Warfarin increases mortality of intracerebral hemorrhage (ICH). The authors investigated whether this effect reflects increased baseline ICH volume at presentation or increased ICH expansion.
...Subjects were drawn from an ongoing prospective cohort study of ICH outcome. The effect of warfarin on baseline ICH volume was studied in 183 consecutive cases of supratentorial ICH age > or = 18 years admitted to the emergency department over a 5-year period. Baseline ICH volume was determined using computerized volumetric analysis. The effect of warfarin on ICH expansion (increase in volume > or = 33% of baseline) was analyzed in 70 consecutive cases in whom ICH volumes were measured on all subsequent CT scans up to 7 days after admission. Multivariable analysis was used to determine warfarin's influence on baseline ICH, ICH expansion, and whether warfarin's effect on ICH mortality was dependent on baseline volume or subsequent expansion.
There was no effect of warfarin on initial volume. Predictors of larger baseline volume were hyperglycemia (p < 0.0001) and lobar hemorrhage (p < 0.0001). Warfarin patients were at increased risk of death, even when controlling for ICH volume at presentation. Warfarin was the sole predictor of expansion (OR 6.2, 95% CI 1.7 to 22.9) and expansion in warfarin patients was detected later in the hospital course compared with non-warfarin patients (p < 0.001). ICH expansion showed a trend toward increased mortality (OR 3.5, 95% CI 0.7 to 8.9, p = 0.14) and reduced the marginal effect of warfarin on ICH mortality.
Warfarin did not increase ICH volume at presentation but did raise the risk of in-hospital hematoma expansion. This expansion appears to mediate part of warfarin's effect on ICH mortality.
To identify and compare clinical and neuroimaging predictors of primary lobar intracerebral hemorrhage (ICH) recurrence, assessing their relative contributions to recurrent ICH.
Subjects were ...consecutive survivors of primary ICH drawn from a single-center prospective cohort study. Baseline clinical, imaging, and laboratory data were collected. Survivors were followed prospectively for recurrent ICH and intercurrent aspirin and warfarin use, including duration of exposure. Cox proportional hazards models were used to identify predictors of recurrence stratified by ICH location, with aspirin and warfarin exposures as time-dependent variables adjusting for potential confounders.
A total of 104 primary lobar ICH survivors were enrolled. Recurrence of lobar ICH was associated with previous ICH before index event (hazard ratio HR 7.7, 95% confidence interval CI 1.4-15.7), number of lobar microbleeds (HR 2.93 with 2-4 microbleeds present, 95% CI 1.3-4.0; HR = 4.12 when >or=5 microbleeds present, 95% CI 1.6-9.3), and presence of CT-defined white matter hypodensity in the posterior region (HR 4.11, 95% CI 1.01-12.2). Although aspirin after ICH was not associated with lobar ICH recurrence in univariate analyses, in multivariate analyses adjusting for baseline clinical predictors, it independently increased the risk of ICH recurrence (HR 3.95, 95% CI 1.6-8.3, p = 0.021).
Recurrence of lobar ICH is associated with previous microbleeds or macrobleeds and posterior CT white matter hypodensity, which may be markers of severity for underlying cerebral amyloid angiopathy. Use of an antiplatelet agent following lobar ICH may also increase recurrence risk.
The emergence of cerebral microbleeds (CMB) as common MR imaging findings raises the question of how MR imaging parameters influence CMB detection. To evaluate the effects of modified gradient ...recalled-echo (GRE) MR imaging methods, we performed an analysis of sequence, section thickness, and field strength on CMB imaging properties and detection in subjects with cerebral amyloid angiopathy (CAA), a condition associated with microhemorrhage.
Multiple MR images were obtained from subjects with probable CAA, with varying sequences (GRE versus susceptibility-weighted imaging SWI), section thicknesses (1.2-1.5 versus 5 mm), and magnetic field strengths (1.5T versus 3T). Individual CMB were manually identified and analyzed for contrast index (lesion intensity normalized to normal-appearing white matter signal intensity) and diameter. CMB counts were compared between 1.5T thick-section GRE and thin-section SWI for 3 subjects who underwent both protocols in the same scanning session.
With other parameters constant, use of SWI, thinner sections, and a higher field strength yielded medium-to-large gains in CMB contrast index (CI; Cohen d 0.71-1.87). SWI was also associated with small increases in CMB diameter (Cohen d <0.3). Conventional thick-section GRE identified only 33% of CMB (103 of 310) seen on thin-section SWI. Lesions prospectively identified on GRE had significantly greater CI and diameter measured on the GRE image than those not prospectively identified.
The examined alternatives to conventional GRE MR imaging yield substantially improved CMB contrast and sensitivity for detection. Future studies based on these techniques will most likely yield even higher prevalence estimates for CMB.
