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.

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.

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.

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.

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.

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

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

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.

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.

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.

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.

Leukocyte Count and Intracerebral Hemorrhage Expansion.

BACKGROUND AND PURPOSE: Acute leukocytosis is a well-established response to intracerebral hemorrhage (ICH). Leukocytes, because of their interaction with platelets and coagulation factors, may in turn play a role in hemostasis. We investigated whether admission leukocytosis was associated with reduced bleeding after acute ICH. METHODS: Consecutive patients with primary ICH were prospectively collected from 1994 to 2015 and retrospectively analyzed. We included subjects with a follow-up computed tomographic scan available and automated complete white blood cell count performed within 48 hours from onset. Baseline and follow-up hematoma volumes were calculated with semiautomated software, and hematoma expansion was defined as volume increase >30% or 6 mL. The association between white blood cell count and ICH expansion was investigated with multivariate logistic regression. RESULTS: A total of 1302 subjects met eligibility criteria (median age, 75 years; 55.8% men), of whom 207 (15.9%) experienced hematoma expansion. Higher leukocyte count on admission was associated with reduced risk of hematoma expansion (odds ratio for 1000 cells increase, 0.91; 95% confidence interval, 0.86-0.96; P=0.001). The risk of hematoma expansion was inversely associated with neutrophil count (odds ratio, 0.90; 95% confidence interval, 0.85-0.96; P=0.001) and directly associated with monocyte count (odds ratio, 2.71; 95% confidence interval, 1.08-6.83; P=0.034). There was no association between lymphocyte count and ICH expansion (odds ratio, 0.96; 95% confidence interval, 0.79-1.17; P=0.718). CONCLUSIONS: Higher admission white blood cell count is associated with lower risk of hematoma expansion. This highlights a potential role of the inflammatory response in modulating the coagulation cascade after acute ICH.

Rate of Perihematomal Edema Expansion Predicts Outcome After Intracerebral Hemorrhage.

OBJECTIVES: Intracerebral hemorrhage is a devastating disorder with no current treatment. Whether perihematomal edema is an independent predictor of neurologic outcome is controversial. We sought to determine whether perihematomal edema expansion rate predicts outcome after intracerebral hemorrhage. DESIGN: Retrospective cohort study. SETTING: Tertiary medical center. PATIENTS: One hundred thirty-nine consecutive supratentorial spontaneous intracerebral hemorrhage patients 18 years or older admitted between 2000 and 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Intracerebral hemorrhage, intraventricular hemorrhage, and perihematomal edema volumes were measured from CT scans obtained at presentation, 24-hours, and 72-hours postintracerebral hemorrhage. Perihematomal edema expansion rate was the difference between initial and follow-up perihematomal edema volumes divided by the time interval. Logistic regression was performed to evaluate the relationship between 1) perihematomal edema expansion rate at 24 hours and 90-day mortality and 2) perihematomal edema expansion rate at 24 hours and 90-day modified Rankin Scale score. Perihematomal edema expansion rate between admission and 24-hours postintracerebral hemorrhage was a significant predictor of 90-day mortality (odds ratio, 2.97; 95% CI, 1.48-5.99; p = 0.002). This association persisted after adjusting for all components of the intracerebral hemorrhage score (odds ratio, 2.21; 95% CI, 1.05-4.64; p = 0.04). Similarly, higher 24-hour perihematomal edema expansion rate was associated with poorer modified Rankin Scale score in an ordinal shift analysis (odds ratio, 2.40; 95% CI, 1.37-4.21; p = 0.002). The association persisted after adjustment for all intracerebral hemorrhage score components (odds ratio, 2.07; 95% CI, 1.12-3.83; p = 0.02). CONCLUSIONS: Faster perihematomal edema expansion rate 24-hours postintracerebral hemorrhage is associated with worse outcome. Perihematomal edema may represent an attractive translational target for secondary injury after intracerebral hemorrhage.

Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment are not well understood. We hypothesized that in patients with cerebral amyloid angiopathy, multiple small spatially distributed lesions affect cognition through disruption of brain connectivity. We therefore compared the structural brain network in patients with cerebral amyloid angiopathy to healthy control subjects and examined the relationship between markers of cerebral amyloid angiopathy-related brain injury, network efficiency, and potential clinical consequences. Structural brain networks were reconstructed from diffusion-weighted magnetic resonance imaging in 38 non-demented patients with probable cerebral amyloid angiopathy (69 ± 10 years) and 29 similar aged control participants. The efficiency of the brain network was characterized using graph theory and brain amyloid deposition was quantified by Pittsburgh compound B retention on positron emission tomography imaging. Global efficiency of the brain network was reduced in patients compared to controls (0.187 ± 0.018 and 0.201 ± 0.015, respectively, P < 0.001). Network disturbances were most pronounced in the occipital, parietal, and posterior temporal lobes. Among patients, lower global network efficiency was related to higher cortical amyloid load (r = -0.52; P = 0.004), and to magnetic resonance imaging markers of small-vessel disease including increased white matter hyperintensity volume (P < 0.001), lower total brain volume (P = 0.02), and number of microbleeds (trend P = 0.06). Lower global network efficiency was also related to worse performance on tests of processing speed (r = 0.58, P < 0.001), executive functioning (r = 0.54, P = 0.001), gait velocity (r = 0.41, P = 0.02), but not memory. Correlations with cognition were independent of age, sex, education level, and other magnetic resonance imaging markers of small-vessel disease. These findings suggest that reduced structural brain network efficiency might mediate the relationship between advanced cerebral amyloid angiopathy and neurologic dysfunction and that such large-scale brain network measures may represent useful outcome markers for tracking disease progression.

CT Angiography Spot Sign, Hematoma Expansion, and Outcome in Primary Pontine Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: The computed tomography angiography (CTA) spot sign is a validated predictor of hematoma expansion and poor outcome in supratentorial intracerebral hemorrhage (ICH), but patients with brainstem ICH have typically been excluded from the analyses. We investigated the frequency of spot sign and its relationship with hematoma expansion and outcome in patients with primary pontine hemorrhage (PPH). METHODS: We performed a retrospective analysis of PPH cases obtained from a prospectively collected cohort of consecutive ICH patients who underwent CTA. CTA first-pass readings for spot sign presence were analyzed by two trained readers. Baseline and follow-up hematoma volumes on non-contrast CT scans were assessed by semi-automated computer-assisted volumetric analysis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive and negative likelihood ratio, and accuracy of spot sign for prediction of in-hospital mortality were calculated. RESULTS: 49 subjects met the inclusion criteria of whom 11 (22.4 %) showed a spot sign. In-hospital mortality was higher in spot sign-positive versus spot sign-negative subjects (90.9 vs 47.4 %, p = 0.020). Spot sign showed excellent specificity (95 %) and PPV (91 %) in predicting in-hospital mortality. Absolute hematoma growth, defined as parenchymal and intraventricular hematoma expansion of any amount, was significantly higher in spot sign-positive versus spot sign-negative subjects (13.72 ± 20.93 vs 3.76 ± 8.55 mL, p = 0.045). CONCLUSIONS: As with supratentorial ICH, the CTA spot sign is a common finding and is associated with higher risk of hematoma expansion and mortality in PPH. This marker may assist clinicians in prognostic stratification.

Measurement of perihematomal edema in intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Perihematomal edema (PHE) is a marker of secondary injury in intracerebral hemorrhage (ICH). PHE measurement on computed tomography (CT) is challenging, and the principles used to detect PHE have not been described fully. We developed a systematic approach for CT-based measurement of PHE. METHODS: Two independent raters measured PHE volumes on baseline and 24-hour post-ICH CT scans of 20 primary supratentorial ICH subjects. Boundaries were outlined with an edge-detection tool and adjusted after inspection of the 3 orthogonal planes. PHE was delineated with the additional principle that it should be (a) more hypodense than the corresponding area in the contralateral hemisphere and (b) most hypodense immediately surrounding the hemorrhage. We examined intra- and interrater reliability using intraclass correlation coefficients and Bland-Altman plots for interrater consistency. CT-based PHE was also compared using magnetic resonance imaging-based PHE detection for 18 subjects. RESULTS: Median PHE volumes were 22.7 cc at baseline and 20.4 cc at 24 hours post-ICH. There were no statistically significant differences in PHE measurements between raters. Interrater and intrarater reliability for PHE were excellent. At baseline and 24 hours, interrater intraclass correlation coefficients were 0.98 (0.96-1.00) and 0.98 (0.97-1.00); intrarater intraclass correlation coefficients were 0.99 (0.99-1.00) and 0.99 (0.98-1.00). Bland-Altman analysis showed the bias for PHE measurements at baseline and 24 hours, -0.5 cc (SD, 5.4) and -3.2 cc (SD, 5.0), was acceptably small. PHE volumes determined by CT and magnetic resonance imaging were similar (23.9±16.9 cc versus 23.9±16.0 cc, R(2) = 0.98, P<0.0001). CONCLUSIONS: Our method measures PHE with excellent reliability at baseline and 24 hours post-ICH.

