischemic strokes are due to cardioembolism, large vessel atherothromboembolism, small vessel occlusive disease, or other unusual mechanisms. However, many ischemic strokes occur without a well-defined etiology and are labeled as cryptogenic. This topic will provide an overview of cryptogenic stroke. A discussion of stroke classification and the clinical diagnosis of stroke subtypes is found separately. (See "Stroke: Etiology, classification, and epidemiology" and "Clinical diagnosis of stroke subtypes".) CLASSIFICATION Cryptogenic stroke The cryptogenic stroke category was devised first, for research purposes, in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Data Bank [1,2] and later modified in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) trial [3]. Classification along these lines has become increasingly used in clinical practice, as optimal management relates to the underlying mechanism. (See "Stroke: Etiology, classification, and epidemiology", section on 'TOAST classification'.) By the TOAST classification ( table 1), which is the one most commonly used in clinical practice, cryptogenic stroke (or stroke of undetermined etiology in TOAST terminology) is defined as brain https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 1/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate infarction that is not attributable to a source of definite cardioembolism, large artery atherosclerosis, or small artery disease despite a standard vascular, cardiac, and serologic evaluation. The category of stroke of undetermined etiology in the TOAST classification includes patients with less well-established potential causes of cardiac embolism, such as patent foramen ovale (PFO), aortic arch atheroma, and mitral valve strands. A limitation of the TOAST classification, however, is that stroke of undetermined etiology also includes patients with two or more equally plausible identified causes of stroke and patients in whom a diagnostic evaluation has not been performed [3]. In its most useful clinical sense, the term cryptogenic stroke designates the category of ischemic stroke for which no probable cause is found despite a thorough diagnostic evaluation [4]. In addition to TOAST, there are several other ischemic stroke classification systems that include a category for stroke of undetermined cause, as discussed in detail separately (see "Stroke: Etiology, classification, and epidemiology", section on 'SSS-TOAST and CCS classification'). Among these, the Causative Classification System (CCS) was designed to determine the most likely cause of stroke even when multiple possible mechanisms are present ( table 2) [5,6]. Embolic stroke of undetermined source Embolic stroke of undetermined source (ESUS) represents a subset of cryptogenic stroke and emphasizes the likelihood that most strokes of unexplained etiology are probably embolic from an unestablished source [4,7,8]. ESUS is defined as a nonlacunar brain infarct without proximal arterial stenosis or cardioembolic sources [7]. The concept of ESUS, moreover, implies that a full standard evaluation was done, whereas the TOAST equivalent of cryptogenic stroke did not require a full evaluation, as noted above. The criteria for ESUS are: Stroke detected by computed tomography (CT) or magnetic resonance imaging (MRI) that is not lacunar (lacunar is defined as a subcortical infarct in the distribution of the small, penetrating cerebral arteries whose largest dimension is 1.5 cm on CT or 2.0 cm on MRI diffusion images) Absence of extracranial or intracranial atherosclerosis causing 50 percent luminal stenosis of the artery supplying the area of ischemia No major-risk cardioembolic source of embolism (ie, no permanent or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumors, mitral stenosis, recent (within four weeks) myocardial infarction, left ventricular ejection fraction <30 percent, valvular vegetations, or infective endocarditis) https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 2/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate No other specific cause of stroke identified (eg, arteritis, dissection, migraine, vasospasm, drug abuse) POSSIBLE MECHANISMS Numerous mechanisms for cryptogenic stroke have been proposed. Details regarding the various mechanisms of embolic stroke of undetermined source (ESUS) are described below and broadly include: Cardiac embolism secondary to occult paroxysmal atrial fibrillation (AF), aortic atheromatous disease, or other cardiac sources Paradoxical embolism, which originates in the systemic venous circulation and enters the systemic arterial circulation through a patent foramen ovale (PFO), atrial septal defect, ventricular septal defect, or extracardiac communication such as a pulmonary arteriovenous malformation Undefined thrombophilia (ie, hypercoagulable states including those related to antiphospholipid antibodies or to occult cancer with hypercoagulability of malignancy) Substenotic cerebrovascular disease (ie, intracranial and extracranial atherosclerotic disease causing less than 50 percent stenosis) and other vasculopathies (eg, dissection) In a single-center analysis using a machine-learning classifier to distinguish between cardioembolic and noncardioembolic subtypes of stroke, the classifier predicted that 44 