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ObjectiveStudies indicate that the functional outcome evolves in the year after ischemic stroke onset. However, the traditional outcome measure in stroke trials is the modified Rankin Scale (mRS) at 90 days from onset. To determine mRS fluctuations in the first year after stroke, we examined data from 3 major stroke trials.MethodsIn a secondary analysis, we evaluated intrapatient mRS between 90 days and 1 year from stroke onset, the mRS shift (∆mRS = 1 year-day 90), and the trials' primary outcome at day 90 and 1 yearResultsWe included 624 patients from the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study, 587 from Albumin Treatment for Acute Ischaemic Stroke, and 611 from Interventional Management of Stroke III, for which the proportion of patients with a ∆mRS change between day 90 and 1 year was 36.5%, 41.7%, and 36.0%. However, the trials' primary outcomes did not differ at 1 year vs 90 days. Similar findings were seen in a second cohort where we pooled the trials and excluded patients with recurrent stroke or death during the follow-up. In those 1,314 patients, 544 (41.4%) had a ∆mRS change, of which 379 (28.9%) had improvement and 165 (12.5%) had worsening, apart from death.ConclusionWe describe the patient-level spectrum of mRS change from day 90 to 1 year after ischemic stroke in 3 high-quality randomized trials. The patient-level shifts consisted of a sufficiently counterbalanced number of mRS improvements and declines, which masked clinical evolution occurring in over one-third of patients. These results may have important implications, both for clinical trial design and outcome adjudication in stroke research and duration of rehabilitative therapy.

Statins, a common drug class for treatment of dyslipidemia, may be neuroprotective for spontaneous intracerebral hemorrhage (ICH) by targeting secondary brain injury pathways in the surrounding brain parenchyma. Statin-mediated neuroprotection may stem from downregulation of mevalonate and its derivatives, targeting key cell signaling pathways that control proliferation, adhesion, migration, cytokine production, and reactive oxygen species generation. Preclinical studies have consistently demonstrated the neuroprotective and recovery enhancement effects of statins, including improved neurologic function, reduced cerebral edema, increased angiogenesis and neurogenesis, accelerated hematoma clearance, and decreased inflammatory cell infiltration. Retrospective clinical studies have reported reduced perihematomal edema, lower mortality rates, and improved functional outcomes in patients who were taking statins before ICH. Several clinical studies have also observed lower mortality rates and improved functional outcomes in patients who were continued or initiated on statins after ICH. Subgroup analysis of a previous randomized trial has raised concerns of a potentially elevated risk of recurrent ICH in patients with previous hemorrhagic stroke who are administered statins. However, most statin trials failed to show an association between statin use and increased hemorrhagic stroke risk. Variable statin dosing, statin use in the pre-ICH setting, and selection biases have limited rigorous investigation of the effects of statins on post-ICH outcomes. Future prospective trials are needed to investigate the association between statin use and outcomes in ICH.

Rationale: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. Objective: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. Methods and Results: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P =1.70×10 −9 ). Conclusions: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

Background and ObjectivesTo test the hypothesis that a predisposition to acquired genetic alterations is associated with ischemic stroke outcome by investigating the association between a polygenic risk score (PRS) for mosaic loss of chromosome Y (mLOY) and outcome in a large international data set.MethodsWe used data from the genome-wide association study performed within the Genetics of Ischemic Stroke Functional Outcome network, which included 6,165 patients (3,497 men and 2,668 women) with acute ischemic stroke of mainly European ancestry. We assessed a weighted PRS for mLOY and examined possible associations with the modified Rankin Scale (mRS) score 3 months poststroke in logistic regression models. We investigated the whole study sample as well as men and women separately.ResultsIncreasing PRS for mLOY was associated with poor functional outcome (mRS score >2) with an odds ratio (OR) of 1.11 (95% confidence interval [CI] 1.03–1.19) per 1 SD increase in the PRS after adjustment for age, sex, ancestry, stroke severity (NIH Stroke Scale), smoking, and diabetes mellitus. In sex-stratified analyses, we found a statistically significant association in women (adjusted OR 1.20, 95% CI 1.08–1.33). In men, the association was in the same direction (adjusted OR 1.04, 95% CI 0.95–1.14), and we observed no significant genotype-sex interaction.DiscussionIn this exploratory study, we found associations between genetic variants predisposing to mLOY and stroke outcome. The significant association in women suggests underlying mechanisms related to genomic instability that operate in both sexes. These findings need replication and mechanistic exploration.

Background: Motor impairment after ischemic stroke is common and has variable recovery that depends on patient factors and stroke severity. An important challenge in rehabilitation research is enrolling patients who may benefit from interventions to improve recovery because they will not recover with standard care. Hypothesis: We can accurately predict persistent upper extremity motor impairment at 90 days after acute ischemic stroke. Methods: The primary outcome was an NIHSS arm domain score of 2-4 at 90 days in patients with a 24-hour NIHSS arm score of 1-4, which we termed persistent arm impairment. With the NINDS tPA trial dataset we used LASSO regression to select baseline demographics and 24-hour NIHSS score domains for a predictive model. We gave one point each for age ≥60 years and 24-hour NIHSS values of worst arm=4, worst leg>2, facial palsy=3, and total NIHSS≥10. The optimal cutpoint for a positive Persistent UPPer extremity Impairment (PUPPI) Score was ≥3 points. We validated the PUPPI score in the ALIAS Part 2, IMS-III, and DEFUSE 3 trials. Results: We included 431, 383, 331, and 71 patients from the NINDS tPA, ALIAS Part 2, IMS-III, and DEFUSE 3 trials. PUPPI was most common in the NINDS tPA trial (62%) and least common in ALIAS (31.3%). The PUPPI Score accurately predicted PUPPI with an area under the receiver operating curve (AUC) of >0.75 for all trials (Table 1). The positive predictive value was 74.6%, 90.9%, 86.1%, and 74.5% in the NINDS tPA, ALIAS Part 2, IMS-III, and DEFUSE 3 trials (Table 1). Conclusion: The PUPPI score uses readily available information to provide accurate prediction of patients who will have persistent upper extremity motor impairment at 90 days from stroke onset.

Objective: To investigate potential genetic susceptibility for moyamoya disease (MMD) in an African American family. Methods: A young girl with MMD (proband), her father and paternal half-brother underwent cerebrovascular imaging with MRI and MRA. Cerebral angiography was also performed on the girl and her father. Genetic analysis of the MMD susceptibility gene RNF213 was conducted on all three relatives, while ACTA2 gene was analysed in the proband only. Results: The proband presented with pseudobulbar affect and chorea, then subsequently had a right hemispheric ischaemic stroke and rapid, ultimately fatal clinical decline. Detailed family history raised suspicion for familial MMD and investigation of her relatives. Her father had a small haemorrhagic thalamic stroke without residual neurologic deficits; a clinically silent ischaemic infarct was incidentally discovered on neuroimaging. He remains clinically stable despite slowly progressive disease on imaging. Her brother is neurologically intact and has normal cerebrovascular imaging to date. They are all heterozygous for the rare Arg4131Cys variant in RNF213. They are the first Black people and only the 3rd, 4th and 5th people in the world known to harbour this variant. MMD was confirmed in the girl and her father with cerebral angiogram. Conclusions: This study illuminates the clinical and genetic complexity of familial MMD. It underscores the importance of genetic testing and surveillance cerebrovascular imaging even in asymptomatic relatives of probands with MMD. Although the clinical significance of Arg4131Cys remains unclear, modest variant-disease segregation in this family is consistent with a growing body of evidence supporting its probable pathogenicity. Furthermore, our study illustrates its wide phenotypic spectrum, from asymptomatic carrier to late presenting, mild disease to fulminant, rapidly fatal childhood disease. To our knowledge, this is also the first report of heritable MMD in a Black family. We demonstrate the value of considering diseases more predominant in one specific ancestry when evaluating patients from other ethnic backgrounds. Finally, we highlight the importance of racially and ethnically diverse participants in biomedical research.

