Background:Spontaneous, non-traumatic intracranial hemorrhage (ICH) is highly heritable disease. However, the identification of the genetic risk factors driving this high genetic predisposition has been limited by small sample sizes and underrepresentation of non-European populations. The ERICH-GENE study will gather and harmonize clinical, neuroimaging and genomic data on the largest and more diverse collection of ICH cases assembled to date. Methods:ERICH-GENE is an NIH-funded, multi-center, international, genetic and neuroimaging study that aims to achieve the necessary sample size and diversity required to accurately describe the genetic architecture and trans-ethnic variation of ICH. ERICH-GENE will collect and harmonize clinical, neuroimaging and genomic data at least 10,000 multi-ethnic ICH cases. These data will be aggregated with 20,000 existing ICH cases and 600,000 ICH-free controls available through completed studies by the International Stroke Genetics Consortium. To ensure validity, data will undergo extensive harmonization, including expert review of neuroimages to ensure spontaneous etiology and hemorrhage location. We will conduct genome-wide association studies of risk, severity and outcome of ICH, testing for effect modification by race/ethnicity, sex and hemorrhage location. We will also conduct pathway, polygenic risk score and Mendelian randomization analyses. Results:This study will include whole genome sequencing data from 10,850 spontaneous ICH samples, including clinical and radiographic phenotypic data to ensure reliability of true non-traumatic, non-lesional ICH and lobar vs nonlobar location. Of these, 1,497 have already been genotyped using genome-wide arrays, 3,753 have undergone whole genome sequencing, and 5,600 will undergo genome-wide genotyping through ERICH-GENE. There are currently 42 contributing sites exceeding study milestone enrollments. 16,175 radiographic studies from 4,974 patients have been uploaded for harmonization to date, including 26% lobar and 64% nonlobar hemorrhages. Neuroimaging assessment will also include grading for white matter hyperintensities, cerebral atrophy, and presence and severity of IVH. Nearly 6,000 ICH cases will complete genotyping by August 2025. Data/material transfer agreements for summary statistics as well as additional samples are on target to meet the study's objectives. Conclusion:ERICH-GENE is the largest trans-ethnic genetic study of ICH conducted to date. Combining a diverse patient population with expert adjudication of neuroimaging data, ERICH-GENE will identify genetic risk loci that drive the high heritability observed for this disease and make a significant contribution to the understanding of the trans-ethnic variation of its genetic architecture.

Objective:Although stroke incidence is decreasing in older ages, it is increasing in young adults. While these divergent trends in stroke incidence are at least partially attributable to diverging prevalence trends in stoke risk factors, age-dependent differences in the impact of stroke risk factors on stroke may also contribute. To address this issue, we utilized Mendelian Randomization (MR) to assess differences in the association of stroke risk factors between early onset ischemic stroke (EOS) and late onset ischemic stroke (LOS). Methods:We employed a two-sample MR design with inverse variance weighting as the primary method of analysis. Using large publicly available genome-wide association summary results, we calculated MR estimates for conventional stroke risk factors (body mass index, total, HDL-and LDL-cholesterol, triglycerides, type 2 diabetes, systolic and diastolic blood pressure, and smoking) in EOS cases (onset 18-59 years, n = 6,728) and controls from the Early Onset Stroke Consortium and in LOS cases (onset ≥ 60 years, n = 9,272) and controls from the Stroke Genetics Network. We then compared odds ratios between EOS and LOS, stratified by TOAST subtypes, to determine if any differences observed between effect sizes could be attributed to differences in the distribution of stroke subtypes. Results:EOS was significantly associated with all risk factors except for total cholesterol levels, and LOS was associated with all risk factors except for triglyceride and total cholesterol levels. The associations of BMI, DBP, SBP, and HDL-cholesterol were significantly stronger in EOS than LOS (all p < 0.004). The differential distribution of stroke subtypes could not explain the difference in effect size observed between EOS and LOS. Conclusion:These results suggest that interventions targeted at lowering body mass index and blood pressure may be particularly important for reducing stroke risk in young adults.

