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Stroke Incidence by Major Pathological Type and Ischemic Subtypes in the Auckland Regional Community Stroke Studies [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—Major pathological stroke types (ischemic stroke [IS], primary intracerebral hemorrhage [ICH], and subarachnoid hemorrhage) and IS subtypes, have differing risk factors, management, and prognosis. We report changes in major stroke types and IS subtypes incidence during 10 years using data from the ARCOS (Auckland Regional Community Stroke Study) III performed during 12 months in 2002 to 2003 and the fourth ARCOS study (ARCOS-IV) performed in 2011 to 2012.Methods—ARCOS-III and ARCOS-IV were population-based registers of all new strokes in the greater Auckland region (population aged >15 years, 1 119 192). Strokes were classified into major pathological types (IS, ICH, subarachnoid hemorrhage, and undetermined type). Crude annual age-, sex-, and ethnic-specific stroke incidence with 95% confidence intervals was calculated. ISs were subclassified using TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria into 5 etiologic groups. Rate ratios with 95% confidence intervals were calculated for differences in age-standardized rates between the 2 studies.Results—In ARCOS-IV, there were 1329 (81%) ISs, 211 (13%) ICHs, 79 (5%) subarachnoid hemorrhages, and 24 (1%) undetermined type strokes. The proportional distribution of IS subtypes was 29% cardioembolism, 21% small-vessel occlusion, 15% large-artery atherosclerosis, 5% other determined etiology, and 31% undetermined type. Between 2002 and 2011, age-standardized incidence decreased for subarachnoid hemorrhage (rate ratios, 0.73; 95% confidence intervals, 0.54–0.99) and undetermined type (rate ratios, 0.14; 95% confidence intervals, 0.09–0.22). Rates were stable for IS and ICH. Among IS subtypes, large-artery atherosclerosis and small-vessel occlusion rates increased significantly. The frequency of all risk factors increased in IS. Ethnic differences were observed for both stroke subtype rates and their risk factor frequencies.Conclusions—A lack of change in IS and ICH incidence may reflect a trend toward increased incidence of younger strokes. Increased rates of large-artery atherosclerosis and small-vessel occlusion are associated with increased smoking and high blood pressure. Ethnic differences in the proportional distribution of pathological stroke subtypes suggest differential exposure and susceptibility to risk factors.






Getting the First Grant [InterSECT]

2017-12-22T10:40:44-08:00







Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—Moyamoya disease (MMD) is a rare cerebral vasculopathy characterized by bilateral internal carotid artery stenosis and often leads to stroke in children or young adults. Although familial inheritance is well recognized, the genetic basis of MMD remains poorly understood.Methods—A 2-stage genome-wide association study was conducted involving 1492 cases and 5084 controls. In the discovery stage, logistic regression was used to test associations, and imputation was conducted based on genotyped single-nucleotide polymorphisms (SNPs). In the validation stage, the top significant SNPs were again genotyped in an independent cohort. Fixed-effects inverse variance-weighted meta-analysis was used in the combined discovery and validation samples. Furthermore, association analysis was conducted in subgroups using patient clinical data.Results—The study identified 10 novel risk loci with genome-wide significance (P<5×10−8) and confirmed a previously reported locus on 17q25. No significant SNP showed evidence of heterogeneity between the 2 stages. Cumulatively, these SNPs explained 14.76% of disease risk variance—a substantial proportion of the 39.02% of risk variance explained by all genome-wide genotyped SNPs. One SNP, rs9916351 in RNF213 (Pcombined=4.57×10−54; odds ratio, 1.96), showed a stronger genetic effect on early-onset than late-onset MMD (P=0.003). Two novel SNPs in genes regulating homocysteine metabolism, rs9651118 in MTHFR (Pcombined=2.49×10−19; odds ratio, 0.65) and rs117353193 in TCN2 (Pcombined=6.15×10−13; odds ratio, 1.43), were associated with high-serum homocysteine in MMD cases. Additionally, another SNP associated with MMD (rs2107595 in HDAC9; Pcombined=1.49×10−29; odds ratio, 1.64) was previously implicated in large-vessel disease. Tissue enrichment analysis showed that the genes of associated loci were highly expressed in the immune system (false discovery rate, <0.05).Conclusions—This study identifies several novel susceptibility genes for MMD. The association with homocysteine metabolism and the immune system enrichment of susceptibility gene expression suggest that therapeutic interventions targeting these pathways may be effective approaches for MMD treatment.


















Arsenic Exposure in Relation to Ischemic Stroke [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—The purpose of this case–cohort study was to examine urinary arsenic levels in relation to incident ischemic stroke in the United States.Methods—We performed a case–cohort study nested within the REGARDS (REasons for Geographic and Racial Differences in Stroke) cohort. A subcohort (n=2486) of controls was randomly sampled within region–race–sex strata while all incident ischemic stroke cases from the full REGARDS cohort (n=671) were included. Baseline urinary arsenic was measured by inductively coupled plasma-mass spectrometry. Arsenic species, including urinary inorganic arsenic and its metabolites monomethylarsonic acid and dimethylarsinic acid, were measured in a random subset (n=199). Weighted Cox’s proportional hazards models were used to calculate hazard ratios and 95% confidence intervals of ischemic stroke by arsenic and its species.Results—The average follow-up was 6.7 years. Although incident ischemic stroke showed no association with total arsenic or total inorganic arsenic, for each unit higher level of urinary monomethylarsonic acid on a log-scale, after adjustment for potential confounders, ischemic stroke risk increased ≈2-fold (hazard ratio=1.98; 95% confidence interval: 1.12–3.50). Effect modification by age, race, sex, or geographic region was not evident.Conclusions—A metabolite of arsenic was positively associated with incident ischemic stroke in this case–cohort study of the US general population, a low-to-moderate exposure area. Overall, these findings suggest a potential role for arsenic methylation in the pathogenesis of stroke, having important implications for future cerebrovascular research.





















Prospective Study of Fasting Blood Glucose and Intracerebral Hemorrhagic Risk [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—Although diabetes mellitus is an established independent risk factor for ischemic stroke, the association between fasting blood glucose and intracerebral hemorrhage (ICH) is limited and inconsistent. The objective of the current study was to examine the potential impact of long-term fasting blood glucose concentration on subsequent risk of ICH.Methods—This prospective study included 96 110 participants of the Kailuan study, living in Kailuan community, Tangshan city, China, who were free of cardiovascular diseases and cancer at baseline (2006). Fasting blood glucose concentration was measured in 2006, 2008, 2010, and 2012. Updated cumulative average fasting blood glucose concentration was used as primary exposure of the current study. Incident ICH from 2006 to 2015 was confirmed by review of medical records.Results—During 817 531 person-years of follow-up, we identified 755 incident ICH cases. The nadir risk of ICH was observed at fasting blood glucose concentration of 5.3 mmol/L. The adjusted hazard ratios and their 95% confidence intervals (CIs) of ICH were 1.59 (95% CI, 1.26–2.02) for diabetes mellitus or fasting blood glucose ≥7.00 mmol/L, 1.31 (95% CI, 1.02–1.69) for impaired fasting blood glucose (fasting blood glucose, 6.10–6.99 mmol/L), 0.98 (95% CI, 0.78–1.22) for fasting blood glucose 5.60 to 6.09 mmol/L, and 2.04 (95% CI, 1.23–3.38) for hypoglycemia (fasting blood glucose, <4.00 mmol/L), comparing with normal fasting blood glucose 4.00 to 5.59 mmol/L. The results persisted after excluding individuals who used hypoglycemic, aspirin, antihypertensive agents, or anticoagulants, and those with intracerebral hemorrhagic cases occurred in the first 2 years of follow-up.Conclusions—In this large community-based cohort, low (<4.0 mmol/L) and high (≥6.1 mmol/L) fasting blood glucose concentrations were associated with higher risk of incident ICH, relative to fasting blood glucose concentrations of 4.00 to 6.09 mmol/L.



Antihyperglycemic Agents Are Inversely Associated With Intracranial Aneurysm Rupture [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—Previous studies have suggested a protective effect of diabetes mellitus on aneurysmal subarachnoid hemorrhage risk. However, reports are inconsistent, and objective measures of hyperglycemia in these studies are lacking. Our aim was to investigate the association between aneurysmal subarachnoid hemorrhage and antihyperglycemic agent use and glycated hemoglobin levels.Methods—The medical records of 4701 patients with 6411 intracranial aneurysms, including 1201 prospective patients, diagnosed at the Massachusetts General Hospital and Brigham and Women’s Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariate and multivariate logistic regression analyses were performed to determine the association between aneurysmal subarachnoid hemorrhage and antihyperglycemic agents and glycated hemoglobin levels. Propensity score weighting was used to account for selection bias.Results—In both unweighted and weighted multivariate analysis, antihyperglycemic agent use was inversely and significantly associated with ruptured aneurysms (unweighted odds ratio, 0.58; 95% confidence interval, 0.39–0.87; weighted odds ratio, 0.57; 95% confidence interval, 0.34–0.96). In contrast, glycated hemoglobin levels were not significantly associated with rupture status.Conclusions—Antihyperglycemic agent use rather than hyperglycemia is associated with decreased risk of aneurysmal subarachnoid hemorrhage, suggesting a possible protective effect of glucose-lowering agents in the pathogenesis of aneurysm rupture.



Cognitive Impairment Before Intracerebral Hemorrhage Is Associated With Cerebral Amyloid Angiopathy [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—Although the association between cerebral amyloid angiopathy (CAA) and cognitive impairment is increasingly recognized, it is not clear whether this is because of the impact of recurrent intracerebral hemorrhage (ICH) events, disruptions caused by cerebral small vessel damage, or both. We investigated this by considering whether cognitive impairment before ICH was associated with neuroimaging features of CAA on magnetic resonance imaging.Methods—We studied 166 patients with neuroimaging-confirmed ICH recruited to a prospective multicentre observational study. Preexisting cognitive impairment was determined using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Magnetic resonance imaging markers of cerebral small vessel disease, including CAA, were rated by trained observers according to consensus guidelines.Results—The prevalence of cognitive impairment before ICH was 24.7% (n=41) and, in adjusted analyses, was associated with fulfilling the modified Boston criteria for probable CAA at presentation (odds ratio, 4.01; 95% confidence interval, 1.53–10.51; P=0.005) and a higher composite CAA score (for each point increase, odds ratio, 1.42; 95% confidence interval, 1.03–1.97; P=0.033). We also found independent associations between pre-ICH cognitive decline and the presence of cortical superficial siderosis, strictly lobar microbleeds, and lobar ICH location, but not with other neuroimaging markers, or a composite small vessel disease score.Conclusions—CAA (defined using magnetic resonance imaging markers) is associated with cognitive decline before symptomatic ICH. This provides evidence that small vessel disruption in CAA makes an independent contribution to cognitive impairment, in addition to effects due to brain injury caused directly by ICH.Clinical Trial Registration—URL: https://www.clinicaltrials.gov. Unique identifier: NCT02513316.



Predictive Value of Pulse Pressure in Acute Ischemic Stroke for Future Major Vascular Events [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—This study aimed to investigate whether pulse pressure (PP) obtained during the acute stage of ischemic stroke can be used as a predictor for future major vascular events.Methods—Using a multicenter prospective stroke registry database, patients who were hospitalized for ischemic stroke within 48 hours of onset were enrolled in this study. We analyzed blood pressure (BP) data measured during the first 3 days from onset. Primary and secondary outcomes were time to a composite of stroke recurrence, myocardial infarction, all-cause death, and time to stroke recurrence, respectively.Results—Of 9840 patients, 4.3% experienced stroke recurrence, 0.2% myocardial infarction, and 7.3% death during a 1-year follow-up period. In Cox proportional hazards models including both linear and quadratic terms of PP, PP had a nonlinear J-shaped relationship with primary (for a quadratic term of PP, P=0.004) and secondary (P<0.001) outcomes. The overall effects of PP and other BP parameters on primary and secondary outcomes were also significant (P<0.05). When predictive power of BP parameters was compared using a statistic of −2 log-likelihood differences, PP was a stronger predictor than systolic BP (8.49 versus 5.91; 6.32 versus 4.56), diastolic BP (11.42 versus 11.05; 10.07 versus 4.56), and mean atrial pressure (8.75 versus 5.91; 7.03 versus 4.56) for the primary and secondary outcomes, respectively.Conclusions—Our study shows that PP when measured in the acute period of ischemic stroke has nonlinear J-shaped relationships with major vascular events and stroke recurrence, and may have a stronger predictive power than other commonly used BP parameters.



Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated With Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—A variant in the histone deacetylase 9 (HDAC9) gene is associated with large artery stroke. Therefore, inhibiting HDAC9 might offer a novel secondary preventative treatment for ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate.Methods—Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack and long-term follow-up: the South London Stroke Register, The Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received antiepileptic drugs other than SVA using survival analysis and Cox Regression.Results—A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis P=0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3–0.7; P=0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29–0.77; P=0.003).Conclusions—These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke.



Prognostic Significance of Blood Pressure Variability on Beat-to-Beat Monitoring After Transient Ischemic Attack and Stroke [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—Visit-to-visit and day-to-day blood pressure (BP) variability (BPV) predict an increased risk of cardiovascular events but only reflect 1 form of BPV. Beat-to-beat BPV can be rapidly assessed and might also be predictive.Methods—In consecutive patients within 6 weeks of transient ischemic attack or nondisabling stroke (Oxford Vascular Study), BPV (coefficient of variation) was measured beat-to-beat for 5 minutes (Finometer), day-to-day for 1 week on home monitoring (3 readings, 3× daily), and on awake ambulatory BP monitoring. BPV after 1-month standard treatment was related (Cox proportional hazards) to recurrent stroke and cardiovascular events for 2 to 5 years, adjusted for mean systolic BP.Results—Among 520 patients, 26 had inadequate beat-to-beat recordings, and 22 patients were in atrial fibrillation. Four hundred five patients had all forms of monitoring. Beat-to-beat BPV predicted recurrent stroke and cardiovascular events independently of mean systolic BP (hazard ratio per group SD, stroke: 1.47 [1.12–1.91]; P=0.005; cardiovascular events: 1.41 [1.08–1.83]; P=0.01), including after adjustment for age and sex (stroke: 1.47 [1.12–1.92]; P=0.005) and all risk factors (1.40 [1.00–1.94]; P=0.047). Day-to-day BPV was less strongly associated with stroke (adjusted hazard ratio, 1.29 [0.97–1.71]; P=0.08) but similarly with cardiovascular events (1.41 [1.09–1.83]; P=0.009). BPV on awake ambulatory BP monitoring was nonpredictive (stroke: 0.89 [0.59–1.35]; P=0.59; cardiovascular events: 1.08 [0.77–1.52]; P=0.65). Despite a weak correlation (r=0.119; P=0.02), beat-to-beat BPV was associated with risk of recurrent stroke independently of day-to-day BPV (1.41 [1.05–1.90]; P=0.02).Conclusions—Beat-to-beat BPV predicted recurrent stroke and cardiovascular events, independently of mean systolic BP and risk factors but short-term BPV on ambulatory BP monitoring did not. Beat-to-beat BPV may be a useful additional marker of cardiovascular risk.



Factors Associated With Focal Computed Tomographic Perfusion Abnormalities in Supratentorial Transient Ischemic Attacks [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—Computed tomographic perfusion (CTP) is useful in diagnosis of patients with transient focal neurological symptoms. In acute imaging of patients with a suspected transient ischemic attack (TIA), it remains unclear which patients develop focal perfusion abnormalities (FPA), that is, hypoperfusion or hyperperfusion. We aimed at determining independent factors associated with FPA in patients with supratentorial TIAs.Methods—We prospectively collected consecutive patients with supratentorial TIAs defined by the traditional time-based definition who underwent CTP within 24 hours of symptom onset. We recorded demographics, risk factors, clinical features, severity, and timing from onset. We documented the Age, Blood Pressure, Clinical Features, Duration, and Diabetes (ABCD2) scores, vascular territories, and presence of relevant arterial pathology. Variables were tested for an association with FPA with univariate and multivariate analyses.Results—A hundred and ten of 265 patients (42%) with supratentorial TIAs had FPA on CTP. Acute noncontrast computed tomography showed early ischemic lesions in 6%, and acute/subacute magnetic resonance imaging was pathological in 52 of the 109 cases (47.7%) where it was performed. Clinical factors associated with FPA were high-admission National Institutes of Health Stroke Scale (odds ratio [OR], 1.22), right hemispheric TIA (OR, 3.09), and cardioembolic mechanism (OR, 2.19). Persistence of symptoms during CTP (OR, 2.59), shorter duration of TIA (OR, 0.93), major intracranial arterial pathology (OR, 12.5), and extracranial arterial occlusion (OR, 7.44) were also associated with FPA.Conclusions—Supratentorial TIAs are often associated with FPA in CTP, even after symptom resolution. FPAs are frequent in severe TIAs and those associated with cardioembolism or specific arterial pathologies. These findings can help clinicians in accurate diagnosis of TIA and its underlying mechanisms.



Induced Hypertension for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—Induced hypertension is widely used to treat delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage, but a literature review shows that its presumed effectiveness is based on uncontrolled case-series only. We here report clinical outcome of aneurysmal subarachnoid hemorrhage patients with DCI included in a randomized trial on the effectiveness of induced hypertension.Methods—Aneurysmal subarachnoid hemorrhage patients with clinical symptoms of DCI were randomized to induced hypertension or no induced hypertension. Risk ratios for poor outcome (modified Rankin Scale score >3) at 3 months, with 95% confidence intervals, were calculated and adjusted for age, clinical condition at admission and at time of DCI, and amount of blood on initial computed tomographic scan with Poisson regression analysis.Results—The trial aiming to include 240 patients was ended, based on lack of effect on cerebral perfusion and slow recruitment, when 21 patients had been randomized to induced hypertension, and 20 patients to no hypertension. With induced hypertension, the adjusted risk ratio for poor outcome was 1.0 (95% confidence interval, 0.6–1.8) and the risk ratio for serious adverse events 2.1 (95% confidence interval, 0.9–5.0).Conclusions—Before this trial, the effectiveness of induced hypertension for DCI in aneurysmal subarachnoid hemorrhage patients was unknown because current literature consists only of uncontrolled case series. The results from our premature halted trial do not add any evidence to support induced hypertension and show that this treatment can lead to serious adverse events.Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01613235.



Challenge and Yield of Enrolling Racially and Ethnically Diverse Patient Populations in Low Event Rate Clinical Trials [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—We report patient enrollment and retention by race and ethnicity in the CREST (Carotid Revascularization Endarterectomy Versus Stent Trial) and assess potential effect modification by race/ethnicity. In addition, we discuss the challenge of detecting differences in study outcomes when subgroups are small and the event rate is low.Methods—We compared 2502 patients by race, ethnicity, baseline characteristics, and primary outcome (any periprocedural stroke, death, or myocardial infarction and subsequent ipsilateral stroke up to 10 years).Results—Two hundred forty (9.7%) patients were minority by race (6.1%) or ethnicity (3.6%); 109 patients (4.4%) were black, 32 (1.3%) Asian, 2332 (93.4%) white, 11 (0.4%) other, and 18 (0.7%) unknown. Ninety (3.6%) were Hispanic, 2377 (95%) non-Hispanic, and 35 (1.4%) unknown. The rate of the primary end point for all patients was 10.9%±0.9% at 10 years and did not differ by race or ethnicity (Pinter>0.24).Conclusions—The proportion of minorities recruited to CREST was below their representation in the general population, and retention of minority patients was lower than for whites. Primary outcomes did not differ by race or ethnicity. However, in CREST (like other studies), the lack of evidence of a racial/ethnic difference in the treatment effect should be interpreted with caution because of low statistical power to detect such a difference.Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732.



Visual Aids for Patient, Family, and Physician Decision Making About Endovascular Thrombectomy for Acute Ischemic Stroke [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—Rapid decision making optimizes outcomes from endovascular thrombectomy for acute cerebral ischemia. Visual displays facilitate swift review of potential outcomes and can accelerate decision processes.Methods—From patient-level, pooled randomized trial data, 100 person-icon arrays (Kuiper–Marshall personographs) were generated showing beneficial and adverse effects of endovascular thrombectomy for patients with acute cerebral ischemia and large vessel occlusion using (1) automated (algorithmic) and (2) expert-guided joint outcome table specification.Results—For the full 7-category modified Rankin Scale, thrombectomy added to IV tPA (intravenous tissue-type plasminogen activator) alone had number needed to treat to benefit 2.9 (95% confidence interval, 2.6–3.3) and number needed to harm 68.9 (95% confidence interval, 40–250); thrombectomy for patients ineligible for IV tPA had number needed to treat to benefit 2.3 (95% confidence interval, 2.1–2.5) and number needed to harm 100 (95% confidence interval, 62.5–250). Visual displays of treatment effects on 100 patients showed: with thrombectomy added to IV tPA alone, 34 patients have better disability outcome, including 14 more normal or near normal (modified Rankin Scale, 0–1); with thrombectomy for patients ineligible for IV tPA, 44 patients have a better disability outcome, including 16 more normal or nearly normal. Displays also showed that harm (increased modified Rankin Scale final disability) occurred in 1 of 100 patients in both populations, mediated by increased new territory infarcts. The person-icon figures integrated these outcomes, and early side-effects, in a single display.Conclusions—Visual decision aids are now available to rapidly educate healthcare providers, patients, and families about benefits and risks of endovascular thrombectomy, both when added to IV tPA in tPA-eligible patients and as the sole reperfusion treatment in tPA-ineligible patients.



Real-World Use of Apixaban for Stroke Prevention in Atrial Fibrillation [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—The use of oral anticoagulant therapy for stroke prevention in atrial fibrillation has been transformed by the availability of the nonvitamin K antagonist oral anticoagulants. Real-world studies on the use of nonvitamin K antagonist oral anticoagulants would help elucidate their effectiveness and safety in daily clinical practice. Apixaban was the third nonvitamin K antagonist oral anticoagulants introduced to clinical practice, and increasing real-world studies have been published. Our aim was to summarize current evidence about real-world studies on apixaban for stroke prevention in atrial fibrillation.Methods—We performed a systematic review and meta-analysis of all observational real-world studies comparing apixaban with other available oral anticoagulant drugs.Results—From the original 9680 results retrieved, 16 studies have been included in the final meta-analysis. Compared with warfarin, apixaban regular dose was more effective in reducing any thromboembolic event (odds ratio: 0.77; 95% confidence interval: 0.64–0.93), but no significant difference was found for stroke risk. Apixaban was as effective as dabigatran and rivaroxaban in reducing thromboembolic events and stroke. The risk of major bleeding was significantly lower for apixaban compared with warfarin, dabigatran, and rivaroxaban (relative risk reduction, 38%, 35%, and 46%, respectively). Similarly, the risk for intracranial hemorrhage was significantly lower for apixaban than warfarin and rivaroxaban (46% and 54%, respectively) but not dabigatran. The risk of gastrointestinal bleeding was lower with apixaban when compared with all oral anticoagulant agents (P<0.00001 for all comparisons).Conclusions—Use of apixaban in real-life is associated with an overall similar effectiveness in reducing stroke and any thromboembolic events when compared with warfarin. A better safety profile was found with apixaban compared with warfarin, dabigatran, and rivaroxaban.



Long-Term Effect of Pravastatin on Carotid Intima-Media Complex Thickness [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—The effect of statins on progression of carotid intima–media complex thickness (IMT) has been shown exclusively in nonstroke Western patients. This study aimed to determine the effect of low-dose pravastatin on carotid IMT in Japanese patients with noncardioembolic ischemic stroke.Methods—This is a substudy of the J-STARS trial (Japan Statin Treatment Against Recurrent Stroke), a multicenter, randomized, open-label, parallel-group trial to examine whether pravastatin reduces stroke recurrence. Patients were randomized to receive pravastatin (10 mg daily, usual dose in Japan; pravastatin group) or not to receive any statins (control group). The primary outcome was IMT change of the common carotid artery for a 5-year observation period. IMT change was compared using mixed-effects models for repeated measures.Results—Of 864 patients registered in this substudy, 71 without baseline ultrasonography were excluded, and 388 were randomly assigned to the pravastatin group and 405 to the control group. Baseline characteristics were not significantly different, except National Institutes of Health Stroke Scale scores (median, 0 [interquartile range, 0–2] versus 1 [interquartile range, 0–2]; P=0.019) between the 2 groups. Baseline IMT (mean±SD) was 0.887±0.155 mm in the pravastatin group and 0.887±0.152 mm in the control group (P=0.99). The annual change in the IMT at 5-year visit was significantly reduced in the pravastatin group as compared with that in the control group (0.021±0.116 versus 0.040±0.118 mm; P=0.010).Conclusions—The usual Japanese dose of pravastatin significantly reduced the progression of carotid IMT at 5 years in patients with noncardioembolic stroke.Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00361530.