Background: The burden of post-stroke disability falls on both stroke survivors and their caregivers. To better understand patient and caregiver perspectives on post-stroke quality of life (QoL), we explored their agreement on a QoL testing instrument in the year after an ischemic stroke. Methods: This is a secondary analysis of the IMS-III trial. The primary outcome are scores of the 5 domains of the EQ-5D-3L during the year after stroke onset. We included pairs of EQ-5D-3L scores obtained from both the patient and their proxy to determine the level of agreement and Cohen’s Kappa for the individual domains. Results: There were 1,042 instances of a paired EQ-5D-3L during the first year of follow-up, derived from six study visits described in Table 1. The agreement between patient and proxy was highest for the Mobility and Self-Care domains of the EQ-5D-3L (Table 2), achieving a Kappa of 0.7407 and 0.7567, respectively. The agreement for the Anxiety/Depression domain of the EQ-5D-3L was lowest, with a Kappa of 0.6009 (Table 2). Conclusion: In the year after ischemic stroke, the agreement between patients and their caregivers was highest for the motor domains of QoL and lowest for the mental health domain. Depression and anxiety are known to be under-diagnosed and under-treated after stroke. Further research is warranted to explore the reasons for less agreement between patient and caregiver perception of the stroke survivor’s mental health QoL after ischemic stroke.

Dissections and aneurysms are two of the more common nonatherosclerotic arteriopathies of the cerebrovascular system and a significant contributor to neurovascular complications, particularly in the young. Specifically, ruptured intracranial aneurysms (IA) account for nearly 500,000 cases of subarachnoid hemorrhage annually with a 30-day mortality approaching 40% and survivors suffering often permanent neurologic deficits and disability. Unruptured IAs require dedicated assessment of risk and often warrant serial radiologic monitoring. Cervical artery dissection, affecting the carotid and vertebral arteries, accounts for nearly 20% of strokes in young and middle-aged adults. While approximately 70% of cervical artery dissection (CeAD) cases present with stroke or TIA, additional neurologic complications include severe headache and neck pain, oculosympathetic defect (i.e., partial Horner's syndrome), acute vestibular syndrome, and rarely lower cranial nerve palsies. Both aneurysms and dissections of the cerebrovascular system may occur frequently in patients with syndromic connective tissue disorders; however, the majority of cases are spontaneously occurring or mildly heritable with both polygenic and environmental associations. Fibromuscular dysplasia, in particular, is commonly associated with both risk of CeAD and IA formation. Further research is needed to better understand the pathophysiology of both IA and CeAD to better understand risk, improve treatments, and prevent devastating neurologic complications.

IntroductionNeuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of describing the texture of conventional images beyond what meets the naked eye, radiomic analyses hold potential for evaluating brain health. We sought to: 1) evaluate this novel approach to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and 2) uncover associations between predictive radiomic features and patients’ clinical phenotypes.MethodsOur analyses were based on a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images and corresponding deep-learning-generated total brain and WMH segmentation. Radiomic features were extracted from normal-appearing brain tissue (brain mask–WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with the most stable selected features predictive of WMH burden and then related this signature to clinical variables (age, sex, hypertension (HTN), atrial fibrillation (AF), diabetes mellitus (DM), coronary artery disease (CAD), and history of smoking) using canonical correlation analysis.ResultsRadiomic features were highly predictive of WMH burden (R2=0.855±0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected p-valuesCV1-6CV7=.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and DM, CV4 by HTN, CV5 by AF and DM, CV6 by CAD, and CV7 by CAD and DM.ConclusionRadiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes. Further research could evaluate radiomics to predict the progression of WMH.Research in contextEvidence before this studyWe did a systematic review on PubMed until December 1, 2020, for original articles and reviews in which radiomics were used to characterize stroke or cerebrovascular diseases. Radiomic analyses cover a broad ensemble of high-throughput quantification methods applicable to digitalized medical images that extract high-dimensional data by describing a given region of interest by its size, shape, histogram, and relationship between voxels. We used the search terms “radiomics” or “texture analysis”, and “stroke”, “cerebrovascular disease”, “small vessel disease”, or “white matter hyperintensities”. Our research identified 24 studies, 18 studying radiomics of stroke lesions and 6 studying cerebrovascular diseases. All the latter six studies were based on MRI (T1-FLAIR, dynamic contrast-enhanced imaging, T1 & T2-FLAIR, T2-FLAIR post-contrast, T2-FLAIR, and T2-TSE images). Four studies were describing small vessel disease, and two were predicting longitudinal progression of WMH. The average sample size was small with 96 patients included (maximum: 204). One study on 141 patients identified 7 T1-FLAIR radiomic features correlated with cardiovascular risk factors (age and hyperlipidemia) using univariate correlations. All studies were monocentric and performed on a single MRI scanner.Added value of this studyTo date and to the best of our knowledge, this is the largest radiomics study performed on cerebrovascular disease or any topic, and one of the very few to include a great diversity of participating sites with diverse clinical MRI scanners. This study is the first one to establish a radiomic signature of WMH and to interpret its relationship with common cardiovascular risk factors. Our findings add to the body of evidence that damage caused by small vessel disease extend beyond the visible white matter hyperintensities, but the added value resides in the detection of that subvisible damage on routinely acquired T2-FLAIR imaging. It also suggests that cardiovascular phenotypes might manifest in distinct textural patterns detectable on conventional clinical-grade T2-FLAIR images.Implications of all the available evidenceAssessing brain structural integrity has implications for treatment selection, follow-up, prognosis, and recovery prediction in stroke patients but also other neurological disease populations. Measuring cerebral parenchymal structural integrity usually requires advanced imaging such as diffusion tensor imaging or functional MRI. Translation of those neuroimaging biomarkers remains uncommon in clinical practice mainly because of their time-consuming and costly acquisition. Our study provides a potential novel solution to assess brains’ structural integrity applicable to standard, routinely acquired T2-FLAIR imaging.Future research could, for instance, benchmark this radiomics approach against diffusion or functional MRI metrics in the prediction of cognitive or functional outcomes after stroke.

Background Recent randomised trials showed benefit for anti-inflammatory therapies in coronary disease but excluded stroke. The prognostic value of blood inflammatory markers after stroke is uncertain and guidelines do not recommend their routine measurement for risk stratification. Methods We performed a systematic review and meta-analysis of studies investigating the association of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen and risk of recurrent stroke or major vascular events (MVEs). We searched EMBASE and Ovid Medline until 10/1/19. Random-effects meta-analysis was performed for studies reporting comparable effect measures. Results Of 2,515 reports identified, 39 met eligibility criteria (IL-6, n = 10; CRP, n = 33; fibrinogen, n = 16). An association with recurrent stroke was reported in 12/26 studies (CRP), 2/11 (fibrinogen) and 3/6 (IL-6). On random-effects meta-analysis of comparable studies, CRP was associated with an increased risk of recurrent stroke [pooled hazard ratio (HR) per 1 standard-deviation (SD) increase in loge-CRP (1.14, 95% CI 1.06–1.22, p Conclusion Despite evidence suggesting an association between inflammatory markers and post-stroke vascular recurrence, substantial methodological heterogeneity was apparent between studies. Individual-patient pooled analysis and standardisation of methods are needed to determine the prognostic role of blood inflammatory markers and to improve patient selection for randomised trials of inflammatory therapies.

Dissections and aneurysms are two of the more common nonatherosclerotic arteriopathies of the cerebrovascular system and a significant contributor to neurovascular complications, particularly in the young. Specifically, ruptured intracranial aneurysms (IA) account for nearly 500,000 cases of subarachnoid hemorrhage annually with a 30-day mortality approaching 40% and survivors suffering often permanent neurologic deficits and disability. Unruptured IAs require dedicated assessment of risk and often warrant serial radiologic monitoring. Cervical artery dissection, affecting the carotid and vertebral arteries, accounts for nearly 20% of strokes in young and middle-aged adults. While approximately 70% of cervical artery dissection (CeAD) cases present with stroke or TIA, additional neurologic complications include severe headache and neck pain, oculosympathetic defect (i.e., partial Horner's syndrome), acute vestibular syndrome, and rarely lower cranial nerve palsies. Both aneurysms and dissections of the cerebrovascular system may occur frequently in patients with syndromic connective tissue disorders; however, the majority of cases are spontaneously occurring or mildly heritable with both polygenic and environmental associations. Fibromuscular dysplasia, in particular, is commonly associated with both risk of CeAD and IA formation. Further research is needed to better understand the pathophysiology of both IA and CeAD to better understand risk, improve treatments, and prevent devastating neurologic complications.

