Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.

BACKGROUND: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography. METHODS: In a systematic review of OVID MEDLINE-with additional hand-searching of relevant studies' bibliographies- from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5-24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known. FINDINGS: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56-76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36-0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46-11·60; p<0·0001), antiplatelet use (1·68, 1·06-2·66; p=0·026), and anticoagulant use (3·48, 1·96-6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75-0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95-6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03-0·07). INTERPRETATION: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials. FUNDING: UK Medical Research Council and British Heart Foundation.

Hypertension and intracerebral hemorrhage recurrence among white, black, and Hispanic individuals.

OBJECTIVE: To clarify whether recurrence risk for intracerebral hemorrhage (ICH) is higher among black and Hispanic individuals and whether this disparity is attributable to differences in blood pressure (BP) measurements and their variability. METHODS: We analyzed data from survivors of primary ICH enrolled in 2 separate studies: (1) the longitudinal study conducted at Massachusetts General Hospital (n = 759), and (2) the ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage) study (n = 1,532). Participants underwent structured interview at enrollment (including self-report of race/ethnicity) and were followed longitudinally via phone calls and review of medical records. We captured systolic BP (SBP) and diastolic BP measurements, and quantified variability as SBP and diastolic BP variation coefficients. We used multivariable (Cox regression) survival analysis to identify risk factors for ICH recurrence. RESULTS: We followed 2,291 ICH survivors (1,121 white, 529 black, 605 Hispanic, and 36 of other race/ethnicity). Both black and Hispanic patients displayed higher SBP during follow-up (p < 0.05). Black participants also displayed greater SBP variability during follow-up (p = 0.032). In univariable analyses, black and Hispanic patients were at higher ICH recurrence risk (p < 0.05). After adjusting for BP measurements and their variability, both Hispanic (hazard ratio = 1.51, 95% confidence interval 1.14-2.00, p = 0.004) and black (hazard ratio = 1.98, 95% confidence interval 1.36-2.86, p < 0.001) patients remained at higher risk of ICH recurrence. CONCLUSION: Black and Hispanic patients are at higher risk of ICH recurrence; hypertension severity (average BP and its variability) does not fully account for this finding. Additional studies will be required to further elucidate determinants for this health disparity.

17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. METHODS: We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P<5×10-8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0-2 versus 3-6) modified Rankin Scale using ordinal and logistic regression, respectively. RESULTS: The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: ß, 1.84; SE, 0.32; P=4.4×10-8) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: ß, 0.95; SE, 0.17; P=4.3×10-8) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 (P=0.04; meta-analysis P=2.5×10-9; heterogeneity, P=0.16) but not for 22q13 (P=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P=0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P=0.045). CONCLUSIONS: We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.

Cerebral Microbleeds and the Effect of Intensive Blood Pressure Reduction on Hematoma Expansion and Functional Outcomes: A Secondary Analysis of the ATACH-2 Randomized Clinical Trial.