Background: The folate one-carbon metabolism pathway (FOCM) provides vital one-carbon units for epigenetic regulation. Genetic variants in FOCM genes may affect methionine metabolism. Elevated circulating homocysteine (Hcy), a FOCM byproduct, is linked to increased stroke risk. However, the protective effects of dietary regulation of methionine and Hcy levels against recurrent stroke are uncertain. Objective: To investigate dietary methionine (METH) and its interaction with post-methionine load Hcy levels (POST) with recurrent stroke risk; to assess if genetically determined POST and its interaction with METH predict recurrent stroke risk. Methods: We utilized the Vitamin Intervention for Stroke Prevention (VISP) trial to estimate hazards ratios of METH and its interaction with POST on recurrent stroke with a Cox proportional hazards model. We also generated a POST polygenic risk score (PRS) with ridge regression using previously identified polymorphisms, located within ALDH1L1, CPS1, GNMT, and PSPH, as indicators of FOCM function. Results: The participants (n = 2,100; 64% men) had a mean (SD) age of 67 (11) years. Ancestry consisted of 82% European, 12% African, and 5.7% Other. A small portion of participants had missing POST values (7.3%). Clinical POST (HR 1.02; 95%CI 0.98, 1.06) and its interaction with METH (HR 0.99; 95% CI 0.97, 1.01) were not associated with recurrent stroke risk. Similarly, there was no significant relationship observed between PRS POST (HR 0.96; 95%CI 0.80, 1.15) and its interaction with METH (HR 1.02; 95% CI 0.94, 1.10). Conclusion: Dietary methionine and post-methionine load Hcy levels neither interact nor predict recurrent stroke risk. Our PRS approach showed similar negative findings. The relationship of the FOCM and recurrent stroke risk may lie in epigenetics.

Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic, progressive microangiopathy caused by mutations in the NOTCH3 gene. Patients often present with migraine and progressive subcortical infarcts resulting in vascular cognitive impairment and death. Currently, there are no disease modifying treatments. Limiting future trials is the lack of an objective construct to classify and monitor severity of disease. The purpose of this study was to gain experience with a novel CADASIL severity grading system. Methods: Neurologists at 5 academic centers retrospectively reviewed charts of those with confirmed CADASIL. Demographic and clinical data were recorded. The CADASIL severity grades were then assigned: 0 (asymptomatic), 1 (migraine alone), 2 (stroke or mild cognitive impairment), 3 (gait impairment or early dementia) and 4 (bedbound) based on available data. Standard descriptive statistical analyses were used. Results: We identified 138 patients; overall mean age of 50.9±13.1 years, 42.8% were men. 15 (10.9%) were grade 0, 50 (36.2%) were grade 1, 41 (44.2%) were grade 2, 12 (8.7%) were grade 3, and none were grade 4. Those with less severe disease tended to be younger, more likely men, had a lower rate of hypertension and diabetes mellitus and were less frequently tobacco users, Table 1. Increasing number of vascular risk factors was associated with higher severity grading. Conclusion: Our study highlights the ability of this severity scale to separate those with CADASIL into an ordinal system. As known in the literature, more advanced phenotypes of CADASIL tend to have more vascular risk factors. Future trials may consider utilizing this ordinal construct to monitor disease progression, response to therapy, or as a screening tool.

Introduction: Social and environment factors are associated with increased stroke risk. It is unclear if favorable cardiovascular health may attenuate this risk. We evaluated the impact of neighborhood socioeconomic characteristics on stroke incidence, and if levels of cardiovascular health modify this relationship. Methods: We conducted a longitudinal cohort study of Black and White participants using data from the Reasons for Geographic and Racial Differences in Stroke. We included all stroke-free participants and geocoded their home addresses to the census-tract level. Our primary exposure was neighborhood socioeconomic condition index (nSES; in quartiles) constructed using data from the U.S. Census on income, education, and occupation of residents by census tract. We evaluated cardiovascular health based on the American Heart Association’s Life Simple 7 (ideal, adequate, inadequate). We used a Cox proportional hazards model to regress nSES and its interaction with Life Simple 7 on stroke incidence, adjusting for individual demographics, socioeconomic status, and clinical characteristics. Results: We included 26,941 adults with a mean follow-up of 11.6 years (SD ± 5.2). During the study, 1,596 (5.9%) participants had a first incidence of stroke. Participants within the lowest nSES quartile, compared to those in the highest, were more likely to be Black, have lower household income, and an inadequate Life Simple 7 score. In multivariable models, there was a non-significant increased incidence of stroke (HR-1.13; 95% CI: 0.95-1.35) between the lowest and highest nSES quartiles. The interaction between nSES and Life Simple 7 was also non-significant for stroke incidence with worse cardiovascular health across all quartiles. Discussion: Among a national cohort of Black and White adults, we found a non-significant difference in stroke incidence between adults who live in worse neighborhood socioeconomic conditions and have inadequate cardiovascular health. Characterizing the potential contribution of social, environmental, and health behaviors could inform clinical and public health strategies to mitigate stroke risk.

