BACKGROUND:Cerebral edema is a life-threatening complication of ischemic stroke that disproportionally affects patients with large established infarction. We assessed whether endovascular thrombectomy (EVT) reduces or exacerbates edema development, and the association between edema with short-term and long-term outcomes in this high-risk population. METHODS:In this prespecified secondary analysis of the SELECT2 randomized clinical trial (Randomized Controlled Trial to Optimize Patient's Selection for Endovascular Treatment in Acute Ischemic Stroke), which tested the efficacy and safety of EVT versus medical management in adult patients with acute anterior circulation large vessel occlusion presenting with large ischemic core (defined as Alberta Stroke Program Early Computed Tomography Score of 3-5 or core volume ≥50 mL on computed tomography perfusion or diffusion magnetic resonance imaging), we assessed maximum midline shift (MLS) within 7 days of randomization between treatment groups using a probabilistic index model. RESULTS:After exclusion of 10 patients who underwent hemicraniectomy before follow-up imaging, 342 patients were analyzed. The median MLS on follow-up magnetic resonance imaging or computed tomography was 6.39 mm (interquartile range, 0-12.0) in the EVT and 4.18 mm (interquartile range, 0-9.66) in medical management patients (P=0.021). EVT was independently associated with greater MLS (adjusted odds ratio, 1.63 [95% CI, 1.25-2.12]; P=0.0027) after adjusting for age and core volume. There was no interaction between EVT and core volume at presentation on the association with MLS (P>0.79). MLS was associated with the development of early neurological worsening (adjusted odds ratio, 1.15 [95% CI, 1.07-1.23]; P<0.001), and a lower likelihood of long-term functional improvement assessed on modified Rankin Scale score at 90 days (adjusted odds ratio, 0.96 [95% CI, 0.93-0.98]; P=0.0029). On mediation analysis, cerebral edema reduced the effect of EVT on functional outcome by 10.6%. CONCLUSIONS:Despite overall clinical benefit, EVT in patients presenting with a large ischemic core was associated with increased cerebral edema, which, in turn, was associated with early neurological worsening and worse functional outcome at 90 days. Early recognition and individualized treatment to prevent secondary injury from cerebral edema in this population are warranted. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03876457.

INTRODUCTION:Genetic deficiency of factor XI is associated with a reduced risk of ischemic stroke. Asundexian is a direct inhibitor of activated factor XIa (FXIa) with a low risk of bleeding in early trials. We seek to determine its efficacy and safety combined with antiplatelet therapy for prevention of ischemic stroke. PATIENTS AND METHODS:Oral faCtor Eleven A iNhibitor asundexian as novel antithrombotiC (OCEANIC-STROKE) is a placebo-controlled, double-blind, event-driven randomised trial including participants with stroke (NIHSS ≤ 15) or high-risk TIA (ABCD2 6 or 7) within 72 h of onset. Participants had at least one of the following: atherosclerosis of extra- or intracranial vessels, a medical history of atherosclerosis or an imaged acute non-lacunar infarct. We excluded sources of stroke requiring anticoagulation and active non-trivial bleeding other than hemorrhagic infarction (HI 1 or 2). Participants received asundexian 50 mg daily or placebo stratified by planned concurrent antiplatelet therapy (single vs dual). The primary endpoint is time to ischemic stroke. We present baseline characteristics as of 5 June 2025. RESULTS:Between January 2023 and February 2025, we randomised 12,327 participants. Participants were 67% male with a mean (SD) age of 68 (11) years. Ischemic stroke was the index event for 95% of whom 27.4% had thrombolysis and/or mechanical thrombectomy. By TOAST classification, 43% of index strokes were LAA, 22% small vessel disease, 30% undetermined and 2% cardioembolic. Dual antiplatelets were planned in 63% as standard initial treatment. Trial completion is anticipated in October 2025. CONCLUSION:OCEANIC-STROKE will be the first completed trial of FXIa inhibition for prevention of stroke after non-cardioembolic stroke or TIA. TRIAL REGISTRATION:ClinicalTrials.gov (NCT05686070).

BACKGROUND AND PURPOSE:Embolic stroke of undetermined source (ESUS) may be associated with carotid artery plaques with <50% stenosis. Plaque vulnerability is multifactorial, possibly related to intraplaque hemorrhage (IPH), lipid-rich necrotic core, perivascular adipose tissue (PVAT), and calcifications. Machine learning (ML)-based plaque classification is increasingly popular but often limited in clinical interpretability by black-box nature. We applied an explainable ML approach, using noncalcified plaque components and calcification features with the SHapley Additive exPlanations (SHAP) framework to classify plaques as culprit or nonculprit. METHODS:This was a retrospective, cross-sectional study. Patients with unilateral anterior circulation ESUS with calcified carotid plaques in neck computed tomography (CT) angiography were analyzed. Calcification-level features were derived from manual segmentations. Plaque-level features were assessed by a neuroradiologist and by semi-automated software. Plaques were classified as culprit if ipsilateral to stroke side. Eight classifiers were benchmarked, and a gradient-boosted decision tree (CatBoost) was further tuned. SHAP explained model decisions. RESULTS:Seventy patients yielded 116 calcified plaques (270 calcifications). Model based on five plaque- and calcification-level features achieved ROC-AUC (receiver operating characteristic area under the curve) 0.79 and precision-recall-AUC 0.86, outperforming classification based on plaque thickness ≥3 mm (ROC-AUC 0.59, p = 0.04) and IPH presence (ROC-AUC 0.51, p = 0.003). SHAP identified plaque thickness and PVAT volume as the most influential features with potential thresholds of >2.6 mm and ≥112 mm3, respectively.f CONCLUSIONS: ML model trained with noncalcified plaque and calcification features can classify culprit calcified carotid plaque better than conventional criteria. Using clinically interpretable features with SHAP, the model explained its decisions and suggested hypothesis-generating thresholds.