Patients who survive the initial ictus of spontaneous intracerebral hemorrhage (ICH) remain vulnerable to subsequent injury of the perilesional parenchyma by molecular and cellular responses to the hematoma. Secondary brain injury after ICH, which contributes to long-term functional impairment and mortality, has emerged as an attractive therapeutic target. This review summarizes preclinical and clinical evidence for neuroprotective therapies targeting secondary injury pathways following ICH. A focus on therapies with pleiotropic antiinflammatory effects that target thrombin-mediated chemotaxis and inflammatory cell migration has led to studies investigating statins, anticholinergics, sphingosine-1-phosphate receptor modulators, peroxisome proliferator activated receptor gamma agonists, and magnesium. Attempts to modulate ICH-induced blood-brain barrier breakdown and perihematomal edema formation has prompted studies of nonsteroidal antiinflammatory agents, matrix metalloproteinase inhibitors, and complement inhibitors. Iron chelators, such as deferoxamine and albumin, have been used to reduce the free radical injury that ensues from erythrocyte lysis. Stem cell transplantation has been assessed for its potential to enhance subacute neurogenesis and functional recovery. Despite promising preclinical results of numerous agents, their outcomes have not yet translated into positive clinical trials in patients with ICH. Further studies are necessary to improve our understanding of the molecular events that promote damage and inflammation of the perihematomal parenchyma after ICH. Elucidating the temporal and pathophysiologic features of this secondary brain injury could enhance the clinical efficacy of neuroprotective therapies for ICH.

Objective To test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH. Methods We performed sequencing across 559 Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in United States–based and 1,381 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling. Results We identified 107 rare nonsynonymous variants in sporadic ICH, of which 2 missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the United States–based cohort. The minor allele of rs201716258 was also present in Scottish patients with ICH, and rs138269346 was observed in 2 ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with nonlobar ICH risk (p = 0.05), but not with lobar ICH (p = 0.08), while associations between rs201716258 and ICH subtypes were nonsignificant (p > 0.12). Both variants were considered pathogenic based on minor allele frequency (

African Americans endure a nearly two-fold greater risk of suffering a stroke and are 2–3 times more likely to die from stroke compared to those of European ancestry. African Americans also have a greater risk of recurrent stroke and vascular events, which are deadlier and more disabling than incident stroke. Stroke is a multifactorial disease with both heritable and environmental risk factors. We conducted an integrative, multi-omic study on 922 plasma metabolites, 473,864 DNA methylation loci, and 556 variants from 50 African American participants of the Vitamin Intervention for Stroke Prevention clinical trial to help elucidate biomarkers contributing to recurrent stroke rates in this high risk population. Sixteen metabolites, including cotinine, N-delta-acetylornithine, and sphingomyelin (d17:1/24:1) were identified in t-tests of recurrent stroke outcome or baseline smoking status. Serum tricosanoyl sphingomyelin (d18:1/23:0) levels were significantly associated with recurrent stroke after adjusting for covariates in Cox Proportional Hazards models. Weighted Gene Co-expression Network Analysis identified moderate correlations between sphingolipid markers and clinical traits including days to recurrent stroke. Integrative analyses between genetic variants in sphingolipid pathway genes identified 29 nominal associations with metabolite levels in a one-way analysis of variance, while epigenomic analyses identified xenobiotics, predominately smoking-associated metabolites and pharmaceutical drugs, associated with methylation profiles. Taken together, our results suggest that metabolites, specifically those associated with sphingolipid metabolism, are potential plasma biomarkers for stroke recurrence in African Americans. Furthermore, genetic variation and DNA methylation may play a role in the regulation of these metabolites.

BackgroundEndogenous apoliloprotein E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apolipoprotein E-mimetic peptides can effectively penetrate the brain and down-regulate acute inflammation. CN-105 is a novel apolipoprotein E-mimetic pentapeptide with excellent preclinical evidence as an acute intracerebral hemorrhage (ICH) therapeutic. TheCN-105 in participants withAcute supraTentorial intraCerebralHemorrhage (CATCH) trial is a first-in-disease-state, multi-center, open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH.MethodsEligible patients were age 30-80 years, had confirmed primary supratentorial ICH, and able to intiate CN-105 administration (1.0 mg/kg every 6 hours for 72 hours) within 12 hours of symptom onset.A prioridefined safety endpoints, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes were analyzed. For comparisons, CATCH participants were matched 1:1 with a contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on Days 0, 1, 2, and 5 and ordinal modified Rankin Score at 30 days after ICH were compared.ResultsIn 39 participants enrolled across six study sites in the United States, adverse events occurred at expected rate without increase in hematoma expansion or neurological deterioration or significant serum accumulation. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31–5.51) for lower 30-day mRS, after adjustment for ICH Score, sex, and race/ethnicity, compared to matched contemporary cohort.ConclusionCN-105 administration represents an excellent translational candidate as an actue ICH therapeutic due to its safety, dosing feasibility, favorable pharmacokinetics, and evidence of improved neurological recovery.

Endogenous apolipoprotein (apo) E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apoE-mimetic peptides effectively penetrate the central nervous system compartment and downregulate acute inflammation. CN-105 is a novel apoE-mimetic pentapeptide with excellent evidence of functional and histological improvement in preclinical models of intracerebral hemorrhage (ICH). The CN-105 in participants with Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial is a first-in-disease-state multicenter open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH.Eligible patients were aged 30-80 years, had confirmed primary supratentorial ICH, and were able to intiate CN-105 administration (1.0 mg/kg every 6 h for 72 h) within 12 h of symptom onset. A priori defined safety end points, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes, were analyzed. For clinical outcomes, CATCH participants were compared 1:1 with a closely matched contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on days 0, 1, 2, and 5 and ordinal modified Rankin Scale score at 30 days after ICH were compared.In 38 participants enrolled across six study sites in the United States, adverse events occurred at an expected rate without increase in hematoma expansion or neurological deterioration. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31-5.51) for lower 30-day modified Rankin Scale score, after adjustment for ICH score, sex, and race/ethnicity, as compared with a matched contemporary cohort.CN-105 administration represents an excellent translational candidate for treatment of acute ICH because of its safety, dosing feasibility, favorable pharmacokinetics, and possible improvement in neurological recovery.

Acute ischemic stroke affects men and women differently in many ways. In particular, women are oftentimes reported to experience a higher acute stroke severity than men. Here, we derived a low-dimensional representation of anatomical stroke lesions and designed a sex-aware Bayesian hierarchical modelling framework for a large-scale, well phenotyped stroke cohort. This framework was tailored to carefully estimate possible sex differences in lesion patterns explaining acute stroke severity (NIHSS) in 1,058 patients (39% female). Anatomical regions known to subserve motor and language functions emerged as relevant regions for both men and women. Female patients, however, presented a more widespread pattern of stroke severity-relevant lesions than male patients. Furthermore, particularly lesions in the posterior circulation of the left hemisphere underlay a higher stroke severity exclusively in women. These sex-sensitive lesion pattern effects could be discovered and subsequently robustly replicated in two large independent, multisite lesion datasets. The constellation of findings has several important conceptual and clinical implications: 1) suggesting sex-specific functional cerebral asymmetries, and 2) motivating a sex-stratified approach to management of acute ischemic stroke. To go beyond sex-averaged stroke research, future studies should explicitly test whether acute therapies administered on the basis of sex-specific cutoff volumes of salvageable tissue will lead to improved outcomes in women after acute ischemic stroke.

