Search

Background and ObjectivesPerihematomal edema (PHE) contributes to poor outcome after deep intraparenchymal hemorrhage (IPH), which is characterized by neuroinflammation and an influx of peripherally derived innate immune cells. We previously identified soluble ST2 (sST2) as a candidate for immune-mediated secondary brain injury. Leveraging prospectively collected cohorts from 2 centers, we sought to determine whether sST2 was associated with functional outcome, PHE, and the immune response following IPH.MethodsPatients with deep IPH were enrolled within 36 hours of ictus, and blood was collected for sST2 and immune cell measurement. Hematoma volume and PHE were measured on serial CT scans. Good outcome was defined as a modified Rankin Scale score of 0–3 at 90 days. Linear mixed-effects models were used to analyze the relationship between sST2 and PHE over time. Flow cytometry was used to identify shifts in immune cell populations associated with sST2. Immunohistochemistry of human brain tissue was used to identify ST2-expressing cells in the perihematomal region.ResultsThe 55 included patients had a median admission Glasgow Coma Scale score of 14 (interquartile range [IQR] 9–15), an intracerebral hemorrhage (ICH) score of 1 (IQR 1–2), and a hematoma volume of 8.6 mL (IQR 3.4–13.8 mL). Receiver operating curve analysis found the sST2 level to be predictive of poor outcome with an area under the curve of 0.763 (95% CI 0.632–0.894) and Youden optimum cut point of 61.8 ng/mL (p< 0.001). sST2 remained an independent predictor after adjustment for ICH score (adjusted odds ratio 2.53, 95% CI 1.03–6.19,p= 0.042). Measurement of PHE found those patients with high sST2 to have greater edema volume over time (β = 1.07, 95% CI 0.51–1.63,p< 0.001). High sST2 was associated with a shift toward an innate peripheral immune response (monocytes and natural killer cells; 68.6% ± 5.1% vs 47.5% ± 4.0%;p= 0.003).DiscussionOur findings demonstrate that elevated sST2 links the peripheral innate immune response to PHE volume and outcome after IPH. This knowledge is relevant to future studies that seek to identify patients with IPH at highest risk for immune-mediated injury or limit injury through targeted interventions.

ObjectiveTo determine the leading causes of death in intracerebral hemorrhage (ICH) survivors, we used administrative data from 3 large US states to identify adult survivors of a first-time spontaneous ICH and track all hospital readmissions resulting in death.MethodsWe performed a longitudinal analysis of prospectively collected claims data from hospitalizations in California (2005–2011), New York (2005–2014), and Florida (2005–2014). Adult residents admitted with a nontraumatic ICH who survived to discharge were included. Patients were followed for a primary outcome of any readmission resulting in death. The cause of death was defined as the primary diagnosis assigned at discharge. Multivariable Cox proportional hazards and multinomial logistic regression were used to determine factors associated with the risk for and cause of death.ResultsOf 72,432 ICH survivors (mean age 68 years [SD 16], 48% female), 12,753 (18%) died during a median follow-up period of 4.0 years (interquartile range 2.3–6.3). The leading causes of death were infection (34%), recurrent intracranial hemorrhage (14%), cardiac disease (8%), respiratory failure (8%), and ischemic stroke (5%). Death in patients with atrial fibrillation (AF) was more likely to be caused by ischemic stroke (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.9–2.9, p < 0.001) and less likely to be caused by recurrent intracranial hemorrhage (OR 0.7, 95% CI 0.6–0.8, p < 0.001) compared to patients without AF.ConclusionsInfection is the leading cause of death in all ICH survivors. Survivors with AF were at increased risk for death from ischemic stroke. These findings will help prioritize interventions aimed to improve long-term survival and recovery in ICH survivors.

