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Patient selection for acute reperfusion therapies of acute ischemic stroke is based on assessment of the core and tissue-at-risk and the time from stroke onset. Response to treatment and clinical outcomes, however, vary significantly since patient-specific cerebrovascular anatomy plays a vital role in governing flow and reperfusion. We developed an end-to-end automated machine learning approach to extract advanced cerebrovascular morphological features, including tortuosity and collateral index, to improve outcome prediction, and patient selection. Methods: Using our validated automatic cerebrovascular segmentation and feature extraction algorithm, we obtained the morphological properties of the brain vasculature, including vessel tortuosity, length, diameter, and bifurcation patterns, in MR angiography scans of 100 anonymized stroke patients. Each patient’s collateral index was also automatically graded using a previously established probabilistic atlas of healthy cerebrovasculature. To predict 90-day functional outcomes (mRS), a statistical model was trained using patients' clinical features (demographics, comorbidities, and baseline NIHSS), imaging features (initial ASPECTS, perfusion mismatch volume, and collateral index), and the extracted morphologic features (length, diameter, number of branches, vessel tortuosity, fractal dimension, and total volume). The predictions were compared against ground truth mRS to assess model accuracy. We also compared the model’s performance against conventional outcome predictors with only the clinical and imaging features. Results: The conventional model including the common clinical and imaging features excluding the collateral index gave an area under the curve (AUC) of 0.63, which is comparable to previously published results. Including the automatically scored collateral index improved the accuracy to 0.74. We found that further including the morphological features to the predictor model significantly improved AUC accuracy to 0.83. Conclusion: Including automatically extracted cerebrovascular morphologic features in traditional clinical and imaging markers significantly improves outcome prediction and response to treatment in stroke patients.

Cerebral edema is associated with worse outcome after acute stroke; however, the minimum clinically relevant threshold remains unknown. This study aimed to identify the minimal degree of midline shift (MLS) that predicts outcome in a cohort encompassing a broad range of patients with acute stroke. Patient-level data from six acute stroke clinical trials were combined with endovascular thrombectomy registries from two academic referral centers, generating a combined cohort of 1977 patients. MLS was extracted from the original trial data or measured on computed tomography or magnetic resonance imaging that was obtained a median of 47.0 h (interquartile range 27.0–75.1 h) after stroke onset. Logistic regression was performed to identify predictors of poor outcome and the minimal clinically relevant MLS threshold. The presence of MLS was a predictor of poor outcome, independent of baseline clinical and demographic factors (adjusted odds ratio 4.46, 95% confidence interval 3.56–5.59, p

Key Points Question Does the prevalence and burden of risk factors for lobar and nonlobar intracerebral hemorrhage (ICH) differ among Black, Hispanic, and White populations? Findings In this case-control study of 3000 cases of ICH among Black, Hispanic, and White patients, the ɛ2 and ɛ4 alleles of APOE, the gene encoding apolipoprotein E, were associated with lobar ICH in White but not Black and Hispanic patients; hypertension was a risk factor for both lobar and nonlobar ICH in all groups; and the mean age for ICH among Black and Hispanic patients was more than 10 years younger than that of their White counterparts. Black and Hispanic patients had a higher attributable risk percentage for treated or untreated hypertension and lack of health insurance than White patients. Meaning These findings suggest that potentially modifiable risk factors and social determinants of health are important contributors to the disproportionate ICH burden experienced by Black and Hispanic populations., This case-control study examines the prevalence, odds, and population attributable risk for established and novel risk factors for intracerebral hemorrhage, stratified by intracerebral hemorrhage location and racial/ethnic group., Importance Black and Hispanic individuals have an increased risk of intracerebral hemorrhage (ICH) compared with their White counterparts, but no large studies of ICH have been conducted in these disproportionately affected populations. Objective To examine the prevalence, odds, and population attributable risk (PAR) percentage for established and novel risk factors for ICH, stratified by ICH location and racial/ethnic group. Design, Setting, and Participants The Ethnic/Racial Variations of Intracerebral Hemorrhage Study was a case-control study of ICH among 3000 Black, Hispanic, and White individuals who experienced spontaneous ICH (1000 cases in each group). Recruitment was conducted between September 2009 and July 2016 at 19 US sites comprising 42 hospitals. Control participants were identified through random digit dialing and were matched to case participants by age (±5 years), sex, race/ethnicity, and geographic area. Data analyses were conducted from January 2019 to May 2020. Main Outcomes and Measures Case and control participants underwent a standardized interview, physical measurement for body mass index, and genotyping for the ɛ2 and ɛ4 alleles of APOE, the gene encoding apolipoprotein E. Prevalence, multivariable adjusted odds ratio (OR), and PAR percentage were calculated for each risk factor in the entire ICH population and stratified by racial/ethnic group and by lobar or nonlobar location. Results There were 1000 Black patients (median [interquartile range (IQR)] age, 57 [50-65] years, 425 [42.5%] women), 1000 Hispanic patients (median [IQR] age, 58 [49-69] years; 373 [37.3%] women), and 1000 White patients (median [IQR] age, 71 [59-80] years; 437 [43.7%] women). The mean (SD) age of patients with ICH was significantly lower among Black and Hispanic patients compared with White patients (eg, lobar ICH: Black, 62.2 [15.2] years; Hispanic, 62.5 [15.7] years; White, 71.0 [13.3] years). More than half of all ICH in Black and Hispanic patients was associated with treated or untreated hypertension (PAR for treated hypertension, Black patients: 53.6%; 95% CI, 46.4%-59.8%; Hispanic patients: 46.5%; 95% CI, 40.6%-51.8%; untreated hypertension, Black patients: 45.5%; 95% CI, 39.%-51.1%; Hispanic patients: 42.7%; 95% CI, 37.6%-47.3%). Lack of health insurance also had a disproportionate association with the PAR percentage for ICH in Black and Hispanic patients (Black patients: 21.7%; 95% CI, 17.5%-25.7%; Hispanic patients: 30.2%; 95% CI, 26.1%-34.1%; White patients: 5.8%; 95% CI, 3.3%-8.2%). A high sleep apnea risk score was associated with both lobar (OR, 1.68; 95% CI, 1.36-2.06) and nonlobar (OR, 1.62; 95% CI, 1.37-1.91) ICH, and high cholesterol was inversely associated only with nonlobar ICH (OR, 0.60; 95% CI, 0.52-0.70); both had no interactions with race and ethnicity. In contrast to the association between the ɛ2 and ɛ4 alleles of APOE and ICH in White individuals (eg, presence of APOE ɛ2 allele: OR, 1.84; 95% CI, 1.34-2.52), APOE alleles were not associated with lobar ICH among Black or Hispanic individuals. Conclusions and Relevance This study found sleep apnea as a novel risk factor for ICH. The results suggest a strong contribution from inadequately treated hypertension and lack of health insurance to the disproportionate burden and earlier onset of ICH in Black and Hispanic populations. These findings emphasize the importance of addressing modifiable risk factors and the social determinants of health to reduce health disparities.