BACKGROUND AND PURPOSE:Carotid webs (CWs) are shelf-like fibrous intimal projections in the carotid bulb that perturb laminar flow, promote local stasis, and predispose to embolic stroke. While morphology correlates with events, in vivo hemodynamic markers of stasis are lacking. We hypothesized that multiphase CT angiography can quantify contrast persistence within web recess, and impaired washout may be associated with stroke/transient ischemic attack. MATERIALS AND METHODS:We retrospectively reviewed head and neck CTA performed between January 2021 and June 2024 in adults whose radiology reports mentioned "web." CWs were confirmed by independent review. Patients were classified as stroke/TIA causing if their ischemic event was attributed to the web, and asymptomatic if the web was incidentally identified or contralateral to the presenting event. Only symptomatic patients and age- and sex-matched asymptomatic patients who underwent multiphase neck CTA were included. ROIs were placed in posterior recess of CWs, proximal and distal arterial lumens. HU were recorded in ROIs on arterial (A) and delayed (D) phases. Aweb and Dweb were defined as web posterior recess HU in both phases; Aref and Dref were defined as the averaged HU from the adjacent proximal and distal arteries. Two indices were derived: contrast-washout ratio (CWR) = (Aweb - Dweb)/(Aref - Dref); contrast-pooling index (CPI) = (Dweb/Dref) - (Aweb/Aref). Continuous variables were compared with t test or Mann-Whitney U test, and categoric variables with Fisher exact tests. RESULTS:Among 190 patients with 206 confirmed webs, we identified 7 symptomatic patients with ischemic stroke/TIA attributed to CW who had neck multiphase CTA and compared with 7 age- and sex-matched asymptomatic patients. Baseline demographics and CW morphology did not differ between cohorts. CWR was lower in symptomatic patients than controls (median [interquartile range (IQR)] 0.672 [0.652-0.920] versus 0.918 [0.819-1.076]; P = .04), indicating reduced washout. CPI was higher in symptomatic patients (median [IQR] 0.098 [0.074-0.212] versus -0.009 [-0.169-0.060]; P = .04), consistent with contrast persistence and blood stasis. CONCLUSIONS:These findings suggest that contrast persistence metrics on multiphase CTA may reflect local stasis within CWs; however, results are preliminary and warrant validation in larger cohorts.

About 10% to 15% of patients with ischemic stroke have a history of cancer, half of whom have active malignancy at the time of stroke. With improved cancer treatments extending patient survival, the coprevalence of these diseases has increased steadily since 2000. This has sparked considerable growth in research and knowledge on this topic. Approximately half of ischemic strokes in patients with active cancer are due to conventional mechanisms, although cancer-related factors may contribute. The remaining half of ischemic strokes in this population are typically classified as cryptogenic or attributed to cancer-specific mechanisms. These cryptogenic strokes often have characteristic risk markers and clinical features and are extremely high risk for recurrent stroke and other adverse events, distinguishing them from other stroke subgroups. Recent epidemiological, translational, and histopathological data indicate that many of these events are likely caused by the cancer itself through multifactorial prothrombotic processes. In this scientific statement incorporating multidisciplinary expertise, we critically appraise and synthesize recent evidence and provide clinical suggestions on the epidemiology, presentation, evaluation, pathophysiology, and treatments for ischemic stroke in patients with active cancer. In addition, we propose a novel classification for ischemic stroke attributed to cancer itself, which we define as cancer-related stroke to enable consistent nomenclature and to harmonize stroke classification across clinical practice and research. This system is based on routinely available clinical data and includes different categories for certainty of causality, relating to the patient's distinctive clinical features and estimated risk for recurrent thromboembolism. We hope this framework spurs dedicated controlled trials to address areas of clinical uncertainty.

