Racial Disparities in Blood Pressure at Time of Acute Ischemic Stroke Presentation: A Population Study.

BACKGROUND: Hypertension is a stroke risk factor with known disparities in prevalence and management between Black and White patients. We sought to identify if racial differences in presenting blood pressure (BP) during acute ischemic stroke exist. METHODS AND RESULTS: Adults with acute ischemic stroke presenting to an emergency department within 24 hours of last known normal during study epochs 2005, 2010, and 2015 within the Greater Cincinnati/Northern Kentucky Stroke Study were included. Demographics, histories, arrival BP, National Institutes of Health Stroke Scale score, and time from last known normal were collected. Multivariable linear regression was used to determine differences in mean BP between Black and White patients, adjusting for age, sex, National Institutes of Health Stroke Scale score, history of hypertension, hyperlipidemia, smoking, stroke, body mass index, and study epoch. Of 4048 patients, 853 Black and 3195 White patients were included. In adjusted analysis, Black patients had higher presenting systolic BP (161 mm Hg [95% CI, 159-164] versus 158 mm Hg [95% CI, 157-159], P<0.01), diastolic BP (86 mm Hg [95% CI, 85-88] versus 83 mm Hg [95% CI, 82-84], P<0.01), and mean arterial pressure (111 mm Hg [95% CI, 110-113] versus 108 mm Hg [95% CI, 107-109], P<0.01) compared with White patients. In adjusted subanalysis of patients <4.5 hours from last known normal, diastolic BP (88 mm Hg [95% CI, 86-90] versus 83 mm Hg [95% CI, 82-84], P<0.01) and mean arterial pressure (112 mm Hg [95% CI, 110-114] versus 108 mm Hg [95% CI, 107-109], P<0.01) were also higher in Black patients. CONCLUSIONS: This population-based study suggests differences in presenting BP between Black and White patients during acute ischemic stroke. Further study is needed to determine whether these differences influence clinical decision-making, outcome, or clinical trial eligibility.

Impact of Poverty on Stroke Recurrence: A Population-Based Study.

BACKGROUND AND OBJECTIVES: Poverty is associated with greater stroke incidence. The relationship between poverty and stroke recurrence is less clear. METHODS: In this population-based study, incident strokes within the Greater Cincinnati/Northern Kentucky region were ascertained during the 2015 study period and followed up for recurrence until December 31, 2018. The primary exposure was neighborhood socioeconomic status (nSES), defined by the percentage of households below the federal poverty line in each census tract in 4 categories (≤5%, >5%-10%, >10%-25%, >25%). Poisson regression models provided recurrence rate estimates per 100,000 residents using population data from the 2015 5-year American Community Survey, adjusting for age, sex, and race. In a secondary analysis, Cox models allowed for the inclusion of vascular risk factors in the assessment of recurrence risk by nSES among those with incident stroke. RESULTS: Of 2,125 patients with incident stroke, 245 had a recurrent stroke during the study period. Poorer nSES was associated with increased stroke recurrence, with rates of 12.5, 17.5, 25.4, and 29.9 per 100,000 in census tracts with ≤5%, >5%-10%, >10%-25%, and >25% below the poverty line, respectively (p < 0.01). The relative risk (95% CI) for recurrent stroke among Black vs White individuals was 2.54 (1.91-3.37) before adjusting for nSES, and 2.00 (1.47-2.74) after adjusting for nSES, a 35.1% decrease. In the secondary analysis, poorer nSES (HR 1.74, 95% CI 1.10-2.76 for lowest vs highest category) and Black race (HR 1.31, 95% CI 1.01-1.70) were both independently associated with recurrence risk, though neither retained significance after full adjustment. Age, diabetes, and left ventricular hypertrophy were associated with increased recurrence risk in fully adjusted models. DISCUSSION: Residents of poorer neighborhoods had a dose-dependent increase in stroke recurrence risk, and neighborhood poverty accounted for approximately one-third of the excess risk among Black individuals. These results highlight the importance of poverty, race, and the intersection of the 2 as potent drivers of stroke recurrence.

Health Factors Associated With Development and Severity of Poststroke Dysphagia: An Epidemiological Investigation.

