Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection: The STOP-CAD Study.

BACKGROUND: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation. METHODS: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments. RESULTS: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45-1.12]; P=0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28-2.24]; P=0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35-5.45]; P=0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53-20.13]; P=0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18-0.88]; Pinteraction=0.009). CONCLUSIONS: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings.

Impact of Decompressive Craniectomy on Hemorrhagic Transformation in Malignant Ischemic Stroke in Mice.

BACKGROUND: Endovascular thrombectomy has changed the management of ischemic stroke. The reperfusion can however lead to a hemorrhagic transformation (HT). Decompressive craniectomy (DC) is a surgical procedure used for malignant ischemic stroke. However, its efficacy was demonstrated before the era of endovascular thrombectomy trials. Here, we hypothesized that DC for ischemic stroke after thrombectomy could lead to a higher risk of HT. We thus evaluated this hypothesis in a mouse model of stroke induced by occlusion of the middle cerebral artery (MCAO) with or without mechanical reperfusion. METHODS: Ninety mice subjected to MCAO were divided into 6 groups: permanent MCAO with or without DC; MCAO followed by a mechanical reperfusion with or without DC and MCAO with a mechanical reperfusion followed by r-tPA (recombinant tissue-type plasminogen activator)-induced reperfusion with or without DC. Mice were evaluated by magnetic resonance imaging 24 hours after the MCAO to assess ischemic lesion volumes, and the rate, type, and volume of HTs. RESULTS: The ischemic volume was higher in the 2 groups without reperfusion than in the 4 groups with reperfusion independently of r-tPA treatment and DC. The distribution of HT types was different between the 6 groups. The HT volumes and HT scores was smaller in the 2 groups without reperfusion and in the reperfusion group without r-tPA and without DC. In mice having reperfusion, the mean HT score was higher in mice who had DC without r-tPA (HT score 5; P=0.048) or with r-tPA (HT score 8; P=0.02), than in mice without DC (HT score 1). CONCLUSIONS: DC for a malignant stroke, after reperfusion, corresponding to an endovascular thrombectomy failure, increases the risk of severe hemorrhagic transformations in a model of ischemic stroke in mice. This result support the need of clinical studies to evaluate the added value of DC at the era of endovascular thrombectomy.

A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke.

BACKGROUND: The use of intensive lipid-lowering therapy by means of statin medications is recommended after transient ischemic attack (TIA) and ischemic stroke of atherosclerotic origin. The target level for low-density lipoprotein (LDL) cholesterol to reduce cardiovascular events after stroke has not been well studied. METHODS: In this parallel-group trial conducted in France and South Korea, we randomly assigned patients with ischemic stroke in the previous 3 months or a TIA within the previous 15 days to a target LDL cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) (lower-target group) or to a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter) (higher-target group). All the patients had evidence of cerebrovascular or coronary-artery atherosclerosis and received a statin, ezetimibe, or both. The composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes. RESULTS: A total of 2860 patients were enrolled and followed for a median of 3.5 years; 1430 were assigned to each LDL cholesterol target group. The mean LDL cholesterol level at baseline was 135 mg per deciliter (3.5 mmol per liter), and the mean achieved LDL cholesterol level was 65 mg per deciliter (1.7 mmol per liter) in the lower-target group and 96 mg per deciliter (2.5 mmol per liter) in the higher-target group. The trial was stopped for administrative reasons after 277 of an anticipated 385 end-point events had occurred. The composite primary end point occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.61 to 0.98; P = 0.04). The incidence of intracranial hemorrhage and newly diagnosed diabetes did not differ significantly between the two groups. CONCLUSIONS: After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg per deciliter. (Funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875.).

Comparison of patients with biopsy positive and negative primary angiitis of the central nervous system.

