Promoting regeneration while blocking cell death preserves motor neuron function in a model of ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease of motor neurons with very few treatment options. We had previously found that motor neuron degeneration in a mouse model of ALS can be delayed by deleting the axon damage sensor MAP3K12 or dual leucine zipper kinase (DLK). However, DLK is also involved in axon regeneration, prompting us to ask whether combining DLK deletion with a way to promote axon regeneration would result in greater motor neuron protection. To achieve this, we used a mouse line that constitutively expresses ATF3, a master regulator of regeneration in neurons. Although there is precedence for each individual strategy in the SOD1G93A mouse model of ALS, these have not previously been combined. By several lines of evidence including motor neuron electrophysiology, histology and behaviour, we observed a powerful synergy when combining DLK deletion with ATF3 expression. The combinatorial strategy resulted in significant protection of motor neurons with fewer undergoing cell death, reduced axon degeneration and preservation of motor function and connectivity to muscle. This study provides a demonstration of the power of combinatorial therapy to treat neurodegenerative disease.

Profiles of Maltreatment in the Child Welfare System: Predicting Mental Health Outcomes and Examining Age as a Moderator.

This longitudinal study explored the unique profiles of maltreatment among youth in the child welfare system and examined their relation to mental health outcomes over time. We additionally examined the moderating role of age. Participants included 316 youth in the foster care system (age range: 6-13 years). Data were collected through the Department of Children and Family Services upon youths' entry into foster care, then quarterly for the duration of care. A latent profile analysis identified five profiles of maltreatment, categorized as primary neglect (PN), neglect and physical abuse (PA), complex trauma, complex trauma with severe sexual abuse (SA), and neglect with SA. A hierarchical general linear model applied to the data revealed that all four classes predicted higher internalizing symptom trajectories compared with the PN reference class, event rate ratios (eRRs) = 1.19-1.37, but none of these associations were significantly moderated by age. Membership in the two classes categorized by complex trauma predicted higher externalizing behavior trajectories as compared to the PN reference class, eRRs = 1.11-1.13. The relation between membership in the neglect with SA class and externalizing behaviors was moderated by age, eRR = 0.83. Finally, membership in all four classes predicted higher posttraumatic stress symptoms as compared with the reference group, eRRs = 1.84-2.45, and with all associations moderated by age, eRRs = 0.51-0.53. These findings provide insight into the maltreatment experiences of youth in the child welfare system and have important implications for treatment needs.

Combining Imaging and Genetics to Predict Recurrence of Anticoagulation-Associated Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: For survivors of oral anticoagulation therapy (OAT)-associated intracerebral hemorrhage (OAT-ICH) who are at high risk for thromboembolism, the benefits of OAT resumption must be weighed against increased risk of recurrent hemorrhagic stroke. The ε2/ε4 alleles of the apolipoprotein E (APOE) gene, MRI-defined cortical superficial siderosis, and cerebral microbleeds are the most potent risk factors for recurrent ICH. We sought to determine whether combining MRI markers and APOE genotype could have clinical impact by identifying ICH survivors in whom the risks of OAT resumption are highest. METHODS: Joint analysis of data from 2 longitudinal cohort studies of OAT-ICH survivors: (1) MGH-ICH study (Massachusetts General Hospital ICH) and (2) longitudinal component of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage). We evaluated whether MRI markers and APOE genotype predict ICH recurrence. We then developed and validated a combined APOE-MRI classification scheme to predict ICH recurrence, using Classification and Regression Tree analysis. RESULTS: Cortical superficial siderosis, cerebral microbleed, and APOE ε2/ε4 variants were independently associated with ICH recurrence after OAT-ICH (all P<0.05). Combining APOE genotype and MRI data resulted in improved prediction of ICH recurrence (Harrell C: 0.79 versus 0.55 for clinical data alone, P=0.033). In the MGH (training) data set, CSS, cerebral microbleed, and APOE ε2/ε4 stratified likelihood of ICH recurrence into high-, medium-, and low-risk categories. In the ERICH (validation) data set, yearly ICH recurrence rates for high-, medium-, and low-risk individuals were 6.6%, 2.5%, and 0.9%, respectively, with overall area under the curve of 0.91 for prediction of recurrent ICH. CONCLUSIONS: Combining MRI and APOE genotype stratifies likelihood of ICH recurrence into high, medium, and low risk. If confirmed in prospective studies, this combined APOE-MRI classification scheme may prove useful for selecting individuals for OAT resumption after ICH.

