Updates in the Management of Cryptogenic Stroke and Patent Foramen Ovale

Background: Stroke is a common neurological disorder and may present with visual symptoms. A thorough workup is warranted to determine the underlying cause of stroke to optimize secondary prevention. Despite a full workup, a high-risk mechanism may not be identified. Optimal treatment in this patient population has been the subject of recent research, particularly with regard to low-risk stroke mechanisms such as patent foramen ovale (PFO). Evidence acquisition: Using PubMed and published stroke guidelines, an evidence-based literature review was performed. Results: In this review, we compare cryptogenic stroke with the newer concept of embolic stroke of undetermined source, summarize the most common causes presumed to underlie these strokes, and review the evidence for optimal antithrombotic management. We also review recent clinical trials demonstrating a benefit for percutaneous closure of PFO for secondary stroke prevention in select patients. Conclusions: Stroke management is based on evaluation of individual patient-risk factors. Evaluation and treatment is ideally directed by a vascular neurologist to ensure optimal secondary prevention, especially in cases where an underlying etiology is not identified on initial workup.

Disease of the Year: Cerebrovascular Disorders Section Editors: Valerie Biousse, MD Koto Ishida, MD Updates in the Management of Cryptogenic Stroke and Patent Foramen Ovale David K. Stone, MD, Natalie Buchwald, MD, Christina A. Wilson, MD, PhD Background: Stroke is a common neurological disorder and may present with visual symptoms. A thorough workup is warranted to determine the underlying cause of stroke to optimize secondary prevention. Despite a full workup, a high-risk mechanism may not be identified. Optimal treatment in this patient population has been the subject of recent research, particularly with regard to low-risk stroke mechanisms such as patent foramen ovale (PFO). Evidence acquisition: Using PubMed and published stroke guidelines, an evidence-based literature review was performed. Results: In this review, we compare cryptogenic stroke with the newer concept of embolic stroke of undetermined source, summarize the most common causes presumed to underlie these strokes, and review the evidence for optimal antithrombotic management. We also review recent clinical trials demonstrating a benefit for percutaneous closure of PFO for secondary stroke prevention in select patients. Conclusions: Stroke management is based on evaluation of individual patient-risk factors. Evaluation and treatment is ideally directed by a vascular neurologist to ensure optimal secondary prevention, especially in cases where an underlying etiology is not identified on initial workup. cardioembolic, atherosclerotic, or lacunar etiology is found; however, approximately 25% of patients are ultimately diagnosed with a cryptogenic stroke. Potential causes of cryptogenic strokes include many lower risk sources of emboli from the heart, cerebral vasculature, and other sources. Embolic stroke of undetermined source (ESUS) is a subset of cryptogenic stroke that appears embolic/nonlacunar on imaging and for which no source is identified despite an appropriate workup. Overall, research on cryptogenic stroke and ESUS has been somewhat limited. However, several recent trials have evaluated the optimal antithrombotic regimen for secondary stroke prevention in these patients. In addition, patent foramen ovale (PFO), a low-risk cause of stroke through paradoxical embolism, has also been the focus of trials evaluating the benefit of percutaneous closure vs more conservative management. Journal of Neuro-Ophthalmology 2020;40:60-66 doi: 10.1097/WNO.0000000000000896 © 2020 by North American Neuro-Ophthalmology Society Definition S troke is the fifth leading cause of death in the United States and the leading neurological cause of disability. Many strokes present with visual symptoms. Accurate identification of the mechanism by which a stroke occurred is critical to ensure appropriate measures for secondary prevention. In most stroke patients, an underlying high-risk First Physicians Group of Sarasota Memorial Health Care System (DKS), Sarasota, Florida; and Department of Neurology (NB, CAW), University of Florida, Gainesville, Florida. The authors report no conflicts of interest. Address correspondence to Christina