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Introduction SARS‐CoV‐2 infection may be associated with uncommon complications such as intracerebral hemorrhage (ICH), with a high mortality rate. We compared a series of hospitalized ICH cases infected with SARS‐CoV‐2 with a non‐SARS‐CoV‐2 infected control group and evaluated if the SARS‐CoV‐2 infection is a predictor of mortality in ICH patients. Methods In a multinational retrospective study, 63 cases of ICH in SARS‐CoV‐2 infected patients admitted to 13 tertiary centers from the beginning of the pandemic were collected. We compared the clinical and radiological characteristics and in‐hospital mortality of these patients with a control group of non‐SARS‐CoV‐2 infected ICH patients of a previous cohort from the country where the majority of cases were recruited. Results Among 63 ICH patients with SARS‐CoV‐2 infection, 23 (36.5%) were women. Compared to the non‐SARS‐CoV‐2 infected control group, in SARS‐CoV‐2 infected patients, ICH occurred at a younger age (61.4± 18.1 years versus 66.8± 16.2 years, P = 0.044). These patients had higher median ICH scores ([3 (IQR 2–4)] versus [2 (IQR 1–3)], P = 0.025), a more frequent history of diabetes (34% versus 16%, P = 0.007), and lower platelet counts (177.8± 77.8 × 109/L versus 240.5± 79.3 × 109/L, P< 0.001). The in‐hospital mortality was not significantly different between cases and controls (65% versus 62%, P = 0.658) in univariate analysis; however, SARS‐CoV‐2 infection was significantly associated with in‐hospital mortality (aOR = 4.3, 95% CI: 1.28‐14.52) in multivariable analysis adjusting for potential confounders. Conclusions Infection with SARS‐CoV‐2 may be associated with increased odds of in‐hospital mortality in ICH patients.

Background and Purpose— There are scarce data regarding the safety of intravenous thrombolysis (IVT) in acute ischemic stroke among patients on direct oral anticoagulants (DOACs). Methods— We performed a systematic review and meta-analysis of the current literature. Data regarding all adult patients pretreated with DOAC who received IVT for acute ischemic stroke were recorded. Meta-analysis was performed by comparing the rate of symptomatic intracerebral hemorrhage in these patients with (1) stroke patients without prior anticoagulation therapy and (2) patients on warfarin with international normalized ratio Results— After reviewing 13 392 reports and communicating with certain authors of 12 published studies, a total of 52 823 acute ischemic stroke patients from 6 studies were enrolled in the present meta-analysis: DOACs: 366, warfarin: 2133, and 50 324 patients without prior anticoagulation. We detected no additional risk of symptomatic intracerebral hemorrhage following IVT among patients taking DOACs within 48 hours—DOACs-warfarin: NINDS (odds ratio [OR], 0.53 [95% CI, 0.18–1.52]), ECASS-II (OR, 0.77 [95% CI, 0.28–2.16]); DOACs-no-anticoagulation: NINDS (OR, 1.23 [95% CI, 0.46–3.31]), ECASS-II (OR, 0.92 [95% CI, 0.33–2.55]). Similarly, no additional risk was detected with no time limit between last DOAC intake—DOACs warfarin: NINDS (OR, 0.85 [95% CI, 0.49–1.45]), ECASS-II (OR, 1.11 [95% CI, 0.67–1.85]); DOACs-no-anticoagulation: NINDS (OR, 1.17 [95% CI, 0.43–3.15]), ECASS-II (OR, 0.87 [95% CI, 0.33–2.41]). There was no evidence of heterogeneity across included studies ( I 2 =0%). We also provided the details of 123 individual cases with or without reversal agents before IVT. There was no significant increase in the risk of hemorrhagic transformation (OR, 1.48 [95% CI, 0.50–4.38]), symptomatic hemorrhagic transformation (OR, 0.47 [95% CI, 0.09–2.55]), or early mortality (OR, 0.60 [95% CI, 0.11–3.43]) between cohorts who did or did not receive prethrombolysis idarucizumab. Conclusions— The results of our study indicated that prior intake of DOAC appears not to increase the risk of symptomatic intracerebral hemorrhage in selected AIS patients treated with IVT.