OBJECTIVE: There is limited evidence on when to obtain a central nervous system (CNS) biopsy in suspected primary angiitis of the central nervous system (PACNS). Our objective was to identify which clinical and radiological characteristics were associated with a positive biopsy in PACNS. METHODS: From the multicenter retrospective Cohort of Patients with Primary Vasculitis of the CNS (COVAC), we included adults with PACNS based on a positive CNS biopsy or otherwise unexplained intracranial stenoses with additional findings supportive of vasculitis. Baseline findings were compared between patients with a positive and negative biopsy using logistic regression models. RESULTS: 200 patients with PACNS were included, among which a biopsy was obtained in 100 (50%) and was positive in 61 (31%). Patients with a positive biopsy were more frequently female (OR 2.90, 95% CI 1.25-7.10, p = 0.01) and more often presented with seizures (OR 8.31, 95% CI 2.77-33.04, p < 0.001) or cognitive impairment (OR 2.58, 95% CI 1.11-6.10, p = 0.03). On imaging, biopsy positive patients more often had non-ischemic parenchymal or leptomeningeal gadolinium enhancement (OR 52.80, 95% CI 15.72-233.06, p < 0.001) or ≥ 1 cerebral microbleed (OR 8.08, 95% CI 3.03-25.13, p < 0.001), and less often had ≥ 1 acute brain infarct (OR 0.02, 95% CI 0.004-0.08, p < 0.001). In the multivariable model, non-ischemic parenchymal or leptomeningeal gadolinium enhancement (aOR 8.27, 95% CI 1.78-38.46), p < 0.01) and absence of ≥ 1 acute brain infarct (aOR 0.13, 95% CI 0.03-0.65, p = 0.01) were significantly associated with a positive biopsy. CONCLUSIONS: Baseline clinical and radiological characteristics differed between biopsy positive and negative PACNS. These results may help physicians individualize the decision to obtain a CNS biopsy in suspected PACNS.

Incidence and Outcomes of Acute Cerebrovascular Events: Methodology of the Population-Based Normandy Stroke Study.

BACKGROUND: The number of strokes has been steadily increasing due to the aging of the population, and its management has changed dramatically in recent years. Nevertheless, there are few unbiased epidemiological studies to investigate the incidence of strokes and their long-term prognosis. METHODS: The Normandy Stroke Study (NSS) is a prospective population-based study of all strokes and transient ischemic attacks in a large urban, suburban, and rural area in the Northwest of France. It was designed to meet the current gold standard in stroke epidemiological study by using multiple overlapping sources for case identification. It also aimed to assess the impact of socioeconomic disparities and long-term prognosis of stroke through an additional follow-up up to 3 years after the event to better understand the functional and cognitive prognostic of stroke as well as the quality of life in patients after stroke. CONCLUSION: NSS will provide important data on the epidemiology and long-term consequences of stroke at the population level and will help care providers adapt resource allocation.

Susceptibility Vessel Sign in Relation With Time From Onset to Magnetic Resonance Imaging.

Background and Purpose: In acute ischemic stroke, the susceptibility vessel sign (SVS) on T2* MR-sequence witnesses the red blood cell content of the clot. Although clot composition strongly depends on its age in vitro, the relationship between SVS and time has not been studied. In this study, we evaluated whether the presence of SVS was related to the time from symptom onset. Methods: We retrospectively analyzed our institutional registry of patients with acute stroke between November 2007 and June 2018. We included patients with an ischemic stroke confirmed by diffusion-weighted imaging magnetic resonance imaging within 8 hours from symptom onset caused by M1 or M2 occlusion and with interpretable T2*-weighted images. We compared clinical and imaging variables among SVS+ and SVS− patients. Time from onset was split into tertiles. Independent markers of SVS+ were identified using multivariable logistic regression. The probability of being SVS+ given time from symptoms onset was modeled using Probit regression. Results: Among the 608 patients included, 433 (71.2%) were SVS+. The odds of being SVS+ increased with time from symptom onset (P trend=0.005). In the multivariable analysis, factors independently associated with a SVS+ were symptom onset to magnetic resonance imaging ([130­180 min] odds ratio [OR], 1.62 [95% CI, 1.03­2.53]; [>180 min] OR, 3.14 [95% CI, 1.92­5.12]), type of magnetic resonance imaging-scanner (OR, 2.83 [95% CI, 1.82­4.41]), cardioembolic cause (OR, 1.51 [95% CI, 1.02­2.24]), and baseline National Institutes of Health Stroke Scale (OR, 1.05 [95% CI, 1.01­1.08]). The probability of being SVS+ increased with time from symptom onset (P=0.004): around 60% at 1 hour, 70% at 3 hours, 80% at 6 hours, and 90% at 8 hours. Conclusions: In acute ischemic stroke, the presence of SVS depends on time from onset to imaging.