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.
Patients with acute intracerebral hemorrhage (ICH) presenting within 3 hours of symptom onset are known to be at increased risk of expansion. However, only a minority arrive within this time frame. ...Therefore, alternative markers for expansion risk are needed.
To examine whether contrast extravasation on CT angiography (CTA) at presentation predicts subsequent hematoma expansion.
Consecutive patients with primary ICH presenting to an urban tertiary care hospital were prospectively captured in a database. We retrospectively reviewed images for all patients receiving a CTA and at least one further CT scan within 48 hours.
Complete data were available for 104 patients. Contrast extravasation at the time of CTA was present in 56% of patients, and associated with an increased risk of hematoma expansion (22% vs 2%, p = 0.003). Patients who received a baseline CTA within 3 hours were more likely to have subsequent expansion (27%, vs 13% for those presenting later, p = 0.1). However, after multivariable analysis, contrast extravasation was the only significant predictor of hematoma expansion (OR 18, 95% CI 2.1 to 162). This effect was independent of time to presentation.
Contrast extravasation is independently associated with hematoma expansion. Patients presenting within the first few hours after symptom onset have traditionally been considered those at highest risk of expansion. However, for those presenting later, the presence of contrast may be a useful marker to guide therapies aimed at decreasing this risk.
A subset of patients with cerebral amyloid angiopathy (CAA) present with cognitive symptoms, seizures, headaches, T2-hyperintense MRI lesions, and neuropathologic evidence of CAA-associated vascular ...inflammation.
To analyze the risk factors, diagnostic characteristics, and long-term course of this disorder.
We assessed 14 consecutive patients with pathologically diagnosed CAA-related inflammation, 12 with available neuroimaging and follow-up data. Patients were evaluated for MRI appearance, APOE genotype, and clinical course over a 46.8 +/- 29.1-month follow-up.
Baseline MRI scans were characterized by asymmetric T2-hyperintense lesions extending to the subcortical white matter and occasionally the overlying gray matter, with signal properties suggesting vasogenic edema. Subjects could be divided into three groups based on response to immunosuppressive treatment: monophasic improvement (7/12), initial improvement followed by symptomatic relapse (3/12), and no evident response to treatment (2/12). The volume of MRI hyperintensities correlated with the severity of clinical symptoms. One patient experienced symptomatic intracerebral hemorrhage within a region of recurrent MRI hyperintensity. The APOE epsilon4/epsilon4 genotype was strongly associated with CAA-related inflammation, present in 76.9% (10/13) of subjects vs 5.1% (2/39) with symptomatic but noninflammatory CAA (p < 0.0001).
Cerebral amyloid angiopathy-related inflammation represents a clinically, pathologically, radiographically, and genetically distinct disease subtype with implications for clinical practice and ongoing immunotherapeutic approaches to Alzheimer disease.
The risk for atrial fibrillation-associated stroke increases at low anticoagulation intensities. However, higher intensities increase hemorrhage risk. Optimal use of warfarin for atrial fibrillation ...requires precise information on the risk for intracranial hemorrhage as a function of patient age and anticoagulation intensity.
To examine the relationship of age, anticoagulation intensity, and risk for intracranial hemorrhage.
Case-control study.
Academic medical center.
170 case-patients who developed intracranial hemorrhage during warfarin therapy and 1020 matched controls who did not; both case-patients and controls were taking warfarin for atrial fibrillation.
The authors performed multivariable conditional logistic regression to determine the odds of intracranial hemorrhage with regard to age and international normalized ratio (INR), controlling for comorbid conditions and aspirin use.
Case-patients were older than controls (median age, 78 years vs. 75 years; P < 0.001) and had higher median INRs (2.7 vs. 2.3; P < 0.001). The risk for intracranial hemorrhage increased at 85 years of age or older (adjusted odds ratio, 2.5 95% CI, 1.3 to 4.7; referent age, 70 to 74 years) and at an INR range of 3.5 to 3.9 (adjusted odds ratio, 4.6 CI, 2.3 to 9.4; referent INR, 2.0 to 3.0). The risk for intracranial hemorrhage at INRs less than 2.0 did not differ statistically from the risk at INRs of 2.0 to 3.0 (adjusted odds ratio, 1.3 CI, 0.8 to 2.2).
Although duration of anticoagulation has been associated with hemorrhage in other studies, the current study could not control for this potential confounder.
The risk for intracranial hemorrhage increases at age 85 years. International normalized ratios less than 2.0 were not associated with lower risk for intracranial hemorrhage compared with INRs between 2.0 and 3.0. Therefore, anticoagulation management should focus on maintaining INRs in the 2.0 to 3.0 range, even in elderly patients with atrial fibrillation, rather than targeting INRs less than 2.0. Similarly, INRs of 3.5 or greater should be avoided.
