Sphingosine-1-Phosphate Signaling in Ischemic Stroke: From Bench to Bedside and Beyond

Sphingosine-1-phosphate (S1P) signaling is being increasingly recognized as a strong modulator of immune cell migration and endothelial function. Fingolimod and other S1P modulators in ischemic stroke treatment have shown promise in emerging experimental models and small-scale clinical trials. In this article, we will review the current knowledge of the role of S1P signaling in brain ischemia from the aspects of inflammation and immune interventions, sustaining endothelial functions, regulation of blood-brain barrier integrity, and functional recovery. We will then discuss the current and future therapeutic perspectives of targeting S1P for the treatment of ischemic stroke. Mechanism studies would help to bridge the gap between preclinical studies and clinical practice. Future success of bench-to-bedside translation shall be based on in depth understanding of S1P signaling during stroke and on the ability to have a fine temporal and spatial regulation of the signal pathway.

Embolic Stroke of Undetermined Source: Approaches in Risk Stratification for Cardioembolism

Ischemic stroke is a leading cause of morbidity and mortality worldwide. Embolic stroke of undetermined source has been recently proposed to categorize nonlacunar ischemic strokes without confirmed etiology after adequate investigation with a likely embolic stroke mechanism. A strategy of empirical anticoagulation for embolic stroke of undetermined source patients is attractive but may only be beneficial in a select subset of patients. Strategies which would help identify the subset of embolic stroke of undetermined source patients most likely to have cardioembolic origin of stroke, and hence benefit from anticoagulation, are needed. This article will review current evidence which may be useful in the development of a risk stratification approach based on arrhythmia monitoring, cardiac imaging, and clinical risk stratification. This approach may be beneficial in clinical practice in improving patient outcomes and reducing stroke recurrence in this population; however, further work is required with active trials underway.

Ischaemic stroke in anticoagulated patients with atrial fibrillation

Anticoagulation substantially reduces the risk of stroke in patients with atrial fibrillation (AF). However, recent studies have shown that up to 22%–36% of patients on anticoagulation will suffer an ischaemic stroke (IS). In this narrative review, we provide an overview of risk factors, mechanisms, management of acute IS and strategies for secondary prevention for patients with AF with stroke despite oral anticoagulation. For this paper, we reviewed available literature from important studies (randomised clinical trials, meta-analyses, reviews and case series) on patients with IS despite anticoagulation. We focused on recent studies that examined safety and efficacy of acute stroke treatments and evaluation and management strategies for secondary prevention. The literature review suggests that patients with AF with IS despite anticoagulation are a heterogeneous group with several possible mechanisms, which may include reduced or non-adherence to anticoagulation, competing non-cardioembolic stroke aetiologies or cardioembolic mechanisms separate from AF. The identification of one or more possible mechanisms of stroke despite anticoagulation may allow for a more targeted and individualised approach for secondary prevention. There are limited data to guide management in such patients, and strategies to prevent recurrent strokes include strict risk factor control and therapies targeting the most likely stroke mechanism. In cases where AF is suspected to be the culprit, clinical trials are needed to test the safety and efficacy of left atrial appendage occlusion plus anticoagulation versus continued anticoagulation alone.

Strokes Following Attempted Suicide: Frequency, Mechanisms, Outcome and Review of the Literature

Background: Only a few patients with strokes following suicide attempt (SFSA) are described in the literature and dissection of cervical arteries is the best-known mechanism. We aimed to determine the frequency, clinical presentation, mechanisms and outcomes of such patients by systematic observation in a single academic institution.Method: We retrospectively identified in our acute ischemic stroke registry all SFSA over 11 years. A thorough work-up was performed to establish the stroke mechanism. We also searched all published SFSA in the world literature for further analysis of demographics, comorbidities and long-term outcome. Results: Work-up showed multiple stroke mechanisms as well as multiple psychiatric. After adding 7 already published SFSA and comparing all SFSA with our stroke registry, SFSA were younger, had similar stroke severity, higher early mortality, and similar long-term functional outcome.Conclusions: SFSA is rare, affects younger patients and may be missed without an appropriate level of suspicion and neuroimaging. Long-term outcome seems comparable to other stroke patients despite an increased early mortality.

