Intensive Blood Pressure Lowering and DWI Lesions in Intracerebral Hemorrhage: Exploratory Analysis of the ATACH-2 Randomized Trial.

BACKGROUND: With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. METHODS: We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110-139 mm Hg versus 140-179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days. RESULTS: Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00-5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71-1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions. CONCLUSIONS: Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).

White Matter Hyperintensities and Blood Pressure Lowering in Acute Intracerebral Hemorrhage: A Secondary Analysis of the ATACH-2 Trial.

BACKGROUND: It is not clear whether subsets of patients with intracerebral hemorrhage (ICH) benefit from intensive blood pressure (BP) lowering. We evaluated whether white matter hyperintensities (WMH) burden influences response to this therapy. METHODS: Retrospective secondary analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 trial. Patients were randomized to intensive (systolic BP target: 110-139 mmHg) versus standard (systolic BP target: 140-179 mmHg) BP treatment with intravenous nicardipine within 4.5 h from onset between May 2011 and September 2015. WMH were rated on magnetic resonance images (fluid-attenuated inversion recovery sequences), defining moderate-severe WMH as total Fazekas scale score ≥ 3 (range 0-6). The main outcome was death or major disability at 90 days (modified Rankin scale ≥ 3). The secondary outcome was ICH expansion, defined as hematoma growth > 33% from baseline to follow-up CT scan. Predictors of the outcomes of interest were explored with multivariable logistic regression. RESULTS: A total of 195/1000 patients had MRI images available for analysis, of whom 161 (82.6%) had moderate-severe WMH. When compared to patients with none-mild WMH, those with moderate-severe WMH did not have an increased risk of death or major disability (adjusted relative risk: 1.83, 95% CI 0.71-4.69) or ICH expansion (adjusted relative risk: 1.14, 95% CI 0.38-3.37). WMH burden did not modify the effect of intensive BP treatment on outcome (all p for interaction ≥ 0.2). CONCLUSION: The majority of acute ICH patients have moderate-severe WMH, but advanced small vessel disease burden marked by WMH does not influence ICH-related outcomes or response to intensive BP reduction.

Cerebral Small Vessel Diseases and Sleep Related Strokes.

BACKGROUND AND PURPOSE: Sleep related Stroke (SRS) is common and has been associated with cerebral small vessel diseases (SVD) in ischemic strokes (ISs). We tested the hypothesis that SRS is associated with SVD in both ischemic and hemorrhagic stroke. METHODS: Prospectively collected data from patients consecutively enrolled after intracerebral hemorrhage (ICH) related to SVD or after IS were analyzed. Symptom onset was recorded as SRS versus awake. Each ICH was grouped according to lobar and deep locations. The IS cohort was etiologically characterized based on the Causative Classification of Stroke system. Frequencies of SRS within and between ICH and IS cohorts as well as its associations (etiology, risk factors) were analyzed. RESULTS: We analyzed 1812 IS (mean age 67.9 years ± 15.9 years, 46.4% female) and 1038 ICH patients (mean age 72.5 years ± 13.0 years, 45.4% female). SRS was significantly more common among SVD-related ICH patients (n = 276, 26.6%) when compared to all IS (n = 363, 20.0%, P < .001) and in both, small artery occlusion (SAO) related IS and lobar ICH within the respective IS and ICH cohorts (16.3% SRS versus 9.1% awake for SAO within all IS, P < .001; and 57.1% SRS versus 47.7% awake for lobar bleeds within all ICH, P = .008). These associations remained significant after controlling for age, sex and risk factors. CONCLUSIONS: SRS was associated with SVD. The SAO etiology and cerebral amyloid angiopathy related lobar ICH suggest that the presence of SVD can interact with sleep or arousal related hemodynamic changes to cause ischemic and hemorrhagic stroke.

Identification and Validation of Hematoma Volume Cutoffs in Spontaneous, Supratentorial Deep Intracerebral Hemorrhage.