BACKGROUND: Dysphagia after stroke is common and can impact morbidity and death. The purpose of this population-based study was to determine specific epidemiological and health risk factors that impact development of dysphagia after acute stroke. METHODS AND RESULTS: Ischemic and hemorrhagic stroke cases from 2010 and 2015 were identified via chart review from the GCNKSS (Greater Cincinnati Northern Kentucky Stroke Study), a representative sample of ≈1.3 million adults from southwestern Ohio and northern Kentucky. Dysphagia status was determined on the basis of clinical assessments and necessity for alternative access to nutrition via nasogastric or percutaneous endoscopic gastrostomy tube placement. Comparisons between patients with and without dysphagia were made to determine differences in baseline characteristics and premorbid conditions. Multivariable logistic regression determined factors associated with increased risk of dysphagia. Dysphagia status was ascertained from 4139 cases (1709 with dysphagia). Logistic regression showed that increased age, Black race, higher National Institutes of Health Stroke Scale score at admission, having a hemorrhagic stroke (versus infarct), and right hemispheric stroke increased the risk of developing dysphagia after stroke. Factors associated with reduced risk included history of high cholesterol, lower prestroke modified Rankin Scale score, and white matter disease. CONCLUSIONS: This study replicated previous findings of variables associated with dysphagia (older age, worse stroke, right-sided hemorrhagic lesions), whereas other variables identified were without clear biological rationale (eg, Black race, history of high cholesterol, and presence of white matter disease) and should be investigated in future studies to determine biological relevance and potential influence in stroke recovery.

Trends Over Time in Stroke Incidence by Race in the Greater Cincinnati Northern Kentucky Stroke Study.

BACKGROUND AND OBJECTIVES: Understanding the current status of and temporal trends of stroke epidemiology by age, race, and stroke subtype is critical to evaluate past prevention efforts and to plan future interventions to eliminate existing inequities. We investigated trends in stroke incidence and case fatality over a 22-year time period. METHODS: In this population-based stroke surveillance study, all cases of stroke in acute care hospitals within a 5-county population of southern Ohio/northern Kentucky in adults aged ≥20 years were ascertained during a full year every 5 years from 1993 to 2015. Temporal trends in stroke epidemiology were evaluated by age, race (Black or White), and subtype (ischemic stroke [IS], intracranial hemorrhage [ICH], or subarachnoid hemorrhage [SAH]). Stroke incidence rates per 100,000 individuals from 1993 to 2015 were calculated using US Census data and age-standardized, race-standardized, and sex-standardized as appropriate. Thirty-day case fatality rates were also reported. RESULTS: Incidence rates for stroke of any type and IS decreased in the combined population and among White individuals (any type, per 100,000, 215 [95% CI 204-226] in 1993/4 to 170 [95% CI 161-179] in 2015, p = 0.015). Among Black individuals, incidence rates for stroke of any type decreased over the study period (per 100,000, 349 [95% CI 311-386] in 1993/4 to 311 [95% CI 282-340] in 2015, p = 0.015). Incidence of ICH was stable over time in the combined population and in race-specific subgroups, and SAH decreased in the combined groups and in White adults. Incidence rates among Black adults were higher than those of White adults in all time periods, and Black:White risk ratios were highest in adults in young and middle age groups. Case fatality rates were similar by race and by time period with the exception of SAH in which 30-day case fatality rates decreased in the combined population and White adults over time. DISCUSSION: Stroke incidence is decreasing over time in both Black and White adults, an encouraging trend in the burden of cerebrovascular disease in the US population. Unfortunately, however, Black:White disparities have not decreased over a 22-year period, especially among younger and middle-aged adults, suggesting the need for more effective interventions to eliminate inequities by race.

Health factors associated with development and severity of post-stroke dysphagia: an epidemiological investigation.