A. Wilson, MD, PhD, Department of Neurology, University of Florida, 3rd Floor McKnight Brain Institute, 1149 Newell Drive, Gainesville, FL 32611; E-mail: christina.wilson@neurology.ufl.edu 60 CRYPTOGENIC STROKE Cryptogenic stroke is a diagnosis of exclusion, in which the stroke mechanism is not identified. The classification scheme for the Trial of Org 10172 in Acute Stroke Treatment (TOAST) study defined 5 broad categories of ischemic stroke: large-artery atherosclerosis, cardioembolism, small-vessel disease, stroke of other determined etiology, and stroke of undetermined etiology (1). This latter category included patients with a negative evaluation for other etiologies, as well as those with 2 or more possible stroke causes or incomplete workup. Similarly, the ASCO phenotypic classification describes cryptogenic stroke as one with workup negative for atherosclerosis (A), small-vessel disease (S), cardiac disease (C), or other cause (O) (2); of note, unlike TOAST, this system draws a distinction between patients with multiple high-risk mechanisms and cryptogenic stroke. Potential causes of cryptogenic stroke include many stroke mechanisms historically deemed "low risk" (Table 1). Stone et al: J Neuro-Ophthalmol 2020; 40: 60-66 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Cerebrovascular Disorders TABLE 1. Potential mechanisms underlying cryptogenic stroke Low-risk cardiac sources of emboli Shunt for paradoxical emboli from venous source Hypercoagulable states Arterial sources Genetic causes Cardiac rhythm abnormalities Atrial cardiopathy Mitral valve annular calcification Atrial septal aneurysm Left ventricular aneurysm Left atrial spontaneous echo contrast ("smoke") Congestive heart failure Ventricular noncompaction/trabeculation Chiari network Patent foramen ovale (PFO) Atrial septal defect Ventricular septal defect Pulmonary arteriovenous malformations Occult malignancy Antiphospholipid antibodies Nonstenotic (,50%) atherosclerosis of cerebral vessels Aortic arch atherosclerosis Dissection Fibromuscular dysplasia Vasculitis Reversible cerebral vasospasm syndrome Sickle cell disease Fabry disease Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) Occult paroxysmal atrial fibrillation Sick sinus syndrome Left atrial enlargement Elevated probrain natriuretic peptide P-wave terminal force velocity Cardiac sources of emboli include cardiac wall motion abnormalities, congestive heart failure with reduced ejection fraction, as well as occult paroxysmal atrial fibrillation and other atrial cardiopathies. Paradoxical emboli from the venous system through a cardiac (e.g., PFO or atrial septal defect) or pulmonary shunt are also possible. Other sources include occult malignancy or other hypercoagulable states, aortic arch plaque, or substenotic (,50%) atherosclerosis of cerebral vessels (especially if ulcerated or irregular), nonatherosclerotic vasculopathies such as dissection or vasculitis, and genetic causes of stroke. ESUS is a subset of cryptogenic stroke, which underscores that most cryptogenic strokes are likely embolic in etiology (3). Unlike cryptogenic stroke, ESUS requires a standard minimal workup to meet criteria. To qualify as ESUS, the stroke must be nonlacunar on brain imaging (lacunar strokes defined as subcortical in location and #1.5 cm on computerized tomography scan or #2.0 cm on MRI). Most ophthalmic and nonarteritic central and branch retinal arterial occlusions fall into this category. Furthermore, there must be no evidence of atherosclerosis causing $50% stenosis in the cerebral vasculature supplying the area of infarction, no high-risk cardiac source of emboli (specifically no evidence of atrial fibrillation, atrial flutter, Stone et al: J Neuro-Ophthalmol 2020; 40: 60-66 cardiac thrombus, prosthetic valve, cardiac tumor, myocardial infarction within past 4 weeks, mitral stenosis, left ventricular ejection fraction ,30%, valve vegetations, or infective endocarditis), nor other specific cause of stroke identified (3). Epidemiology Cryptogenic stroke accounts for approximately 25% of ischemic strokes and may be disproportionally represented in younger patients and minorities. In the Northern Manhattan Stroke study (NOMASS), cryptogenic stroke accounted for a higher percentage of stroke in young adults (#45 years old) compared with older patients (4). In a study performed in Finland, rare or undetermined causes of stroke, classified ultimately as cryptogenic stroke, accounted