Background and Purpose: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. Methods: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. Results: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance ( P =4.62×10 −8 ) and an additional 29 variants with suggestive evidence of association ( P −6 ), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10 −3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN ( P =8.18×10 −4 ) and METASTROKE ( P =1.72×10 −3 ) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. Conclusions: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.

Background and Purpose: For survivors of oral anticoagulation therapy (OAT)–associated intracerebral hemorrhage (OAT-ICH) who are at high risk for thromboembolism, the benefits of OAT resumption must be weighed against increased risk of recurrent hemorrhagic stroke. The ε2/ε4 alleles of the apolipoprotein E ( APOE ) gene, MRI-defined cortical superficial siderosis, and cerebral microbleeds are the most potent risk factors for recurrent ICH. We sought to determine whether combining MRI markers and APOE genotype could have clinical impact by identifying ICH survivors in whom the risks of OAT resumption are highest. Methods: Joint analysis of data from 2 longitudinal cohort studies of OAT-ICH survivors: (1) MGH-ICH study (Massachusetts General Hospital ICH) and (2) longitudinal component of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage). We evaluated whether MRI markers and APOE genotype predict ICH recurrence. We then developed and validated a combined APOE -MRI classification scheme to predict ICH recurrence, using Classification and Regression Tree analysis. Results: Cortical superficial siderosis, cerebral microbleed, and APOE ε2/ε4 variants were independently associated with ICH recurrence after OAT-ICH (all P APOE genotype and MRI data resulted in improved prediction of ICH recurrence (Harrell C: 0.79 versus 0.55 for clinical data alone, P =0.033). In the MGH (training) data set, CSS, cerebral microbleed, and APOE ε2/ε4 stratified likelihood of ICH recurrence into high-, medium-, and low-risk categories. In the ERICH (validation) data set, yearly ICH recurrence rates for high-, medium-, and low-risk individuals were 6.6%, 2.5%, and 0.9%, respectively, with overall area under the curve of 0.91 for prediction of recurrent ICH. Conclusions: Combining MRI and APOE genotype stratifies likelihood of ICH recurrence into high, medium, and low risk. If confirmed in prospective studies, this combined APOE -MRI classification scheme may prove useful for selecting individuals for OAT resumption after ICH.

Global outcome measures that are widely used in stroke clinical trials, such as the modified Rankin Scale (mRS), lack sufficient detail to detect changes within specific domains (e.g., sensory, motor, visual, linguistic, or cognitive function). Yet such data are vital for understanding stroke recovery and its mechanisms. Poststroke deficits in specific domains differ in their rate and degree of recovery and in their effects on overall independence and quality of life. For example, even in a patient with complete recovery of strength, persistent deficits in the nonmotor domains such as language and cognition may make a return to independent living impossible. In such cases, global measures based solely on the patient's degree of independence would overlook a complete recovery in the motor domain. Capturing these important aspects of recovery demands a domain-specific approach. If stroke outcomes trials are to incorporate finer-grained recovery metrics—which can require substantial time, effort, and expertise to implement—efficiency must be a priority. In this article, we discuss how commonly collected clinical data from the NIH Stroke Scale can guide the judicious selection of relevant recovery domains for more detailed testing. Our overarching goal is to make the implementation of domain-specific testing more feasible for large-scale clinical trials on stroke recovery.

Introduction: CTP and MRI are increasingly used to assess endovascular thrombectomy (EVT) candidacy in large vessel occlusion stroke. Unfortunately, availability of these advanced neuroimaging techniques is not widespread and this can lead to over-triage to EVT-capable centers. Hypothesis: ASPECTS scoring applied to computed tomography angiography source images (CTA-SI) will be predictive of final infarct volume (FIV) and functional outcome. Methods: We reviewed data from consecutive patients undergoing EVT at our institution for anterior circulation occlusion between 01/14 - 01/19. We recorded demographics, comorbidities, NIHSS, treatment time parameters, and outcomes as defined by mRS (0-2 = good outcome). Cerebrovascular images were assessed by outcome-blinded raters and collateral score, TICI score, FIV, and both CT and CTA-SI ASPECTS scores were noted. Patients were grouped by ASPECTS score into low (0-4), intermediate (5-7), and high (8-10) for some analyses. FIV was predicted using a linear regression with NIHSS, good reperfusion (TICI 2b/3), collateral score, CT to groin puncture, CT and CTA-SI ASPECTS as independent variables. After excluding those with baseline mRS≥2, a binary logistic regression was performed including covariates of age, NIHSS, good reperfusion, and diabetes (factors significant at p Results: Analysis included 137 patients for FIV and 102 for outcome analysis (35 excluded for baseline mRS≥ 2). Linear regression found CTA-SI ASPECTS (Beta -10.8, p=0.002), collateral score (Beta -42.9, p=0.001) and good reperfusion (Beta 72.605, p=0.000) were independent predictors of FIV. Relative to the low CTA-SI ASPECTS group, the high CTA-SI ASPECTS group was more likely to have good outcome (OR 3.75 [95% CI 1.05-13.3]; p=0.41). CT ASPECTS was not predictive of FIV or good outcome. Outcomes: In those undergoing EVT for anterior circulation occlusion, CTA-SI ASPECTS is predictive of both FIV and functional outcome, while CT ASPECTS predicts neither. CTA-SI ASPECTS holds promise as a lower-cost, more widely available option for triage of patients with large vessel occlusion. Further study is needed comparing CTA-SI ASPECTS to CTP parameters.

Objective Observational studies point to an inverse correlation between low‐density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. Methods We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high‐density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. Results We identified 410, 339, 393, and 317 lipid‐related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65–0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42–0.82; p = 0.002), respectively. Interpretation Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH.

The aims of this single-center, retrospective cohort study are to assess the outcomes of endovascular mechanical thrombectomy (EMT) for acute ischemic stroke (AIS) and determine predictors of 30-day mortality at an academic comprehensive stroke center (CSC).We retrospectively collected data from consecutive patients who underwent EMT for AIS at our institution between April 2016 and January 2018. Primary outcome was defined as mortality within 30 days from EMT. Successful revascularization was defined as a modified Thrombolysis in Cerebral Infarction (mTICI) grade 2b-3. Statistical analyses were performed to identify predictors of 30-day mortality.The study cohort was comprised 57 patients (51% male) with mean age of 72 years. Intravenous tissue plasminogen activator was administered in 51%. The median Alberta Stroke Program Early Computed Tomography Score (ASPECTS) and National Institutes of Health Stroke Scale (NIHSS) score were 8 and 20, respectively. The 30-day mortality rate was 39%. Univariate analyses found that older age (mean 77 vs. 68 years, p = 0.022), higher baseline NIHSS score (median 23 vs. 19, p = 0.032), NIHSS score at 24 h after EMT (median 14.5 vs. 7.5, p 0.001), and lower rates of successful revascularization (59% vs. 89%, p = 0.021) were associated with 30-day mortality.We observed a moderate rate of 30-day mortality after EMT at an academic CSC. Older age, higher baseline NIHSS score, higher NIHSS score at 24 h after thrombectomy, and lower rates of successful revascularization were predictive of 30-day mortality in univariate analysis. Further efforts to identify modifiable risk factors of mortality are warranted.

