Post-Stroke Impairments of Manual Dexterity and Finger Proprioception: Their Contribution to Upper Limb Activity Capacity.

BACKGROUND: Knowing how impaired manual dexterity and finger proprioception affect upper limb activity capacity is important for delineating targeted post-stroke interventions for upper limb recovery. OBJECTIVES: To investigate whether impaired manual dexterity and finger proprioception explain variance in post-stroke activity capacity, and whether they explain more variance than conventional clinical assessments of upper limb sensorimotor impairments. METHODS: Activity capacity and hand sensorimotor impairments were assessed using clinical measures in N = 42 late subacute/chronic hemiparetic stroke patients. Dexterity was evaluated using the Dextrain Manipulandum to quantify accuracy of visuomotor finger force-tracking (N = 36), timing of rhythmic tapping (N = 36), and finger individuation (N = 24), as well as proprioception (N = 27). Stepwise multivariate and hierarchical linear regression models were used to identify impairments best explaining activity capacity. RESULTS: Dexterity and proprioceptive components significantly increased the variance explained in activity capacity: (i) Box and Block Test was best explained by baseline tonic force during force-tracking and tapping frequency (adjusted R2 = .51); (ii) Motor Activity Log was best explained by success rate in finger individuation (adjusted R2 = .46); (iii) Action Research Arm Test was best explained by release of finger force and proprioceptive measures (improved reaction time related to use of proprioception; adjusted R2 = .52); and (iv) Moberg Pick-Up test was best explained by proprioceptive function (adjusted R2 = .18). Models excluding dexterity and proprioception variables explained up to 19% less variance. CONCLUSIONS: Manual dexterity and finger proprioception explain unique variance in activity capacity not captured by conventional impairment measures and should be assessed when considering the underlying causes of post-stroke activity capacity limitations.URL: https://www.clinicaltrials.gov. Unique identifier: NCT03934073.

Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

Does Atrial Septal Anatomy Still Matter in the Etiological Evaluation of Ischemic Stroke Beyond the Age of 60?

BACKGROUND: Patent foramen ovale (PFO) is causally associated with stroke in some patients younger than 60 years, especially when it is large or associated with an atrial septal aneurysm (ASA). After 60 years of age, this association is less well understood. We assessed the relationships between detailed atrial septal anatomy and the cryptogenic nature of stroke in this population. METHODS AND RESULTS: We reviewed all patients aged 60 to 80 years admitted to our stroke center for ischemic stroke who underwent contrast echocardiography between 2016 and 2021. The atherosclerosis, small-vessel disease, cardiac pathology, other causes, and dissection (ASCOD) classification was used to reevaluate the etiological workup. Associations between cryptogenic stroke and (1) PFO presence or (2) categories of PFO anatomy (nonlarge PFO without ASA, nonlarge PFO with ASA, large PFO without ASA, and large PFO with ASA) were assessed using logistic regression. Among 533 patients (median National Institutes of Health Stroke Scale score=1), PFO was present in 152 (prevalence, 28.5% [95% CI, 24.9-32.5]). Compared with noncryptogenic stroke, cryptogenic stroke (n=218) was associated with PFO presence (44.5% versus 17.5%; P<0.0001). Among patients with a PFO, septal anatomy categories were associated with cryptogenic stroke (P=0.02), with a strong association for patients with both large PFO and ASA (38.1% versus 14.5%, P=0.002). CONCLUSIONS: PFO presence remains strongly associated with cryptogenic stroke between 60 and 80 years of age. Large PFO, ASA, and their association were strongly associated with cryptogenic stroke in this age group. Our results support performing contrast echocardiography even after 60 years of age, although the optimal secondary prevention therapy in this population remains to be determined in randomized trials.

Effect of the Factor XIa Inhibitor Asundexian According to Baseline Infarct Pattern and on MRI Covert Infarct Outcomes.