for most stroke etiologies in a population of young stroke patients (5). The incidence of cryptogenic stroke is higher in minorities than whites (4). Diagnostic Workup Cryptogenic stroke and ESUS are diagnoses of exclusion. At minimum, all stroke patients should undergo brain imaging with CT or MRI to confirm the diagnosis of stroke, identify location and size suggestive of lacunar 61 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Cerebrovascular Disorders etiology, and further determine the pattern of infarction for clues toward etiology-for example, stroke in multiple vascular territories suggests a proximal embolic source, whereas stroke in borderzone areas suggests hypoperfusion. In addition, patient should undergo imaging of the cervical and intracranial blood vessels for atherosclerotic stenosis or other vasculopathy, as well as basic cardiac monitoring to include, at minimum, 12-lead electrocardiography, 24 hours of rhythm monitoring, and a transthoracic echocardiogram (TTE). Additional tests can be considered in select patients. A transesophageal echocardiogram (TEE) can more readily visualize valvular, aortic, and left atrial appendage pathology and should be pursued in patients for whom a proximal embolic source is highly suspected despite negative TTE and rhythm monitoring. A bubble study (performed either with echocardiogram or transcranial dopplers) can identify a rightto-left shunt for paradoxical embolism. Workup of a hypercoagulable state can include antiphopholipid antibody testing or occult malignancy. Vasculitis can be further evaluated by cerebrospinal fluid sampling, brain biopsy, or testing for serum markers in patient with potential stigmata of systemic disease. The patient's age should factor into choice of diagnostic testing because younger patients are more likely to have atypical causes of stroke such as dissection, stroke secondary to pregnancy, or inherited causes of stroke. Overall, the specific workup is tailored to the individual patient and the type of stroke and thus best performed in a stroke center with the help of a neurologist with expertise in stroke. A key component to the workup of cryptogenic stroke/ ESUS is prolonged rhythm monitoring for occult atrial fibrillation/flutter. Although most patients undergo monitoring with telemetry on stroke units, paroxysmal atrial fibrillation may still remain undetected. Prolonged outpatient monitoring increases the yield of detection and is warranted in cryptogenic stroke patients given that identification of atrial fibrillation would necessitate initiation of long-term anticoagulation. The 30-day Cardiac Event Monitor Belt for Recording Atrial Fibrillation after a Cerebral Ischemic Event (EMBRACE) trial randomized patients with cryptogenic stroke to noninvasive ambulatory cardiac monitoring for 30 days compared with a control group that received only one additional day of monitoring. Extended monitoring revealed atrial fibrillation in 16.1% of patients compared with 3.2% of controls (6). The Cryptogenic Stroke and Underlying AF (CRYSTAL-AF) trial used implantable cardiac monitors to evaluate the detection rate of atrial fibrillation in patients with cryptogenic stroke and found that atrial fibrillation was detected in 8.9% of the patients after 6 months and in 12.4% of patients after 12 months (7). Prolonged monitoring for paroxysmal atrial fibrillation is especially important in older patients with cryptogenic stroke/ESUS because the risk of atrial fibrillation increases with age. The clinical significance of atrial fibrillation detected years after a stroke may raise question 62 as to the mechanistic relationship to the initial stroke, and the duration of atrial fibrillation to be considered a significant stroke risk has not been well defined. Nevertheless, atrial fibrillation identified post hoc may be mechanistically related to the antecedent stroke and generally warrants initiation of anticoagulation by CHADS2 or CHA2DS2-VASc criteria. Antithrombotic Treatment for Cryptogenic Stroke and ESUS Currently, the standard of care endorses the use of an antiplatelet medication for secondary stroke prevention unless a definitive indication for anticoagulation, such as atrial fibrillation, is identified (8). Alternatively, patients with noncardioembolic minor stroke or TIA can be placed on a brief (w21-day) course of dual antiplatelet therapy with aspirin and clopidogrel (9), although this regimen has not been