Background:CTP has increasingly been incorporated into the evaluation of all patients with suspected acute ischemic stroke (AIS), including those with minor symptoms. We aimed to assess the frequency with which CTP is performed in patients with possible AIS based on NIHSS as well as the role of CTP in acute treatment decision-making among patients with low NIHSS. Methods:We performed a retrospective cohort study of all patients who underwent CTP upon presentation to the ED at 3 academic, urban hospitals in Philadelphia, PA between January 1, 2022 and December 31, 2022. We collected data on initial NIHSS score, AIS treatment decisions, subsequent neuroimaging, and final diagnosis. The study was deemed exempt by the Hospital of the University of Pennsylvania IRB. Results:There were 530 patients with a median age of 65 years (IQR 54-73) and 56% were women. The frequency of CTP by NIHSS is displayed in the figure. A total of 89 CTP studies (16.8%) were performed in patients with very low NIHSS (defined as NIHSS ≤ 2). Of these, just 2 (2.2%) received thrombolysis and 0 (0%) received thrombectomy. CTP did not influence the treatment decision in either case. Conclusions:CTP is frequently performed in patients with low NIHSS. It had limited impact on acute treatment decisions, notably none among those with NIHSS ≤ 2, suggesting that CTP may be over-utilized in this subset of patients with AIS.

Importance:Patent foramen ovale (PFO) closure decreases recurrent stroke but increases atrial fibrillation (AF). Careful selection of patients in whom PFO is more likely to be the cause of stroke may improve outcomes by avoiding closure in patients unlikely to benefit. Objective:To determine whether the PFO-Associated Stroke Causal Likelihood (PASCAL) classification system identifies who will experience net benefit and net harm from PFO closure. Design, Setting, and Participants:This meta-analysis was a secondary analysis of individual participant-level data from the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) consortium meta-analysis, including all 6 randomized trials of transcatheter PFO closure vs antithrombotic therapy alone. Participants were young and middle-aged adults (mean [SD] age, 45 [10] years) with a PFO and an otherwise cryptogenic stroke. The trials were conducted in hospitals in North America, Europe, Australia, Brazil, and South Korea from 2000 to 2017. The current analysis, involving all trial participants, was performed from January to August 2025. Interventions:Transcatheter PFO closure plus antithrombotic therapy vs antithrombotic therapy alone. Main Outcomes and Measures:The primary efficacy end point was recurrent ischemic stroke. The primary safety end point was first-ever detection of AF beyond the periprocedural period (>45 days after randomization). Results:The 6 trials enrolled 3740 patients (1889 who had PFO closure, 1851 who had medical therapy); 2058 patients (55.0%) were male, and 1682 (45.0%) were female. Among patients in all 6 trials, PASCAL classified PFO relatedness to the index stroke as probable in 1382 patients (37.0%), possible in 1811 (48.4%), and unlikely in 547 (14.6%); among the 2967 patients in the 4 trials with broad entry criteria, PASCAL classified PFO relatedness as probable in 860 patients (29.0%), possible in 1565 (52.7%), and unlikely in 543 (18.3%). The reduction in the absolute rate of recurrent ischemic strokes over 5 years was greater than the increase in first-ever detection of AF in the postperiprocedural period as follows: in the probable group, fewer strokes, -2.5% (95% CI, -4.2% to -1.3%) vs more late AF, 1.3% (95% CI, 0.0% to 2.5%), and in the possible group, fewer strokes -3.4% (95% CI, -5.4% to -1.3%) vs more late AF, 1.1% (95% CI, -0.5% to 2.6%). Reduction in recurrent ischemic strokes was not observed and increase in first-ever detected postperiprocedural AF was magnified in the unlikely group (more strokes, 0.4%; 95% CI, -4.0% to 4.8%, vs more late AF, 4.6%; 95% CI, 0.3% to 8.9%). Conclusion and Relevance:Among young and middle-aged patients with PFO and otherwise cryptogenic stroke, the PASCAL classification algorithm distinguished the 4 of every 5 patients in the probable and possible groups with net benefit and the 1 of every 5 patients in the unlikely group with net harm from closure.

In this post hoc analysis of the ANNEXa-I trial (n = 434), we evaluated non-contrast computed tomography (NCCT) markers of hematoma expansion (HE) in factor Xa inhibitor (FXai) -associated intracerebral hemorrhage (ICH). At least one NCCT marker was present in 72.1%, and HE (≥12.5 mL or ≥ 35% increase in hematoma volume) occurred in 31.8%. Heterogeneous density, hypodensity, and the black hole sign were independently associated with HE. The effect of andexanet on HE was generally consistent across NCCT marker subgroups. These findings support the utility of NCCT markers for identifying patients at high risk of HE in FXai-associated ICH. ANN NEUROL 2026.

