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As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread globally, it became evident that the SARS-CoV-2 virus infects multiple organs including the brain. Several clinical studies revealed that patients with COVID-19 infection experience an array of neurological signs ranging in severity from headaches to life-threatening strokes. Although the exact mechanism by which the SARS-CoV-2 virus directly impacts the brain is not fully understood, several theories have been suggested including direct and indirect pathways induced by the virus. One possible theory is the invasion of SARS-CoV-2 to the brain occurs either through the bloodstream or via the nerve endings which is considered to be the direct route. Such findings are based on studies reporting the presence of viral material in the cerebrospinal fluid and brain cells. Nevertheless, the indirect mechanisms, including blood-clotting abnormalities and prolonged activation of the immune system, can result in further tissue and organ damages seen during the course of the disease. This overview attempts to give a thorough insight into SARS-CoV-2 coronavirus neurological infection and highlights the possible mechanisms leading to the neurological manifestations observed in infected patients.

Background: Since the COVID-19 pandemic, several cases of cerebral venous sinus thrombosis (CVST) have been reported in SARS-CoV-2 infected individuals. This study provides a series of patients with CVST and SARS-CoV-2 infection.Methods: Consecutive patients with documented SARS-CoV-2 infection, as well as clinical and radiological characteristics of CVST, were reported from three teaching hospitals in the South West, North West, and the center of Iran from June to July 2020. We also searched the abstract archives until the end of August 2020 and gathered 28 reported cases. The diagnostic criteria for SARS-CoV-2 infection were determined according to SARS-CoV-2 detection in oropharyngeal or nasopharyngeal samples in clinically suspected patients. Demographics, main COVID-19 symptoms, confirmatory tests for SARS-CoV-2 infection diagnosis, the interval between the diagnosis of SARS-CoV-2 infection and CVST, clinical and radiological features of CVST, therapeutic strategies, CVST outcomes, rate of hemorrhagic transformation, and mortality rate were investigated.Results: Six patients (aged 31 to 62 years old) with confirmed CVST and SARS-CoV-2 infection were admitted to our centers. Four patients had no respiratory symptoms of SARS-CoV-2 infection. Five out of six patients developed the clinical manifestations of CVST and SARS-CoV-2 infection simultaneously. Three patients had known predisposing factors for CVST. Despite receiving CVST and SARS-CoV-2 infection treatments, four out of six patients passed away.Conclusions: The role of SARS-CoV-2 as a “cause” versus an “additive contributor” remains to be elucidated. Practitioners should be aware of the possibility of CVST in SARS-CoV-2 infection.

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.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.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 × 10Infection 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: The rise of ischemic stroke among young adults has stressed the need to understand their risk profiles and outcomes better. This study aimed to examine the five-year ischemic stroke recurrence and survival probability among young patients in rural Pennsylvania. Methods: This retrospective cohort study included first-time ischemic stroke patients from the Geisinger Health System between September 2003 and May 2014. The outcomes included all-cause mortality and ischemic stroke recurrence at five years. Kaplan-Meier estimator, cumulative incidence function, Cox proportional hazards model, and Cause-specific hazard model were used to examine the association of independent variables with the outcomes. Results: A total of 4459 first-time ischemic stroke patients were included in the study, with 664 (14.9%) patients in the 18–55 age group and 3795 (85.1%) patients in the >55 age group. In the 18–55 age group, the five-year survival probability was 87.2%, and the cumulative incidence of recurrence was 8%. Patients in the 18–55 age group had significantly lower hazard for all-cause mortality (HR = 0.37, 95% CI 0.29–0.46, p < 0.001), and non-significant hazard for five-year recurrence (HR = 0.81, 95% CI 0.58–1.12, p = 0.193) compared to the >55 age group. Chronic kidney disease was found to be associated with increased mortality in the 18–55 age group. Conclusion: In our rural population, younger ischemic stroke patients were at the same risk of long-term ischemic stroke recurrence as the older ischemic stroke patients. Identifying the factors and optimizing adequate long-term secondary prevention may reduce the risk of poor outcomes among younger ischemic stroke patients.