Background and Purpose: Dysphagia is a common post-stroke occurrence and has been shown to impact patients' morbidity and mortality. The purpose of this study was to use a large population-based dataset to determine specific epidemiological and patient health risk factors that impact development and severity of dysphagia after acute stroke. Methods: Using data from the Greater Cincinnati Northern Kentucky Stroke Study, GCNKSS, involving a representative sample of approximately 1.3 million people from Southwest Ohio and Northern Kentucky of adults (age ≥18), ischemic and hemorrhagic stroke cases from 2010 and 2015 were identified via chart review. Dysphagia status was determined based on bedside and clinical assessments, and severity by necessity for alternative access to nutrition via nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tube placement. Comparisons between patients with and without dysphagia were made to determine differences in baseline characteristics and pre-morbid conditions. Multivariable logistic regression was used to determine factors associated with increased risk of developing dysphagia. Results: Dysphagia status was ascertained from 4139 cases (1709 with dysphagia). Logistic regression showed: increased age, Black race, higher NIHSS score at admission, having a hemorrhagic stroke (vs infarct), and right hemispheric stroke increased risk of developing dysphagia after stroke. Factors associated with reduced risk included history of high cholesterol, lower pre-stroke mRS score, and white matter disease. Conclusions: This study replicated many previous findings of variables associated with dysphagia (older age, worse stroke, right sided hemorrhagic lesions), while other variables identified were without clear biological rationale (e.g. Black race, history of high cholesterol and presence of white matter disease). These factors should be investigated in future, prospective studies to determine biological relevance and potential influence in stroke recovery.

Trends in Disparities in Advanced Neuroimaging Utilization in Acute Stroke: A Population-Based Study.

BACKGROUND: Our primary objective was to evaluate if disparities in race, sex, age, and socioeconomic status (SES) exist in utilization of advanced neuroimaging in year 2015 in a population-based study. Our secondary objective was to identify the disparity trends and overall imaging utilization as compared with years 2005 and 2010. METHODS: This was a retrospective, population-based study that utilized the GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study) data. Patients with stroke and transient ischemic attack were identified in the years 2005, 2010, and 2015 in a metropolitan population of 1.3 million. The proportion of imaging use within 2 days of stroke/transient ischemic attack onset or hospital admission date was computed. SES determined by the percentage below the poverty level within a given respondent's US census tract of residence was dichotomized. Multivariable logistic regression was used to determine the odds of advanced neuroimaging use (computed tomography angiogram/magnetic resonance imaging/magnetic resonance angiogram) for age, race, gender, and SES. RESULTS: There was a total of 10 526 stroke/transient ischemic attack events in the combined study year periods of 2005, 2010, and 2015. The utilization of advanced imaging progressively increased (48% in 2005, 63% in 2010, and 75% in 2015 [P<0.001]). In the combined study year multivariable model, advanced imaging was associated with age and SES. Younger patients (≤55 years) were more likely to have advanced imaging compared with older patients (adjusted odds ratio, 1.85 [95% CI, 1.62-2.12]; P<0.01), and low SES patients were less likely to have advanced imaging compared with high SES (adjusted odds ratio, 0.83 [95% CI, 0.75-0.93]; P<0.01). A significant interaction was found between age and race. Stratified by age, the adjusted odds of advanced imaging were higher for Black patients compared with White patients among older patients (>55 years; adjusted odds ratio, 1.34 [95% CI, 1.15-1.57]; P<0.01), but no racial differences among the young. CONCLUSIONS: Racial, age, and SES-related disparities exist in the utilization of advanced neuroimaging for patients with acute stroke. There was no evidence of a change in trend of these disparities between the study periods.

Changing Trends in Demographics, Risk Factors, and Clinical Features of Patients With Infective Endocarditis-Related Stroke, 2005-2015.

BACKGROUND AND OBJECTIVES: There is a rising incidence of infective endocarditis-related stroke (IERS) in the United States attributed to the opioid epidemic. A contemporary epidemiologic description is necessary to understand the impact of the opioid epidemic on clinical characteristics of IERS. We describe and analyze trends in the demographics, risk factors, and clinical features of IERS. METHODS: This is a retrospective cohort study within a biracial population of 1.3 million in the Greater Cincinnati/Northern Kentucky region. All hospitalized patients with hemorrhagic or ischemic stroke were identified and physician verified from the 2005, 2010, and 2015 calendar years using ICD-9 and ICD-10 codes. IERS was defined as an acute stroke attributed to infective endocarditis meeting modified Duke Criteria for possible or definite endocarditis. Unadjusted comparison of demographics, risk factors, outcome, and clinical characteristics was performed between each study period for IERS and non-IERS. An adjusted model to compare trends used the Cochran-Armitage test for categorical variables and a general linear model or Kruskal-Wallis test for numerical variables. Examination for interaction of endocarditis status in trends was performed using a general linear or logistic model. RESULTS: A total of 54 patients with IERS and 8,204 without IERS were identified during the study periods. Between 2005 and 2015, there was a decline in rates of hypertension (91.7% vs 36.0%; p = 0.0005) and increased intravenous drug users (8.3% vs 44.0%; p = 0.02) in the IERS cohort. The remainder of the stroke population demonstrated a significant rise in hypertension, diabetes, atrial fibrillation, and perioperative stroke. Infective endocarditis status significantly interacted with the trend in hypertension prevalence (p = 0.001). DISCUSSION: From 2005 to 2015, IERS was increasingly associated with intravenous drug use and fewer risk factors, specifically hypertension. These trends likely reflect the demographics of the opioid epidemic, which has affected younger patients with fewer comorbidities.