Lacunar infarcts and vascular dementia are important phenotypic characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, the most common inherited cerebral small vessel disease. Individuals with the disease show variability in the nature and onset of symptoms and rates of progression, which are only partially explained by differences in pathogenic mutations in the NOTCH3 gene. Recognizing the disease early in its course and securing a molecular diagnosis are important clinical goals, despite the lack of proven disease-modifying treatments. The purposes of this scientific statement are to review the clinical, genetic, and imaging aspects of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, contrasting it with other inherited small vessel diseases, and to provide key prevention, management, and therapeutic considerations with the intent of reducing practice variability and encouraging production of high-quality evidence to support future treatment recommendations.

Background There are several reports of the association between SARS-CoV-2infection (COVID-19) and cerebral venous sinus thrombosis (CVST). In this study, we aimed to compare the hospitalization rate of CVST before and during the COVID-19 pandemic (before vaccination program). Methods In this retrospective cohort study, the hospitalization rate of adult CVST patients in Namazi hospital, a tertiary referral center in the south of Iran, was compared in two periods of time. We defined March 2018 to March 2019 as the pre-COVID-19 period and March 2020 to March 2021 as the COVID-19 period. Results 50 and 77 adult CVST patients were hospitalized in the pre-COVID-19 and COVID-19 periods, respectively. The crude CVST hospitalization rate increased from 14.33 in the pre-COVID-19 period to 21.7 per million in the COVID-19 era (P=0.021). However, after age and sex adjustment, the incremental trend in hospitalization rate was not significant (95% CrI: -2.2, 5.14). Patients > 50-year-old were more often hospitalized in the COVID-19 period. (P=0.042) SARS-CoV-2 PCR test was done in 49.3% out of all COVID-19 period patients, which were positive in 6.5%. Modified Rankin Scale (mRS) score ≥3 at three-month follow-up was associated with age (P=0.015) and malignancy (P=0.014) in pre-COVID period; and was associated with age (P=0.025), altered mental status on admission time (P<0.001), malignancy (P=0.041) and COVID-19 infection (P=0.008) in COVID-19 period. Conclusion Since there was a more dismal outcome in COVID-19 associated CVST, a high index of suspicion for CVST among COVID-19 positive is recommended.

Introduction Intracerebral hemorrhage (ICH) is the most severe subtype of stroke. Its mortality rate is high, and most survivors experience significant disability. Objective To assess primary patient risk factors associated with mortality and neurologic disability 3 months after ICH in a large, racially and ethnically balanced cohort. Design, Setting, and Participants This cohort study included participants from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, which prospectively recruited 1000 non-Hispanic White, 1000 non-Hispanic Black, and 1000 Hispanic patients with spontaneous ICH to study the epidemiological characteristics and genomics associated with ICH. Participants included those with uniform data collection and phenotype definitions, centralized neuroimaging review, and telephone follow-up at 3 months. Analyses were completed in November 2021. Exposures Patient demographic and clinical characteristics as well as hospital event and imaging variables were examined, with characteristics meeting P < .20 considered candidates for a multivariate model. Elements included in the ICH score were specifically analyzed. Main Outcomes and Measures Individual characteristics were screened for association with 3-month outcome of neurologic disability or mortality, as assessed by a modified Rankin Scale (mRS) score of 4 or greater vs 3 or less under a logistic regression model. A total of 25 characteristics were tested in the final model, which minimized the Akaike information criterion. Analyses were repeated removing individuals who had withdrawal of care. Results A total of 2568 patients (mean [SD] age, 62.4 [14.7] years; 1069 [41.6%] women and 1499 [58.4%] men) had a 3-month outcome determination available, including death. The final logistic model had a significantly higher area under the receiver operating characteristics curve (C = 0.88) compared with ICH score alone (C = 0.76;P < .001). Among characteristics associated with neurologic disability and mortality were larger log ICH volume (OR, 2.74; 95% CI, 2.36-3.19;P < .001), older age (OR per 1-year increase, 1.04; 95% CI, 1.02-1.05;P < .001), pre-ICH mRS score (OR, 1.62; 95% CI, 1.41-1.87;P < .001), lobar location (OR, 0.22; 95% CI, 0.16-0.30;P < .001), and presence of infection (OR, 1.85; 95% CI, 1.42-2.41;P < .001). Conclusions and Relevance The findings of this cohort study validate ICH score elements and suggest additional baseline and interim patient characteristics were associated with variation in 3-month outcome.