BACKGROUND AND OBJECTIVES:Carotid webs are an underrecognized cause of ischemic stroke in young adults and are associated with a high risk of recurrence when managed with medical therapy alone. Although carotid endarterectomy (CEA) is increasingly performed, histopathological confirmation remains infrequently reported, and the underlying pathological substrate of symptomatic carotid webs is not well defined. In this study, we present the largest pathologically confirmed series of symptomatic carotid webs treated with CEA, providing a comprehensive clinicopathological characterization and evaluation of long-term surgical outcomes. METHODS:Patients with symptomatic carotid webs were retrospectively identified from institutional databases encompassing both inpatient and outpatient encounters. Clinical features, imaging characteristics, surgical findings, and histopathological results from CEA specimens are presented. RESULTS:Among 39 patients with symptomatic carotid web, 34 underwent CEA with histopathological confirmation of the diagnosis, characterized by focal eccentric intimal fibromyxoid tissue, fibromuscular dysplasia, hyperplasia, or thickening. Notably, concurrent atheromatous changes were noted in 6 patients. All webs were located within 3 cm of the carotid bifurcation, and most (76%) were localized on the posterior wall. Competing stroke mechanisms were identified in 15% of patients. Two-thirds of patients presented with a large or medium vessel occlusion and over half received acute reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy). Two patients experienced transient, minor cranial nerves injuries (hypoglossal nerve and marginal mandibular branch) after CEA. At a median follow-up of 29 months, no patients experienced recurrent stroke (95% CI: 0%-10%), and the median modified Rankin Scale score was 1 (0-1). CONCLUSION:This study supports CEA as a safe and effective therapeutic option for patients with symptomatic carotid webs and demonstrates its diagnostic value through direct histopathological confirmation. By presenting the largest pathologically validated series to date, our findings further define the vascular pathology underlying carotid webs and underscore the diagnostic value of surgical resection for definitive diagnosis.

BACKGROUND:Patients with noncardioembolic ischemic stroke or transient ischemic attack (TIA) are at risk for recurrent stroke. Low factor XI levels are associated with a reduced risk of ischemic stroke. Asundexian inhibits activated factor XI. Whether the addition of asundexian to antiplatelet therapy would be superior to antiplatelet therapy alone for the secondary prevention of ischemic stroke is unclear. METHODS:In this phase 3, double-blind trial, we randomly assigned patients within 72 hours after the onset of a noncardioembolic ischemic stroke or high-risk TIA to receive asundexian (50 mg once daily) or placebo, in addition to planned dual or single antiplatelet therapy. Patients had at least one of the following: a nonlacunar infarct on imaging, a history of atherosclerosis, or evidence of atherosclerotic plaque at any location on cerebrovascular imaging. The primary efficacy outcome was ischemic stroke. The composite of death from cardiovascular causes, myocardial infarction, or stroke was a key secondary outcome. The primary safety outcome was major bleeding. RESULTS:Among 12,327 patients who underwent randomization (6162 to the asundexian group and 6165 to the placebo group), the incidence of ischemic stroke was lower in the asundexian group than in the placebo group (6.2% vs. 8.4%; cause-specific hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.84; P<0.001). The incidence of the composite of death from cardiovascular causes, myocardial infarction, or stroke was lower in the asundexian group than in the placebo group. The incidence of major bleeding was similar in the asundexian group and the placebo group (1.9% and 1.7%, respectively; cause-specific hazard ratio, 1.10; 95% CI, 0.85 to 1.44). The incidence of adverse events was 69.3% in the asundexian group and 70.1% in the placebo group; the incidence of serious adverse events was 19.2% and 19.5%, respectively. CONCLUSIONS:Among patients with noncardioembolic ischemic stroke or high-risk TIA treated with antiplatelet therapy, asundexian at a daily dose of 50 mg resulted in lower risks of ischemic stroke and major cardiovascular events than placebo, without a higher risk of major bleeding. (Funded by Bayer; OCEANIC-STROKE ClinicalTrials.gov number, NCT05686070.).

BACKGROUND:Carotid webs are increasingly recognized as a cause of ischemic stroke, but less is known about morphologically similar lesions in other arteries. We present the first study characterizing the clinical and radiographic features of extra-carotid arterial webs through a single-center case series and systematic review. METHODS:Patients with possible extra-carotid webs were identified from 2017 to 2025 using a natural language processing search of radiology reports at our institution. Candidate cases underwent imaging review with multiplanar and 3-dimensional reconstructions to distinguish webs from fenestrations, vessel tortuosity, dissection, or atherosclerotic plaque. In parallel, we performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review (Web of Science and PubMed, inception to September 2025) to identify published cases of extra-carotid web. Data on demographics, vascular location, imaging modality, clinical presentation, treatment, and outcomes were extracted and synthesized descriptively. RESULTS:Four extra-carotid webs were identified at our institution (3 basilar and 1 subclavian). None were associated with stroke, and all patients remained stable on conservative management during 9 months to 4 years of follow-up. Across 16 published studies, 22 additional extra-carotid webs were identified, yielding 26 patients in aggregate (mean age, 52.7 years; 61.5% male). The vertebral artery was the most common site (53.8%), followed by the basilar (30.8%) and subclavian (15.4%) arteries. Ten patients with vertebral or basilar web presented with posterior circulation ischemic stroke, with recurrent events in 4 patients. Most patients were managed with antiplatelet therapy or observation, while 3 vertebral webs with recurrent stroke were successfully treated with stenting. CONCLUSIONS:Extra-carotid webs share morphological and clinical features with carotid webs and may represent a unified disease spectrum of cervical artery webs. Vertebral and basilar webs, though rare, may be an underrecognized source of posterior circulation stroke. Recognition of these lesions may broaden the differential for cryptogenic stroke though the lack of histopathologic visualization remains a critical limitation of our study.