Stroke Prevention by Anticoagulants in Daily Practice Depending on Atrial Fibrillation Pattern and Clinical Risk Factors.

Background and Purpose: The objective of the study was to assess the effectiveness of individual direct oral anticoagulants versus vitamin K antagonists for primary prevention of stroke (ischemic and hemorrhagic) in routine clinical practice in patients with various clinical risk factors depending on their atrial fibrillation (AF) patterns. Methods: A nested case-referent study was conducted using data from 2 national registries of patients with stroke and AF. Stroke cases with previous history of AF were matched to up to 2 randomly selected referent patients with AF and no stroke. The association of individual anticoagulant use with ischemic or hemorrhagic stroke was studied in patients with or without permanent AF using multivariable conditional logistic models, controlled for clinically significant risk factors and multiple other cardiovascular risk factors. Results: In total, 2586 stroke cases with previous AF and 4810 nonstroke referent patients with AF were retained for the study. Direct oral anticoagulant users had lower odds of stroke of any type than vitamin K antagonist users: the adjusted-matched OR for ischemic stroke were 0.70 (95% CI, 0.50­0.98) for dabigatran, 0.68 (95% CI, 0.53­0.86) for rivaroxaban, and 0.73 (95% CI, 0.52­1.02) for apixaban while for hemorrhagic stroke they were 0.31 (95% CI, 0.14­0.68), 0.64 (95% CI, 0.39­1.06), and 0.70 (95% CI, 0.33­1.49), respectively. The effects of individual direct oral anticoagulants relative to vitamin K antagonists were similar in permanent AF and nonpermanent AF patients. Conclusions: Similar results were observed for each direct oral anticoagulant in real life as those observed in the pivotal clinical trials. The pattern of AF did not affect the outcome.

Impact of Prior Antiplatelet Therapy on Outcomes After Endovascular Therapy for Acute Stroke: Endovascular Treatment in Ischemic Stroke Registry Results.

BACKGROUND AND PURPOSE: The influence of prior antiplatelet therapy (APT) uses on the outcomes of patients with acute ischemic stroke treated with endovascular therapy is unclear. We compared procedural and clinical outcomes of endovascular therapy in patients on APT or not before stroke onset. METHODS: We analyzed 2 groups from the ongoing prospective multicenter Endovascular Treatment in Ischemic Stroke registry in France: patients on prior APT (APT+) and patients without prior APT (APT-) treated by endovascular therapy, with and without intravenous thrombolysis. Multilevel mixed-effects logistic models including center as random effect were used to compare angiographic (rates of reperfusion at the end of procedure, procedural complications) and clinical (favorable and excellent outcome, 90-day all-cause mortality, and hemorrhagic complications) outcomes according to APT subgroups. Comparisons were adjusted for prespecified confounders (age, admission National Institutes of Health Stroke Scale score, Alberta Stroke Program Early CT Score, intravenous thrombolysis, and time from onset to puncture), as well as for meaningful baseline between-group differences. RESULTS: A total of 2939 patients were analyzed, of whom 877 (29.8%) were on prior APT. Patients with prior APT were older, had more frequent vascular risk factors, cardioembolic stroke mechanism, and prestroke disability. Rates of complete reperfusion (37.9% in the APT- group versus 42.7 % in the APT+ group; aOR, 1.09 [95% CI, 0.88-1.34]; P=0.41) and periprocedural complication (16.9% versus 13.3%; aOR, 0.90 [95% CI, 0.7-1.2]; P=0.66) did not differ between the two groups. Symptomatic intracerebral hemorrhage (aOR, 0.93 [95% CI, 0.63-1.37]; P=0.73), 3 months favorable clinical outcome (modified Rankin Scale score of 0-2; aOR, 0.98 [95% CI, 0.77-1.25]; P=0.89), and mortality (aOR, 0.95 [95% CI, 0.72-1.26]; P=0.76) at 90 days did not differ between the groups. CONCLUSIONS: Prior APT does not influence angiographic and functional outcomes following endovascular therapy and should not be taken into account for acute revascularization strategies.