Rate of Contrast Extravasation on Computed Tomographic Angiography Predicts Hematoma Expansion and Mortality in Primary Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: In primary intracerebral hemorrhage, the presence of contrast extravasation after computed tomographic angiography (CTA), termed the spot sign, predicts hematoma expansion and mortality. Because the biological underpinnings of the spot sign are not fully understood, we investigated whether the rate of contrast extravasation, which may reflect the rate of bleeding, predicts expansion and mortality beyond the simple presence of the spot sign. METHODS: Consecutive intracerebral hemorrhage patients with first-pass CTA followed by a 90-second delayed postcontrast CT (delayed CTA) were included. CTAs were reviewed for spot sign presence by 2 blinded readers. Spot sign volumes on first-pass and delayed CTA and intracerebral hemorrhage volumes were measured using semiautomated software. Extravasation rates were calculated and tested for association with hematoma expansion and mortality using uni- and multivariable logistic regressions. RESULTS: One hundred and sixty-two patients were included, 48 (30%) of whom had ≥1 spot sign. Median spot sign volume was 0.04 mL on first-pass CTA and 0.4 mL on delayed CTA. Median extravasation rate was 0.23 mL/min overall and 0.30 mL/min among expanders versus 0.07 mL/min in nonexpanders. Extravasation rates were also significantly higher in patients who died in hospital: 0.27 mL/min versus 0.04 mL/min. In multivariable analysis, the extravasation rate was independently associated with in-hospital mortality (odds ratio, 1.09 [95% confidence interval, 1.04-1.18], P=0.004), 90-day mortality (odds ratio, 1.15 [95% confidence interval, 1.08-1.27]; P=0.0004), and hematoma expansion (odds ratio, 1.03 [95% confidence interval, 1.01-1.08]; P=0.047). CONCLUSIONS: Contrast extravasation rate, or spot sign growth, further refines the ability to predict hematoma expansion and mortality. Our results support the hypothesis that the spot sign directly measures active bleeding in acute intracerebral hemorrhage.

Rare Coding Variation and Risk of Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage has a substantial genetic component. We performed a preliminary search for rare coding variants associated with intracerebral hemorrhage. METHODS: A total of 757 cases and 795 controls were genotyped using the Illumina HumanExome Beadchip (Illumina, Inc, San Diego, CA). Meta-analyses of single-variant and gene-based association were computed. RESULTS: No rare coding variants were associated with intracerebral hemorrhage. Three common variants on chromosome 19q13 at an established susceptibility locus, encompassing TOMM40, APOE, and APOC1, met genome-wide significance (P<5e-08). After adjusting for the APOE epsilon alleles, this locus was no longer convincingly associated with intracerebral hemorrhage. No gene reached genome-wide significance level in gene-based association testing. CONCLUSIONS: Although no coding variants of large effect were detected, this study further underscores a major challenge for the study of genetic susceptibility loci; large sample sizes are required for sufficient power except for loci with large effects.

Association Between Blood Pressure Control and Risk of Recurrent Intracerebral Hemorrhage.

IMPORTANCE: Intracerebral hemorrhage (ICH) is the most severe form of stroke. Survivors are at high risk of recurrence, death, and worsening functional disability. OBJECTIVE: To investigate the association between blood pressure (BP) after index ICH and risk of recurrent ICH. DESIGN, SETTING, AND PARTICIPANTS: Single-site, tertiary care referral center observational study of 1145 of 2197 consecutive patients with ICH presenting from July 1994 to December 2013. A total of 1145 patients with ICH survived at least 90 days and were followed up through December 2013 (median follow-up of 36.8 months [minimum, 9.8 months]). EXPOSURES: Blood pressure measurements at 3, 6, 9, and 12 months, and every 6 months thereafter, obtained from medical personnel (inpatient hospital or outpatient clinic medical or nursing staff) or via patient self-report. Exposure was characterized in 3 ways: (1) recorded systolic and diastolic measurements; (2) classification as adequate or inadequate BP control based on American Heart Association/American Stroke Association recommendations; and (3) stage of hypertension based on Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure 7 criteria. MAIN OUTCOMES AND MEASURES: Recurrent ICH and its location within the brain (lobar vs nonlobar). RESULTS: There were 102 recurrent ICH events among 505 survivors of lobar ICH and 44 recurrent ICH events among 640 survivors of nonlobar ICH. During follow-up adequate BP control was achieved on at least 1 measurement by 625 patients (54.6% of total [range, 49.2%-58.7%]) and consistently (ie, at all available time points) by 495 patients (43.2% of total [range, 34.5%-51.0%]). The event rate for lobar ICH was 84 per 1000 person-years among patients with inadequate BP control compared with 49 per 1000 person-years among patients with adequate BP control. For nonlobar ICH the event rate was 52 per 1000 person-years with inadequate BP control compared with 27 per 1000 person-years for patients with adequate BP control. In analyses modeling BP control as a time-varying variable, inadequate BP control was associated with higher risk of recurrence of both lobar ICH (hazard ratio [HR], 3.53 [95% CI, 1.65-7.54]) and nonlobar ICH (HR, 4.23 [95% CI, 1.02-17.52]). Systolic BP during follow-up was associated with increased risk of both lobar ICH recurrence (HR, 1.33 per 10-mm Hg increase [95% CI, 1.02-1.76]) and nonlobar ICH recurrence (HR, 1.54 [95% CI, 1.03-2.30]). Diastolic BP was associated with increased risk of nonlobar ICH recurrence (HR, 1.21 per 10-mm Hg increase [95% CI, 1.01-1.47]) but not with lobar ICH recurrence (HR, 1.36 [95% CI, 0.90-2.10]). CONCLUSIONS AND RELEVANCE: In this observational single-center cohort study of ICH survivors, reported BP measurements suggesting inadequate BP control during follow-up were associated with higher risk of both lobar and nonlobar ICH recurrence. These data suggest that randomized clinical trials are needed to address the benefits and risks of stricter BP control in ICH survivors.

