Optimal Timing for Resumption of Anticoagulation After Intracranial Hemorrhage in Patients With Mechanical Heart Valves.

BACKGROUND: Anticoagulation in patients with intracranial hemorrhage (ICH) and mechanical heart valves is often held for risk of ICH expansion; however, there exists a competing risk of acute ischemic stroke (AIS). Optimal timing to resume anticoagulation remains uncertain. METHODS AND RESULTS: We retrospectively studied patients with ICH and mechanical heart valves from 2000 to 2018. The primary outcome was a composite end point of symptomatic hematoma expansion or new ICH, AIS, and intracardiac thrombus up to 30 days post-ICH. The exposure was timing of reinitiation of anticoagulation classified as early (resumed up to 7 days after ICH), late (≥7 and up to 30 days after ICH), and never if not resumed or resumed after 30 days post-ICH. We included 184 patients with ICH and mechanical heart valves (65 anticoagulated early, 100 late, 19 not resumed by day 30 post-ICH). Twelve patients had AIS, 16 new ICH, and 6 intracardiac thromboses. The mean time from ICH to anticoagulation was 12.7 days. Composite outcomes occurred in 12 patients resumed early (18.5%), 14 resumed late (14.0%), and 4 never resumed (21.1%). There was no increased hazard of the composite outcome (hazard ratio [HR], 1.1 [95% CI, 0.2-6.0]), AIS, or worsening or new ICH among patients resumed early versus late. There was no difference in the composite among patients never resumed versus resumed. Patients who never resumed anticoagulation had significantly more severe ICH (median Glasgow Coma Scale: 10.6, 13.9, and 13.9 among those who resumed never, early, and late, respectively; P=0.0001), higher in-hospital mortality (56.5%, 0%, and 0%, respectively; P<0.0001), and an elevated 30-day AIS risk (HR, 15.9 [95% CI, 1.9-129.7], P=0.0098). CONCLUSIONS: In this study of patients with ICH and mechanical heart valves, there was no difference in 30-day thrombotic and hemorrhagic brain-related outcomes when anticoagulation was resumed within 7 versus 7 to 30 days after ICH. Withholding anticoagulation >30 days was associated with severe baseline ICH, higher in-hospital case fatality, and elevated AIS risk.

Peak Width of Skeletonized Mean Diffusivity as Neuroimaging Biomarker in Cerebral Amyloid Angiopathy.

BACKGROUND AND PURPOSE: Whole-brain network connectivity has been shown to be a useful biomarker of cerebral amyloid angiopathy and related cognitive impairment. We evaluated an automated DTI-based method, peak width of skeletonized mean diffusivity, in cerebral amyloid angiopathy, together with its association with conventional MRI markers and cognitive functions. MATERIALS AND METHODS: We included 24 subjects (mean age, 74.7 [SD, 6.0] years) with probable cerebral amyloid angiopathy and mild cognitive impairment and 62 patients with MCI not attributable to cerebral amyloid angiopathy (non-cerebral amyloid angiopathy-mild cognitive impairment). We compared peak width of skeletonized mean diffusivity between subjects with cerebral amyloid angiopathy-mild cognitive impairment and non-cerebral amyloid angiopathy-mild cognitive impairment and explored its associations with cognitive functions and conventional markers of cerebral small-vessel disease, using linear regression models. RESULTS: Subjects with Cerebral amyloid angiopathy-mild cognitive impairment showed increased peak width of skeletonized mean diffusivity in comparison to those with non-cerebral amyloid angiopathy-mild cognitive impairment (P < .001). Peak width of skeletonized mean diffusivity values were correlated with the volume of white matter hyperintensities in both groups. Higher peak width of skeletonized mean diffusivity was associated with worse performance in processing speed among patients with cerebral amyloid angiopathy, after adjusting for other MRI markers of cerebral small vessel disease. The peak width of skeletonized mean diffusivity did not correlate with cognitive functions among those with non-cerebral amyloid angiopathy-mild cognitive impairment. CONCLUSIONS: Peak width of skeletonized mean diffusivity is altered in cerebral amyloid angiopathy and is associated with performance in processing speed. This DTI-based method may reflect the degree of white matter structural disruption in cerebral amyloid angiopathy and could be a useful biomarker for cognition in this population.