Background and Purpose- Clinical trials in spontaneous intracerebral hemorrhage (ICH) have used volume cutoffs as inclusion criteria to select populations in which the effects of interventions are likely to be the greatest. However, optimal volume cutoffs for predicting poor outcome in deep locations (thalamus versus basal ganglia) are unknown. Methods- We conducted a 2-phase study to determine ICH volume cutoffs for poor outcome (modified Rankin Scale score of 4-6) in the thalamus and basal ganglia. Cutoffs with optimal sensitivity and specificity for poor outcome were identified in the ERICH ([Ethnic/Racial Variations of ICH] study; derivation cohort) using receiver operating characteristic curves. The cutoffs were then validated in the ATACH-2 trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) by comparing the c-statistic of regression models for outcome (including dichotomized volume) in the validation cohort. Results- Of the 3000 patients enrolled in ERICH, 1564 (52%) had deep ICH, of whom 1305 (84%) had complete neuroimaging and outcome data (660 thalamic and 645 basal ganglia hemorrhages). Receiver operating characteristic curve analysis identified 8 mL in thalamic (area under the curve, 0.79; sensitivity, 73%; specificity, 78%) and 18 mL in basal ganglia ICH (area under the curve, 0.79; sensitivity, 70%; specificity, 83%) as optimal cutoffs for predicting poor outcome. The validation cohort included 834 (84%) patients with deep ICH and complete neuroimaging data enrolled in ATACH-2 (353 thalamic and 431 basal ganglia hemorrhages). In thalamic ICH, the c-statistic of the multivariable outcome model including dichotomized ICH volume was 0.80 (95% CI, 0.75-0.85) in the validation cohort. For basal ganglia ICH, the c-statistic was 0.81 (95% CI, 0.76-0.85) in the validation cohort. Conclusions- Optimal hematoma volume cutoffs for predicting poor outcome in deep ICH vary by the specific deep brain nucleus involved. Utilization of location-specific volume cutoffs may improve clinical trial design by targeting deep ICH patients that will obtain maximal benefit from candidate therapies.

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

PURPOSE: We aimed to identify the effect of hyperosmolar therapy (mannitol and hypertonic saline) on outcomes after intracerebral hemorrhage (ICH) in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study. METHODS: Comparison of ICH cases treated with hyperosmolar therapy versus untreated cases was performed using a propensity score based on age, initial Glasgow Coma Scale, location of ICH (lobar, deep, brainstem, and cerebellar), log-transformed initial ICH volume, presence of intraventricular hemorrhage, and surgical interventions. ERICH subjects with a pre-ICH modified Rankin Scale (mRS) score of 3 or lower were included. Treated cases were matched 1:1 to untreated cases by the closest propensity score (difference ≤.15), gender, and race and ethnicity (non-Hispanic white, non-Hispanic black, or Hispanic). The McNemar and the Wilcoxon signed-rank tests were used to compare 3-month mRS outcomes between the 2 groups. Good outcome was defined as a 3-month mRS score of 3 or lower. RESULTS: As of December 31, 2013, the ERICH study enrolled 2279 cases, of which 304 hyperosmolar-treated cases were matched to 304 untreated cases. Treated cases had worse outcome at 3 months compared with untreated cases (McNemar, P = .0326), and the mean 3-month mRS score was lower in the untreated group (Wilcoxon, P = .0174). Post hoc analysis revealed more brain edema, herniation, and death at discharge for treated cases. CONCLUSIONS: Hyperosmolar therapy was not associated with better 3-month mRS outcomes for ICH cases in the ERICH study. This finding likely resulted from greater hyperosmolar therapy use in patients with edema and herniation rather than those agents leading to worse outcomes. Further studies should be performed to determine if hyperosmolar agents are effective in preventing poor outcomes.

Phantom-based standardization of CT angiography images for spot sign detection.

PURPOSE: The CT angiography (CTA) spot sign is a strong predictor of hematoma expansion in intracerebral hemorrhage (ICH). However, CTA parameters vary widely across centers and may negatively impact spot sign accuracy in predicting ICH expansion. We developed a CT iodine calibration phantom that was scanned at different institutions in a large multicenter ICH clinical trial to determine the effect of image standardization on spot sign detection and performance. METHODS: A custom phantom containing known concentrations of iodine was designed and scanned using the stroke CT protocol at each institution. Custom software was developed to read the CT volume datasets and calculate the Hounsfield unit as a function of iodine concentration for each phantom scan. CTA images obtained within 8 h from symptom onset were analyzed by two trained readers comparing the calibrated vs. uncalibrated density cutoffs for spot sign identification. ICH expansion was defined as hematoma volume growth >33%. RESULTS: A total of 90 subjects qualified for the study, of whom 17/83 (20.5%) experienced ICH expansion. The number of spot sign positive scans was higher in the calibrated analysis (67.8 vs 38.9% p < 0.001). All spot signs identified in the non-calibrated analysis remained positive after calibration. Calibrated CTA images had higher sensitivity for ICH expansion (76 vs 52%) but inferior specificity (35 vs 63%) compared with uncalibrated images. CONCLUSION: Normalization of CTA images using phantom data is a feasible strategy to obtain consistent image quantification for spot sign analysis across different sites and may improve sensitivity for identification of ICH expansion.