BACKGROUND Patients with spontaneous intracerebral hemorrhage (ICH) are predisposed to venous thromboembolic (VTE) complications, such as deep vein thrombosis and pulmonary embolism. OBJECTIVE To evaluate, in a multicenter, retrospective cohort study, the rate of VTE complications in ICH patients during acute hospitalization, identify potential risk factors, and assess their association with functional outcome. METHODS We retrospectively analyzed prospectively collected data from 19 centers and 41 sites that participated in the Ethnic/Racial Variations of Intracerebral Hemorrhage study, from August 2010 to February 2016. We compared ICH patients with VTE complications to those without VTE complications. Statistical analyses were performed to determine predictors of VTE complications and poor outcome (modified Rankin Scale ≥ 4) at discharge and 3-mo follow-up. RESULTS Of the 2902 ICH patients who were eligible for analysis, 87 (3.0%) had VTE complications: 57 (2.0%) had only deep vein thrombosis, 19 (0.7%) had only pulmonary embolism, and 11 (0.4%) had both. In the multivariable logistic regression analysis, a prior history of VTE (odds ratio [OR] = 6.8; P

ObjectiveTo compare the functional outcomes and health-related quality of life metrics of restarting vs not restarting antiplatelet therapy (APT) in patients presenting with intracerebral hemorrhage (ICH) in the ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage) study.MethodsAdult patients aged 18 years and older who were on APT before ICH and were alive at hospital discharge were included. Patients were dichotomized based on whether or not APT was restarted after hospital discharge. The primary outcome was a modified Rankin Scale score of 0–2 at 90 days. Secondary outcomes were excellent outcome (modified Rankin Scale score 0–1), mortality, Barthel Index, and health status (EuroQol–5 dimensions [EQ-5D] and EQ-5D visual analog scale scores) at 90 days.ResultsThe APT and no APT cohorts comprised 127 and 732 patients, respectively. Restarting APT was associated with lower rates of good functional outcome (36.5% vs 40.8%; p = 0.021) and lower Barthel Index scores at 90 days (p = 0.041). The 2 cohorts were then matched in a 1:1 ratio, and the matched cohorts each comprised 107 patients. No difference in primary outcome was observed between restarting vs not restarting APT (35.5% vs 43.9%; p = 0.105). There were also no differences between the secondary outcomes of the 2 cohorts.ConclusionRestarting APT in patients with ICH of mild to moderate severity after acute hospitalization is not associated with worse functional outcomes or health-related quality of life at 90 days. In patients with significant cardiovascular risk factors who experience an ICH, restarting APT remains the decision of the treating practitioner.

Background Endovascular mechanical thrombectomy (EMT) is the standard of care for eligible patients presenting with anterior circulation acute ischemic stroke (AIS) due to emergent large vessel occlusion (ELVO). The aim of this systematic review and meta-analysis is to compare the outcomes between patients undergoing general anesthesia (GA) versus conscious sedation (CS) for these procedures. Methods A literature review was performed to identify studies reporting the EMT outcomes of AIS patients who underwent GA or CS for the procedure. Baseline, treatment, and outcomes data were analyzed. Good outcome was defined as a modified Rankin Scale score of 0–2 at 3 months, and successful reperfusion was defined as modified thrombolysis in cerebral infarction grade of 2b–3. Results Nine studies, comprising a total of 1379 patients treated with GA (n = 761) or CS (n = 618) for EMT, were included. Based on pooled data, GA achieved good outcome in 35% and successful reperfusion in 81%, whereas CS achieved good outcome in 41% and successful reperfusion in 75%. Meta-analyses showed no significant differences in the rates of good outcome (P = 0.51) or successful reperfusion (P = 0.39) between the GA and CS groups. The rates of pneumonia were significantly higher in the GA group (21% vs. 11%; P = 0.01). Conclusions The use of either GA or CS during EMT for patients with anterior circulation acute ELVO does not yield significantly different rates of functional independence at 3 months.

Background and Purpose: The majority of published data in cervical artery dissection (CeAD), a common cause of stroke in young adults, derive from populations of European ancestry (EA), including a recent genome-wide study identifying an association with the rs9349379 polymorphism of the PHACTR1 gene. Little is known about CeAD in individuals of African ancestry (AA) despite robust epidemiological data showing increased risk of stroke at younger ages. We hypothesize that AA patients with CeAD have different epidemiology and clinical profiles compared to those of EA, and a different genetic architecture related to rs9349379 of the PHACTR1 gene. Methods: We searched a single-center database of CeAD to identify AA and EA patients. We compared differential prevalence of CeAD versus all young stroke between AA and EA patients. We characterized clinical profiles via electronic medical record review. Data include descriptive statistics reported as medians or percentages. We also obtained publicly available allele frequencies of rs9349379 in AA and EA populations. Results: AA patients comprise 7% of CeAD cases and 27% of young stroke cases while EA patients comprise 90% of CeAD cases and 70% of young stroke cases. Prevalence of hypertension, diabetes mellitus, and hyperlipidemia were 74, 30, and 50%, respectively, in AA patients compared to 37, 6, and 25% in EA patients. Allele frequencies for the CeAD risk allele, rs9349379(A), are higher in AA populations compared to EA populations. Conclusion: AA patients represent a smaller proportion of CeAD cases compared to young stroke cases at our center. AA patients suffering CeAD have higher prevalence of both vascular risk factors and frequency of the CeAD risk allele compared to EA patients. These findings suggest a complex interplay between traditional vascular risk factors and genetic predisposition underlying CeAD pathogenesis. Further prospective research is needed to clarify these associations and disparities.

Objective To investigate potential genetic susceptibility for moyamoya disease (MMD) in an African American family. Materials and methods Neurovascular imaging and analyses of MMD susceptibility genes RNF213 and/or ACTA2 in a young proband with MMD and two first-degree relatives. Results The proband presented with pseudobulbar affect and chorea, then had a right hemispheric ischaemic stroke and rapidly fatal course. One relative had a mild haemorrhagic thalamic stroke and clinically silent ischaemic infarct. Despite evidence of slowly progressive disease, he remained clinically stable. Another relative was neurologically intact with normal cerebrovascular imaging to date. All three have the rare R4131C (p.Arg4131Cys or p.R4131C, c.12391C>T) variant of the RNF213 gene. They are the first Black people and only the 5th family worldwide known to harbour this variant. MMD was confirmed in both of the patients with neurological events. Conclusions Our report provides compelling evidence that MMD is a clinically complex, heritable genetic disease. It supports the probable pathogenicity of R4131C. Furthermore, it illustrates the wide phenotypic spectrum of R4131C, from asymptomatic carrier to late presenting, mild disease to catastrophic, rapidly fatal childhood disease. To our knowledge, this is also the first report of heritable MMD in a Black family. Finally, this study highlights the importance of racially and ethnically diverse participants in biomedical research.

Altres ajuts: National Institutes of Health (grant U01HG005160); National Human Genome Research Institute (Supplement U01HG005160-03S1); American Heart Association Scientist Development Award (12SDG9180012); Faith Christian Center International (Charlottesville, VA). National Institute of Neurological Disorders and Stroke (R01 NS34447). Aberrant DNA methylation profiles have been implicated in numerous cardiovascular diseases; however, few studies have investigated how these epigenetic modifications contribute to stroke recurrence. The aim of this study was to identify methylation loci associated with the time to recurrent cerebro- and cardiovascular events in individuals of European and African descent. DNA methylation profiles were generated for 180 individuals from the Vitamin Intervention for Stroke Prevention clinical trial using Illumina HumanMethylation 450K BeadChip microarrays, resulting in beta values for 470,871 autosomal CpG sites. Ethnicity-stratified survival analyses were performed using Cox Proportional Hazards regression models for associations between each methylation locus and the time to recurrent stroke or composite vascular event. Results were validated in the Vall d'Hebron University Hospital cohort from Barcelona, Spain. Network analyses of the methylation loci were generated using weighted gene coexpression network analysis. Primary analysis identified four significant loci, cg04059318, ch.2.81927627R, cg03584380, and cg24875416, associated with time to recurrent stroke. Secondary analysis identified three loci, cg00076998, cg16758041, and cg02365967, associated with time to composite vascular endpoint. Locus cg03584380, which is located in an intron of ZDHHC6, was replicated in the Vall d'Hebron University Hospital cohort. The results from this study implicate the degree of methylation at cg03584380 is associated with the time of recurrence for stroke or composite vascular events across two ethnically diverse groups. Furthermore, modules of loci were associated with clinical traits and blood biomarkers including previous number of strokes, prothrombin fragments 1 + 2, thrombomodulin, thrombin-antithrombin complex, triglyceride levels, and tissue plasminogen activator. Ultimately, these loci could serve as potential epigenetic biomarkers that could identify at-risk individuals in recurrence-prone populations.