BACKGROUND: Exploratory analysis of the phase 2 PACIFIC-Stroke (Program of Anticoagulation via Inhibition of FXIa by the Oral Compound BAY 2433334-Non-Cardioembolic Stroke) randomized trial suggested that asundexian, an oral factor XIa inhibitor, prevents recurrent stroke and transient ischemic attacks in patients with atherosclerotic stroke. In this post hoc exploratory analysis, we hypothesized that asundexian would be more effective in patients enrolled with large, multiple, or cortical acute infarcts on magnetic resonance imaging than in patients enrolled with a single small subcortical acute infarct, and asundexian would prevent incident cortical covert infarcts. METHODS: In this placebo-controlled double-blinded randomized controlled trial, patients with mild-to-moderate noncardioembolic ischemic stroke were assigned to asundexian (10, 20, or 50 mg once daily) or placebo, in addition to antiplatelet therapy. Brain magnetic resonance imagings were required within 72 hours of randomization and repeated at 26 weeks or at discontinuation of the study drug. RESULTS: Of 1808 randomized patients, 1780 (98.5%) had interpretable baseline magnetic resonance imagings, of which 1628 (91.5%) had ≥1 diffusion-weighted imaging positive acute infarcts. Magnetic resonance imaging follow-up was obtained in 1439 patients, of whom 1358 had no symptomatic stroke during the trial period. Compared with placebo, asundexian 50 mg daily conferred a trend toward reduced risk of recurrent ischemic stroke or incident covert infarcts (hazard ratio, 0.71 [95% CI, 0.45-1.11]) and recurrent ischemic stroke or transient ischemic attack (secondary outcome; hazard ratio, 0.59 [95% CI, 0.33-1.06]) that was not evident in patients with single small subcortical infarcts (hazard ratios, 1.14 [95% CI, 0.62-2.10] and 0.93 [95% CI, 0.28-3.06]). Incident cortical covert infarcts were reduced in patients taking asundexian 50 mg, but the difference was not statistically significant (crude incidence ratio, 0.56 [95% CI, 0.28-1.12]). CONCLUSIONS: These exploratory, unconfirmed results suggest that asundexian may prevent new embolic infarcts but not small artery occlusion. The hypothesis that subtypes of covert brain infarcts respond differently to anticoagulant prevention should be tested in future trials. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04304508.

Case report: Meningitis: a cause of reversible cerebral vasoconstriction syndrome?

Introduction: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by thunderclap headache and reversible cerebral arteries vasoconstriction. The pathophysiology remains unclear, but many triggers were reported. Case reports: We reported two cases of patients with meningitis who developed RCVS confirmed by brain imaging. They presented clinical and CSF features of meningitis that are suspected to be infectious, but no agent was identified. Headache and artery irregularities were resolved with the improvement of CSF. Conclusion: These cases suggest that in the context of meningitis, modification or atypical headaches should lead to brain imaging to rule out RCVS. We hypothesized that CSF inflammation may trigger cerebral arteries vasoconstriction.

Efficacy of interactive manual dexterity training after stroke: a pilot single-blinded randomized controlled trial.

OBJECTIVE: To compare the efficacy of Dextrain Manipulandum™ training of dexterity components such as force control and independent finger movements, to dose-matched conventional therapy (CT) post-stroke. METHODS: A prospective, single-blind, pilot randomized clinical trial was conducted. Chronic-phase post-stroke patients with mild-to-moderate dexterity impairment (Box and Block Test (BBT) > 1) received 12 sessions of Dextrain or CT. Blinded measures were obtained before and after training and at 3-months follow-up. Primary outcome was BBT-change (after-before training). Secondary outcomes included changes in motor impairments, activity limitations and dexterity components. Corticospinal excitability and short intracortical inhibition (SICI) were measured using transcranial magnetic stimulation. RESULTS: BBT-change after training did not differ between the Dextrain (N = 21) vs CT group (N = 21) (median [IQR] = 5[2-7] vs 4[2-7], respectively; P = 0.36). Gains in BBT were maintained at the 3-month post-training follow-up, with a non-significant trend for enhanced BBT-change in the Dextrain group (median [IQR] = 3[- 1-7.0], P = 0.06). Several secondary outcomes showed significantly larger changes in the Dextrain group: finger tracking precision (mean ± SD = 0.3 ± 0.3N vs - 0.1 ± 0.33N; P < 0.0018), independent finger movements (34.7 ± 25.1 ms vs 7.7 ± 18.5 ms, P = 0.02) and maximal finger tapping speed (8.4 ± 7.1 vs 4.5 ± 4.9, P = 0.045). At follow-up, Dextrain group showed significantly greater improvement in Motor Activity Log (median/IQR = 0.7/0.2-0.8 vs 0.2/0.1-0.6, P = 0.05). Across both groups SICI increased in patients with greater BBT-change (Rho = 0.80, P = 0.006). Comparing Dextrain subgroups with maximal grip force higher/lower than median (61.2%), BBT-change was significantly larger in patients with low vs high grip force (7.5 ± 5.6 vs 2.9 ± 2.8; respectively, P = 0.015). CONCLUSIONS: Although immediate improvements in gross dexterity post-stroke did not significantly differ between Dextrain training and CT, our findings suggest that Dextrain enhances recovery of several dexterity components and reported hand-use, particularly when motor impairment is moderate (low initial grip force). Findings need to be confirmed in a larger trial. Trial registration ClinicalTrials.gov NCT03934073 (retrospectively registered).