Thrombophilia Testing After Ischemic Stroke

Thrombophilia testing is frequently performed after an ischemic stroke, particularly when cryptogenic. However, there is minimal evidence supporting a significant association between most conditions assessed through thrombophilia testing and ischemic stroke, and the rationale for thrombophilia testing in many clinical situations remains uncertain. In this topical review, we review and contextualize the existing data on the risks, predictors, and outcomes of thrombophilic conditions in patients with ischemic stroke. We report that inherited thrombophilias have an uncertain relationship with ischemic stroke. Conversely, antiphospholipid syndrome, an acquired immune-mediated thrombophilia, seems to be a strong risk factor for arterial thromboembolic events, including ischemic stroke, and especially among young patients. Our findings suggest that certain circumstances may warrant targeted thrombophilia testing, such as stroke in the young, cryptogenic stroke, and high estrogen states. Future prospective studies should investigate the utility and cost effectiveness of thrombophilia testing in various stroke settings, including among patients with patent foramen ovale; as well as the optimal secondary stroke prevention regimen in patients with confirmed thrombophilia, particularly if no other potential stroke mechanism is identified.

Abstract P260: Ischemic Strokes on Direct Oral Anticoagulants

Introduction: The objective of our study was to identify the underlying causes of acute ischemic strokes (AIS) in patients prescribed direct oral anticoagulants (DOACs). Methods: This is a retrospective study of patients presenting to a large urban comprehensive stroke center from December 1, 2019 to May 31, 2020 who were prescribed DOACs at the index event. Two board-certified vascular neurologists independently reviewed medical charts including patient baseline characteristics, laboratory results, stroke mechanism, and patient-reported adherence. DOAC “failure” was defined as AIS occurring in the setting of self-reported adherence to the FDA-indicated dosing regimen. Results: Of 302 AIS patients admitted during the study period, 18 (6.0%) patients had AIS while on DOACs. Median age was 82 (IQR 72, 86) years, 9 (50%) were black and 14 (78%) were female. Eight patients (44%) presented within the IV Alteplase window and 5 (28%) patients presented with large vessel occlusion. At the time of stroke, 13 (72%) patients were on apixaban, 4 (22%) were on rivaroxaban and 1 (6%) on dabigatran. Atrial fibrillation (mean CHADS-VASc score 4.7) was the most common indication for DOAC (72%), followed by deep venous thrombosis (17%), and embolic stroke (11%). The most frequent causes of AIS on DOACs were underdosing in patients ≥ 80 years (n=6), known active malignancy (n=5), and non-adherence (n=4). The remaining cases included procedure-related discontinuation of the DOAC (n=1), symptomatic extracranial internal carotid artery stenosis (n=1), and unknown cause (n=1). Overall, the frequency of DOAC “failure” was 39%. In 6 (33%) patients, the initial anticoagulant was switched to an alternative anticoagulant at discharge. Conclusion: In this cohort of patients who had AIS while on DOAC therapy, 39% of cases were attributed to DOAC “failure” and primarily occurred in patients with active malignancy. Underdosing in the elderly and non-adherence remained the leading cause of AIS in patients on DOAC. Our findings highlight the importance of accurate dosing in the elderly and reinforcing adherence to medications. Further studies are needed to understand the role of DOACs in patients with active malignancy.