Various studies on oral anticoagulants (OAC) use among atrial fibrillation (AF) patients have shown high rates of undertreatment and the presence of sex disparity. This study used the ‘Geisinger Neuroscience Ischemic Stroke’ (GNSIS) database to examine sex differences in OAC treatment among ischemic stroke patients with the pre-event diagnosis of AF in rural Pennsylvania between 2004 and 2019. We examined sex disparities in OAC undertreatment and associated risks based on age group and ischemic stroke year. A total of 1062 patients were included in the study and 1015 patients (96%) had CHA2DS2-VASc score ≥ 2, of which 549 (54.1%) were women. Undertreatment rates were not statistically significant between men and women in the overall cohort (50.0% vs. 54.5%, p = 0.18), and male sex was not found to be a significant factor in undertreatment (OR 0.82, 95% CI 0.62–1.09, p = 0.17). The result persisted even when patients were divided into four age groups and two groups based on the study time period. The undertreatment rates in both sex groups remained consistent following the introduction of novel oral anticoagulants. In conclusion, there was no evidence of sex disparity with respect to OAC treatment, even after stratifying the cohort by age and ischemic stroke year.

Laboratory data from Electronic Health Records (EHR) are often used in prediction models where estimation bias and model performance from missingness can be mitigated using imputation methods. We demonstrate the utility of imputation in two real-world EHR-derived cohorts of ischemic stroke from Geisinger and of heart failure from Sutter Health to: (1) characterize the patterns of missingness in laboratory variables; (2) simulate two missing mechanisms, arbitrary and monotone; (3) compare cross-sectional and multi-level multivariate missing imputation algorithms applied to laboratory data; (4) assess whether incorporation of latent information, derived from comorbidity data, can improve the performance of the algorithms. The latter was based on a case study of hemoglobin A1c under a univariate missing imputation framework. Overall, the pattern of missingness in EHR laboratory variables was not at random and was highly associated with patients’ comorbidity data; and the multi-level imputation algorithm showed smaller imputation error than the cross-sectional method.

Supplemental Digital Content is available in the text., Background and Purpose: We systematically evaluated the impact of the coronavirus 2019 (COVID-19) pandemic on stroke care across the world. Methods: Observational studies comparing characteristics, acute treatment delivery, or hospitalization outcomes between patients with stroke admitted during the COVID-19 pandemic and those admitted before the pandemic were identified by Medline, Scopus, and Embase databases search. Random-effects meta-analyses were conducted for all outcomes. Results: We identified 46 studies including 129 491 patients. Patients admitted with stroke during the COVID-19 pandemic were found to be younger (mean difference, −1.19 [95% CI, −2.05 to −0.32]; I2=70%) and more frequently male (odds ratio, 1.11 [95% CI, 1.01–1.22]; I2=54%) compared with patients admitted with stroke in the prepandemic era. Patients admitted with stroke during the COVID-19 pandemic, also, had higher baseline National Institutes of Health Stroke Scale scores (mean difference, 0.55 [95% CI, 0.12–0.98]; I2=90%), higher probability for large vessel occlusion presence (odds ratio, 1.63 [95% CI, 1.07–2.48]; I2=49%) and higher risk for in-hospital mortality (odds ratio, 1.26 [95% CI, 1.05–1.52]; I2=55%). Patients with acute ischemic stroke admitted during the COVID-19 pandemic had higher probability of receiving endovascular thrombectomy treatment (odds ratio, 1.24 [95% CI, 1.05–1.47]; I2=40%). No difference in the rates of intravenous thrombolysis administration or difference in time metrics regarding onset to treatment time for intravenous thrombolysis and onset to groin puncture time for endovascular thrombectomy were detected. Conclusions: The present systematic review and meta-analysis indicates an increased prevalence of younger patients, more severe strokes attributed to large vessel occlusion, and higher endovascular treatment rates during the COVID-19 pandemic. Patients admitted with stroke during the COVID-19 pandemic had higher in-hospital mortality. These findings need to be interpreted with caution in view of discrepant reports and heterogeneity being present across studies.