Racial Disparities in Stroke Recurrence: A Population-Based Study.

BACKGROUND AND OBJECTIVE: There are significant racial disparities in stroke in the United States, with Black individuals having a higher risk of incident stroke even when adjusted for traditional stroke risk factors. It is unknown whether Black individuals are also at a higher risk of recurrent stroke. METHODS: Over an 18-month period spanning 2014-2015, we ascertained index stroke cases within the Greater Cincinnati/Northern Kentucky population of 1.3 million. We then followed up all patients for 3 years and determined the risk of recurrence. Multivariable survival analysis was performed to determine the effect of Black race on recurrence. RESULTS: There were 3,816 patients with index stroke/TIA events in our study period, and 476 patients had a recurrent event within 3 years. The Kaplan-Meier estimate of 3-year recurrence rate was 15.4%. Age-adjusted and sex-adjusted stroke recurrence rate was higher in Black individuals (HR 1.34, 95% CI 1.1-1.6; p = 0.003); however, when adjusted for traditional stroke risk factors including hypertension, diabetes, smoking status, age, and left ventricular hypertrophy, the association between Black race and recurrence was significantly attenuated and became nonsignificant (HR 1.1, 95% CI 0.9-1.36, p = 0.32). At younger ages, Black race was more strongly associated with recurrence, and this effect may not be fully attenuated by traditional stroke risk factors. DISCUSSION: Recurrent stroke was more common among Black individuals, but the magnitude of the racial difference was substantially attenuated and became nonsignificant when adjusted for traditional stroke risk factors. Interventions targeting these risk factors could reduce disparities in stroke recurrence.

Automated grading of enlarged perivascular spaces in clinical imaging data of an acute stroke cohort using an interpretable, 3D deep learning framework.

Enlarged perivascular spaces (EPVS), specifically in stroke patients, has been shown to strongly correlate with other measures of small vessel disease and cognitive impairment at 1 year follow-up. Typical grading of EPVS is often challenging and time consuming and is usually based on a subjective visual rating scale. The purpose of the current study was to develop an interpretable, 3D neural network for grading enlarged perivascular spaces (EPVS) severity at the level of the basal ganglia using clinical-grade imaging in a heterogenous acute stroke cohort, in the context of total cerebral small vessel disease (CSVD) burden. T2-weighted images from a retrospective cohort of 262 acute stroke patients, collected in 2015 from 5 regional medical centers, were used for analyses. Patients were given a label of 0 for none-to-mild EPVS (< 10) and 1 for moderate-to-severe EPVS (≥ 10). A three-dimensional residual network of 152 layers (3D-ResNet-152) was created to predict EPVS severity and 3D gradient class activation mapping (3DGradCAM) was used for visual interpretation of results. Our model achieved an accuracy 0.897 and area-under-the-curve of 0.879 on a hold-out test set of 15% of the total cohort (n = 39). 3DGradCAM showed areas of focus that were in physiologically valid locations, including other prevalent areas for EPVS. These maps also suggested that distribution of class activation values is indicative of the confidence in the model's decision. Potential clinical implications of our results include: (1) support for feasibility of automated of EPVS scoring using clinical-grade neuroimaging data, potentially alleviating rater subjectivity and improving confidence of visual rating scales, and (2) demonstration that explainable models are critical for clinical translation.

Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm: Prevalence and Practice Patterns.