Abstract P90: Clinical Features of Patients With Cryptogenic Stroke and Covid-19

Introduction: While coronavirus disease 2019 (COVID-19) has been associated with acute ischemic stroke (AIS), the causal relationship has yet to be elucidated. Factors that likely confer increased stroke risk are COVID-19-associated coagulopathy and hyperinflammatory response. Studying clinical features of patients with otherwise undetermined cause of AIS could help better define COVID-19-associated stroke. Methods: We performed a multicenter cross-sectional study of consecutive patients presenting with AIS and COVID-19 to one of two large healthcare systems in New York City during the local COVID-19 surge from March 1, 2020 to May 31, 2020. In-hospital stroke cases were excluded. We compared demographic and clinical features of patients with COVID-19 and a cryptogenic AIS subtype to patients with COVID-19 and a determined subtype. Baseline characteristics and clinical variables were compared using chi-squared and Fisher exact tests. Results: A total of 62 patients with AIS and COVID-19 at the time of hospital arrival were identified. Of these, 30 were classified as having a cryptogenic subtype (80% after complete diagnotics evaluation), and 32 had an identifiable stroke mechanism. Patients with cryptogenic AIS were significantly younger (p=0.011) and less likely to have co-morbid hypertension (p=0.019), coronary artery disease (p=0.024), heart failure (p=0.039), atrial fibrillation (<0.0001), and prior stroke or TIA (p=0.033) compared to those with defined mechanisms. Further, d-dimer, but not C-reactive protein, was significantly higher in patients with cryptogenic stroke compared to those with defined causes (p=0.009). Conclusion: Patients with AIS in the setting of COVID-19 and no other determined stroke mechanism were younger, less likely to have classic risk factors, and had higher d-dimer levels when compared to those with a determined mechanism. Further study of COVID-19-associated hypercoagulability as a mechanism of stroke is warranted.

Abstract P572: Cerebral Hemodynamics Underlying Artery-To-Artery Embolism in Symptomatic Intracranial Atherosclerotic Disease

Background: Artery-to-artery embolism (AAE) is a common stroke mechanism in patients with symptomatic intracranial atherosclerotic disease (ICAD), which might be associated with a higher risk of recurrent stroke than other stroke mechanisms. We aimed to investigate cerebral hemodynamic features associated with AAE in symptomatic ICAD patients. Methods: Patients with acute, anterior-circulation ischemic stroke attributed to ICAD (50-99% stenosis) confirmed in CT angiography (CTA) were recruited from two teaching hospitals. We classified probable stroke mechanisms as isolated parent artery atherosclerosis occluding penetrating artery (PAO), AAE, hypoperfusion, and mixed mechanisms, based on infarct topography in MRI and ICAD lesion features. CTA-based computational fluid dynamics (CFD) models were built to simulate blood flow across culprit ICAD lesions. Translesional pressure ratio (PR=Pressure post-stenotic /Pressure pre-stenotic ) and translesional wall shear stress ratio (WSSR=WSS stenotic-throat /WSS pre-stenotic ) were calculated, to reflect the relative change of the two hemodynamic metrics across an ICAD lesion. PR ≤ median was defined as low PR, indicating a larger pressure gradient across the lesion; and WSSR ≥ 4 th quartile as high WSSR, indicating elevated WSS upon the lesion. We associated PR and WSSR with presence of AAE as a probable stroke mechanism. Results: Among 99 symptomatic ICAD patients, 44 had AAE as a probable stroke mechanism, 13 with AAE alone and 31 with coexisting hypoperfusion; the remaining patients respectively had isolated PAO (n=18) and isolated hypoperfusion (n=37) as the probable stroke mechanisms. High WSSR was independently associated with AAE (adjusted OR 4.21; 95% CI 1.33-13.26; p=0.014). The significant, positive relationship between high WSSR and higher risk of AAE remained in those with a low PR (adjusted OR 4.01; 95% CI 1.03-15.46; p=0.044), but not in those with a normal PR (p=0.621). Conclusions: High WSS upon ICAD lesions may increase plaque vulnerability and lead to distal embolism, while sustained antegrade flow across the ICAD lesion (normal PR) may help clear the emboli. In secondary prevention of symptomatic ICAD with AAE, impaired cerebral perfusion may be a therapeutic target.