Determinants of white matter hyperintensity burden differ at the extremes of ages of ischemic stroke onset.

BACKGROUND: Age is a well-known risk factor for both stroke and increased burden of white matter hyperintensity (WMH), as detected on magnetic resonance imaging (MRI) scans. However, in patients diagnosed with ischemic stroke (IS), WMH volume (WMHv) varies significantly across age groups. We sought to examine the determinants of WMH burden across the ages of stroke onset with the goal to uncover potential age-specific stroke prevention targets. METHODS: Adult subjects from an ongoing hospital-based cohort study of IS patients with admission brain MRI were categorized as having early (<55 years), late (>75 years), or average (55-75 years) age of stroke onset. WMHv was measured using a previously validated, MRI-based semi-automated method and normalized for linear regression analyses. RESULTS: Of 1008 IS subjects, 249 had early-onset stroke (24.7%), and 311 had late-onset stroke (30.9%). In multivariable analysis of WMHv using backward stepwise selection, only age (ß = .02, P = .018), hypertension (ß = .24, P = .049), and history of tobacco use (ß = .38, P = .001) were independently associated with WMHv in patients with early-onset stroke, whereas male sex (ß = -.30, P = .007), hyperlipidemia (ß = -.27, P = .015), and current alcohol use (ß = .23, P = .034) were independently associated with WMHv in patients with late-onset stroke. CONCLUSIONS: History of tobacco use is a strong independent predictor of WMH burden in patients with early-onset stroke, whereas age is no longer associated with WMHv in IS patients older than 75 years of age. These findings suggest that the major risk factors to target for stroke prevention differ across age groups and may be modifiable.

Incidence of symptomatic hemorrhage in patients with lobar microbleeds.

BACKGROUND AND PURPOSE: Lobar microbleeds suggestive of cerebral amyloid angiopathy (CAA) are often identified on MRI in the absence of lobar intracerebral hemorrhage (ICH). We compared the baseline characteristics and risk of subsequent ICH among such patients to those presenting with CAA-related lobar ICH. METHODS: Clinical data (demographics, risk factors), apolipoprotein E genotype, neuroimaging markers of CAA severity (microbleed counts, leukoaraiosis volume), and clinical outcomes (incidence rates of ICH and death during a mean follow-up of 5.3±3.8 years) were compared between 63 patients enrolled because of incidentally found microbleeds and 316 with CAA-related ICH, in our prospectively enrolled cohort. Predictors of incident ICH were explored in the microbleed-only patients using multivariable Cox regression models. RESULTS: Microbleed-only patients shared similar demographic, apolipoprotein E, and vascular risk profiles with lobar ICH patients, but had more lobar microbleeds (median, 10 versus 2; P<0.001) and higher leukoaraiosis volumes (median, 31 versus 23 mL; P=0.02). Microbleed-only patients had a nontrivial incidence rate of ICH, not different from patients presenting with ICH (5 versus 8.9 per 100 person-years; adjusted hazard ratio, 0.58; 95% confidence interval, 0.31-1.06; P=0.08). Microbleed-only patients had a higher mortality rate (hazard ratio, 1.67; 95% confidence interval, 1.1-2.6) compared with ICH survivors. Warfarin use and increasing age were independent predictors of future ICH among microbleed-only patients after correction for other covariates. CONCLUSIONS: Patients presenting with isolated lobar microbleeds on MRI have a genetic, neuroimaging, and hemorrhagic risk profile suggestive of severe CAA pathology. They have a substantial risk of incident ICH, potentially affecting decisions regarding anticoagulation in clinical situations.