ObjectiveTo determine whether race is associated with the development of epilepsy after subdural hematoma (SDH), we identified adult survivors of SDH in a statewide administrative dataset and followed them up for at least 1 year for revisits associated with epilepsy.MethodsWe performed a retrospective cohort study using claims data on all discharges from emergency departments (EDs) and hospitals in California. We identified adults (age ≥18 years) admitted from 2005 to 2011 with first-time traumatic and nontraumatic SDH. We used validated diagnosis codes to identify a primary outcome of ED or inpatient revisit for epilepsy. We used multivariable Cox regression for survival analysis to identify demographic and medical risk factors for epilepsy.ResultsWe identified 29,342 survivors of SDH (mean age 71.2 [SD 16.4] years, female sex 11,954 [41.1%]). Three thousand two hundred thirty (11.0%) patients had revisits to EDs or hospitals with a diagnosis of epilepsy during the study period. Black patients (n = 1,684 [5.7%]) had significantly increased risk compared to White patients (n = 16,945 [57.7%]; hazard ratio [HR] 1.45, 95% confidence interval [CI] 1.28–1.64, p < 0.001). Status epilepticus during the index SDH admission, although infrequent (n = 94 [0.3%]), was associated with a nearly 4-fold risk of epilepsy (HR 3.75, 95% CI 2.80–5.03, p < 0.001). Alcohol use, drug use, smoking, renal disease, and markers of injury severity (i.e., intubation, surgical intervention, length of stay, disposition other than home) were also associated with epilepsy (all p < 0.05).ConclusionsWe found an association between Black race and ED and hospital revisits for epilepsy after SDH, establishing the presence of a racial subgroup that is particularly vulnerable to post-SDH epileptogenesis.

ObjectivesWe investigated the predictors of functional outcome in young patients enrolled in a multiethnic study of intracerebral hemorrhage (ICH).MethodsThe Ethnic/Racial Variations in Intracerebral Hemorrhage (ERICH) study is a prospective multicenter study of ICH among adult (age ≥18 years) non-Hispanic white, non-Hispanic black, and Hispanic participants. The study recruited 1,000 participants per racial/ethnic group. The present study utilized the subset of ERICH participants aged ResultsOf the 3,000 patients with ICH enrolled in ERICH, 418 were studied (mean age 43 years, 69% male), of whom 48 (12%) were white, 173 (41%) were black, and 197 (47%) were Hispanic. For supratentorial ICH, black participants (odds ratio [OR], 0.42; p = 0.046) and Hispanic participants (OR, 0.34; p = 0.01) had better outcomes than white participants after adjustment for other factors associated with poor outcome: age, baseline disability, admission blood pressure, admission Glasgow Coma Scale score, ICH volume, deep ICH location, and intraventricular extension.ConclusionsIn young patients with supratentorial ICH, black and Hispanic race/ethnicity is associated with better functional outcomes, compared with white race. Additional studies are needed to identify the biological and social mediators of this association.

ObjectiveTo estimate the risk of intracerebral hemorrhage (ICH) recurrence in a large, diverse, US-based population and to identify racial/ethnic and socioeconomic subgroups at higher risk.MethodsWe performed a longitudinal analysis of prospectively collected claims data from all hospitalizations in nonfederal California hospitals between 2005 and 2011. We used validated diagnosis codes to identify nontraumatic ICH and our primary outcome of recurrent ICH. California residents who survived to discharge were included. We used log-rank tests for unadjusted analyses of survival across racial/ethnic groups and multivariable Cox proportional hazards regression to determine factors associated with risk of recurrence after adjusting for potential confounders.ResultsWe identified 31,355 California residents with first-recorded ICH who survived to discharge, of whom 15,548 (50%) were white, 6,174 (20%) were Hispanic, 4,205 (14%) were Asian, and 2,772 (9%) were black. There were 1,330 recurrences (4.1%) over a median follow-up of 2.9 years (interquartile range 3.8). The 1-year recurrence rate was 3.0% (95% confidence interval [CI] 2.8%–3.2%). In multivariable analysis, black participants (hazard ratio [HR] 1.22; 95% CI 1.01–1.48; p = 0.04) and Asian participants (HR 1.29; 95% CI 1.10–1.50; p = 0.001) had a higher risk of recurrence than white participants. Private insurance was associated with a significant reduction in risk compared to patients with Medicare (HR 0.60; 95% CI 0.50–0.73; p < 0.001), with consistent estimates across racial/ethnic groups.ConclusionsBlack and Asian patients had a higher risk of ICH recurrence than white patients, whereas private insurance was associated with reduced risk compared to those with Medicare. Further research is needed to determine the drivers of these disparities.