Purpose Recovery from aphasia after stroke has a decelerating trajectory, with the greatest gains taking place early and the slope of change decreasing over time. Despite its importance, little is known regarding evolution of language function in the early postonset period. The goal of this study was to characterize the dynamics and nature of recovery of language function in the acute and early subacute phases of stroke. Method Twenty-one patients with aphasia were evaluated every 2–3 days for the first 15 days after onset of acute ischemic or hemorrhagic stroke. Language function was assessed at each time point with the Quick Aphasia Battery (Wilson, Eriksson, Schneck, & Lucanie, 2018), which yields an overall summary score and a multidimensional profile of 7 different language domains. Results On a 10-point scale, overall language function improved by a mean of 1.07 points per week, confidence interval [0.46, 1.71], with 19 of 21 patients showing positive changes. The trajectory of recovery was approximately linear over this time period. There was significant variability across patients, and patients with more impaired language function at Day 2 poststroke experienced greater improvements over the subsequent 2 weeks. Patterns of recovery differed across language domains, with consistent improvements in word finding, grammatical construction, repetition, and reading, but less consistent improvements in word comprehension and sentence comprehension. Conclusion Overall language function typically improves substantially and steadily during the first 2 weeks after stroke, driven mostly by recovery of expressive language. Information on the trajectory of early recovery will increase the accuracy of prognoses and establish baseline expectations against which to evaluate the efficacy of interventions. Supplemental Material https://doi.org/10.23641/asha.7811876

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 (

Introduction: The etiology and significance of diffusion weighted imaging (DWI) lesions in patients with acute intracerebral hemorrhage (ICH) remain unclear. We evaluated which factors were associated with DWI lesions, whether associated factors differed by ICH location, and whether DWI lesions were associated with functional outcomes. Methods: We pooled individual patient data from the MISTIE III trial, the ATACH-II trial, the i-DEF trial, and the ERICH study. We included only patients who underwent protocolized magnetic resonance imaging (MRI) of the brain. A poor functional outcome was defined as a modified Rankin Scale (mRS) score of 4-6 at 3-6 months. We used mixed effects logistic regression with the study database as a random effect. Results: Among 1,775 ICH patients, there were 621 (35.6%) lobar, 978 (55.9%) deep, and 148 (8.5%) infratentorial ICHs. Median time to MRI scan was 1.5 days (IQR, 1-4). DWIHLs occurred in 559 (31.5%) patients, with 190 (34.3%) in lobar ICH and 320 (57.8%) in deep ICHs. In mixed effects regression models, factors associated with DWIHLs included younger age factors associated with DWIHLs after acute ICH included younger age (OR, 0.98; 95% CI, 0.97-0.99), black race (OR, 1.59; 95% CI, 1.18-2.16), admission systolic blood pressure (SBP per 10 mm Hg, OR, 1.13; 95% CI, 1.05-1.22), cerebral microbleeds (OR, 1.71, 95% CI, 1.24-2.35), and leukoaraiosis (OR, 1.60; 95% CI, 1.14-2.25). Patients with DWIHLs had higher odds of mRS 4-6 (OR, 1.57; 95% CI, 1.24-1.99) compared to those without, after adjustment for demographics and ICH severity. In subgroup analyses, similar factors influenced DWIHLs in deep ICH. However, in lobar ICH, younger age, admission SBP, and leukoaraiosis were associated with DWIHLs. Presence of DWIHLs was independently associated with poor mRS in deep ICH but not in lobar ICH. There was no relationship between acute BP lowering and DWIHLs, regardless of location. Conclusions: In a large, heterogeneous cohort of ICH patients, our results are consistent with the hypothesis that DWIHLs represent the effects of chronic hypertensive vasculopathy and acute blood pressure elevation. Furthermore, DWIHLs portend poor prognosis after ICH, particularly in deep hemorrhages.

Background and Purpose— The purpose of these guidelines is to provide an up-to-date comprehensive set of recommendations in a single document for clinicians caring for adult patients with acute arterial ischemic stroke. The intended audiences are prehospital care providers, physicians, allied health professionals, and hospital administrators. These guidelines supersede the 2013 Acute Ischemic Stroke (AIS) Guidelines and are an update of the 2018 AIS Guidelines. Methods— Members of the writing group were appointed by the American Heart Association (AHA) Stroke Council’s Scientific Statements Oversight Committee, representing various areas of medical expertise. Members were not allowed to participate in discussions or to vote on topics relevant to their relations with industry. An update of the 2013 AIS Guidelines was originally published in January 2018. This guideline was approved by the AHA Science Advisory and Coordinating Committee and the AHA Executive Committee. In April 2018, a revision to these guidelines, deleting some recommendations, was published online by the AHA. The writing group was asked review the original document and revise if appropriate. In June 2018, the writing group submitted a document with minor changes and with inclusion of important newly published randomized controlled trials with >100 participants and clinical outcomes at least 90 days after AIS. The document was sent to 14 peer reviewers. The writing group evaluated the peer reviewers’ comments and revised when appropriate. The current final document was approved by all members of the writing group except when relationships with industry precluded members from voting and by the governing bodies of the AHA. These guidelines use the American College of Cardiology/AHA 2015 Class of Recommendations and Level of Evidence and the new AHA guidelines format. Results— These guidelines detail prehospital care, urgent and emergency evaluation and treatment with intravenous and intra-arterial therapies, and in-hospital management, including secondary prevention measures that are appropriately instituted within the first 2 weeks. The guidelines support the overarching concept of stroke systems of care in both the prehospital and hospital settings. Conclusions— These guidelines provide general recommendations based on the currently available evidence to guide clinicians caring for adult patients with acute arterial ischemic stroke. In many instances, however, only limited data exist demonstrating the urgent need for continued research on treatment of acute ischemic stroke.

ObjectiveTo clarify whether recurrence risk for intracerebral hemorrhage (ICH) is higher among black and Hispanic individuals and whether this disparity is attributable to differences in blood pressure (BP) measurements and their variability.MethodsWe analyzed data from survivors of primary ICH enrolled in 2 separate studies: (1) the longitudinal study conducted at Massachusetts General Hospital (n = 759), and (2) the ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage) study (n = 1,532). Participants underwent structured interview at enrollment (including self-report of race/ethnicity) and were followed longitudinally via phone calls and review of medical records. We captured systolic BP (SBP) and diastolic BP measurements, and quantified variability as SBP and diastolic BP variation coefficients. We used multivariable (Cox regression) survival analysis to identify risk factors for ICH recurrence.ResultsWe followed 2,291 ICH survivors (1,121 white, 529 black, 605 Hispanic, and 36 of other race/ethnicity). Both black and Hispanic patients displayed higher SBP during follow-up (p < 0.05). Black participants also displayed greater SBP variability during follow-up (p = 0.032). In univariable analyses, black and Hispanic patients were at higher ICH recurrence risk (p < 0.05). After adjusting for BP measurements and their variability, both Hispanic (hazard ratio = 1.51, 95% confidence interval 1.14–2.00, p = 0.004) and black (hazard ratio = 1.98, 95% confidence interval 1.36–2.86, p < 0.001) patients remained at higher risk of ICH recurrence.ConclusionBlack and Hispanic patients are at higher risk of ICH recurrence; hypertension severity (average BP and its variability) does not fully account for this finding. Additional studies will be required to further elucidate determinants for this health disparity.

Background: Apparent diffusion coefficient (ADC) imaging is a biomarker of cytotoxic injury that predicts edema formation and outcome after ischemic stroke. It therefore has the potential to serve as a “tissue clock” to describe the extent of ischemic injury and potentially predict response to therapy. The goal of this study was to determine the relationship between baseline ADC signal intensity, revascularization, and edema formation. Methods: We examined the ADC signal intensity ratio (ADCr) of the stroke lesion (defined as the baseline DWI hyperintense region) compared to the contralateral normal hemisphere in 65 subjects from the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy trial. The associations between ADCr, neurologic outcome, and cerebral edema were examined. Finally, we explored the interaction between baseline ADCr and vessel recanalization at day 7 on post-stroke edema. Results: We found that lower initial ADCr was associated with a worse outcome on the modified Rankin Scale (mRS) at 90 days (52.2% of those with ADCr p = 0.006). Those subjects with reconstitution of flow distal to the initial vessel occlusion showed greater normalization of ADCr on follow-up scan (increase in ADCr of 16.4 ± 2.07 vs. 1.99 ± 4.33%, p = 0.0039). In those patients with low baseline ADCr, successful revascularization was associated with reduced edema (median swelling volume 164 mL [interquartile range (IQR) 53.3–190 mL] vs. 20.7 mL [IQR 3.20–55.1 mL], p = 0.024). Conclusions: This study reaffirms the association of ADCr with outcome after stroke, supports the idea that reperfusion may attenuate rather than enhance post-stroke edema, and indicates that the degree of edema with and without revascularization may be predicted by ADCr.