Introduction: Stroke hospitalization and mortality are influenced by various social determinants. This ecological study aimed to determine the associations between social determinants and stroke hospitalization and outcome at county-level in the United States. Methods: County-level data were recorded from the Centers for Disease Control and Prevention as of January 7, 2020. We considered four outcomes: all-age (1) Ischemic and (2) Hemorrhagic stroke Death rates per 100,000 individuals (ID and HD respectively), and (3) Ischemic and (4) Hemorrhagic stroke Hospitalization rate per 1,000 Medicare beneficiaries (IH and HH respectively). Results: Data of 3,225 counties showed IH (12.5 ± 3.4) and ID (22.2 ± 5.1) were more frequent than HH (2.0 ± 0.4) and HD (9.8 ± 2.1). Income inequality as expressed by Gini Index was found to be 44.6% ± 3.6% and unemployment rate was 4.3% ± 1.5%. Only 29.8% of the counties had at least one hospital with neurological services. The uninsured rate was 11.0% ± 4.7% and people living within half a mile of a park was only 18.7% ± 17.6%. Age-adjusted obesity rate was 32.0% ± 4.5%. In regression models, age-adjusted obesity (OR for IH: 1.11; HH: 1.04) and number of hospitals with neurological services (IH: 1.40; HH: 1.50) showed an association with IH and HH. Age-adjusted obesity (ID: 1.16; HD: 1.11), unemployment (ID: 1.21; HD: 1.18) and income inequality (ID: 1.09; HD: 1.11) showed an association with ID and HD. Park access showed inverse associations with all four outcomes. Additionally, population per primary-care physician was associated with HH while number of pharmacy and uninsured rate were associated with ID. All associations and OR had p ≤0.04. Conclusion: Unemployment and income inequality are significantly associated with increased stroke mortality rates.

Objective: To determine whether Polygenic Risk Scores (PRS) derived from MEGASTROKE is associated with ischemic stroke (IS) and its subtypes in an independent tertiary healthcare system and to identify PRS derived from gene-sets of known biological pathways associated with IS and its outcomes (mortality and recurrent stroke). Methods: Controls(n=19806/7484, age≥69/79) and cases(n=1184/951 for discovery/replication) of acute IS with European ancestry and clinical risk factors identified by leveraging the Geisinger Electronic Health Record (EHR) and chart review confirmation. All Geisinger MyCode patients with age ≥69/79, without any stroke-related diagnostic codes as low-risk control. Genetic heritability and genetic correlation between Geisinger and MEGASTROKE(EUR) using the summary statistics of GWAS by LDSC. All PRS for any stroke — AS, any ischemic stroke — AIS, large artery stroke — LAS, cardioembolic stroke — CES, and small vessel stroke — SVS constructed by PRSice-2. PRS (top or bottom quantiles) derived from 7350 gene-sets of GO Biological Process was used to stratify the IS. Results: A moderate heritability (10-20%) for Geisinger sample as well as the genetic correlation between MEGASTROKE and the Geisinger cohort was identified. Gene sets analyses highlighted the association of PRS with Gene Ontology terms (vascular endothelial growth factor, amyloid precursor protein, and atherosclerosis). The PRS LAS , PRS CES , and PRS SVS explained the most variance of the corresponding subtypes of Geisinger IS suggesting shared etiologies and corroborated Geisinger TOAST subtyping. We further evaluate PRS derived from the gene-sets of which GO terms may best differentiate the survival in IS cases with the corresponding high or low genetic burden. The result from the Cox regression analysis showed simultaneously the effect of several risk factors including PRS on mortality and recurrent stroke probabilities. Conclusions: We provide the first evidence that PRSs derived from MEGASTROKE have value in identifying shared etiologies and determining stroke subtypes.