Effect of Hyperosmolar Therapy on Outcome Following Spontaneous Intracerebral Hemorrhage: Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) Study.

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.

Untreated Hypertension: A Powerful Risk Factor for Lobar and Nonlobar Intracerebral Hemorrhage in Whites, Blacks, and Hispanics.

BACKGROUND: Hypertension is a significant risk factor for intracerebral hemorrhage (ICH). Although ethnic/racial disparities related to hypertension and ICH have been reported, these previous studies were limited by a lack of Hispanics and inadequate power to analyze by ICH location. In the current study, while overcoming these prior limitations, we investigated whether there was variation by ethnicity/race of treated and untreated hypertension as risk factors for ICH. METHODS: The ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage) is a prospective, multicenter, case-control study of ICH among whites, blacks, and Hispanics. Cases were enrolled from 42 recruitment sites. Controls matched to cases 1:1 by age (±5 years), sex, ethnicity/race, and metropolitan area were identified by random-digit dialing. Subjects were interviewed to determine history of hypertension and use of antihypertensive medications. Cases and controls within ethnic groups were compared by using conditional logistic regression. Multivariable conditional logistic regression models were computed for ICH as an overall group and separately for the location subcategories deep, lobar, and infratentorial (brainstem/cerebellar). RESULTS: Nine hundred fifty-eight white, 880 black, and 766 Hispanic ICH patients were enrolled. For ICH cases, untreated hypertension was higher in blacks (43.6%, P<0.0001) and Hispanics (46.9%, P<0.0001) versus whites (32.7%). In multivariable analyses adjusted for alcohol use, anticoagulation, hypercholesterolemia, education, and medical insurance status, treated hypertension was a significant risk factor across all locations of ICH in whites (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.24-1.98; P<0.0001), blacks (OR, 3.02; 95% CI, 2.16-4.22; P<0.0001), and Hispanics (OR, 2.50; 95% CI, 1.73-3.62; P<0.0001). Untreated hypertension was a substantially greater risk factor for all 3 racial/ethnic groups across all locations of ICH: whites (OR, 8.79; 95% CI, 5.66-13.66; P<0.0001), blacks (OR, 12.46; 95% CI, 8.08-19.20; P<0.0001), and Hispanics (OR, 10.95; 95% CI, 6.58-18.23; P<0.0001). There was an interaction between race/ethnicity and ICH risk (P<0.0001). CONCLUSIONS: Untreated hypertension confers a greater ICH risk in blacks and Hispanics relative to whites across all anatomic locations of ICH. Accelerated research efforts are needed to improve overall hypertension treatment rates and to monitor the impact of such efforts on racial/ethnic disparities in stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01202864.

Use of Statins and Outcomes in Intracerebral Hemorrhage Patients.

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.

Factors Considered by Clinicians when Prognosticating Intracerebral Hemorrhage Outcomes.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 < 0.0001; GCS verbal, 12.4 vs. 0.0%, p < 0.0001) and non-clinical/radiographic factors (31.4 vs. 12.4%, p = 0.0005). Physicians more frequently listed neuroimaging factors (ICH location, 33.9 vs. 7.4%, p < 0.0001; intraventricular hemorrhage, 13.2 vs. 2.5%, p = 0.003). There was no difference in listed factors between accurate versus inaccurate surveys. CONCLUSIONS: Clinicians frequently utilize factors outside of the components of clinical scales for prognostication, with physician and nurses focusing on different factors despite having similar accuracy.