Background and Purpose— We assessed whether the presence, number, and distribution of cerebral microbleeds (CMBs) on pre-intravenous thrombolysis MRI scans of acute ischemic stroke patients are associated with an increased risk of intracerebral hemorrhage (ICH) or poor functional outcome. Methods— We performed an individual patient data meta-analysis, including prospective and retrospective studies of acute ischemic stroke treated with intravenous tissue-type plasminogen activator. Using multilevel mixed-effects logistic regression, we investigated associations of pre-treatment CMB presence, burden (1, 2–4, ≥5, and >10), and presumed pathogenesis (cerebral amyloid angiopathy defined as strictly lobar CMBs and noncerebral amyloid angiopathy) with symptomatic ICH, parenchymal hematoma (within [parenchymal hemorrhage, PH] and remote from the ischemic area [remote parenchymal hemorrhage, PHr]), and poor 3- to 6-month functional outcome (modified Rankin score >2). Results— In 1973 patients from 8 centers, the crude prevalence of CMBs was 526 of 1973 (26.7%). A total of 77 of 1973 (3.9%) patients experienced symptomatic ICH, 210 of 1806 (11.6%) experienced PH, and 56 of 1720 (3.3%) experienced PHr. In adjusted analyses, patients with CMBs (compared with those without CMBs) had increased risk of PH (odds ratio: 1.50; 95% confidence interval: 1.09–2.07; P =0.013) and PHr (odds ratio: 3.04; 95% confidence interval: 1.73–5.35; P P =0.014), PH ( P =0.013), and PHr ( P 10 CMBs independently predicted poor 3- to 6-month outcome (odds ratio: 1.85; 95% confidence interval: 1.10–3.12; P =0.020; and odds ratio: 3.99; 95% confidence interval: 1.55–10.22; P =0.004, respectively). Conclusions— Increasing CMB burden is associated with increased risk of ICH (including PHr) and poor 3- to 6-month functional outcome after intravenous thrombolysis for acute ischemic stroke.

Background and Purpose— Statin use may be associated with improved outcome in intracerebral hemorrhage patients. However, the topic remains controversial. Our analysis examined the effect of prior, continued, or new statin use on intracerebral hemorrhage outcomes using the ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage) data set. Methods— We analyzed ERICH (a multicenter study designed to examine ethnic variations in the risk, presentation, and outcomes of intracerebral hemorrhage) to explore the association of statin use and hematoma growth, mortality, and 3-month disability. We computed subset analyses with respect to 3 statin categories (prior, continued, or new use). Results— Two thousand four hundred and fifty-seven enrolled cases (mean age, 62 years; 42% females) had complete data on mortality and 3-month disability (modified Rankin Scale). Among those, 1093 cases were on statins (prior, n=268; continued, n=423; new, n=402). Overall, statin use was associated with reduced mortality and disability without any effect on hematoma growth. This association was primarily driven by continued/new statin use. A multivariate analysis adjusted for age and major predictors for poor outcome showed that continued/new statins users had good outcomes compared with prior users. However, statins may have been continued/started more frequently among less severe patients. When a propensity score was developed based on factors that could influence a physician’s decision in prescribing statins and used as a covariate, continued/new statin use was no longer a significant predictor of good outcome. Conclusions— Although statin use, especially continued/new use, was associated with improved intracerebral hemorrhage outcomes, this effect may merely reflect the physician’s view of a patient’s prognosis rather than a predictor of survival.

Rapid revascularization is highly effective for acute stroke, but animal studies suggest that reperfusion edema may attenuate its beneficial effects. We investigated the relationship between reperfusion and edema in patients from the Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) and Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) cohorts. Reperfusion percentage was measured as the difference in perfusion-weighted imaging lesion volume between baseline and follow-up (day 3–5 for EPITHET; day 6–8 for MR RESCUE). Midline shift (MLS) and swelling volume were quantified on follow-up MRI. We found that reperfusion was associated with less MLS (EPITHET: Spearman ρ = −0.46; P

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.

Introduction: Intracerebral hemorrhage (ICH) is the most severe subtype of stroke. Its mortality rate is high, and the majority of survivors suffer significant disability. The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study prospectively recruited 1000 non-Hispanic white, 1000 non-Hispanic black, and 1000 Hispanic spontaneous ICH cases to study the epidemiology and genomics of ICH. Herein, we report the primary determinants of 3-month outcome after ICH in a large, multi-ethnic cohort. Methods: Between 2010 and 2015, cases were prospectively recruited with uniform data collection and phenotype definitions, centralized neuroimaging review, and telephone follow-up at 3 months. Individual characteristics were screened for association with 3-month outcome of modified Rankin Scale (mRS) ≥4 versus ≤3 under a logistic regression model, and those meeting P

Highlights • Probabilistic filter with active contours to automate cerebrovascular segmentation. • Geometric features of vessel network to study cerebrovascular diseases. • Quantitative comparison of stroke and healthy cerebral vasculature. • Vascular changes with aging and cerebrovascular disease. • Comparison of CTA and MRA imaging modalities., Accurate segmentation of cerebral vasculature and a quantitative assessment of its morphology is critical to various diagnostic and therapeutic purposes and is pertinent to studying brain health and disease. However, this is still a challenging task due to the complexity of the vascular imaging data. We propose an automated method for cerebral vascular segmentation without the need of any manual intervention as well as a method to skeletonize the binary segmented map to extract vascular geometric features and characterize vessel structure. We combine a Hessian-based probabilistic vessel-enhancing filtering with an active-contour-based technique to segment magnetic resonance and computed tomography angiograms (MRA and CTA) and subsequently extract the vessel centerlines and diameters to calculate the geometrical properties of the vasculature. Our method was validated using a 3D phantom of the Circle-of-Willis region, demonstrating 84% mean Dice similarity coefficient (DSC) and 85% mean Pearson’s correlation coefficient (PCC) with minimal modified Hausdorff distance (MHD) error (3 surface pixels at most), and showed superior performance compared to existing segmentation algorithms upon quantitative comparison using DSC, PCC and MHD. We subsequently applied our algorithm to a dataset of 40 subjects, including 1) MRA scans of healthy subjects (n = 10, age = 30 ± 9), 2) MRA scans of stroke patients (n = 10, age = 51 ± 15), 3) CTA scans of healthy subjects (n = 10, age = 62 ± 12), and 4) CTA scans of stroke patients (n = 10, age = 68 ± 11), and obtained a quantitative comparison between the stroke and normal vasculature for both imaging modalities. The vascular network in stroke patients compared to age-adjusted healthy subjects was found to have a significantly (p