Effect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive Men [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—We aimed to examine whether the efficacy of folic acid therapy in the primary prevention of stroke is jointly affected by smoking status and baseline folate levels in a male population in a post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial).Methods—Eligible participants of the CSPPT were randomly assigned to a double-blind daily treatment of a combined enalapril 10-mg and folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone. In total, 8384 male participants of the CSPPT were included in the current analyses. The primary outcome was first stroke.Results—The median treatment duration was 4.5 years. In the enalapril-alone group, the first stroke risk varied by baseline folate levels and smoking status (never versus ever). Specifically, there was an inverse association between folate levels and first stroke in never smokers (P for linear trend=0.043). However, no such association was found in ever smokers. A test for interaction between baseline folate levels and smoking status on first stroke was significant (P=0.045). In the total sample, folic acid therapy significantly reduced the risk of first stroke in never smokers with folate deficiency (hazard risk, 0.36; 95% confidence interval, 0.16–0.83) and in ever smokers with normal folate levels (hazard risk, 0.69; 95% confidence interval, 0.48–0.99).Conclusions—Baseline folate levels and smoking status can interactively affect the risk of first stroke. Our data suggest that compared with never smokers, ever smokers may require a higher dosage of folic acid to achieve a greater beneficial effect on stroke. Our findings need to be confirmed by future randomized trials.Clinical Trial Registration—URL: https://www.clinicaltrials.gov. Unique identifier: NCT00794885.



Early Elevated Troponin Levels After Ischemic Stroke Suggests a Cardioembolic Source [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—Elevated cardiac troponin is a marker of cardiac disease and has been recently shown to be associated with embolic stroke risk. We hypothesize that early elevated troponin levels in the acute stroke setting are more prevalent in patients with embolic stroke subtypes (cardioembolic and embolic stroke of unknown source) as opposed to noncardioembolic subtypes (large-vessel disease, small-vessel disease, and other).Methods—We abstracted data from our prospective ischemic stroke database and included all patients with ischemic stroke during an 18-month period. Per our laboratory, we defined positive troponin as ≥0.1 ng/mL and intermediate as ≥0.06 ng/mL and <0.1 ng/mL. Unadjusted and adjusted regression models were built to determine the association between stroke subtype (embolic stroke of unknown source and cardioembolic subtypes) and positive and intermediate troponin levels, adjusting for key confounders, including demographics (age and sex), clinical characteristics (hypertension, hyperlipidemia, diabetes mellitus, renal function, coronary heart disease, congestive heart failure, current smoking, and National Institutes of Health Stroke Scale score), cardiac variables (left atrial diameter, wall-motion abnormalities, ejection fraction, and PR interval on ECG), and insular involvement of infarct.Results—We identified 1234 patients, of whom 1129 had admission troponin levels available; 10.0% (113/1129) of these had a positive troponin. In fully adjusted models, there was an association between troponin positivity and embolic stroke of unknown source subtype (adjusted odds ratio, 4.46; 95% confidence interval, 1.03–7.97; P=0.003) and cardioembolic stroke subtype (odds ratio, 5.00; 95% confidence interval, 1.83–13.63; P=0.002).Conclusions—We found that early positive troponin after ischemic stroke may be independently associated with a cardiac embolic source. Future studies are needed to confirm our findings using high-sensitivity troponin assays and to test optimal secondary prevention strategies in patients with embolic stroke of unknown source and positive troponin.



Transoceanic Management and Treatment of Aneurysmal Subarachnoid Hemorrhage [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—Because of the small number of yearly cases of ruptured cerebral aneurysms, endovascular treatment is not performed in Martinique. Therefore, patients from Martinique are sent 7000 km to Paris on commercial flights as soon as possible, where treatment is performed. Nontransportable patients are treated locally with either surgery or symptomatic care. The objective of our study was to assess patient outcomes and safety of this treatment strategy.Methods—We retrospectively examined all cases of aneurysmal subarachnoid hemorrhage in Martinique diagnosed during 2004 to 2013. Medical case records were searched for the type and location of treatment, clinical status, and transfer duration.Results—A total of 119 patients had an aneurysmal subarachnoid hemorrhage during the 10-year period. Of these, 91 were transferred to Paris, 12 were surgically treated locally, and 16 received symptomatic treatment. None of the transferred patients experienced any hemorrhagic recurrence, and none suffered a significant complication related to the air transportation. The median time between aneurysmal subarachnoid hemorrhage diagnosis and arrival at the referral center was 32 hours. The 30-day case fatality rate for treated cases was 14.6% (8.8% for those treated in Paris and 58.3% for those treated locally).Conclusions—Our treatment strategy for aneurysmal subarachnoid hemorrhage resulted in a 30-day case fatality rate similar to those observed elsewhere, despite an 8-hour flight and a median treatment delay of 32 hours. This strategy therefore seems to be safe and reliable for isolated regions with small populations.



Novel Telestroke Program Improves Thrombolysis for Acute Stroke Across 21 Hospitals of an Integrated Healthcare System [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—Faster treatment with intravenous alteplase in acute ischemic stroke is associated with better outcomes. Starting in 2015, Kaiser Permanente Northern California redesigned its acute stroke workflow across all 21 Kaiser Permanente Northern California stroke centers to (1) follow a single standardized version of a modified Helsinki model and (2) have all emergency stroke cases managed by a dedicated telestroke neurologist. We examined the effect of Kaiser Permanente Northern California’s Stroke EXpediting the PRrocess of Evaluating and Stopping Stroke program on door-to-needle (DTN) time, alteplase use, and symptomatic intracranial hemorrhage rates.Methods—The program was introduced in a staggered fashion from September 2015 to January 2016. We compared DTN times for a seasonally adjusted 9-month period at each center before implementation to the corresponding 9-month calendar period from the start of implementation. The primary outcome was the DTN time for alteplase administration. Secondary outcomes included rate of alteplase administrations per month, symptomatic intracranial hemorrhage, and disposition at time of discharge.Results—This study included 310 patients treated with alteplase in the pre–EXpediting the PRrocess of Evaluating and Stopping Stroke period and 557 patients treated with alteplase in the EXpediting the PRrocess of Evaluating and Stopping Stroke period. After implementation, alteplase administrations increased to 62/mo from 34/mo at baseline (P<0.001). Median DTN time decreased to 34 minutes after implementation from 53.5 minutes prior (P<0.001), and DTN time of <60 minutes was achieved in 87.1% versus 61.0% (P<0.001) of patients. DTN times <30 minutes were much more common in the Stroke EXpediting the PRrocess of Evaluating and Stopping Stroke period (40.8% versus 4.2% before implementation). There was no significant difference in symptomatic intracranial hemorrhage rates in the 2 periods (3.8% versus 2.2% before implementation; P=0.29).Conclusions—Introduction of a standardized modified Helsinki protocol across 21 hospitals using telestroke management was associated with increased alteplase administrations, significantly shorter DTN times, and no increase in adverse outcomes.



Determinants of Informal Care, Burden, and Risk of Burnout in Caregivers of Stroke Survivors [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—The aim of this article was to analyze the likelihood of receiving informal care after a stroke and to study the burden and risk of burnout of primary caregivers in Spain.Methods—The CONOCES study is an epidemiological, observational, prospective, multicenter study of patients diagnosed with stroke and admitted to a Stroke Unit in the Spanish healthcare system. At 3 and 12 months post-event, we estimated the time spent caring for the patient and the burden borne by primary caregivers. Several multivariate models were applied to estimate the likelihood of receiving informal caregiving, the burden, and the likelihood of caregivers being at a high risk of burnout.Results—Eighty percent of those still alive at 3 and 12 months poststroke were receiving informal care. More than 40% of those receiving care needed a secondary caregiver at 3 months poststroke. The likelihood of receiving informal care was associated with stroke severity and the individual’s health-related quality of life. When informal care was provided, both the burden borne by caregivers and the likelihood of caregivers being at a high risk of burnout was associated with (1) caregiving hours; (2) the patient’s health-related quality of life; (3) the severity of the stroke measured at discharge; (4) the patient having atrial fibrillation; and (5) the degree of dependence.Conclusions—This study reveals the heavy burden borne by the caregivers of stroke survivors. Our analysis also identifies explanatory and predictive variables for the likelihood of receiving informal care, caregiver burden, and high risk of burnout.



PROMIS GH (Patient-Reported Outcomes Measurement Information System Global Health) Scale in Stroke [Clinical Sciences]

2017-12-22T10:40:43-08:00

Background and Purpose—The International Consortium for Health Outcomes Measurement recently included the 10-item PROMIS GH (Patient-Reported Outcomes Measurement Information System Global Health) scale as part of their recommended Standard Set of Stroke Outcome Measures. Before collection of PROMIS GH is broadly implemented, it is necessary to assess its performance in the stroke population. The objective of this study was to evaluate the psychometric properties of PROMIS GH in patients with ischemic stroke and intracerebral hemorrhage.Methods—PROMIS GH and 6 PROMIS domain scales measuring same/similar constructs were electronically collected on 1102 patients with ischemic and hemorrhagic strokes at various stages of recovery from their stroke who were seen in a cerebrovascular clinic from October 12, 2015, through June 2, 2017. Confirmatory factor analysis was performed to evaluate the adequacy of 2-factor structure of component scores. Test–retest reliability and convergent validity of PROMIS GH items and component scores were assessed. Discriminant validity and responsiveness were compared between PROMIS GH and PROMIS domain scales measuring the same or related constructs. Analyses were repeated stratified by stroke subtype and modified Rankin Scale score <2 versus ≥2.Results—There was moderate internal reliability (ordinal α, 0.82–0.88) and marginal model fit for the 2-factor solution for component scores (root mean square error of approximation, 0.11). Convergent validity was good with significant correlations between all PROMIS GH items and PROMIS domain scales (P<0.001 for all). There was excellent discrimination for all PROMIS GH items and component scores across modified Rankin Scale levels. Good responsiveness (effect size, >0.5) was demonstrated for 8 of the 10 PROMIS GH items. Reliability and validity remained consistent across stroke subtype and disability level (modified Rankin Scale, <2 versus ≥2).Conclusions—PROMIS GH exhibits acceptable performance in patients with stroke. Our findings support International Consortium for Health Outcomes Measurement recommendation to use PROMIS GH as part of the standard set of outcome measures in stroke.



IL-23 (Interleukin-23)-Producing Conventional Dendritic Cells Control the Detrimental IL-17 (Interleukin-17) Response in Stroke [Basic Sciences]

2017-12-22T10:40:44-08:00

Background and Purpose—Inflammatory mechanisms can exacerbate ischemic tissue damage and worsen clinical outcome in patients with stroke. Both αβ and γδ T cells are established mediators of tissue damage in stroke, and the role of dendritic cells (DCs) in inducing the early events of T cell activation and differentiation in stroke is not well understood.Methods—In a murine model of experimental stroke, we defined the immune phenotype of infiltrating DC subsets based on flow cytometry of surface markers, the expression of ontogenetic markers, and cytokine levels. We used conditional DC depletion, bone marrow chimeric mice, and IL-23 (interleukin-23) receptor-deficient mice to further explore the functional role of DCs.Results—We show that the ischemic brain was rapidly infiltrated by IRF4+/CD172a+ conventional type 2 DCs and that conventional type 2 DCs were the most abundant subset in comparison with all other DC subsets. Twenty-four hours after ischemia onset, conventional type 2 DCs became the major source of IL-23, promoting neutrophil infiltration by induction of IL-17 (interleukin-17) in γδ T cells. Functionally, the depletion of CD11c+ cells or the genetic disruption of the IL-23 signaling abrogated both IL-17 production in γδ T cells and neutrophil infiltration. Interruption of the IL-23/IL-17 cascade decreased infarct size and improved neurological outcome after stroke.Conclusions—Our results suggest a central role for interferon regulatory factor 4-positive IL-23–producing conventional DCs in the IL-17–dependent secondary tissue damage in stroke.



Astrocytic Lrp4 (Low-Density Lipoprotein Receptor-Related Protein 4) Contributes to Ischemia-Induced Brain Inȷury by Regulating ATP Release and Adenosine-A2AR (Adenosine A2A Receptor) Signaling [Basic Sciences]

2017-12-22T10:40:44-08:00

Background and Purpose—Lrp4 (low-density lipoprotein receptor–related protein 4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here, we investigated Lrp4’s function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis.Methods—The brain-specific Lrp4 conditional knockout mice (Lrp4GFAP-Cre), astrocytic-specific Lrp4 conditional knockout mice (Lrp4GFAP-creER), and their control mice (Lrp4f/f) were subjected to photothrombotic ischemia and the transient middle cerebral artery occlusion. After ischemia/stroke, mice or their brain samples were subjected to behavior tests, brain histology, immunofluorescence staining, Western blot, and quantitative real-time polymerase chain reaction. In addition, primary astrocytes and neurons were cocultured with or without oxygen and glucose deprivation and in the presence or absence of the antagonist for adenosine-A2AR (adenosine A2A receptor) or ATP-P2X7R (P2X purinoceptor 7) signaling. Gliotransmitters, such as glutamate, d-serine, ATP, and adenosine, in the condition medium of cultured astrocytes were also measured.Results—Lrp4, largely expressed in astrocytes, was increased in response to ischemia/stroke. Both Lrp4GFAP-Cre and Lrp4GFAP-creER mice showed less brain injury, including reduced neuronal death, and impaired reactive astrogliosis. Mechanistically, Lrp4 conditional knockout in astrocytes increased ATP release and the production of ATP derivative, adenosine, which were further elevated by oxygen and glucose deprivation. Pharmacological inhibition of ATP-P2X7R or adenosine-A2AR signaling diminished Lrp4GFAP-creER’s protective effect.Conclusions—The astrocytic Lrp4 plays an important role in ischemic brain injury response. Lrp4 deficiency in astrocytes seems to be protective in response to ischemic brain injury, likely because of the increased ATP release and adenosine-A2AR signaling.