BACKGROUND:Delayed cerebral ischemia (DCI) after spontaneous subarachnoid hemorrhage (SAH) is not well understood. Recent studies suggest the involvement of neutrophil-mediated immunothrombosis via neutrophil extracellular traps (NETs). We aimed to assess whether trajectories of NET biomarkers in patients with acute SAH are associated with DCI. METHODS:This was a prospective single-center study of patients within 48 hours of SAH onset. We collected clinical, laboratory, imaging, and 3-month outcome data. NET markers (H3Cit [citrullinated histone H3]-DNA complexes, myeloperoxidase-DNA complexes, cell-free DNA), along with peptidylarginine deiminase 4, and deoxyribonuclease activity were measured in plasma collected on admission (baseline), and post-SAH days 5 and 10. DCI was defined by clinical and imaging criteria. Generalized estimating equations examined differences in NET trajectories comparing patients with and without DCI. RESULTS:We enrolled 40 patients with SAH (mean age, 57 years; n=21 [53%] women; 32 [80%] aneurysmal). DCI occurred in 12 (30%) patients. All NET levels were similar between groups at baseline. On day 5, those with DCI compared with those without DCI had elevated median H3Cit-DNA complex (63 ng/mL versus 31 ng/mL, P=0.049), myeloperoxidase-DNA complex (5.9 ng/mL versus 0.4 ng/mL, P=0.029), and cell-free DNA (651 ng/mL versus 515 ng/mL, P=0.04) levels, which trended back down on day 10. In the DCI group, generalized estimating equations indicated heightened trajectories of H3Cit-DNA complex (day 5 [compared with baseline]: β=0.7; SE, 0.3; P=0.01; day 10: β=0.5; SE, 0.3; P=0.09), and myeloperoxidase-DNA complex levels (day 5: β=3.1; SE, 0.4; P<0.001; day 10: β=1.6; SE, 1.0; P=0.10). CONCLUSIONS:In patients with acute SAH, elevated plasma trajectories of NETs are associated with DCI.

Introduction: Embolic stroke of undetermined source (ESUS) may be associated with nonstenotic carotid artery plaques. Noncalcified plaque components such as intraplaque hemorrhage (IPH) as well as perivascular adipose tissue (PVAT) are associated with increased stroke risk, but the role of plaque calcifications is unclear. We examine a machine-learning approach using eXtreme Gradient Boosting (XGBoost) to classify carotid plaques as vulnerable or stable using non-calcified plaque features and calcification morphology. Methods: Patients with neck CT angiography and unilateral anterior circulation ESUS with calcific carotid plaque were retrospectively analyzed. Derived by a combination of manual scoring by a neuroradiologist blinded to stroke side and semi-automated plaque composition segmentation software (Elucid), plaque-level features included plaque thickness, ulceration, composition volumes (IPH, lipid-rich necrotic core, matrix) and PVAT. Calcification-level features, segmented/scored manually with 3D Slicer, included spotty calcification (arc <90 degrees, thickness <3 mm), rim-sign (adventitial site, >90 degrees arc, and 2 mm non-calcified plaque), volume, surface area, roundness, flatness and density. Plaques ipsilateral to stroke side were defined as vulnerable and stable if contralateral. XGBoost models were trained to classify plaques as vulnerable/stable using 1) plaque-level, 2) calcification-level and 3) combination of both features. Data were split into training (80%) and test (20%) sets with 5-fold cross-validation (CV) to ensure consistency. Performance was measured by ROC AUC and accuracy. Results: 71 patients were included [116 calcific carotid plaques; 60 ipsi-, 56 contralateral to stroke; 270 calcifications (146 ipsi-, 124 contralateral)]. 11 plaque-level and 16 calcification-level metrics were extracted. Plaque-level model achieved AUC 0.38 and accuracy 0.38. Calcification-level model achieved AUC 0.60 and accuracy 0.56. Combined model achieved AUC 0.97 and accuracy 0.93, with 5-fold CV score range 0.70-0.93 and mean 0.80. Five most important features for the Combined model were plaque ulceration, calcification surface area, ratio of PVAT to total plaque volume, plaque thickness and PVAT volume. Conclusions: XGBoost model trained with a combination of noncalcified plaque and calcification features can classify plaque as vulnerable with > 90% accuracy, superior to models exclusively trained with plaque-level or calcification-level features.