Importance The etiology and significance of diffusion-weighted imaging (DWI) lesions in patients with acute intracerebral hemorrhage (ICH) remain unclear. Objective To evaluate which factors are associated with DWI lesions, whether associated factors differ by ICH location, and whether DWI lesions are associated with functional outcomes. Design, Setting, and Participants This analysis pooled individual patient data from 3 randomized clinical trials (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial, Antihypertensive Treatment of Acute Cerebral Hemorrhage trial, and Intracerebral Hemorrhage Deferoxamine phase 2 trial) and 1 multicenter prospective study (Ethnic/Racial Variations of Intracerebral Hemorrhage). Patients were enrolled from August 1, 2010, to September 30, 2018. Of the 4782 patients, 1788 who underwent magnetic resonance imaging scans of the brain were included. Data were analyzed from July 1 to December 31, 2019. Main Outcomes and Measures The primary outcome consisted of factors associated with DWI lesions. Secondary outcomes were poor functional outcome, defined as a modified Rankin score (mRS) of 4 to 6, and mortality, both assessed at 3 months. Mixed-effects logistic regression was used to evaluate the association between exposures and outcomes. Subgroup analyses stratified by hematoma location were performed. Results After exclusion of 36 patients with missing data on DWI lesions, 1752 patients were included in the analysis (1019 men [58.2%]; mean [SD] age, 60.8 [13.3] years). Diffusion-weighted imaging lesions occurred in 549 patients (31.3%). In mixed-effects regression models, factors associated with DWI lesions included younger age (odds ratio [OR] per year, 0.98; 95% CI, 0.97-0.99), black race (OR, 1.64; 95% CI, 1.17-2.30), admission systolic blood pressure (OR per 10–mm Hg increase, 1.13; 95% CI, 1.08-1.18), baseline hematoma volume (OR per 10-mL increase, 1.12; 95% CI, 1.02-1.22), cerebral microbleeds (OR, 1.85; 95% CI, 1.39-2.46), and leukoaraiosis (OR, 1.59; 95% CI, 1.67-2.17). Diffusion-weighted imaging lesions were independently associated with poor mRS (OR, 1.50; 95% CI, 1.13-2.00), but not with mortality (OR, 1.11; 95% CI, 0.72-1.71). In subgroup analyses, similar factors were associated with DWI lesions in lobar and deep ICH. Diffusion-weighted imaging lesions were associated with poor mRS in deep but not lobar ICH. Conclusions and Relevance In a large, heterogeneous cohort of prospectively identified patients with ICH, results were consistent with the hypothesis that DWI lesions represent acute sequelae of chronic cerebral small vessel disease, particularly hypertensive vasculopathy. Diffusion-weighted imaging lesions portend a worse prognosis after ICH, mainly deep hemorrhages.

Background and Purpose— Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. Methods— We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P − 8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0–2 versus 3–6) modified Rankin Scale using ordinal and logistic regression, respectively. Results— The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; P =4.4×10 −8 ) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; P =4.3×10 −8 ) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 ( P =0.04; meta-analysis P =2.5×10 −9 ; heterogeneity, P =0.16) but not for 22q13 ( P =0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P =0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P =0.045). Conclusions— We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.

For stroke rehabilitation and recovery, 2017 was a year of reviews and research advances. Reviews included all aspects of poststroke rehabilitation and recovery. Cognitive rehabilitation for memory deficits was effective for memory improvements in the short term, but not in the long term.1 Circuit class therapy could improve mobility after stroke in a clinically meaningful way, even after 12 months poststroke.2 Electromechanical-assisted training for walking was most beneficial for subacute stroke survivors who were not ambulatory.3 Repetitive task training was effective regardless of the amount of task practice, type of intervention, or time since stroke.4 Physical activity training could positively affect poststroke cognition with small-to-moderate treatment effects that were apparent even in the chronic stroke phase.5 In all cases, more research was required to improve the quality of the findings, and a review of poststroke fatigue reported that the overall quality of the research was poor.6 Discovery research provided more insight into basic aspects of stroke rehabilitation and recovery. Stradecki-Cohan et al7 studied Sprague–Dawley rats subjected to 5 to 6 days of no (0 m/min), mild (6 m/min), moderate (10 m/min), or heavy (15–18 m/min) treadmill exercise 3 to 4 days poststroke and demonstrated that moderate exercise enhanced cognitive function for 1 week after exercise completion, independent of changes in physical fitness. Chang et al8 demonstrated that the number of Met alleles in brain-derived neurotrophic factor genotypes and corticospinal tract (CST) functional integrity may be independent predictors of upper extremity motor outcome 3 months poststroke. Tu et al9 found that concentrations of FABP4 (fatty acid–binding protein 4), an intracellular lipid chaperone involved in coordination of lipid transportation and atherogenesis, were a novel independent prognostic marker for poor functional outcome and mortality 3 months poststroke. Imaging of the CST also played a …

The purpose of these guidelines is to provide an up-to-date comprehensive set of recommendations for clinicians caring for adult patients with acute arterial ischemic stroke in a single document. The intended audiences are prehospital care providers, physicians, allied health professionals, and hospital administrators. These guidelines supersede the 2013 guidelines and subsequent updates.Members of the writing group were appointed by the American Heart Association Stroke Council's Scientific Statements Oversight Committee, representing various areas of medical expertise. Strict adherence to the American Heart Association conflict of interest policy was maintained. Members were not allowed to participate in discussions or to vote on topics relevant to their relations with industry. The members of the writing group unanimously approved all recommendations except when relations with industry precluded members voting. Prerelease review of the draft guideline was performed by 4 expert peer reviewers and by the members of the Stroke Council's Scientific Statements Oversight Committee and Stroke Council Leadership Committee. These guidelines use the American College of Cardiology/American Heart Association 2015 Class of Recommendations and Levels of Evidence and the new American Heart Association guidelines format.These guidelines detail prehospital care, urgent and emergency evaluation and treatment with intravenous and intra-arterial therapies, and in-hospital management, including secondary prevention measures that are appropriately instituted within the first 2 weeks. The guidelines support the overarching concept of stroke systems of care in both the prehospital and hospital settings.These guidelines are based on the best evidence currently available. In many instances, however, only limited data exist demonstrating the urgent need for continued research on treatment of acute ischemic stroke.

Introduction: Hyperacute injury marker (HARM) is extrahematomal CNS barrier disruption in ICH marked by enhancement on post-gadolinium FLAIR sequences. We sought to identify factors associated with HARM development over time in a prospective ICH pilot study. Methods: We conducted a longitudinal MRI-based study of primary ICH with images at baseline and 90 days. After excluding subjects without post-gadolinium FLAIR sequences and those without usable images, we evaluated HARM formation along with other MRI markers of vasculopathy, including microbleeds, lacunes, white matter disease, cortical superficial siderosis, and enlarged perivascular spaces. HARM severity was scored as 0 (absent), 1 (1 to 3 sulci affected across fewer than 10 slices), 2 (dispersed involvement; more than 3 sulci), or 3 (widespread, confluent involvement over the hemisphere). Imaging review was blinded to clinical variables. Univariate analyses were performed at both time points. Results: Of 29 subjects with usable baseline sequences, 11 (37.9%) had HARM, compared to 12/18 (66.7%) at 90 days. Twelve subjects had usable sequences at both time points, and 4 (33%) of these had HARM at both time points. HARM was most frequently noted in the temporal and occipital lobes. At baseline, HARM severity was 1 in 7 subjects, 2 in 2 subjects, and 3 in 2 subjects. At 90 days, HARM severity was 1 in 10 subjects, 2 in 1 subject, and 3 in 1 subject. HARM was distinct from parenchymal T1 enhancement on visual inspection. We did not identify statistically significant associations between HARM formation and subject demographics, vascular risk factors, hematoma characteristics, or MRI markers of vasculopathy. Conclusions: In this pilot study we found a high prevalence of HARM at baseline and 90 days. Future studies will examine whether HARM is associated with the formation of new CNS lesions or poor outcomes. HARM appears to be a second type of CNS barrier disruption and may represent a therapeutic target.