Impact of Cerebral Microbleeds in Stroke Patients with Atrial Fibrillation.

OBJECTIVES: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet). METHODS: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use. RESULTS: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years). INTERPRETATION: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023;94:61-74.

Safety of Carotid Endarterectomy for Symptomatic Stenosis by Age: Meta-Analysis With Individual Patient Data.

BACKGROUND: There is uncertainty whether elderly patients with symptomatic carotid stenosis have higher rates of adverse events following carotid endarterectomy. In trials, recurrent stroke risk on medical therapy alone increased with age, whereas operative stroke risk was not related. Few octogenarians were included in trials and there has been no systematic analysis of all study types. We aimed to evaluate the safety of carotid endarterectomy in symptomatic elderly patients, particularly in octogenarians. METHODS: We did a systematic review and meta-analysis of studies (from January 1, 1980 through March 1, 2022) reporting post carotid endarterectomy risk of stroke, myocardial infarction, and death in patients with symptomatic carotid stenosis. We included observational studies and interventional arms of randomized trials if the outcome rates (or the raw data to calculate these) were provided. Individual patient data from 4 prospective cohorts enabled multivariate analysis. RESULTS: Of 47 studies (107 587 patients), risk of perioperative stroke was 2.04% (1.94-2.14) in octogenarians (390 strokes/19 101 patients) and 1.85% (1.75-1.95) in nonoctogenarians (1395/75 537); P=0.046. Perioperative death was 1.09% (0.94-1.25) in octogenarians (203/18 702) and 0.53% (0.48-0.59) in nonoctogenarians (392/73 327); P<0.001. Per 5-year age increment, a linear increase in perioperative stroke, myocardial infarction, and death were observed; P=0.04 to 0.002. However, during the last 3 decades, perioperative stroke±death has declined significantly in octogenarians (7.78% [5.58-10.55] before year 2000 to 2.80% [2.56-3.04] after 2010); P<0.001. In Individual patient data multivariate-analysis (5111 patients), age ≥85 years was independently associated with perioperative stroke (P<0.001) and death (P=0.005). Yet, survival was similar for octogenarians versus nonoctogenarians at 1-year (95.0% [93.2-96.5] versus 97.5% [96.4-98.6]; P=0.08), as was 5-year stroke risk (11.93% [9.98-14.16]) versus 12.78% [11.65-13.61]; P=0.24). CONCLUSIONS: We found a modest increase in perioperative risk with age in symptomatic patients undergoing carotid endarterectomy. As stroke risk increases with age when on medical therapy alone, our findings support selective urgent intervention in symptomatic elderly patients.

Association of Atrial Septal Aneurysm and Shunt Size With Stroke Recurrence and Benefit From Patent Foramen Ovale Closure.