Background Health-related quality of life (utility) measures are essential components of effectiveness analyses. The health-related quality of life of health states in pediatric patients who underwent spinal surgery have not been reported previously. Objectives To estimate the utility of complications after spinal surgeries and side effects of acetazolamide administration. Methods Parent caregivers, nurses, neurosurgeons, and orthopedists were interviewed as proxies to evaluate the preference of health conditions in pediatric patients who underwent intradural surgeries. We measured the utility of spinal surgery complications (cerebrospinal fluid leakage and collection, wound dehiscence, operation site infection, and secondary repair of operation site), side effects of acetazolamide administration (loss of appetite, mild gastroenteritis, and severe acid/base and/or electrolyte imbalance), taking pills (for 10 days, 1 month, and 1 year), and 24 hours of ward or intensive care unit admission by visual analogue scale. Results One hundred individuals were interviewed (pilot study: 20 individuals; main study: 40 parents, 27 nurses, 8 neurosurgeons, and 5 orthopedists). Sixty-four (80%) of the respondents were female. Taking pills for 10 days had the highest utility value (0.71 ± 0.13), whereas secondary surgical repair of the operation site and acid/base and/or electrolyte imbalance had the lowest preference (0.19 ± 0.16 and 0.23 ± 0.11, respectively). Conclusions This study provides the utility measures for quality assessment of temporary postsurgical events in pediatric patients.

Small blood vessels express specific phenotypical and functional characteristics throughout the body. Alterations in the microcirculation contribute to many correlated physiological and pathological events in related organs. Factors such as comorbidities and genetics contribute to the complexity of this topic. Small vessel disease primarily affects end organs that receive significant cardiac output, such as the brain, kidney, and retina. Despite the differences in location, concurrent changes are seen in the micro-vasculature of the brain, retina, and kidneys under pathological conditions due to their common histological, functional, and embryological characteristics. While the cardiovascular basis of pathology in association with the brain, retina, or kidneys has been well documented, this is a simple review that uniquely considers the relationship between all three organs and highlights the prevalence of coexisting end organ injuries in an attempt to elucidate connections between the brain, retina, and kidneys, which has the potential to transform diagnostic and therapeutic approaches.

(1) Background: Stroke incidence and outcomes are influenced by socioeconomic status. There is a paucity of reported population-level studies regarding these determinants. The goal of this ecological analysis was to determine the county-level associations of social determinants of stroke hospitalization and death rates in the United States. (2) Methods: Publicly available data as of 9 April 2021, for the socioeconomic factors and outcomes, was extracted from the Centers for Disease Control and Prevention. The outcomes of interest were “all stroke hospitalization rates per 1000 Medicare beneficiaries” (SHR) and “all stroke death rates per 100,000 population” (SDR). We used a multivariate binomial generalized linear mixed model after converting the outcomes to binary based on their median values. (3) Results: A total of 3226 counties/county-equivalents of the states and territories in the US were analyzed. Heart disease prevalence (odds ratio, OR = 2.03, p < 0.001), blood pressure medication nonadherence (OR = 2.02, p < 0.001), age-adjusted obesity (OR = 1.24, p = 0.006), presence of hospitals with neurological services (OR = 1.9, p < 0.001), and female head of household (OR = 1.32, p = 0.021) were associated with high SHR while cost of care per capita for Medicare patients with heart disease (OR = 0.5, p < 0.01) and presence of hospitals (OR = 0.69, p < 0.025) were associated with low SHR. Median household income (OR = 0.6, p < 0.001) and park access (OR = 0.84, p = 0.016) were associated with low SDR while no college degree (OR = 1.21, p = 0.049) was associated with high SDR. (4) Conclusions: Several socioeconomic factors (e.g., education, income, female head of household) were found to be associated with stroke outcomes. Additional research is needed to investigate intermediate and potentially modifiable factors that can serve as targeted interventions.