percent of ESUS was due to occult cardioembolic sources [9]. In an analysis of the NAVIGATE-ESUS trial, which enrolled 7213 patients, the most commonly identified potential sources of embolism were atrial cardiopathy (37 percent), left ventricular disease (36 percent), and arterial atherosclerotic disease (29 percent) [10]. In studies of thrombi extracted from cerebral vessels in the setting of large vessel occlusions, the histologic composition of thrombi from patients with cryptogenic stroke is similar to that of those with cardioembolic stroke, providing further indirect evidence that most cryptogenic strokes are due to emboli from undetermined cardiac causes [11]. It is also likely that important but unidentified mechanisms exist, awaiting discovery. Embolism from occult sources in the heart or aorta The embolic appearance of most cryptogenic strokes implies that the cause is embolism from an occult source in the heart, aorta, or large artery. Cardioaortic conditions with a low or uncertain risk for embolic stroke include difficult to diagnose ("occult") or subclinical atrial fibrillation and related atrial cardiopathies, atrial septal abnormalities, complex aortic atheroma, and others listed in the table ( table 3). https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 3/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Occult atrial fibrillation Occult paroxysmal AF refers to asymptomatic paroxysmal AF in a patient without a prior history of AF, which is detected only by monitoring techniques. Evidence linking occult AF and cryptogenic stroke comes from the prospective ASSERT study of 2580 subjects, age 65 years, with hypertension and no history of AF who had recent implantation of a pacemaker or defibrillator [12]. At three months, subclinical atrial tachyarrhythmias detected by the implanted devices had occurred in 10 percent of patients and were associated with an increased risk (at a mean of 2.5 years) for clinical AF (hazard ratio [HR] 5.6, 95% CI 3.8-8.2) and for the combined endpoint of ischemic stroke or systemic embolism (HR 2.5, 95% CI 1.3-4.9). Among subjects with at least three months of continuous monitoring who experienced ischemic stroke or systemic embolism (n = 51), subclinical AF was detected overall in 26 (51 percent) [13]. However, subclinical AF occurring 30 days before ischemic stroke or systemic embolism was detected in only 4 subjects (8 percent). Thus, while subclinical AF was associated with an increased risk of embolic events, there was no definite temporal relationship of subclinical AF with stroke in most subjects. Atrial septal abnormalities Atrial septal abnormalities, including PFO, atrial septal aneurysm, and atrial septal defect, have been associated with cryptogenic stroke. There is an increased prevalence of PFO and atrial septal aneurysm in patients who have had an otherwise unexplained stroke. In addition, there is high-quality evidence that PFO closure reduces the risk of recurrence in patients age 60 years with an embolic-appearing ischemic stroke who have a medium- to high-risk PFO and no other evident source of stroke despite a comprehensive evaluation. In this setting. it is reasonable to conclude that paradoxical embolism through a PFO is the most likely stroke mechanism. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Risk of embolic stroke' and "Stroke associated with patent foramen ovale (PFO): Evaluation".) Atrial cardiopathies Structural and functional changes in the atria may increase the risk of thrombus formation and embolization. Markers of left atrial cardiopathy include left atrial enlargement, atrial fibrosis, elevated pro-brain natriuretic peptide (proBNP), increased P wave terminal force velocity in lead V1 (PWTFV1), and atrial fibrillation. Even in the absence of diagnosed atrial fibrillation, biomarkers of atrial dysfunction are associated with an increased risk of ischemic stroke [14-16]. For example, serum troponin and proBNP are associated with both AF and stroke. Similarly, PWTFV1, a measure of atrial contraction that can be measured on the electrocardiogram, is associated with stroke risk even in the absence of AF [17]. Although cardioembolism is presumed to be the most likely mechanism of stroke in patients with elevated proBNP or PWTFV1, it is difficult to establish a cause-and-effect relationship between these elevated cardiac biomarkers and occult cardioembolism; the association is confounded because https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 4/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate cardiac disease and elevated cardiac biomarkers are also markers of systemic atherosclerosis. In addition, these biomarkers are not widely available in clinical practice and their utility for management is still uncertain. However, biomarkers have the advantage of being measurable at the time of stroke without the need for long-term monitoring, and thus provide the potential to detect a high risk of cardioembolism. Further prospective study, including clinical trials, is needed to confirm that any of these biomarkers reliably predict a cardioembolic stroke mechanism and response to anticoagulant therapy in secondary stroke prevention. Aortic embolism Thoracic aortic atherosclerotic plaques are an important potential source of