Introduction The benefit of endovascular mechanical thrombectomy (EMT) for acute distal occlusions of the middle cerebral artery M2 segment is incompletely defined. The aim of this systematic review is to analyze the recent literature regarding EMT for acute M2 occlusions. Methods We reviewed the literature to identify all studies of patients with acute M2 occlusions who underwent EMT that were published after January 1, 2015. Excellent and good outcomes were defined as modified Rankin Scale score of 0–1 and 0–2, respectively, at 3 months. Successful reperfusion was defined as modified Thrombolysis In Cerebral Infarction (mTICI) score of 2b–3. Results Eight studies, comprising 630 EMT-treated patients with acute M2 occlusions, were included in the analysis. The median National Institute of Health Stroke Scale score ranged from 10 to 16, and the median Alberta Stroke Program Computed Tomography Score ranged from 9 to 10. Excellent and good outcomes at 3-month follow-up were observed in 40% and 62%, respectively, of patients with acute M2 occlusion who underwent EMT, with a mortality of 11%. Successful reperfusion was achieved in 78% of cases. Postprocedural intracerebral hemorrhage (ICH) occurred in 14% of patients, including a symptomatic ICH rate of 5%. Conclusions EMT for acute M2 occlusion affords functional independence to most patients, with a modest rate of symptomatic ICH. However, compared with the natural history of distal MCA occlusions, the benefit of M2 thrombectomy using stent retriever or direct aspiration techniques remains unclear.

Background and Purpose— von Willebrand factor (vWF) plays an important role in thrombus formation during cerebrovascular damage. We sought to investigate the potential role of circulating vWF in recurrent cerebrovascular events and identify genetic contributors to variation in vWF level in an ischemic stroke population. Methods— We analyzed the effect of circulating vWF on risk of recurrent stroke using survival models in the VISP trial (Vitamin Intervention for Stroke Prevention) and the use of vWF in reclassification over traditional factors. We conducted a genome-wide association study) with imputation, based on 1000 Genomes Project data, for circulating vWF levels and then interrogated loci previously associated with vWF levels. We performed expression quantitative trait locus analysis for vWF across different tissues. Results— Elevated vWF levels were associated with increased risk for recurrent stroke in VISP. Adding vWF to traditional clinical parameters also improved recurrent stroke risk prediction. We identified single-nucleotide polymorphisms significantly associated with circulating vWF at the ABO locus ( P −8 ) and replicated findings from previous genetic associations of vWF levels in humans. Expression quantitative trait locus analyses demonstrate that most associated ABO single-nucleotide polymorphisms were also associated with vWF gene expression. Conclusions— Elevated vWF levels are associated with recurrent stroke in VISP. In the VISP population, genetic determinants of vWF levels that impact vWF gene expression were identified. These data add to our knowledge of the pathophysiologic and genetic basis for recurrent stroke risk and may have implications for clinical care decision making.

Objective:To analyze the dose–risk relationship for alcohol consumption and intracerebral hemorrhage (ICH) in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study.Methods:ERICH is a multicenter, prospective, case-control study, designed to recruit 1,000 non-Hispanic white patients, 1,000 non-Hispanic black patients, and 1,000 Hispanic patients with ICH. Cases were matched 1:1 to ICH-free controls by age, sex, race/ethnicity, and geographic area. Comprehensive interviews included questions regarding alcohol consumption. Patterns of alcohol consumption were categorized as none, rare (2 drinks per day and Results:Multivariable analyses demonstrated an ordinal trend for alcohol consumption: rare (odds ratio [OR] 0.57, p < 0.0001), moderate (OR 0.65, p < 0.0001), intermediate (OR 0.82, p = 0.2666), and heavy alcohol consumption (OR 1.77, p = 0.0003). Subgroup analyses demonstrated an association of rare and moderate alcohol consumption with decreased risk of both lobar and nonlobar ICH. Heavy alcohol consumption demonstrated a strong association with increased nonlobar ICH risk (OR 2.04, p = 0.0003). Heavy alcohol consumption was associated with significant increase in nonlobar ICH risk in black (OR 2.34, p = 0.0140) and Hispanic participants (OR 12.32, p < 0.0001). A similar association was not found in white participants.Conclusions:This study demonstrated potential protective effects of rare and moderate alcohol consumption on ICH risk. Heavy alcohol consumption was associated with increased ICH risk. Race/ethnicity was a significant factor in alcohol-associated ICH risk; heavy alcohol consumption in black and Hispanic participants poses significant nonlobar ICH risk.

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.

Systemic, institutional, and organizational barriers and unconscious biases have led to the underrepresentation of women in the medical profession, particularly in academic medicine. Women comprise 40% of faculty in US departments of neurology and only 31% of faculty at the top-ranked programs.1,2 The proportion of women who are full professors among US programs is 21%, and 14% at among top-ranked programs.1,2 In the European Union, 24% of university professors are women.3 In 2018, only 14 women chaired one of the 129 neurology departments in the United States.4 Women are underrepresented in the most visible academic leadership positions, including editorial boards of medical journals. In a cross-sectional study published in this issue of Neurology® , Mariotto et al.5 found that, in 247 neurology journals, only 12% of editors-in-chief, 23% of associate editors, and 21% of editorial board members were women.

Variation in the phosphatase and actin regulator-1 (PHACTR1) gene, a downstream regulator of the endothelin-1 (EDN1) gene, has been implicated in the pathogenesis of several related vascular phenotypes including atherosclerotic coronary artery disease, non-atherosclerotic coronary artery dissection, and carotid artery dissection, though it has not been studied in carotid atherosclerosis. We analyzed differential expression of PHACTR1 and EDN1 between atheromatous and non-atheromatous carotid artery tissue within the same individual and found lower levels of PHACTR1 expression in the atheromatous carotid tissue.

To investigate potential association between collateral arterial supply and stroke in patients with isolated internal carotid artery dissection (iCeAD). We hypothesized a lower risk of stroke in patients with more robust collateral supply. This is a single-center, retrospective review of iCeAD patients between 1994 and 2018. iCeAD patients with sufficient neuroimaging data were included. Patients were categorized based on cerebral infarction (stroke) on neuroimaging. The collaterals score, ranging from 0 to 8 with higher scores indicating more robust collaterals, was assessed based on contributions from leptomeningeal arteries (0-2 points), anterior communicating artery (0-2 points) and anterior cerebral artery A1 segment (0-2 points), and posterior communicating artery (0-2 points). The study included 62 iCeAD patients, comprising 33 and 29 patients in the stroke and no stroke groups, respectively. Neurological motor deficit (p 0.001) and internal carotid artery occlusion (p = 0.033) were independent predictors of stroke. More robust collaterals was associated with lower stroke risk (p = 0.032) in univariable analysis, but not after adjustment for baseline differences. The collaterals score performed poorly in receiver-operating characteristics (ROC) curve analysis, with area under the ROC (AUROC) curve of 0.640. A collaterals score of4 had a sensitivity and specificity of 89.7% and 36.4% for no stroke, respectively. The covariate-adjusted AUROC curve was 0.514. Collateral circulation appeared to be a poor predictor of cerebral infarction in patients with isolated iCeAD. Future studies in larger, independent cohorts are needed to better understand the interaction of collaterals with stroke in cervical artery dissection.