Importance: Response to intensive blood pressure (BP) lowering in acute intracerebral hemorrhage (ICH) might vary with the degree of underlying cerebral small vessel disease. Objectives: To characterize cerebral microbleeds (CMBs) in acute ICH and to assess the potential for interaction between underlying small vessel disease (as indicated by CMB number and location) and assignment to acute intensive BP targeting for functional outcomes and hematoma expansion. Design, Setting, and Participants: Preplanned subgroup analyses in the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial were performed. The ATACH-2 was an open-label international randomized clinical trial that investigated optimal acute BP lowering in 1000 patients with acute ICH. Analyses followed the intent-to-treat paradigm. Participants were enrolled between May 2011 and September 2015 and followed up for 3 months. Eligible participants were aged at least 18 years with ICH volumes less than 60 mL on computed tomography (CT) and a Glasgow Coma Scale score of at least 5 on initial assessment, in whom study drug could be initiated within 4.5 hours of symptom onset. Eight hundred thirty-three participants were excluded, leaving 167 who had an interpretable axial T2*-weighted gradient-recalled echo sequence on magnetic resonance imaging to assess CMBs for inclusion in these subgroup analyses. Main Outcomes and Measures: The primary outcome of interest was death or disability (modified Ranking Scale score, 4-6) at 3 months. The secondary outcome of interest was hematoma volume expansion of at least 33% on a CT scan obtained 24 hours after randomization compared with the entry scan. Results: A total of 167 patients were included; their mean (SD) age was 61.9 (13.2) years, and 98 (58.7%) were male. Cerebral microbleeds were present in 120 patients. Forty-six of 157 (29.3%) patients had poor outcome (modified Ranking Scale score, ≥4), and hematoma expansion was observed in 29 of 144 (20.1%) patients. Risk of poor outcome was similar for those assigned to intensive vs standard acute BP lowering among patients with CMBs (relative risk, 1.19; 95% CI, 0.61-2.33; P = .61) and those without CMBs (relative risk, 1.42; 95% CI, 0.43-4.70; P = .57), and no significant interaction was observed (interaction coefficient, 0.18; 95% CI, -1.20 to 1.55; P = .80). Risk of hematoma expansion was also similar, and no significant interaction between treatment and CMBs was observed (interaction coefficient, 0.62; 95% CI, -1.08 to 2.31; P = .48). Conclusions and Relevance: Cerebral microbleeds are highly prevalent among patients with ICH but do not seem to influence response to acute intensive BP treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT01176565.

Timing of INR reversal using fresh-frozen plasma in warfarin-associated intracerebral hemorrhage.

Rapid reversal of coagulopathy is recommended in warfarin-associated intracerebral hemorrhage (WAICH). However, rapid correction of the INR has not yet been proven to improve clinical outcomes, and the rate of correction with fresh-frozen plasma (FFP) can be variable. We sought to determine whether faster INR reversal with FFP is associated with decreased hematoma expansion and improved outcome. We performed a retrospective analysis of a prospectively collected cohort of consecutive patients with WAICH presenting to an urban tertiary care hospital from 2000 to 2013. Patients with baseline INR > 1.4 treated with FFP and vitamin K were included. The primary outcomes are occurrence of hematoma expansion, discharge modified Rankin Scale (mRS), and 30-day mortality. The association between timing of INR reversal, ICH expansion, and outcome was investigated with logistic regression analysis. 120 subjects met inclusion criteria (mean age 76.9, 57.5% males). Median presenting INR was 2.8 (IQR 2.3-3.4). Hematoma expansion is not associated with slower INR reversal [median time to INR reversal 9 (IQR 5-14) h vs. 10 (IQR 7-16) h, p = 0.61]. Patients with ultimately poor outcome received more rapid INR reversal than those with favorable outcome [9 (IQR 6-14) h vs. 12 (8-19) h, p = 0.064). We find no evidence of an association between faster INR reversal and either reduced hematoma expansion or better outcome.

Acute convexity subarachnoid haemorrhage and cortical superficial siderosis in probable cerebral amyloid angiopathy without lobar haemorrhage.

INTRODUCTION: Acute non-traumatic convexity subarachnoid haemorrhage (cSAH) is increasingly recognised in cerebral amyloid angiopathy (CAA). We investigated: (a) the overlap between acute cSAH and cortical superficial siderosis-a new CAA haemorrhagic imaging signature and (b) whether acute cSAH presents with particular clinical symptoms in patients with probable CAA without lobar intracerebral haemorrhage. METHODS: MRI scans of 130 consecutive patients meeting modified Boston criteria for probable CAA were analysed for cortical superficial siderosis (focal, ≤3 sulci; disseminated, ≥4 sulci), and key small vessel disease markers. We compared clinical, imaging and cortical superficial siderosis topographical mapping data between subjects with versus without acute cSAH, using multivariable logistic regression. RESULTS: We included 33 patients with probable CAA presenting with acute cSAH and 97 without cSAH at presentation. Patients with acute cSAH were more commonly presenting with transient focal neurological episodes (76% vs 34%; p<0.0001) compared with patients with CAA without cSAH. Patients with acute cSAH were also more often clinically presenting with transient focal neurological episodes compared with cortical superficial siderosis-positive, but cSAH-negative subjects with CAA (76% vs 30%; p<0.0001). Cortical superficial siderosis prevalence (but no other CAA severity markers) was higher among patients with cSAH versus those without, especially disseminated cortical superficial siderosis (49% vs 19%; p<0.0001). In multivariable logistic regression, cortical superficial siderosis burden (OR 5.53; 95% CI 2.82 to 10.8, p<0.0001) and transient focal neurological episodes (OR 11.7; 95% CI 2.70 to 50.6, p=0.001) were independently associated with acute cSAH. CONCLUSIONS: This probable CAA cohort provides additional evidence for distinct disease phenotypes, determined by the presence of cSAH and cortical superficial siderosis.