Rationale Endovascular treatment has been shown to restore blood flow effectively. Second-generation medical devices such as stent retrievers are now showing overwhelming efficacy in clinical trials, particularly in conjunction with intravenous recombinant tissue plasminogen activator. Aims and Design This statistical analysis plan utilizing a novel, sequential approach describes a prospective, individual patient data analysis of endovascular therapy in conjunction with intravenous recombinant tissue plasminogen activator agreed upon by the Thrombectomy and Tissue Plasminogen Activator Collaborative Group. Study outcomes This protocol will specify the primary outcome for efficacy, as ‘favorable’ outcome defined by the ordinal distribution of the modified Rankin Scale measured at three-months poststroke, but with modified Rankin Scales 5 and 6 collapsed into a single category. The primary analysis will aim to answer the questions: ‘what is the treatment effect of endovascular therapy with intravenous recombinant tissue plasminogen activator compared to intravenous tissue plasmi-nogen activator alone on full scale modified Rankin Scale at 3 months?’ and ‘to what extent do key patient characteristics influence the treatment effect of endovascular therapy?’. Key secondary outcomes include effect of endovascular therapy on death within 90 days; analyses of modified Rankin Scale using dichotomized methods; and effects of endovascular therapy on symptomatic intracranial hemorrhage. Several secondary analyses will be considered as well as expanding patient cohorts to intravenous recombinant tissue plasminogen activator-ineligible patients, should data allow. Discussion This collaborative meta-analysis of individual participant data from randomized trials of endovascular therapy vs. control in conjunction with intravenous thrombolysis will demonstrate the efficacy and generalizability of endovascular therapy with intravenous thrombolysis as a concomitant medication.

Endovascular therapy for acute stroke has evolved with the use of intra-arterial thrombolytics, intravenous/intra-arterial bridging strategies, and mechanical thrombectomy/aspiration devices. Despite widespread use in clinical practice, randomized trials of first-generation devices failed to demonstrate improved outcomes compared with standard care. New-generation stent retriever devices demonstrate higher rates of revascularization and clinical outcomes compared with first-generation devices. Additional randomized trials are underway and have the potential to confirm clinical efficacy of new-generation devices compared with standard care. The role of additional advanced imaging for patient selection remains unclear, and further trials are needed to demonstrate the role of these techniques for patient selection.

OBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease. METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084). RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes. CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry./n© 2015 American Academy of Neurology. Kristiina Rannikmäe is supported by the Edinburgh and Lothians Health Foundation REMIND Fund and Stroke Research and Amenities Endowments Fund; Cathie Sudlow is supported by the Scottish Funding Council; Gail Davies is supported by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1), BBSRC and Medical Research Council (MSRC). Tom Van Agtmael is supported by the Kidney Research UK project grant RP19/2012. Details of funding for the studies contributing to the ICH GWAS can be found in: Woo D, Falcone GJ, Devan WJ, et al. Meta-analysis of genome-wide association studies identifies 1q22 as a novel susceptibility locus for intracerebral hemorrhage. American Journal of Human Genetics 2014;pii: S0002-9297(14)00070-6. doi:10.1016/j.ajhg.2014.02.012. [Epub ahead of print]. Details of funding for the studies contributing to the ischaemic stroke GWAS can be found in: Traylor M, Farrall M, Holliday EG, et al. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies. Lancet Neurology 2012;11:951-962. Details of funding for the studies contributing to the WMH in ischaemic stroke GWAS can be found in: Adib-Samii P, Rost N, Traylor M, et al. 17q25 Locus Is Associated With White Matter Hyperintensity Volume in Ischaemic Stroke, But Not With Lacunar Stroke Status. Stroke 2013;44:1609-1615. Details of funding for the studies contributing to the WMH in population GWAS can be found in: Fornage M, Debette S, Bis JC, et al. Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium. Annals of Neurology 2011;69:928-939. Martin Dichgans is supported by the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain); Guido J Falcone is supported by the NIH / NINDS grant P50NS061343; Chistopher D Anderson is supported by the American Brain Foundation Clinical Research Training Fellowship, NIH-NINDS K23NS086873, Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care SPARK award; Jonathan Rosand is supported by the NIH / NINDS grant R01NS059727.

Acute endovascular therapy for ischemic stroke is at a pivotal juncture. Until recently, on the basis of randomized trials comparing devices, we knew that endovascular treatment options were effective in quickly restoring blood flow and that successful early recanalization was associated with better functional outcome when compared with sustained occlusion.1,2 We did not have randomized evidence that available acute endovascular therapy improved patient outcomes; the 3 initial randomized controlled trials of endovascular recanalization treatment published in February of 2013—the Phase II Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), Phase III Interventional Management of Stroke (IMS) III, and Local Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS) trials—failed to demonstrate improved clinical outcomes.3–5 Many factors may have contributed to the failure of these 3 initial trials to show endovascular benefits. These trials were performed during a period of rapid evolution of imaging and treatment options, and used intra-arterial thrombolysis, or first-generation device therapies at best, with little use of newer generation devices, such as stent retrievers, demonstrated to achieve significantly higher rates of recanalization.1,2 Patients with mild or moderate stroke severity may have been less likely to benefit from endovascular reperfusion based on IMS III and Prolyse in Acute Cerebral Thromboembolism (PROACT) II post hoc analyses and others.3,6,7 The power of these trials was diluted by including subjects without intracranial vessel occlusions, and post hoc analyses of IMS III suggested a potential treatment effect among stroke patients with baseline computed tomographic (CT) angiographic occlusions.8 Larger vessel occlusions, which are more resistant to recanalization by intravenous recombinant tissue-type plasminogen activator (r-tPA), such as intracranial internal carotid artery (ICA) location or occlusions >8 mm, may have been more likely to show a treatment effect …

Background and Purpose— Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) has been used to estimate diffusion-weighted imaging (DWI) lesion volume in acute stroke. We aimed to assess correlations of DWI-ASPECTS with lesion volume in different middle cerebral artery (MCA) subregions and reproduce existing ASPECTS thresholds of a malignant profile defined by lesion volume ≥100 mL. Methods— We analyzed data of patients with MCA stroke from a prospective observational study of DWI and fluid-attenuated inversion recovery in acute stroke. DWI-ASPECTS and lesion volume were calculated. The population was divided into subgroups based on lesion localization (superficial MCA territory, deep MCA territory, or both). Correlation of ASPECTS and infarct volume was calculated, and receiver-operating characteristics curve analysis was performed to identify the optimal ASPECTS threshold for ≥100-mL lesion volume. Results— A total of 496 patients were included. There was a significant negative correlation between ASPECTS and DWI lesion volume ( r =–0.78; P r =–0.19; P =0.038) when compared with superficial ( r =–0.72; P r =–0.72; P Conclusions— ASPECTS has limitations when lesion location is not considered. Identification of patients with malignant profile by DWI-ASPECTS may be unreliable. ASPECTS may be a useful tool for the evaluation of noncontrast computed tomography. However, if MRI is used, ASPECTS seems dispensable because lesion volume can easily be quantified on DWI maps.

Background and Purpose- We assessed whether the presence, number, and distribution of cerebral microbleeds (CMBs) on pre-intravenous thrombolysis MRI scans of acute ischemic stroke patients are associated with an increased risk of intracerebral hemorrhage (ICH) or poor functional outcome. Methods- We performed an individual patient data meta-analysis, including prospective and retrospective studies of acute ischemic stroke treated with intravenous tissue-type plasminogen activator. Using multilevel mixed-effects logistic regression, we investigated associations of pre-treatment CMB presence, burden (1, 2-4, ≥5, and10), and presumed pathogenesis (cerebral amyloid angiopathy defined as strictly lobar CMBs and noncerebral amyloid angiopathy) with symptomatic ICH, parenchymal hematoma (within [parenchymal hemorrhage, PH] and remote from the ischemic area [remote parenchymal hemorrhage, PHr]), and poor 3- to 6-month functional outcome (modified Rankin score2). Results- In 1973 patients from 8 centers, the crude prevalence of CMBs was 526 of 1973 (26.7%). A total of 77 of 1973 (3.9%) patients experienced symptomatic ICH, 210 of 1806 (11.6%) experienced PH, and 56 of 1720 (3.3%) experienced PHr. In adjusted analyses, patients with CMBs (compared with those without CMBs) had increased risk of PH (odds ratio: 1.50; 95% confidence interval: 1.09-2.07; P=0.013) and PHr (odds ratio: 3.04; 95% confidence interval: 1.73-5.35; P0.001) but not symptomatic ICH. Both cerebral amyloid angiopathy and noncerebral amyloid angiopathy patterns of CMBs were associated with PH and PHr. Increasing CMB burden category was associated with the risk of symptomatic ICH ( P=0.014), PH ( P=0.013), and PHr ( P0.00001). Five or more and10 CMBs independently predicted poor 3- to 6-month outcome (odds ratio: 1.85; 95% confidence interval: 1.10-3.12; P=0.020; and odds ratio: 3.99; 95% confidence interval: 1.55-10.22; P=0.004, respectively). Conclusions- Increasing CMB burden is associated with increased risk of ICH (including PHr) and poor 3- to 6-month functional outcome after intravenous thrombolysis for acute ischemic stroke.