Dihydrolipoic Acid Inhibits Lysosomal Rupture and NLRP3 Through Lysosome-Associated Membrane Protein-1/Calcium/Calmodulin-Dependent Protein Kinase II/TAK1 Pathways After Subarachnoid Hemorrhage in Rat [Basic Sciences]

2017-12-22T10:40:44-08:00

Background and Purpose—The NLRP3 (nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a crucial component of the inflammatory response in early brain injury after subarachnoid hemorrhage (SAH). In this study, we investigated a role of dihydrolipoic acid (DHLA) in lysosomal rupture, NLRP3 activation, and determined the underlying pathway.Methods—SAH was induced by endovascular perforation in male Sprague–Dawley rats. DHLA was administered intraperitoneally 1 hour after SAH. Small interfering RNA for lysosome-associated membrane protein-1 and CaMKIIα (calcium/calmodulin-dependent protein kinase II α) was administered through intracerebroventricular 48 hours before SAH induction. SAH grade evaluation, short- and long-term neurological function testing, Western blot, and immunofluorescence staining experiments were performed.Results—DHLA treatment increased the expression of lysosome-associated membrane protein-1 and decreased phosphorylated CaMKIIα and NLRP3 inflammasome, thereby alleviating neurological deficits after SAH. Lysosome-associated membrane protein-1 small interfering RNA abolished the neuroprotective effects of DHLA and increased the level of phosphorylated CaMKIIα, p-TAK1 (phosphorylated transforming growth factor-β-activated kinase), p-JNK (phosphorylated c-Jun-N-terminal kinase), and NLRP3 inflammasome. CaMKIIα small interfering RNA downregulated the expression of p-TAK1, p-JNK, and NLRP3 and improved the neurobehavior after SAH.Conclusions—DHLA treatment improved neurofunction and alleviated inflammation through the lysosome-associated membrane protein-1/CaMKII/TAK1 pathway in early brain injury after SAH. DHLA may provide a promising treatment to alleviate early brain injury after SAH.



Selective NLRP3 (Pyrin Domain-Containing Protein 3) Inflammasome Inhibitor Reduces Brain Inȷury After Intracerebral Hemorrhage [Basic Sciences]

2017-12-22T10:40:44-08:00

Background and Purpose—Intracerebral hemorrhage (ICH) is a devastating disease without effective treatment. As a key component of the innate immune system, the NOD-like receptor (NLR) family, NLRP3 (pyrin domain–containing protein 3) inflammasome, when activated after ICH, promotes neuroinflammation and brain edema. MCC950 is a potent, selective, small-molecule NLRP3 inhibitor that blocks NLRP3 activation at nanomolar concentrations. Here, we examined the effect of MCC950 on brain injury and inflammation in 2 models of ICH in mice.Methods—In mice with ICH induced by injection of autologous blood or bacterial collagenase, we determined the therapeutic potential of MCC950 and its mechanisms of neuroprotection.Results—MCC950 reduced IL-1β (interleukin-1β) production and attenuated neurodeficits and perihematomal brain edema after ICH induction by injection of either autologous blood or collagenase. In mice with autologous blood-induced ICH, the protection of MCC950 was associated with reduced leukocyte infiltration into the brain and microglial production of IL-6. MCC950 improved blood–brain barrier integrity and diminished cell death. Notably, the protective effect of MCC950 was abolished in mice depleted of either microglia or Gr-1+ myeloid cells.Conclusions—These results indicate that the NLRP3 inflammasome inhibitor, MCC950, attenuates brain injury and inflammation after ICH. Hence, NLRP3 inflammasome inhibition is a potential therapy for ICH that warrants further investigation.



Novel Interactive Data Visualization [Brief Report]

2017-12-22T10:40:44-08:00

Background and Purpose—The ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times) randomized clinical trial collected a large diverse data set. However, it is difficult to fully understand the effects of the study on certain patient groups and disease progression. We developed and evaluated an interactive visualization of the ESCAPE trial data.Methods—We iteratively designed an interactive visualization using Python’s Bokeh software library. The design was evaluated through a user study, which quantitatively evaluated its efficiency and accuracy against traditional modified Rankin Scalegraphic. Qualitative feedback was also evaluated.Results—The novel interactive visualization of the ESCAPE data are publicly available at http://escapevisualization.herokuapp.com/. There was no difference in the efficiency and accuracy when comparing the use of the novel with the traditional visualization. However, users preferred the novel visualization because it allowed for greater exploration. Some insights obtained through exploration of the ESCAPE data are presented.Conclusions—Novel interactive visualizations can be applied to acute stroke trial data to allow for greater exploration of the results.Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01778335.



Cerebral Venous Thrombosis in Older Patients [Brief Report]

2017-12-22T10:40:44-08:00

Background and Purpose—Cerebral venous thrombosis (CVT) is rare in older patients. We investigated whether clinical features and outcomes differ in older and younger patients.Methods—We used data from a multicenter observational registry of consecutive adult patients with CVT admitted between 1987 and 2016. We compared demographics, clinical manifestations, and outcomes between older (upper quartile of the age distribution) and younger (lower 3 quartiles of the age distribution) patients.Results—Data for 843 patients with CVT were available. The median age was 43 years (interquartile range, 30–55 years). Older patients (≥55 years; n=222) were less often women than younger patients (48% versus 71%; P<0.001) and less often reported headache (63% versus 87%; P<0.001). Cancer was more common in older patients (24% versus 9%; P<0.001), especially solid malignancies (19% versus 5%; P<0.001). Outcome at follow-up was worse in older patients (modified Rankin Scale, 3–6; adjusted odds ratio, 2.68; 95% confidence interval, 1.78–4.03; mortality, adjusted odds ratio, 2.13; 95% confidence interval, 1.09–4.19).Conclusions—The sex ratio of CVT is evenly distributed in older patients, probably because of the dissipation of hormonal influences. Malignancy should be considered as a potential precipitant in older patients with CVT.



Do Intracerebral Hemorrhage Nonexpanders Actually Expand Into the Ventricular Space? [Brief Report]

2017-12-22T10:40:44-08:00

Background and Purpose—The computed tomographic angiography spot sign as a predictor of hematoma expansion is limited by its modest sensitivity and positive predictive value. It is possible that hematoma expansion in spot-positive patients is missed because of decompression of intracerebral hemorrhage (ICH) into the ventricular space. We hypothesized that revising hematoma expansion definitions to include intraventricular hemorrhage (IVH) expansion will improve the predictive performance of the spot sign. Our objectives were to determine the proportion of ICH nonexpanders who actually have IVH expansion, determine the proportion of false-positive spot signs that have IVH expansion, and compare the known predictive performance of the spot sign to a revised definition incorporating IVH expansion.Methods—We analyzed patients from the multicenter PREDICT ICH spot sign study. We defined hematoma expansion as ≥6 mL or ≥33% ICH expansion or >2 mL IVH expansion and compared spot sign performance using this revised definition with the conventional 6 mL/33% definition using receiver operating curve analysis.Results—Of 311 patients, 213 did not meet the 6-mL/33% expansion definition (nonexpanders). Only 13 of 213 (6.1%) nonexpanders had ≥2 mL IVH expansion. Of the false-positive spot signs, 4 of 40 (10%) had >2 mL ventricular expansion. The area under the curve for spot sign to predict significant ICH expansion was 0.65 (95% confidence interval, 0.58–0.72), which was no different than when IVH expansion was added to the definition (area under the curve, 0.66; 95% confidence interval, 0.58–0.71).Conclusions—Although IVH expansion does indeed occur in a minority of ICH nonexpanders, its inclusion into a revised hematoma expansion definition does not alter the predictive performance of the spot sign.



Prehospital Systolic Blood Pressure Is Related to Intracerebral Hemorrhage Volume on Admission [Brief Report]

2017-12-22T10:40:44-08:00

Background and Purpose—Ultra-early blood pressure (BP) management in the prehospital setting could improve the efficacy of this treatment on attenuating intracerebral hemorrhage (ICH) expansion. We aimed to determine the association of prehospital systolic BP (SBP) with ICH volume, ultra-early hematoma growth, and the spot sign on admission.Methods—We conducted a retrospective study of a prospective database of 219 consecutive patients with spontaneous ICH admitted to the emergency department of a tertiary stroke center during a 3-year period. Prehospital SBP and ICH volume, ultra-early hematoma growth (ICH volume/onset-to-imaging time), and presence of the spot sign on admission were prospectively recorded. Primary outcome was ICH volume on admission. Secondary outcomes included ultra-early hematoma growth and frequency of the spot sign in patients scanned within 6 hours from symptom onset (hyperacute group).Results—Prehospital SBP was positively correlated with both SBP (r=0.552; P<0.001) and ICH volume (ρ=0.189; P=0.006) on admission. Patients with ICH volume above the median value presented higher prehospital SBP (172.3±35.0 versus 163.7±27.8 mm Hg; P=0.049). This association remained significant in adjusted multiple logistic regression analysis (odds ratio, 1.01 for a 1-U increase in SBP; 95% confidence interval, 1.01–1.02; P=0.018). In the hyperacute group (n=126), prehospital SBP was unrelated to ultra-early hematoma growth (ρ=0.115; P=0.203) nor the presence of the spot sign (172.2±27.6 versus 171.8±31.6 mm Hg; P=0.959).Conclusions—Prehospital SBP is correlated with SBP on admission and independently associated with ICH volume on admission. These findings support the rationale of testing whether prehospital initiation of BP-lowering attenuates ICH expansion.



Cerebellar Hematoma Location [Brief Report]

2017-12-22T10:40:44-08:00

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.



Serum Galectin-3 and Poor Outcomes Among Patients With Acute Ischemic Stroke [Brief Report]

2017-12-22T10:40:44-08:00

Background and Purpose—Elevated galectin-3 has been associated with atherosclerosis and poor outcomes in patients with heart failure. However, it remains unclear whether galectin-3 has any effect on the poor outcomes of ischemic stroke. The aim of the present study was to examine the association between galectin-3 with poor outcomes among patients with acute ischemic stroke.Methods—Serum galectin-3 was measured in 3082 patients with acute ischemic stroke. The primary outcome was a combination of death or major disability (modified Rankin Scale score, ≥3) at 3 months after stroke.Results—Compared with the lowest quartile of galectin-3, multivariate adjusted odds ratios (95% confidence intervals) for the highest quartile of galectin-3 were 1.55 (1.15–2.09) for composite outcome, 2.10 (0.89–4.95) for death, and 1.43 (1.05–1.93) for major disability. The addition of galectin-3 to the conventional risk factors significantly improved prediction of the combined outcome of death or major disability in patients with ischemic stroke (net reclassification index, 18.9%; P<0.001; integrated discrimination improvement, 0.4%; P=0.001).Conclusions—Higher levels of serum galectin-3 were independently associated with increased risk of death or major disability after stroke onset, suggesting that galectin-3 may have prognostic value in poor outcomes of ischemic stroke.