systemically studied in a cryptogenic stroke population. Several studies have evaluated whether an anticoagulant regimen is indicated for cryptogenic stroke and ESUS. The Warfarin-Aspirin Recurrent Stroke Study (WARSS) demonstrated no benefit for warfarin over aspirin in patients with cryptogenic stroke (10). In theory, ESUS should be amenable to anticoagulation, given the embolic nature and likelihood of underlying occult atrial fibrillation. Indeed, subgroup analysis of patients with embolic stroke in WARSS demonstrated a nonsignificant trend toward improved prevention with warfarin (12% stroke rate vs 18% with aspirin) (11). However, the RESPECT ESUS trial, which compared the oral direct thrombin inhibitor dabigatran with aspirin in patients with ESUS, found that dabigatran was not superior to aspirin in secondary stroke prevention in this population (12). Similarly, NAVIGATEESUS compared reduced-dose rivaroxaban (15 mg daily) with aspirin in patients with ESUS; this study was terminated early due to absence of efficacy of rivaroxaban over aspirin and increased hemorrhage in patients receiving rivaroxaban (13). Anticoagulation may be indicated for a more select population of ESUS patients with underlying cardiac source. The ongoing ARCADIA trial is comparing apixaban and aspirin in patients with ESUS and cardiac features suggestive of atrial cardiopathy (14). For now, empiric anticoagulation is not recommended for secondary stroke prevention in cryptogenic stroke or ESUS patients. Currently, the standard of care is aspirin with placement of an implantable cardiac monitor to detect occult atrial fibrillation, and if this is detected, anticoagulation is started. To date, studies have failed to prove the superiority of anticoagulation to aspirin for secondary stroke prevention in patients with cryptogenic stroke or ESUS. Future investigation in a subpopulation of patients who may benefit from anticoagulation is ongoing. Determination of the clinical significance of brief episodes of atrial fibrillation detected Stone et al: J Neuro-Ophthalmol 2020; 40: 60-66 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Cerebrovascular Disorders well after a stroke, as well as the threshold for duration of atrial fibrillation to be deemed a significant stroke risk, is unknown. Thus, continued investigation to determine optimal antithrombotic recommendations for preventing stroke recurrence in this patient population is warranted. MANAGEMENT OF PATENT FORAMEN OVALE An important potential mechanism of stroke in patients with ESUS/cryptogenic stroke is paradoxical embolism from the venous system through a PFO, especially in younger patients without typical stroke risk factors. PFO is found in approximately 25% of the adult population and up to 40%-50% of patients with cryptogenic stroke (15). PFO may be diagnosed by TTE (46% sensitive), TEE (63%-100% sensitive), or transcranial doppler (97% sensitive) after injection of agitated saline contrast, although only TEE will directly visualize the PFO. Two important questions for management are 1) whether the PFO is likely causative of the stroke and 2) whether closure of the PFO will reduce the risk of stroke in an individual patient more than medical therapy. It is important to determine whether paradoxical embolism through the PFO is the most likely mechanism of stroke in an individual patient, or if it is an incidental finding. Closure of an incidental PFO would expose a patient to the risk of procedure, while potentially leaving the underlying true stroke mechanism unaddressed. Age of the patient is an important consideration in determining whether the PFO is pathogenic in the patient's stroke. Calculation of a RoPE (Risk of Paradoxical Embolism) score, which takes into account the age of the patient, presence of traditional vascular risk factors, and the embolic appearance of the stroke can be useful for estimating the probability that PFO is incidental or causative of cryptogenic stroke (16). A high RoPE score (i.e., a younger patient with an embolic-appearing stroke and few vascular risk factors) suggest a pathologic role of the PFO, whereas a lower score (older patient with a lacunar stroke and multiple risk factors) suggests the PFO may be an incidental finding. Historical elements can also provide clues as to whether a PFO played a causal role. For example, stroke symptoms that were preceded by Valsalva/abdominal straining may implicate right-to-left