BACKGROUND: There are limited data about the epidemiology and secondary stroke prevention strategies used for patients with depressed left ventricular ejection fraction (LVEF) and sinus rhythm following an acute ischemic stroke (AIS). We sought to describe the prevalence of LVEF ≤40% and sinus rhythm among patients with AIS and antithrombotic treatment practice in a multi-center cohort from 2002 to 2018. METHODS: This was a multi-center, retrospective cohort study comprised of patients with AIS hospitalized in the Greater Cincinnati Northern Kentucky Stroke Study and 4 academic, hospital-based cohorts in the United States. A 1-stage meta-analysis of proportions was undertaken to calculate a pooled prevalence. Univariate analyses and an adjusted multivariable logistic regression model were performed to identify demographic, clinical, and echocardiographic characteristics associated with being prescribed an anticoagulant upon AIS hospitalization discharge. RESULTS: Among 14 338 patients with AIS with documented LVEF during the stroke hospitalization, the weighted pooled prevalence of LVEF ≤40% and sinus rhythm was 5.0% (95% CI, 4.1-6.0%; I2, 84.4%). Of 524 patients with no cardiac thrombus and no prior indication for anticoagulant who survived postdischarge, 200 (38%) were discharged on anticoagulant, 289 (55%) were discharged on antiplatelet therapy only, and 35 (7%) on neither. There was heterogeneity by site in the proportion discharged with an anticoagulant (22% to 45%, P<0.0001). Cohort site and National Institutes of Health Stroke Severity scale >8 (odds ratio, 2.0 [95% CI, 1.1-3.8]) were significant, independent predictors of being discharged with an anticoagulant in an adjusted analysis. CONCLUSIONS: Nearly 5% of patients with AIS have a depressed LVEF and are in sinus rhythm. There is significant variation in the clinical practice of antithrombotic therapy prescription by site and stroke severity. Given this clinical equipoise, further study is needed to define optimal antithrombotic treatment regimens for secondary stroke prevention in this patient population.

What is the median volume of intracerebral hemorrhage and is it changing?

OBJECTIVES: Population-level estimates of the median intracerebral hemorrhage (ICH) volume would allow for the evaluation of clinical trial external validity and determination of temporal trends. We previously reported the median ICH volume in 1988. However, differences in risk factor management, neuroimaging, and demographics may have affected ICH volumes. The goal of this study is to determine the median volume of ICH within a population-based cross-sectional study, including whether it has changed over time. METHODS: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke study was a population-based study of ICH among residents of the Greater Cincinnati/Northern Kentucky region from 2008 through 2012. This study utilizes those data and compares with ICH cases from the same region in 1988. Initial computed tomography images of the head were reviewed, and ICH volumes were calculated using consistent methodology. RESULTS: From 2008 through 2012, we identified 1117 cases of ICH. The median volume of ICH was 14.0 mL and was lower in black (11.6) than in white (15.5) patients. Median volumes of lobar and deep ICH were 28.8 mL and 9.8 mL, respectively. Median ICH volume changed significantly from 1988 to 2008-2012, with age-and-race-adjusted volume decreasing from 18.3 mL to 13.76 mL (p = 0.025). CONCLUSIONS: Median volume of ICH was 13.76 mL, and this should be considered in clinical trial design. Median ICH volume has apparently decreased from 1988 to 2008-2012.

White Matter Lesion Severity is Associated with Intraventricular Hemorrhage in Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Intraventricular hemorrhage (IVH) and white matter lesion (WML) severity are associated with higher rates of death and disability in intracerebral hemorrhage (ICH). A prior report identified an increased risk of IVH with greater WML burden but did not control for location of ICH. We sought to determine whether a higher degree of WML is associated with a higher risk of IVH after controlling for ICH location. METHODS: Utilizing the patient population from 2 large ICH studies; the Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS III) Study and the Ethnic/Racial Variations of Intracerebral Hemorrhage study, we graded WML using the Van Swieten Scale (0-1 for mild, 2 for moderate, and 3-4 for severe WML) and presence or absence of IVH in baseline CT scans. We used multivariable regression models to adjust for relevant covariates. RESULTS: Among 3023 ICH patients, 1260 (41.7%) had presence of IVH. In patients with IVH, the proportion of severe WML (28.6%) was higher compared with patients without IVH (21.8%) (P < .0001). Multivariable analysis demonstrated that moderate-severe WML, deep ICH, and increasing ICH volume were independently associated with presence of IVH. We found an increased risk of IVH with moderate-severe WML (OR = 1.38; 95%Cl 1.03-1.86, P = .0328) in the subset of lobar hemorrhages. CONCLUSIONS: Moderate to severe WML is a risk for IVH. Even in lobar ICH hemorrhages, severe WML leads to an independent increased risk for ventricular rupture.