Importance: The Patent Foramen Ovale (PFO)-Associated Stroke Causal Likelihood classification system combines information regarding noncardiac patient features (vascular risk factors, infarct topography) and PFO features (shunt size and presence of atrial septal aneurysm [ASA]) to classify patients into 3 validated categories of responsiveness to treatment with PFO closure. However, the distinctive associations of shunt size and ASA, alone and in combination, have not been completely delineated. Objective: To evaluate the association of PFO closure with stroke recurrence according to shunt size and/or the presence of an ASA. Design, Setting, and Participants: Pooled individual patient data from 6 randomized clinical trials conducted from February 2000 to October 2017 that compared PFO closure with medical therapy. Patients in North America, Europe, Australia, Brazil, and South Korea with PFO-associated stroke were included. Analysis was completed in January 2022. Exposures: Transcatheter PFO closure plus antithrombotic therapy vs antithrombotic therapy alone, stratified into 4 groups based on the combination of 2 features: small vs large PFO shunt size and the presence or absence of an ASA. Main Outcomes and Measures: Recurrent ischemic stroke. Results: A total of 121 recurrent ischemic strokes occurred in the pooled 3740 patients (mean [SD] age, 45 [10] years; 1682 [45%] female) during a median (IQR) follow-up of 57 (23.7-63.8) months. Treatment with PFO closure was associated with reduced risk for recurrent ischemic stroke (adjusted hazard ratio [aHR], 0.41 [95% CI, 0.28-0.60]; P < .001). The reduction in hazard for recurrent stroke was greater for patients with both a large shunt and an ASA (aHR, 0.15 [95% CI, 0.06-0.35]) than for large shunt without ASA (aHR, 0.27 [95% CI, 0.14-0.56]), small shunt with ASA (aHR, 0.36 [95% CI, 0.17-0.78]), and small shunt without ASA (aHR, 0.68 [95% CI, 0.41-1.13]) (interaction P = .02). At 2 years, the absolute risk reduction of recurrent stroke was greater (5.5% [95% CI, 2.7-8.3]) in patients with large shunt and ASA than for patients in the other 3 categories (1.0% for all). Conclusions and Relevance: Patients with both a large shunt and an ASA showed a substantially greater beneficial association with PFO closure than patients with large shunt alone, patients with small shunt and ASA, and patients with neither large shunt nor ASA. These findings, combined with other patient features, may inform shared patient-clinician decision-making.

Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Asundexian (Bayer AG, Leverkusen, Germany), an oral small molecule factor XIa (FXIa) inhibitor, might prevent thrombosis without increasing bleeding. Asundexian's effect for secondary prevention of recurrent stroke is unknown. METHODS: In this randomised, double-blind, placebo-controlled, phase 2b dose-finding trial (PACIFIC-Stroke), patients with acute (within 48 h) non-cardioembolic ischaemic stroke were recruited from 196 hospitals in 23 countries. Patients were eligible if they were aged 45 years or older, to be treated with antiplatelet therapy, and able to have a baseline MRI (either before or within 72 h of randomisation). Eligible participants were randomly assigned (1:1:1:1), using an interactive web-based response system and stratified according to anticipated antiplatelet therapy (single vs dual), to once daily oral asundexian (BAY 2433334) 10 mg, 20 mg, or 50 mg, or placebo in addition to usual antiplatelet therapy, and were followed up during treatment for 26-52 weeks. Brain MRIs were obtained at study entry and at 26 weeks or as soon as possible after treatment discontinuation. The primary efficacy outcome was the dose-response effect on the composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischaemic stroke at or before 26 weeks after randomisation. The primary safety outcome was major or clinically relevant non-major bleeding as defined by International Society on Thrombosis and Haemostasis criteria. The efficacy outcome was assessed in all participants assigned to treatment, and the safety outcome was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04304508, and is now complete. FINDINGS: Between June 15, 2020, and July 22, 2021, 1880 patients were screened and 1808 participants were randomly assigned to asundexian 10 mg (n=455), 20 mg (n=450), or 50 mg (n=447), or placebo (n=456). Mean age was 67 years (SD 10) and 615 (34%) participants were women, 1193 (66%) were men, 1505 (83%) were White, and 268 (15%) were Asian. The mean time from index stroke to randomisation was 36 h (SD 10) and median baseline National Institutes of Health Stroke Scale score was 2·0 (IQR 1·0-4·0). 783 (43%) participants received dual antiplatelet treatment for a mean duration of 70·1 days (SD 113·4) after randomisation. At 26 weeks, the primary efficacy outcome was observed in 87 (19%) of 456 participants in the placebo group versus 86 (19%) of 455 in the asundexian 10 mg group (crude incidence ratio 0·99 [90% CI 0·79-1·24]), 99 (22%) of 450 in the asundexian 20 mg group (1·15 [0·93-1·43]), and 90 (20%) of 447 in the asundexian 50 mg group (1·06 [0·85-1·32]; t statistic -0·68; p=0·80). The primary safety outcome was observed in 11 (2%) of 452 participants in the placebo group versus 19 (4%) of 445 in the asundexian 10 mg group, 14 (3%) of 446 in the asundexian 20 mg group, and 19 (4%) of 443 in the asundexian 50 mg group (all asundexian doses pooled vs placebo hazard ratio 1·57 [90% CI 0·91-2·71]). INTERPRETATION: In this phase 2b trial, FXIa inhibition with asundexian did not reduce the composite of covert brain infarction or ischaemic stroke and did not increase the composite of major or clinically relevant non-major bleeding compared with placebo in patients with acute, non-cardioembolic ischaemic stroke. FUNDING: Bayer AG.