Patent foramen ovale closure in stroke patients with migraine in the CLOSE trial. The CLOSE-MIG study.

BACKGROUND AND PURPOSE: The efficacy of patent foramen ovale (PFO) closure to reduce the frequency of migraine attacks remains controversial. METHODS: This was a planned sub-study in migraine patients enrolled in a randomized, clinical trial designed to assess the superiority of PFO closure plus antiplatelet therapy over antiplatelet therapy alone to prevent stroke recurrence in patients younger than 60 years with a PFO-associated cryptogenic ischaemic stroke. The main outcome was the mean annual number of migraine attacks in migraine patients with aura and in those without aura, as recorded at each follow-up visit by study neurologists. RESULTS: Of 473 patients randomized to PFO closure or antiplatelet therapy, 145 (mean age 41.9 years; women 58.6%) had migraine (75 with aura and 70 without aura). Sixty-seven patients were randomized to PFO closure and 78 to antiplatelet therapy. During a mean follow-up of about 5 years, there were no differences between antiplatelet-only and PFO closure groups in the mean annual number of migraine attacks, both in migraine patients with aura (9.2 [11.9] vs. 12.0 [19.1], p = 0.81) and in those without aura (12.1 [16.1] vs. 11.8 [18.4], p > 0.999). There were no differences between treatment groups regarding cessation of migraine attacks, migraine-related disability at 2 years and use of migraine-preventive drugs during follow-up. CONCLUSIONS: In young and middle-aged adults with PFO-associated cryptogenic stroke and migraine, PFO closure plus antiplatelet therapy did not reduce the mean annual number of migraine attacks compared to antiplatelet therapy alone, in migraine patients both with and without aura.

Diffusion-Weighted Imaging Hyperintensities in Subtypes of Acute Intracerebral Hemorrhage: Meta-Analysis.

Background and Purpose- Diffusion-weighted imaging (DWI) hyperintensities in intracerebral hemorrhage (ICH) are associated with increased risk of recurrent ICH, cognitive impairment, and death, but whether these lesions are specific to a subtype of ICH remains uncertain. We investigated the association between DWI lesions and ICH subtype and explored the risk factors for DWI lesions. Methods- In a systematic review of ICH studies, we identified those reporting prevalence of DWI lesions. Two reviewers independently assessed study eligibility and risk of bias and collected data. We determined the pooled prevalence of DWI lesions within 90 days after ICH onset for cerebral amyloid angiopathy- and hypertensive angiopathy-related ICH using random-effects meta-analysis. We calculated odds ratios to compare prevalence of DWI lesions by ICH subtype and to assess risk factors for DWI lesions. Results- Eleven studies (1910 patients) were included. The pooled prevalence of DWI lesions was 18.9% (95% CI, 11.1-26.7) in cerebral amyloid angiopathy- and 21.0% (95% CI, 15.3-26.6) in hypertensive angiopathy-related ICH. There was no difference in the prevalence of DWI lesions between cerebral amyloid angiopathy- (64/292 [21.9%]) and hypertensive angiopathy-related ICH (79/370 [21.4%]; odds ratio, 1.25; 95% CI, 0.73-2.15) in the 5 studies reporting data on both ICH pathogeneses. In all ICH, presence of DWI lesions was associated with neuroimaging features of microangiopathy (leukoaraiosis extension, previous ICH, and presence, and number of microbleeds) but not with vascular risk factors or the use of antithrombotic therapies. Conclusions- Prevalence of DWI lesions in acute ICH averages 20%, with no difference between cerebral amyloid angiopathy- and hypertensive angiopathy-related ICH. Detection of DWI lesions may add valuable information to assess the progression of the underlying microangiopathy.