Autonomic Dysfunction Predicts Clinical Outcomes After Acute Ischemic Stroke [Brief Report]

2017-12-22T10:40:44-08:00

Background and Purpose—Central autonomic dysfunction increases stroke morbidity and mortality. We aimed to investigate whether poststroke autonomic dysfunction graded by Ewing battery can predict clinical outcome.Methods—In this prospective observational study, we assessed autonomic function of ischemic stroke patients within 7 days from symptom onset by Ewing battery. On the basis of the magnitude of autonomic dysfunction, we stratified patients into significant (definite, severe, or atypical) or minor (normal or early) autonomic function impairment groups and correlated the impairment with the 3-month modified Rankin Scale score (good outcome: modified Rankin Scale score 0≈2; poor outcome: modified Rankin Scale score 3≈6).Results—Among the 150 patients enrolled (mean age, 66.4±9.9 years; 70.7% males), minor autonomic dysfunction was identified in 36 patients (24.0%), and significant autonomic dysfunction was identified in 114 patients (76.0%) based on Ewing battery. In 3 months, a poor functional outcome was found in 32.5% of significant group patients compared with 13.9% in the minor group (P=0.031). Crude odds ratios of the magnitude of autonomic dysfunction and 3-month unfavorable functional outcome after acute ischemic stroke were 2.979 (95% confidence interval, 1.071–8.284; P=0.036). After adjusting for confounding variables with statistical significance between the 2 functional outcome subgroups identified in univariate analysis (including sex and National Institutes of Health Stroke Scale score on admission), the magnitude of autonomic dysfunction still independently predicted an unfavorable outcome, with an odds ratio of 3.263 (95% confidence interval, 1.141–9.335; P=0.027).Conclusions—Autonomic dysfunction gauged by Ewing battery predicts poor functional outcome after acute ischemic stroke.



Ischemic Stroke Profile, Risk Factors, and Outcomes in India [Brief Report]

2017-12-22T10:40:44-08:00

Background and Purpose—The Indo-US Collaborative Stroke Project was designed to characterize ischemic stroke across 5 high-volume academic tertiary hospitals in India.Methods—From January 2012 to August 2014, research coordinators and physician coinvestigators prospectively collected data on 2066 patients with ischemic stroke admitted <2 weeks after onset. Investigator training and supervision and data monitoring were conducted by the US site (Massachusetts General Hospital, Boston).Results—The mean age was 58.3±14.7 years, 67.2% men. The median admission National Institutes of Health Stroke Scale score was 10 (interquartile range, 5–15) and 24.5% had National Institutes of Health Stroke Scale ≥16. Hypertension (60.8%), diabetes mellitus (35.7%), and tobacco use (32.2%, including bidi/smokeless tobacco) were common risk factors. Only 4% had atrial fibrillation. All patients underwent computed tomography or magnetic resonance imaging; 81% had cerebrovascular imaging. Stroke etiologic subtypes were large artery (29.9%), cardiac (24.9%), small artery (14.2%), other definite (3.4%), and undetermined (27.6%, including 6.7% with incomplete evaluation). Intravenous or intra-arterial thrombolysis was administered in 13%. In-hospital mortality was 7.9%, and 48% achieved modified Rankin Scale score 0 to 2 at 90 days. On multivariate analysis, diabetes mellitus predicted poor 3-month outcome and younger age, lower admission National Institutes of Health Stroke Scale and small-artery etiology predicted excellent 3-month outcome.Conclusions—These comprehensive and novel clinical imaging data will prove useful in refining stroke guidelines and advancing stroke care in India.



DWI-ASPECTS (Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Scores) and DWI-FLAIR (Diffusion-Weighted Imaging-Fluid Attenuated Inversion Recovery) Mismatch in Thrombectomy Candidates [Brief Report]

2017-12-22T10:40:44-08:00

Background and Purpose—We aimed to study the intrarater and interrater agreement of clinicians attributing DWI-ASPECTS (Diffusion-Weighted Imaging–Alberta Stroke Program Early Computed Tomography Scores) and DWI-FLAIR (Diffusion-Weighted Imaging–Fluid Attenuated Inversion Recovery) mismatch in patients with acute ischemic stroke referred for mechanical thrombectomy.Methods—Eighteen raters independently scored anonymized magnetic resonance imaging scans of 30 participants from a multicentre thrombectomy trial, in 2 different reading sessions. Agreement was measured using Fleiss κ and Cohen κ statistics.Results—Interrater agreement for DWI-ASPECTS was slight (κ=0.17 [0.14–0.21]). Four raters (22.2%) had a substantial (or higher) intrarater agreement. Dichotomization of the DWI-ASPECTS (0–5 versus 6–10 or 0–6 versus 7–10) increased the interrater agreement to a substantial level (κ=0.62 [0.48–0.75] and 0.68 [0.55–0.79], respectively) and more raters reached a substantial (or higher) intrarater agreement (17/18 raters [94.4%]). Interrater agreement for DWI-FLAIR mismatch was moderate (κ=0.43 [0.33–0.57]); 11 raters (61.1%) reached a substantial (or higher) intrarater agreement.Conclusions—Agreement between clinicians assessing DWI-ASPECTS and DWI-FLAIR mismatch may not be sufficient to make repeatable clinical decisions in mechanical thrombectomy. The dichotomization of the DWI-ASPECTS (0–5 versus 0–6 or 0–6 versus 7–10) improved interrater and intrarater agreement, however, its relevance for patients selection for mechanical thrombectomy needs to be validated in a randomized trial.



Intravenous Thrombolysis for Stroke and Presumed Stroke in Human Immunodeficiency Virus-Infected Adults [Brief Report]

2017-12-22T10:40:44-08:00

Background and Purpose—Human immunodeficiency virus (HIV) infection has been shown to increase both ischemic and hemorrhagic stroke risks, but there are limited data on the safety and outcomes of intravenous thrombolysis with tPA (tissue-type plasminogen activator) for acute ischemic stroke in HIV-infected patients.Methods—A retrospective chart review of intravenous tPA-treated HIV patients who presented with acute stroke symptoms was performed in 7 large inner-city US academic centers (various search years between 2000 and 2017). We collected data on HIV, National Institutes of Health Stroke Scale score, ischemic stroke risk factors, opportunistic infections, intravenous drug abuse, neuroimaging findings, and modified Rankin Scale score at last follow-up.Results—We identified 33 HIV-infected patients treated with intravenous tPA (mean age, 51 years; 24 men), 10 of whom were stroke mimics. Sixteen of 33 (48%) patients had an HIV viral load less than the limit of detection while 10 of 33 (30%) had a CD4 count <200/mm3. The median National Institutes of Health Stroke Scale score at presentation was 9, and mean time from symptom onset to tPA was 144 minutes (median, 159). The median modified Rankin Scale score for the 33-patient cohort was 1 and for the 23-patient actual stroke cohort was 2, measured at a median of 90 days poststroke symptom onset. Two patients had nonfatal hemorrhagic transformation (6%; 95% confidence interval, 1%–20%), both in the actual stroke group. Two patients had varicella zoster virus vasculitis of the central nervous system, 1 had meningovascular syphilis, and 7 other patients were actively using intravenous drugs (3 cocaine, 1 heroin, and 3 unspecified), none of whom had hemorrhagic transformation.Conclusions—Most HIV-infected patients treated with intravenous tPA for presumed and actual acute ischemic stroke had no complications, and we observed no fatalities. Stroke mimics were common, and thrombolysis seems safe in this group. We found no data to suggest an increased risk of intravenous tPA-related complications because of concomitant opportunistic infections or intravenous drug abuse.



Successful Reperfusion With Intravenous Thrombolysis Preceding Mechanical Thrombectomy in Large-Vessel Occlusions [Brief Report]

2017-12-22T10:40:44-08:00

Background and Purpose—Although current guidelines advocate pretreatment with intravenous thrombolysis (IVT) in all eligible patients with acute ischemic stroke with large-vessel occlusion before mechanical thrombectomy, there are observational data questioning the efficacy of this approach. One of the main arguments in favor of IVT pretreatment is the potential for tissue-type plasminogen activator–induced successful reperfusion (SR) before the onset of endovascular procedure.Methods—We performed a systematic review and meta-analysis of randomized controlled clinical trials and observational cohorts providing rates of SR with IVT in patients with large-vessel occlusion before the initiation of mechanical thrombectomy. We also performed subgroup analyses according to study type (randomized controlled clinical trials versus observational) and according to the inclusion per protocol of patients with tandem (intracranial/extracranial) occlusions.Results—We identified 13 eligible studies (7 randomized controlled clinical trials and 6 observational cohorts), including 1561 patients with acute ischemic stroke (median National Institutes of Health Stroke Scale score, 17) with large-vessel occlusion. SR following IVT and before mechanical thrombectomy was documented in 11% (95% confidence interval, 7%–16%), with no difference among cohorts derived from randomized controlled clinical trials and observational studies. There was significant heterogeneity across included studies both in the overall analysis and among subgroups (I2>84%; P for Cochran Q, <0.001). Higher tissue-type plasminogen activator–induced SR rates were documented in studies reporting the exclusion of tandem occlusions (17%; 95% confidence interval, 11%–23%) compared with the rest (7%; 95% confidence interval, 4%–11%; P for subgroup differences, 0.003).Conclusions—Pretreatment with systemic thrombolysis in patients with large-vessel occlusion eligible for mechanical thrombectomy results in SR in 1 of 10 cases, negating the need for additional endovascular reperfusion. Tandem occlusions seem to be the least responsive to IVT pretreatment.



PINGS (Phone-Based Intervention Under Nurse Guidance After Stroke) [Brief Report]

2017-12-22T10:40:44-08:00

Background and Purpose—Stroke exacts an immense toll in sub-Saharan Africa where there are few resources, and stroke prevention research is limited. The aim of this study is to test the feasibility and preliminary efficacy of an m-Health technology–enabled, nurse-guided intervention in improving blood pressure (BP) control among Ghanaian stroke patients within 1 month of symptom onset.Methods—We conducted a 2-arm cluster pilot randomized controlled trial involving 60 recent stroke survivors encountered within a single tertiary medical system in Ghana. Subjects in the intervention arm (n=30) received a Blue-toothed UA-767Plus BT BP device and smartphone for monitoring and reporting BP measurements and medication intake for 3 months compared with standard of care (n=30). Primary outcome measure was systolic BP <140 mm Hg at month 3; secondary outcomes included medication adherence and autonomous self-regulation. Analysis accounting for clustering was made using generalized linear mixed model by intention to treat.Results—Mean±SD age was 55±13 years, 65% male. Systolic BP <140 mm Hg at month 3 was found in 20/30 subjects (66.7%) in the intervention arm versus 14/30 subjects (46.7%) in the control arm (P=0.12). Medication possession ratio scores at month 3 were better in the intervention (0.88±0.40) versus control (0.64±0.45) arm (P=0.03). One subject in control arm died from a recurrent hemorrhagic stroke.Conclusions—It is feasible to conduct an m-Health–based, nurse-guided BP control intervention among recent stroke patients in sub-Saharan Africa. We observed a potential signal of efficacy with the intervention, which will need to be tested in a future large definitive study.Clinical Trial Registration—URL: https://www.clinicaltrials.gov. Unique identifier: NCT02568137.



























Treatment and Outcome of Hemorrhagic Transformation After Intravenous Alteplase in Acute Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association [AHA/ASA Scientific Statement]

2017-11-27T10:40:53-08:00

Purpose—Symptomatic intracranial hemorrhage (sICH) is the most feared complication of intravenous thrombolytic therapy in acute ischemic stroke. Treatment of sICH is based on expert opinion and small case series, with the efficacy of such treatments not well established. This document aims to provide an overview of sICH with a focus on pathophysiology and treatment.Methods—A literature review was performed for randomized trials, prospective and retrospective studies, opinion papers, case series, and case reports on the definitions, epidemiology, risk factors, pathophysiology, treatment, and outcome of sICH. The document sections were divided among writing group members who performed the literature review, summarized the literature, and provided suggestions on the diagnosis and treatment of patients with sICH caused by systemic thrombolysis with alteplase. Several drafts were circulated among writing group members until a consensus was achieved.Results—sICH is an uncommon but severe complication of systemic thrombolysis in acute ischemic stroke. Prompt diagnosis and early correction of the coagulopathy after alteplase have remained the mainstay of treatment. Further research is required to establish treatments aimed at maintaining integrity of the blood-brain barrier in acute ischemic stroke based on inhibition of the underlying biochemical processes.

































Substitution of Linoleic Acid for Other Macronutrients and the Risk of Ischemic Stroke [Clinical Sciences]

2017-11-27T10:40:52-08:00

Background and Purpose—Ischemic stroke is a major health problem worldwide, but the influence of dietary factors on stroke risk is not well known. This study aimed to investigate the risk of ischemic stroke and its subtypes with a higher intake from linoleic acid and a concomitant lower intake from saturated fatty acids, monounsaturated fatty acids, or glycemic carbohydrates.Methods—In the Danish prospective Diet, Cancer, and Health Study of 57 053 participants aged 50 to 64 years at baseline, information on diet was collected using a validated semiquantitative food frequency questionnaire. Information on ischemic stroke was obtained from the Danish National Patient Register, and cases were all validated and subclassified according to the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification. Substitution of linoleic acid for saturated fatty acid, monounsaturated fatty acid, or glycemic carbohydrates was investigated in relation to the risk of ischemic stroke and subtypes. Cox proportional hazards regression was used to estimate the associations with ischemic stroke adjusting for appropriate confounders.Results—During 13.5 years of follow-up 1879 participants developed ischemic stroke. A slightly lower risk of ischemic stroke was found with a 5% higher intake of linoleic acid and a concomitant lower intake of saturated fatty acid (hazard ratio, 0.98; 95% confidence interval, 0.83–1.16), monounsaturated fatty acid (hazard ratio, 0.80; 95% confidence interval, 0.63–1.02), and glycemic carbohydrates (hazard ratio, 0.92; 95% confidence interval, 0.78–1.09), although not statistically significant. Similar patterns of association were found for large-artery atherosclerosis and small-vessel occlusions.Conclusions—This study suggests that replacing saturated fatty acid, glycemic carbohydrate, or monounsaturated fatty acid with linoleic acid may be associated with a lower risk of ischemic stroke.