A novel tablet-based application for assessment of manual dexterity and its components: a reliability and validity study in healthy subjects.

BACKGROUND: We developed five tablet-based tasks (applications) to measure multiple components of manual dexterity. AIM: to test reliability and validity of tablet-based dexterity measures in healthy participants. METHODS: Tasks included: (1) Finger recognition to assess mental rotation capacity. The subject taps with the finger indicated on a virtual hand in three orientations (reaction time, correct trials). (2) Rhythm tapping to evaluate timing of finger movements performed with, and subsequently without, an auditory cue (inter-stimulus interval). (3) Multi-finger tapping to assess independent finger movements (reaction time, correct trials, unwanted finger movements). (4) Sequence tapping to assess production and memorization of visually cued finger sequences (successful taps). (5) Line-tracking to assess movement speed and accuracy while tracking an unpredictably moving line on the screen with the fingertip (duration, error). To study inter-rater reliability, 34 healthy subjects (mean age 35 years) performed the tablet tasks twice with two raters. Relative reliability (Intra-class correlation, ICC) and absolute reliability (Standard error of measurement, SEM) were established. Task validity was evaluated in 54 healthy subjects (mean age 49 years, range: 20-78 years) by correlating tablet measures with age, clinical dexterity assessments (time taken to pick-up objects in Box and Block Test, BBT and Moberg Pick Up Test, MPUT) and with measures obtained using a finger force-sensor device. RESULTS: Most timing measures showed excellent reliability. Poor to excellent reliability was found for correct trials across tasks, and reliability was poor for unwanted movements. Inter-session learning occurred in some measures. Age correlated with slower and more variable reaction times in finger recognition, less correct trials in multi-finger tapping, and slower line-tracking. Reaction times correlated with those obtained using a finger force-sensor device. No significant correlations between tablet measures and BBT or MPUT were found. Inter-task correlation among tablet-derived measures was weak. CONCLUSIONS: Most tablet-based dexterity measures showed good-to-excellent reliability (ICC ≥ 0.60) except for unwanted movements during multi-finger tapping. Age-related decline in performance and association with finger force-sensor measures support validity of tablet measures. Tablet-based components of dexterity complement conventional clinical dexterity assessments. Future work is required to establish measurement properties in patients with neurological and psychiatric disorders.

Diagnostic performance of dynamic 3D magnetic resonance angiography in daily practice for the detection of intracranial arteriovenous shunts in patients with non-traumatic intracranial hemorrhage.

Introduction: Identification of treatable causes of intracranial hemorrhage (ICH) such as intracranial arteriovenous shunt is crucial to prevent recurrence. However, diagnostic approaches vary considerably across centers, partly because of limited knowledge of the diagnostic performance of first-line vascular imaging techniques. We assessed the diagnostic performance of dynamic three-dimensional magnetic resonance angiography (dynamic 3D MRA) in daily practice to detect intracranial arteriovenous shunts in ICH patients against subsequent digital subtraction angiography (DSA) as reference standard. Methods: We reviewed all adult patients who underwent first-line dynamic 3D MRA and subsequent DSA for non-traumatic ICH between January 2016 and September 2021 in a tertiary center. Sensitivity, specificity, accuracy, positive and negative predictive values of dynamic 3D MRA for the detection of intracranial arteriovenous shunt were calculated with DSA as reference standard. Results: Among 104 included patients, 29 (27.9%) had a DSA-confirmed arteriovenous shunt [19 pial arteriovenous malformations, 10 dural arteriovenous fistulae; median onset-to-DSA: 17 (IQR: 3-88) days]. The sensitivity and specificity of dynamic 3D MRA [median onset-to-dynamic 3D MRA: 14 (3-101) h] for the detection of intracranial arteriovenous shunt were 66% (95% CI: 48-83) and 91% (95% CI: 84-97), respectively. The corresponding accuracy, positive and negative predictive values were 84% (95% CI: 77-91), 73% (95% CI: 56-90), and 87% (95% CI: 80-95), respectively. Conclusion: This study suggests that although first-line evaluation with dynamic 3D MRA may be helpful for the detection of intracranial arteriovenous shunts in patients with ICH, additional vascular imaging work-up should not be withheld if dynamic 3D MRA is negative. Comparative prospective studies are needed to determine the best imaging strategy to diagnose arteriovenous shunts after non-traumatic ICH.