Essen Risk Score in Prediction of Myocardial Infarction After Transient Ischemic Attack or Ischemic Stroke Without Prior Coronary Artery Disease.

Background and Purpose- More intensive secondary prevention with newer drugs may be cost-effective in patients with coronary artery disease (CAD). Whether some subgroups of patients who had a transient ischemic attack (TIA) or ischemic stroke, but no prior CAD are at similar high risk of myocardial infarction as those with prior CAD remains unclear. We determined whether the Essen score identified a subset of TIA/stroke patients without known prior CAD who, nevertheless, had a high risk of myocardial infarction on current secondary prevention management. Methods- In a population-based cohort (Oxford Vascular Study) of consecutive TIA or ischemic stroke patients recruited from 2002 to 2014, 10-year actuarial risks of myocardial infarction and of recurrent ischemic stroke were determined by face-to-face follow-up in patients with and without prior CAD using Kaplan-Meier analyses. Predictive value of the Essen score was assessed with C statistic. Results- Of 2555 patients with TIA/stroke (13 070 patient-years of follow-up), 10-year risk of myocardial infarction in those without prior CAD (n=2017, 78.9%) ranged from 0.9% (95% CI, 0-1.9) at Essen score ≤1 to 29.8% (95% CI, 7.7-46.6) in those with a score ≥5 (C statistic =0.64 [95% CI, 0.57-0.71]; P<0.001). The score tended to be less predictive (difference: P=0.0460) for the risk of recurrent ischemic stroke (C statistic =0.57 [95% CI, 0.54-0.60]). Compared with patients with prior CAD (n=538, 21.1%), an Essen risk score of ≥4 (n=294, 11.5%) in those without prior CAD identified a subgroup at similar high 10-year risks of myocardial infarction (17.2% [95% CI, 6.9-26.3] versus 16.9% [95% CI, 11.5-22.0]) and of recurrent stroke (40.4% [95% CI, 26.7-51.6] versus 32.4% [95% CI, 25.2-38.8]). Conclusions- The Essen score is a simple clinical score to risk-stratify patients with TIA/stroke without prior CAD and to identify subsets who may be at sufficiently high risk of myocardial infarction and recurrent stroke to justify more intensive treatment or inclusion in trials.

Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke.

Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

First International Consensus on the diagnosis and management of fibromuscular dysplasia.

This article is a comprehensive document on the diagnosis and management of fibromuscular dysplasia (FMD), which was commissioned by the working group 'Hypertension and the Kidney' of the European Society of Hypertension (ESH) and the Society for Vascular Medicine (SVM). This document updates previous consensus documents/scientific statements on FMD published in 2014 with full harmonization of the position of European and US experts. In addition to practical consensus-based clinical recommendations, including a consensus protocol for catheter-based angiography and percutaneous angioplasty for renal FMD, the document also includes the first analysis of the European/International FMD Registry and provides updated data from the US Registry for FMD. Finally, it provides insights on ongoing research programs and proposes future research directions for understanding this multifaceted arterial disease.

Development and Validation of a Questionnaire to Assess Barriers to Physical Activity After Stroke: The Barriers to Physical Activity After Stroke Scale.