Perihematomal Edema Expansion Rates and Patient Outcomes in Deep and Lobar Intracerebral Hemorrhage.

BACKGROUND: Perihematomal edema (PHE) expansion rate may predict functional outcome following spontaneous intracerebral hemorrhage (ICH). We hypothesized that the effect of PHE expansion rate on outcome is greater for deep versus lobar ICH. METHODS: Subjects (n = 115) were retrospectively identified from a prospective ICH cohort enrolled from 2000 to 2013. Inclusion criteria were age ≥ 18 years, spontaneous supratentorial ICH, and known onset time. Exclusion criteria were primary intraventricular hemorrhage (IVH), trauma, subsequent surgery, or warfarin-related ICH. ICH and PHE volumes were measured from CT scans and used to calculate expansion rates. Logistic regression assessed the association between PHE expansion rates and 90-day mortality or poor functional outcome (modified Rankin Scale > 2). Odds ratios are per 0.04 mL/h. RESULTS: PHE expansion rate from baseline to 24 h (PHE24) was associated with mortality for deep (p = 0.03, OR 1.13[1.02-1.26]) and lobar ICH (p = 0.02, OR 1.03[1.00-1.06]) in unadjusted regression and in models adjusted for age (deep p = 0.02, OR 1.15[1.02-1.28]; lobar p = 0.03, OR 1.03[1.00-1.06]), Glasgow Coma Scale (deep p = 0.03, OR 1.13[1.01-1.27]; lobar p = 0.02, OR 1.03[1.01-1.06]), or time to baseline CT (deep p = 0.046, OR 1.12[1.00-1.25]; lobar p = 0.047, OR 1.03[1.00-1.06]). PHE expansion rate from baseline to 72 h (PHE72) was associated with mRS > 2 for deep ICH in models that were unadjusted (p = 0.02, OR 4.04[1.25-13.04]) or adjusted for ICH volume (p = 0.02, OR 4.3[1.25-14.98]), age (p = 0.03, OR 5.4[1.21-24.11]), GCS (p = 0.02, OR 4.19[1.2-14.55]), or time to first CT (p = 0.03, OR 4.02[1.19-13.56]). CONCLUSIONS: PHE72 was associated with poor functional outcomes after deep ICH, whereas PHE24 was associated with mortality for deep and lobar ICH.

Noncontrast Computed Tomography Hypodensities Predict Poor Outcome in Intracerebral Hemorrhage Patients.

BACKGROUND AND PURPOSE: Noncontrast computed tomographic (CT) hypodensities have been shown to be associated with hematoma expansion in intracerebral hemorrhage (ICH), but their impact on functional outcome is yet to be determined. We evaluated whether baseline noncontrast CT hypodensities are associated with poor clinical outcome. METHODS: We performed a retrospective review of a prospectively collected cohort of consecutive patients with primary ICH presenting to a single academic medical center between 1994 and 2016. The presence of CT hypodensities was assessed by 2 independent raters on the baseline CT. Unfavorable outcome was defined as a modified Rankin score >3 at 90 days. The associations between CT hypodensities and unfavorable outcome were investigated using uni- and multivariable logistic regression models. RESULTS: During the study period, 1342 patients presented with ICH and 800 met restrictive inclusion criteria (baseline CT available for review, and 90-day outcome available). Three hundred and four (38%) patients showed hypodensities on CT, and 520 (65%) patients experienced unfavorable outcome. In univariate analysis, patients with unfavorable outcome were more likely to demonstrate hypodensities (48% versus 20%; P<0.0001). After adjustment for age, admission Glasgow coma scale, warfarin use, intraventricular hemorrhage, baseline ICH volume, and location, CT hypodensities were found to be independently associated with an increase in the odds of unfavorable outcome (odds ratio 1.70, 95% confidence interval [1.10-2.65]; P=0.018). CONCLUSIONS: The presence of noncontract CT hypodensities at baseline independently predicts poor outcome and comes as a useful and widely available addition to our ability to predict ICH patients' clinical evolution.

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.