Background and ObjectivesAlthough previous trials have established the efficacy and safety of endovascular thrombectomy (EVT) in large ischemic core strokes, most of them excluded patients with extracranial internal carotid artery (e-ICA) occlusion. We aimed to compare outcomes in patients with e-ICA occlusion and large ischemic core infarcts treated with EVT vs medical management (MM).MethodsThis was a secondary analysis of the SELECT2 trial, a randomized controlled trial conducted at 31 international sites. Adult patients with proximal intracranial anterior circulation large ischemic strokes, defined as Alberta Stroke Program Early CT Score (ASPECTS) 3-5 on noncontrast CT or ischemic core >= 50 mL on CT-perfusion/magnetic resonance-diffusion imaging, and concomitant e-ICA occlusion were selected. The primary outcomes were the distribution of modified Rankin Scale (mRS) score at 90-day follow-up and symptomatic intracranial hemorrhage (sICH).ResultsAmong 352 enrolled patients, 62 (17.6%) with e-ICA occlusions were included. Of those 62 patients, 37 received EVT (median [interquartile range (IQR)] age, 65 [58-71] years; 15 women [38.5%]) and 25 received MM (median [IQR] age, 66 [61-71] years; 7 women [28%]). ASPECTS (EVT: 5 [3-5] vs MM: 5 [4-5]) and ischemic core volume (EVT: 100 [69-134] mL vs MM: 103 [78-135] mL) were similar between groups. The successful reperfusion rate with EVT was 64.9%. Patients receiving EVT demonstrated significantly better functional outcomes (adjusted generalized odds ratio 2.51; 95% CI 1.43-4.39; p = 0.001) and a higher proportion of patients achieving 90-day independent ambulation (EVT: 37.8% vs MM: 8%; adjusted relative ratio [aRR] 4.58; 95% CI 1.18-17.79; p = 0.037) and functional independence (EVT: 21.6% vs MM: 8%; aRR 2.16; 95% CI 0.53-8.83; p = 0.285). Furthermore, no heterogeneity of EVT benefit was observed by the presence or absence of e-ICA occlusion (p-interaction = 0.248). There were no sICH or parenchymal hemorrhage type 2 events in either group, and mortality was similar in the 2 groups (aRR 0.75; 95% CI 0.39-1.45; p = 0.388).DiscussionAmong patients with e-ICA occlusions and large ischemic core stroke, EVT was associated with better functional outcomes without significant safety concerns when compared with MM. Our findings suggest that EVT in these patients is beneficial, while the optimal treatment of the extracranial carotid occlusion remains unclear.Trial Registration InformationName of the trial: SELECT2 trial. Registration number: ClinicalTrials.gov Identifier: NCT03876457. Date of registration submission: August 3, 2019. Date of first patient enrollment: November 10, 2019.Classification of EvidenceThis study provides Class II evidence that for patients with large core acute ischemic stroke and concomitant e-ICA occlusion, EVT is associated with better functional outcome at 90 days compared with MM alone.

Novel strategies are needed for the treatment of acute ischemic stroke when revascularization therapies are not clinically appropriate or are unsuccessful. rKLK1 (recombinant human tissue kallikrein-1), a bradykinin-producing enzyme, offers a promising potential solution. In animal studies of acute stroke, there is a marked 36-fold increase in bradykinin B2 receptor on brain endothelial cells of the ischemic region. Due to this environment, rKLK1-generated bradykinin will exert a potent local vasodilation and increase brain perfusion via 3 synergistic signaling pathways downstream to the B2 receptor. Because of its preferential effect on ischemic tissue, systemic adverse effects such as hypotension are avoided with proper dosing. In addition, with initial vasodilation through recruitment of preexisting collaterals, rKLK1 promotes long-term benefit of brain perfusion by promoting new collateral formation. With an extended course of therapy for weeks after acute ischemic stroke, these multifaceted effects may also reduce the risk of stroke recurrence. A prior phase II trial demonstrated a favorable impact on clinical outcomes and recurrent strokes, particularly among patients who were not eligible for mechanical thrombectomy. A phase II/III trial has launched in this population, though opportunities for combination revascularization therapies deserve further investigation.

BACKGROUND:We aimed to determine whether extensive severe computed tomography (CT) hypodensity, representing blood-brain barrier injury, would be associated with a reduced benefit of endovascular therapy (EVT) in patients presenting with large core stroke. METHODS:This study is an exploratory analysis of SELECT2 (Randomized Controlled Trial to Optimize Patient's Selection for Endovascular Treatment in Acute Ischemic Stroke), a randomized controlled trial of EVT versus medical management in patients with large ischemic core who presented to 31 comprehensive stroke centers across the United States, Canada, Europe, Australia, and New Zealand. Visible CT hypodensity was outlined, and a threshold of severe CT hypodensity was defined as the lower 99% CI of contralateral thalamic gray matter in Hounsfield units (HU). The association between the volume of severe CT hypodensity and modified Rankin Scale (mRS) score of 0 to 3 was evaluated using logistic regression models, with adjustment for age, National Institutes of Health Stroke Scale, total noncontrast CT core volume, and a volume-by-treatment interaction. The relationship between severe CT hypodensity volume and the probability of an mRS score of 0 to 3 was used to select clinically relevant volume cut points for further evaluation. The treatment effect of EVT versus medical management on independent ambulation and hemicraniectomy was assessed in 2 subgroups based on these volume cut points. RESULTS:In 322 patients, the median CT density was 31 HU (interquartile range, 28-34). The selected threshold of severe CT hypodensity was 26 HU. The volume of ischemic core ≤26 HU (per 1 mL increase) was associated with lower odds of mRS score of 0 to 3 after EVT (adjusted odds ratio [aOR], 0.96 [95% CI, 0.94-0.99]), but not medical management (aOR, 1.01 [95% CI, 0.98-1.03]; Pinteraction<0.01). In 101 patients with ≥26 mL of severe CT hypodensity, EVT, compared with medical management, was not associated with mRS score of 0 to 3 (aOR, 0.98 [95% CI, 0.33-2.88]) and was associated with hemicraniectomy (≥26 mL: aOR, 3.45 [95% CI, 1.09-10.86] versus <26 mL: aOR, 0.74 [95% CI, 0.31-1.75]; Pinteraction=0.03), whereas among 221 patients with <26 mL of severe hypodensity EVT was associated with mRS score of 0 to 3 (aOR, 7.20 [95% CI, 3.55-15.47]; Pinteraction<0.01). CONCLUSIONS:Severe hypodensity within large ischemic regions modifies the thrombectomy treatment effect and increases the likelihood of hemicraniectomy, independent of lesion volume. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03876457.