Importance: Management of transient ischemic attack (TIA)and the concept of urgent TIA clinic have gained significant attention over the past years. Objective: To calculate the odds of subsequent ischemic stroke within 2, 7, 30, and 90 days and death within 90 days among the TIA patients who received acute care in a TIA clinic versus those admitted to a hospital. Data Sources: We performed a systematic review and meta-analysis of all the published TIA outcome studies. Included studies were obtained by searching Medline, Web of Science, Scopus, All EBM reviews series, International Clinical Trial Registry Platform (ICTRP), Trip database, and CINAHL, last updated in March 2020, irrespective of the study design, document type, or language. Study Selection: We accepted both the classic time-based definition of TIA and the new tissue-based definition and studies with a combined record of TIA and minor ischemic stroke patients. We excluded studies with a diagnosis of index TIA event after ischemic stroke occurrence, low suspicious for TIA, TIA acute care in settings other than an outpatient clinic or hospital, multicentric studies, or duplicate reports of the same database. Data Extraction and Synthesis: The study was conducted and reported according to PRISMA, MOOSE, and EQUATOR guidelines. Critical appraisal and methodological quality were conducted by ROBINS-E tool. Data were pooled under random-effects models. Results: Systematic review yielded to 19,547 reports, of which titles and abstracts of 9,113 reports were screened. The overall subsequent ischemic stroke odds ratios were estimated by meta-analyses as follows: 4 studies within 2 days with 1,829 patients (OR: 0.93, 95% CI: -0.52-2.38), 5 studies within 7 days with 1,801 patients (OR: 0.68, 95% CI: -0.73-2.08), 4 studies within 30 days with 1,768 patients (OR:1.01, 95% CI: -0.72 - 2.73), and 6 studies within 90 days with 2,319 population (OR: 0.94, 95% CI: 0.22-1.66). The 90-day risk of death by analyzing 3 studies, 1162 patients, was calculated as OR:1.29, 95% CI: 0.76-3.34. Conclusion and Relevance: Hospital management of TIA patients in the acute phase may not be associated with a lower risk of stroke and death compared with urgent outpatient management.

Objective: The long-term risk of recurrent ischemic stroke, estimated to be between 17%-30%, cannot be reliably assessed. Our goal was to study whether machine-learning can be trained to predict stroke recurrence and identify key clinical variables and assess whether performance metrics can be optimized. Methods: We used patient-level data from electronic health records, 6 algorithms (Logistic Regression, Extreme Gradient Boosting, Gradient Boosting Machine, Random Forest, Support Vector Machine, Decision Tree), 4 feature selection strategies, 5 prediction windows, and 2 sampling strategies to develop 288 models for up to 5-year stroke recurrence prediction. We further identified important clinical features and different optimization strategies. Results: We included 2,091 ischemic stroke patients for this study. Model AUROC was stable for prediction windows of 1,2,3,4 and 5 years, with the highest score for the 1-year (0.79) and the lowest score for the 5-year prediction window (0.69). A total of 21(7%) models reached an AUROC above 0.73 while 110(38%) models reached an AUROC greater than 0.7. Among the 53 features analyzed, age, body mass index, and laboratory-based features (such as high-density lipoprotein, hemoglobin A1C, and creatinine) had the highest overall importance scores. The balance between specificity and sensitivity improved through sampling strategies. Conclusion: All the selected six modeling algorithms could be trained to predict the long-term stroke recurrence and laboratory-based variables were highly associated with stroke recurrence. The latter could be targeted for personalized interventions. Model performance metrics could be optimized, and models can be implemented in the same healthcare system as intelligent decision support to improve outcomes.