systemic emboli, leading to stroke, transient ischemic attack, and embolization to other arterial beds. The risk of thromboembolism in patients with aortic atherosclerosis is increased when there is complex plaque, which is defined as thickness >4 mm or ulceration. (See "Thromboembolism from aortic plaque", section on 'Complex aortic plaque'.) Besides proximal aortic atheromas, distal aortic sources of embolism have been proposed as a potential cause for cryptogenic stroke. One study using cardiac MRI suggested that complex atheromas in the descending aortic arch could lead to stroke via retrograde flow [18]. During diastole, retrograde flow in the descending aorta reached the great vessels supplying the brain in up to 24 percent of patients with cryptogenic stroke. This finding suggests that embolic material in the descending aortic arch could enter the cerebral vasculature during retrograde flow and cause ischemic stroke. Other potential causes of stroke include coarctation of the aorta and aortic dissection. The relationship of aortic embolism and stroke is reviewed in detail separately. (See "Stroke: Etiology, classification, and epidemiology", section on 'Aortic atherosclerosis' and "Thromboembolism from aortic plaque".) Pulmonary shunts Based on limited evidence, intrapulmonary right-to-left shunts due to pulmonary arteriovenous malformations or arteriovenous fistulas have been associated with cryptogenic stroke in several small studies [19-23]. This association does not prove causation; further studies are needed to define the relationship between intrapulmonary shunt and cryptogenic stroke. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults", section on 'Neurologic'.) Substenotic atherosclerotic disease Some cases of cryptogenic stroke may be caused by undetected large vessel disease, including occult atherosclerosis and nonstenosing, unstable plaques [24-28]. Imaging features of substenotic (<50 percent) carotid disease that have been https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 5/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate associated with increased stroke risk include plaque ulceration, plaque thickness >3 mm, intraplaque hemorrhage, fibrous cap rupture, lipid-rich core, and plaque echolucency [26]. In a Canadian cohort of 138 patients with ESUS, nonstenotic carotid plaques (<50 percent stenosis) were present in 39 percent of patients and were more frequently ipsilateral to the side of the stroke compared with contralateral (61 versus 39 percent, adjusted odds ratio 1.83, 95% CI 1.05-3.18) [27]. In another report of 579 patients who had anterior circulation stroke and were studied with brain magnetic resonance imaging (MRI) and neck magnetic resonance angiography (MRA) intraplaque hemorrhage on neck MRA was more common ipsilateral to brain infarction in cryptogenic stroke compared with contralateral (relative risk 2.1, 95% CI 1.4-3.1) [25]. Among 197 patients with ESUS, the presence of intraplaque hemorrhage ipsilateral to brain infarction allowed 41 patients (21 percent) to be reclassified from ESUS to large artery atherosclerosis. Data from autopsy studies suggest that ischemic stroke can be associated with lesser degrees of extracranial and intracranial large vessel stenosis (eg, 30 to 70 percent) or with vulnerable plaques without appreciable luminal compromise. In a case-control study that included 259 patients with fatal ischemic stroke, intracranial atherosclerotic plaques (with or without stenosis) were noted in 62 percent [29]. Furthermore, plaques with superimposed thrombi and stenosis of 30 to 70 percent were considered responsible for infarcts in four cases (1.5 percent), a group that would have been classified as cryptogenic in nonautopsy studies. In a subsequent study from the same investigators, plaques and stenoses involving the origin or proximal vertebral artery were present in more than twice as many patients with infarcts in posterior circulation as compared with anterior circulation infarcts (adjusted odds ratio 2.10, 95% CI 1.01-4.38) [30]. These lesions may be responsible for a larger proportion of strokes in the brainstem and posterior circulation than previously appreciated. Other causes Infection and associated thrombophilia may be a cause of unexplained stroke in young, otherwise healthy patients. As an example, coronavirus disease 2019 (COVID-19) may be a cause of otherwise unexplained strokes. In addition to traditional stroke mechanisms, potential mechanisms of ischemic stroke related to COVID-19 include thromboinflammation, severe inflammation, renin-angiotensin-aldosterone system dysfunction, cardiac dysfunction, and the consequences of severe respiratory illness [31]. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Cerebrovascular disease'.) Furthermore, subtle or undetected abnormalities of the large arteries, coagulation system, and genetic factors may be missed during the initial evaluation. These conditions include: https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 6/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Nonatherosclerotic vasculopathies, such as dissection, fibromuscular dysplasia, reversible cerebral vasoconstriction syndromes (RCVS), and vasculitis. Occult hypercoagulable states, such as the antiphospholipid syndrome, genetic thrombophilia, and hypercoagulable state associated with malignancy. Rare genetic conditions may present with stroke in the young; monogenic syndromes associated with an increased risk of ischemic stroke include Fabry disease, cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), sickle cell disease, and hereditary thrombotic thrombocytopenic purpura (TTP). However, detection of any of the above conditions would generally alter the diagnostic classification of stroke from cryptogenic stroke to stroke of other determined cause. In practice, an initial diagnosis of cryptogenic stroke may thus yield over time to a later diagnosis of a specific cause. Therefore, a diagnosis of cryptogenic stroke can be regarded as provisional until diagnostic testing is completed. EPIDEMIOLOGY AND RISK FACTORS Large epidemiologic studies have consistently reported that cryptogenic stroke accounts for 25 to 40 percent of ischemic stroke [32-40]. The incidence and prevalence of stroke subtypes among these studies may vary based upon the demographics of the study population, diagnostic definitions, extent of diagnostic evaluation, and methodology. Thus, it is conceivable that some strokes of other determined cause (eg, migraine, dissection, vasculitis) were misclassified in the undetermined category (ie, as cryptogenic) due to inadequate work-up or the limitations of diagnostic detection. However, given the rarity of these other causes in most registries (usually representing less than 5 percent of all strokes), this would not account for all cryptogenic strokes. Demographic factors The risk of cryptogenic stroke may vary by demographics, with higher incidence rates in Black and Hispanic populations compared with White populations, but no clear association has been found for age or sex. With the exception of the strokes classified in TOAST as "other determined etiology" (which includes dissection), all stroke subtypes are rare in the young, and incidence rates rise dramatically with increasing age. A few studies have reported that cryptogenic stroke disproportionately affects younger individuals, but the evidence is inconsistent. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 7/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate In the Northern Manhattan Stroke Study (NOMASS, 1993 to 1996), 55 percent of strokes in the young (age <45 years) were cryptogenic versus 42 percent in the older (age >45 years) group [41]. In a 2003 meta-analysis, young age (defined as <50 years) was inversely associated with cryptogenic stroke with a total odds ratio of 0.6 (95% CI 0.4-1.0, p = 0.05) [34]. Other stroke registries found lower rates (23 to 34 percent) in younger age groups, which were similar to those in older age groups [42-44]. The incidence of cryptogenic stroke may be higher in Black Americans and Hispanic Americans than in White Americans. In NOMASS, incidence rates of all ischemic stroke subtypes, including cryptogenic stroke, were higher in Black Americans and Hispanic Americans than in White Americans [45]. In the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS), Black Americans had twice the annual incidence rate of cryptogenic stroke as White Americans (125 versus 65 per 100,000 persons), a result not confounded by differential testing patterns among Black American versus White American patients [46]. In San Diego, an increased prevalence (nearly 46 percent) of cryptogenic stroke was seen in Mexican American patients, a statistic again that was not explained by differences in diagnostic testing [47]. The higher rates of cryptogenic stroke in Black and Hispanic Americans may be due to several dynamics affecting these populations, including higher rates of all ischemic stroke subtypes, possible underdetection of cardioembolic and large vessel stroke, and/or other unidentified factors [45,48]. Other risk factors Although risk factors often help unravel stroke mechanisms and may overlap with mechanisms, stroke risk factors and mechanisms are conceptually distinct. Thus, the presence of hypertension (ie, a risk factor) does not preclude the etiologic classification (ie, mechanism) of cryptogenic stroke. While it is possible to compare risk factors for cryptogenic stroke versus other stroke subtypes, the comparison is hindered in large part by definitional constraints. As an example, atrial fibrillation will be rare in cryptogenic stroke because of the way in which the subtypes are defined. In addition, risk factors that are associated with large artery ischemic stroke (eg, hypertension, hyperlipidemia, peripheral vascular disease, and diabetes mellitus) and cardioembolic stroke (eg, acute coronary events) are underrepresented in patients with cryptogenic stroke [37]. Several studies have documented that hypertension is less common in cryptogenic stroke compared with other stroke subtypes [34,35,37,38,46,49]. However, patients with cryptogenic stroke may have an increased prevalence of hypertension compared with stroke-free controls, https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 8/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate and one case-control study found that hypertension was associated with cryptogenic stroke (odds ratio 4.5, 95% CI 1.5-13.2) [50]. The prevalence of cardiac disease among