Jaime Masjuan

BACKGROUND: OCEANIC-STROKE (XXX) showed that asundexian added to antiplatelet therapy reduced ischemic stroke without significantly increasing bleeding in patients with noncardioembolic ischemic stroke or high-risk transient ischemic attack. We characterized bleeding categories, sites, and key subgroups. METHODS: In the safety population, 12 254 participants received at least 1 dose of asundexian (n=6124) or placebo (n=6130). Bleeding was categorized by International Society on Thrombosis and Haemostasis criteria as major, clinically relevant nonmajor (CRNM), or minor. While-on-treatment analyses included events through 2 days after the last dose, with death and permanent discontinuation as competing risks. RESULTS: Major bleeding occurred in 117 (1.9%) participants with asundexian and 107 (1.7%) with placebo (cause-specific hazard ratio [csHR], 1.10 [95% CI, 0.85–1.44]; P =0.46). Major or CRNM bleeding occurred in 339 (5.5%) and 307 (5.0%), respectively (csHR, 1.12 [95% CI, 0.96–1.30]; P =0.16), and any bleeding in 763 (12.5%) and 752 (12.3%) (csHR, 1.02 [95% CI, 0.93–1.13]; P =0.65). Treatment effects for major and major or CRNM bleeding were consistent across prespecified subgroups, including planned dual antiplatelet therapy. Symptomatic intracranial hemorrhage occurred in 41 (0.7%) and 36 (0.6%) participants. Any gastrointestinal bleeding occurred in 186 (3.0%) and 147 (2.4%) (csHR, 1.28 [95% CI, 1.03–1.59]), and lower gastrointestinal bleeding in 102 (1.7%) and 59 (1.0%) (csHR, 1.75 [95% CI, 1.27–2.41]), primarily rectal bleeding. Any procedure-related bleeding and any mucosal bleeding did not differ significantly. CONCLUSIONS: Asundexian added to antiplatelet therapy reduced ischemic stroke without significantly increasing major, major or CRNM, or any bleeding. Lower gastrointestinal bleeding was more frequent with asundexian, whereas treatment effects on major and major or CRNM bleeding were consistent across prespecified subgroups. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT05686070.

BACKGROUND Progression independent of relapse activity (PIRA) is a major driver of long-term disability in multiple sclerosis (MS), yet its diagnosis remains retrospective, delaying treatment adaptation. Objective, real-time tools to anticipate PIRA are lacking. OBJECTIVE This study aimed to identify the most effective machine-learning model for PIRA prediction using passively acquired smartphone data and to evaluate its diagnostic performance. METHODS We conducted a prospective observational cohort study at a single MS center (November 2021–January 2024). Adults (≥18 years) with confirmed MS, compatible smartphone use, and ≥12 months follow-up were included. A custom mobile application continuously captured typing dynamics, extracting tapping speed as a digital biomarker. Time-series were analyzed using mixed linear regression and ARIMA models. Longitudinal data were transformed into a supervised learning dataset by segmenting the time series into overlapping temporal windows, each treated as an independent sample. The dataset was split into training, validation, and test sets (70/15/15) to develop and evaluate machine-learning models (XGBoost, TimesNet, and Transformers). The primary outcome was prediction of a clinically confirmed PIRA event. RESULTS Ninety-nine patients (median age 47 years, 63% women, median Expanded Disability Status Scale 2.5) completed follow-up; 14 developed PIRA. Baseline characteristics were comparable between groups. Time-series decomposition revealed distinct dynamics (Akaike Information Criterion [AIC]: 69.7 vs 108.0) between patients who developed PIRA and those who did not. A total of 25,440 temporal windows were generated. Among all models, TimesNet achieved the best performance, with accuracy 99.7%, precision 97% (95% CI 94–99), sensitivity 100% (95% CI 95–100), specificity 100% (95% CI 96–100), and F1-score 98%. CONCLUSIONS Passive smartphone monitoring enables continuous assessment of motor function in MS. TimesNet outperformed other models for early PIRA detection, supporting its potential as a digital biomarker of progression risk. These findings warrant prospective multicenter validation for individualized disease monitoring.

Background: Plasma exchange (PE) is a therapeutic option for CNS demyelinating attacks unresponsive to corticosteroids, but the potential benefit of adding rituximab and IV immunoglobulins to PE (RTX-IVIG-PE), which has shown its efficacy and safety in other immune-mediated conditions, has not been investigated. Objective: We aimed to determine the overall effectiveness of PE in severe demyelinating attacks, identify predictors of response, and compare outcomes between standard PE and RTX-IVIG-PE protocols. Design: Retrospective analysis of patients with CNS demyelinating attacks treated with PE between 2012 and 2023 across five Spanish hospitals. Methods: Clinical response was measured as an improvement or a complete recovery at discharge and 6 months. Uni- and multivariable logistic regression models were developed to identify predictors of PE response. A logistic regression analysis, after inverse probability of treatment weighting (IPTW), was performed to compare the outcome of attacks treated with standard PE and RTX-IVIG-PE. Results: A total of 162 attacks in 150 patients (81 multiple sclerosis; 37 others acquired demyelinating syndromes; 27 neuromyelitis optica spectrum disorder; 5 myelin oligodendrocyte glycoprotein antibody-associated disease; 73% female; median age 43 years (interquartile range 33–52.75)) were analyzed. At discharge, 60% of all attacks showed clinical improvement, and 15% achieved complete recovery. At 6 months, these rates increased to 77% and 31%, respectively. Younger age, lower preattack Expanded Disability Status Scale, and treatment with RTX-IVIG-PE were independent predictors of complete recovery at 6 months. IPTW analysis showed that attacks treated with RTX-IVIG-PE (33) were associated with improvement (adjusted odds ratio (aOR) 5.4, p < 0.001) and complete recovery (aOR 4.55, p < 0.001) at 6 months compared to those treated with standard PE (129), without significant differences in the adverse event profile between the two protocols. Conclusion: PE improves the outcome of steroid-refractory CNS demyelinating attacks, and the addition of rituximab and IVIG to PE may increase the likelihood of long-term recovery.