Variability in the Use of Platelet Transfusion in Patients with Intracerebral Hemorrhage: Observations from the Ethnic/Racial Variations of Intracerebral Hemorrhage Study.

BACKGROUND: We examined platelet transfusion (PTx) in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, hypothesizing that rates of PTx would vary among hospitals and depend on whether patients were on an antiplatelet therapy or underwent intracerebral hemorrhage (ICH) surgical treatment. METHODS: The ERICH study is a prospective observational study evaluating risk factors for ICH among whites, blacks, and Hispanics. We identified factors associated with PTx, examined practice patterns of PTx across the United States, and explored the association of PTx with mortality and poor outcome (modified Rankin Scale score 4-6). RESULTS: Nineteen centers enrolled 2572 ICH cases; 11.7% received PTx. Factors significantly associated with PTx were antiplatelet use before onset (odds ratio [OR], 5.02; 95% confidence interval [CI], 3.81-6.61, P < .0001), thrombocytopenia (OR, 13.53; 95% CI, 8.43-21.72, P < .0001), and ventriculostomy placement (OR, 1.85; 95% CI, 1.36-2.52, P < .0001). Blacks were less likely (OR, .57; 95% CI, .41-0.80) to receive PTx. Among patients who received PTx, 42.4% were not on an antiplatelet therapy before onset. Twenty-three percent of patients on antiplatelet therapy received PTx, but percentages varied from 0% to 71% across centers. There was no difference in mortality or poor outcome at 3 months between patients receiving PTx and those who did not. CONCLUSIONS: The frequency of PTx for ICH varies across academic centers. Thrombocytopenia, antiplatelet use, vascular risk factors, and ventriculostomy placement were associated with PTx. PTx was not associated with improved outcomes. We anticipate reduced PTx use over time given recent clinical trial data suggesting its use could be harmful; however, the issue of whether surgical management warrants PTx remains.

Monocyte Count and 30-Day Case Fatality in Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Monocytes may contribute to secondary injury after intracerebral hemorrhage (ICH). We tested the association of absolute monocyte count with 30-day ICH case fatality in a multiethnic cohort. METHODS: Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a prospective, multicenter, case-control study of ICH among white, black, and Hispanic patients. In 240 adults with nontraumatic ICH within 24 hours of symptom onset, we evaluated the influence of ICH score and complete blood count components on 30-day case fatality using generalized linear models. RESULTS: Mean age was 62.8 years (SD, 14 years); 61.7% were men, 33.3% black, and 29.6% Hispanic. Median ICH volume was 9.9 mL (interquartile range, 4.4-26.7). After adjusting for patient age and initial hemoglobin, higher total white blood cell count (P=0.0011), driven by higher absolute neutrophil count (P=0.002), was associated with larger ICH volume, whereas absolute monocyte count was not (P=0.15). After adjusting for age, Glasgow Coma Scale, ICH volume, location, and the presence or absence of intraventricular hemorrhage, baseline absolute monocyte count was independently associated with higher 30-day case-fatality (odds ratio, 5.39; 95% confidence interval, 1.87-15.49; P=0.0018), whereas absolute neutrophil count (odds ratio, 1.04; 0.46-2.32; P=0.93) and white blood cell count (odds ratio, 1.62; 0.58-4.54; P=0.36) were not. CONCLUSIONS: These data support an independent association between higher admission absolute monocyte count and 30-day case-fatality in ICH. Inquiry into monocyte-mediated pathways of inflammation and apoptosis may elucidate the basis for the observed association and may be targets for ICH neuroprotection.

Prophylactic Antiepileptic Drug Use and Outcome in the Ethnic/Racial Variations of Intracerebral Hemorrhage Study.