Cerebellar Hematoma Location: Implications for the Underlying Microangiopathy.

BACKGROUND AND PURPOSE: Spontaneous cerebellar intracerebral hemorrhage (ICH) has been reported to be mainly associated with vascular changes secondary to hypertension. However, a subgroup of cerebellar ICH seems related to vascular amyloid deposition (cerebral amyloid angiopathy). We sought to determine whether location of hematoma in the cerebellum (deep and superficial regions) was suggestive of a particular hemorrhage-prone small-vessel disease pathology (cerebral amyloid angiopathy or hypertensive vasculopathy). METHODS: Consecutive patients with cerebellar ICH from a single tertiary care medical center were recruited. Based on data from pathological reports, patients were divided according to the location of the primary cerebellar hematoma (deep versus superficial). Location of cerebral microbleeds (CMBs; strictly lobar, strictly deep, and mixed CMB) was evaluated on magnetic resonance imaging. RESULTS: One-hundred and eight patients (84%) had a deep cerebellar hematoma, and 20 (16%) a superficial cerebellar hematoma. Hypertension was more prevalent in deep than in patients with superficial cerebellar ICH (89% versus 65%, respectively; P<0.05). Among patients who underwent magnetic resonance imaging, those with superficial cerebellar ICH had higher prevalence of strictly lobar CMB (43%) and lower prevalence of strictly deep or mixed CMB (0%) compared with those with deep superficial cerebellar ICH (6%, 17%, and 38%, respectively). In a multivariable model, presence of strictly lobar CMB was associated with superficial cerebellar ICH (odds ratio, 3.8; 95% confidence interval, 1.5-8.5; P=0.004). CONCLUSIONS: Our study showed that superficial cerebellar ICH is related to the presence of strictly lobar CMB-a pathologically proven marker of cerebral amyloid angiopathy. Cerebellar hematoma location may thus help to identify those patients likely to have cerebral amyloid angiopathy pathology.

Oral Anticoagulation and Functional Outcome after Intracerebral Hemorrhage.

OBJECTIVE: Oral anticoagulation treatment (OAT) resumption is a therapeutic dilemma in intracerebral hemorrhage (ICH) care, particularly for lobar hemorrhages related to amyloid angiopathy. We sought to determine whether OAT resumption after ICH is associated with long-term outcome, accounting for ICH location (ie, lobar vs nonlobar). METHODS: We meta-analyzed individual patient data from: (1) the multicenter RETRACE study (n = 542), (2) a U.S.-based single-center ICH study (n = 261), and (3) the Ethnic/Racial Variations of Intracerebral Hemorrhage study (n = 209). We determined whether, within 1 year from ICH, OAT resumption was associated with: (1) mortality, (2) favorable functional outcome (modified Rankin Scale = 0-3), and (3) stroke incidence. We separately analyzed nonlobar and lobar ICH cases using propensity score matching and Cox regression models. RESULTS: We included 1,012 OAT-related ICH survivors (633 nonlobar and 379 lobar). Among nonlobar ICH survivors, 178/633 (28%) resumed OAT, whereas 86/379 (23%) lobar ICH survivors did. In multivariate analyses, OAT resumption after nonlobar ICH was associated with decreased mortality (hazard ratio [HR] = 0.25, 95% confidence interval [CI] = 0.14-0.44, p < 0.0001) and improved functional outcome (HR = 4.22, 95% CI = 2.57-6.94, p < 0.0001). OAT resumption after lobar ICH was also associated with decreased mortality (HR = 0.29, 95% CI = 0.17-0.45, p < 0.0001) and favorable functional outcome (HR = 4.08, 95% CI = 2.48-6.72, p < 0.0001). Furthermore, OAT resumption was associated with decreased all-cause stroke incidence in both lobar and nonlobar ICH (both p < 0.01). INTERPRETATION: These results suggest novel evidence of an association between OAT resumption and outcome following ICH, regardless of hematoma location. These findings support conducting randomized trials to explore risks and benefits of OAT resumption after ICH. Ann Neurol 2017;82:755-765.

Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke.

Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10-6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.

Sex differences in intracerebral hemorrhage expansion and mortality.

BACKGROUND AND OBJECTIVE: Due to conflicting results in multiple studies, uncertainty remains regarding sex differences in severity and mortality after intracerebral hemorrhage (ICH). We investigated the impact of sex on ICH severity, expansion, and mortality. METHODS: We analyzed prospectively collected ICH patients and assessed clinical variables and mortality rate. Mediation analyses were used to examine associations between sex and mortality and sex and hematoma expansion. RESULTS: 2212 patients were investigated, 53.5% male. Men with ICH were younger (72 vs. 77years), had greater smoking and alcohol use, and were more likely to have hypertension, diabetes, hypercholesterolemia and coronary artery disease (all p<0.05). Lobar hemorrhages were more frequent in women (47.6% vs 38.4%, p<0.001). Male sex was a risk factor for hematoma expansion (Odd Ratio (OR) 1.7, 95% confidence interval (CI) 1.15-2.50, p=0.007). Multivariable analysis found that male sex was independently associated with 90-day mortality (OR 2.15 (95% CI 1.46-3.19), p<0.001), and one-year mortality (Hazard Ratio 1.28 (95% CI: 1.09-1.50), p=0.003). Early hematoma expansion mediated a portion of the association between sex and mortality (mediation p=0.02). CONCLUSIONS: Men with ICH experience a higher risk of both expansion and early and late mortality, even after controlling for known risk factors. Further research is needed to explore the biological mechanisms underlying these observed differences.

Chaplaincy Visitation and Spiritual Care after Intracerebral Hemorrhage.

To better understand factors influencing spiritual care during critical illness, we examined the use of spiritual care in patients hospitalized with intracerebral hemorrhage (ICH), a frequently disabling and fatal disease. Specifically, the study was designed to examine which demographic and clinical characteristics were associated with chaplain visits to critically ill patients. The charts of consecutive adults (>18) with spontaneous ICH presenting to a single academic medical center between January 2014 and September 2015 were reviewed. Chaplains visited 86 (32%) of the 266 patients. Family requests initiated the majority of visits (57%). Visits were disproportionately to Catholic patients and those with more severe injury. Even among Catholics, 28% of those who died had no chaplaincy visit. Standardized chaplaincy screening methods and note templates may help maximize access to spiritual care and delineate the religious and spiritual preferences of patients and families.

Significance of admission hypoalbuminemia in acute intracerebral hemorrhage.