Background and ObjectivesTo study the relationship between the presence of cerebral microbleeds (CMBs) and acute hematoma characteristics among patients with primary intracerebral hemorrhage (ICH).MethodsWe pooled individual patient data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 (MISTIE III) trial. We included individuals with a brain MRI scan. Exposure was the presence of a CMB. The coprimary outcomes were admission ICH volume and hematoma expansion. Mixed-effects linear and logistic regression models were used, with demographics and comorbid conditions considered fixed effects and the study cohort treated as a random effect. Additional analyses assessed the relationship between CMB topography and number and hematoma characteristics.ResultsOf the 1,499 patients with ICH enrolled in the parent trials, 466 (31.1%) were included in this analysis, and 231 (49.6%) patients had CMBs. In adjusted models, presence of CMBs was associated with smaller ICH volume (β = −0.26, 95% confidence interval [CI] −0.44 to −0.08) and lower odds of hematoma expansion (odds ratio 0.65, 95% CI 0.40–0.95; p = 0.04). The strength of association between CMBs and hematoma characteristics increased with increasing number of CMBs. The location of the CMBs and the severity of leukoaraiosis did not modify these results.DiscussionIn a pooled cohort of patients with ICH, our results are consistent with the hypothesis that more severe underlying small vessel disease, as represented by CMBs, leads to smaller baseline hematoma volumes and reduced hematoma expansion. Underlying cerebral small vessel disease may be of prognostic significance after ICH.Trial Registration InformationClinicalTrials.gov Identifier: NCT01176565 and NCT01827046.Classification of EvidenceThis study provides Class II evidence that the presence of microbleeds on MRI is associated with a smaller ICH volume at presentation and a lower rate of hematoma expansion on follow-up imaging.

The interrelationship among cholesterol levels, statin treatment, and risk of primary (nontraumatic) intracerebral hemorrhage (ICH) remains controversial. Some evidence indicates an inverse relationship between cholesterol levels and risk of ICH. A separate body of evidence suggests that treatment with statins may increase the risk of ICH. These two different, albeit related, observations drive this story and have attracted substantial attention. This interaction could represent an exception to the “rule” that low cholesterol, on its own or after statin treatment, leads to a reduction in risk of cardiovascular events. Furthermore, there are potentially important implications for the clinical management of patients with cerebral small vessel disease, especially vis-a-vis secondary prevention. These observations may point to potentially important new biological pathways and treatment targets for ICH, a condition with a dismal prognosis and limited effective therapies.

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

Objective: We sought to explore the mechanisms leading to cerebral amyloid angiopathy (CAA)-related cortical superficial siderosis (cSS) by examining its neuroimaging and genetic association with cerebral microbleeds (CMBs). Methods: MRI scans of 84 subjects with probable or definite CAA participating in a longitudinal research study were graded for cSS presence and severity (focal, restricted to ≤3 sulci vs disseminated, ≥4 sulci), and CMB count. APOE e variants were directly genotyped. We performed cross-sectional analysis comparing CMB counts and APOE e2 and e4 allele frequency between subjects with no, focal, or disseminated cSS. Results: cSS was present in 48% (n = 40) of the population. APOE e2 was overrepresented among participants with focal (odds ratio [OR] 7.0, 95% confidence interval [CI] 1.7–29.3, p = 0.008) and disseminated (OR 11.5, 95% CI 2.8–46.2, p = 0.001) cSS relative to individuals without cSS. CMB counts decreased with increasing severity of cSS (median: 41, 38, and 15 for no cSS, focal cSS, and disseminated cSS, respectively, p = 0.09). The highest CMB count tertile was associated with APOE e4 (OR 3.0, 95% CI 1.4–6.6, p = 0.006) relative to the lowest tertile. Conclusions: Among individuals with advanced CAA, cSS tends to occur in individuals with relatively lower CMB counts and with a distinct pattern of APOE genotypes. These results suggest that CAA-related cSS and CMBs may arise from distinct vasculopathic mechanisms.