Fatal oral anticoagulant-related intracranial hemorrhage: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Intracranial hemorrhage (ICH) is the most feared complication in patients treated with oral anticoagulants due to non-valvular atrial fibrillation. Non-vitamin K oral anticoagulants (NOACs) reduce the risk of ICH compared with vitamin K antagonists (VKAs). We performed a systematic review and meta-analysis to evaluate the risk of fatal NOAC-related ICH compared with VKA-related ICH. METHODS: We calculated the corresponding risk ratios (RRs) in each included study to express the relative risk of fatal ICH amongst all patients receiving oral anticoagulation with either NOACs or VKAs. We additionally evaluated the mortality rates in NOAC-related ICH in patients treated with and without NOAC-specific reversal agents (idarucizumab and factor Xa inhibitors antidote). Case fatality was evaluated at 30-90 days following symptom onset. RESULTS: Our literature search identified six eligible studies (four randomized controlled trials and two open-label trials of NOAC-specific reversal agents). In pairwise analyses, NOACs were found to have a lower risk of fatal ICH compared with VKAs [RR, 0.46; 95% confidence interval (CI), 0.36-0.58] with no heterogeneity (I2 = 0%) across included randomized controlled trials. However, the case fatality rate was similar in NOAC-related and VKA-related (RR, 1.00; 95% CI, 0.84-1.19) ICH with no evidence of heterogeneity (I2 = 0%). In the indirect analysis, the case fatality rate of NOAC-related ICH in patients treated with specific reversal agents was lower compared with the remainder of the patients [17% (95% CI, 11-24%) vs. 41% (95% CI, 34-49%); P < 0.001]. CONCLUSIONS: Non-vitamin K oral anticoagulants halve the risk of fatal ICH in patients with non-valvular atrial fibrillation compared with VKAs, whereas indirect comparisons indicate that NOAC-specific reversal agents may be associated with a lower case fatality rate in NOAC-related ICH.

Effect of CTA Tube Current on Spot Sign Detection and Accuracy for Prediction of Intracerebral Hemorrhage Expansion.

BACKGROUND AND PURPOSE: Reduction of CT tube current is an effective strategy to minimize radiation load. However, tube current is also a major determinant of image quality. We investigated the impact of CTA tube current on spot sign detection and diagnostic performance for intracerebral hemorrhage expansion. MATERIALS AND METHODS: We retrospectively analyzed a prospectively collected cohort of consecutive patients with primary intracerebral hemorrhage from January 2001 to April 2015 who underwent CTA. The study population was divided into 2 groups according to the median CTA tube current level: low current (<350 mA) and high current (≥350 mA). CTA first-pass readings for spot sign presence were independently analyzed by 2 readers. Baseline and follow-up hematoma volumes were assessed by semiautomated computer-assisted volumetric analysis. Sensitivity, specificity, positive and negative predictive values, and accuracy of spot sign in predicting hematoma expansion were calculated. RESULTS: This study included 709 patients (288 and 421 in the low- and high-current groups, respectively). A higher proportion of low-current scans identified at least 1 spot sign (20.8% versus 14.7%, P = .034), but hematoma expansion frequency was similar in the 2 groups (18.4% versus 16.2%, P = .434). Sensitivity and positive and negative predictive values were not significantly different between the 2 groups. Conversely, high-current scans showed superior specificity (91% versus 84%, P = .015) and overall accuracy (84% versus 77%, P = .038). CONCLUSIONS: CTA obtained at high levels of tube current showed better diagnostic accuracy for prediction of hematoma expansion by using spot sign. These findings may have implications for future studies using the CTA spot sign to predict hematoma expansion for clinical trials.

Decoupling of structural and functional brain connectivity in older adults with white matter hyperintensities.

Age-related impairments in the default network (DN) have been related to disruptions in connecting white matter tracts. We hypothesized that the local correlation between DN structural and functional connectivity is negatively affected in the presence of global white matter injury. In 125 clinically normal older adults, we tested whether the relationship between structural connectivity (via diffusion imaging tractography) and functional connectivity (via resting-state functional MRI) of the posterior cingulate cortex (PCC) and medial prefrontal frontal cortex (MPFC) of the DN was altered in the presence of white matter hyperintensities (WMH). A significant correlation was observed between microstructural properties of the cingulum bundle and MPFC-PCC functional connectivity in individuals with low WMH load, but not with high WMH load. No correlation was observed between PCC-MPFC functional connectivity and microstructure of the inferior longitudinal fasciculus, a tract not passing through the PCC or MPFC. Decoupling of connectivity, measured as the absolute difference between structural and functional connectivity, in the high WMH group was related to poorer executive functioning and memory performance. These results suggest that such decoupling may reflect reorganization of functional networks in response to global white matter pathology and may provide an early marker of clinically relevant network alterations.

Progression of white matter lesions and hemorrhages in cerebral amyloid angiopathy.

OBJECTIVE: To determine the rate of progression of white matter lesions and hemorrhages in a cohort with cerebral amyloid angiopathy (CAA). METHODS: The authors analyzed data from 26 patients with possible (3) or probable (23) CAA, diagnosed by the Boston Criteria. Brain maps of white matter hyperintensities, normalized to head size (nWMH), were created by blinded computer-assisted segmentation of MRI images obtained at baseline and after a median follow-up interval of 1.1 year. RESULTS: There was a substantial nWMH volume increase over the interscan interval (median 0.5 mL/year, interquartile range 0.1 to 2.8, p < 0.001). The median yearly increase, expressed as a percentage of the baseline WMH volume, was 18%. The characteristic most strongly associated with nWMH volume increase was the baseline nWMH volume (r = 0.57, p = 0.002). The volume of nWMH progression was also associated with history of cognitive impairment (median 5.0 mL/year in cognitively impaired subjects vs 0.3 mL/year in cognitively unimpaired, p = 0.02) but not age or hypertension. This association remained present in an analysis stratified by baseline WMH volume. New hemorrhages, including asymptomatic microbleeds, were seen in 46% of subjects. The number of new MRI hemorrhages correlated strongly with baseline nWMH (r = 0.53, p = 0.005) but not with nWMH progression (r = 0.22, p = 0.28). CONCLUSIONS: There is a progressive increase in white matter lesions in subjects with cerebral amyloid angiopathy. The association of white matter lesions with incident lobar hemorrhages suggests that white matter damage may reflect a progressive microangiopathy due to cerebral amyloid angiopathy.

Plasma beta-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy.

BACKGROUND: Microvascular brain injury, typically measured by extent of white matter hyperintensity (WMH) on MRI, is an important contributor to cognitive impairment in the elderly. Recent studies suggest a role for circulating beta-amyloid peptide in microvascular dysfunction and white matter disease. METHODS: The authors performed a cross-sectional study of clinical, biochemical, and genetic factors associated with WMH in 54 subjects with Alzheimer disease (AD) or mild cognitive impairment (AD/MCI) and an independent group of 42 subjects with cerebral amyloid angiopathy (CAA). Extent of WMH was determined by computer-assisted volumetric measurement normalized to intracranial size (nWMH). Biochemical measurements included plasma concentrations of the 40- and 42-amino acid species of beta-amyloid (Abeta40 and Abeta42) detected by specific enzyme-linked immunosorbent assays. RESULTS: Plasma Abeta40 concentrations were associated with nWMH in both groups (correlation coefficient = 0.48 in AD/MCI, 0.42 in CAA, p < or = 0.005). Plasma Abeta40 remained independently associated with nWMH after adjustment for potential confounders among age, hypertension, diabetes, homocysteine, creatinine, folate, vitamin B12, and APOE genotype. The presence of lacunar infarctions was also associated with increased Abeta40 in both groups. nWMH was greater in CAA (19.8 cm3) than AD (11.1 cm3) or MCI (10.0 cm3; p < 0.05 for both comparisons). CONCLUSIONS: Plasma beta-amyloid 40 concentration is independently associated with extent of white matter hyperintensity in subjects with Alzheimer disease, mild cognitive impairment, or cerebral amyloid angiopathy. If confirmed in longitudinal studies, these data would suggest circulating beta-amyloid peptide as a novel biomarker or risk factor for microvascular damage in these common diseases of the elderly.

Association of homocysteine with plasma amyloid beta protein in aging and neurodegenerative disease.

