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Introduction: Intracranial atherosclerosis (ICAS) is a leading cause of ischemic stroke (IS) worldwide and carries a high risk of recurrence. Current guidelines favor 90 days of dual antiplatelet therapy (DAPT) for severe symptomatic ICAS, but recurrence remain high. Limited data suggest possible benefit of single antiplatelet plus anticoagulation (SAPT+AC). We compared the effectiveness and safety of DAPT versus SAPT+AC. We hypothesized that DAPT would lower 90-day recurrent IS risk without significantly increasing bleeding. Methods: This substudy of the Biomarkers and Recurrence Risk in Symptomatic Intracranial Arterial Stenosis (BIORISK-ICAS) included patients from 35 centers (Jan 2019–Jun 2024) with symptomatic 50–99% ICAS in the intracranial internal carotid, vertebral, basilar, or M1 segment of the MCA, presenting ≤72 hours from last known well. The primary efficacy outcome was recurrent IS in the same vascular territory at 90 days; the primary safety outcome was severe bleeding (symptomatic intracranial hemorrhage or major extracranial bleeding). Categorical variables were compared using χ 2 and continuous variables with the Student's t test; multivariable Cox regression adjusted for key covariates. Results: Of 2050 BIORISK-ICAS patients, 1658 met criteria (DAPT n=1499; SAPT+AC n=159). Mean age was 67 vs. 73 years, and 44% were women. At 90 days, recurrent IS occurred in 121 DAPT patients (8.07%) vs. 13 SAPT+AC patients (8.17%); unadjusted HR 0.83 (95% CI, 0.50–1.36; p=0.46). After adjustment for age, diabetes, coronary heart disease, atrial fibrillation, active smoking, and borderzone infarct, the adjusted HR was 0.99 (95% CI, 0.52–1.86; p=0.97). Severe bleeding occurred in 34 DAPT patients (2.26%) and 5 SAPT+AC patients (3.14%); unadjusted HR 0.79 (95% CI, 0.28–1.85; p=0.50), adjusted HR 0.66 (95% CI, 0.21–2.09; p=0.47). Conclusions: In patients with symptomatic ICAS, DAPT and SAPT+AC were associated with similar risks of 90-day recurrent ischemic stroke and severe bleeding. Well-powered randomized trials are needed to determine the optimal antithrombotic regimen in this high-risk population.

Background: Although the embolic stroke of undetermined source (ESUS) construct was proposed as a unifying concept for embolic-appearing strokes without an identified cause, it includes patients with diverse and often unrecognized underlying mechanisms. This study investigates the differential rate of recurrent stroke according to the completeness of neurodiagnostic testing in a diverse multicenter cohort. Methods: This was a retrospective analysis of a multicenter observational cohort study (n=27 sites). Patients with ESUS were categorized into three groups: (1) established mechanism after further work up (ESUS-E), (2) patients who underwent a comprehensive diagnostic workup without an identified etiology (ESUS 2.0), and (3) no advanced workup (ESUS-NAW). The primary outcome of recurrent ischemic stroke was assessed by comparing ESUS 2.0 to both ESUS-E and ESUS-NAW groups using adjusted Cox proportional hazards models. Results: Of the 2,281 patients included, 694 (30%) were classified as ESUS-E, 344 (15%) as ESUS 2.0, and 1,443 (55%) as ESUS-NAW. The ESUS 2.0 group had a significantly lower annualized recurrence rate (1.98 per 100 person-years) compared to both the ESUS-NAW group (7.7 per 100 person-years; aHR 0.27, 95% CI: 0.11–0.62; p=0.002) and the ESUS-E group (6.10 per 100 person-years; aHR = 0.35; 95% CI 0.15–0.85, p=0.020). Within the ESUS-E group, cancer (aHR 5.33; 95% CI: 2.09–13.63; p < 0.001) and non-stenosing atherosclerotic disease or arch atheroma (aHR 3.40; 95% CI: 1.18–9.83; p = 0.023) were associated with significantly increased risk of recurrence when compared to ESUS 2.0. Conclusion: These findings demonstrate a lower risk of recurrent stroke in patients classified as ESUS 2.0, diverging from the 5–6% annual recurrence rates observed in prior ESUS trials. These findings suggest that patients who receive comprehensive diagnostic evaluation without identification of a specific etiology have a lower risk of recurrent stroke, an important consideration for the design of future ESUS studies.