Objective: We aimed to assess the effect of APOE e variants on warfarin-related intracerebral hemorrhage (wICH), evaluated their predictive power, and tested for interaction with warfarin in causing wICH. Methods: This was a prospective, 2-stage (discovery and replication), case-control study. wICH was classified as lobar or nonlobar based on the location of the hematoma. Controls were sampled from ambulatory clinics (discovery) and random digit dialing (replication). APOE e variants were directly genotyped. A case-control design and logistic regression analysis were utilized to test for association between APOE e and wICH. A case-only design and logistic regression analysis were utilized to test for interaction between APOE e and warfarin. Receiver operating characteristic curves were implemented to evaluate predictive power. Results: The discovery stage included 319 wICHs (44% lobar) and 355 controls. APOE e2 was associated with lobar (odds ratio [OR] 2.46; p p = 0.04), whereas e4 was associated with lobar (OR 2.09; p p = 0.35). The replication stage (63 wICHs and 1,030 controls) confirmed the association with e2 ( p = 0.03) and e4 ( p = 0.003) for lobar but not for nonlobar wICH ( p > 0.20). Genotyping information on APOE e variants significantly improved case/control discrimination of lobar wICH (C statistic 0.80). No statistical interaction between warfarin and APOE was found ( p > 0.20). Conclusions: APOE e variants constitute strong risk factors for lobar wICH. APOE exerts its effect independently of warfarin, although power limitations render this absence of interaction preliminary. Evaluation of the predictive ability of APOE in cohort studies is warranted.

Objective: To determine whether the CT angiography (CTA) spot sign marks bleeding complications during and after surgery for spontaneous intracerebral hemorrhage (ICH). Methods: In a 2-center study of consecutive spontaneous ICH patients who underwent CTA followed by surgical hematoma evacuation, 2 experienced readers (blinded to clinical and surgical data) reviewed CTAs for spot sign presence. Blinded raters assessed active intraoperative and postoperative bleeding. The association between spot sign and active intraoperative bleeding, postoperative rebleeding, and residual ICH volumes was evaluated using univariable and multivariable logistic regression. Results: A total of 95 patients met inclusion criteria: 44 lobar, 17 deep, 33 cerebellar, and 1 brainstem ICH; ≥1 spot sign was identified in 32 patients (34%). The spot sign was the only independent marker of active bleeding during surgery (odds ratio [OR] 3.4; 95% confidence interval [CI] 1.3–9.0). Spot sign (OR 4.1; 95% CI 1.1–17), female sex (OR 6.9; 95% CI 1.7–37), and antiplatelet use (OR 4.6; 95% CI 1.2–21) were predictive of postoperative rebleeding. Larger residual hematomas and postoperative rebleeding were associated with higher discharge case fatality (OR 3.4; 95% CI 1.1–11) and a trend toward increased case fatality at 3 months (OR 2.9; 95% CI 0.9–8.8). Conclusions: The CTA spot sign is associated with more intraoperative bleeding, more postoperative rebleeding, and larger residual ICH volumes in patients undergoing hematoma evacuation for spontaneous ICH. The spot sign may therefore be useful to select patients for future surgical trials.

To identify predictors of early lobar intracerebral hemorrhage (ICH) recurrence, defined as a new ICH within 6 months of the index event, in patients with cerebral amyloid angiopathy (CAA).Participants were consecutive survivors (age ≥55 years) of spontaneous symptomatic probable or possible CAA-related lobar ICH according to the Boston criteria, drawn from an ongoing single-center cohort study. Neuroimaging markers ascertained in CT or MRI included focal (≤3 sulci) or disseminated (3 sulci) cortical superficial siderosis (cSS), acute convexity subarachnoid hemorrhage (cSAH), cerebral microbleeds, white matter hyperintensities burden and location, and baseline ICH volume. Participants were followed prospectively for recurrent symptomatic ICH. Cox proportional hazards models were used to identify predictors of early recurrent ICH adjusting for potential confounders.A total of 292 patients were enrolled. Twenty-one patients (7%) had early recurrent ICH. Of these, 24% had disseminated cSS on MRI and 19% had cSAH on CT scan. In univariable analysis, the presence of disseminated cSS, cSAH, and history of previous ICH were predictors of early recurrent ICH (p0.05 for all comparisons). After adjusting for age and history of previous ICH, disseminated cSS on MRI and cSAH on CT were independent predictors of early recurrent ICH (hazard ratio [HR] 3.92, 95% confidence interval [CI] 1.38-11.17, p = 0.011, and HR 3.48, 95% CI 1.13-10.73, p = 0.030, respectively).Disseminated cSS on MRI and cSAH on CT are independent imaging markers of increased risk for early recurrent ICH. These markers may provide additional insights into the mechanisms of ICH recurrence in patients with CAA.