shunting, or a period of prolonged immobility may have facilitated venous clot formation. A thorough workup for alternate causes of stroke, including testing for hypercoagulability or prolonged cardiac monitoring for paroxysmal atrial fibrillation in the appropriate patient, should be pursued before labeling a PFO as causal and considering treatment. Percutaneous Closure Early trials did not show a statistically significant benefit to percutaneous closure over antithrombotic therapy, although Stone et al: J Neuro-Ophthalmol 2020; 40: 60-66 point estimates suggested a trend toward benefit. However, several recent studies have provided evidence that, in carefully selected patients, PFO closure in addition to antiplatelet therapy is superior to antithrombotic therapy alone (17-20). Closure I, the first trial to evaluate safety of percutaneous PFO closure vs an antithrombotic agent (aspirin, warfarin, or both), did not show a benefit for PFO closure in the primary endpoint of stroke, TIA, or death after 2 years (21). Problems with the STARFlex closure device used in the study, including higher-than-expected rates of atrial fibrillation and residual right-to-left shunting after the procedure, may have contributed to the negative results. The PC Trial also showed no benefit to closure but included patients with peripheral (i.e., noncerebral) embolism and was statistically underpowered (22). These initial trials, as well as short-term data from the RESPECT trial, which compared PFO closure vs medical treatment with an antiplatelet agent or warfarin and followed patients for a mean of 2.6 years, suggested there was no clear benefit to closure (23). Despite these negative results, subsequent metaanalyses of these early trials did support potential benefit with PFO closure (24,25). More recently, data from 4 trials have provided evidence in favor of percutaneous closure in cryptogenic stroke select patients with PFO; these trials also added important information about patient selection (17,26-28). Long-term follow-up data from the RESPECT trial, which followed patients with cryptogenic stroke and TEE-proven PFO for nearly 6 years, showed a significant reduction in recurrent stroke with PFO closure vs medical therapy with antiplatelet or warfarin alone (3.6% vs 5.8%) (17). The benefit was stronger if the patient had a concomitant atrial septal aneurysm (1.7% vs 7.6%) or a large shunt (2.0% vs 6.9%). The CLOSE trial enrolled only patients with recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt; patient were randomized to undergo PFO closure plus an antiplatelet agent, an antiplatelet agent alone, or anticoagulation alone, with a median follow-up of 5 years (26). The main arm of the treatment compared PFO closure with antiplatelet therapy. PFO closure demonstrated superiority to antiplatelet therapy; in fact, there were no recurrent stroke in the PFO closure group, compared to 14 in the group treated with antiplatelet therapy. The REDUCE trial only included patients with PFO and right-to-left shunt demonstrated by TEE, for whom no other potential stroke mechanism had been identified after an extensive workup (27). Of note, approximately 80% of patients had moderate or large-sized shunts. This study demonstrated reduction in recurrent symptomatic stroke after closure compared with an antiplatelet agent alone (1.4% vs 5.4%) as well as reduction in the number of recurrent (clinically silent) infarcts on brain imaging (5.7% vs 11.3%). 63 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Cerebrovascular Disorders The DEFENSE-PFO trial enrolled patients with cryptogenic stroke and "high-risk" PFO (defined as those with an atrial septal aneurysm of at least 15 mm, hypermobility of at least $10 mm, or PFO size $2 mm); patients were randomized to closure vs a medical arm of antiplatelet or anticoagulation treatment at the discretion of the local investigator (28). Unlike the previous trials, this smaller trial of 123 patients included patients older than 60 years, with a mean age of 51.8 years. Recurrent ischemic stroke was noted only in the medical arm (with an event rate of 10.5%); overall, closure was beneficial compared with medical therapy. Additional meta-analyses of the available PFO closure trial data were also supportive of closure being beneficial (29-31). The more strict selection of patients, including specification of comprehensive workup to rule out alternate stroke mechanisms, is likely a major