OBJECTIVE: To develop and validate a self-reported questionnaire assessing the barriers to physical activity (PA) among stroke survivors. DESIGN: Psychometric study. SETTING: Ambulatory stroke care. PARTICIPANTS: A total of one hundred and forty-six (N=146) individuals were included in this study. In stage 1, community-living stroke survivors (n=37; 13 women) with low-moderate disability (modified Rankin Score 0-3, stroke >3mo) were included. In stage 2, participants (n=109; 40 women) with same characteristics were included. Nine professionals experienced in PA for poststroke patients formed an expert panel. INTERVENTIONS: In stage 1, semistructured interviews identified perceived barriers to PA, which were then selected by the expert panel and grouped on a Barriers to Physical Activity After Stroke (BAPAS) scale. In stage 2, stroke participants completed a personal information questionnaire and the BAPAS scale. MAIN OUTCOME MEASURES: An item selection process with factor analysis was carried out. The suitability of the data set was analyzed using the Kaiser-Meyer-Olkin coefficient, internal consistency was evaluated by Cronbach α, and concurrent validity was assessed with Spearman correlation coefficients between the BAPAS scale and the modified Rankin Scale. Test-retest repeatability was estimated using 2-way random effects intraclass correlation coefficient model 2,1 at 4-6 day follow-up (n=21). RESULTS: Factor analysis supported a 14-item BAPAS that explained 62% of total variance (Kaiser-Meyer-Olkin=0.82) and total score calculated higher than 70 (higher scores for higher barriers). Cronbach α was 0.86, Spearman correlation with the modified Rankin Scale was r=0.65 (P<.001), and test-retest intraclass correlation coefficient was 0.91 (95% CI, 0.79-0.97). The BAPAS scores were higher in patients with greater disabilities and in those with a longer time since the stroke event (P<.01). CONCLUSION: We developed and validated the BAPAS scale to assess barriers to PA in stroke survivors with low-moderate disability with promising psychometric properties.

Potent Thrombolytic Effect of N-Acetylcysteine on Arterial Thrombi.

BACKGROUND: Platelet cross-linking during arterial thrombosis involves von Willebrand Factor (VWF) multimers. Therefore, proteolysis of VWF appears promising to disaggregate platelet-rich thrombi and restore vessel patency in acute thrombotic disorders such as ischemic stroke, acute coronary syndrome, or acute limb ischemia. N-Acetylcysteine (NAC, a clinically approved mucolytic drug) can reduce intrachain disulfide bonds in large polymeric proteins. In the present study, we postulated that NAC might cleave the VWF multimers inside occlusive thrombi, thereby leading to their dissolution and arterial recanalization. METHODS: Experimental models of thrombotic stroke induced by either intra-arterial thrombin injection or ferric chloride application followed by measurement of cerebral blood flow using a combination of laser Doppler flowmetry and MRI were performed to uncover the effects of NAC on arterial thrombi. To investigate the effect of NAC on larger vessels, we also performed ferric chloride-induced carotid artery thrombosis. In vitro experiments were performed to study the molecular bases of NAC thrombolytic effect, including platelet aggregometry, platelet-rich thrombi lysis assays, thromboelastography (ROTEM), and high-shear VWF string formation using microfluidic devices. We also investigated the putative prohemorrhagic effect of NAC in a mouse model of intracranial hemorrhage induced by in situ collagenase type VII injection. RESULTS: We demonstrated that intravenous NAC administration promotes lysis of arterial thrombi that are resistant to conventional approaches such as recombinant tissue-type plasminogen activator, direct thrombin inhibitors, and antiplatelet treatments. Through in vitro and in vivo experiments, we provide evidence that the molecular target underlying the thrombolytic effects of NAC is principally the VWF that cross-link platelets in arterial thrombi. Coadministration of NAC and a nonpeptidic GpIIb/IIIa inhibitor further improved its thrombolytic efficacy, essentially by accelerating thrombus dissolution and preventing rethrombosis. Thus, in a new large-vessel thromboembolic stroke model in mice, this cotreatment significantly improved ischemic lesion size and neurological outcome. It is important to note that NAC did not worsen hemorrhagic stroke outcome, suggesting that it exerts thrombolytic effects without significantly impairing normal hemostasis. CONCLUSIONS: We provide evidence that NAC is an effective and safe alternative to currently available antithrombotic agents to restore vessel patency after arterial occlusion.

Treatment and Long-Term Outcomes of Primary Central Nervous System Vasculitis.