The neuroimaging workup for patients with suspected acute ischemic stroke has advanced significantly over the past few decades. Evaluation is no longer limited to noncontrast computed tomography (CT), but now frequently also includes vascular and perfusion imaging. Although acute stroke imaging has made significant progress with the development of multimodal approaches, there are still many unanswered questions regarding their appropriate use in daily patient care. It is important for all physicians taking care of stroke patients to be familiar with current multimodal CT and magnetic resonance imaging (MRI) techniques, including their strengths, limitations, and their role in guiding therapy.

Objective:To evaluate the associations among diffusion-weighted imaging (DWI) lesions, blood pressure (BP) dysregulation, MRI markers of small vessel disease, and poor outcome in a large, prospective study of primary intracerebral hemorrhage (ICH).Methods:The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a multicenter, observational study of ICH among white, black, and Hispanic patients.Results:Of 600 patients, mean (±SD) age was 60.8 ± 13.6 years, median (interquartile range) ICH volume was 9.1 mL (3.5–20.8), and 79.6% had hypertension. Overall, 26.5% of cases had DWI lesions, and this frequency differed by race/ethnicity (black 33.8%, Hispanic 24.9%, white 20.2%, overallp= 0.006). A logistic regression model of variables associated with DWI lesions included lower age (odds ratio [OR] 0.721,p= 0.002), higher first recorded systolic BP (10-unit OR 1.12,p= 0.002), greater change in mean arterial pressure (MAP) prior to the MRI (10-unit OR 1.10,p= 0.037), microbleeds (OR 1.99,p= 0.008), and higher white matter hyperintensity (WMH) score (1-unit OR 1.16,p= 0.002) after controlling for race/ethnicity, leukocyte count, and acute in-hospital antihypertensive treatment. A second model of variables associated with poor 90-day functional outcome (modified Rankin Scale scores 4–6) included DWI lesion count (OR 1.085,p= 0.034) as well as age, ICH volume, intraventricular hemorrhage, Glasgow Coma Scale score, WMH score, race/ethnicity, acute in-hospital antihypertensive treatment, and ICH location.Conclusions:These results support the hypotheses that acute BP dysregulation is associated with the development of DWI lesions in primary ICH and that DWI lesions are, in turn, associated with poor outcomes.

Background: Since the introduction of recombinant tissue plasminogen activator (rt-PA) for acute ischemic stroke, rt-PA rate and number of stroke centers have increased. Despite this, studies have shown racial and ethnic disparities in stroke care especially in Black and Hispanic populations. How Hispanic ethnicity affects rt-PA evaluations has to date been unclear. In our patient population, we investigated whether ethnicity is associated with rt-PA use for acute ischemic strokes in the Hispanic population. Methods: We performed a retrospective review of IRB approved, prospectively collected data from the UC San Diego Stroke Registry. Patients were selected based on the presentation and primary diagnosis of Transient Ischemic Attack or Ischemic Stroke. Characteristics including risk factors were compared in Hispanic vs non-Hispanic samples to assess rt-PA treatment rates, process of care intervals for Hispanics vs non-Hispanics and rt-PA vs non-rt-PA patients. Results: We assessed 1489 patients (300 Hispanic vs. 1189 non-Hispanic whites) from July 2004 to July 2016. Comparing Hispanics to non-Hispanics, there was no difference in rt-PA rate (35.3% vs. 33.1%; p=0.49). In a subset evaluation of Hispanics only, comparing rt-PA(-) to rt-PA(+), there was no difference for male sex (56%), Hypertension (71%), Hyperlipidemia (29%), Diabetes (43%), Atrial Fibrillation (23%), and Smoking (20%). There was a noted difference in the Hispanic-only untreated vs treated subset for initial NIHSS (7.24 vs. 13.27; p Conclusions: This study shows the rate of rt-PA treatment and “door to treatment” intervals were not significantly different in Hispanic vs non-Hispanic patients. This data is supportive of current overall treatment decision models. However, the “onset to treatment” interval was significantly longer for Hispanic patients showing that it may take longer for this population to reach the treating hospital. This supports the need to develop culturally relevant education programs to address barriers in this population.

Introduction: In observational studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of spontaneous intracerebral hemorrhage (ICH). Common DNA sequence variants within the cholesteryl ester transfer protein ( CETP ) gene decrease CETP protein activity and increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development to combat coronary artery disease. Hypothesis: Common CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. Methods: We performed a two-stage case-control genetic association study in Caucasians. The discovery phase utilized data on 12 independent loci within CETP (+/- 50 kilobases) from 3 genome-wide association studies of ICH. Replication involved direct genotyping in 5 additional studies. We also constructed a genetic risk score with 7 independent CETP variants and tested it for association with HDL-C and ICH risk. We used principal component analysis to account for population structure and a Bonferroni-adjusted p Results: The discovery phase included 1149 ICH cases (43% lobar hemorrhages) and 1238 controls. Twelve variants were nominally associated (p-4 ) and no heterogeneity across studies (I 2 =0%). This association was replicated in 1625 cases (43% lobar hemorrhages) and 1845 controls (OR 1.12, 95%CI 1.02-1.24; p=0.03). A genetic score of independent CETP variants known to increase HDL-C by ~2.85 mg/dL was strongly associated with ICH risk (OR 1.86, 95%CI 1.44-2.40; p=1.4x10 -6 ). Conclusion: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes is warranted.

Background and Purpose— Acute stroke education has focused on stroke symptom recognition. Lack of education about stroke preparedness and appropriate actions may prevent people from seeking immediate care. Few interventions have rigorously evaluated preparedness strategies in multiethnic community settings. Methods— The Acute Stroke Program of Interventions Addressing Racial and Ethnic Disparities (ASPIRE) project is a multilevel program using a community-engaged approach to stroke preparedness targeted to underserved black communities in the District of Columbia. This intervention aimed to decrease acute stroke presentation times and increase intravenous tissue-type plasminogen activator utilization for acute ischemic stroke. Results— Phase 1 included (1) enhancement of focus of emergency medical services on acute stroke; (2) hospital collaborations to implement and enrich acute stroke protocols and transition District of Columbia hospitals toward primary stroke center certification; and (3) preintervention acute stroke patient data collection in all 7 acute care District of Columbia hospitals. A community advisory committee, focus groups, and surveys identified perceptions of barriers to emergency stroke care. Phase 2 included a pilot intervention and subsequent citywide intervention rollout. A total of 531 community interventions were conducted, reaching >10 256 participants; 3289 intervention evaluations were performed, and 19 000 preparedness bracelets and 14 000 stroke warning magnets were distributed. Phase 3 included an evaluation of emergency medical services and hospital processes for acute stroke care and a year-long postintervention acute stroke data collection period to assess changes in intravenous tissue-type plasminogen utilization. Conclusions— We report the methods, feasibility, and preintervention data collection efforts of the ASPIRE intervention. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00724555.