patients with cryptogenic stroke varies from 10 to 30 percent. In Rochester, coronary artery disease was less common in the undetermined (ie, cryptogenic) subtype than in the large artery atherosclerosis subtype [32]. Studies assessing the prevalence of prothrombotic states and genetic polymorphisms predisposing individuals to thrombosis have not yielded convincing evidence that these are more common in patients with cryptogenic stroke than nonstroke controls [51-54]. Nevertheless, the available reports are small and not definitive. CLINICAL FEATURES Like patients with embolic stroke, patients with cryptogenic stroke typically present with sudden onset of focal neurologic deficits; most will have a superficial hemispheric ("embolic") infarct topography on brain imaging. They may also present with syndromes indicative of cortical involvement, such as aphasia, or faciobrachial motor syndromes rather than syndromes involving the entire hemibody. In one study of patients with cryptogenic stroke, cortical signs were present in 27 percent, and abrupt onset occurred in 59 percent [55]. Lacunar syndromes are rare, accounting for usually less than 5 percent [56,57]. The severity of the initial presentation varies but, on average, tends to be milder than cardioembolic strokes and worse than lacunar strokes [38,55,57-59]. Superficial hemispheric infarction is present in 62 to 84 percent of patients [56,57]. Forty percent of cryptogenic strokes in the Stroke Data Bank were found to have cortical infarcts [56]. Among 314 patients with cryptogenic stroke in the PFO-ASA study, 56 percent had superficial infarcts [55]. The German Stroke Study found that parenchymal hemorrhagic transformation occurred in approximately 2 percent of patients with stroke of unknown etiology in the first seven days, comparable to the percentage among cardioembolic stroke, suggesting an embolic mechanism [38]. Large subcortical strokes (>15 mm) also tend to be either cryptogenic or cardioembolic in origin. In a nationwide study of registry data from the United States, patients with cryptogenic stroke had milder presentations based on the National Institutes of Health Stroke Scale (NIHSS) score than patients with cardioembolic stroke (median NIHSS 3 versus 5) [60]. While cryptogenic stroke is often associated with cortical syndromes and milder deficits, stroke subtypes cannot be distinguished on the basis of clinical symptoms alone. In patients with cryptogenic stroke, the most frequently found abnormalities with echocardiography are patent foramen ovale (PFO), atrial septal aneurysm (ASA), and aortic https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 9/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate atheromas [61,62]. The timing of transesophageal echocardiography (<72 hours versus >72 hours) in relation to the index stroke does not appear to alter sensitivity [63]. The clinical significance of many of these findings is still unclear, with conflicting studies on the relative risks and appropriate management. EVALUATION AND DIAGNOSIS In its most useful clinical role, cryptogenic stroke is a diagnosis of exclusion based upon a thorough investigation for potential stroke etiologies. The diagnosis of cryptogenic stroke is made when a standard evaluation (see 'Standard evaluation' below) reveals no probable cause; there is no definite evidence of cardioembolism, large artery atherosclerosis (stenosis >50 percent) in the vessel supplying the area of infarction, small artery disease, or other determined etiology, and no evidence of atrial fibrillation on a 12-lead electrocardiogram (ECG) or on 24-hour cardiac monitoring. Patient age influences the relative likelihood of possible ischemic stroke mechanisms [4]. Cervicocephalic artery dissection is the most common cause in young adults (variably defined as <45 years of age); other considerations include congenital cardiac defects, recent pregnancy, hypercoagulable states, illicit drug use, metabolic disorders, and migraine. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Etiologies and risk factors in young adults'.) Premature atherosclerosis and acquired cardiac disease are increasingly prevalent in adults older than 30 years of age, and occult atrial fibrillation is increasingly discovered in patients older than 60 years of age [4]. Standard evaluation The standard evaluation of patients with acute ischemic stroke includes a history and physical examination, brain imaging to determine the location and topography of the lesion, and vessel imaging and a cardiac evaluation to help determine the most likely cause. Laboratory testing typically includes a complete blood count, cardiac enzymes and troponin, prothrombin time, international normalized ratio (INR), and activated partial thromboplastin time. Additional studies can be pursued if the standard evaluation fails to determine the probable cause. (See "Initial assessment and management of acute stroke" and "Overview of the evaluation of stroke".) Brain imaging Urgent brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is mandatory in all patients with sudden neurologic deterioration or https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 10/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate acute stroke (see "Neuroimaging of acute