Background and Purpose— Clinical trials in spontaneous intracerebral hemorrhage (ICH) have used volume cutoffs as inclusion criteria to select populations in which the effects of interventions are likely to be the greatest. However, optimal volume cutoffs for predicting poor outcome in deep locations (thalamus versus basal ganglia) are unknown. Methods— We conducted a 2-phase study to determine ICH volume cutoffs for poor outcome (modified Rankin Scale score of 4–6) in the thalamus and basal ganglia. Cutoffs with optimal sensitivity and specificity for poor outcome were identified in the ERICH ([Ethnic/Racial Variations of ICH] study; derivation cohort) using receiver operating characteristic curves. The cutoffs were then validated in the ATACH-2 trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) by comparing the c-statistic of regression models for outcome (including dichotomized volume) in the validation cohort. Results— Of the 3000 patients enrolled in ERICH, 1564 (52%) had deep ICH, of whom 1305 (84%) had complete neuroimaging and outcome data (660 thalamic and 645 basal ganglia hemorrhages). Receiver operating characteristic curve analysis identified 8 mL in thalamic (area under the curve, 0.79; sensitivity, 73%; specificity, 78%) and 18 mL in basal ganglia ICH (area under the curve, 0.79; sensitivity, 70%; specificity, 83%) as optimal cutoffs for predicting poor outcome. The validation cohort included 834 (84%) patients with deep ICH and complete neuroimaging data enrolled in ATACH-2 (353 thalamic and 431 basal ganglia hemorrhages). In thalamic ICH, the c-statistic of the multivariable outcome model including dichotomized ICH volume was 0.80 (95% CI, 0.75–0.85) in the validation cohort. For basal ganglia ICH, the c-statistic was 0.81 (95% CI, 0.76–0.85) in the validation cohort. Conclusions— Optimal hematoma volume cutoffs for predicting poor outcome in deep ICH vary by the specific deep brain nucleus involved. Utilization of location-specific volume cutoffs may improve clinical trial design by targeting deep ICH patients that will obtain maximal benefit from candidate therapies.

White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery. In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95; p < 0.01) and Pearson correlation of total brain volume (r = 0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N = 2783) and identify a decrease in total brain volume of -2.4 cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing. Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 753896 (M.D. Schirmer). This study was supported by NIH-NINDS (MRI-GENIE: R01NS086905 - PI N.Rost, K23NS064052, R01NS082285 - N. Rost, SiGN: U01 NS069208 - J. Rosand, S. Kittner, R01NS059775, R01NS063925, R01NS082285,P50NS051343, R01NS086905, U01 NS069208 - O. Wu), NIH NIBIBNAC (P41EB015902–P. Golland).

Background and Purpose— Although cigarette use may be a risk for intracerebral hemorrhage (ICH), animal models suggest that nicotine has a potential neuroprotective effect. The aim of this multicenter study is to determine the effect of smoking history on outcome in ICH patients. Methods— We analyzed prospectively collected data from the Ethnic/Racial Variations of Intracerebral Hemorrhage study and included patients with smoking status data in the analysis. Patients were dichotomized into nonsmokers versus ever-smokers, and the latter group was further categorized as former (>30 days before ICH) or current (≤30 days before ICH) smokers. The primary outcome was 90-day modified Rankin Scale score shift analysis. Secondary outcomes were in-hospital mortality and mortality, Barthel Index, and self-reported health status measures at 90 days. Results— The overall study cohort comprised 1509 nonsmokers and 1423 ever-smokers (841 former, 577 current, 5 unknown). No difference in primary outcome was observed between nonsmokers versus ever-smokers (adjusted odds ratio [aOR], 1.041; 95% CI, 0.904–1.199; P =0.577). No differences in primary outcome were observed between former (aOR, 0.932; 95% CI, 0.791–1.178; P =0.399) or current smokers (aOR, 1.178; 95% CI, 0.970–1.431; P =0.098) versus nonsmokers. Subgroup analyses by race/ethnicity demonstrated no differences in primary outcome when former and current smokers were compared with nonsmokers. Former, but not current, smokers had a lower in-hospital mortality rate (aOR, 0.695; 95% CI, 0.500–0.968; P =0.031), which was only observed in Hispanics (aOR, 0.533; 95% CI, 0.309–0.921; P =0.024). Differences in self-reported health status measures were only observed in whites. Conclusions— Cigarette smoking history does not seem to provide a beneficial effect on 90-day functional outcome in patients with ICH.

Despite no clear evidence from randomized trials, surgical intervention of spontaneous intracerebral hemorrhage (ICH) still occurs. We sought to describe the characteristics of patients undergoing surgical intervention in ICH.Data from the ERICH (ERICH Ethnic/Racial Variations of Intracerebral Hemorrhage) study were analyzed, and patients with ICH were categorized into surgical intervention or nonoperative management groups. Patients with primary intraventricular hemorrhage and those without data regarding the use of surgical intervention were excluded.The study cohort comprised 2947 patients, and surgical intervention was performed in 289 (10%). Younger age (odds ratio [OR], 0.967; P0.001), lower baseline modified Rankin Scale score (OR, 0.728; P0.001), higher admission Glasgow Coma Scale score (OR, 1.059; P = 0.007), larger ICH volume (OR, 1.037; P0.001), infratentorial ICH location (OR, 5.966; P0.001), lobar ICH location (OR, 1.906; P = 0.001), lack of intraventricular hemorrhage (OR, 0.567; P = 0.001), intracranial pressure (ICP) monitoring (OR, 5.022; P0.001), and mannitol use (OR, 2.389; P0.001) were independent predictors of surgical intervention. Younger age (OR, 0.953; P0.001), lower baseline modified Rankin Scale score (OR, 0.713; P = 0.002), larger ICH volume (OR, 1.033; P0.001), lobar ICH location (OR, 2.467; P0.001), ICP monitoring (OR, 3.477; P0.001), and mannitol use (OR, 2.139; P0.001) were independent predictors of surgical interventions in supratentorial ICHs. Larger ICH volume (OR, 1.078; P 0.001), ICP monitoring (OR, 6.099; P0.001), and mannitol use (OR, 2.952; P = 0.005) were independent predictors of surgical interventions in infratentorial ICHs.We identified multiple factors associated with surgical intervention for patients with ICH. Younger age, good neurologic function at baseline, large ICH volume on presentation, and lobar or infratentorial hematomas were independently associated with surgical intervention in patients with ICH .

Objective: Despite no clear evidence from randomized trials, surgical intervention of spontaneous intracerebral hemorrhage (ICH) still occurs. We sought to describe the characteristics of patients undergoing surgical intervention in ICH. Methods: Data from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study were analyzed, and ICH patients were categorized into surgical intervention or nonoperative management groups. Patients with primary intraventricular hemorrhage (IVH) and those without data regarding the use of surgical intervention data were excluded. Multivariable models were developed to identify predictors of surgical intervention. Results: The study cohort comprised 2,947 patients, and surgical intervention was performed in 289 (10%). Younger age (p Conclusion: We identified multiple factors associated with surgical intervention for patients with ICH. Younger age, good neurological function at baseline, large ICH volume on presentation, and lobar or infratentorial hematomas were independently associated with surgical intervention in ICH patients. Additional studies are necessary to determine the risk to benefit profile of ICH surgery.

Objective: The role of ICP monitoring in patients with spontaneous ICH is unknown, andthe associated complications may offset its benefits. The aim of the study was to compare the outcomes of ICH patients who underwent ICP monitoring to those who were managed by care-guided imaging and/or clinical exam alone. Methods: This was aretrospective, matched cohort analysis from a multicenter, prospective study with recruitment of 3,000 multi-ethnic cases of spontaneous ICH between September 2010 and October 2015. ICH patients with ICP monitoring were propensity-score matched, in a 1:1 ratio, to those without ICP monitoring. The primary outcome was mortality at 90 days. Secondary outcomes were in-hospital mortality, use of hyperosmolar (mannitol or hypertonic saline) therapy, surgical ICH evacuation, length of hospital stay, and the following 90-day outcomes: modified Rankin Scale (mRS) excellent (0-1) and good (0-2), Barthel Index, and health-related quality of life (HRQoL) (EuroQol Group 5-Dimension [EQ-5D] and EQ-5D Visual Analog Scale [VAS] scores). Results: The ICP and no ICP monitoring cohorts comprised 566 and 2,434 patients, respectively. The matched cohorts each included 420 patients. The 90-day and in-hospital mortality rates were similar between the matched cohorts. Infection rate was higher in the ICP monitoring cohort (5.7% vs. 1.2%, aOR=5.066, p=0.001).Shift analysis 90-day mRS favored no ICP monitoring (aOR=1.628, p Conclusion: The findings of this study do not support the routine utilization of ICP monitoring in patients with ICH.