reason for the success of the later trials, as well as the longer duration of monitoring given the low event rate overall. In addition, these trials helped demonstrate features of the PFO itself (e.g., larger size, associated atrial septal aneurysm, eustachian valve, or Chiari network) that may indicate increased risk of stroke due to paradoxical embolism and thus support benefit of closure (29). The major complication associated with PFO closure in the clinical trials was new-onset atrial fibrillation, with a risk increase of 3.4%. Other rare but potential adverse events include groin hematoma, local cardiac erosion (either through the septum or cardiac wall), thrombus formation, or device migration. Of note, with the exception of DEFENSE-PFO, these trials only included patients who were aged 60 years or younger. The risk of atrial fibrillation increases with age and is a more likely mechanism in older patients. Some groups have advocated for 6 months of prolonged cardiac monitoring in those in the upper age range of treatment (50-60 years) before consideration of closure (32,33). Antithrombotic Therapy All patients with stroke presumed related to PFO regardless of percutaneous intervention should receive antithrombotic therapy. Studies to date have not demonstrated a clear role for anticoagulation over antiplatelets in patients with a stroke secondary to PFO. The PFO in Cryptogenic Stroke Study (PICSS) comparing warfarin and aspirin for secondary stroke prevention in this population did not demonstrate a significant reduction in 2-year stroke or death with warfarin (34). Of note, this was a subset analysis of the larger WARSS trial, and it was not clearly determined that PFO was causative rather than incidental in these patients. Comparison of antiplatelet therapy vs anticoagulation in the CLOSE trial also did not show a significant difference in secondary stroke prevention, although point estimate did suggest a benefit (26). In a meta-analysis of PICSS, CLOSE, and patients with PFO in NAVIGATE-ESUS, the overall risk of stroke was lower with anticoagulation (odds ratio 64 0.48, 95% confidence interval 0.24-0.96) (35). However, as these data were derived from subset analyses, further randomized trials are warranted. At this time, anticoagulation is generally reserved for those patients with identified concomitant deep-vein thrombosis or pulmonary embolism. In summary, in patients aged 60 years or younger with embolic, nonlacunar strokes on brain imaging who are found to have a PFO with high-risk features, percutaneous closure may be beneficial in addition to antiplatelet therapy to reduce the risk of recurrent stroke due to paradoxical embolism. This should only be undertaken after a thorough investigation for alternate causes of stroke. In patients older than 60, there are limited data to suggest a role for PFO closure, and thus, optimal management includes antiplatelet therapy plus prolonged cardiac monitoring for paroxysmal atrial fibrillation in appropriate patients. Anticoagulation is currently reserved for those patients with evidence of concurrent venous thromboembolism. CONCLUSIONS A cryptogenic stroke is one without identified high-risk cause; ESUS is a similar concept but specifically refers to those strokes with an embolic pattern. A stroke should only be deemed cryptogenic/ESUS after thorough workup tailored to the individual patient, ideally under the direction of a vascular neurologist, not simply because an incomplete workup failed to find an obvious stroke mechanism. Antiplatelet therapy, rather than anticoagulation, is indicated for secondary stroke prevention in most cryptogenic stroke/ESUS patients, although additional percutaneous closure may be beneficial in select patients with stroke secondary to paradoxical embolization through PFO. The best method to ensure optimal treatment is to direct patients with suspected stroke to the nearest stroke center for immediate management, with longitudinal care under the direction of a vascular neurologist. REFERENCES 1. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE III. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST: Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35-41. 2. Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Hennerici MG. New approach to stroke subtyping: the A-S-C-O (phenotypic) classification of stroke. Cerebrovasc Dis. 2009;27:502-508. 3. 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