Failed Back Surgery Syndrome (FBSS) is persistent pain and disability following lumbar laminectomy which is associated with decreased quality of life and disability and has been reported in up to 40% of the patients undergoing lumbar laminectomy. Several approaches have been introduced to reduce the rate of the FBSS. Among these, applying anti-adhesive barrier gels have been studied with interest with controversial results. The aim of the current study was to determine the effects of anti-adhesive barrier gels on functional outcome and recurrence of patients undergoing lumbar disc surgery. We searched databases including EMBASE, PUBMED, Web of Science, Scopus, Cochrane Library, and scholar databases until November 2019. To assess the heterogeneity across included studies was used Cochran's Q and I-square (I2) statistics. Standardized mean difference (SMD) and 95% CI between were used to estimate pooled effect sizes. Out of 4507, 10 clinical trials found to be appropriate for current meta-analysis. The pooled results of included clinical trials indicated that adhesion barrier gel significantly decreased leg pain (LP) (SMD = −0.31; 95% CI, −0.60, −0.03; P = 0.032; I2: 59.2%) among patients with lumbar disc herniation surgery. Back pain (BP) (SMD = −0.03; 95% CI, −0.23, 0.16; P = 0.734; I2: 40.2%), and Oswestry disability index (ODI) (SMD = −0.11; 95% CI, −0.27, 0.05; P = 0.178; I2: 0.0%), were not significantly affected following adhesion barrier gel application. Application of adhesion barrier gel in single level lumbar disc surgery is associated with deceased leg pain. However, its application does not affect the low back pain, disability and gate. Further, larger randomized clinical trials are required., Adhesion barrier gel; Functional outcome; Lumbar disc surgery; Meta-analysis.

Background. Temporary artery clipping facilitates safe cerebral aneurysm management, besides a risk for cerebral ischemia. We developed an artificial neural network (ANN) to predict the safe clipping time of temporary artery occlusion (TAO) during intracranial aneurysm surgery. Method. We devised a three-layer model to predict the safe clipping time for TAO. We considered age, the diameter of the right and left middle cerebral arteries (MCAs), the diameter of the right and left A1 segment of anterior cerebral arteries (ACAs), the diameter of the anterior communicating artery, mean velocity of flow at the right and left MCAs, and the mean velocity of flow at the right and left ACAs, as well as the Fisher grading scale of brain CT scans as the input values for the model. Results. This study included 125 patients: 105 patients from a retrospective cohort for training the model and 20 patients from a prospective cohort for validating the model. The output of the neural network yielded up to 960 s overall safe clipping time for TAO. The input values with the greatest impact on safe TAO were mean velocity of blood at left MCA and left ACA, and Fisher grading scale of brain CT scan. Conclusion. This study presents an axillary framework to improve the accuracy of the estimated safe clipping time interval of temporary artery occlusion in intracranial aneurysm surgery.

Since the early days of the pandemic, there have been several reports of cerebrovascular complications during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Numerous studies proposed a role for SARS-CoV-2 in igniting stroke. In this review, we focused on the pathoetiology of stroke among the infected patients. We pictured the results of the SARS-CoV-2 invasion to the central nervous system (CNS) via neuronal and hematogenous routes, in addition to viral infection in peripheral tissues with extensive crosstalk with the CNS. SARS-CoV-2 infection results in pro-inflammatory cytokine and chemokine release and activation of the immune system, COVID-19-associated coagulopathy, endotheliitis and vasculitis, hypoxia, imbalance in the renin-angiotensin system, and cardiovascular complications that all may lead to the incidence of stroke. Critically ill patients, those with pre-existing comorbidities and patients taking certain medications, such as drugs with elevated risk for arrhythmia or thrombophilia, are more susceptible to a stroke after SARS-CoV-2 infection. By providing a pictorial narrative review, we illustrated these associations in detail to broaden the scope of our understanding of stroke in SARS-CoV-2-infected patients. We also discussed the role of antiplatelets and anticoagulants for stroke prevention and the need for a personalized approach among patients with SARS-CoV-2 infection.