Background and Purpose- We aimed to analyze the long-term outcomes of patients with primary central nervous system vasculitis according to the different therapeutic strategies used to induce remission. Methods- We assessed the rate of prolonged remission (defined by the absence of relapse at ≥12 months after diagnosis) and the functional status at last follow-up in patients with primary central nervous system vasculitis included in the French cohort, who achieved a first remission according to the 3 main groups of treatments administered: glucocorticoids only (group 1); induction treatment with glucocorticoids and an immunosuppressant, but no maintenance (group 2); and combined treatment with glucocorticoids and an immunosuppressant for induction followed by maintenance therapy (group 3). Good functional status was defined as a modified Rankin Scale score ≤2 at the last follow-up. Results- Remission was achieved with the initial induction treatment in 106 (95%) of the 112. Prolonged remission without relapse was observed in 70 (66%) patients after 57 (12-198) months of follow-up. A good functional status at last follow-up (ie, modified Rankin Scale score ≤2) was observed in 63 (56%) patients. Overall mortality was 8%. The initial severity and the radiological presentations were comparable in the 3 treatment groups. More prolonged remissions ( P=0.003) and a better functional status at the last follow-up ( P=0.0004) were observed in group 3. In multivariate analysis, the use of maintenance therapy was associated with prolonged remission (odds ratio, 4.32 [1.67-12.19]; P=0.002) and better functional status (odds ratio, 8.09 [3.24-22.38]; P<0.0001). Conclusions- This study suggests that maintenance therapy with an immunosuppressant combined with glucocorticoids lead to the best long-term clinical and functional outcomes in patients with primary central nervous system vasculitis after having achieved remission with either glucocorticoids alone or in combination with another immunosuppressant.

Molecular magnetic resonance imaging discloses endothelial activation after transient ischaemic attack.

SEE SUN ET AL DOI101093/AWW306 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: About 20% of patients with ischaemic stroke have a preceding transient ischaemic attack, which is clinically defined as focal neurological symptoms of ischaemic origin resolving spontaneously. Failure to diagnose transient ischaemic attack is a wasted opportunity to prevent recurrent disabling stroke. Unfortunately, diagnosis can be difficult, due to numerous mimics, and to the absence of a specific test. New diagnostic tools are thus needed, in particular for radiologically silent cases, which correspond to the recommended tissue-based definition of transient ischaemic attack. As endothelial activation is a hallmark of cerebrovascular events, we postulated that this may also be true for transient ischaemic attack, and that it would be clinically relevant to develop non-invasive in vivo imaging to detect this endothelial activation. Using transcriptional and immunohistological analyses for adhesion molecules in a mouse model, we identified brain endothelial P-selectin as a potential biomarker for transient ischaemic attack. We thus developed ultra-sensitive molecular magnetic resonance imaging using antibody-based microparticles of iron oxide targeting P-selectin. This highly sensitive imaging strategy unmasked activated endothelial cells after experimental transient ischaemic attack and allowed discriminating transient ischaemic attack from epilepsy and migraine, two important transient ischaemic attack mimics. We provide preclinical evidence that combining conventional magnetic resonance imaging with molecular magnetic resonance imaging targeting P-selectin might aid in the diagnosis of transient ischaemic attack.

Vascular Tissue-Type Plasminogen Activator Promotes Intracranial Aneurysm Formation.