BACKGROUND AND PURPOSE: The role of antiepileptic drug (AED) prophylaxis after intracerebral hemorrhage (ICH) remains unclear. This analysis describes prevalence of prophylactic AED use, as directed by treating clinicians, in a prospective ICH cohort and tests the hypothesis that it is associated with poor outcome. METHODS: Analysis included 744 patients with ICH enrolled in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study before November 2012. Baseline clinical characteristics and AED use were recorded in standardized fashion. ICH location and volume were recorded from baseline neuroimaging. We analyzed differences in patient characteristics by AED prophylaxis, and we used logistic regression to test whether AED prophylaxis was associated with poor outcome. The primary outcome was 3-month modified Rankin Scale score, with 4 to 6 considered poor outcome. RESULTS: AEDs were used for prophylaxis in 289 (39%) of the 744 subjects; of these, levetiracetam was used in 89%. Patients with lobar ICH, craniotomy, or larger hematomas were more likely to receive prophlyaxis. Although prophylactic AED use was associated with poor outcome in an unadjusted model (odds ratio, 1.40; 95% confidence interval, 1.04-1.88; P=0.03), this association was no longer significant after adjusting for clinical and demographic characteristics (odds ratio, 1.11; 95% confidence interval, 0.74-1.65; P=0.62). CONCLUSIONS: We found no evidence that AED use (predominantly levetiracetam) is independently associated with poor outcome. A prospective study is required to assess for a more modest effect of AED use on outcome after ICH.

Infection after intracerebral hemorrhage: risk factors and association with outcomes in the ethnic/racial variations of intracerebral hemorrhage study.

BACKGROUND AND PURPOSE: Risk factors for infections after intracerebral hemorrhage (ICH) and their association with outcomes are unknown. We hypothesized there are predictors of poststroke infection and infections drive worse outcomes. METHODS: We determined prevalence of infections in a multicenter, triethnic study of ICH. We performed univariate and multivariate analyses to determine the association of infection with admission characteristics and hospital complications. We performed logistic regression on association of infection with outcomes after controlling for known determinants of prognosis after ICH (volume, age, infratentorial location, intraventricular hemorrhage, and Glasgow Coma Scale). RESULTS: Among 800 patients, infections occurred in 245 (31%). Admission characteristics associated with infection in multivariable models were ICH volume (odds ratio [OR], 1.02/mL; 95% confidence interval [CI], 1.01-1.03), lower Glasgow Coma Scale (OR, 0.91 per point; 95% CI, 0.87-0.95), deep location (reference lobar: OR, 1.90; 95% CI, 1.28-2.88), and black race (reference white: OR, 1.53; 95% CI, 1.01-2.32). In a logistic regression of admission and hospital factors, infections were associated with intubation (OR, 3.1; 95% CI, 2.1-4.5), dysphagia (with percutaneous endoscopic gastrostomy: OR, 3.19; 95% CI, 2.03-5.05 and without percutaneous endoscopic gastrostomy: OR, 2.11; 95% CI, 1.04-4.23), pulmonary edema (OR, 3.71; 95% CI, 1.29-12.33), and deep vein thrombosis (OR, 5.6; 95% CI, 1.86-21.02), but not ICH volume or Glasgow Coma Scale. Infected patients had higher discharge mortality (16% versus 8%; P=0.001) and worse 3-month outcomes (modified Rankin Scale ≥3; 80% versus 51%; P<0.001). Infection was an independent predictor of poor 3-month outcome (OR, 2.6; 95% CI, 1.8-3.9). CONCLUSIONS: There are identifiable risk factors for infection after ICH, and infections predict poor outcomes.

The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study protocol.