Midlife Systemic Inflammation, Late-Life White Matter Integrity, and Cerebral Small Vessel Disease [Clinical Sciences]

2017-11-27T10:40:52-08:00

Background and Purpose—It is currently unclear whether midlife systemic inflammation promotes the development of white matter (WM) abnormalities and small vessel disease in the elderly. We examined the association of midlife systemic inflammation with late-life WM hyperintensity volume, deep and periventricular WM microstructural integrity (fractional anisotropy and mean diffusivity [MD]), cerebral infarcts, and microbleeds in a biracial prospective cohort study.Methods—Linear and logistic regression examined the relation between midlife high-sensitivity C-reactive protein (CRP)—a nonspecific marker of inflammation—and brain magnetic resonance imaging markers assessed 21 years later in the Atherosclerosis Risk in Communities Study.Results—We included 1485 participants (baseline age, 56[5]; 28% black). After adjusting for demographic factors and cardiovascular disease, each SD increase in midlife CRP was associated with lower fractional anisotropy (−0.09 SD; 95% confidence interval, −0.15 to −0.02) and greater MD (0.08 SD; 95% confidence interval, 0.03–0.15) in deep WM and lower fractional anisotropy (−0.07 SD; 95% confidence interval, −0.13 to 0.00) in periventricular WM. We found stronger associations between CRP and periventricular WM microstructural integrity among black participants (P interaction=0.011). Although an association between higher CRP levels and greater WM hyperintensity volume was found only among APOE ε4-positive participants in our primary analysis (0.14 SD; 95% confidence interval, 0.01–0.26; P interaction=0.028), this relationship extended to the entire sample after accounting for differential attrition. Midlife CRP was not associated with the presence of cerebral infarcts or microbleeds in late life.Conclusions—Our findings support the hypothesis that midlife systemic inflammation may promote the development of chronic microangiopathic structural WM abnormalities in the elderly.



Whole Grain Consumption and Risk of Ischemic Stroke [Clinical Sciences]

2017-11-27T10:40:52-08:00

Background and Purpose—Higher intake of whole grains may exert cardiometabolic benefits, although findings on stroke risk are inconclusive. The potentially differential effects of individual whole grain foods on ischemic stroke have not been examined.Methods—We analyzed whole grain consumption in relation to ischemic stroke among 71 750 women from the Nurses’ Health Study and 42 823 men from the Health Professionals Follow-up Study who were free of cardiovascular disease, diabetes mellitus, and cancer at baseline (1984 and 1986, respectively) through 2010 using a Cox proportional hazards model. Validated semiquantitative food frequency questionnaires were used to assess consumption of whole grain intake, including whole grain cold breakfast cereal, dark bread, oatmeal, brown rice, popcorn, bran, and germ. Self-reported incident cases of ischemic stroke were confirmed through medical record review.Results—During 2 820 128 person-years of follow-up in the 2 cohorts, 2458 cases of ischemic stroke were identified and confirmed. Intake of total whole grains was not associated with risk of ischemic stroke after adjustment for covariates: the pooled hazard ratio (95% confidence interval) comparing extreme intake levels was 1.04 (0.91–1.19). However, intake of whole grain cold breakfast cereal and total bran was inversely associated with ischemic stroke after multivariate adjustment: the pooled hazard ratios (95% confidence intervals) were 0.88 (0.80–0.96; Ptrend=0.008) and 0.89 (0.79–1.00; Ptrend=0.004), respectively. Other whole grain foods were not associated with a lower risk of ischemic stroke.Conclusions—Although overall consumption of whole grains was not associated with lower risk of ischemic stroke, greater consumption of whole grain cold breakfast cereal and bran was significantly associated with a lower risk of ischemic stroke. More studies are needed to replicate these associations between individual whole grain foods and risk of ischemic stroke among other populations.



Prevalence and Natural History of Superficial Siderosis [Clinical Sciences]

2017-11-27T10:40:52-08:00

Background and Purpose—Superficial siderosis (SS) is characterized by hemosiderin deposition in the superficial layers of the central nervous system and can be seen during postmortem examination or with iron-sensitive magnetic resonance imaging techniques. The distribution of SS may predict the probable underlying cause. This study aimed to report the prevalence and natural history of SS in a population-based study.Methods—Brain magnetic resonance imaging scans from the MCSA (Mayo Clinic Study of Aging), a population-based study of residents 50 to 89 years of age in Olmsted County, Minnesota, were reviewed. Participants with imaging consistent with SS were identified from 2011 through 2016. An inverse probability weighting approach was used to convert our observed frequencies to population prevalence of SS. Additional data abstracted included amyloid positron emission tomography, Apolipoprotein E genotype, coexisting cerebral microbleeds, and extent of SS.Results—A total of 1412 participants had eligible magnetic resonance imaging scans. Two participants had infratentorial SS, restricted to the posterior fossa. Thirteen participants had cortical SS involving the cerebral convexities (7 focal and 6 disseminated). Only 3 of the participants with cortical SS (23%) also had cerebral microbleeds. The population prevalence of SS was 0.21% (95% confidence interval, 0–0.45) in those 50 to 69 years old and 1.43% (confidence interval, 0.53–2.34) in those over 69 years old. Apolipoprotein E ε2 allele was more common in those with SS (57.1% versus 15.0%; P[...]



Angiographic and Clinical Characteristics of Thoracolumbar Spinal Epidural and Dural Arteriovenous Fistulas [Clinical Sciences]

2017-11-27T10:40:52-08:00

Background and Purpose—The purpose of this study is to compare the angiographic and clinical characteristics of spinal epidural arteriovenous fistulas (SEAVFs) and spinal dural arteriovenous fistulas (SDAVFs) of the thoracolumbar spine.Methods—A total of 168 cases diagnosed as spinal dural or extradural arteriovenous fistulas of the thoracolumbar spine were collected from 31 centers. Angiography and clinical findings, including symptoms, sex, and history of spinal surgery/trauma, were retrospectively reviewed. Angiographic images were evaluated, with a special interest in spinal levels, feeders, shunt points, a shunted epidural pouch and its location, and drainage pattern, by 6 readers to reach a consensus.Results—The consensus diagnoses by the 6 readers were SDAVFs in 108 cases, SEAVFs in 59 cases, and paravertebral arteriovenous fistulas in 1 case. Twenty-nine of 59 cases (49%) of SEAVFs were incorrectly diagnosed as SDAVFs at the individual centers. The thoracic spine was involved in SDAVFs (87%) more often than SEAVFs (17%). Both types of arteriovenous fistulas were predominant in men (82% and 73%) and frequently showed progressive myelopathy (97% and 92%). A history of spinal injury/surgery was more frequently found in SEAVFs (36%) than in SDAVFs (12%; P=0.001). The shunt points of SDAVFs were medial to the medial interpedicle line in 77%, suggesting that SDAVFs commonly shunt to the bridging vein. All SEAVFs formed an epidural shunted pouch, which was frequently located in the ventral epidural space (88%) and drained into the perimedullary vein (75%), the paravertebral veins (10%), or both (15%).Conclusions—SDAVFs and SEAVFs showed similar symptoms and male predominance. SDAVFs frequently involve the thoracic spine and shunt into the bridging vein. SEAVFs frequently involve the lumbar spine and form a shunted pouch in the ventral epidural space draining into the perimedullary vein.



Association of Osteopontin, Neopterin, and Myeloperoxidase With Stroke Risk in Patients With Prior Stroke or Transient Ischemic Attacks [Clinical Sciences]

2017-11-27T10:40:52-08:00

Background and Purpose—Established risk factors do not fully identify patients at risk for recurrent stroke. The SPARCL trial (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) evaluated the effect of atorvastatin on stroke risk in patients with a recent stroke or transient ischemic attack and no known coronary heart disease. This analysis explored the relationships between 13 plasma biomarkers assessed at trial enrollment and the occurrence of outcome strokes.Methods—We conducted a case–cohort study of 2176 participants; 562 had outcome strokes and 1614 were selected randomly from those without outcome strokes. Time to stroke was evaluated by Cox proportional hazards models.Results—There was no association between time to stroke and lipoprotein-associated phospholipase A2, monocyte chemoattractant protein-1, resistin, matrix metalloproteinase-9, N-terminal fragment of pro-B-type natriuretic peptide, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1, or soluble CD40 ligand. In adjusted analyses, osteopontin (hazard ratio per SD change, 1.362; P[...]



Risk of Stroke in Patients With Short-Run Atrial Tachyarrhythmia [Clinical Sciences]

2017-11-27T10:40:52-08:00

Background and Purpose—The risk of stroke in patients with short-run atrial tachyarrhythmia (AT) remains unclear. This study aimed to investigate the relationship between short-run AT and the stroke and the use of the CHA2DS2-VASc score for the risk stratification.Methods—From the registry of 24-hour Holter monitoring, 5342 subjects without known atrial fibrillation or stroke were enrolled. Short-run AT was defined as episodes of supraventricular ectopic beats <5 seconds.Results—There were 1595 subjects (29.8%) with short-run AT. During the median follow-up period of 9.0 years, 494 subjects developed new-onset stroke. Patients with short-run AT had significantly higher stroke rates compared with patients without short-run AT (11.4% versus 8.3%; P<0.001). In patients with short-run AT, the number of strokes per 100 person-years for patients with CHA2DS2-VASc score of 0 and 1 were 0.23 and 0.67, respectively. However, the number of them for patients with CHA2DS2-VASc score of 2, 3, 4, and ≥5 were 1.62, 1.89, 1.30, and 2.91, respectively. In patients with CHA2DS2-VASc score of 0 or 1, age (>61 years old) and burden of premature atrial contractions (>25 beats/d) independently predicted the risk of stroke. In subgroup analyses, short-run AT patients were divided into 3 groups based on their CHA2DS2-VASc scores: low score (score of 0 [men] or 1 [women]; n=324), intermediate score (score of 1 [men] or 2 [women]; n=275), and high score (score of ≥2 [men] or ≥3 [women]; n=996). When compared with low score, intermediate and high scores were independent predictors for stroke (hazard ratio, 6.165; P<0.001 and hazard ratio, 8.577; P<0.001, respectively).Conclusions—Short-run AT increases the risk of stroke. Therefore, the CHA2DS2-VASc score could be used for the risk stratification. Age and burden of premature atrial contractions were independent predictors for stroke in patients with CHA2DS2-VASc score of 0 or 1.



Intracerebral Hemorrhage and Outcome After Thrombolysis in Stroke Patients Using Selective Serotonin-Reuptake Inhibitors [Clinical Sciences]

2017-11-27T10:40:52-08:00

Background and Purpose—Selective serotonin-reuptake inhibitors (SSRIs) impair platelet function and have been linked to a higher risk of spontaneous intracerebral hemorrhage—an association that may be augmented by oral anticoagulants (OAC). We aimed to assess whether preadmission treatment with SSRIs in patients with acute ischemic stroke is associated with post-thrombolysis symptomatic intracerebral hemorrhage (sICH) and functional outcome.Methods—A multicenter retrospective analysis was conducted in prospective registries of patients treated by thrombolysis within 4.5 hours of stroke onset. The association between preadmission treatment with SSRIs and sICH (ECASS II definition [European Cooperative Acute Stroke Study]) or unfavorable 3-month outcome (modified Rankin Scale >2) was assessed by logistic regression, taking into account potential interaction with concomitant use of antithrombotics.Results—Six thousand two hundred forty-two patients were included (mean age, 70.1±14.0 years; median National Institutes of Health Stroke Scale, 9 [5–16]). Preadmission treatment with SSRIs was present in 4.3% (n=266) of patients. Overall, SICH rate was 3.9% (95% confidence interval [CI], 3.5%–4.4%; n=244), and SSRI use was not significantly associated with sICH in unadjusted (odds ratio [OR], 1.28; 95% CI, 0.72–2.27) or adjusted (OR, 1.30; 95% CI, 0.71–2.40) analysis. However, there was a significant interaction of concomitant use of OACs (international normalized ratio [...]