Ischemic Stroke and Bleeding: Clinical Benefit of Anticoagulation in Atrial Fibrillation After Intracerebral Hemorrhage.

Background and Purpose- Patients with intracerebral hemorrhage (ICH) and atrial fibrillation (AF) are at risk for ischemic events. While risk calculators (CHA2DS2-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. CHA2DS2-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.

Incontinence and gait disturbance after intraventricular extension of intracerebral hemorrhage.

OBJECTIVE: We tested the hypothesis that intraventricular hemorrhage (IVH) is associated with incontinence and gait disturbance among survivors of intracerebral hemorrhage (ICH) at 3-month follow-ups. METHODS: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke study was used as the discovery set. The Ethnic/Racial Variations of Intracerebral Hemorrhage study served as a replication set. Both studies performed prospective hot-pursuit recruitment of ICH cases with 3-month follow-up. Multivariable logistic regression analyses were computed to identify risk factors for incontinence and gait dysmobility at 3 months after ICH. RESULTS: The study population consisted of 307 ICH cases in the discovery set and 1,374 cases in the replication set. In the discovery set, we found that increasing IVH volume was associated with incontinence (odds ratio [OR] 1.50; 95% confidence interval [CI] 1.10-2.06) and dysmobility (OR 1.58; 95% CI 1.17-2.15) after controlling for ICH location, initial ICH volume, age, baseline modified Rankin Scale score, sex, and admission Glasgow Coma Scale score. In the replication set, increasing IVH volume was also associated with both incontinence (OR 1.42; 95% CI 1.27-1.60) and dysmobility (OR 1.40; 95% CI 1.24-1.57) after controlling for the same variables. CONCLUSION: ICH subjects with IVH extension are at an increased risk for developing incontinence and dysmobility after controlling for factors associated with severity and disability. This finding suggests a potential target to prevent or treat long-term disability after ICH with IVH.

Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage.

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

Peripheral monocyte count is associated with case fatality after intracerebral hemorrhage.

BACKGROUND: Leukocytosis is associated with hemorrhage volume and early neurologic deterioration after intracerebral hemorrhage (ICH). We examined total white blood cell (WBC) count, absolute monocyte count (AMC), and absolute neutrophil count (ANC) as potential readily available prognostic biomarkers in human ICH. METHODS: In a retrospective study, adult patients aged 18 years or older who presented to 1 of 2 local hospitals with nontraumatic ICH from July 2008 to December 2009 within 12 hours of symptom onset were identified. Demographics, Glasgow Coma Scale (GCS), ICH volume, ICH location, and 30-day case fatality rates were determined. Total WBC count, ANC, AMC, and hemoglobin concentration were determined. Linear and logistic regressions were used to evaluate factors associated with baseline ICH volume (log transformed) and 30-day case fatality, respectively. RESULTS: Of the 186 patients, mean (±SD) age was 67.3 ± 14.8 years; 51% were men and 22% were black. Median (interquartile range) ICH volume was 12.8 (4.9, 29.4) mL. After adjusting for patient age and initial hemoglobin, higher initial WBC count (P = .0009) and higher ANC (P = .006) were associated with higher ICH volume, whereas AMC was not (P = .4). After adjusting for patient age, GCS, intraventricular hemorrhage (+/-), stroke location, and ICH volume, baseline AMC was associated with greater odds of 30-day case fatality (odds ratio 2.26, 95% confidence interval 1.10-4.65, P = .03). CONCLUSIONS: The association of AMC with higher 30-day case fatality after ICH is hypothesis generating. Given the lack of association between presenting AMC and ICH volume, AMC may contribute to secondary injury after ICH (hematoma expansion and/or cerebral edema).