Low levels of serum albumin may increase the risk of infections and mortality in critically ill patients. We tested the hypothesis that admission hypoalbuminemia predicted infectious complications and poor outcome in subjects with acute intracerebral hemorrhage (ICH). We analyzed a single center cohort of ICH patients collected between 1994 and 2015. Pneumonia, urinary tract infection and sepsis were retrospectively identified, according to validated criteria. Serum albumin was measured on admission and hypoalbuminemia was defined as total albumin ≤3.5 g/dL. The association between albumin levels, infections, and mortality at 90 days was tested with multivariable logistic regression analyses. A total of 2010 patients were included (median age 74 years, 54.5% males) of whom 444 (22.1%) had hypoalbuminemia on admission and 763 (38%) died within 90 days. The frequency of pneumonia, urinary tract infection, and sepsis was 19.9, 15.1, and 2.7%, respectively. Hypoalbuminemic patients had lower admission Glasgow coma scale, higher frequency of intraventricular hemorrhage and were more likely to have a history of chronic kidney or liver disease. After adjustment for potential confounders, hypoalbuminemia was an independent predictor of pneumonia [odds ratio (OR) 1.76, 95% confidence interval (CI) 1.34-2.33, p < 0.001] and sepsis (OR 2.29, 95% CI 1.22-4.30, p = 0.010). Low levels of albumin were also independently associated with higher mortality at 90 days (OR 1.78, 95% CI 1.30-2.44, p < 0.001). In conclusion, early hypoalbuminemia is common and predicts poor outcome in ICH patients. Increased susceptibility to pneumonia and sepsis may be the pathophysiological mechanism underlying this association.

Lymphopenia, Infectious Complications, and Outcome in Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Lymphopenia is increasingly recognized as a consequence of acute illness and may predispose to infections. We investigated whether admission lymphopenia (AL) is associated with increased risk of infectious complications and poor outcome in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: We retrospectively analyzed a prospectively collected cohort of ICH patients ascertained between 1994 and 2015. We identified subjects with lymphocyte count obtained within 24 h from onset, and AL was defined as lymphocyte count <1000/µL. Infectious complications were assessed through retrospective chart review. Association between AL, infections, and mortality was investigated using multivariable logistic regression. RESULTS: Of the 2014 patients meeting inclusion criteria, 548 (27.2%) had AL and 605 (30.0%) developed an infectious complication. Case-fatality at 90 days was 36.9%. Patients with AL had larger hematoma volumes, higher frequency of intraventricular hemorrhage, and lower Glasgow Coma Scale score on presentation (all p < 0.001). AL was independently associated with increased risk of pneumonia [odds ratio (OR) 1.97, 95% confidence interval (CI) 1.50-2.58, p < 0.001] and multiple infections (OR 1.84, 95% CI 1.24-2.71, p = 0.003). AL was also an independent predictor of 90-day mortality (OR 1.55, 95% CI 1.18-2.04, p = 0.002) after adjusting for confounders. CONCLUSIONS: AL is common in ICH patients and independently associated with increased risk of infectious complications and poor outcome. Further studies will be needed to determine whether prophylactic antibiotics in ICH patients with AL can improve outcome.

Genetic variants in CETP increase risk of intracerebral hemorrhage.

OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10-4 ) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10-6 ). INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.

Association of Key Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease With Hematoma Volume and Expansion in Patients With Lobar and Deep Intracerebral Hemorrhage.