Introduction: Several studies suggest women may be disproportionately affected by poorer stroke outcomes than men. This study aimed to investigate if women had a higher risk of all-cause mortality and recurrence after an ischemic stroke in a rural population in central Pennsylvania, United States. Methods: We analyzed consecutive ischemic stroke patients captured in our comprehensive research database from 2004 to 2019. Kaplan-Meier (KM) estimator curves stratified by gender and age were used to plot survival probabilities and Cox Proportional Hazards Ratios were used to analyze outcomes of all-cause mortality and the composite outcome of ischemic stroke recurrence or death. Fine-Gray Competing Risk models were used for the outcome of recurrent ischemic stroke, with death as the competing risk. Two models were generated; Model 1 was adjusted by data-driven associated health factors, and Model 2 was adjusted by traditional vascular risk factors. Results: Among 8,900 adult ischemic stroke patients (median age of 71.6 [IQR:61.1-81.2] years and 48% women), women had a higher crude all-cause mortality. The KM curves demonstrated a 63.3% survival in women compared to a 65.7% survival in men (p=0.003) at five years; however, the survival difference was not present after adjustment by the associated factors of age, atrial fibrillation or flutter, myocardial infarction, diabetes mellitus, dyslipidemia, heart failure, chronic lung diseases, rheumatic disease, chronic kidney disease, neoplasm, peripheral vascular disease, past ischemic stroke, past hemorrhagic stroke, and depression. There was no adjusted or unadjusted sex difference in terms of recurrent ischemic stroke or composite outcome. Conclusion: Sex was not an independent risk factor for all-cause mortality and ischemic stroke recurrence in the rural population in central Pennsylvania.

The goal of this study was to better depict the short-term risk of stroke and its associated factors among SARS-CoV-2 hospitalized patients. Data Source: This multicenter, multinational observational study includes hospitalized SARS-CoV-2 patients from North and South America (United States, Canada, and Brazil), Europe (Greece, Italy, Finland, and Turkey), Asia (Lebanon, Iran, and India), and Oceania (New Zealand). Main Outcomes and Measures: The outcome was the risk of subsequent stroke (ischemic stroke, intracranial hemorrhage, cerebral venous/sinus thrombosis). The counts and clinical characteristics including laboratory findings and imaging of the patients with and without a subsequent stroke were recorded according to a predefined study protocol. Data Extraction and Synthesis: Quality, risk of bias, and heterogeneity assessments were conducted according to ROBINS-E and Cochrane Q-test. The risk of subsequent stroke was estimated through meta-analyses with random effect models. Binary logistic regression was used to determine the associated factors with the outcome measure. The study was reported according to the STROBE, MOOSE, and EQUATOR guidelines. Results: We received data from 18,311 hospitalized SARS-CoV-2 patients from 77 tertiary centers in 46 regions of 11 countries until May 1 st , 2020. A total of 17,799 patients were included in meta-analyses. Among them, 156(0.9%) patients had a stroke—123(79%) ischemic stroke, 27(17%) intracerebral/subarachnoid hemorrhage, and 6(4%) cerebral sinus thrombosis. Subsequent stroke risks calculated with meta-analyses, under low to moderate heterogeneity, were 0.5% among all centers in all countries, and 0.7% among countries with higher health expenditures. The need for mechanical ventilation (OR: 1.9, 95% CI:1.1-3.5, p = 0.03) and the presence of ischemic heart disease (OR: 2.5, 95% CI:1.4-4.7, p =0·006) were predictive of stroke. Conclusion and Relevance: The results of this multi-national study on hospitalized patients with SARS-CoV-2 infection indicated an overall stroke risk of 0.5% (pooled risk: 0.9%). The need for mechanical ventilation and the history of ischemic heart disease are the independent predictors of stroke among SARS-CoV-2 patients.

