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Background and Purpose— Patients with intracerebral hemorrhage (ICH) and atrial fibrillation (AF) are at risk for ischemic events. While risk calculators (CHA 2 DS 2 -VASc and HAS-BLED) have been validated to assess risk for ischemic stroke and major bleeding in AF patients, decisions about anticoagulation must consider the net clinical benefit of anticoagulation. Furthermore, stroke and bleeding risk are highly correlated, making decisions more difficult. Methods— We examined patients in the GERFHS III study (Genetic and Environmental Risk Factors for Hemorrhagic Stroke)—a population-based retrospective study of spontaneous ICH patients without a structural or traumatic cause in the Greater Cincinnati/Northern Kentucky region between July 2008 and December 2012. CHA 2 DS 2 -VASc and HAS-B(L)ED (minus L because labile international normalized ratio was unavailable) scores were calculated for ICH patients with AF. Using a Markov state transition model, we estimated net clinical benefit of anticoagulation relative to no treatment in quality-adjusted life years (QALYs). We defined minimal clinically relevant benefit as 0.1 QALYs. Results— Among 1186 cases of spontaneous ICH, 95 cases had AF and met our survival criteria. Within 1 year, 8 of 95 (8%) would be expected to have a major bleeding event on anticoagulation, and 5 of 95 (5%) of patients would be expected to have an ischemic stroke off anticoagulation. Sixty-eight of 95 (71%) patients would have higher risk for major bleeding than for ischemic stroke. Anticoagulation with directly acting anticoagulants would result in no clinically significant gain or loss in 73%. Roughly 12% would gain >0.1 QALYs, and 15% would lose >0.1 QALYs. Among patients receiving aspirin, most have no significant net clinical benefit or loss. Overall, anticoagulation of the entire cohort would result in an aggregate loss of 0.92 QALYs. Conclusions— Our analysis suggests that universal anticoagulation after ICH would be associated with a net loss of QALY. Additional factors should be considered before anticoagulating patients with AF after ICH. Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00930280.

Introduction: Data from the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS) through 2010 showed that over time, stroke incidence rates decreased to a greater extent in men than in women. We aimed to determine whether this difference continued through 2015 and whether the differences are driven by particular age groups. Methods: Within the GCNKSS population of 1.3 million, all incident strokes among residents ≥20 years old were ascertained at all local hospitals during 7/93–6/94 and calendar years 1999, 2005, 2010, and 2015. Out-of-hospital cases were sampled. Sex-specific incidence rates per 100,000 were adjusted for age and race, standardized to the 2010 U.S. Census. Trends over time by sex were compared (overall and age-stratified); a Bonferroni correction was applied for multiple comparisons. Results: In total over the five study periods, there were 9721 incident strokes (ischemic, ICH, and SAH); 56.4% were women. Incidence of ischemic strokes decreased from 254 (95%CI 236,272) in 1993/4 to 177 (95%CI 164,189) in 2015 among men (p Conclusions: Stroke incidence decreased between the early 1990s and 2015 for both sexes, contrary to previous data on trends through 2010 which demonstrated a significant decrease in men but not women. Temporal changes are being driven by the 65–84 year age group in both men and women, as well as the ≥ 85 age group in men. Future prevention strategies should target young and middle age adults for both sexes as well as those over 85 for women.

Background: Cerebellar lesions reportedly account for 2-7% of acute infarct visits, but this may be an underestimate since prior studies were not population-based or from the modern imaging era. Cerebellar symptoms are also often nonspecific such that increased MRI use might lead to a higher proportion of stroke due to cerebellar lesions. Details about presenting features of cerebellar infarcts and baseline medication use are also not well known. Methods: We used the 2010 Greater Cincinnati/Northern Kentucky Stroke Study. Strokes were identified by screening ICD9 codes 430-436 and physician verification. Infarct location was categorized as isolated cerebellar, mixed cerebellar (cerebellar plus ≥1 other location), or non-cerebellar. Isolated dizziness was defined as dizziness/vertigo without other focal symptoms. Atherosclerotic cardiovascular disease (ASCVD) 10-year risk scores were calculated. Descriptive statistics and multivariable logistic regression were used to compare infarct categories. Results: Isolated cerebellar lesions occurred in 4.6% (90/1940; 95% CI, 3.7%-5.7%) of infarct events. An additional 4% (77/1940; 95%CI, 3.1%-4.9%) were mixed cerebellar infarcts. Mixed cerebellar infarcts had clinical characteristics more similar to non-cerebellar events than to cerebellar events. The multivariable model found an association of isolated cerebellar infarct with low NIHSS (odds ratio [OR] 2.3, 95% CI 1.1-4.8) and any dizziness/vertigo (OR 5.1, 95% CI, 2.4-10.6), but not with isolated dizziness/vertigo, age, or sex. Median ASCVD scores were high in all infarct categories (21, interquartile range [IQR] 9-35 for isolated cerebellar; 32, IQR 15-42 for mixed cerebellar; 31, IQR 16-52 for all others). Both cerebellar and non-cerebellar strokes had a high frequency of baseline antiplatelet or anticoagulant use (52.1% vs 56.2%), whereas baseline statin therapy was less common in isolated cerebellar infarcts (34.1% vs 43.8%). Conclusions: This population-based study during the modern imaging era found that about 5% of stroke cases have isolated cerebellar infarcts and nearly 9% have any cerebellar infarct. Both cerebellar and non-cerebellar presentations have high baseline vascular risk and antiplatelet/anticoagulant use.

Introduction: Observational evidence from single center studies indicates that lower admission hemoglobin (Hb) levels are associated with poor outcome after spontaneous intracerebral hemorrhage (ICH). We combined data from three multicenter studies to test the hypothesis that Hb levels inversely correlate with functional outcome in ICH. Methods: We conducted a meta-analysis of individual patient data from the clinical trials ATACH-II and FAST and the multi-ethnic study ERICH. We included participants with available Hb and outcome data. We used multivariable logistic regression to test for association between admission Hb levels and 3-month dichotomized (0-3 versus 4-6) modified Rankin Scale (mRS), adjusting for the variables contained in the ICH score. We pooled study-specific estimates using inverse-variance weighted, fixed effects meta-analysis. Results: A total of 4106 ICH patients were included in the analysis. Each additional g/dL of admission Hb was associated with a 12% (OR 0.88, 95%CI 0.85-0.91; p0.05). Conclusion: Lower hemoglobin levels are associated with poor outcome in ICH. Further studies of the underlying biological mechanisms are warranted. If replicated, this pathway could become an appealing target to be tested in clinical trials.

Objective: We sought to assess whether the proportion of stroke patients who utilized Emergency Medical Services (EMS) has changed over time in a population-based epidemiological study. Methods: Stroke and transient ischemic attack (TIA) patients were identified in a population of 1.3 million in the Cincinnati area from data in 1999, 2005, 2010, and 2015. Patient charts and EMS records were analyzed by research nurses and reviewed by study physicians. This analysis excluded strokes/TIAs that occurred while in a hospital, out of town, during EMS transport, or at unknown location. Patients with unknown EMS utilization, stroke severity, baseline pre-stroke disability, race, stroke type, or under age 18 were excluded. Proportion of EMS utilization by stroke patients was calculated and Cochran-Armitage Trend Test was used to analyze trends in EMS utilization over time. Multivariable logistic regression was used to determine the association between age, race, sex, prior stroke, stroke type, where the stroke occurred, stroke severity, and pre-stroke disability with EMS use. Results: In 1999, 2005, 2010 and 2015, 2968 of 3860, 2900 of 3643, 3010 of 3503, and 3327 of 3767 stroke cases were included, respectively. EMS use by stroke patients did not change significantly over time (52%, 51%, 52%, 53%, p=0.12 for trend). In 1999 and 2015, age, pre-stroke disability, stroke severity, hemorrhagic stroke and stroke occurring at work were significantly associated with EMS use. Race, sex, and prior stroke were not. Slight variation in associations occurred in 2005 and 2010, with stroke at work not reaching significance in 2005 and 2010, and pre-stroke disability not reaching significance in 2005. Conclusion: EMS use by stroke patients in our population did not change from 1999 to 2015. With the recent advances in treatment options for stroke, novel and effective approaches to increase EMS use are warranted.

Introduction: Obstructive sleep apnea (OSA) is a treatable condition and well-established risk factor for ischemic stroke, but the prevalence in ICH is unknown. We aim to characterize the frequency of OSA in spontaneous intracerebral hemorrhage (ICH). Methods: The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a prospective observational study evaluating risk factors for ICH among whites, blacks, and Hispanics. OSA status was determined using two different strategies: (1) the Berlin Questionnaire, a validated screening tool to identify those with a high likelihood of OSA where “high risk” is defined as > 1 point in at least 2 of 3 categories assessing snoring, fatigue, and hypertension, and (2) self-reported history of diagnosed sleep apnea. Results: We evaluated 3000 ICH cases. Within this group, 2896 (96.5%) completed the Berlin questionnaire, with 2064 (71%) patients being high risk for OSA. Compared to patients with low risk of OSA, those at high risk were more likely to be male (61% versus 53%, p Conclusions: OSA is highly prevalent and underdiagnosed in our cohort of ICH patients. Given the effective treatments available for OSA, which have been shown to improve morbidity and mortality in patients with ischemic stroke, further studies are needed to assess the role of OSA as both a determinant of both risk and outcome in ICH.

Walking impairment impacts nearly 66% of stroke survivors and is a rising cause of morbidity worldwide. Despite conventional post-stroke rehabilitative care, the majority of stroke survivors experience continued limitations in their walking speed, temporospatial dynamics and walking capacity. Hence, novel and comprehensive approaches are needed to improve the trajectory of walking recovery in stroke survivors. Herein, we test the safety, feasibility and preliminary efficacy of two approaches for post-stroke walking recovery: backward locomotor treadmill training and transcutaneous spinal direct current stimulation. In this double-blinded study, 30 chronic stroke survivors (>6 months post-stroke) with mild-severe residual walking impairment underwent six 30-min sessions (three sessions/week) of backward locomotor treadmill training, with concurrent anodal (N = 19) or sham transcutaneous spinal direct current stimulation (N = 11) over the thoracolumbar spine, in a 2:1 stratified randomized fashion. The primary outcomes were: per cent participant completion, safety and tolerability of these two approaches. In addition, we collected data on training-related changes in overground walking speed, cadence, stride length (baseline, daily, 24-h post-intervention, 2 weeks post-intervention) and walking capacity (baseline, 24-h post-intervention, 2 weeks post-intervention), as secondary exploratory aims testing the preliminary efficacy of these interventions. Eighty-seven per cent (N = 26) of randomized participants completed the study protocol. The majority of the study attrition involved participants with severe baseline walking impairment. There were no serious adverse events in either the backward locomotor treadmill training or transcutaneous spinal direct current stimulation approaches. Also, both groups experienced a clinically meaningful improvement in walking speed immediately post-intervention that persisted at the 2-week follow-up. However, in contrast to our working hypothesis, anodal-transcutaneous spinal direct current stimulation did not enhance the degree of improvement in walking speed and capacity, relative to backward locomotor treadmill training + sham, in our sample. Backward locomotor treadmill training and transcutaneous spinal direct current stimulation are safe and feasible approaches for walking recovery in chronic stroke survivors. Definitive efficacy studies are needed to validate our findings on backward locomotor treadmill training-related changes in walking performance. The results raise interesting questions about mechanisms of locomotor learning in stroke, and well-powered transcutaneous spinal direct current stimulation dosing studies are needed to understand better its potential role as a neuromodulatory adjunct for walking rehabilitation., Graphical Abstract Graphical Abstract

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.

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 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.

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.

Purpose We aimed to identify the effect of hyperosmolar therapy (mannitol and hypertonic saline) on outcomes after intracerebral hemorrhage (ICH) in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study. Methods Comparison of ICH cases treated with hyperosmolar therapy versus untreated cases was performed using a propensity score based on age, initial Glasgow Coma Scale, location of ICH (lobar, deep, brainstem, and cerebellar), log-transformed initial ICH volume, presence of intraventricular hemorrhage, and surgical interventions. ERICH subjects with a pre-ICH modified Rankin Scale (mRS) score of 3 or lower were included. Treated cases were matched 1:1 to untreated cases by the closest propensity score (difference ≤.15), gender, and race and ethnicity (non-Hispanic white, non-Hispanic black, or Hispanic). The McNemar and the Wilcoxon signed-rank tests were used to compare 3-month mRS outcomes between the 2 groups. Good outcome was defined as a 3-month mRS score of 3 or lower. Results As of December 31, 2013, the ERICH study enrolled 2279 cases, of which 304 hyperosmolar-treated cases were matched to 304 untreated cases. Treated cases had worse outcome at 3 months compared with untreated cases (McNemar, P = .0326), and the mean 3-month mRS score was lower in the untreated group (Wilcoxon, P = .0174). Post hoc analysis revealed more brain edema, herniation, and death at discharge for treated cases. Conclusions Hyperosmolar therapy was not associated with better 3-month mRS outcomes for ICH cases in the ERICH study. This finding likely resulted from greater hyperosmolar therapy use in patients with edema and herniation rather than those agents leading to worse outcomes. Further studies should be performed to determine if hyperosmolar agents are effective in preventing poor outcomes.

Background: We previously developed predictive models for 3-month mortality and modified Rankin Score (mRS) after ischemic stroke. Aim: The aim was to test model validity for 3-month mortality and mRS after ischemic stroke in two independent data sets. Methods: Our derivation models used data from 451 subjects with ischemic stroke in 1999 enrolled in the Greater Cincinnati/Northern Kentucky Stroke Study (GCKNSS). We utilized two separate cohorts of ischemic strokes through GCKNSS (460 in 2005 and 504 in 2010) to assess external validity by utilizing measures of agreement between predicted and observed values, calibration, and discrimination using Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis. Results: The 3-month mortality model performed well in the validation datasets with an average prediction error (Brier score) of 0.045 for 2005 and 0.053 for 2010 and excellent discrimination with an area under the curve of 0.86 (95% CI: 0.79, 0.93) for 2005 and 0.84 (0.76, 0.92) for 2010. Predicted 3-month mRS also performed well in the validation datasets with R2 of 0.57 for 2005 and 0.50 for 2010 and a root mean square error of 0.85 for 2005 and 1.05 for 2010. Predicted mRS tended to be higher than actual in both validation datasets. Re-estimation of the model parameters for age and severe white matter hyperintensity in both 2005 and 2010, and for diabetes in 2005, improved predictive accuracy. Conclusions: Our previously developed stroke models performed well in two study periods, suggesting validity of the model predictions.

BACKGROUND AND PURPOSE: Limited information is available regarding differences in neuroimaging use for acute stroke work-up. Our objective was to assess whether race, sex, or age differences exist in neuroimaging use and whether these differences depend on the care center type in a population-based study. MATERIALS AND METHODS: Patients with stroke (ischemic and hemorrhagic) and transient ischemic attack were identified in a metropolitan, biracial population using the Greater Cincinnati/Northern Kentucky Stroke Study in 2005 and 2010. Multivariable regression was used to determine the odds of advanced imaging use (CT angiography/MR imaging/MR angiography) for race, sex, and age. RESULTS: In 2005 and 2010, there were 3471 and 3431 stroke/TIA events, respectively. If one adjusted for covariates, the odds of advanced imaging were higher for younger (55 years or younger) compared with older patients, blacks compared with whites, and patients presenting to an academic center and those seen by a stroke team or neurologist. The observed association between race and advanced imaging depended on age; in the older age group, blacks had higher odds of advanced imaging compared with whites (odds ratio, 1.34; 95% CI, 1.12–1.61; P < .01), and in the younger group, the association between race and advanced imaging was not statistically significant. Age by race interaction persisted in the academic center subgroup (P < .01), but not in the nonacademic center subgroup (P = .58). No significant association was found between sex and advanced imaging. CONCLUSIONS: Within a large, biracial stroke/TIA population, there is variation in the use of advanced neuroimaging by age and race, depending on the care center type.

Background We aimed to compare sex-specific associations between cardiovascular risk factors and diabetes mellitus (DM) among patients with acute ischemic stroke (AIS) in the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS). Methods The GCNKSS ascertained AIS cases in 2005 and 2010 among adult (age ≥20 years) residents of a biracial population of 1.3 million. Past and current stroke risk factors were compared between those with and without DM using chi-square and multiple logistic regression to examine sex-specific profiles. Results There were 3515 patients with incident AIS; 1919 (55%) were female, 697 (20%) were black, and 1146 (33%) had DM. Among both women and men with DM, significantly more were obese, and had hypertension, high cholesterol, and coronary artery disease (CAD) compared with those without DM. For women with AIS, in multivariable sex-specific adjusted analyses, older age was associated with a decreased odds of having DM (aOR=0.88, 95%CI 0.80-0.98). For women with CAD, the odds of DM were increased (aOR=1.76, 95%CI 1.33-2.32). Age and CAD were not significant factors in differentiating the profiles of men with and without DM. Conclusions Women with DM had strokes at a younger age, whereas no such age difference existed in men. As opposed to men, women with DM were also more likely to have CAD compared with those without DM, suggesting a sex difference in the association between DM and vascular disease. These findings may suggest a need for more aggressive risk factor management in diabetic women.

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.

The early subjective clinical judgment of clinicians outperforms formal prognostic scales for accurate determination of outcome after intracerebral hemorrhage (ICH), with the judgment of physicians and nurses having equivalent accuracy. This study assessed specific decisional factors that physicians and nurses incorporate into early predictions of functional outcome. This prospective observational study enrolled 121 ICH patients at five US centers. Within 24 h of each patient’s admission, one physician and one nurse on the clinical team were each surveyed to predict the patient’s modified Rankin Scale (mRS) at 3 months and to list up to 10 subjective factors used in prognostication. Factors were coded and compared between (1) physician and nurse and (2) accurate and inaccurate surveys, with accuracy defined as an exact prediction of mRS. Aside from factors that are components of the ICH or FUNC scores, surveys reported pre-existing comorbidities (40.0%), other clinical or radiographic factors not in clinical scales (43.0%), and non-clinical/radiographic factors (21.9%) as important. Compared to physicians, nurses more frequently listed neurologic examination components (Glasgow Coma Scale motor, 27.3 vs. 5.8%, p

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.

Background and Purpose— Computed tomographic angiography and conventional angiography provide timely vascular anatomic information in patients with stroke. However, iodinated contrast dye may cause acute kidney injury (AKI). Within a large, biracial population, we examined in-hospital incidence of new or worsening kidney disease in patients with stroke and its association with administration of intravenous dye. Methods— All adult residents of the Greater Cincinnati/Northern Kentucky region with acute ischemic stroke or intracerebral hemorrhage who presented to an emergency department in 2010 were included. Prevalence of unsuspected kidney disease at the time of emergency department presentation and the incidence of AKI after admission in 2 groups of patients—those who did and those who did not receive intravenous dye—were determined. Results— In 2010, 2299 patients met inclusion criteria (89% ischemic stroke and 11% intracerebral hemorrhage); mean age 69 years (SD 15), 22% black, and 54% women. Among these patients, 37% had kidney disease at baseline, including 22% (516/2299) in whom this was unsuspected. Two percent (2%; 15/853) of patients with baseline kidney disease developed AKI during the hospital stay. Of those with no baseline kidney disease, 1% (14/14 467) developed AKI. There was no association between dye administration and new or worsening kidney disease. Conclusions— Although 22% of patients in the Greater Cincinnati/Northern Kentucky stroke population had unsuspected kidney disease, the incidence of new or worsening kidney disease was low, and AKI was not associated with dye administration. These findings confirm single-center reports that the risk of severe renal complications after contrast dye is small.

OBJECTIVE To develop a research priority list for the International Stroke Genetics Consortium (ISGC). BACKGROUND Previously, stroke progress review groups and other activities provided an opportunity for members within the field to develop priorities for research. These filtered into larger categories which then published the top research priorities of their given field. However, these review groups are no longer forming and thus there has been no clear direction on what the research priorities and needs for stroke genetics research. DESIGN/METHODS We polled members of the stroke genetics community from around the world including collaborations of the major stroke genetics research efforts currently under way asking each respondent to provide their top 3 research priorities. Each priority was then sorted by the authors into major categories based upon the type of suggestion made. The results were presented for commentary and feedback during the presentation. RESULTS Deeper Phenotyping related topics were presented in 84% of respondent top research priorities. These included topics related to ethnic/racial variation, third world countries, deeper evaluation of subtypes of stroke. Translational science related topics were present in 40% of respondent top research priorities and consisted of translating our current findings into a greater understanding of their relationship to stroke and clinical pathophysiology. Pooling of our resources through data banking and sample banking was a topic in 36% of respondents. Recovery/outcome related topics were suggested in 32% of respondents and utilizing novel techniques such as epigenetics, whole genome sequencing, proteomics and metabolomics were present in 28% of respondents. Other topics were not present in more than 25% of the responses for top research priorities. CONCLUSIONS To summarize, greater sample size and research within subtypes and endophenotypes of stroke was the top research priority of the ISGC. In addition, translating our existing findings, pooling our resources, recovery/outcomes research and utilization of novel techniques were among the top research priorities of the ISGC. A working group will be assembled to draft the ISGC Research Priorities paper.

Past clinical trials of putative neuroprotective therapies have targeted PD as a single pathogenic disease entity. From an Oslerian clinicopathological perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: A single-mechanism therapy can affect most of those sharing the classic pathological hallmark. From a systems-biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine-neuron degeneration, exhibit unique genetic, biological, and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker-defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker-discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers), rather than clinical definitions, are used to define disease phenotypes. Successful development of disease-modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision-medicine approach will likely yield smaller, but well-defined, subsets of PD amenable to successful neuroprotection. Fil: Espay, Alberto J.. University of Cincinnati; Estados Unidos Fil: Schwarzschild, Michael A.. Massachusetts General Hospital; Estados Unidos Fil: Tanner, Caroline M.. University of California; Estados Unidos Fil: Fernandez, Hubert H.. Cleveland Clinic; Estados Unidos Fil: Simon, David K.. Harvard Medical School; Estados Unidos Fil: Leverenz, James B.. Cleveland Clinic; Estados Unidos Fil: Merola, Aristide. University of Cincinnati; Estados Unidos Fil: Chen Plotkin, Alice. University of Pennsylvania; Estados Unidos Fil: Brundin, Patrik. Van Andel Research Institute. Center for Neurodegenerative Science; Estados Unidos Fil: Kauffman, Marcelo Andres. Universidad Austral; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina Fil: Erro, Roberto. Universita di Verona; Italia. University College London; Reino Unido Fil: Kieburtz, Karl. University of Rochester Medical Center; Estados Unidos Fil: Woo, Daniel. University of Cincinnati; Estados Unidos Fil: Macklin, Eric A.. Massachusetts General Hospital; Estados Unidos Fil: Standaert, David G.. University of Alabama at Birmingahm; Estados Unidos Fil: Lang, Anthony E.. University of Toronto; Canadá

ObjectiveTo test the hypothesis that patients with deep intracerebral hemorrhage (ICH) would encounter hematoma expansion (HE) more frequently compared to patients with lobar ICH.MethodsPatients with ICH with neuroimaging to calculate HE were analyzed from the multicenter Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) cohort. Patients with laboratory coagulopathy or preceding anticoagulant use were excluded to assess relationships of ICH location alone (deep vs lobar) with HE, defined as >33% relative growth. Odds ratios (ORs) and 95% confidence intervals (CIs) for these relationships were estimated with logistic regression. Sensitivity and specificity determined HE thresholds best associated with poor 3-month outcomes (modified Rankin score 4-6) stratified by location.ResultsThere were 1,049 patients with deep and 408 patients with lobar ICH analyzed. Deep ICH locations were more likely to have HE (adjusted OR 1.57, 95% CI 1.08–2.29) after adjustment for age, sex, race, baseline hematoma size, and intraventricular hemorrhage. However, this difference was nonsignificant (adjusted OR 1.35, 95% CI 0.81–2.24) after controlling for time from symptom onset to admission CT in a subgroup analysis of 729 patients with these data. Yet, the threshold of HE best associated with poor outcomes was smaller in deep (30%) compared to lobar (50%) ICH.ConclusionsWhile HE was more frequent in deep than lobar ICH, this could be due to differences in symptom onset to admission CT times in our cohort. However, patients with deep ICH appear particularly vulnerable to the deleterious effects of small volumes of HE. Further studies should clarify whether ICH location needs to be considered in HE treatment paradigms.

Background: Postmenopausal hormone therapy (HT) increases the risk of stroke. Here we evaluate whether leisure time physical activity (LTPA) can change stroke risk in women using HT, leveraging data from the California Teachers Study. Methods: Female California educators without a prior history of stroke (n = 118,294) were followed from 1995 through 2015 for stroke end points. Based on statewide hospitalization data, 4,437 women had ischemic (n = 3,162; International Classification of Diseases [ICD]-9 433, 434, 436) or hemorrhagic (n = 1,275; ICD-9 430–432, excluding 432.1) stroke. LTPA and HT use were evaluated at 2 time points (baseline [1995–1996] and 10-year follow-up [2005–2006]). LTPA was assessed using American Heart Association (AHA) recommendations (>150 min/week moderate or >75 min/week strenuous physical activity). Using multivariable Cox proportional hazards models, we estimated the hazard ratios (HRs) and 95% CIs for the associations between HT use and concurrent LTPA with incident stroke. Results: Compared to women who never used HT, stroke risk was highest among women who were current HT users and did not meet AHA recommendations for LTPA at the time of their HT use: HRbaseline 1.28 (95% CI 1.13–1.44); HR10-year follow-up 1.17 (95% CI 0.91–1.50). Based on the baseline questionnaire, current HT users who met AHA recommendations for LTPA in 1995–1996 still had elevated stroke risk in the 20-year follow-up (HR 1.22, 95% CI 1.08–1.37). However, among current HT users who met AHA recommendations for LTPA at the 2005–2006 follow-up questionnaire, stroke risk was not elevated (HR 1.01, 95% CI 0.80–1.29). Evaluation of the 2 time points in concert further demonstrated that meeting AHA recommendations for LTPA at the most recent follow-up time point was required to reduce HT-related stroke risk. Conclusion: Concurrent physical activity may attenuate the short-term increase in risk of stroke risk associated with HT use.

Background Studies have demonstrated causal effects of educational attainment on cardiovascular disease (CVD). We aimed to investigate the role of body mass index (BMI), systolic blood pressure (SBP) and smoking in explaining the effect of education on risk of CVD outcomes triangulating across multivariable regression analysis of observational data and one- and two-sample Mendelian randomisation (MR) analysis; an instrumental variable approach more robust to bias from confounding and reverse causation. Methods Individual level data from UK Biobank (N=217 013) was used for multivariable analyses and one-sample MR. Summary statistics from genome-wide association studies were used in two-sample MR. The total effect of education on risk of coronary heart disease (CHD), CVD (all subtypes), myocardial infarction (MI) and stroke (all measured in odds ratio, OR) was assessed using multivariable regression and univariable Mendelian randomization (MR). The degree to which this effect is mediated through BMI, SBP and smoking respectively (the indirect effect and proportion mediated) was estimated using the product of coefficients method, where the effect of education on each mediator, and each mediator on each outcome was assessed using multivariable regression and Network MR. The joint contribution of all three risk factors was assessed via the difference method, using multivariable regression or multivariable MR. Results Each additional standard deviation of education (3.6 years) associated with 13% lower risk of coronary heart disease (OR 0.87, 95% confidence interval [CI] 0.84 to 0.89) in observational analysis and 37% lower risk (OR 0.63, 95% CI 0.60 to 0.67) in MR analysis. As a proportion of the total risk reduction, BMI mediated 15% (95% CI 13% to 17%) and 18% (95% CI 14% to 23%) in the observational and MR estimates respectively. Corresponding estimates for SBP were 11% (95% CI 9% to 13%) and 21% (95% CI 15% to 27%), and for smoking, 19% (15% to 22%) and 34% (95% CI 17% to 50%). All three risk factors combined mediated 42% (95% CI 36% to 48%) and 36% (95% CI 16% to 63%) of the effect of education on CHD in observational and MR respectively. Similar results were obtained for risk of stroke, MI and all-cause CVD. Conclusion BMI, SBP and smoking mediate a substantial proportion of the protective effect of education on risk of cardiovascular outcomes. Intervening on these would reduce cases of CVD attributable to lower education. However, more than half of the protective effect of education remains unexplained.

Background and Purpose— In this study, we aim to investigate the association of computed tomography–based markers of cerebral small vessel disease with functional outcome and recovery after intracerebral hemorrhage. Methods— Computed tomographic scans of patients in the ERICH study (Ethnic and Racial Variations of Intracerebral Hemorrhage) were evaluated for the extent of leukoaraiosis and cerebral atrophy using visual rating scales. Poor functional outcome was defined as a modified Rankin Scale (mRS) of ≥3. Multivariable logistic and linear regression models were used to explore the associations of cerebral small vessel disease imaging markers with poor functional outcome at discharge and, as a measure of recovery, change in mRS from discharge to 90 days poststroke. Results— After excluding in-hospital deaths, data from 2344 patients, 583 (24.9%) with good functional outcome (mRS of 0–2) at discharge and 1761 (75.1%) with poor functional outcome (mRS of 3–5) at discharge, were included. Increasing extent of leukoaraiosis ( P for trend, 0.01) and only severe (grade 4) global atrophy (odds ratio, 2.02; 95% CI, 1.22–3.39, P =0.007) were independently associated with poor functional outcome at discharge. Mean (SD) mRS change from discharge to 90-day follow-up was 0.57 (1.18). Increasing extent of leukoaraiosis ( P for trend, 0.002) and severe global atrophy (β [SE], −0.23 [0.115]; P =0.045) were independently associated with less improvement in mRS from discharge to 90 days poststroke. Conclusions— In intracerebral hemorrhage survivors, the extent of cerebral small vessel disease at the time of intracerebral hemorrhage is associated with poor functional outcome at hospital discharge and impaired functional recovery from discharge to 90 days poststroke.

Background and Purpose— It is unknown whether blood pressure (BP) reduction influences secondary brain injury in spontaneous intracerebral hemorrhage (ICH). We tested the hypothesis that intensive BP reduction is associated with decreased perihematomal edema expansion rate (PHER) in deep ICH. Methods— We performed an exploratory analysis of the ATACH-2 randomized trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2). Patients with deep, supratentorial ICH were included. PHER was calculated as the difference in perihematomal edema volume between baseline and 24-hour computed tomography scans divided by hours between scans. We used regression analyses to determine whether intensive BP reduction was associated with PHER and if PHER was associated with poor outcome (3-month modified Rankin Scale score 4–6). We then used interaction analyses to test whether specific deep location (basal ganglia versus thalamus) modified these associations. Results— Among 1000 patients enrolled in ATACH-2, 870 (87%) had supratentorial, deep ICH. Of these, 780 (90%) had neuroimaging data (336 thalamic and 444 basal ganglia hemorrhages). Baseline characteristics of the treatment groups remained balanced ( P >0.2). Intensive BP reduction was associated with a decrease in PHER in univariable (β= −0.15; 95% CI, −0.26 to −0.05; P =0.007) and multivariable (β=−0.12; 95% CI, −0.21 to −0.02; P =0.03) analyses. PHER was not independently associated with outcome in all deep ICH (odds ratio, 1.14; 95% CI, 0.93–1.41; P =0.20), but this association was modified by the specific deep location involved (multivariable interaction P =0.02); in adjusted analyses, PHER was associated with poor outcome in basal ganglia (odds ratio, 1.42; 1.05–1.97; P =0.03) but not thalamic (odds ratio, 1.02; 95% CI, 0.74–1.40; P =0.89) ICH. Conclusions— Intensive BP reduction was associated with decreased 24-hour PHER in deep ICH. PHER was not independently associated with outcome in all deep ICH but was associated with poor outcome in basal ganglia ICH. PHER may be a clinically relevant end point for clinical trials in basal ganglia ICH.

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).

ObjectivesTo investigate the role of body mass index (BMI), systolic blood pressure, and smoking behaviour in explaining the effect of education on the risk of cardiovascular disease outcomes.DesignMendelian randomisation study.SettingUK Biobank and international genome-wide association study data.ParticipantsPredominantly participants of European ancestry.ExposureEducational attainment, BMI, systolic blood pressure, and smoking behaviour in observational analysis, and randomly allocated genetic variants to instrument these traits in mendelian randomisation.Main outcomes measureThe risk of coronary heart disease, stroke, myocardial infarction, and cardiovascular disease (all subtypes; all measured in odds ratio), and the degree to which this is mediated through BMI, systolic blood pressure, and smoking behaviour respectively.ResultsEach additional standard deviation of education (3.6 years) was associated with a 13% lower risk of coronary heart disease (odds ratio 0.86, 95% confidence interval 0.84 to 0.89) in observational analysis and a 37% lower risk (0.63, 0.60 to 0.67) in mendelian randomisation analysis. As a proportion of the total risk reduction, BMI was estimated to mediate 15% (95% confidence interval 13% to 17%) and 18% (14% to 23%) in the observational and mendelian randomisation estimates, respectively. Corresponding estimates were 11% (9% to 13%) and 21% (15% to 27%) for systolic blood pressure and 19% (15% to 22%) and 34% (17% to 50%) for smoking behaviour. All three risk factors combined were estimated to mediate 42% (36% to 48%) and 36% (5% to 68%) of the effect of education on coronary heart disease in observational and mendelian randomisation analyses, respectively. Similar results were obtained when investigating the risk of stroke, myocardial infarction, and cardiovascular disease.ConclusionsBMI, systolic blood pressure, and smoking behaviour mediate a substantial proportion of the protective effect of education on the risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of cardiovascular disease attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation.

Importance Hypertension is the strongest risk factor for spontaneous intracerebral hemorrhage (ICH) involving deep brain regions, but it appears to be unknown if intensive blood pressure reduction in the acute care setting decreases hematoma expansion or improves outcomes in patients with deep ICH. Objective To determine whether intensive blood pressure reduction is associated with decreased risk of hematoma expansion and changes in 90-day modified Rankin Scale scores and if these associations are modified by the specific deep-brain nuclei involved. Design, Setting, and Participants This study is an exploratory analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage–2 international, multicenter randomized clinical trial, which was conducted from May 2011 to September 2015, enrolled eligible patients with primary ICH, and followed up with them for 90 days. Patients who had ICH and complete neuroimaging data were included in the analysis. Data analysis was completed from July 2018 to December 2018. Exposures Participants were randomized to either intensive treatment (with a systolic blood pressure target of 110-139 mm Hg) or standard treatment (with a systolic blood pressure target of 140-179 mm Hg). Main Outcomes and Measures The main outcome was hematoma expansion, defined as an increase greater than 33% in hematoma volume between baseline and 24 hours. Functional outcome was evaluated 90 days after the ICH via the modified Rankin Scale. Results Of 1000 trial participants, 870 (87.0%) had deep ICH, of whom 780 (89.7%) had complete neuroimaging data (of 336 thalamic and 444 basal ganglia hemorrhages). The baseline characteristics of the intensive and standard treatment groups remained balanced in this subgroup of the original study. Intensive treatment was associated with a decreased risk of hematoma expansion in univariable analysis (odds ratio [OR], 0.62 [95% CI, 0.43-0.87];P = .006) and multivariable analysis (OR, 0.61 [95% CI, 0.42-0.88];P = .009). This association was modified by the specific deep location of the ICH (OR, 0.44 [95% CI, 0.22-0.96]; interactionP = .02), with stratified analyses showing a reduction in risk of hematoma expansion with intensive vs standard treatment among basal ganglia ICH (OR, 0.44 [95% CI, 0.27-0.72];P = .001) but not thalamic ICH (OR, 0.91 [95% CI, 0.51-0.64];P = .76). Intensive treatment was not associated with an improvement in the modified Rankin Scale score distribution. Conclusions and Relevance Compared with standard treatment, intensive blood pressure treatment was associated with reduced hematoma expansion in deep ICH, specifically among basal ganglia hemorrhages.

OBJECTIVE: Previously we reported that ischemic stroke incidence is declining over time for men but not women. We sought to describe temporal trends of sex differences in incidence of transient ischemic attack (TIA) within the same large, biracial population. METHODS: Among the population of 1.3 million in the Greater Cincinnati Northern Kentucky Stroke Study (GCNKSS) region, TIAs among area residents (≥20 years old) were identified at all local hospitals. Out of hospital cases were ascertained using a sampling scheme. First-ever cases and first within each study period for a patient were included in incidence rates. All cases were physician-adjudicated. Incidence rates (during 7/93-6/94 and calendar years 1999, 2005, and 2010) were calculated using the age-, race-, and sex-specific number of TIAs divided by the GCNKSS population in that group; rates were standardized to the 2010 U.S. population. T-tests with Bonferroni correction were used to compare rates over time. RESULTS: There were a total of 4746 TIA events; 53% were female, and 12% were black. In males, incidence decreased from 153 (95%CI 139-167) per 100,000 in 1993/4 to 117 (95%CI 107-128) in 2010 (p0.05). CONCLUSIONS: Within the GCNKSS population, TIA incidence decreased significantly over time in males but not females, data which parallels trends in ischemic stroke in the GCNKSS over the same time period. Future research is needed to determine if these sex differences in incidence over time continue past 2010.

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.