IMPORTANCE: Hematoma expansion is an important determinant of outcome in spontaneous intracerebral hemorrhage (ICH) due to small vessel disease (SVD), but the association between the severity of the underlying SVD and the extent of bleeding at the acute phase is unknown to date. OBJECTIVE: To investigate the association between key magnetic resonance imaging (MRI) markers of SVD (as per the Standards for Reporting Vascular Changes on Neuroimaging [STRIVE] guidelines) and hematoma volume and expansion in patients with lobar or deep ICH. DESIGN, SETTING, AND PARTICIPANTS: Analysis of data collected from 418 consecutive patients admitted with primary lobar or deep ICH to a single tertiary care medical center between January 1, 2000, and October 1, 2012. Data were analyzed on March 4, 2016. Participants were consecutive patients with computed tomographic images allowing ICH volume calculation and MRI allowing imaging markers of SVD assessment. MAIN OUTCOMES AND MEASURES: The ICH volumes at baseline and within 48 hours after symptom onset were measured in 418 patients with spontaneous ICH without anticoagulant therapy, and hematoma expansion was calculated. Cerebral microbleeds, cortical superficial siderosis, and white matter hyperintensity volume were assessed on MRI. The associations between these SVD markers and ICH volume, as well as hematoma expansion, were investigated using multivariable models. RESULTS: This study analyzed 254 patients with lobar ICH (mean [SD] age, 75 [11] years and 140 [55.1%] female) and 164 patients with deep ICH (mean [SD] age 67 [14] years and 71 [43.3%] female). The presence of cortical superficial siderosis was an independent variable associated with larger ICH volume in the lobar ICH group (odds ratio per quintile increase in final ICH volume, 1.49; 95% CI, 1.14-1.94; P = .004). In multivariable models, the absence of cerebral microbleeds was associated with larger ICH volume for both the lobar and deep ICH groups (odds ratios per quintile increase in final ICH volume, 1.41; 95% CI, 1.11-1.81; P = .006 and 1.43; 95% CI, 1.04-1.99; P = .03; respectively) and with hematoma expansion in the lobar ICH group (odds ratio, 1.70; 95% CI, 1.07-2.92; P = .04). The white matter hyperintensity volumes were not associated with either hematoma volume or expansion. CONCLUSIONS AND RELEVANCE: In patients admitted with primary lobar or deep ICH to a single tertiary care medical center, the presence of cortical superficial siderosis was an independent variable associated with larger lobar ICH volume, and the absence of cerebral microbleeds was associated with larger lobar and deep ICHs. The absence of cerebral microbleeds was independently associated with more frequent hematoma expansion in patients with lobar ICH. We provide an analytical framework for future studies aimed at limiting hematoma expansion.

Association Between Serum Calcium Level and Extent of Bleeding in Patients With Intracerebral Hemorrhage.

IMPORTANCE: Calcium is a key cofactor of the coagulation cascade and may play a role in the pathophysiology of intracerebral hemorrhage (ICH). OBJECTIVE: To investigate whether a low serum calcium level is associated with an increase in the extent of bleeding in patients with ICH as measured by baseline hematoma volume and risk of hematoma expansion. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 2103 consecutive patients with primary ICH ascertained during the period between 1994 and 2015 at an academic medical center. The statistical analysis was performed in January 2016. MAIN OUTCOMES AND MEASURES: Total calcium level was measured on admission, and hypocalcemia was defined as a serum calcium level of less than 8.4 mg/dL. Baseline and follow-up hematoma volumes, detected by noncontrast computed tomography, were measured using a computer-assisted semiautomatic analysis. Hematoma expansion was defined as an increase of more than 30% or 6 mL from baseline ICH volume. Associations between serum calcium level and baseline hematoma volume and between serum calcium level and ICH expansion were investigated in multivariable linear and logistic regression models, respectively. RESULTS: A total of 2123 patients with primary ICH were screened, and 2103 patients met the inclusion criteria (mean [SD] age, 72.7 [12.5] years; 54.3% male patients), of whom 229 (10.9%) had hypocalcemia on admission. Hypocalcemic patients had a higher median baseline hematoma volume than did normocalcemic patients (37 mL [IQR, 15-72 mL] vs 16 mL [IQR, 6-44 mL]; P < .001). Low calcium levels were independently associated with higher baseline ICH volume (ß = -0.13, SE = .03, P < .001). A total of 1393 patients underwent follow-up noncontrast computed tomography and were included in the ICH expansion analysis. In this subgroup, a higher serum calcium level was associated with reduced risk of ICH expansion (odds ratio, 0.55 [95% CI, 0.35-0.86]; P = .01), after adjusting for other confounders. CONCLUSIONS AND RELEVANCE: Hypocalcemia correlates with the extent of bleeding in patients with ICH. A low calcium level may be associated with a subtle coagulopathy predisposing to increased bleeding and might therefore be a promising therapeutic target for acute ICH treatment trials.

Recurrent hemorrhage risk and mortality in hereditary and sporadic cerebral amyloid angiopathy.