Heterogeneity of Treatment Effects in an Analysis of Pooled Individual Patient Data From Randomized Trials of Device Closure of Patent Foramen Ovale After Stroke.

Importance: Patent foramen ovale (PFO)-associated strokes comprise approximately 10% of ischemic strokes in adults aged 18 to 60 years. While device closure decreases stroke recurrence risk overall, the best treatment for any individual is often unclear. Objective: To evaluate heterogeneity of treatment effect of PFO closure on stroke recurrence based on previously developed scoring systems. Design, Setting, and Participants: Investigators for the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) Consortium pooled individual patient data from all 6 randomized clinical trials that compared PFO closure plus medical therapy vs medical therapy alone in patients with PFO-associated stroke, and included a total of 3740 participants. The trials were conducted worldwide from 2000 to 2017. Exposures: PFO closure plus medical therapy vs medical therapy alone. Subgroup analyses used the Risk of Paradoxical Embolism (RoPE) Score (a 10-point scoring system in which higher scores reflect younger age and the absence of vascular risk factors) and the PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System, which combines the RoPE Score with high-risk PFO features (either an atrial septal aneurysm or a large-sized shunt) to classify patients into 3 categories of causal relatedness: unlikely, possible, and probable. Main Outcomes and Measures: Ischemic stroke. Results: Over a median follow-up of 57 months (IQR, 24-64), 121 outcomes occurred in 3740 patients. The annualized incidence of stroke with medical therapy was 1.09% (95% CI, 0.88%-1.36%) and with device closure was 0.47% (95% CI, 0.35%-0.65%) (adjusted hazard ratio [HR], 0.41 [95% CI, 0.28-0.60]). The subgroup analyses showed statistically significant interaction effects. Patients with low vs high RoPE Score had HRs of 0.61 (95% CI, 0.37-1.00) and 0.21 (95% CI, 0.11-0.42), respectively (P for interaction = .02). Patients classified as unlikely, possible, and probable using the PASCAL Classification System had HRs of 1.14 (95% CI, 0.53-2.46), 0.38 (95% CI, 0.22-0.65), and 0.10 (95% CI, 0.03-0.35), respectively (P for interaction = .003). The 2-year absolute risk reduction was -0.7% (95% CI, -4.0% to 2.6%), 2.1% (95% CI, 0.6%-3.6%), and 2.1% (95% CI, 0.9%-3.4%) in the unlikely, possible, and probable PASCAL categories, respectively. Device-associated adverse events were generally higher among patients classified as unlikely; the absolute risk increases in atrial fibrillation beyond day 45 after randomization with a device were 4.41% (95% CI, 1.02% to 7.80%), 1.53% (95% CI, 0.33% to 2.72%), and 0.65% (95% CI, -0.41% to 1.71%) in the unlikely, possible, and probable PASCAL categories, respectively. Conclusions and Relevance: Among patients aged 18 to 60 years with PFO-associated stroke, risk reduction for recurrent stroke with device closure varied across groups classified by their probabilities that the stroke was causally related to the PFO. Application of this classification system has the potential to guide individualized decision-making.

Statistical reanalysis of vascular event outcomes in primary and secondary vascular prevention trials.

BACKGROUND: Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them. METHODS: Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared individual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p-value given the smallest rank. Friedman and Duncan's multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test. RESULTS: Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes. CONCLUSIONS: Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials.

Balancing Benefits and Risks of Long-Term Antiplatelet Therapy in Noncardioembolic Transient Ischemic Attack or Stroke.