Background and Objectives: Cervical artery dissection (CeAD) is a common cause of ischemic stroke in young adults. We aim to identify age-based differences in clinical presentation, imaging findings, and outcomes after CeAD. Methods: This was a sub-study using the STOP-CAD registry, a multicenter cross-sectional international retrospective study of patients diagnosed with CeAD and treated with an antithrombotic from January 1, 2015 to December 31, 2021. Baseline clinical and imaging characteristics were compared between younger and older adults with CeAD (≤45 versus >45 years of age) using multivariable logistic regression. We chose this age cut off due to its frequent usage in stroke in the young literature. Multiple logistic regression models were used to determine association between young age and outcomes after CeAD (ischemic stroke at 180 days, excellent functional outcome with modified Rankin Scale of 0-1 at 90 days, and mortality) after adjusting for sex, vascular risk factors, CeAD characteristics, and NIHSS on presentation. Results: Among 4023 CeAD patients included in the study, 1901 (47.3%) were ≤45 years of age. Patients were followed for a median of 307 days (IQR 102-831). Young adults with CeAD were more likely to be women (Odds Ratio [OR], 2.4; 95% CI, 2.1-2.9; p<0.001), of Hispanic ethnicity (OR, 1.8; 95% CI 1.3-2.5; p<0.001), have a history of migraines (OR, 1.6; 95% CI, 1.3-2.0; p<0.001) and recent neck trauma (OR, 1.6; 95% CI, 1.3-1.9; p<0.001) while having fewer traditional vascular risk factors. Young adults with CeAD had higher odds of a non-ischemic presentation (OR, 1.3; 95% CI, 1.1-1.5; p=0.013), vertebral artery dissection (OR 2.5; 95% CI, 2.2-3.0; p<0.001), and multivessel involvement (OR 1.5; 95% CI, 1.1-1.9; p=0.004). In adjusted analysis, younger age was not associated with an increased risk of recurrent ischemic stroke (adjusted Hazard Ratio [HR], 0.48; 95% CI 0.2-1.2; p=0.119). Younger age was associated with significantly greater odds of excellent functional outcome at 90 days (aOR, 1.48; 1.20-1.84, p<0.001) and lower risk of death at follow up (aHR, 0.37; 95% CI, 0.17-0.81; p=0.012) after CeAD. Conclusion: In a large international cohort, young adults with CeAD had a distinct clinical phenotype with higher odds of non-ischemic presentation, vertebral artery dissection, and multivessel involvement while having fewer traditional vascular risk factors. Young adults had a decreased odds of disability and mortality after CeAD.

BACKGROUND: Cervical artery dissection (CeAD) may result in dissecting aneurysm (DA) formation. We aimed to characterize risk factors and clinical outcomes associated with DA in a large, international CeAD cohort. METHODS: We performed a secondary analysis of STOP-CAD (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection), an international, multicenter, retrospective cohort. Patients with spontaneous CeAD were assessed for DA at baseline and de novo DA formation. Significant covariates in univariable analysis were included in multivariable regression models aiming to identify factors associated with DA formation. Logistic regression and Cox proportional hazards models evaluated the association of DA with ischemic and hemorrhagic outcomes. RESULTS: Among 4008 patients with CeAD, 546 (13.6%) had a DA at baseline, and 221/2938 (7.5%) patients developed a de novo DA during follow-up, of which 172/221 (78.2%) were detected in the first 180 days. Patients with DA had a mean age of 47 years, and 383 (49.9%) were women. Baseline or de novo DA was associated with a history of connective tissue disorder (adjusted odds ratio [aOR], 2.02 [95% CI, 1.22–3.36]), fibromuscular dysplasia (aOR, 1.69 [95% CI, 1.28–2.25]), and multiple vessel dissection (aOR, 1.53 [95% CI, 1.19–1.98]). Lower odds of DA were seen in Hispanic ethnicity (aOR, 0.64 [95% CI, 0.43–0.97]) and ischemic stroke presentation (aOR, 0.41 [95% CI, 0.34–0.49]). Fibromuscular dysplasia was associated with de novo DA formation (aOR, 2.30 [95% CI, 1.52–3.49]). DA was not associated with ischemic stroke (hazard ratio, 0.71 [95% CI, 0.44–1.16]; P =0.173) or intracranial hemorrhage (HR, 1.09 [95% CI, 0.42–2.84]; P =0.86) by day 180. CONCLUSIONS: DAs are relatively common manifestations of CeAD, typically occurring within 6 months of CeAD diagnosis. DA was not associated with an increased risk of subsequent ischemic stroke or intracranial hemorrhage.