BACKGROUND: Elevated plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease and is reported to be an independent risk factor for Alzheimer disease (AD) and cognitive decline. tHcy may potentiate neurotoxic and vasculopathic processes, including amyloid beta protein (Abeta) metabolism, implicated in neurodegenerative diseases. OBJECTIVE: To examine the relationship of plasma total tHcy levels with clinical, demographic, biochemical, and genetic factors in aging, mild cognitive impairment (MCI), AD, cerebral amyloid angiopathy (CAA), and Parkinson disease (PD). METHODS: Plasma tHcy, folate, vitamin B(12), creatinine, and Abeta levels were assessed in individuals evaluated in the Memory, Stroke, and Movement Disorders Units of Massachusetts General Hospital with diagnoses of AD (n = 145), MCI (n = 47), PD (n = 93), CAA (67), hypertensive intracerebral hemorrhage (hICH) (n = 25), and no dementia (n = 88). RESULTS: The tHcy levels did not differ across AD, MCI, CAA, hICH, and nondemented control subjects but were increased in the PD group (p < 0.01). The elevated levels within the PD group were due to high tHcy in individuals taking levodopa (p < 0.0001). Increasing tHcy was associated with worse cognition in the PD cases, but not the other diagnostic groups. tHcy levels positively correlated with plasma Abeta levels even after adjustments for age and creatinine (p < 0.0001). CONCLUSIONS: Mean tHcy levels increased with age but did not discriminate diagnostic groups aside from significant elevation in patients with PD taking levodopa. The positive association between tHcy and plasma Abeta levels raises the possibility that these circulating factors could interact to affect AD risk and cognition in PD.

White matter lesions, cognition, and recurrent hemorrhage in lobar intracerebral hemorrhage.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Stroke unit versus neurology ward--a before and after study.

INTRODUCTION: Few studies have tested the hypothesis of whether the beneficial effect of Stroke Units (SUs) can be reproduced in routine clinical practice and whether SU are also superior to neurological wards [NWs]. We aimed to compare the outcomes of patients of a newly implemented SU to the outcomes of patients hospitalized in a NW. METHODS: We made a before-after comparison of 352 SUs and 352 NWs patients after adjusting for case-mixes by the multivariate method. Subgroup analyses were also performed to evaluate which patient groups benefit the most. In-hospital case-fatality, proportion of independent patients at discharge, length of hospital stay (LOHS), medical complication rate were the main outcome measures. RESULTS: Adjusted in-hospital case fatality was significantly reduced in the SUs (OR: 0.44, 95 % CI: 0.26-0.76; p = 0.003). The proportion of independent patients at discharge and patients having medical complications was not different. Length of hospital stay was shorter in SU patients (13.76 days vs. 16.72 days, p = 0.003). Treatment in the SUs decreased case fatality in many subgroups [men, elderly, early admitted, severe stroke, co-morbidity present and ischemic stroke groups]. DISCUSSION: The results of randomized trials in favor of SUs can be reproduced in routine clinical practice. The benefit of SU care seems to be more apparent with advancing age and increasing stroke severity. Stroke Unit seems to be a better alternative to an experienced NW.

Stiff leg syndrome: case report.

We report on a 28-year-old woman with insulin-resistant diabetes mellitus with a 5-year history of progressive stiffness and painful spasms of the right leg, exaggerated by sudden auditory and tactile stimuli or by emotional stress. There were no signs of truncal rigidity or exaggerated lumbar lordosis. Anti-glutamic acid decarboxylase antibodies were positive in her serum. She improved substantially with clonazepam 4 mg/day. She presented with electrophysiological findings not previously reported in stiff leg syndrome, which may suggest increased inhibition in the uninvolved upper extremities.

Venous infarction of brainstem and cerebellum.

The authors describe 2 cases of posterior fosa venous infarction. A 56-year-old woman with essential thrombocytemia presented with fluctuating complaints of headache, nausea, vomiting, left-sided numbness-weakness, and dizziness and became progressively stuporous. Cranial magnetic resonance imaging (MRI) showed bilateral parasagittal fronto-parietal and left cerebellar contrast-enhancing hemorrhagic lesions. On magnetic resonance venography, the left transverse and sigmoid sinuses were occluded. The second patient, a 39-year-old woman, presented with acute onset of diplopia, numbness of the tongue, vertigo, and right-sided weakness following a gestational age stillbirth. MRI revealed lesions in the right half of midbrain and pons and in the superior part of the right cerebellar hemisphere. Digital subtraction angiography showed right transverse and sigmoid sinus occlusion. The authors suggest that one should investigate the possibility of venous infarction in the presence of posterior fossa lesions that are often hemorrhagic and are not within any arterial territory distribution but respect a known venous drainage pattern. Recognition of the observed clinical and neuroimaging features can lead to earlier diagnosis and, potentially, more effective management.