Background and Purpose: Lifelong treatment with antiplatelet drugs is recommended following a transient ischemic attack or ischemic stroke. Bleeding complications may offset the benefit of antiplatelet drugs in patients at increased risk of bleeding and low risk of recurrent ischemic events. We aimed to investigate the net benefit of antiplatelet treatment according to an individuals' bleeding risk. Methods: We pooled individual patient data from 6 randomized clinical trials (CAPRIE [Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events], ESPS-2 [European Stroke Prevention Study-2], MATCH [Management of Atherothrombosis With Clopidogrel in High-Risk Patients], CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance], ESPRIT [European/Australasian Stroke Prevention in Reversible Ischemia Trial], and PRoFESS [Prevention Regimen for Effectively Avoiding Second Strokes]) investigating antiplatelet therapy in the subacute or chronic phase after noncardioembolic transient ischemic attack or stroke. Patients were stratified into quintiles according to their predicted risk of major bleeding with the S2TOP-BLEED score. The annual risk of major bleeding and recurrent ischemic events was assessed per quintile for 4 scenarios: (1) aspirin monotherapy, (2) aspirin-clopidogrel versus aspirin or clopidogrel monotherapy, (3) aspirin-dipyridamole versus clopidogrel, and (4) aspirin versus clopidogrel. Net benefit was calculated for the second, third, and fourth scenario. Results: Thirty seven thousand eighty-seven patients were included in the analyses. Both risk of major bleeding and recurrent ischemic events increased over quintiles of predicted bleeding risk, but risk of ischemic events was consistently higher (eg, from 0.7%/y (bottom quintile) to 3.2%/y (top quintile) for major bleeding on aspirin and from 2.5%/y to 10.2%/y for risk of ischemic events on aspirin). Treatment with aspirin-clopidogrel led to more major bleedings (0.9%­1.7% per year), than reduction in ischemic events (ranging from 0.4% to 0.9/1.0% per year) across all quintiles. There was no clear preference for either aspirin-dipyridamole or clopidogrel according to baseline bleeding risk. Conclusions: Among patients with a transient ischemic attack or ischemic stroke included in clinical trials of antiplatelet therapy, the risk of recurrent ischemic events and of major bleeding increase in parallel. Antiplatelet treatment cannot be individualized solely based on bleeding risk assessment.

[Patent foramen ovale and stroke]. / Foramen ovale perméable et infarctus cérébral.

"Patent foramen ovale and stroke Patent foramen ovale (PFO) is a remnant of the fetal circulation whose role in the occurrence of ischemic stroke is now well established. Trancatheter PFO closure followed by long-term antiplatelet therapy reduces by approximately 60% compared to antithrombotic therapy alone, the risk of stroke recurrence in patients aged 60 years or less with an ischemic stroke attributed to a PFO. Patients with PFO associated with an atrial septal aneurysm or with a large right-to-left shunt might be the best candidates. The superiority of oral anticoagulants over aspirin is uncertain. Their benefit compared to PFO closure is unknown. Other studies are needed to: (i) precisely define the patients who benefit the most, little or not at all from PFO closure, (ii) assess the long-term prognosis of atrial fibrillation induced by PFO closure, (iii) evaluate the benefit of the closure in patients not included in the therapeutic trials, in particular patients over the age of 60, (iv) evaluate the role of oral anticoagulants compared to aspirin and to PFO closure."

"Foramen ovale perméable et infarctus cérébral Le foramen ovale perméable est un vestige de la circulation foetale, dont le rôle dans la survenue d'infarctus cérébraux est désormais bien établi. Sa fermeture par voie endovasculaire suivie d'un traitement antiplaquettaire au long cours réduit d'environ 60 % par rapport à un traitement antithrombotique seul le risque de récidive chez les patients âgés de 60 ans ou moins ayant un infarctus cérébral attribué à un foramen ovale perméable. Les patients ayant un foramen ovale perméable associé à anévrisme du septum auriculaire et ceux ayant un foramen ovale perméable isolé avec shunt important pourraient être les meilleurs candidats. La supériorité des anticoagulants oraux comparativement à l'aspirine est incertaine. Leur bénéfice, comparativement à la fermeture du foramen, est inconnu. D'autres études sont nécessaires notamment pour : définir précisément les patients qui bénéficient le plus, peu ou pas du tout de la fermeture du foramen ovale perméable ; évaluer le pronostic à long terme des fibrillations atriales induites par la fermeture du foramen ovale perméable ; évaluer le bénéfice de la fermeture chez les patients non inclus dans les essais thérapeutiques, notamment ceux de plus de 60 ans ; et pour évaluer le rôle des anticoagulants oraux comparativement à l'aspirine et à la fermeture du foramen."

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.

Depressive-, Cognitive- or Stroke-Related Risk Factors of Post-Stroke Depression: Which One Could Better Help Clinicians and Patients?