Cortical Superficial Siderosis in Memory Clinic Patients: Further Evidence for Underlying Cerebral Amyloid Angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is associated with many cases of spontaneous symptomatic lobar intracerebral haemorrhage in older individuals and is emerging as an important contributor to cognitive impairment. Cortical superficial siderosis (cSS) is an increasingly recognized haemorrhagic neuroimaging manifestation of CAA. We sought to investigate its prevalence and its association with underlying CAA among memory clinic patients. METHODS: We included consecutive eligible patients who presented to the out-patient memory clinic at the Massachusetts General Hospital from 2007 to 2010 and had appropriate MRI, including blood-sensitive sequences. We analyzed the prevalence and topography of cSS according to demographic, clinical, APOE and MRI data. RESULTS: Our cohort consisted of 339 memory clinic patients: Alzheimer's disease (n = 86); mild cognitive impairment (n = 162); vascular dementia/mixed dementia (n = 18); other dementia/undetermined (n = 42); and subjective cognitive complains (n = 31). cSS was detected in 10 patients (3%; 95% CI 1.4-5.4): in 7 cases cSS was focal and in 3 cases, it was disseminated. In multivariable logistic regression analysis, the presence of cSS was associated with lobar microbleeds (OR 1.08; 95% CI 1.03-1.13; p = 0.001, per each additional microbleed) and severe white matter hyperintensities (Fazekas score 5-6, OR 4.43; 95% CI 1.21-26.28; p = 0.028) after adjusting for age. These associations were not influenced by the clinical diagnosis. In patients with APOE data, the APOE ε4/ε4 genotype was overrepresented among subjects with vs. without cSS. In the subgroup of patients with probable CAA (n = 68; 9 with cSS) based on the presence of strictly lobar microbleeds, cSS was also associated with a higher prevalence of severe white matter hyperintensities (66.7 vs. 10.2%; p = 0.001), high centrum semiovale perivascular spaces burden (88.9 vs. 52.4%; p = 0.041) and higher counts of lobar microbleeds (median 13; IQR 10-36 vs. median 1; IQR 1-2; p < 0.00001), compared to patients without cSS. CONCLUSIONS: Our data provide further evidence supporting the hypothesis that cSS is a manifestation of advanced CAA in memory clinic populations. Future longitudinal studies should explore any direct effect of cSS on cognition or haemorrhage risk and disease progression.

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.

Estimating Total Cerebral Microinfarct Burden From Diffusion-Weighted Imaging.

BACKGROUND AND PURPOSE: Cerebral microinfarcts (CMI) are important contributors to vascular cognitive impairment. Magnetic resonance imaging diffusion-weighted imaging (DWI) hyperintensities have been suggested to represent acute CMI. We aim to describe a mathematical method for estimating total number of CMI based on the presence of incidental DWI lesions. METHODS: We reviewed magnetic resonance imaging scans of subjects with cognitive decline, cognitively normal subjects and previously reported subjects with past intracerebral hemorrhage (ICH). Based on temporal and spatial characteristics of DWI lesions, we estimated the annual rate of CMI needed to explain the observed rate of DWI lesion detection in each group. To confirm our estimates, we performed extensive sampling for CMI in the brain of a deceased subject with past lobar ICH who found to have a DWI lesion during life. RESULTS: Clinically silent DWI lesions were present in 13 of 343 (3.8%) cognitively impaired and 10 of 199 (5%) cognitively intact normal non-ICH patients, both lower than the incidence in the past ICH patients (23 of 178; 12.9%; P<0.0006). The predicted annual incidence of CMI ranges from 16 to 1566 for non-ICH and 50 to 5041 for ICH individuals. Histological sampling revealed a total of 60 lesions in 32 sections. Based on previously reported methods, this density of CMI yields an estimated total brain burden maximum likelihood estimate of 9321 CMIs (95% confidence interval, 7255-11 990). CONCLUSIONS: Detecting even a single DWI lesion suggests an annual incidence of hundreds of new CMI. The cumulative effects of these lesions may directly contribute to small-vessel-related vascular cognitive impairment.

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.

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

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

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.

Risk factors for computed tomography angiography spot sign in deep and lobar intracerebral hemorrhage are shared.