Objective: While cigarette use may be a risk for intracerebral hemorrhage (ICH), animal models suggest that nicotine has a potential neuroprotective effect. The aim of this multicenter study is to determine the effect of smoking on outcome in ICH patients. Methods: We analyzed prospectively collected data from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, and included patients with smoking status data in the analysis. Patients were dichotomized into non-smokers versus ever-smokers, and the latter group was further categorized as former (>30 days before ICH) or current (≤30 days before ICH) smokers. The primary outcome was 90-day modified Rankin Scale (mRS) score shift analysis. Secondary outcomes were in-hospital mortality and mortality, Barthel Index, and self-reported health status measures at 90 days. Results: The overall study cohort comprised 1,509 non-smokers and 1,423 ever-smokers (841 former, 577 current, 5 unknown). No difference in primary outcome was observed between non-smokers versus ever-smokers (aOR=1.041 [0.904-1.199], p=0.577). No differences in primary outcome were observed between former (aOR=0.932 [0.791-1.178], p=0.399) or current smokers (aOR=1.178 [0.970-1.431], p=0.098) versus non-smokers. Subgroup analyses by race/ethnicity demonstrated no differences in primary outcome when former and current smokers were compared to non-smokers. Former, but not current, smokers had a lower in-hospital mortality rate (aOR=0.695 [0.500-0.968], p=0.031), which was only observed in Hispanics (aOR=0.533 [0.309-0.921], p=0.024). Differences in self-reported health status measures were only observed in whites. Conclusion: Cigarette smoking history does not appear to provide a beneficial effect on 90-day functional outcome in patients with ICH.

Introduction: Several related neurovascular phenotypes, including cervical artery dissection, fibromuscular dysplasia, large artery stroke, hypertension, and migraine headache are associated with a single nucleotide polymorphism (rs9349378) in the phosphatase and actin regulator-1 ( PHACTR1 ) gene recently identified as a distal regulator of the endothelin-1 ( EDN1 ) gene. Vascular endothelial cells release EDN1, a potent vasoconstrictor. We hypothesize that atheromatous and normal carotid tissue will differentially express PHACTR1 and EDN1 . Methods: We obtained gene expression data from the publically available Gene Expression Omnibus Carotid Atheroma Dataset (GSE43292). This resource contains 32 paired samples of carotid atheroma and distant macroscopically intact carotid tissue from the same individual and gene expression data from the Affymetrix Human Gene 1.0 ST Array. We compared log transformed count of signal intensity of PHACTR1 and EDN1 expression in the 32 paired samples using a two-sample t-test assuming equal variance with SPSS (IBM, Armonk, NY). Results: PHACTR1 expression was lower in atheromatous compared to normal carotid tissue (7.152 vs. 7.399, delta 0.248, 95%CI 0.180 - 0.315, p=1.9 E -8 ). EDN1 expression did not differ (6.514 and 6.339, delta 0.176, 95%CI -0.004 - 0.356, p = 0.055). with genetic data associating the rs9349378[G] allele with lower levels of expression and atherosclerotic vascular diseases. The lack of differential EDN1 expression may reflect the small sample size or may challenge the assertion that EDNI is the mediator of the PHACTR1 association. Our data support the hypothesis that this pathway may play an important and potentially variable role in neurovascular phenotypes including large artery atherosclerotic stroke and non-atherosclerotic arteriopathies.

Introduction: Risk of lobar and non-lobar intracerebral hemorrhage (ICH) varies among blacks, whites and Hispanics. We sought to determine whether these differences could be due to variability in the effects of Apolipoprotein E (APOE) epsilon (ε) alleles, the most potent genetic risk factor for ICH. Methods: Primary ICH cases and controls were collected from US and European sites contributing to the International Stroke Genetic Consortium (ISGC). We meta-analyzed the effects of APOE allele status on ICH risk applying a two-stage clustering approach based on race/ethnicity and the contributing study. Models were adjusted for age, sex, history of hypertension, hypercholesterolemia, warfarin, statin and antiplatelet use, smoking and alcohol use. A propensity score analysis was used to model the influence of APOE against the burden of hypertension across races/ethnicities. Results: 13,124 subjects (54.5% male, median age 66 years) were included. In whites, APOE ε2 (odds ratio (OR)=1.85, 95% confidence interval (CI)=1.27-2.69, p Conclusion: APOE ε4 and ε2 alleles affect lobar ICH risk variably by race and ethnicity. Associations are confirmed in whites but can be shown in Hispanics only when the excess burden of hypertension is propensity score-matched. Further studies are needed to explore interactions between APOE alleles and environmental exposures that vary by race and ethnicity in representative populations at risk for ICH.

Introduction: Intracerebral hemorrhage (ICH) is the most severe subtype of stroke with a high mortality rate and majority of survivors suffering significant disability. The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study prospectively recruited 1000 white, 1000 black and 1000 Hispanic spontaneous ICH cases. Herein, we report the main results of the predictors of 3 month outcome after ICH. Hypothesis: We hypothesized that ICH Score variables of age, ICH volume, ICH location, presence of intraventricular hemorrhage (IVH), and presenting Glasgow Coma Scale would predict long-term disability in addition to prior validation of mortality. Methods: Between 2010-2015, cases were prospectively recruited with uniform phenotype definitions, centralized neuroimaging review and with telephone follow-up at 3 months. Apolipoprotein E genotyping was performed centrally. Individual characteristics were screened for association under a logistic regression model, 90-day mRS ≥ 4 versus 0-3, and those meeting P Results: The Table presents the prevalence/average of each variable entering the final multivariate model for association with poor (mRS 4-6) compared to good (mRS 0-3) outcome at 3 months. When analyses were repeated excluding withdrawal of care, overall Graeb (IVH) score fell out of the model (with presence of IVH replacing it) but the remaining variables were retained and in the same direction of effect. C-statistic for the multivariate model = 0.884 compared to 0.763 for ICH score alone (p=1.7E-22). Conclusion: ICH score elements were validated as predictive of 3 month outcome. Novel baseline characteristics such as white matter hyperintensity as well as subsequent clinical events that may affect outcomes were identified. Location specific results to be presented.

Background and Purpose— We evaluated deep learning algorithms’ segmentation of acute ischemic lesions on heterogeneous multi-center clinical diffusion-weighted magnetic resonance imaging (MRI) data sets and explored the potential role of this tool for phenotyping acute ischemic stroke. Methods— Ischemic stroke data sets from the MRI-GENIE (MRI-Genetics Interface Exploration) repository consisting of 12 international genetic research centers were retrospectively analyzed using an automated deep learning segmentation algorithm consisting of an ensemble of 3-dimensional convolutional neural networks. Three ensembles were trained using data from the following: (1) 267 patients from an independent single-center cohort, (2) 267 patients from MRI-GENIE, and (3) mixture of (1) and (2). The algorithms’ performances were compared against manual outlines from a separate 383 patient subset from MRI-GENIE. Univariable and multivariable logistic regression with respect to demographics, stroke subtypes, and vascular risk factors were performed to identify phenotypes associated with large acute diffusion-weighted MRI volumes and greater stroke severity in 2770 MRI-GENIE patients. Stroke topography was investigated. Results— The ensemble consisting of a mixture of MRI-GENIE and single-center convolutional neural networks performed best. Subset analysis comparing automated and manual lesion volumes in 383 patients found excellent correlation (ρ=0.92; P 3 (0.9–16.6 cm 3 ). Patients with small artery occlusion stroke subtype had smaller lesion volumes ( P Conclusions— Automated accurate clinical diffusion-weighted MRI lesion segmentation using deep learning algorithms trained with multi-center and diverse data is feasible. Both lesion volume and topography can provide insight into stroke subtypes with sufficient sample size from big heterogeneous multi-center clinical imaging phenotype data sets.

Comment inThe yin and yang of magnesium and calcium: New genetic insights for stroke? [Neurology. 2019]; International audience; Objective To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. Methods Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). Results In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10 −4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10 −4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. Conclusions This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.