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.

Background. SARS-CoV-2 infected patients are suggested to have a higher incidence of thrombotic events such as acute ischemic strokes (AIS). This study aimed at exploring vascular comorbidity patterns among SARS-CoV-2 infected patients with subsequent stroke. We also investigated whether the comorbidities and their frequencies under each subclass of TOAST criteria were similar to the AIS population studies prior to the pandemic. Methods. This is a report from the Multinational COVID-19 Stroke Study Group. We present an original dataset of SASR-CoV-2 infected patients who had a subsequent stroke recorded through our multicenter prospective study. In addition, we built a dataset of previously reported patients by conducting a systematic literature review. We demonstrated distinct subgroups by clinical risk scoring models and unsupervised machine learning algorithms, including hierarchical K-Means (ML-K) and Spectral clustering (ML-S). Results. This study included 323 AIS patients from 71 centers in 17 countries from the original dataset and 145 patients reported in the literature. The unsupervised clustering methods suggest a distinct cohort of patients (ML-K: 36% and ML-S: 42%) with no or few comorbidities. These patients were more than 6 years younger than other subgroups and more likely were men (ML-K: 59% and ML-S: 60%). The majority of patients in this subgroup suffered from an embolic-appearing stroke on imaging (ML-K: 83% and ML-S: 85%) and had about 50% risk of large vessel occlusions (ML-K: 50% and ML-S: 53%). In addition, there were two cohorts of patients with large-artery atherosclerosis (ML-K: 30% and ML-S: 43% of patients) and cardioembolic strokes (ML-K: 34% and ML-S: 15%) with consistent comorbidity and imaging patterns. Binominal logistic regression demonstrated that ischemic heart disease (odds ratio (OR), 4.9, 95% confidence interval (CI), 1.6–14.7), atrial fibrillation (OR, 14.0, 95% CI, 4.8–40.8), and active neoplasm (OR, 7.1, 95% CI, 1.4–36.2) were associated with cardioembolic stroke. Conclusions. Although a cohort of young and healthy men with cardioembolic and large vessel occlusions can be distinguished using both clinical sub-grouping and unsupervised clustering, stroke in other patients may be explained based on the existing comorbidities.

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.

International audience; Objective: Emerging data indicate an increased risk of cerebrovascular events with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and highlight 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 (CIs).Results: We identified 18 cohort studies including 67,845 patients. Among patients with SARS-CoV-2, 1.3% (95% CI = 0.9-1.6%, I2 = 87%) were hospitalized for cerebrovascular events, 1.1% (95% CI = 0.8-1.3%, I2 = 85%) for ischemic stroke, and 0.2% (95% CI = 0.1-0.3%, I2 = 64%) for hemorrhagic stroke. Compared to noninfected 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, I2 = 43%) and cryptogenic stroke (OR = 3.98, 95% CI = 1.62-9.77, I2 = 0%). Diabetes mellitus was found to be more prevalent among SARS-CoV-2 stroke patients compared to noninfected historical controls (OR = 1.39, 95% CI = 1.00-1.94, I2 = 0%). SARS-CoV-2 infection status was not associated with the likelihood of receiving intravenous thrombolysis (OR = 1.42, 95% CI = 0.65-3.10, I2 = 0%) or endovascular thrombectomy (OR = 0.78, 95% CI = 0.35-1.74, I2 = 0%) among hospitalized ischemic stroke patients during the COVID-19 pandemic. Odds of in-hospital mortality were higher among SARS-CoV-2 stroke patients compared to noninfected contemporary or historical stroke patients (OR = 5.60, 95% CI = 3.19-9.80, I2 = 45%).Interpretation: SARS-CoV-2 appears to be associated with an increased risk of ischemic stroke, and potentially cryptogenic stroke in particular. It may also be related to an increased mortality risk. ANN NEUROL 2021;89:380-388.