Hematoma expansion (HE) after intracerebral hemorrhage (ICH) is associated with worse outcome. Lobar ICHs are known to have better outcomes compared to deep ICH; however, it is unclear whether there are HE differences between these locations. We sought to investigate the hypothesis that lobar ICH has less HE compared to deep ICH. Primary ICH patients admitted between 2009 and 2016 were included in a prospective single-center ICH cohort study. Patients with preceding anticoagulant use, coagulopathy on admission labs, or presenting after 24 h from symptom onset were excluded. Lobar and deep ICH patients with baseline and follow-up computed tomography (CT) (within 24 h of admission CT) were evaluated. HE was defined primarily as relative growth > 33% given expected baseline hematoma volume differences between locations. Other commonly utilized definitions of HE: > 6 mL, and > 33% or > 6 mL, were additionally assessed. Multivariable logistic regression was used to assess the association of ICH location with HE while adjusting for previously identified covariates of HE. There were 59 lobar and 143 deep ICH patients analyzed. Lobar ICH patients had significantly larger baseline hematoma volumes, lower admission systolic blood pressure, and longer times to admission CT compared to deep ICH. Multivariable logistic regression revealed an association of lobar ICH with lower odds of HE (> 33%) [odds ratio (OR) 0.32; 95% confidence interval (CI) 0.11–0.93; p = 0.04] compared to deep ICH after adjusting for baseline ICH volume, blood pressure, and time to CT. Secondary analysis did not identify an association of lobar ICH with HE defined as > 6 mL (adjusted OR 1.44; 95% CI 0.59–3.50; p = 0.41) or > 33% or > 6 mL (adjusted OR 0.71; 95% CI 0.29–1.70; p = 0.44). We identified less HE in lobar compared to deep ICH. The use of absolute growth thresholds in defining HE may be limited when assessing groups with largely different baseline hematoma sizes. Further study is required to replicate our findings and investigate mechanisms for HE differences between lobar and deep ICH locations.

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 .

Background: Observational studies found an inverse correlation between cholesterol levels and risk of spontaneous intracerebral hemorrhage (ICH). We investigated whether the cumulative burden of known genetic risk loci for cholesterol levels influences the risk of sustaining an ICH. Methods: We utilized genetic risk scores (GRSs) to model the cumulative burden of cholesterol-related common genetic variants (CGVs). GRSs were constructed using an approach that allows the implementation of GRS analysis by combining summary statistics from GCVs known to influence the exposure (cholesterol levels) and outcome (ICH) of interest. Summary statistics were identified and abstracted using the Cerebrovascular Disease Knowledge Portal. For cholesterol levels (derivation dataset), we abstracted summary statistics for independent CGVs associated with cholesterol levels at p-5 in a large genetic meta-analysis that included data from Kaiser Permanente, UK Biobank and Global Lipids Genetics Consortium. We excluded CGVs at CETP , a cholesterol-related locus known to modify ICH risk. For ICH (testing dataset), we abstracted summary statistics from a meta-analysis of 5 genetic studies. Results: We identified 711 CGVs associated with cholesterol levels in the derivation dataset (study population 76,627, mean age 56 [SD 9], female sex 44,856 [59%]). Summary statistics were available for 468 of these CGVs in the ICH testing dataset (study population 3,026, mean age 67 [SD 10], female sex 1,362 [45%]). The GRSs for total cholesterol (OR 0.87, 95%CI 0.73-1.01; p =0.04), LDL (OR 0.78, 95%CI 0.65-0.91; p =0.0002) and triglycerides (OR 1.18, 95%CI 1.04-1.32; p =0.02) were associated with risk of all ICH. After stratifying by location, the association became stronger for deep ICH and total cholesterol (OR 0.77, 95%CI 0.61-0.93; p =0.001) and LDL (OR 0.70, 95%CI 0.55-0.85; p =8x10 -6 ). Only the triglycerides-based GRS was associated with lobar ICH (OR 1.26, 95%CI 1.08-1.44; p =0.01). Conclusions: The cumulative burden of cholesterol-related mutations is associated with risk of ICH. Our results point to an inverse correlation between genetically-determined total cholesterol and LDL levels and ICH risk. These associations are stronger for deep ICH.

Background: Race/ethnicity is associated with risk of first-ever spontaneous intracerebral hemorrhage (ICH), but the influence of race/ethnicity on risk of ICH recurrence has not been well studied in a large, diverse population. Methods: We used claims data on all discharges from community hospital inpatient stays in California between January 1, 2005 and December 31, 2011 to identify patients who were hospitalized for ICH. California residents who survived to discharge were included. We used validated diagnosis codes to identify a primary outcome of recurrent ICH. We then used survival curves and log-rank tests for unadjusted analyses of survival across race/ethnic groups and multivariable Cox proportional-hazards regression to determine factors associated with risk of ICH recurrence after adjusting for potential confounders. Results: Between 2005-2011, we identified 31,554 first-ever ICH patients who survived to discharge, of which 15,828 (50%) were white, 6,254 (20%) Hispanic, 4,268 (14%) Asian, and 2,820 (9%) black. There were 1339 recurrences (4.2%) over a median follow-up time of 2.9 years (IQR 3.8). The 1-year recurrence rate was 3.0% (95% CI 2.8%-3.2%). In univariable and multivariable analysis, blacks (HR 1.22, 95% CI 1.01-1.48; p=0.035) and Asians (HR 1.29, 95% CI 1.10-1.50; p=0.001) had a higher risk of ICH recurrence than whites (reference categories). Private insurance was associated with a significant reduction in the risk of ICH recurrence compared to subjects with Medicare (HR 0.60, 95% CI 0.50-0.73, p Conclusions: Black and Asian subjects had a higher risk of ICH recurrence than white or Hispanic subjects. Further research is needed to determine drivers of these disparities.

Background and Objective: Cerebral small vessel disease (CSVD) is a chronic, cumulative cerebrovascular disease and is the most common cause of intracerebral hemorrhage (ICH). The effects of pre-existing CSVD on the severity of acute ICH are incompletely understood. We aim to clarify associations between computed tomography (CT) markers of CSVD and 1) acute ICH volume and 2) presence and severity of concomitant intraventricular hemorrhage (IVH). Methods: Baseline CT scans of patients from the Ethnic and Racial Variations of Intracerebral Hemorrhage (ERICH) study were evaluated for the extent of leukoaraiosis and cerebral atrophy using visual rating scales and for the Graeb Score, as a measure of IVH severity. ICH volume was measured on baseline CT scans using semi-automated software. The associations of leukoaraiosis and atrophy and ICH volume, IVH presence and the Graeb Score were tested using multivariable linear, ordinal and binary logistic regression models. Secondary analyses were stratified by hemorrhage location (lobar versus non-lobar). Bonferroni correction was applied. Results: The study included 2579 patients, 774 (30.0%) with a lobar ICH and 1805 (70.0%) with a non-lobar ICH. Median ICH volume was higher for lobar ICH and non-lobar ICH was more frequently associated with IVH. Increasing grades of central, cortical and total atrophy were inversely and dose-dependently associated with baseline ICH volume (P for trend Conclusions: In this study, increasing grades of cerebral atrophy were associated with smaller ICH volume and decreased risk of IVH presence and severity, while increasing extent of leukoaraiosis was associated with higher risk of IVH. These findings suggest that cerebral atrophy might be protective in the setting of acute ICH. Future studies are needed to confirm our findings and identify the underlying mechanisms.

Background: Intracerebral hemorrhage (ICH) and small vessel ischemic stroke (SVS) are the most severe manifestation of cerebral small vessel disease (CSVD) with no established preventive approaches beyond hypertension management. Cross-phenotype analysis of these two correlated diseases will improve statistical power to detect novel genetic factors for CSVD, elucidating underlying disease mechanisms that may form the basis for future treatments. Methods: We performed genome-wide association studies (GWAS) for ICH by location in 1,813 ICH patients (797 lobar and 1,005 nonlobar) and 1,711 stroke-free controls after imputation using Haplotype Reference Consortium reference panels. Each ICH GWAS by location was meta-analyzed with GWAS summary statistics for SVS from MEGASTROKE ( Malik et al. 2018 ), using “Multi-Trait Analysis of GWAS” (MTAG; Turley et al. 2018 ) to integrate GWAS summary data across traits and generate combined trait-specific effect estimates. Results: By combining GWAS datasets using MTAG, our functional sample size increased to 241,024 participants (6,255 ICH or SVS cases and 234,769 controls). Genome-wide significant (P < 5x10 -8 ) associations were observed for the nonlobar ICH model enhanced by SVS with 1) rs2758605 (MTAG P-value [P] = 2.6x10 -11 ) at 1q22; 2) rs72932727 (P = 1.7x10 -8 ) at 2q33; and 3) rs9515201 (P = 5.3x10 -10 ) at 13q34. The MTAG association strengths of these loci were at least one order of magnitude more significant than those from their individual GWAS. According to the GTEx database, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1x10 -4 in nerve), NBEAL1 , ICA1L , and CARF (P < 7.7x10 -7 in artery tibial) and COL4A2 and COL4A1 (P < 0.008 in thyroid), respectively. Conclusion: Our cross-phenotype study of ICH and SVS reveals two novel CSVD loci, including 2q33 and 13q34. The 2q33 locus was recently identified in a GWAS of white matter hyperintensity burden ( Jian et al. 2018 ). We also identified the same PMF1 association as previously seen in ICH ( Woo et al. 2014 ), supporting the validity of this novel multi-trait approach. We have begun to replicate these associations and to identify functional causal variants in independent whole genome sequencing studies of 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.

Background: Perihematomal edema (PHE) has been associated with poor outcomes in deep spontaneous intracerebral hemorrhage (ICH). However, it is unknown if specific deep location (thalamus versus basal ganglia) modifies the effect of PHE on functional outcome. Methods: We used data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial. We included patients who had deep ICH and available neuroimaging and 3-month functional outcome data. We calculated the 24-hour PHE expansion rate as the difference in PHE volume between baseline and 24-hour CT scan divided by hours between scans. We used logistic regression models to evaluate the relationship between PHE expansion rate (natural-log transformed) and poor outcome (3-month modified Rankin Scale [mRS] score 4-6), with subgroup analyses to determine the effect of thalamic vs basal ganglia location on this association. Results: Out of 1000 subjects enrolled in ATACH-2, 870 (87%) had supratentorial, deep ICH. Of these, 754 (87%) had complete neuroimaging and outcome data (thalamus n=324, basal ganglia n=430). Overall, PHE expansion rate was associated with poor outcome in univariable (OR 1.3, 1.2-1.5, p Conclusions: In the ATACH-2 trial population, 24-hour PHE expansion rate was associated with poor functional outcome among basal ganglia, but not thalamic, bleeds. These results provide further evidence that PHE is associated with functional outcomes and supports the existence of effect modification by the specific deep location involved.

Introduction: We previously reported that the incidence of stroke was decreasing for whites but stable for blacks from 1993/94 to 2005. We sought to describe recent temporal trends and racial disparities in stroke incidence within our large, bi-racial population, by including 2010 and preliminary data from 2015. Methods: The Greater Cincinnati/Northern Kentucky region includes two southern Ohio and three Northern Kentucky counties on the Ohio River, a population of 1.3 million representative of the US population in terms of sociodemographics and percent black race. Our study ascertained all hospitalized strokes that occurred in the population between 7/1/93 and 6/30/94 and in calendar years 1999, 2005, 2010 and 2015. For 2015, nursing review of medical records is complete but physician review is not; thus 2015 rates are preliminary. The denominator for the calculation of incidence rates (in those aged ≥20 years) was estimated from the U.S. Census Bureau website (www.census.gov). The 95% confidence intervals (CI) for the incidence rates were calculated assuming a Poisson distribution. Rates are age, sex, and race adjusted, as appropriate, and standardized to the 2010 U.S. population. Results: First-ever stroke incidence rates stratified by subtype, race, and study period are presented in the Table. We project that stroke incidence did not significantly change in 2015 vs. 2010 for either blacks or whites, regardless of stroke subtype. Blacks have a substantially higher incidence of stroke compared with whites in all study periods, without significant change in disparity over time. Discussion: In contrast to the significant decline in stroke incidence among whites from 1993-94 to 2005, we did not observe a statistically significant decrease in 2010 and 2015. This may be due to true stabilization of rates over time, or less statistical power to detect smaller declines. The substantial black/white racial disparity in stroke incidence has not changed over time.

Background: Both intraventricular hemorrhage (IVH) and white matter lesion (WML) severity are associated with higher rates of death and disability among cases of intracerebral hemorrhage (ICH). Prior reports suggest higher WML burden is associated with propensity of IVH. However, those analyses were not stratified by location. Our objective was to investigate the hypothesis that a higher degree of WML would be associated with a higher risk of IVH after controlling for ICH location. Methods: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) III study was a prospective study of hemorrhagic stroke in the Greater Cincinnati/Northern Kentucky region. We utilized the interviewed cohort from the study and systematically graded WML using the Van Swieten Scale (0-4) and presence or absence of IVH in baseline head CT scans. Additional variables included ICH volume, location of ICH and vascular risk factors. We used multiple logistic regression with backward elimination to adjust for relevant covariates. Results: Among the included 426 ICH patients (mean± SD age 71.2± 13.8; 49% females), 161 (38%) had presence of IVH. In patients with IVH, the proportion of severe WML (39.7%) was significantly higher compared with patients without IVH (27.2%) (p=0.0044). The median volume of ICH was 14.4 mL (IQR, 4.9-46.3) in patients with IVH as compared with 8.9 ml (IQR, 2.6-20.8) in patients without IVH (p Conclusion: Moderate to severe white matter lesions are a risk for intraventricular hemorrhage. Further studies are needed to determine if greater severity of IVH or subsequent rupture into IVH are associated with higher grades of WML.

Introduction: Blacks in the U.S. face twice the risk of ischemic stroke as whites, and this disparity is not fully explained by established stroke risk factors. Although atrial fibrillation (AF) is a major risk factor for stroke, blacks are less often diagnosed with AF than whites. It is unclear whether this paradox exists because AF is less thoroughly ascertained in blacks compared to whites or because blacks have less predisposing substrate and thus a truly lower risk of AF. Hypothesis: Based on our prior work, we hypothesized that black patients with ischemic stroke less often have left atrial enlargement, a major predisposing factor for AF. Methods: We compared left atrial size in black versus white patients in the Greater Cincinnati/Northern Kentucky Stroke Study, a study of racial disparities in stroke incidence in a nationally representative population of 1.3 million. We obtained reports of echocardiograms performed for stroke evaluation among patients in the 2010 and 2015 study periods. Patients with known AF or atrial flutter were excluded. Investigators blinded to patients’ characteristics abstracted left atrial diameter from echocardiogram reports. Linear regression was used to examine the association between race and left atrial diameter after adjustment for demographics, body mass index, and comorbidities. Results: Among 2,980 cases of ischemic stroke without AF, the median age was 66 years, 52% were female, and 30% were black. The overall mean left atrial diameter was 3.65 (±0.69) cm. Despite a higher burden of vascular risk factors and comorbidities, blacks had significantly smaller left atrial diameters (mean difference, -0.10 cm; 95% CI, -0.04 to -0.17 cm). This difference persisted after adjustment for demographics, comorbidities, and body mass index (adjusted mean difference, -0.15 cm; 95% CI, -0.09 to -0.21 cm). Conclusions: In a population-based sample, we found that black patients with ischemic stroke had smaller left atrial size than white patients. Our results suggest that the paradox of greater stroke risk but lower AF risk in blacks compared with whites at least partly stems from a lesser degree of AF substrate in blacks.