Background: Emerging data indicates an increased risk for cerebrovascular events with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and highlights the potential impact of coronavirus disease (COVID-19) on the management and outcomes of acute stroke. We conducted a systematic review and meta-analysis to evaluate the aforementioned considerations. Methods: We performed a meta-analysis of observational cohort studies reporting on the occurrence and/or outcomes of patients with cerebrovascular events in association with their SARS-CoV-2 infection status. We used a random-effects model. Summary estimates were reported as odds ratios (ORs) and corresponding 95% confidence intervals (95%CI). Results: We identified 16 cohort studies including 44,004 patients. Among patients with SARS-CoV-2, 1.3% (95%CI: 0.9-1.8%; I 2 =88%) were hospitalized for cerebrovascular events, 1.2% (95%CI: 0.8-1.5%; I 2 =85%) for ischemic stroke, and 0.2% (95%CI: 0.1-0.4%; I 2 =69%) for hemorrhagic stroke. Compared to non-infected contemporary or historical controls, patients with SARS-CoV-2 infection had increased odds of ischemic stroke (OR=3.58, 95%CI: 1.43-8.92; I 2 =43%) and cryptogenic stroke (OR=3.98, 95%CI: 1.62-9.77; I 2 =0%). Odds for in-hospital mortality were higher among SARS-CoV-2 stroke patients compared to non-infected contemporary or historical stroke patients (OR=5.60, 95%CI: 3.19-9.80; I 2 =45%). SARS-CoV-2 infection status was not associated to the likelihood of receiving intravenous thrombolysis (OR=1.42, 95%CI: 0.65-3.10; I 2 =0%) or endovascular thrombectomy (OR=0.78, 95%CI: 0.35-1.74; I 2 =0%) among hospitalized ischemic stroke patients during the COVID-19 pandemic. Diabetes mellitus was found to be more prevalent among SARS-CoV-2 stroke patients compared to non-infected contemporary or historical controls (OR=1.39, 95%CI: 1.04-1.86; I 2 =0%). Conclusion: SARS-CoV-2 appears to be associated with an increased risk of ischemic stroke, particularly the cryptogenic subtype. SARS-CoV-2 infection in stroke substantially increases the mortality risk.

Introduction: The stroke mortality rate has gradually declined due to improved interventions and controlled risk factors. We investigated the trends in stroke risk factors and outcomes among a rural population in the United States between 2004 and 2018. Methods: We built a comprehensive stroke database called “Geisinger NeuroScience Ischemic Stroke (GNSIS)” for this study. Clinical data were extracted from multiple sources, including electronic health records and quality data. Results: Our cohort comprised of 8,561 consecutive ischemic stroke patients (mean age: 70.1±13.9 years, men: 51.6%, 95.1% Caucasian). Hypertension was the most prevalent risk factor (75.2%). The rate of hypertension, diabetes, dyslipidemia, and history of stroke increased significantly over the fifteen years window. The one-year recurrence and mortality rates were 6.3% and 15.8%, respectively. Although the one-year stroke recurrence increased from 2004 to 2018 (Cochran-Armitage test Z = -3.66, p65 years, atrial fibrillation or flutter, heart failure, and prior ischemic stroke were independently associated with one-year all-cause mortality in stratified Cox proportional hazards model. In the Fine-Gray competing risk model, diabetes mellitus and age 65 years, atrial fibrillation or flutter, CKD, heart failure, prior hemorrhagic and ischemic stroke, history of neoplasm, myocardial infarction, and rheumatic diseases were predictors of one-year mortality. Conclusion: Although stroke mortality has decreased, stroke recurrence and several vascular risk factors have significantly increased in our rural population between 2004-2018. Older age, atrial fibrillation or flutter, heart failure, and prior ischemic stroke were independently associated with one-year all-cause mortality while diabetes mellitus and age less than 65 years were predictors of ischemic stroke recurrence.

Objective and Design: We conducted a multinational observational study on features of consecutive acute ischemic stroke (AIS), intracranial hemorrhage (ICH), and cerebral venous or sinus thrombosis (CVST) among SARS-CoV-2 infected patients. Main Outcome Measures: We investigated the association of demographics, clinical data, geographical regions, and countries’ health expenditure among AIS patients with the risk of large vessel occlusion (LVO), stroke severity as measured by National Institute of Health stroke scale (NIHSS), and stroke subtype as measured by the TOAST criteria. Additionally, we applied unsupervised machine learning algorithms to uncover possible similarities among stroke patients. Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least one eligible stroke patient. Out of 432 patients included, 323(74.8%) had AIS, 91(21.1%) ICH, and 18(4.2%) CVST. Among 23 patients with subarachnoid hemorrhage, 16(69.5%) had no evidence of aneurysm. A total of 183(42.4%) patients were women, 104(24.1%) patients were younger than 55 years, and 105(24.4%) patients had no identifiable vascular risk factors. Among 380 patients who had known interval onset of the SARS-CoV-2 and stroke, 144(37.8%) presented to the hospital with chief complaints of stroke-related symptoms, with asymptomatic or undiagnosed SARS-CoV-2 infection. Among AIS patients 44.5% had LVO; 10% had small artery occlusion according to the TOAST criteria. We observed a lower median NIHSS (8[3-17], versus 11[5-17]; p=0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; p Conclusions and Relevance: We observed a relatively high number of young, and asymptomatic SARS-CoV-2 infections among stroke patients. Traditional vascular risk factors were absent among a relatively large cohort of patients. The stroke severity was lower and rate of mechanical thrombectomy was higher among countries with middle to high-health expenditure.