OBJECTIVE: To determine whether hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), a monogenetic disease model for the sporadic variant of amyloid angiopathy (sCAA), has a comparable recurrent intracerebral hemorrhage (ICH) risk and mortality after a first symptomatic ICH. METHODS: We included patients with HCHWA-D from the Leiden University Medical Center and patients with sCAA from the Massachusetts General Hospital in a cohort study. Baseline characteristics, hemorrhage recurrence, and short- and long-term mortality were compared. Hazard ratios (HRs) adjusted for age and sex were calculated with Cox regression analyses. RESULTS: We included 58 patients with HCHWA-D and 316 patients with sCAA. Patients with HCHWA-D had fewer cardiovascular risk factors (≥1 risk factor 24% vs 70% in sCAA) and were younger at the time of presenting hemorrhage (mean age 54 vs 72 years in sCAA). Eight patients (14%) with HCHWA-D and 46 patients (15%) with sCAA died before 90 days. During a mean follow-up time of 5 ± 4 years (total 1,550 person-years), the incidence rate of recurrent ICH in patients with HCHWA-D was 20.9 vs 8.9 per 100 person-years in sCAA. Patients with HCHWA-D had a long-term mortality of 8.2 vs 8.4 per 100 person-years in patients with sCAA. After adjustments, patients with HCHWA-D had a higher risk of recurrent ICH (HR 2.8; 95% confidence interval 1.6-4.9; p < 0.001) and a higher long-term mortality (HR 2.8; 95% confidence interval 1.5-5.2; p = 0.001). CONCLUSIONS: Patients with HCHWA-D have worse long-term prognosis after a first ICH than patients with sCAA. The absence of cardiovascular risk factors in most patients with HCHWA-D suggests that vascular amyloid is responsible for the recurrent hemorrhages. HCHWA-D is therefore a pure form of cerebral amyloid angiopathy with an accelerated clinical course and provides a good model to study the pathophysiology and future therapeutic interventions of amyloid-related hemorrhages.

Progression of Brain Network Alterations in Cerebral Amyloid Angiopathy.

BACKGROUND AND PURPOSE: We recently showed that cerebral amyloid angiopathy (CAA) is associated with functionally relevant brain network impairments, in particular affecting posterior white matter connections. Here we examined how these brain network impairments progress over time. METHODS: Thirty-three patients with probable CAA underwent multimodal brain magnetic resonance imaging at 2 time points (mean follow-up time: 1.3±0.4 years). Brain networks of the hemisphere free of intracerebral hemorrhages were reconstructed using fiber tractography and graph theory. The global efficiency of the network and mean fractional anisotropies of posterior-posterior, frontal-frontal, and posterior-frontal network connections were calculated. Patients with moderate versus severe CAA were defined based on microbleed count, dichotomized at the median (median=35). RESULTS: Global efficiency of the intracerebral hemorrhage-free hemispheric network declined from baseline to follow-up (-0.008±0.003; P=0.029). The decline in global efficiency was most pronounced for patients with severe CAA (group×time interaction P=0.03). The decline in global network efficiency was associated with worse executive functioning (ß=0.46; P=0.03). Examination of subgroups of network connections revealed a decline in fractional anisotropies of posterior-posterior connections at both levels of CAA severity (-0.006±0.002; P=0.017; group×time interaction P=0.16). The fractional anisotropies of posterior-frontal and frontal-frontal connections declined in patients with severe but not moderate CAA (group×time interaction P=0.007 and P=0.005). Associations were independent of change in white matter hyperintensity volume. CONCLUSIONS: Brain network impairment in patients with CAA worsens measurably over just 1.3-year follow-up and seem to progress from posterior to frontal connections with increasing disease severity.

Delayed seizures after intracerebral haemorrhage.