Background: The long-term risk of recurrent ischemic stroke, estimated to be between 17% and 30%, cannot be reliably assessed at an individual level. 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, six interpretable algorithms (Logistic Regression, Extreme Gradient Boosting, Gradient Boosting Machine, Random Forest, Support Vector Machine, Decision Tree), four feature selection strategies, five prediction windows, and two 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 2091 ischemic stroke patients. Model area under the receiver operating characteristic (AUROC) curve 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 of the selected six 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 for targeted intervention.

Objective This study aimed to investigate the prevalence and factors associated with oral anticoagulant undertreatment of atrial fibrillation (AF) among a cohort of rural patients with stroke outcomes and examine how undertreatment may influence a patient's one-year survival after stroke. Methods This retrospective cohort study examined ischemic stroke patients with pre-stroke AF diagnosis from September 2003 to May 2019 and divided them into proper treatment and undertreatment group. Analysis included chi-square test, variance analysis, Kruskal-Wallis test, logistic regression, Kaplan-Meier estimator, and Cox proportional-hazards model. Results Out of 1062 ischemic stroke patients with a pre-stroke AF diagnosis, 1015 patients had a CHA2DS2-VASc score ≥2, and 532 (52.4%) of those were undertreated. Median time from AF diagnosis to index stroke was significantly lower among undertreated patients (1.9 years vs. 3.6 years, p Conclusions More than half of our rural stroke patients with a pre-index AF diagnosis were not on guideline-recommended treatment. The study highlights a large care gap and an opportunity to improve AF management.

SARS-CoV-2 infects cells through angiotensin-converting enzyme 2 (ACE2), a ubiquitous receptor that interacts with the virus’ surface S glycoprotein. Recent reports show that the virus affects the central nervous system (CNS) with symptoms and complications that include dizziness, altered consciousness, encephalitis, and even stroke. These can immerge as indirect immune effects due to increased cytokine production or via direct viral entry into brain tissue. The latter is possible through neuronal access via the olfactory bulb, hematogenous access through immune cells or directly across the blood-brain barrier (BBB), and through the brain’s circumventricular organs characterized by their extensive and highly permeable capillaries. Last, the COVID-19 pandemic increases stress, depression, and anxiety within infected individuals, those in isolation, and high-risk populations like children, the elderly, and health workers. This review surveys the recent updates of CNS manifestations post SARS-CoV-2 infection along with possible mechanisms that lead to them.

Background and Purpose: Stroke is reported as a consequence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in several reports. However, data are sparse regarding the details of these patients in a multinational and large scale. Methods: We conducted a multinational observational study on features of consecutive acute ischemic stroke, intracranial hemorrhage, and cerebral venous or sinus thrombosis among SARS-CoV-2–infected patients. We further investigated the risk of large vessel occlusion, stroke severity as measured by the National Institutes of Health Stroke Scale, and stroke subtype as measured by the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria among patients with acute ischemic stroke. In addition, we explored the neuroimaging findings, features of patients who were asymptomatic for SARS-CoV-2 infection at stroke onset, and the impact of geographic regions and countries’ health expenditure on outcomes. Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least 1 eligible stroke patient. Of 432 patients included, 323 (74.8%) had acute ischemic stroke, 91 (21.1%) intracranial hemorrhage, and 18 (4.2%) cerebral venous or sinus thrombosis. A total of 183 (42.4%) patients were women, 104 (24.1%) patients were P =0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; P Conclusions: We observed a considerably higher rate of large vessel occlusions, a much lower rate of small vessel occlusion and lacunar infarction, and a considerable number of young stroke when compared with the population studies before the pandemic. The rate of mechanical thrombectomy was significantly lower in countries with lower health expenditures.