BACKGROUND AND PURPOSE: Epidemiological studies of intracerebral hemorrhage (ICH) have consistently demonstrated variation in incidence, location, age at presentation, and outcomes among non-Hispanic white, black, and Hispanic populations. We report here the design and methods for this large, prospective, multi-center case-control study of ICH. METHODS: The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a multi-center, prospective case-control study of ICH. Cases are identified by hot-pursuit and enrolled using standard phenotype and risk factor information and include neuroimaging and blood sample collection. Controls are centrally identified by random digit dialing to match cases by age (±5 years), race, ethnicity, sex, and metropolitan region. RESULTS: As of March 22, 2013, 1655 cases of ICH had been recruited into the study, which is 101.5% of the target for that date, and 851 controls had been recruited, which is 67.2% of the target for that date (1267 controls) for a total of 2506 subjects, which is 86.5% of the target for that date (2897 subjects). Of the 1655 cases enrolled, 1640 cases had the case interview entered into the database, of which 628 (38%) were non-Hispanic black, 458 (28%) were non-Hispanic white, and 554 (34%) were Hispanic. Of the 1197 cases with imaging submitted, 876 (73.2%) had a 24 hour follow-up CT available. In addition to CT imaging, 607 cases have had MRI evaluation. CONCLUSIONS: The ERICH study is a large, case-control study of ICH with particular emphasis on recruitment of minority populations for the identification of genetic and epidemiological risk factors for ICH and outcomes after ICH.

PIEZO2 and perineal mechanosensation are essential for sexual function.

Despite the potential importance of genital mechanosensation for sexual reproduction, little is known about how perineal touch influences mating. We explored how mechanosensation affords exquisite awareness of the genitals and controls reproduction in mice and humans. Using genetic strategies and in vivo functional imaging, we demonstrated that the mechanosensitive ion channel PIEZO2 (piezo-type mechanosensitive ion channel component 2) is necessary for behavioral sensitivity to perineal touch. PIEZO2 function is needed for triggering a touch-evoked erection reflex and successful mating in both male and female mice. Humans with complete loss of PIEZO2 function have genital hyposensitivity and experience no direct pleasure from gentle touch or vibration. Together, our results help explain how perineal mechanoreceptors detect the gentlest of stimuli and trigger physiologically important sexual responses, thus providing a platform for exploring the sensory basis of sexual pleasure and its relationship to affective touch.

Risk Factors Associated With Mortality and Neurologic Disability After Intracerebral Hemorrhage in a Racially and Ethnically Diverse Cohort.

Introduction: Intracerebral hemorrhage (ICH) is the most severe subtype of stroke. Its mortality rate is high, and most survivors experience significant disability. Objective: To assess primary patient risk factors associated with mortality and neurologic disability 3 months after ICH in a large, racially and ethnically balanced cohort. Design, Setting, and Participants: This cohort study included participants from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, which prospectively recruited 1000 non-Hispanic White, 1000 non-Hispanic Black, and 1000 Hispanic patients with spontaneous ICH to study the epidemiological characteristics and genomics associated with ICH. Participants included those with uniform data collection and phenotype definitions, centralized neuroimaging review, and telephone follow-up at 3 months. Analyses were completed in November 2021. Exposures: Patient demographic and clinical characteristics as well as hospital event and imaging variables were examined, with characteristics meeting P < .20 considered candidates for a multivariate model. Elements included in the ICH score were specifically analyzed. Main Outcomes and Measures: Individual characteristics were screened for association with 3-month outcome of neurologic disability or mortality, as assessed by a modified Rankin Scale (mRS) score of 4 or greater vs 3 or less under a logistic regression model. A total of 25 characteristics were tested in the final model, which minimized the Akaike information criterion. Analyses were repeated removing individuals who had withdrawal of care. Results: A total of 2568 patients (mean [SD] age, 62.4 [14.7] years; 1069 [41.6%] women and 1499 [58.4%] men) had a 3-month outcome determination available, including death. The final logistic model had a significantly higher area under the receiver operating characteristics curve (C = 0.88) compared with ICH score alone (C = 0.76; P < .001). Among characteristics associated with neurologic disability and mortality were larger log ICH volume (OR, 2.74; 95% CI, 2.36-3.19; P < .001), older age (OR per 1-year increase, 1.04; 95% CI, 1.02-1.05; P < .001), pre-ICH mRS score (OR, 1.62; 95% CI, 1.41-1.87; P < .001), lobar location (OR, 0.22; 95% CI, 0.16-0.30; P < .001), and presence of infection (OR, 1.85; 95% CI, 1.42-2.41; P < .001). Conclusions and Relevance: The findings of this cohort study validate ICH score elements and suggest additional baseline and interim patient characteristics were associated with variation in 3-month outcome.

