Farhan Khan

BACKGROUND: Cerebral venous thrombosis is an uncommon cause of stroke that primarily affects young adults. Several clinical trials and observational studies have compared vitamin K antagonists (VKAs) with direct oral anticoagulants (DOACs) for treating cerebral venous thrombosis, but the small sample sizes limit the ability to draw firm conclusions. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials and observational studies comparing DOACs with VKAs for the treatment of cerebral venous thrombosis. Studies published between January 2007 and July 2025 were included. Prespecified subgroup analyses were conducted by study design, DOAC class (anti–factor Xa inhibitors versus direct thrombin inhibitors), and VKA. Risk of bias was assessed using the Cochrane Risk-of-Bias Tool 2 for randomized trials and the Risk of Bias in Nonrandomized Studies of Interventions for observational studies. Pooled risk ratios (RRs) with 95% CIs were calculated using random-effects models. RESULTS: Fourteen studies (8 randomized clinical trials [RCTs] and 6 observational studies) were included. Among 3698 patients, 1669 (45.1%) received DOACs and 2029 (54.9%) received VKAs. Rates of recurrent venous thromboembolism (10.24% versus 10.99%), major bleeding (4.26% versus 6.18%), clinically relevant nonmajor bleeding (2.63% versus 1.66%), good functional outcomes (95.09% versus 89.25%), and mortality (3.37% versus 3.30%) were similar in DOACs and VKAs. Recurrent venous thromboembolism was similar between DOACs and VKAs in RCTs (RR, 1.06 [95% CI, 0.35–3.24]) and in the overall pooled analysis of all studies (RR, 0.92 [95% CI, 0.55–1.53]). Major bleeding did not differ between DOACs and VKAs in RCTs (RR, 0.73 [95% CI, 0.24–2.22]) or in the overall analysis (RR, 0.74 [95% CI, 0.44–1.25]; P =0.26). Clinically relevant nonmajor bleeding was also comparable in RCTs (RR, 1.06 [95% CI, 0.25–4.48]) and overall (RR, 1.22 [95% CI, 0.38–3.86]). Good functional outcomes (modified Rankin Scale score of 0–2) were similar between DOACs and VKAs in RCTs (RR, 1.00 [95% CI, 0.84–1.19]) and in the combined analysis of all studies (RR, 1.02 [95% CI, 0.93–1.11]). