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Background and Purpose— Selective serotonin reuptake inhibitors (SSRIs) have a well-established association with bleeding complications and conflicting reports on outcome after stroke. We sought to evaluate whether pre–intracerebral hemorrhage (ICH) SSRI use increased ICH risk and post-ICH SSRI use improved ICH outcome. Methods— Through post hoc analysis of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage), SSRI use was categorized into no use, pre-ICH only, pre- and post-ICH use (termed “continuous”), and post-ICH only (termed “new”). Using multivariable modeling, associations were sought between pre-ICH SSRI use and ICH risk in the case-control set, and associations between post-ICH SSRI use and 3-month outcome were analyzed in the ICH case set. Exploratory analyses sought to assess influence of race/ethnicity in models. Results— The final study cohort consisted of 2287 ICH cases and 2895 controls. Pre-ICH SSRI use was not associated with ICH risk (odds ratio, 0.824 [95% CI, 0.632–1.074]) nor potentiation of ICH risk with anticoagulant or antiplatelet use. New post-ICH SSRI use was associated with unfavorable modified Rankin Scale score at 3 months after ICH (odds ratio, 1.673 [95% CI, 1.162–2.408]; P =0.006) in multivariable analyses. Additional propensity score analysis indicated a similar trend but did not reach statistical significance ( P =0.107). When stratified by race/ethnicity, multivariable modeling demonstrated reduced ICH risk with pre-ICH SSRI use in Hispanics (odds ratio, 0.513 [95% CI, 0.301–0.875]; P =0.014), but not non-Hispanic whites or blacks, and no associations between post-ICH SSRI use and 3-month outcome in any racial/ethnic group. Conclusions— In a large multiethnic cohort, pre-ICH SSRI use was not associated with increased ICH risk, but post-ICH SSRI use was associated with unfavorable 3-month neurological outcome after ICH. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01202864.

Background: Intracerebral hemorrhage (ICH) patients may appear disabled despite intact cortical spinal tracts (CST). ICH lesions may also vary in volume and location relative to the CST with differential impacts on motor outcome. In this study, we evaluated whether diffusion tensor imaging (DTI) integrity of CST fiber tracking associates with mobility three months post ICH. Methods: The Recovery and Outcomes from StrokE (ROSE) Study is a prospective, multi-center study of ICH serially assessed with motor, cognitive, and functional outcomes and MRI/DTI. Outcome data were collected by hospital chart review and interview/exam. Acute MRI images were analyzed by a central neuroimaging core for ICH location, size, intraventricular hemorrhage, and fractional anisotropy (FA) derived from DTI of the CST. Mobility was assessed at 3-month follow-up using the Barthel Mobility Index. We computed single variable logistic regression analyses (outcome = Barthel mobility at 3 months). We also computed a stepwise logistic model, with and without age, sex, and race, including variables that met P Results: There were 76 ICH patients with DTI FA data available for analysis; 61 with complete data for the multivariate model. Poor mobility after ICH (N = 21; 27.6%) was associated with ICH volume, presence of IVH, Glasgow coma score, ipsilesional CST FA, ipsilesional CP FA and CP FA asymmetry index (Table 1). The multivariate model that adjusted for age, sex, and race identified ipsilesional CP FA, admission GCS and presence of IVH as associated with poor mobility at 3 months; notably, log ICH volume was not associated after controlling for CST injury (Table 1). Conclusions: The presence of IVH and the GCS score at baseline were associated with poor mobility. In addition, the CP FA asymmetry index was independently associated with poor mobility even after accounting for log ICH volume, suggesting that DTI is informative of outcome beyond classic ICH outcome predictors.

Objective: There is a high prevalence of progressive cognitive impairment in intracerebral hemorrhage (ICH) survivors. We sought to identify gene expression changes, in association with long-term neurodegeneration, among patients 12-24 months post-ICH. Methods: The Recovery and Outcomes from StrokE (ROSE) study prospectively recruits patients with spontaneous, supratentorial ICH, collecting baseline peripheral blood samples and MRI with diffusion tract imaging (DTI). The Recovery of StrokE-Longitudinal Assessment with Neuroimaging (ROSE-LAWN) study performs long term follow-up at 12-24 months on cases enrolled in ROSE. We report on the first five cases enrolled in the ROSE-LAWN study from December 2020 to March 2021. Controls were matched to an overall ICH population by age, sex, and race. RNA-sequencing, aligned to human genome assembly GRCh38, was tested for differential gene expression. Canonical pathway enrichment and network analyses were computed for differentially expressed genes using Ingenuity Pathway Analysis, STRING and MCODE. Results: RNA-seq analysis of 5 ICH cases [male, 80%; median age, 61 (45 - 73); black, 40%; ICH volume, 14.88cc ± 13.07] and 13 controls [male, 54%; median age, 74 (69 - 79); black, 15%] identified 554 differentially expressed genes (genomic control adjusted p < 0.01), of which 24 met the false discovery rate correction for multiple comparisons (FDR < 0.05). The most significant difference was observed in hypoxia up-regulated 1 ( HYOU1), a heat shock protein related gene (p = 2.64E-11). Pathway analysis identified enrichment of dopamine and serotonin receptor signaling (p = 8.74E-03, 2.23E-02), cell cycle regulation (p = 1.75E-02) and agranulocyte adhesion pathways (p = 2.18E-02). Comparison of baseline and follow-up MRI DTI demonstrated extensive cortical tract degeneration, beyond the initial injury. Conclusion: These results provide novel evidence of significant gene expression changes occurring years after the initial ICH. Despite resolution of the ICH, persistent inflammation may correlate with progressive neurodegeneration and subsequent cognitive impairment in ICH survivors. Future studies with greater sample sizes are supported by this work.

Background: Intracerebral hemorrhage (ICH) has the highest morbidity and mortality rate of the major stroke subtypes. Volume is a well-established predictor of outcome. Theoretically, ICH should expand more in areas of less resistance. We hypothesize that 1) expansion perpendicular to neural tracts (axially) will be less great than expansion parallel to tracts (vertically) and 2) differing effect on outcome will occur based on axial and vertical areas of hemorrhage. Methods: The Genetic and Environmental Risk Factors of Hemorrhagic Stroke (GERFHS) study is a population-based case-control study. Each case of ICH within the 5 county region of Greater Cincinnati was evaluated for volume of hemorrhage with a subset completing 3 month telephone follow-up to obtain data including modified Rankin Scale (mRS). Baseline variables were assessed for poor outcome, defined as mRS greater than or equal to 3 at 90 days. Results: From July 2009 to December 2012, 1205 cases of ICH were identified, of which 304 had 3-month follow up. The table presents univariate association with outcome. More than 86% of hemorrhages had greater vertical area than axial area. On multivariable analysis controlling for ICH score variables, vertical area showed a trend toward worse outcome (OR 1.09, p= 0.06) vs axial area (OR 0.97, p=0.69) which was not found to have a significant effect on outcome independent of total volume. Conclusion: Most patients have greater vertical expansion of ICH than axial expansion. This pattern of hemorrhage growth is consistent with neural tracts having less resistance vertically. If the greater impact on outcome is confirmed, improved outcome and trial inclusion criteria may be determined.

Background: The risk of intracerebral hemorrhage (ICH) with hypertension (HTN) is well documented, with prior studies showing that HTN is the most important risk factor associated with ICH. Prior studies have shown that while the prevalence of HTN increases with age, the odds ratio (OR) of HTN for non-lobar ICH is greater earlier in life. We have previously found a lack of Apolipoprotein E allele association with lobar ICH in minority populations. Here we seek to determine if, similar to non-lobar ICH, the odds ratio of HTN for lobar ICH is greater at an earlier age. Methods: The Ethnic/Racial Variations of ICH (ERICH) study is a prospective multicenter case-control study of ICH among whites, blacks, and Hispanics. Cases were enrolled from 42 sites. Controls matched to cases 1:1 by age (±5 years), sex, ethnicity/race, and metropolitan area were identified by random-digit dialing. Participants were interviewed to determine history of HTN. Participants were divided into age groups based on ethnicity-specific quartiles. Cases in each ethnic/age group were compared to controls using logistic regression (i.e., cases and controls unmatched). ORs were calculated to show the risk of lobar ICH associated with HTN by quartile. Results: Overall, 917 lobar ICH cases and 932 controls were included. The Table shows the multivariable OR. ORs were highest in the youngest age quartile across all races (6.47 for blacks, 5.72 for Hispanics and 2.74 for whites). HTN produced a significant increase in risk for the youngest two quartiles in blacks and Hispanics, but only the youngest quartile in whites. However, the age of the lowest quartile in whites was equivalent to the bottom two quartiles in minorities. Discussion: Similar to non-lobar ICH, HTN earlier in life bears a greater risk of lobar ICH than later in life and this risk is across a greater range in disproportionately affected minorities. Research into how new onset or early life HTN leads to disproportionate risk compared to late life is needed.

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

Introduction: Intracerebral hemorrhage (ICH) results in high mortality and high rate of disability among survivors. The effects of preexisting small vessel disease (SVD) on functional outcomes after ICH is uncertain and understanding manifestations of brain health such as white matter lesions (WML) and atrophy are a top priority for developing prognostic indicators. Our objective was to determine whether WML and brain atrophy is associated with functional outcomes in ICH patients. Hypothesis: We hypothesized that higher burden of WML and atrophy will have a poor outcome independent of age, ICH volume, ICH location, IVH, and presenting Glasgow Coma Scale (GCS) score. Methods: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) III study is 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 measured brain atrophy (2 linear measurements) in baseline head CT scans. The outcome measures included modified Rankin Scale (mRS) at 3 months. Primary outcome was disability or death (mRS 3-6). Results: A total of 441 CT scans were graded; 48 patients were excluded due to missing mRS. Among the included 393 ICH patients (mean±SD age 71.5± 13.8; 48% females), old age, high ICH volume, low GCS score, severe WML (Van Swieten score 3-4), and atrophy were significantly associated with poor outcomes (mRS 3-6) in univariate analysis. In multivariate analysis, severe WML (p=0.039), atrophy (p= 0.0131), old age (p Conclusion: Poor brain health manifesting as cerebral SVD markers of WML and atrophy are simple and independent baseline predictors of poor outcome in acute ICH. Further study for inclusion into outcome measures such as ICH Score should be considered.

Introduction: The National Institute of Health Stroke Scale (NIHSS) is the most widely used measure of neurological deficits in clinical trials. Using the placebo arm of the NINDS t-PA Stroke Trial, it has been demonstrated that the total volume of cerebral infarction in patients with similar NIHSS scores is greater for right compared to left hemisphere strokes. Our objective was to verify this finding in a non-clinical trial, independent data set of acute ischemic strokes. Methods: The Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS) is a population-based study that tracks the incidence of stroke. A convenient subsample from the 2010 GCNKSS ischemic stroke cohort (N= 368) underwent detailed imaging analysis. Research nurses abstracted patient reords to include baseline retrospective NIHSS score. The 24 hour infarct volume was segmented using manual tracing. NIHSS was compared between left and right brain using Wilcoxon rank sum test. Spearman rank correlation determined the association between the NIHSS score and infarct volume by hemisphere. Patients were stratified by NIHSS (0 to 5, 6 to 20, and greater than 20). Results: Among 368 ischemic stroke subjects with imaging data, excluded were 77 brainstem or cerebellar infarcts, 37 undetermined volume, 1 missing NIHSS, and 3 undetermined laterality. For the remaining 250 patients, 132 were left and 118 were right hemisphere strokes, and 210 had an MRI and 40 had CT. Median time from onset to imaging was 24 hours. Baseline NIHSS was similar by hemisphere and correlated with stroke volume (r=0.38, p Conclusion: The NIHSS score correlates with volume by hemisphere, but has a larger infarct volume for right hemisphere than left hemisphere for similar NIHSS. This likely reflects the different weighting of the NIHSS with regard to language. This finding confirms prior results in an independent dataset.

Introduction: Cryptogenic stroke is defined as not attributable to an identified source despite standard evaluation. The absence of small vessel or large artery disease in such evaluation suggests that cryptogenic stroke may be largely cardioembolic. We hypothesized that cryptogenic stroke would be similar to cardioembolic stroke in clinical and imaging characteristics. Methods: The Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS) is a population-based study that tracks the regional incidence of stroke. A convenient subsample from the 2010 GCNKSS ischemic stroke cohort (N= 368) was selected for detailed neuroimaging analysis. The study physician subtyped cases based on clinical, radiographic and laboratory findings (carotid ultrasound, echocardiography, vascular imaging). Subtypes included cryptogenic, cardioembolic, large-vessel, small-vessel, undetermined, and other. Three radiologists performed imaging analysis including number of acute infarcts, location and white matter hyperintensity (WMH). Infarct volume was segmented using manual tracing. Results: Of 368 ischemic stroke cases with imaging data, subtypes were 26.4% cryptogenic, 16.3% large vessel, 15.5% small vessel, 24.7% cardioembolic, 5.4% undetermined, and 11.7% other. Compared to cardioembolic, cryptogenic stroke patients were younger, had less hypertension, higher alcohol use, smaller infarct volume and differed in location of stroke. Cryptogenic stroke had more clinical and radiological features in common with large and small-vessel stroke (Table). Undetermined and other had no significant differences to cryptogenic. Conclusion: Contrary to our hypothesis, cryptogenic stroke was different from cardioembolic stroke and appeared more similar to large vessel stroke in clinical and radiological characteristics. Further testing on a larger sample size to evaluate the impact of cardiac event monitoring on subtype distribution is needed.