Introduction: Direct oral anticoagulants (DOACs) are increasingly being administered for atrial fibrillation and stroke prevention. The risk of symptomatic hemorrhagic transformation (sHT) following intravenous thrombolysis (IVT) among stroke patients who take DOACs is not clear. Methods: We conducted a systematic review of literature through six different resources—PubMed, Scopus, Embase, Clinicaltrial.gov, ICTRP and Cochrane library. The control groups included patients who took warfarin with INR Results: A total of 12606 search results were retrieved. After reduction of the duplication, screening the title and abstracts and review of the candidate manuscripts, 44877 stroke patients were enrolled in this study—DOACs: 369 patients, warfarin: 1997 patients and 42511 patients without prior anticoagulation use. Pretreatment use of DOACs was not associated with increased risk of sHT compared to those who received warfarin (OR: 0.62; 95% CI: 0.23-1.71; P=0.74) or patients without prior anticoagulation use (OR: 0.89; 95% CI: 0.31- 2.56; P=0.98). Similarly, by restricting the results to last DOACs-IVT interval of 48 hours, DOACs was not associated with increased risk of sICH; neither in comparison with warfarin (OR: 0.63; 95% CI: 0.39- 1.02; P=0.82), nor with patients without prior anticoagulation use (OR: 0.89; 95% CI: 0.53- 1.48; P=0.36). Conclusion: Pretreatment use of DOACs appears not to be associated with increased risk of sHT among patients who presented with stroke symptoms and treated with IVT.

Introduction: Acute multiple cerebral infarcts in multiple arterial territories are thought to suggest the presence of cardioembolic sources. However, several studies have shown other etiologies for simultaneous cerebral infarcts in multiple arterial territories. Methods: We conducted a systematic review of the literature through PubMed, Scopus, Embase, Clinicaltrial.gov, ICTRP and Cochrane library. Studies containing multiple acute strokes in more than one arterial territory based on diffusion weighted imaging (DWI) findings were screened. Articles were excluded if they had limited inclusion criteria, performed limited subgroup analysis, or did not use DWI. Results: Out of 16551 stroke patients from 25 studies included in this study, 1967 (12%) patients had simultaneous acute cerebral infarcts in multiple arterial territories. 199 patients were excluded as their workup and diagnosis were not reported. Out of 1768 patients, 491 (28%) patients had an undetermined etiology. Cardioembolism was the most common cause of stroke in multiple arterial territories (38%, 95%CI: 36-40%) followed by large artery atherosclerosis including aortic arch atheroma (23%, 95%CI: 21-25%). Hematological disorders were found to be the cause of cerebral infarcts in 52 (3%, 95%CI: 2-4%) patients. Out of 143 patients who were reported to have simultaneous brain infarcts in bilateral hemispheres or anterior and posterior circulations, 78 (54%, 95%CI: 46-62%) were found to have cardiacembolism. Other etiologies for stroke in multiple arterial territories were intracranial atherosclerosis, vasculitis and other inflammatory diseases, infection, and iatrogenic causes. Conclusion: Simultaneous cerebral infarcts in multiple arterial territories occur among 12% of stroke patients. Although cardioembolism is the most common cause, there are several other etiologies that require a different workup and secondary prevention strategy.