Abstract Introduction Cervical arterial dissections (CeAD) can involve either single (sCeAD) or multiple (mCeAD) arteries. Whether the involvement of a single versus multiple arteries is associated with outcomes remains unclear. We aimed to study associations between the number of affected arteries and clinical, imaging and outcome parameters. Patients and methods Patients with CeAD from the STOP-CAD multicenter registry study were included. Clinical, imaging, treatment and outcome parameters were compared between patients with sCeAD and mCeAD. Regression analyses were performed to identify associations with multi-arteries involvement. Results Overall, 3858 STOP-CAD patients were included in this analysis and 443 (11.5%) had mCeAD. The presence of mCeAD was associated with age (adjusted odds ratio [aOR] 95% confidence intervals [95% CI] 0.99; (0.98–1.00)), female sex (aOR 1.5; 95% CI 1.17–1.91), recent upper respiratory infection (aOR 2.25; 95% CI 1.55–3.27), presence of connective tissue disease (aOR 3.11; 95% CI 2.32–4.17), severe arterial stenosis (aOR 1.95; 95% CI 1.95–2.58), intracranial extension (aOR 1.47; 95% CI 1.04–2.09), vertebral artery involvement (aOR 2.50; 95% CI 1.94–3.22) and presence of dissecting aneurysm (aOR 2.59; 95% CI 1.95–3.42). In adjusted analyses, mCeAD was not associated with clinical outcomes (ischemic stroke, mortality, and sICH; all p &gt; 0.05). Conclusions mCeAD does not appear to increase risk of subsequent stroke as compared to sCAD despite baseline risk factors suggestive of vasculopathy. mCeAD patients who did develop a stroke presented with milder strokes and less often had vessel occlusions compared to those with sCeAD. The presence of mCeAD did not impact outcomes.

BACKGROUND: Patients with cervical artery dissection (CeAD) may experience a recurrent dissection, but its frequency, risk factors, and clinical implications are not well defined. We aimed to determine the risk, associated factors, and clinical impact of recurrent CeAD. METHODS: The STOP-CAD study (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection) was a multicenter international retrospective observational study of patients with CeAD treated between January 2015 and June 2022. Recurrent dissection was defined as a CeAD occurring at least 7 days after the diagnosis of the index event that affects a different artery or a different segment of the same artery. Patients were followed from day 7 up to 2 years. The absolute risk of recurrent CeAD over time was calculated using Kaplan-Meier survival estimates. Multivariable logistic and Cox regression models were used to assess predictors of CeAD recurrence. RESULTS: Of the 4023 patients included in STOP-CAD, 3836 (median age 46 years, 45% women) were eligible for this analysis. During a median (interquartile range) follow-up of 295 (97–720) days, 88 (2.29%) patients had a CeAD recurrence. Median time-to-recurrent CeAD was 53 (interquartile range, 18–157) days. The estimated risk of recurrent CeAD at 2 years was 3.22% (95% CI, 2.59%–4.00%). In multivariable analyses, younger age (adjusted odds ratios, 0.98 [95% CI, 0.96–0.99]), migraine (adjusted odds ratio, 1.88 [95% CI, 1.14–3.07]), and fibromuscular dysplasia (adjusted odds ratio, 2.90 [95% CI, 1.66–5.06]) were associated with CeAD recurrence, while presenting with an ischemic stroke was associated with a lower likelihood of recurrence (adjusted odds ratio, 0.47 [95% CI, 0.29–0.75]). These associations with CeAD recurrence over time were confirmed by Cox regression analyses. Among the 88 patients with recurrent CeAD, only 5 had accompanying ischemic events (3 strokes, 2 transient ischemic attacks). CONCLUSIONS: In this retrospective study, recurrent CeAD was uncommon, approximately half of the events were diagnosed within the first 2 months of the index event, and recurrent events rarely caused new ischemic events. Younger age, migraine, absence of ischemic stroke at presentation, and signs of fibromuscular dysplasia may help identify high-risk patients.

Objective Cervical artery dissection (CeAD) may be limited to the extracranial extradural space or extend to the intradural space. Intradural extension can potentially increase the risk of stroke and subarachnoid hemorrhage. However, the factors associated with intradural extension and its impact on clinical outcome remain unclear. Methods This was a secondary analysis of the STOP‐CAD observational, multi‐center study. Patients with CeAD and intradural extension (CeADid) were compared with those with pure CeAD extradural dissections (CeADed) using multiple regression analyses. Results Of 4,023 patients with CeAD, 534 (13.3%) had CeADid. In comparison to patients with CeADed, those with CeADid more often had clinical overt stroke or transient ischemic attack (TIA) at presentation, acute infarcts on imaging, a vertebral artery affected, and severe stenosis of the involved vessel ( p < 0.001 for all). In contrast, carotid involvement and complete occlusions were more frequent in patients with CeADed ( p < 0.001 for both). CeADid was associated with a shift in the distribution of scores on the modified Rankin Scale (mRS) toward worse functional outcome (odds ratio [OR] = 0.76, 95% confidence interval [CI] = 0.62–0.92) but the odds for favorable outcomes (mRS = 0–2) did not differ between the groups after appropriate adjustments on multivariate analysis. CeADid was independently associated with higher mortality at 180 days on multivariate analysis (adjusted OR = 2.84, 95% CI = 1.50–5.38). Interpretation CeADid is associated with more severe clinical presentation, a shift toward less favorable outcomes, and higher mortality rates. These findings suggest that CeADid may represent a high‐risk type of CeAD. ANN NEUROL 2026;99:1189–1197