BACKGROUND: Glenzocimab, a platelet glycoprotein VI antagonist, is a novel agent that inhibits platelet activation and aggregation. Its safety was demonstrated in the ACTIMIS trial (Acute Ischemic Stroke Interventional Study; URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03803007) for patients with stroke receiving thrombolysis, with or without mechanical thrombectomy, and results suggested a reduction in intracranial hemorrhages and mortality. The ACTISAVE trial was designed as a confirmatory study to evaluate the efficacy and safety of glenzocimab in acute ischemic stroke. METHODS: ACTISAVE (Acute Ischemic Stroke Study Evaluating Glenzocimab Used as Add-On Therapy Versus Placebo) was an international, randomized, double-blind, placebo-controlled phase 2/3 study in patients with stroke, treated by thrombolysis within 4.5 hours of symptoms onset with or without mechanical thrombectomy. The study was conducted at 54 primary and comprehensive stroke centers located in 10 countries. Patients were randomized 1:1 to glenzocimab (1000 mg-IV) or placebo. The primary outcome was the modified Rankin Scale (mRS) score of 4 to 6 at day 90. Key secondary outcome was the mRS score of 0 to 2 at day 90. Mortality, mRS shift, National Institutes of Health Stroke Scale score, quality of life, and safety outcomes were assessed. RESULTS: Between September 2021 and October 2023, 438 patients were randomized, 421 treated, and included as randomized in the primary analysis set. Median age was 73 (63–80) years, and 43% were female. Thrombolysis was performed 2.3 hours (median) after symptom onset and followed by mechanical thrombectomy in 36% of patients. The assigned treatment began a median of 1.2 (interquartile range, 0.8–1.6) hours after thrombolysis initiation. Prethrombolysis National Institutes of Health Stroke Scale score median was 9 (6–15). At day 90, there was no statistically significant difference in the primary outcome between the treatment groups: the incidence of poor outcome (mRS score 4–6 versus 0–3) was 21.6% in the glenzocimab group compared with 15.3% placebo group (odds ratio, 1.51 [95% CI, 0.90–2.54]; P =0.120). No statistically significant difference in secondary outcomes was observed. There were no major safety signals with any intracerebral hemorrhage occurring respectively in 60 (28.6%) and 63 (29.9%) patients in glenzocimab and placebo arms. CONCLUSIONS: ACTISAVE failed to confirm a beneficial effect of glenzocimab on mRS in patients with acute ischemic stroke treated by thrombolysis. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05070260.

Introduction: The incidence and outcomes of seizures among patients with severe cerebral venous thrombosis treated with decompressive surgery are unknown as are potential predictors of seizures in these patients. Patients and methods: We report data from a multicenter, consecutive cohort including patients with cerebral venous thrombosis treated with decompressive surgery from 15 hospitals in 10 different countries between December 2011 and December 2019. We analyzed the cumulative incidence of seizures within one year after decompressive surgery and performed an exploratory analysis of potential factors associated with the incidence of post-surgery seizures, adjusted for competing mortality risk. Results: Of 116 included patients (median age 38 years [IQR 27–46], 68% female), 26 (22%) had seizures within one year after decompressive surgery. The mortality-adjusted cumulative one-year incidence of a first seizure after surgery was 23% (95% CI 16–31). Only aphasia at presentation predicted post-surgery seizures. Among patients who had a post-surgery seizure, the first seizure occurred despite active treatment with anti-seizure medications in 83% of patients. Recurrent seizures within the first year after surgery were reported in 63% of patients. Discussion and conclusion: Despite extensive use of anti-seizure medications, in patients with cerebral venous thrombosis treated with decompressive surgery the rate of seizures was 23% (95% CI 16–31) within one year after surgery. Of the patients who had a seizure after surgery, 63% had a recurrent seizure within the first year post-surgery.

Knowing the precise etiology in ischemic stroke is necessary to ensure accurate diagnosis and decide on appropriate preventive treatments, especially in those of undetermined cause. Analysis of the thrombus protein composition could be useful to identify diagnostic biomarkers to help determine the stroke origin. Thrombi from 54 ischemic stroke patients with large vessel occlusion (LVO), of cardioembolic and atherothrombotic etiology, were analyzed using a proteomics approach. The proteome profile was compared between them to detect differential proteins of each etiology. Peptides of those differential proteins were quantified and related to the neurological function and clinical status of the patients. Of the 516 proteins identified, three showed significant differences between atherothrombotic and cardioembolic thrombi. These were fibronectin (FINC), 2,3-bisphosphoglycerate mutase (PMGE), and tropomyosin-1 (TPM1). Combining these proteins in a biomarker panel provided good sensitivity and high specificity for differentiating cardioembolic and atherothrombotic strokes. In addition, several of the quantified peptide levels correlated with clinical parameters related to stroke severity and prognosis. Three proteins differentially detected in ischemic stroke thrombi could be useful tools for accurately diagnosing ischemic stroke etiology, particularly in cases of undetermined cause. These biomarkers should be further analyzed in prospective multicenter studies to demonstrate their usefulness.