Apolipoprotein E, statins, and risk of intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Apolipoprotein E (ApoE) genotypes have been associated with lobar intracerebral hemorrhage (ICH). Although statins have been associated with an increased risk of ICH, meta-analyses have not consistently shown a statin-induced risk of ICH. Here, we test whether hypercholesterolemia (HC) and ApoE polymorphisms affect the risk of ICH by statin use. METHODS: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study is a prospective, demographically matched case-control study of ICH. A similar study of ICH, Genetic Risks for Medication-Related Hemorrhagic Stroke (GOCHA), was used as a replication cohort. Subjects were classified as normocholesterolemia, HC without statin use, and HC with statin use. Statistical comparisons were performed using Fisher exact test, χ2 tests, and the Breslow-Day test. RESULTS: The discovery cohort consisted of 558 ICH cases and 1444 controls, and the replication cohort consisted of 1020 ICH cases and 382 controls. The association of lower risk for HC was not attenuated by statin use. Statin use was observed to confer a higher risk for lobar ICH in those carrying ApoE4/E4 and ApoE2/E4 genotypes in both discovery and replication cohorts, and a test for interaction showed a trend towards significance (P=0.11 for statin and ApoE4/E4). CONCLUSIONS: Statin use does not seem to attenuate the association of HC with decreased risk for nonlobar ICH. Our data support a gene-by-drug effect for lobar ICH, but larger sample sizes are needed to confirm the association before any clinical change is warranted. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov. Unique identifier: NCT00930280.

Risk factors for intracerebral hemorrhage differ according to hemorrhage location.

OBJECTIVES: Risk factors have been described for spontaneous intracerebral hemorrhage (ICH); their relative contribution to lobar vs nonlobar hemorrhage location is less clear. Our purpose here was to investigate risk factors by hemorrhage location. METHODS: This case-control study prospectively enrolled subjects with first-ever spontaneous ICH and matched each with up to 3 controls by age, race, and gender. Conditional stepwise logistic regression modeling was used to determine significant independent risk factors for lobar and nonlobar ICH. RESULTS: From December 1997 through December 2006, 597 cases and 1,548 controls qualified for the analysis. Hypertension, warfarin use, first-degree relative with ICH, personal history of ischemic stroke, less than a high school education, and APOE ε2 or ε4 genotype were more common in ICH cases. Hypercholesterolemia and moderate alcohol consumption (≤ 2 drinks per day) were less common in ICH cases. The associations of hypertension and hypercholesterolemia were specific for nonlobar ICH. Conversely, the association of APOE ε2 or ε4 genotype was specific for lobar ICH. CONCLUSIONS: APOE ε2 or ε4 genotype was associated specifically with lobar ICH. Hypertension was associated specifically with nonlobar ICH. A protective association was seen between hypercholesterolemia and nonlobar ICH; no such association was identified for lobar ICH.

Quantitative criteria for improving performance of buccal DNA for high-throughput genetic analysis.

BACKGROUND: DNA from buccal brush samples is being used for high-throughput analyses in a variety of applications, but the impact of sample type on genotyping success and downstream statistical analysis remains unclear. The objective of the current study was to determine laboratory predictors of genotyping failure among buccal DNA samples, and to evaluate the successfully genotyped results with respect to analytic quality control metrics. Sample and genotyping characteristics were compared between buccal and blood samples collected in the population-based Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study (https://gerfhs.phs.wfubmc.edu/public/index.cfm). RESULTS: Seven-hundred eight (708) buccal and 142 blood DNA samples were analyzed for laboratory-based and analysis metrics. Overall genotyping failure rates were not statistically different between buccal (11.3%) and blood (7.0%, p = 0.18) samples; however, both the Contrast Quality Control (cQC) rate and the dynamic model (DM) call rates were lower among buccal DNA samples (p < 0.0001). The ratio of double-stranded to total DNA (ds/total ratio) in the buccal samples was the only laboratory characteristic predicting sample success (p < 0.0001). A threshold of at least 34% ds/total DNA provided specificity of 98.7% with a 90.5% negative predictive value for eliminating probable failures. After genotyping, median sample call rates (99.1% vs. 99.4%, p < 0.0001) and heterozygosity rates (25.6% vs. 25.7%, p = 0.006) were lower for buccal versus blood DNA samples, respectively, but absolute differences were small. Minor allele frequency differences from HapMap were smaller for buccal than blood samples, and both sample types demonstrated tight genotyping clusters, even for rare alleles. CONCLUSIONS: We identified a buccal sample characteristic, a ratio of ds/total DNA <34%, which distinguished buccal DNA samples likely to fail high-throughput genotyping. Applying this threshold, the quality of final genotyping resulting from buccal samples is somewhat lower, but compares favorably to blood. Caution is warranted if cases and controls have different sample types, but buccal samples provide comparable results to blood samples in large-scale genotyping analyses.