Neuropathologic studies suggest an association between cerebral amyloid angiopathy (CAA) and small ischemic infarctions as well as hemorrhages. We examined the prevalence and associated risk factors ...for infarcts detected by diffusion-weighted imaging (DWI).
We performed retrospective analysis of MR images from 78 subjects with a diagnosis of probable CAA and a similar aged group of 55 subjects with Alzheimer disease or mild cognitive impairment (AD/MCI) for comparison. DWI and apparent diffusion coefficient (ADC) maps were inspected for acute or subacute infarcts. We also examined the association between DWI lesions and demographic variables, conventional vascular risk factors, and radiographic markers of CAA severity such as number of hemorrhages on gradient-echo MRI and volume of T2-hyperintense white matter lesions.
Twelve of 78 subjects with CAA (15%) had a total of 17 DWI-hyperintense lesions consistent with subacute cerebral infarctions vs 0 of 55 subjects with AD/MCI (p = 0.001). The DWI lesions were located primarily in cortex and subcortical white matter. CAA subjects with DWI lesions had a higher median number of total hemorrhages (22 vs 4, p = 0.025) and no difference in white matter hyperintensity volume or conventional vascular risk factors compared to subjects with CAA without lesions.
MRI evidence of small subacute infarcts is present in a substantial proportion of living patients with advanced cerebral amyloid angiopathy (CAA). The presence of these lesions is associated with a higher burden of hemorrhages, but not with conventional vascular risk factors. This suggests that advanced CAA predisposes to ischemic infarction as well as intracerebral hemorrhage.
Accumulating evidence suggests that white matter lesions are associated with vascular cognitive impairment. The authors investigated the relationships between white matter lesions, cognitive ...impairment, and risk of recurrent hemorrhage in a prospectively identified cohort of patients with lobar intracerebral hemorrhage (ICH).
The authors collected clinical and genetic information on 182 consecutive patients age > or = 55 who had CT scan at admission for lobar ICH. White matter disease was graded on CT in all subjects and on MRI in a subset of 82 patients. All scans were interpreted blinded to clinical information. Survivors were followed for recurrent ICH by telephone interview.
White matter damage was common (present on CT in 77%) and severe (advanced CT grade in 32%). White matter damage was correlated with the total number of hemorrhages on gradient-echo MRI and with risk of recurrent ICH. Subjects with cognitive impairment prior to their index ICH were more likely to have severe white matter damage on CT (OR 3.6, 95% CI 1.6 to 8.1, p = 0.003) and more likely to have advanced periventricular hyperintensities on MRI. The relationships between white matter damage and cognitive impairment were similar in the subset of 88 subjects meeting criteria for probable or definite cerebral amyloid angiopathy and remained independent after adjustment for age, cortical atrophy, and APOE genotype.
White matter damage in lobar ICH is common and is associated with cognitive impairment. These data support the possibility that an underlying vasculopathy in lobar ICH patients, possibly cerebral amyloid angiopathy, can cause clinically important vascular dysfunction.
Antiplatelet therapy (APT) promotes bleeding; therefore, APT might worsen outcome in patients with intracerebral hemorrhage (ICH). We performed a systematic review and meta-analysis to address the ...hypothesis that pre-ICH APT use is associated with mortality and poor functional outcome following ICH.
The Medline and Embase databases were searched in February 2008 using relevant key words, limited to human studies in the English language. Cohort studies of consecutive patients with ICH reporting mortality or functional outcome according to pre-ICH APT use were identified. Of 2,873 studies screened, 10 were judged to meet inclusion criteria by consensus of 2 authors. Additionally, we solicited unpublished data from all authors of cohort studies with >100 patients published within the last 10 years, and received data from 15 more studies. Univariate and multivariable-adjusted odds ratios (ORs) for mortality and poor functional outcome were abstracted as available and pooled using a random effects model.
We obtained mortality data from 25 cohorts (15 unpublished) and functional outcome data from 21 cohorts (14 unpublished). Pre-ICH APT users had increased mortality in both univariate (OR 1.41, 95% confidence interval CI 1.21 to 1.64) and multivariable-adjusted (OR 1.27, 95% CI 1.10 to 1.47) pooled analyses. By contrast, the pooled OR for poor functional outcome was no longer significant when using multivariable-adjusted estimates (univariate OR 1.29, 95% CI 1.09 to 1.53; multivariable-adjusted OR 1.10, 95% CI 0.93 to 1.29).
In cohort studies, APT use at the time of ICH compared to no APT use was independently associated with increased mortality but not with poor functional outcome.
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