Statins and the Risk of Intracerebral Hemorrhage in Patients With Previous Ischemic Stroke or Transient Ischemic Attack [Clinical Sciences]

2017-11-27T10:40:52-08:00

Background and Purpose—Although there is no overall association between statin use and intracerebral hemorrhage (ICH), whether there is an increased risk among those with a history of ischemic stroke (IS) or transient ischemic attack (TIA) remains controversial. We evaluated the relationship of preadmission statin use with the risk of ICH in patients with a history of IS or TIA in a population-based cohort.Methods—The Health Improvement Network primary care database in the United Kingdom was used to identify new users of low-dose aspirin and a matched comparison. Both cohorts were followed to identify incident cases of ICH, with validation by manual review of patient records and linkage to hospitalization data. In a nested case–control study, we compared the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for ICH based on statin use in the subgroup of individuals with history of IS/TIA.Results—Last statin use within 1 year of ICH (OR, 0.92; 95% CI [confidence interval], 0.60–1.4), last use between 8 days and 1 year (OR, 1.81; 95% CI, 0.99–3.28), and statin use at the time of ICH (OR, 0.77; 95% CI, 0.49–1.21) were not associated with the overall ICH risk among 157 patients with ICH and 884 controls with a history of IS/TIA. There was also no difference in 30-day rates of fatal (OR, 0.82; 95% CI, 0.41–1.64) or nonfatal (OR, 0.90; 95% CI, 0.51–1.57) ICH.Conclusions—Statin use was not associated with an increased risk of ICH among patients with a previous history of IS/TIA.



Predictors of Good Outcome After Endovascular Therapy for Vertebrobasilar Occlusion Stroke [Clinical Sciences]

2017-11-27T10:40:52-08:00

Background and Purpose—Endovascular therapy is increasingly used in acute ischemic stroke treatment and is now considered the gold standard approach for selected patient populations. Prior studies have demonstrated that eventual patient outcomes depend on both patient-specific factors and procedural considerations. However, these factors remain unclear for acute basilar artery occlusion stroke. We sought to determine prognostic factors of good outcome in acute posterior circulation large vessel occlusion strokes treated with endovascular therapy.Methods—We reviewed our prospectively collected endovascular databases at 2 US tertiary care academic institutions for patients with acute posterior circulation strokes from September 2005 to September 2015 who had 3-month modified Rankin Scale documented. Baseline characteristics, procedural data, and outcomes were evaluated. A good outcome was defined as a 90-day modified Rankin Scale score of 0 to 2. The association between clinical and procedural parameters and functional outcome was assessed.Results—A total of 214 patients qualified for the study. Smoking status, creatinine levels, baseline National Institutes of Health Stroke Scale score, anesthesia modality (conscious sedation versus general anesthesia), procedural length, and reperfusion status were significantly associated with good outcomes in the univariate analysis. Multivariate logistic regression indicated that only smoking (odds ratio=2.61; 95% confidence interval, 1.23–5.56; P=0.013), low baseline National Institutes of Health Stroke Scale score (odds ratio=1.09; 95% confidence interval, 1.04–1.13; P[...]



Imaging Characteristics of Venous Parenchymal Abnormalities [Clinical Sciences]

2017-11-27T10:40:52-08:00

Background and Purpose—There are few published data on the patterns of parenchymal imaging abnormalities in a context of cerebral venous thrombosis (CVT). The objectives of the present study were to describe the patterns of parenchymal lesions associated with CVT and to determine the lesion sites.Methods—We included 44 consecutively hospitalized patients with CVT and parenchymal lesions on magnetic resonance imaging. The diagnosis of CVT had been confirmed by magnetic resonance imaging/magnetic resonance venography. Magnetic resonance imaging patterns for CVT were retrospectively analyzed with regard to the lesion’s type, shape, and site.Results—The most frequent stroke subtype was hemorrhagic ischemia (in 56.8% of cases), followed by intracerebral hematoma (in 22.72% of cases) and nonhemorrhagic ischemia (in 20.45% of cases). Although there were no significant differences between these 3 groups with regard to the clinical and radiological characteristics, we observed a nonsignificant trend (P=0.08) toward a shorter time interval between hospital admission and magnetic resonance imaging for nonhemorrhagic stroke. The CVT parenchymal abnormalities were centered on 6 main foci and were related to the site of venous occlusion: (1) the inferior parietal lobule (n=20; 44.5%), associated mainly with occlusion of the transverse sinus (n=10) or pure cortical veins (n=10); (2) the inferior and posterior temporal regions (n=10; 22.75%), associated mainly with occlusion of the transverse sinus (n=9); (3) the parasagittal frontal region (n=6; 13.6%), associated mainly with occlusion of the superior sagittal sinus (n=4) or the transverse sinus (n=4); (4) the thalamus (n=5; 11.3%) associated with occlusion of the straight sinus (n=5); (5) the cerebellar hemisphere (n=2; 4.5%), associated in both cases wi[...]



Echocardiographic Risk Factors for Stroke and Outcomes in Patients With Atrial Fibrillation Anticoagulated With Apixaban or Warfarin [Clinical Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—Few data exist on the long-term outcomes of patients with spontaneous echo contrast (SEC), left atrial/left atrial appendage (LA/LAA) thrombus, and complex aortic plaque (CAP), in patients with atrial fibrillation receiving oral anticoagulation. We explored the relationship between these 3 echocardiographic findings and clinical outcomes, and the comparative efficacy and safety of apixaban and warfarin for each finding.Methods—Patients from the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) with SEC, LA/LAA thrombus, or CAP diagnosed by either transthoracic or transesophageal echocardiography were compared with patients with none of these findings on transesophageal echocardiography.Results—A total of 1251 patients were included: 217 had SEC, 127 had LA/LAA thrombus, 241 had CAP, and 746 had none. The rates of stroke/systemic embolism were not significantly different among patients with and without these echocardiographic findings (hazard ratio, 0.96; 95% confidence interval, 0.25–3.60 for SEC; hazard ratio, 1.27; 95% confidence interval, 0.23–6.86 for LA/LAA thrombus; hazard ratio, 2.21; 95% confidence interval, 0.71–6.85 for CAP). Rates of ischemic stroke, myocardial infarction, cardiovascular death, and all-cause death were also not different between patients with and without these findings. For patients with either SEC or CAP, there was no evidence of a differential effect of apixaban over warfarin. For patients with LA/LAA thrombus, there was also no significant interaction, with the exception of all-cause death and any bleeding where there was a greater benefit of apixaban compared with warfarin among patients with no LA/LAA thrombus.Conclusions—In anticoagulated patients[...]



Mechanical Thrombectomy for Minor and Mild Stroke Patients Harboring Large Vessel Occlusion in the Anterior Circulation [Clinical Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—Proximal large vessel occlusion (LVO) is present in up to 30% of minor strokes. The effectiveness of mechanical thrombectomy (MT) in the subgroup of minor stroke with LVO in the anterior circulation is still open to debate. Data about MT in this subgroup of patients are sparse, and their optimal management has not yet been defined. The purpose of this multicenter cohort study was to evaluate the effectiveness of MT in patients experiencing acute ischemic stroke (AIS) because of LVO in the anterior circulation, presenting with minor-to-mild stroke symptoms (National Institutes of Health Stroke Scale score of [...]



Direct Mechanical Intervention Versus Bridging Therapy in Stroke Patients Eligible for Intravenous Thrombolysis [Clinical Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—Randomized controlled trials have shown that mechanical thrombectomy (MT) plus best medical treatment improves outcome in stroke patients with large-vessel occlusion in the anterior circulation. Whether direct MT is equally effective as bridging thrombolysis (intravenous thrombolysis plus MT) in intravenous thrombolysis eligible patients remains unclear.Methods—We compared clinical and radiological outcomes at 3 months in 249 bridging patients with 111 patients receiving direct MT for large-vessel occlusion anterior circulation stroke from 2 prospective registries (study period Essen: June 2012 to August 2013, Bern February 2009 to August 2014). We matched all patients from the direct MT group who would have qualified for intravenous thrombolysis with controls from the bridging group, using multivariate and propensity score methods. Subgroup analyses for internal carotid artery occlusions were performed.Results—Baseline characteristics did not differ between the direct MT group and bridging cohort, except for higher rates of coronary heart disease (P=0.029) and shorter intervals from onset to endovascular therapy (P[...]



Low-Dose Tirofiban Improves Functional Outcome in Acute Ischemic Stroke Patients Treated With Endovascular Thrombectomy [Clinical Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—Chinese patients largely experience acute ischemic stroke (AIS) because of large artery atherosclerosis rather than cardioembolism, and whether tirofiban is safe and effective in these patients treated with endovascular thrombectomy (ET) is unknown. This study evaluated the safety and efficacy of tirofiban in Chinese patients with AIS treated with ET.Methods—This observational study is based on a single-center prospective registry study. Patients with AIS undergoing ET with second-generation stent retrievers from January 2013 to February 2017 were treated with ET alone or ET plus low dose of tirofiban. The primary outcome was symptomatic intracerebral hemorrhage (sICH). The secondary outcomes included rate of early reocclusion, any ICH, fatal ICH, and 3-month and long-term functional outcomes.Results—One hundred eighty AIS subjects were included in the analysis, including 90 subjects treated with tirofiban and 90 subjects without tirofiban. Sixty-three subjects (35%) had any ICH, 19 of them (11%) were sICH, and 9 of them (5%) were fatal ICH. Ten subjects (11%) treated with tirofiban experienced sICH and 9 subjects (10%) not given tirofiban experienced sICH, not a significant difference (P=0.808). Early reocclusion happened in 4 of 90 subjects (4.4%) treated with tirofiban and 8 of 90 subjects (8.9%) not treated with tirofiban (P=0.370). One hundred sixty-one subjects (89%) completed long-term follow-up, subjects treated tirofiban were associated with lower odds of death (23% versus 44%, P=0.005) when compared with those who were not treated. Additionally, tirofiban was associated with better odds of long-term functional independence (adjusted odds ratio, 4.37; 95[...]



Mobile Interventional Stroke Teams Lead to Faster Treatment Times for Thrombectomy in Large Vessel Occlusion [Clinical Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—Endovascular recanalization treatment for acute ischemic stroke is a complex, time-sensitive intervention. Trip-and-treat is an interhospital service delivery model that has not previously been evaluated in the literature and consists of a shared mobile interventional stroke team that travels to primary stroke centers to provide on-site interventional capability. We compared treatment times between the trip-and-treat model and the traditional drip-and-ship model.Methods—We performed a retrospective analysis on 86 consecutive eligible patients with acute ischemic stroke secondary to large vessel occlusion who received endovascular treatment at 4 hospitals in Manhattan. Patients were divided into 2 cohorts: trip-and-treat (n=39) and drip-and-ship (n=47). The primary outcome was initial door-to-puncture time, defined as the time between arrival at any hospital and arterial puncture. We also recorded and analyzed the times of last known well, IV-tPA (intravenous tissue-type plasminogen activator) administration, transfer, and reperfusion.Results—Mean initial door-to-puncture time was 143 minutes for trip-and-treat and 222 minutes for drip-and-ship (P[...]



Circulating Endothelial Markers in Retinal Vasculopathy With Cerebral Leukoencephalopathy and Systemic Manifestations [Clinical Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a monogenic small vessel disease, caused by C-terminal truncating TREX1 mutations, that can be considered a model for stroke and vascular dementia. The pathophysiology of RVCL-S is largely unknown, but systemic endothelial involvement has been suggested, leading to pathology in the brain and other highly vascularized organs. Here, we investigated circulating endothelial markers to confirm endothelial involvement and identify biomarkers for disease activity.Methods—We measured circulating levels of von Willebrand factor (VWF) antigen, VWF propeptide, and angiopoietin-2 in members of 3 Dutch RVCL-S families and matched unrelated healthy controls. Stratified analyses based on symptomatology and age were performed.Results—We found elevated levels of VWF antigen, VWF propeptide, and angiopoietin-2 in TREX1 mutation carriers (n=31) compared with family members without a TREX1 mutation (n=33) and unrelated healthy controls (n=31; Kruskal–Wallis test P[...]