Risk of intracerebral haemorrhage from hypertension is greatest at an early age.

INTRODUCTION: The risk of intracerebral haemorrhage (ICH) associated with hypertension (HTN) is well documented. While the prevalence of HTN increases with age, the greatest odds ratio (OR) for HTN as a risk for ischemic stroke is at an early age. We sought to evaluate if the risk for ICH from HTN was higher in the youngest patients of each race. PATIENTS AND METHODS: The Ethnic/Racial Variations of ICH (ERICH) study is a prospective multicenter case-control study of ICH among whites, blacks, and Hispanics. Participants were divided into age groups based on race-specific quartiles. Cases in each race/age group were compared to controls using logistic regression (i.e., cases and controls unmatched). The probability of ICH among cases and controls for each race were compared against independent variables of HTN, quartile of age and interaction of quartile and age also using logistic regression. RESULTS: Overall, 2033 non-lobar ICH cases and 2060 controls, and 913 lobar ICH cases with 927 controls were included. ORs were highest in the youngest age quartile for non-lobar haemorrhage for blacks and Hispanics and highest in the youngest quartile for lobar haemorrhage for all races. The formal test of interaction between age and HTN was significant in all races for all locations with the exception of lobar ICH in whites (p = 0.2935). DISCUSSION: Hypertension is a strong independent risk factor for ICH irrespective of location among persons of younger age, consistent with the hypothesis that first exposure to HTN is a particularly sensitive time for all locations of ICH.

Ethnic and Racial Variation in Intracerebral Hemorrhage Risk Factors and Risk Factor Burden.

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

Risk factors for seizures after intracerebral hemorrhage: Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) Study.

OBJECTIVE: We aimed to identify risk factors for seizures after intracerebral hemorrhage, and to validate the prognostic value of the previously reported CAVE score (0-4 points: cortical involvement, age <65, volume >10 mL, and early seizures within 7 days of hemorrhage). PATIENTS AND METHODS: Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) was a prospective study of spontaneous intracerebral hemorrhage. We included patients who did not have a prior history of seizure and survived to discharge. Univariate analysis and multiple logistic regression modeling were used to identify risk factors for seizure. RESULTS: From 2010-2015, 3000 cases were recruited, and 2507 patients were included in this study. Seizures after hospital discharge developed in 77 patients 3.1 %). Patients with lobar (cortical) hemorrhage (OR 3.0, 95 % CI 1.8-5.0), larger hematoma volume (OR 1.5 per cm3, 95 % CI 1.2-2.0), and surgical evacuation of hematoma (OR 2.6, 95 % CI 1.4-4.8) had a higher risk of late seizure, and older patients had a lower risk (OR 0.88 per 5-year interval increase, 95 % CI 0.81-0.95). The CAVE score was highly associated with seizure development (OR 2.5 per unit score increase, 95 % CI 2.0-3.2, p < 0.0001). The CAVS score, substituting surgical evacuation for early seizure, increased the OR per unit score to 2.8 (95 % CI 2.2-3.5). CONCLUSIONS: Lobar hemorrhage, larger hematoma volume, younger age, and surgical evacuation are strongly associated with the development of seizures. We validated the CAVE score in a multi-ethnic population, and found the CAVS score to have similar predictive value while representing the current practice of AED use.

Venous Thromboembolism in Patients With Spontaneous Intracerebral Hemorrhage: A Multicenter Study.

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 < .0001), intubation (OR = 4.0; P < .0001), and presence of IVH (OR = 1.8; P = .0157) were independent predictors of VTE complications. After controlling for ICH volume and location, IVH, age, and presenting Glasgow Coma Scale, the occurrence of VTE complications was an independent predictor of poor outcome at discharge (OR = 2.9; P = .002) and 3-mo follow-up (OR = 2.1; P = .02). CONCLUSION: Although VTE complications are uncommon after ICH, they are associated with significantly worse outcomes. Further studies will be needed to determine the optimal treatment regimen for the prevention and treatment of VTE complications in ICH patients.