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: Anticoagulant therapy after intracerebral hemorrhage (ICH) in patients with atrial fibrillation or deep vein thrombosis has been associated with a marked reduction of death. Prevention of ischemic stroke could explain this reduction. We sought to describe the causes of death after discharge and beyond 30 days in a longitudinal follow-up of a multi-racial/ethnic cohort of ICH. We hypothesized that recurrent ICH and ischemic stroke are the most common cause of death after ICH. Methods: The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) Study was a prospective, multi-center, case-control study of ICH among whites, blacks, and Hispanics. Subjects previously in the ERICH study were approached for enrollment in the Longitudinal Follow-up of ICH Survivors (ERICH-L) study. A standardized research interview was completed over the phone and 959 contacts were made with participants and surrogates to capture outcomes of interest at 6-month intervals, including information on ICH recurrence, ischemic stroke, cognitive performance, and cause of death. The median follow-up was 4.3 years with an IQR of 3.2-5.4. The cause of death categories were ICH, cardiac, ischemic CVA, other, cancer, pulmonary, renal, endocrine, accidents, infection, dementia and unknown. Results: There were 180 deaths (18.8%) reported by surrogates contacted in the ERICH-L study. Of those, 63 causes of death were unknown or considered unverifiable. The most common cause of death reported was decline from the index ICH (32.7%). The next most common cause of death was cardiac (14%), other (12.1%), infection (11.2%), cancer (10.3%) and ischemic stroke (1.9%). Some examples reported as other are liver failure, old age, myelodysplastic syndrome, suicide and Parkinson’s Disease. Recurrent ICH occurred in 4 out of 107 known causes of death. By year 5, cardiac causes surpassed ICH as the cause of death. Conclusion: Cardiac causes of death were more common than either recurrent ICH or ischemic stroke, surpassed only by decline from the index ICH. Future efforts to prevent causes of death after ICH should address cardiac disease and risk factors. This finding may explain the effect of restarting anticoagulant or antiplatelet therapy and improved mortality.

Introduction: The REGARDS study previously reported a lack of racial disparity in recurrent ischemic stroke (IS) events, despite large racial differences in incident IS. We sought to evaluate recurrent stroke rates at 1 year after an index ischemic (IS) or hemorrhagic (ICH and SAH) stroke or TIA within a large, biracial population representative of the US in terms of % blacks and sociodemographics with a large number of index events Methods: The Greater Cincinnati/Northern Kentucky Stroke Study ascertained all hospitalized strokes and TIAs among residents of a 5-county population of 1.3 million in 7/1/14-12/31/14 (blacks only) and 2015 (all residents), as well as recurrent strokes (but not TIAs) in 2016. One year risk of recurrent stroke was estimated by Kaplan-Meier analysis. Association between recurrent stroke and demographics/risk factors was assessed by proportional hazards analysis. Results: Among the 2014-15 cases, there were 3883 index events (2512 IS, 374 ICH, 92 SAH, 900 TIA, 5 unknown type). Median age was 70 (IQR 59, 81); 27% were black and 54% female. Recurrent events within 12 months of the index event occurred in 319 patients (276 IS, 38 ICH, 5 SAH). Those with recurrence were more likely black than those without (34% vs 27%, p Discussion: The risk of recurrent stroke was significantly associated with index event type and stroke risk factors (hypertension, diabetes, smoking, and prior stroke). Black race was not a significant independent predictor of recurrent stroke after adjusting for other known stroke risk factors.

Introduction: The NIH StrokeNet trial network aims to improve recruitment and retention into stroke clinical trials. In addition to StrokeNet infrastructure, a population-based feasibility assessment is performed prior to submission to NIH. We sought to describe the impact of this assessment on the design and recruitment efficiency of the DEFUSE 3 trial, the first trial to be proposed and completed entirely within NIH StrokeNet. Methods: We identified all ischemic stroke (IS) cases in the region in 2005 by screening all local hospital ICD-9 codes 430-436 among residents of the Greater Cincinnati/Northern Kentucky (GCNK) region, a biracial population of 1.3 million through chart abstraction and physician review. Initial proposed, and final revised DEFUSE 3 trial entry criteria were analyzed for population-based eligibility. Results: DEFUSE 3 is an acute reperfusion ischemic stroke (IS) trial conducted at 38 US centers between 5/16-5/17. Initial inclusion/exclusion criteria proposed by trial PIs predicted that 2.4% (46 of 1843 in 2005) of IS patients would be eligible for DEFUSE-3. After criteria revision, this increased to 4.0% (74/1843). Four exclusion criteria were changed by study PIs after receiving feedback: upper age limit, baseline disability, time since last seen normal, and NIHSS (Table). Overall, 57% (104/182) of enrolled patients qualified via the broadened study entry criteria. In subsequent implementation, the trial randomized 0.47 patients per site per month which was nearly twice the expected enrollment rate. Conclusion: Feedback from formal epidemiologic feasibility assessment to trial investigators during multicenter clinical trial design led to a broadening of entry criteria, and more than half of eventually enrolled patients were eligible only because of the expanded criteria. Iterative trialist-epidemiologist interaction is a promising approach to improve multicenter clinical trial planning and efficient study conduct.

Introduction: Hypertension is the strongest risk factor for spontaneous intracerebral hemorrhage (ICH) involving deep brain regions. We tested the hypothesis that intensive blood pressure (BP) treatment reduces hematoma expansion and improves functional outcomes in deep ICH, and evaluated whether this effect is modified by the specific deep structure involved (thalamus versus basal ganglia). Methods: We performed a secondary analysis of data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial, which randomly assigned ICH patients with symptom onset within 4.5 hours and hematoma volume 33% increase in volume between baseline and 24-hour CT. We used chi-square and Mann–Whitney U tests and logistic and ordinal logistic regression models as appropriate. Results: Of 1000 trial subjects, 870 (87%) had deep ICH, of whom 780 (90%) had complete neuroimaging/outcome data (thalamus n=336, basal ganglia n=444) and 405 (52%) were randomized to intensive treatment. Significant hematoma expansion was less frequent in the intensive vs standard arm (17% vs 26%, p=0.008). Intensive treatment was associated with a lower risk of significant hematoma expansion (OR 0.6, 95% CI 0.4-0.9; p=0.01) even in multivariable models (OR 0.6, 95% CI 0.4-0.9; p=0.01) including age, sex, baseline INR and time to scan. This treatment effect was modified by the specific deep location of the ICH (interaction p=0.02): there was less hematoma expansion with intensive versus standard treatment among basal ganglia bleeds (0.4 [IQR 2] mL vs 0.9 [IQR 6] mL, p=0.002) but not among thalamic bleeds (0.3 [IQR 2] mL vs 0.4 [IQR 2] mL, p=0.48). Intensive treatment was not associated with a shift in the distribution of 3-month modified Rankin Scale scores (overall p=0.9, basal ganglia p=0.9, thalamus p=0.8). Conclusions: Compared to standard treatment, intensive BP reduction was associated with less hematoma expansion in deep ICH, specifically among hemorrhages located in the basal ganglia. In this underpowered subgroup analysis, intensive BP reduction was not associated with improved outcomes.