stroke"). Brain MRI with diffusion-weighted imaging is superior to noncontrast CT for the detection of acute ischemia, small infarcts, and infarcts located in the brainstem. The localization, topography, and distribution of ischemic brain lesions on MRI and CT can suggest a specific stroke mechanism [4,64]: Isolated superficial cerebral or cerebellar infarction suggests an embolic mechanism from a large artery, heart, or aorta Cortical or large subcortical infarcts in multiple vascular territories suggest a proximal source of embolism from the heart or aorta Infarcts of varying age in a single vascular territory suggest a large artery source of embolism Infarcts along the boundary regions between the major cerebral arteries (ie, border zone or watershed regions) suggest the stroke mechanism is low flow (hypoperfusion) or multiple small emboli Small subcortical infarcts suggest lacunar infarction from small vessel disease The diagnosis of small vessel disease as the cause of ischemic stroke is generally confirmed by neuroimaging when the location of a small noncortical infarct on CT or MRI correlates with the clinical features of a lacunar stroke syndrome. However, a small deep infarct may be considered cryptogenic when found in a patient <50 years of age with no standard vascular risk factors and no white matter hyperintensities or prior small deep infarcts [4,65]. Vessel imaging Vessel imaging to identify the lesion (eg, atherosclerotic stenosis or occlusion, dissection) responsible for stroke can be done with magnetic resonance angiography (MRA), computed tomography angiography (CTA), carotid duplex ultrasonography and transcranial Doppler ultrasonography, or conventional angiography (see "Neuroimaging of acute stroke"). Neurovascular imaging should assess the extracranial (internal carotid and vertebral) and intracranial (internal carotid, vertebral, basilar, and Circle of Willis) large vessels. Noninvasive methods are generally used unless urgent endovascular therapy is planned. MRA or CTA is preferred, while the combination of ultrasound methods (duplex and transcranial Doppler) can be used if CTA and MRA are unavailable or contraindicated. Availability and expertise at individual centers are major factors in the choice of the initial noninvasive neurovascular studies. Various neuroimaging modalities may be used to confirm a diagnosis of dissection, but fat- saturated T1 MRI is capable of revealing the intramural hematoma caused by dissection in vessels that otherwise have a normal appearance on MRA and CTA. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Choice of neuroimaging study'.) https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 11/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Conventional angiography is usually reserved for situations where acute intraarterial intervention is being considered and for follow-up when noninvasive studies are inconclusive. Cardiac and aortic evaluation The basic cardiac evaluation of acute ischemic stroke includes an electrocardiogram, cardiac monitoring for at least the first 24 hours after stroke onset to look for occult atrial fibrillation (AF), and echocardiography. (See "Overview of the evaluation of stroke", section on 'Cardiac evaluation'.) Both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) are effective diagnostic tests for the evaluation of suspected cardioaortic source of embolism. In most patients, TEE yields higher quality images and has a greater sensitivity and specificity than TTE, but a few conditions (eg, left ventricular thrombus) are better seen on TTE. However, TEE is an uncomfortable invasive procedure that may not be tolerated by very ill patients. Because it is less invasive and readily available in most institutions, TTE is often reasonable as the initial test of choice (see "Echocardiography in detection of cardiac and aortic sources of systemic embolism"). TTE is the preferred initial test for the majority of patients with a suspected cardiac or aortic source of emboli, including: Patients 45 years Patients with a high suspicion of left ventricular thrombus Patients in whom TEE is contraindicated (eg, esophageal stricture, unstable hemodynamic status) or who refuse TEE TEE may be especially helpful to localize the source of embolism in the following circumstances: Patients <45 years without known cardiovascular disease (ie, absence of myocardial infarction or valvular disease history) Patients with a high pretest probability of a cardiac embolic source in whom a negative TTE would be likely to be falsely negative Patients with atrial fibrillation and suspected left atrial or left atrial appendage thrombus, especially in the absence of therapeutic anticoagulation, but only if the TEE would impact management Patients with a mechanical or bioprosthetic heart valve or suspected infectious or marantic endocarditis Patients with suspected aortic pathology For patients 60 years of age with an embolic-appearing cryptogenic stroke or TIA, particularly those who lack cardiovascular risk factors, we suggest TEE when TTE is nondiagnostic. The TEE https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 12/46 7/6/23, 12:29 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 7/6/23, 12:29 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