Development and Validation of a Predictive Model for Functional Outcome After Stroke Rehabilitation [Clinical Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—Prediction of outcome after stroke rehabilitation may help clinicians in decision-making and planning rehabilitation care. We developed and validated a predictive tool to estimate the probability of achieving improvement in physical functioning (model 1) and a level of independence requiring no more than supervision (model 2) after stroke rehabilitation.Methods—The models were derived from 717 patients admitted for stroke rehabilitation. We used multivariable logistic regression analysis to build each model. Then, each model was prospectively validated in 875 patients.Results—Model 1 included age, time from stroke occurrence to rehabilitation admission, admission motor and cognitive Functional Independence Measure scores, and neglect. Model 2 included age, male gender, time since stroke onset, and admission motor and cognitive Functional Independence Measure score. Both models demonstrated excellent discrimination. In the derivation cohort, the area under the curve was 0.883 (95% confidence intervals, 0.858–0.910) for model 1 and 0.913 (95% confidence intervals, 0.884–0.942) for model 2. The Hosmer–Lemeshow χ2 was 4.12 (P=0.249) and 1.20 (P=0.754), respectively. In the validation cohort, the area under the curve was 0.866 (95% confidence intervals, 0.840–0.892) for model 1 and 0.850 (95% confidence intervals, 0.815–0.885) for model 2. The Hosmer–Lemeshow χ2 was 8.86 (P=0.115) and 34.50 (P=0.001), respectively. Both improvement in physical functioning (hazard ratios, 0.43; 0.25–0.71; P=0.001) and a level of independence requiring no more than supervision (hazard ratio[...]



Impact on Prehospital Delay of a Stroke Preparedness Campaign [Clinical Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—Public campaigns to increase stroke preparedness have been tested in different contexts, showing contradictory results. We evaluated the effectiveness of a stroke campaign, designed specifically for the Italian population in reducing prehospital delay.Methods—According to an SW-RCT (Stepped-Wedge Cluster Randomized Controlled Trial) design, the campaign was launched in 4 provinces in the northern part of the region Emilia Romagna at 3-month intervals in randomized sequence. The units of analysis were the patients admitted to hospital, with stroke and transient ischemic attack, over a time period of 15 months, beginning 3 months before the intervention was launched in the first province to allow for baseline data collection. The proportion of early arrivals (within 2 hours of symptom onset) was the primary outcome. Thrombolysis rate and some behavioral end points were the secondary outcomes. Data were analyzed using a fixed-effect model, adjusting for cluster and time trends.Results—We enrolled 1622 patients, 912 exposed and 710 nonexposed to the campaign. The proportion of early access was nonsignificantly lower in exposed patients (354 [38.8%] versus 315 [44.4%]; adjusted odds ratio, 0.81; 95% confidence interval, 0.60–1.08; P=0.15). As for secondary end points, an increase was found for stroke recognition, which approximated but did not reach statistical significance (P=0.07).Conclusions—Our campaign was not effective in reducing prehospital delay. Even if some limitations of the intervention, mainly in terms of duration, are taken into account, our [...]



Executive Function Declines in the First 6 Months After a Transient Ischemic Attack or Transient Neurological Attack [Clinical Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—Although by definition transient, both transient ischemic attack (TIA) and transient neurological attack (TNA) are associated with cognitive impairment. Determinants and course of cognitive function afterward are, however, unclear. We prospectively determined cognitive performance after TIA and TNA in relation to clinical diagnosis and diffusion-weighted imaging (DWI) results.Methods—TIA and TNA patients aged ≥45 years without prior stroke or dementia underwent comprehensive cognitive assessment and magnetic resonance imaging within 7 days after the qualifying event. Cognitive tests were repeated after 6 months. Domain-specific compound z scores based on the baseline mean and SD were calculated. Repeated-measures analysis was used to test for differences in domain-specific cognitive performance over time between DWI-positive and DWI-negative patients, as well as between TIA and TNA patients.Results—One hundred twenty-one patients were included (mean age (SD), 64.6 years (9.2 years), 60% TIA and 40% TNA) of whom 32 (26%) had a DWI lesion. Executive function performance decreased over time (mean change in compound score −0.23; P=0.01 adjusted for age, sex, education), whereas attention improved (0.11; P=0.02), and information processing speed and episodic memory remained unchanged. Patients with a DWI lesion had worse executive function at baseline than those without a DWI lesion (compound scores −0.26 versus 0.08; P=0.048), which persisted throughout the study period (P=0.04). Clinical diagnosis (TIA or TNA) was not related[...]



No Racial Difference in Rehabilitation Therapy Across All Post-Acute Care Settings in the Year Following a Stroke [Clinical Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—Black stroke survivors experience greater poststroke disability than whites. Differences in post-acute rehabilitation may contribute to this disparity. Therefore, we estimated racial differences in rehabilitation therapy utilization, intensity, and the number of post-acute care settings in the first year after a stroke.Methods—We used national Medicare data to study 186 168 elderly black and white patients hospitalized with a primary diagnosis of stroke in 2011. We tabulated the proportion of stroke survivors receiving physical, occupational, and speech and language therapy in each post-acute care setting (inpatient rehabilitation facility, skilled nursing facility, and home health agency), minutes of therapy, and number of transitions between settings. We then used generalized linear models to determine whether racial differences in minutes of physical therapy were influenced by demographics, comorbidities, thrombolysis, and markers of stroke severity.Results—Black stroke patients were more likely to receive each type of therapy than white stroke patients. Compared with white stroke patients, black stroke patients received more minutes of physical therapy (897.8 versus 743.4; P[...]



Fingolimod Protects Against Ischemic White Matter Damage by Modulating Microglia Toward M2 Polarization via STAT3 Pathway [Basic Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—White matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of demyelination after WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model.Methods—Chronic WM ischemic injury model was induced by bilateral carotid artery stenosis. Cognitive function, WM integrity, microglial activation, and potential pathway involved in microglial polarization were assessed after bilateral carotid artery stenosis.Results—Disruption of WM integrity was characterized by demyelination in the corpus callosum and disorganization of Ranvier nodes using Luxol fast blue staining, immunofluorescence staining, and electron microscopy. In addition, radial maze test demonstrated that working memory performance was decreased at 1-month post–bilateral carotid artery stenosis–induced injury. Interestingly, FTY720 could reduce cognitive decline and ameliorate the disruption of WM integrity. Mechanistically, cerebral hypoperfusion induced microglial activation, production of associated proinflammatory cytokines, and priming of microglial polarization toward the M1 phenotype, whereas FTY720 attenuated microglia-mediated neuroinflammation after WM ischemia and promoted oli[...]



Sickle Mice Are Sensitive to Hypoxia/Ischemia-Induced Stroke but Respond to Tissue-Type Plasminogen Activator Treatment [Basic Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—The effects of lytic stroke therapy in patients with sickle cell anemia are unknown, although a recent study suggested that coexistent sickle cell anemia does not increase the risk of cerebral hemorrhage. This finding calls for systemic analysis of the effects of thrombolytic stroke therapy, first in humanized sickle mice, and then in patients. There is also a need for additional predictive markers of sickle cell anemia-associated vasculopathy.Methods—We used Doppler ultrasound to examine the carotid artery of Townes sickle mice tested their responses to repetitive mild hypoxia–ischemia- and transient hypoxia–ischemia-induced stroke at 3 or 6 months of age, respectively. We also examined the effects of tPA (tissue-type plasminogen activator) treatment in transient hypoxia–ischemia-injured sickle mice.Results—Three-month-old sickle cell (SS) mice showed elevated resistive index in the carotid artery and higher sensitivity to repetitive mild hypoxia–ischemia-induced cerebral infarct. Six-month-old SS mice showed greater resistive index and increased flow velocity without obstructive vasculopathy in the carotid artery. Instead, the cerebral vascular wall in SS mice showed ectopic expression of PAI-1 (plasminogen activator inhibitor-1) and P-selectin, suggesting a proadhesive and prothrombotic propensity. Indeed, SS mice showed enhanced leukocyte and platelet adherence to the cerebral vascular wall, broader fibrin deposition, and higher mortali[...]



Inhibition of CD147 (Cluster of Differentiation 147) Ameliorates Acute Ischemic Stroke in Mice by Reducing Thromboinflammation [Basic Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—Inflammation and thrombosis currently are recognized as critical contributors to the pathogenesis of ischemic stroke. CD147 (cluster of differentiation 147), also known as extracellular matrix metalloproteinase inducer, can function as a key mediator of inflammatory and immune responses. CD147 expression is increased in the brain after cerebral ischemia, but its role in the pathogenesis of ischemic stroke remains unknown. In this study, we show that CD147 acts as a key player in ischemic stroke by driving thrombotic and inflammatory responses.Methods—Focal cerebral ischemia was induced in C57BL/6 mice by a 60-minute transient middle cerebral artery occlusion. Animals were treated with anti-CD147 function–blocking antibody (αCD147) or isotype control antibody. Blood–brain barrier permeability, thrombus formation, and microvascular patency were assessed 24 hours after ischemia. Infarct size, neurological deficits, and inflammatory cells invaded in the brain were assessed 72 hours after ischemia.Results—CD147 expression was rapidly increased in ischemic brain endothelium after transient middle cerebral artery occlusion. Inhibition of CD147 reduced infarct size and improved functional outcome on day 3 after transient middle cerebral artery occlusion. The neuroprotective effects were associated with (1) prevented blood–brain barrier damage, (2) decreased intravascular fibrin and platelet deposition, which in turn reduce[...]



2-Cl-MGV-1 Ameliorates Apoptosis in the Thalamus and Hippocampus and Cognitive Deficits After Cortical Infarct in Rats [Basic Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—Focal cortical infarction causes neuronal apoptosis in the ipsilateral nonischemic thalamus and hippocampus, which is potentially associated with poststroke cognitive deficits. TSPO (translocator protein) is critical in regulating mitochondrial apoptosis pathways. We examined the effects of the novel TSPO ligand 2-(2-chlorophenyl) quinazolin-4-yl dimethylcarbamate (2-Cl-MGV-1) on poststroke cognitive deficits, neuronal mitochondrial apoptosis, and secondary damage in the ipsilateral thalamus and hippocampus after cortical infarction.Methods—One hundred fourteen hypertensive rats underwent successful distal middle cerebral artery occlusion (n=76) or sham procedures (n=38). 2-Cl-MGV-1 or dimethyl sulfoxide as vehicle was administrated 2 hours after distal middle cerebral artery occlusion and then for 6 or 13 days (n=19 per group). Spatial learning and memory were tested using the Morris water maze. Secondary degeneration and mitochondrial apoptosis in the thalamus and hippocampus were assessed using Nissl staining, immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end labeling, JC-1 staining, and immunoblotting 7 and 14 days after surgery.Results—Infarct volumes did not significantly differ between the vehicle and 2-Cl-MGV-1 groups. There were more neurons and fewer glia in the ipsilateral thalamus and hippocampus in the vehicle groups than in the sham-operated group 7 and 14 d[...]



Optogenetic Inhibition of Striatal GABAergic Neuronal Activity Improves Outcomes After Ischemic Brain Injury [Basic Sciences]

2017-11-27T10:40:53-08:00

Background and Purpose—Striatal GABAergic neuron is known as a key regulator in adult neurogenesis. However, the specific role of striatal GABAergic neuronal activity in the promotion of neurological recovery after ischemic stroke remains unknown. Here, we used optogenetic approach to investigate these effects and mechanism.Methods—Laser stimulation was delivered via an implanted optical fiber to inhibit or activate the striatal GABAergic neurons in Gad2-Arch-GFP or Gad2-ChR2-tdTomato mice (n=80) 1 week after 60-minute transient middle cerebral artery occlusion. Neurological severity score, brain atrophy volume, microvessel density, and cell morphological changes were examined using immunohistochemistry. Gene expression and protein levels of related growth factors were further examined using real-time polymerase chain reaction and Western blotting.Results—Inhibiting striatal GABAergic neuronal activity improved functional recovery, reduced brain atrophy volume, and prohibited cell death compared with the control (P[...]



Climatic and Seasonal Circumstances of Hypertensive Intracerebral Hemorrhage in a Worldwide Cohort [Brief Report]

2017-11-27T10:40:53-08:00

Background and Purpose—Numerous studies have investigated the influence of meteorologic factors and seasons on the incidence of spontaneous intracerebral hemorrhage (ICH) with ambiguous results. In the present study, data from a large, international multicenter trial in patients with ICH were used to identify seasonal and meteorologic determinants for hypertensive-ICH with greater applicability.Methods—Patients were grouped according to the presumptive ICH cause, that is, hypertensive when located in the basal ganglia brain stem as well as cerebellum and nonhypertensive when located lobar. Both groups were compared with regard to air temperature and air pressure and their occurrence during the year. A regression analysis was performed to identify independent predictors of hypertensive-ICH.Results—Only hypertensive-ICH showed a seasonal pattern and occurred with higher air pressure values and at younger age. Independent predictors of hypertensive-ICH were increased air pressure on the actual day of the event and younger age as well as higher temperature.Conclusions—In the present study with an international cohort, besides age air pressure, more than temperature, had an influence on the occurrence of hypertensive-ICH, only.