BACKGROUND AND PURPOSE: Patients with intracerebral hemorrhage (ICH) who present with a spot sign on computed tomography angiography are at increased risk of hematoma expansion and poor outcome. Because primary ICH is the acute manifestation of chronic cerebral small vessel disease, we investigated whether different clinical or imaging characteristics predict spot sign presence, using ICH location as a surrogate for arteriolosclerosis- and cerebral amyloid angiopathy-related ICH. METHODS: Patients with primary ICH and available computed tomography angiography at presentation were included. Predictors of spot sign were assessed using uni- and multivariable regression, stratified by ICH location. RESULTS: Seven hundred forty-one patients were eligible, 335 (45%) deep and 406 (55%) lobar ICH. At least one spot sign was present in 76 (23%) deep and 102 (25%) lobar ICH patients. In multivariable regression, warfarin (odds ratio [OR], 2.42; 95% confidence interval [CI], 1.01-5.71; P=0.04), baseline ICH volume (OR, 1.20; 95% CI, 1.09-1.33, per 10 mL increase; P<0.001), and time from symptom onset to computed tomography angiography (OR, 0.89; 95% CI, 0.80-0.96, per hour; P=0.009) were associated with the spot sign in deep ICH. Predictors of spot sign in lobar ICH were warfarin (OR, 3.95; 95% CI, 1.87-8.51; P<0.001) and baseline ICH volume (OR, 1.20; 95% CI, 1.10-1.31, per 10 mL increase; P<0.001). CONCLUSIONS: The most potent associations with spot sign are shared between deep and lobar ICH, suggesting that the acute bleeding process that arises in the setting of different chronic small vessel diseases shares commonalities.

Anatomic pattern of intracerebral hemorrhage expansion: relation to CT angiography spot sign and hematoma center.

BACKGROUND AND PURPOSE: We sought to identify baseline determinants of the anatomic pattern of hematoma expansion in patients with intracerebral hemorrhage and spot sign. METHODS: We coregistered baseline and follow-up CT scans from 15 intracerebral hemorrhage patients and measured growth at each surface node from baseline to follow-up hematoma. We analyzed the effects of proximity to the spot sign or hematoma center on distance of expansion, controlling for covariates. RESULTS: There was substantial node-to-node variation in the extent of expansion around each hematoma surface (mean coefficient of variation for expansion distance, 0.43; 95% confidence interval, 0.39-0.48), indicating nonuniform expansion. Closer proximity to the hematoma center was independently associated with increased expansion (0.185 mm greater expansion for each 1 mm closer to the center; P<0.0001). Closer proximity to the spot sign was not independently associated with increased expansion in models including both terms. CONCLUSIONS: Hemorrhages expand nonuniformly around their surface with a tendency for greater expansion closer to their center. These findings provide a novel framework for analyzing mechanisms underlying hemorrhage growth and response to treatment.

Cerebral amyloid angiopathy burden associated with leukoaraiosis: a positron emission tomography/magnetic resonance imaging study.

OBJECTIVE: We hypothesized that vascular amyloid contributes to chronic brain ischemia, therefore amyloid burden measured by Pittsburgh compound B retention on positron emission tomography (PiB PET) would correlate with the extent of magnetic resonance imaging (MRI) white matter hyperintensities (WMH; or leukoaraiosis) in patients with high vascular amyloid deposition (cerebral amyloid angiopathy [CAA]) but not in patients with high parenchymal amyloid deposition (Alzheimer disease [AD]; mild cognitive impairment [MCI]) or in healthy elderly (HE) subjects. METHODS: Forty-two nondemented CAA patients, 50 HE subjects, and 43 AD/MCI patients had brain MRI and PiB PET. Multivariate linear regression was used to assess the independent association between PiB retention and white matter disease volume, controlling for age, gender, apolipoprotein E genotype, and vascular risk factors within each group. RESULTS: CAA patients were younger than HE and AD subjects (68 ± 10 vs 73.3 ± 7 and 74 ± 7.4, p < 0.01) but had higher amounts of WMH (median = 21 vs 3.2 and 10.8 ml, respectively, p < 0.05 for both comparisons). Global PiB retention and WMH showed strong correlation (rho = 0.52, p < 0.001) in the CAA group but not in HE or AD. These associations did not change in the multivariate models. Lobar microbleed count, another marker of CAA severity, also remained as an independent predictor of WMH volume. INTERPRETATION: Our results indicate that amyloid burden in CAA subjects (with primarily vascular amyloid) but not AD subjects (with primarily parenchymal amyloid) independently correlates with WMH volume. These findings support the idea that vascular amyloid burden directly contributes to chronic cerebral ischemia and highlights the possible utility of amyloid imaging as a marker of CAA severity.