Stroke is a leading cause of long-term adult disability worldwide. Only a small proportion of stroke survivors (≈14%) achieve full recovery of activities of daily living, whereas 25% to 50% require some assistance and approximately half experience long-term dependency.1 Prediction of outcome after ischemic stroke, therefore, is important for setting realistic and attainable treatment goals, informing patients and their relatives properly, facilitating discharge planning, and anticipating possible consequences for home adjustments and community support.2 Moreover, knowledge of the expected recovery pattern is necessary to assess the effectiveness of new therapeutic interventions and their contribution to recovery and should be applied to select comparable patients populations for treatment trials.3 Several standardized measures assess various aspects of stroke outcome and recovery, including quantification of neurological deficits, functional outcome measures, and quality of life measures. Activities of daily living, including dressing, mobility, and bathing, are assessed most frequently by the Barthel Index4 and by the modified Rankin Scale (mRS)5 but also by the Glasgow Outcome Scale,6 the Functional Independence Measure,7 or other activities of daily living assessment tools.8 Frequently used measures of quality of life include the Stroke Impact Scale and European Quality of Life Scale (EQ-5D).9,10 A considerable number of prognostic stroke studies used the Barthel Index and the mRS as the primary outcome measure reached after 3 to 6 months and found that scores on scales assessing severity of neurological deficits such as the National Institutes of Healt Stroke Scale (NIHSS)11–13 and Canadian Neurological Scale14 in acute stroke (ie, within 72 hours) are strongly associated with outcome beyond 3 months.2,15 A systemic review of prognostic studies8 indicated that age and motor weakness were important predictive variables of outcome in addition to stroke …

Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.

In the article entitled "Imaging Recommendations for Acute Stroke and Transient Ischemic Attack Patients: A Joint Statement by the American Society of Neuroradiology, the American College of Radiology and the Society of NeuroInterventional Surgery", we are proposing a simple, pragmatic approach that will allow the reader to develop an optimal imaging algorithm for stroke patients at their institution.

BackgroundWhether brain imaging can identify patients who are most likely to benefit from therapies for acute ischemic stroke and whether endovascular thrombectomy improves clinical outcomes in such patients remains unclear. MethodsIn this study, we randomly assigned patients within 8 hours after the onset of large-vessel, anterior-circulation strokes to undergo mechanical embolectomy (Merci Retriever or Penumbra System) or receive standard care. All patients underwent pretreatment computed tomography or magnetic resonance imaging of the brain. Randomization was stratified according to whether the patient had a favorable penumbral pattern (substantial salvageable tissue and small infarct core) or a nonpenumbral pattern (large core or small or absent penumbra). We assessed outcomes using the 90-day modified Rankin scale, ranging from 0 (no symptoms) to 6 (dead). ResultsAmong 118 eligible patients, the mean age was 65.5 years, the mean time to enrollment was 5.5 hours, and 58% had a favorable penumbral patt...

Historically, recruitment of minority subjects for clinical research has been challenging. We developed culturally-tailored recruitment materials for a longitudinal, natural history study of intracerebral hemorrhage (ICH) and trained recruiting coordinators in cultural competence. Of 285 subjects meeting inclusion criteria, 158 (55% of those eligible) agreed to participate (60% of eligible Blacks vs. 45% of eligible non-Blacks, p..02). Of those enrolled, 138 (87%) agreed to participate in the genetic sub-study (86% of Blacks vs. 90% of non-Blacks enrolled, p..78). Of those subjects who refused enrollment, lack of interest in research (42%) was the most common reason given for the study as a whole. A higher rate of enrollment was achieved in Blacks vs. non-Blacks in this ICH clinical research study employing culturally tailored recruitment approaches and training of recruitment coordinators to overcome traditional recruitment barriers to research participation in minority patients.

Background and Purpose— Patients with acute ischemic stroke are at increased risk of developing parenchymal hemorrhage (PH), particularly in the setting of reperfusion therapies. We have developed a predictive model to examine the risk of PH using combined magnetic resonance perfusion and diffusion parameters, including cerebral blood volume (CBV), apparent diffusion coefficient, and microvascular permeability (K2). Methods— Voxel-based values of CBV, K2, and apparent diffusion coefficient from the ischemic core were obtained using pretreatment magnetic resonance imaging data from patients enrolled in the MR RESCUE clinical trial (Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy). The associations between PH and extreme values of imaging parameters were assessed in univariate and multivariate analyses. Receiver-operating characteristic curve analysis was performed to determine the optimal parameter(s) and threshold for predicting PH. Results— In 83 patients included in this analysis, 20 developed PH. Univariate analysis showed significantly lower 10th percentile CBV and 10th percentile apparent diffusion coefficient values and significantly higher 90th percentile K2 values within the infarction core of patients with PH. Using classification tree analysis, the 10th percentile CBV at threshold of 0.47 and 90th percentile K2 at threshold of 0.28 resulted in overall predictive accuracy of 88.7%, sensitivity of 90.0%, and specificity of 87.3%, which was superior to any individual or combination of other classifiers. Conclusions— Our results suggest that combined 10th percentile CBV and 90th percentile K2 is an independent predictor of PH in patients with acute ischemic stroke with diagnostic accuracy superior to individual classifiers alone. This approach may allow risk stratification for patients undergoing reperfusion therapies. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00389467.

Approximately 60% of patients with a clinical transient ischemic attack (TIA) do not have DWI evidence of cerebral ischemia. The purpose of this study was to assess the added diagnostic value of perfusion MRI in the evaluation of patients with TIA who have normal DWI findings.The inclusion criteria for this retrospective study were clinical presentation of TIA at admission with a discharge diagnosis of TIA confirmed by a stroke neurologist, MRI including both DWI and perfusion-weighted imaging within 48 hours of symptom onset, and no DWI lesion. Cerebral blood flow (CBF) and time to maximum of the residue function (Tmax) maps were evaluated independently by two observers. Multivariate analysis was used to assess perfusion findings; clinical variables; age, blood pressure, clinical symptoms, diabetes (ABCD2) score; duration of TIA; and time between MRI and onset and resolution of symptoms.Fifty-two patients (33 women, 19 men; age range, 20-95 years) met the inclusion criteria. A regional perfusion abnormality was identified on either Tmax or CBF maps of 12 of 52 (23%) patients. Seven (58%) of the patients with perfusion abnormalities had hypoperfused lesions best detected on Tmax maps; the other five had hyperperfusion best detected on CBF maps. In 11 of 12 (92%) patients with abnormal perfusion MRI findings, the regional perfusion deficit correlated with the initial neurologic deficits. Multivariable analysis revealed no significant difference in demographics, ABCD2 scores, or presentation characteristics between patients with and those without perfusion abnormalities.Perfusion MRI that includes Tmax and CBF parametric maps adds diagnostic value by depicting regions with delayed perfusion or postischemic hyperperfusion in approximately one-fourth of TIA patients who have normal DWI findings.