Background and ObjectivesThe most effective antiseizure medications (ASMs) for poststroke seizures (PSSs) remain unclear. We aimed to determine outcomes associated with ASMs in people with PSS.MethodsWe systematically searched electronic databases for studies on patients with PSS on ASMs. Our outcomes were seizure recurrence, adverse events, drug discontinuation rate, and mortality. We assessed the risk of bias using Cochrane Risk of Bias tool for randomized controlled trials and Risk Of Bias In Non-randomized Studies of Interventions tools. Using levetiracetam as the reference treatment, we conducted a frequentist network meta-analysis and determined the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation methodology.ResultsOur search yielded 15 studies (3 randomized, 12 nonrandomized, N = 18,676 patients (121 early and 18,547 late seizures), 60% male, mean age 69 years) comparing 13 ASMs. Three studies had moderate and 12 had high risk of bias. Seizure recurrence was 24.8%. Compared with levetiracetam, very low-certainty evidence suggested that phenytoin was associated with higher seizure recurrences (odds ratio [OR] 7.3, 95% CI 3.7-14.5) and more adverse events (OR 5.2, 95% CI 1.2-22.9). Low-certainty evidence suggested that carbamazepine (OR 1.8, 95% CI 1.5-2.2) and phenytoin (OR 1.9, 95% CI 1.4-2.8) were associated with high drug discontinuation rates. Moderate to high-certainty evidence suggested that valproic acid (OR 4.7, 95% CI 3.6-6.3) and phenytoin (OR 8.3, 95% CI 5.7-11.9) were associated with higher mortality rates. Considering all treatments and using the GRADE approach for treatment ranking, very low-certainty evidence suggested that eslicarbazepine, lacosamide, and levetiracetam had the fewest seizure recurrences. Low to very low-certainty evidence suggested that lamotrigine had the fewest adverse events and drug discontinuations, whereas lamotrigine and levetiracetam exhibited low mortality rates with moderate-certainty evidence.DiscussionWe found that levetiracetam and lamotrigine may be safe and tolerable ASMs for PSS. Despite ASM use, the seizure recurrence rate remains high in the PSS population. Owing to bias and confounding risks, these findings should be interpreted cautiously.Trial Registration InformationPROSPERO: CRD42022363844.

BACKGROUND: A modified computed tomography angiography (CTA)–based Carotid Plaque Reporting and Data System (Plaque-RADS) classification was applied to a cohort of patients with embolic stroke of undetermined source to test whether high-risk Plaque-RADS subtypes are more prevalent on the ipsilateral side of stroke. With the widespread use of CTA for stroke evaluation, a CTA-based Plaque-RADS would be valuable for generalizability. METHODS: A retrospective observational cross-sectional study was conducted at a single integrated health system comprised of 3 hospitals with a comprehensive stroke center between October 1, 2015, and April 1, 2017. Patients with unilateral anterior circulation stroke and <50% carotid stenosis on CTA were retrospectively identified. Maximum plaque thickness and ulceration were assessed by a neuroradiologist blinded to the stroke side. A semiautomated segmentation software measured intraplaque hemorrhage volumes. Modified CTA-based Plaque-RADS classification was defined as (1) no plaque, (2) plaque thickness <3 mm, (3) plaque thickness ≥3 mm or ulcerated, and (4) plaque with intraplaque hemorrhage >50 mm 3 irrespective of plaque thickness. High-risk plaque subtypes (Plaque-RADS 3 and 4) were compared with low-risk subtypes (Plaque-RADS 1 and 2). RESULTS: Ninety-four patients (55% women; median age, 66 years) were included. CTA-based Plaque-RADS categories for plaques ipsilateral to the stroke side were as follows: (1) 14.9%, (2) 42.6%, (3) 41.5%, and (4) 1.1%. Carotid plaques contralateral to stroke side were Plaque-RADS: (1) 21.3%, (2) 46.8%, (3) 31.9%, and (4) 0%. When compared with the contralateral side, plaques ipsilateral to the stroke side were significantly associated with high-risk Plaque-RADS subtypes in a mixed-effects logistic model adjusting for age and sex (adjusted odds ratio, 2.10 [95% CI, 1.20–3.71]; P =0.01). CONCLUSIONS: Carotid plaque ipsilateral to the stroke side was significantly associated with CTA-based high-risk Plaque-RADS subtypes in an embolic stroke of undetermined source cohort. A CTA-based Plaque-RADS classification may be useful for identifying potentially causative carotid plaque phenotypes in patients with embolic stroke of undetermined source.