BACKGROUND AND PURPOSE: Although the mechanisms that contribute to intracranial aneurysm (IA) formation and rupture are not totally elucidated, inflammation and matrix remodeling are incriminated. Because tPA (tissue-type plasminogen activator) controls both inflammatory and matrix remodeling processes, we hypothesized that tPA could be involved in the pathophysiology of IA. METHODS: Immunofluorescence analyses of tPA and its main substrate within the aneurysmal wall of murine and human samples were performed. We then compared the formation and rupture of IAs in wild-type, tPA-deficient and type 1 plasminogen activator inhibitor-deficient mice subjected to a model of elastase-induced IA. The specific contribution of vascular versus global tPA was investigated by performing hepatic hydrodynamic transfection of a cDNA encoding for tPA in tPA-deficient mice. The formation and rupture of IAs were monitored by magnetic resonance imaging tracking for 28 days. RESULTS: Immunofluorescence revealed increased expression of tPA within the aneurysmal wall. The number of aneurysms and their symptomatic ruptures were significantly lower in tPA-deficient than in wild-type mice. Conversely, they were higher in plasminogen activator inhibitor-deficient mice. The wild-type phenotype could be restored in tPA-deficient mice by selectively increasing circulating levels of tPA via hepatic hydrodynamic transfection of a cDNA encoding for tPA. CONCLUSIONS: Altogether, this preclinical study demonstrates that the tPA present in the blood stream is a key player of the formation of IAs. Thus, tPA should be considered as a possible new target for the prevention of IAs formation and rupture.

Adult primary angiitis of the central nervous system: isolated small-vessel vasculitis represents distinct disease pattern.

Objectives: We aimed to identify whether presentations and outcomes in adult patients with isolated small-vessel primary angiitis of the CNS (PACNS) would differ from other patients with large/medium-vessel involvement. Methods: In the French PACNS cohort, we compared the characteristics, treatments and outcomes of patients with isolated small-vessel disease (normal CT, MR and/or conventional angiograms, brain biopsy positive for vasculitis) with other patients who had large/medium-vessel involvement (vessel abnormalities on CT, MR or conventional angiograms). A good functional outcome was defined as a modified Rankin scale ⩽2 at last follow-up, regardless of the occurrence of relapse. Results: Among the 102 patients in the cohort, 26 (25%) had isolated small-vessel PACNS, whereas the 76 others demonstrated large/medium-vessel involvement. Patients with isolated small-vessel PACNS had more seizures (P < 0.0001), cognitive (P = 0.02) or consciousness impairment (P = 0.03) and more dyskinesias (P = 0.002) but less focal deficits (P = 0.0002) than other PACNS patients. They also had more abnormal cerebrospinal fluid analysis (P = 0.008) and gadolinium enhancements on MRI (P = 0.001) but less frequent acute ischaemic lesions (P < 0.0001) than patients with large/medium-vessel involvement. Treatments and modified Rankin scale at last follow-up did not differ between groups. Thirty-two (31%) patients relapsed; 14 (54%) with isolated small-vessel PACNS vs 18 (24%) with large/medium-vessel involvement (P = 0.004). Eight patients died, with no difference between the groups (P = 0.97). Conclusion: In our cohort, adult patients with isolated small-vessel PACNS presented some distinct disease features and relapsed more often than other PACNS patients who had large/medium-vessel involvement. Functional outcomes and mortality did not differ.

Genetic Imbalance in Patients with Cervical Artery Dissection.

BACKGROUND: Genetic and environmental risk factors are assumed to contribute to the susceptibility to cervical artery dissection (CeAD). To explore the role of genetic imbalance in the etiology of CeAD, copy number variants (CNVs) were identified in high-density microarrays samples from the multicenter CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study and from control subjects from the CADISP study and the German PopGen biobank. Microarray data from 833 CeAD patients and 2040 control subjects (565 subjects with ischemic stroke due to causes different from CeAD and 1475 disease-free individuals) were analyzed. Rare genic CNVs were equally frequent in CeAD-patients (16.4%; n=137) and in control subjects (17.0%; n=346) but differed with respect to their genetic content. Compared to control subjects, CNVs from CeAD patients were enriched for genes associated with muscle organ development and cell differentiation, which suggests a possible association with arterial development. CNVs affecting cardiovascular system development were more common in CeAD patients than in control subjects (p=0.003; odds ratio (OR) =2.5; 95% confidence interval (95% CI) =1.4-4.5) and more common in patients with a familial history of CeAD than in those with sporadic CeAD (p=0.036; OR=11.2; 95% CI=1.2-107). CONCLUSION: The findings suggest that rare genetic imbalance affecting cardiovascular system development may contribute to the risk of CeAD. Validation of these findings in independent study populations is warranted.