Introduction: Diffusion-weighted imaging (DWI) lesions in intracerebral hemorrhage (ICH) have been associated with vasculopathy, blood pressure (BP) lowering, and poor functional outcomes. We sought to identify predictors of DWI lesion formation and one-year case-fatality in ICH. Methods: In this retrospective study of primary ICH at our institution from 2009-2011, cases were identified by ICD-9 code and verified by physician review. Only subjects undergoing brain MRI within 72 hours of presentation were included. In addition to standard chart review, we abstracted all BPs available prior to MRI. Vasculopathy severity was assessed by white matter disease score and microbleed burden. Univariate analysis was stratified by DWI lesion presence; logistic regression analyses assessed predictors of DWI lesions and all-cause one-year case-fatality. Results: Of 500 subjects in the overall ICH cohort 98 met inclusion criteria for this analysis, of which 20 (20.4%) had DWI lesions. Selected univariate analysis is shown in the Table. In the best clinical model fit, intraventricular extension (OR 5.63 (1.60, 19.85), p=0.007), microbleeds (OR 3.43 (0.95, 12.34), p=0.06), and delta systolic BP lowering (((max systolic BP-min systolic BP)/max systolic BP)*100) (OR 0.97 (0.95, 0.99), p=0.0005) were associated with DWI lesion presence. Overall one-year case-fatality was 16.3%; age (OR 1.04 (1.00, 1.07), p=0.05), GCS (OR 1.30 (1.09, 1.56), p=0.004), and DWI lesions (OR 3.80 (1.14, 12.61), p=0.03) were independently associated. Conclusions: Predictors of DWI lesions in ICH include underlying vasculopathy but the impact of BP lowering on DWI lesion formation remains unclear. Further investigation of BP effects on DWI lesion formation is warranted with larger cohorts given the association with DWI lesions and one-year case-fatality. Future trials of BP control in ICH should consider stratifying by imaging biomarkers for underlying vasculopathy.

Purpose: Ischemic stroke patients with low cerebral blood volume (CBV), low apparent diffusion coefficient (ADC) and increased microvascular permeability (K2) have increased risk of parenchymal hemorrhage (PH) after recanalization therapies. We have developed a predictive model to examine the risk of PH following revascularization therapies using combined MR perfusion and diffusion biomarkers. Methods: Voxel-based values of rCBV, K2, and ADC from the infarction core were obtained using pre-treatment MRI data from patients enrolled in the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) clinical trial. Using histogram analyses the 10 th and 90 th percentile values were calculated for the rCBV, ADC, and K2 variables for each patient. The associations between PH and extreme values of CBV (10%rCBV), ADC (10%ADC), and K2 (90%K2) in each patient were assessed in univariate and multivariate analyses. Receiver operating characteristic (ROC) analysis was performed to determine the optimal parameter/s and threshold for predicting PH. Results: In 83 patients included in this analysis, 20 (24%, 13 PH1, 7 PH2) developed PH. Univariate analysis showed significantly lower 10%rCBV and 10%ADC values and significantly higher 90%K2 values in patients with PH. After controlling for age, baseline NIHSS, infarct volume, and status of recanalization, multivariate logistic regression analysis identified 10%rCBV (p=0.002) and 90%K2 (p=0.03), but not 10%ADC (p=0.07), as independent predictors of PH. For 10%RCBV, ROC analysis showed the greatest AUC (0.87) at a threshold < 0.45 with sensitivity/specificity of 95%70%. For 90%K2, the greatest AUC (0.75) was obtained at a threshold of > 0.27 with sensitivity/specificity of 90%/60%. In a separate model, a combined K2-rCBV classifier remained the single independent predictor of PH (OR=33). Conclusion: Our results suggest that combined increased permeability and decreased rCBV derived from MR perfusion can be used for risk stratification in patients with AIS before undergoing revascularization therapies.

Contains fulltext : 167830.pdf (Publisher’s version ) (Open Access) OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 x 10-4 ) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by approximately 2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 x 10-6 ). INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.

Background and Purpose— The National Institute of Neurological Disorders and Stroke initiated development of stroke-specific Common Data Elements (CDEs) as part of a project to develop data standards for funded clinical research in all fields of neuroscience. Standardizing data elements in translational, clinical, and population research in cerebrovascular disease could decrease study start-up time, facilitate data sharing, and promote well-informed clinical practice guidelines. Methods— A working group of diverse experts in cerebrovascular clinical trials, epidemiology, and biostatistics met regularly to develop a set of stroke CDEs, selecting among, refining, and adding to existing, field-tested data elements from national registries and funded trials and studies. Candidate elements were revised on the basis of comments from leading national and international neurovascular research organizations and the public. Results— The first iteration of the National Institute of Neurological Disorders and Stroke (NINDS) stroke-specific CDEs comprises 980 data elements spanning 9 content areas: (1) biospecimens and biomarkers; (2) hospital course and acute therapies; (3) imaging; (4) laboratory tests and vital signs; (5) long-term therapies; (6) medical history and prior health status; (7) outcomes and end points; (8) stroke presentation; and (9) stroke types and subtypes. A CDE website provides uniform names and structures for each element, a data dictionary, and template case report forms, using the CDEs. Conclusions— Stroke-specific CDEs are now available as standardized, scientifically vetted, variable structures to facilitate data collection and data sharing in cerebrovascular patient-oriented research. The CDEs are an evolving resource that will be iteratively improved based on investigator use, new technologies, and emerging concepts and research findings.

Objective: The objective of the study was to characterize a previously unreported form of CNS barrier disruption in intracerebral hemorrhage (ICH): hyperacute injury marker (HARM). Methods: In this retrospective cohort analysis of patients presenting with primary ICH, precontrast and postcontrast MRI scans obtained within 5 days of symptom onset were analyzed. The presence of CNS barrier disruption was defined by 1) perihematomal or intrahematomal enhancement visualized on postcontrast T1-weighted MRI or 2) HARM: sulcal or ventricular hyperintensity visualized on postcontrast fluid-attenuated inversion recovery sequences (graded on a 5-point scale). Results: Forty-six patients were included in the analysis. Mean age was 65 years, median NIH Stroke Scale score was 7, and mean ICH volume was 12.2 mL (range 0.3–46.9 mL). HARM was visualized in 85% of patients, and this was moderate to severe in 50%. In all cases, the sulcal enhancement was noncontiguous with the hematoma. Of those patients with postcontrast T1-weighted imaging, perihematomal or intrahematomal contrast enhancement was visualized in 75% of patients. Conclusions: This study demonstrates that HARM occurs in intracerebral hemorrhage and that it likely represents a second type of CNS barrier disruption distinct from parenchymal postcontrast T1-weighted enhancement. Similar to T1 enhancement, this phenomenon may serve as a clinically useful biomarker to test therapies aimed at stabilizing acute ICH and CNS barrier disruption. Future studies are needed to further define the time course and prognostic implications of this finding.

Rationale PROTECT DC examines whether stroke navigators can improve cardiovascular risk factors in urban underserved individuals newly hospitalized for stroke or ischemic attack. Within one-year of hospital discharge, up to one-third of patients no longer adhere to secondary prevention behaviors. Adherence rates are lower in minority-underserved groups, contributing to health disparities. In-hospital programs increase use of stroke prevention therapies but may not be as successful in underserved individuals. In these groups, low literacy, limited healthcare access, and sparse community resources may reduce adherence. Lay community health workers (navigators) improve adherence in other illnesses through education and assisting in overcoming barriers to achieving desired health behaviors and obtaining needed healthcare services. Aims and design PROTECT DC is a Phase II, single-blind, randomized, controlled trial comparing in-hospital education plus stroke navigators to usual care. Atherogenic ischemic stroke and transient ischemic attack survivors are recruited from Washington, DC hospitals. Navigators meet with participants during the index hospitalization, perform home visits, and meet by phone. They focus on stroke education, medication compliance, and overcoming practical barriers to adherence. The interventions are driven by the theories of reasoned action and planned behavior. Study outcomes The primary dependent measure is a summary score of four objective measures of stroke risk factor control: systolic blood pressure, low-density lipoprotein, hemoglobin Hb A1C, and antiplatelet agent pill counts. Secondary outcomes include stroke knowledge, exercise, dietary modification, and smoking cessation. Conclusion PROTECT DC will determine whether a Phase III trial of stroke navigation for urban underserved individuals to improve adherence to secondary stroke prevention behaviors is warranted.