PURPOSE: Post-stroke depression (PSD) affects one third of stroke survivors, with multiple severe negative consequences. We aim to assess the weight of four different types of clinical risk factors for PSD. PATIENTS AND METHODS: We conducted a prospective cohort study in a stroke centre. After stroke, patients were assessed for cognitive performances, psychiatric standardized questionnaires and socio-demographic features. They were called three months after and assessed for major depressive episode using DSM criteria. RESULTS: PSD was diagnosed in 8 of the 59 (13.6%) patients enrolled in the study. After multivariate analysis, only "previous history of depressive episode" remained a significant predictive factor for PSD, the model explaining 19% of the total variance (OR=18.0; p=0.002). Patients with a previous history of depression had a 10-fold increased risk for PSD. CONCLUSION: Previous history of depression is confirmed as a strong risk factor for PDS and allow the identification of an at-risk sub-group of patients.

Transcranial color-coded duplex sonography reliably identifies intracranial vasculopathy in adult patients with sickle cell disease.

In order to prevent stroke, screening for disease-related intracranial vasculopathy using Doppler ultrasound is recommended in sickle-cell disease (SCD) children. How to screen such vasculopathy in adults remains largely unknown. The objective of this study was to assess whether transcranial color-coded duplex sonography (TCCD) is sensitive and specific enough to identify SCD adult patients with vasculopathy, compared with magnetic resonance angiography (MRA). Sickle cell disease adults followed in referral centers at high risk of vasculopathy were included in this study. Transcranial color-coded duplex sonography examination and 3-D time-of-flight MRA were performed on the same day. On MRA, vasculopathy was defined by the presence of at least one ≥50% arterial stenosis. On TCCD, vasculopathy was defined by a time-averaged mean of the maximum velocity (TAMx) stenotic/prestenotic ratio ≥ 3, an occlusion, or a Moyamoya pattern. Vasculopathy was also considered as present when TAMx ratio could not be calculated because of the presence of severe cervical lesions. Among 80 included patients, quality of MRA was insufficient in three patients. Among the 38 patients with vasculopathy on MRA, 37 had a vasculopathy according to TCCD criteria: TAMx ratio ≥ 3 or intracranial occlusion in 33 patients and cervical lesion in four patients. A Moyamoya pattern was identified with TCCD in all 17 patients with Moyamoya on MRA. Sensitivity and specificity of TCCD to identify patients with ≥50% vasculopathy on MRA were (n = 37/38) 97% and (n = 28/34) 82%, respectively. Positive and negative predictive values were (n = 37/43) 86% and (n = 28/29) 97%, respectively. Note, TCCD may be used to identify SCD adult patients with vasculopathy.

Editor's Choice - Risk of Stroke before Revascularisation in Patients with Symptomatic Carotid Stenosis: A Pooled Analysis of Randomised Controlled Trials.

OBJECTIVE: Current guidelines recommending rapid revascularisation of symptomatic carotid stenosis are largely based on data from clinical trials performed at a time when best medical therapy was potentially less effective than today. The risk of stroke and its predictors among patients with symptomatic carotid stenosis awaiting revascularisation in recent randomised controlled trials (RCTs) and in medical arms of earlier RCTs was assessed. METHODS: The pooled data of individual patients with symptomatic carotid stenosis randomised to stenting (CAS) or endarterectomy (CEA) in four recent RCTs, and of patients randomised to medical therapy in three earlier RCTs comparing CEA vs. medical therapy, were compared. The primary outcome event was any stroke occurring between randomisation and treatment by CAS or CEA, or within 120 days after randomisation. RESULTS: A total of 4 754 patients from recent trials and 1 227 from earlier trials were included. In recent trials, patients were randomised a median of 18 (IQR 7, 50) days after the qualifying event (QE). Twenty-three suffered a stroke while waiting for revascularisation (cumulative 120 day risk 1.97%, 95% confidence interval [CI] 0.75 - 3.17). Shorter time from QE until randomisation increased stroke risk after randomisation (χ2 = 6.58, p = .011). Sixty-one patients had a stroke within 120 days of randomisation in the medical arms of earlier trials (cumulative risk 5%, 95% CI 3.8 - 6.2). Stroke risk was lower in recent than earlier trials when adjusted for time between QE and randomisation, age, severity of QE, and degree of carotid stenosis (HR 0.47, 95% CI 0.25 - 0.88, p = .019). CONCLUSION: Patients with symptomatic carotid stenosis enrolled in recent large RCTs had a lower risk of stroke after randomisation than historical controls. The added benefit of carotid revascularisation to modern medical care needs to be revisited in future studies. Until then, adhering to current recommendations for early revascularisation of patients with symptomatic carotid stenosis considered to require invasive treatment is advisable.