Systemic inflammatory response syndrome, infection, and outcome in intracerebral hemorrhage.

OBJECTIVE: Systemic inflammatory response syndrome (SIRS) may be related to poor outcomes after intracerebral hemorrhage (ICH). METHODS: The Ethnic/Racial Variations of Intracerebral Hemorrhage study is an observational study of ICH in whites, blacks, and Hispanics throughout the United Sates. SIRS was defined by standard criteria as 2 or more of the following on admission: (1) body temperature <36°C or >38°C, (2) heart rate >90 beats per minute, (3) respiratory rate >20 breaths per minute, or (4) white blood cell count <4,000/mm3 or >12,000/mm3. The relationship among SIRS, infection, and poor outcome (modified Rankin Scale [mRS] 3-6) at discharge and 3 months was assessed. RESULTS: Of 2,441 patients included, 343 (14%) met SIRS criteria at admission. Patients with SIRS were younger (58.2 vs 62.7 years; p < 0.0001) and more likely to have intraventricular hemorrhage (IVH; 53.6% vs 36.7%; p < 0.0001), higher admission hematoma volume (25.4 vs 17.5 mL; p < 0.0001), and lower admission Glasgow Coma Scale (GCS; 10.7 vs 13.1; p < 0.0001). SIRS on admission was significantly related to infections during hospitalization (adjusted odds ratio [OR] 1.36, 95% confidence interval [CI] 1.04-1.78). In unadjusted analyses, SIRS was associated with poor outcomes at discharge (OR 1.96, 95% CI 1.42-2.70) and 3 months (OR 1.75, 95% CI 1.35-2.33) after ICH. In analyses adjusted for infection, age, IVH, hematoma location, admission GCS, and premorbid mRS, SIRS was no longer associated with poor outcomes. CONCLUSIONS: SIRS on admission is associated with ICH score on admission and infection, but it was not an independent predictor of poor functional outcomes after ICH.

Racial/ethnic variation of APOE alleles for lobar intracerebral hemorrhage.

OBJECTIVE: APOE ε2 and ε4 alleles have been associated with lobar intracerebral hemorrhage (ICH) in predominately white populations; we sought to evaluate whether this held true among black and Hispanic populations. METHODS: The Ethnic/Racial Variations of Intracerebral Hemorrhage study is a prospective, multicenter case-control study of ICH among white, black, and Hispanic participants. Controls were recruited to match cases based on age, ethnicity/race, sex, and geographic location. APOE genotyping and ICH location was determined blinded to clinical data. RESULTS: There were 907 cases of lobar ICH and 2,660 controls with APOE results. Both APOE ε2 (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.1-2.0, p = 0.01) and APOE ε4 (OR 2.0, 95% CI 1.5-2.6, p < 1 × 10-4) were associated with lobar ICH among white participants. Among black participants, neither APOE ε2 (OR 1.0, 95% CI 0.7-1.5, p = 0.97) nor APOE ε4 (OR 1.0, 95% CI 0.7-1.4, p = 0.90) were independent risk factors for lobar ICH. Similarly, among Hispanic participants, neither APOE ε2 (OR 1.0, 95% CI 0.6-1.8, p = 0.89) nor APOE ε4 (OR 1.2, 95% CI 0.8-1.7, p = 0.36) were associated with lobar ICH. Hypertension was a significant risk factor for lobar ICH in all 3 racial/ethnic groups. CONCLUSION: In contrast to Caucasian patients, in which amyloid risk factors predominate in lobar ICH, we found that hypertension was the predominant risk factor for lobar ICH. While APOE alleles are a risk factor for lobar ICH in white patients, they appear to have a much lower effect in lobar ICH in African American and Hispanic American populations. This suggests APOE ε2 and APOE ε4 do not affect lobar ICH risk homogeneously across ethnic populations. In addition, hypertension has a prominent role in lobar ICH risk, particularly among minorities.