BackgroundIndividuals with chronic stroke are less active, which is both a consequence of stroke-related impairments and a risk factor for future health complications. The PROWALKS clinical trial found significant gains in real-world walking activity (steps/day) after 12 weeks of a step activity monitoring behavioral intervention, provided either alone (SAM) or with high-intensity gait training (FAST + SAM), but not after high-intensity gait training alone (FAST). Previous research in individuals after stroke suggests that tailored behavioral counseling may lead to better long-term physical activity participation, but no previous work has focused on post-intervention maintenance of walking activity changes.ObjectiveTo investigate whether steps/day changes after training (POST) were maintained at 6 months (6MO) and 12 months (12MO) after baseline. We hypothesized that SAM and FAST + SAM groups would have better maintenance of steps/day changes than the FAST group. Methods. This analysis included all participants who completed the PROWALKS intervention (n = 200, mean[SD] age: 63.27[12.41], 102 male/98 female, >6 months post-stroke). Analysis outcomes were steps/day change from POST-6MO, and from POST-12MO.ResultsAll groups significantly decreased in steps/day from POST-6MO (P = .001, FAST decreased by mean[SE] 160[272], SAM by 1016[270], FAST + SAM by 400[300]), and POST-12MO (P < .001, FAST decreased by 610[280], SAM by 1072[306], FAST + SAM by 568[313]). There were no significant differences between groups.ConclusionsAll intervention groups showed significant declines in steps/day between POST and 6MO and between POST and 12MO. These results add to a growing body of literature suggesting that a behavioral intervention to initiate behavior change may not be sufficient for maintenance of change.Registration:This study is registered at ClinicalTrials.gov, NCT02835313.

The association of anesthesia approach during endovascular thrombectomy (EVT) with clinical outcomes in large strokes is unexplored. We aimed to evaluate whether general anesthesia (GA), compared with non-GA, was associated with better functional outcomes in the SELECT2 trial. In a prespecified secondary analysis of the SELECT2 trial that enrolled patients with large strokes on noncontrast CT (Alberta Stroke Program Early CT Score [ASPECTS] 3-5), CT perfusion/MRI (core volume ≥50 mL), or both, functional outcomes were compared in EVT-treated patients who received GA or non-GA and whether this association was modified by stroke severity (NIH Stroke Scale score), ischemic injury estimates, and collateral status was evaluated. The primary outcome was 90-day functional status (ordinal modified Rankin Scale [mRS]). Secondary outcomes were functional independence (mRS scores 0-2), independent ambulation (mRS scores 0-3), complete dependence or death (mRS scores 5-6), and mortality. Of 178 EVT patients (median [interquartile range] age 66 [58-75] years, stroke severity 19 [15-23], CT-ASPECTS 4 [3-5], and core volume 101.5 [70-138] mL, 71 women [39.9%]), 104 (58%) received GA. Time from randomization to arterial puncture was longer with GA (40 [23-59] minutes) vs non-GA (27 [18-47] minutes), but procedural duration (GA: 57 [31.5-77] minutes vs non-GA: 49.5 [30-71] minutes) was similar. Successful reperfusion (modified treatment in cerebral infarction [mTICI] score 2b-3) rates were similar (GA 81 (78%) vs non-GA 62 (84%), adjusted relative risk [aRR] 0.91, 95% CI 0.79-1.06). In addition, mRS distribution did not differ between GA and non-GA groups (adjusted generalized odds ratio 1.21, 95% CI 0.86-1.70), as well as independent ambulation (GA: 41% vs non-GA: 34%, aRR 1.22, 95% CI 0.86-1.74) and functional independence (GA: 22% vs non-GA: 18%, aRR 1.32, 95% CI 0.75-2.35). Stroke severity, ASPECTS, ischemic core volume, or collaterals did not modify the association between anesthesia and functional outcome (all p-interaction >0.05). Patients experienced systolic blood pressure (SBP) variability ≥40 mm Hg and minimum intraprocedural SBP (<100 mm Hg) more frequently with GA, but this did not modify GA association with functional outcomes (p-interaction = 0.77 and 0.89, respectively). In patients with large core strokes randomized in SELECT2, EVT outcomes did not differ significantly based on anesthesia approach (GA or non-GA) without heterogeneity across stroke severity and size. While GA was associated with higher SBP variability and lower minimum SBP, this did not modify GA association with functional outcomes. While allocation to anesthesia approach was nonrandomized, our findings suggest that optimizing institutional protocols for preferred anesthesia technique, whether GA or non-GA, may enhance EVT procedural outcomes. ClinicalTrials.gov ID: NCT03876457. This study provides Class II evidence that in patients presenting within 24 hours with large vessel occlusion strokes undergoing EVT, the 90-day mRS score is comparable in those with or without GA.