Neurological manifestations are not uncommon during infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A clear association has been reported between cerebrovascular disease and coronavirus disease 2019 (COVID-19). However, whether this association is causal or incidental is still unknown. In this narrative review, we sought to present the possible pathophysiological mechanisms linking COVID-19 and cerebrovascular disease, describe the stroke syndromes and their prognosis and discuss several clinical, radiological, and laboratory characteristics that may aid in the prompt recognition of cerebrovascular disease during COVID-19. A systematic literature search was conducted, and relevant information was abstracted. Angiotensin-converting enzyme-2 receptor dysregulation, uncontrollable immune reaction and inflammation, coagulopathy, COVID-19-associated cardiac injury with subsequent cardio-embolism, complications due to critical illness and prolonged hospitalization can all contribute as potential etiopathogenic mechanisms leading to diverse cerebrovascular clinical manifestations. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been described in case reports and cohorts of COVID-19 patients with a prevalence ranging between 0.5% and 5%. SARS-CoV-2-positive stroke patients have higher mortality rates, worse functional outcomes at discharge and longer duration of hospitalization as compared with SARS-CoV-2-negative stroke patients in different cohort studies. Specific demographic, clinical, laboratory and radiological characteristics may be used as ‘red flags’ to alarm clinicians in recognizing COVID-19-related stroke.

Background: Several studies suggest women may be disproportionately affected by poorer stroke outcomes than men. This study aims to investigate whether women have a higher risk of all-cause mortality and recurrence after an ischemic stroke than men in a rural population in central Pennsylvania, United States. Methods: We analyzed consecutive ischemic stroke patients captured in the Geisinger NeuroScience Ischemic Stroke 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 8900 adult ischemic stroke patients [median age of 71.6 (interquartile range: 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 with a 65.7% survival in men ( p = 0.003) at 5 years; however, the survival difference was not present after controlling for covariates, including 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.

BACKGROUND AND PURPOSE The ongoing Coronavirus Disease 2019 (COVID‐19) pandemic is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). COVID‐19 is occasionally associated with manifold diseases of the central nervous system (CNS). We sought to present the neuroimaging features of such CNS involvement. In addition, we sought to identify typical neuroimaging patterns that could indicate possible COVID‐19‐associated neurological manifestations. METHODS In this systematic literature review, typical neuroimaging features of cerebrovascular diseases and inflammatory processes associated with COVID‐19 were analyzed. Reports presenting individual patient data were included in further quantitative analysis with descriptive statistics. RESULTS We identified 115 studies reporting a total of 954 COVID‐19 patients with associated neurological manifestations and neuroimaging alterations. A total of 95 (82.6%) of the identified studies were single case reports or case series, whereas 660 (69.2%) of the reported cases included individual information and were thus included in descriptive statistical analysis. Ischemia with neuroimaging patterns of large vessel occlusion event was revealed in 59.9% of ischemic stroke patients, whereas 69.2% of patients with intracerebral hemorrhage exhibited bleeding in a location that was not associated with hypertension. Callosal and/or juxtacortical location was identified in 58.7% of cerebral microbleed positive images. Features of hemorrhagic necrotizing encephalitis were detected in 28.8% of patients with meningo‐/encephalitis. CONCLUSIONS Manifold CNS involvement is increasingly reported in COVID‐19 patients. Typical and atypical neuroimaging features have been observed in some disease entities, so that familiarity with these imaging patterns appears reasonable and may assist clinicians in the differential diagnosis of COVID‐19 CNS manifestations.