BACKGROUND: Intracranial atherosclerosis (ICAS) is associated with an increased risk of early recurrent ischemic stroke. We evaluated whether biomarkers of impaired distal perfusion—specifically, anterior circulation borderzone infarct, and hypoperfusion mismatch volume—were associated with recurrent ischemic stroke within 90 days. METHODS: The BIORISK ICAS (Biomarkers and Recurrence Risk in Symptomatic Intracranial Atherosclerosis) is a multicenter retrospective international study (35 sites) that included hospitalized patients with symptomatic ICAS (50%–99% luminal stenosis of the intracranial vertebral, basilar, distal internal carotid, or proximal middle cerebral artery) from January 2019 to June 2024. The primary outcome was recurrent ischemic stroke in the territory of the symptomatic artery within 90 days. In the primary analysis, the exposure was an acute anterior circulation borderzone infarct. In secondary analysis of the subset with presentation within 72 hours of last known normal and perfusion imaging completed, the exposure of interest was prespecified as hypoperfusion mismatch volume at T max (time to maximum) threshold of 6 seconds, dichotomized at the Youden index. We performed multivariable Cox regression to test associations between exposure variables and the outcome, adjusting for clinically relevant variables and those associated with the outcome ( P <0.1). RESULTS: Of 2050 patients with symptomatic ICAS, 1737 (84.7%) presented within 72 hours of symptom onset, among whom 509 (29.3%) underwent perfusion imaging. The primary analysis included 1891 patients; 174 (9.2%) patients had recurrent ischemic stroke in the symptomatic arterial territory. In adjusted Cox regression models, there was an association between anterior circulation borderzone infarct and recurrent ischemic stroke at 90 days (adjusted hazard ratio, 1.40 [95% CI, 1.02–1.93]). In the perfusion imaging analysis, hypoperfusion mismatch of ≥10 mL was associated with recurrent ischemic stroke (adjusted hazard ratio, 1.83 [95% CI, 1.03–3.28]). CONCLUSIONS: Biomarkers of impaired distal perfusion, anterior circulation borderzone infarct, and hypoperfusion mismatch were associated with increased risk of recurrent ischemic stroke. These findings support the use of perfusion imaging in ICAS as well as future trials investigating early reperfusion in high-risk patients with ICAS.

Background Intracranial occlusions in embolic stroke of undetermined source are histopathologically similar to cardiac sources of embolism. Whether patients with embolic stroke of undetermined source and intracranial occlusion benefit from anticoagulation is unknown. Methods A multicenter retrospective cohort of adults with cryptogenic stroke was queried for patients with proximal or medium/distal vessel occlusion. The primary outcome was recurrent ischemic stroke, which was assessed in unadjusted and adjusted Cox proportional hazards models and repeated following 1:1 propensity score matching and biweight kernel density matching. Results Of the 2328 patients who were followed over a median of 1.31 years (interquartile range, 0.34–2.85), 999 (42.6%) had an intracranial occlusion. When compared with patients without an intracranial occlusion, those with an occlusion had fewer atherosclerotic vascular risk factors, more severe symptoms, and less severe cerebral microvascular disease. The rate of recurrent stroke was similar between patients with versus without an intracranial occlusion (6.8%/year [95% CI, 5.7–8.2] versus 7.0%/year [95% CI 6.0–8.1]; adjusted hazard ratio [HR], 1.09 [95% CI, 0.77–1.55]). There was no association between occlusion and recurrent stroke in the adjusted propensity score matching (HR, 1.01 [95% CI, 0.64–1.59]) or kernel density models (HR, 0.95 [95% CI, 0.62–1.45]). There was no interaction between occlusion and treatment with anticoagulation, sex, age, or high‐risk sources of embolism for the primary outcome in the unmatched and matched analyses. Conclusions Intracranial occlusion in patients with embolic stroke of undetermined source is not associated with a greater risk of recurrence when compared with patients without an intracranial occlusion. There was no difference in rate of recurrent stroke with anticoagulation when stratified by presence or absence of occlusion.