Objective To examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways. Methods MR neuroimaging and National Institutes of Health Stroke Scale data at index stroke, as well as modified Rankin Scale (mRS) at 3-6 months post-stroke were obtained from MRI-GENIE study of acute ischemic stroke (AIS) patients. Individual WMH volume was automatically derived from FLAIR-images. Stroke lesions were automatically segmented from DWI-images, spatially normalized and parcellated into atlas-defined brain regions. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS>2) were modeled within a purpose-built machine learning and Bayesian regression framework. In particular, interaction effects between stroke lesions and a high versus low WMH burden were integrated via hierarchical model structures. Models were adjusted for the covariates age, age 2 , sex, total DWI-lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts. Results A total of 928 AIS patients contributed to stroke severity analyses (mean age: 64.8(14.5), 40% women), 698 patients to functional outcome analyses (mean age: 65.9(14.7), 41% women). Individual stroke lesions were represented in five anatomically distinct left-hemispheric and five right-hemispheric lesion patterns. Across all patients, acute stroke severity was substantially explained by three of these patterns, that were particularly focused on bilateral subcortical and left-hemispherically pronounced cortical regions. In high WMH burden patients, two lesion patterns consistently emerged as more pronounced in case of stroke severity: the first pattern was centered on left-hemispheric insular, opercular and inferior frontal regions, while the second pattern combined right-hemispheric temporo-parietal regions. Bilateral subcortical regions were most relevant in explaining long term unfavorable outcome. No WMH-specific lesion patterns of functional outcomes were substantiated. However, a higher overall WMH burden was associated with higher odds of unfavorable outcomes. Conclusions Higher WMH burden increases stroke severity in case of stroke lesions involving left-hemispheric insular, opercular and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporo-parietal regions (potentially linked to attention). These findings may contribute to augment stroke outcome predictions and motivate a WMH burden and stroke lesion pattern-specific clinical management of AIS patients.

A 73-year-old woman presented with acute impaired eye movements with preserved left eye abduction, right peripheral facial weakness (video 1), and left hemiparesis/hemihypesthesia. These deficits localized to the right pontine tegmentum involving the medial longitudinal fasciculus, facial nerve, abducens nucleus, medial lemniscus, and corticospinal tracts, as shown in figure 1. After tissue plasminogen activator, her left hemiparesis and hemihypesthesia resolved. Rosini et al.1 first described these deficits as 9 syndrome (7th nerve + 1.5 syndrome + 0.5 hemiparesis/hypesthesia = 9). Classically, 1-and-a-half syndrome consists of intranuclear ophthalmoplegia and conjugate horizontal gaze palsy; preserved abduction will be present in the contralateral eye. Our patient's right eye adduction was paretic and not plegic. Our patient was left with an “8-and-a-half syndrome” (figure 2). Infarct, hemorrhage, vasculitis, and demyelination are etiologies of 8-and-a-half syndromes reported in the literature.

Sunday, April 26April 14, 2020Free AccessDeveloping a Local Teleneurology Programme With Global Implications in Africa (5533)N. Abimbola Sunmonu, Rufus Akinyemi, Bradford Worrall, Mayowa Owolabi, and Nina SolenskiAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.5533 Letters to the Editor

Thursday, April 30April 14, 2020Free AccessPatterns of Domain-Specific Recovery Over 90 days from Acute Ischemic Stroke Onset (4648)Laura Heitsch, Robynne Braun, Adam DeHavenon, John Cole, Arne Lindgren, Steven Cramer, and Bradford WorrallAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.4648 Letters to the Editor