Late seizures after intracerebral haemorrhage occur after the initial acute haemorrhagic insult subsides, and represent one of its most feared long-term sequelae. Both susceptibility to late seizures and their functional impact remain poorly characterized. We sought to: (i) compare patients with new-onset late seizures (i.e. delayed seizures), with those who experienced a recurrent late seizure following an immediately post-haemorrhagic seizure; and (ii) investigate the effect of late seizures on long-term functional performance after intracerebral haemorrhage. We performed prospective longitudinal follow-up of consecutive intracerebral haemorrhage survivors presenting to a single tertiary care centre. We tested for association with seizures the following neuroimaging and genetic markers of cerebral small vessel disease: APOE variants ε2/ε4, computer tomography-defined white matter disease, magnetic resonance imaging-defined white matter hyperintensities volume and cerebral microbleeds. Cognitive performance was measured using the Modified Telephone Interview for Cognitive Status, and functional performance using structured questionnaires obtained every 6 months. We performed time-to-event analysis using separate Cox models for risk to develop delayed and recurrent seizures, as well as for functional decline risk (mortality, incident dementia, and loss of functional independence) after intracerebral haemorrhage. A total of 872 survivors of intracerebral haemorrhage were enrolled and followed for a median of 3.9 years. Early seizure developed in 86 patients, 42 of whom went on to experience recurrent seizures. Admission Glasgow Coma Scale, increasing haematoma volume and cortical involvement were associated with recurrent seizure risk (all P < 0.01). Recurrent seizures were not associated with long-term functional outcome (P = 0.67). Delayed seizures occurred in 37 patients, corresponding to an estimated incidence of 0.8% per year (95% confidence interval 0.5-1.2%). Factors associated with delayed seizures included cortical involvement on index haemorrhage (hazard ratio 1.63, P = 0.036), pre-haemorrhage dementia (hazard ratio 1.36, P = 0.044), history of multiple prior lobar haemorrhages (hazard ratio 2.50, P = 0.038), exclusively lobar microbleeds (hazard ratio 2.22, P = 0.008) and presence of ≥ 1 APOE ε4 copies (hazard ratio 1.95, P = 0.020). Delayed seizures were associated with worse long-term functional outcome (hazard ratio 1.83, P = 0.005), but the association was removed by adjusting for neuroimaging and genetic markers of cerebral small vessel disease. Delayed seizures after intracerebral haemorrhage are associated with different risk factors, when compared to recurrent seizures. They are also associated with worse functional outcome, but this finding appears to be related to underlying small vessel disease. Further investigations into the connections between small vessel disease and delayed seizures are warranted.

APOE polymorphisms influence longitudinal lipid trends preceding intracerebral hemorrhage.

OBJECTIVE: We sought to determine whether APOE genotype influences a previously observed decline in serum total cholesterol (TC) and low-density lipoprotein (LDL) levels preceding primary intracerebral hemorrhage (ICH), as a potential demonstration of nonamyloid mechanisms of APOE in ICH risk. METHODS: We performed a single-center retrospective longitudinal analysis using patients with known APOE genotype drawn from an ongoing cohort study of ICH. Serum lipid measurements for TC, triglycerides (TGs), LDL, and high-density lipoprotein (HDL) collected within 2 years before and after index ICH were extracted from electronic medical records. Piecewise linear mixed-effects models were used to compare APOE allele-specific effects on temporal serum lipid trends in ICH. Demographics, medical history, medications, and health maintenance data were included as fixed effects. Inter- and intraindividual variations in lipid levels were modeled as random effects. RESULTS: A total of 124 ICH cases were analyzed. APOE ε4 carriers had greater rates of decline in serum TC and LDL within 6 months preceding ICH (TC: -7.30 mg/dL/mo, p = 0.0035; LDL: -8.44 mg/dL/mo, p = 0.0001). Conversely, serum TC and LDL levels in APOE ε2 carriers were unchanged within the same time period. APOE genotype had no associations with serum HDL or TG trends. CONCLUSIONS: APOE allele status predicts serum TC and LDL changes preceding acute ICH. Our results have implications for ongoing efforts in dissecting the role of dyslipidemia in cerebrovascular disease risk. APOE genotype-specific influence on lipid trends provides a clue for one mechanism by which APOE may influence risk of ICH. Further characterization of the metabolic roles of APOE is needed to improve the understanding of APOE biology in cerebrovascular disease risk.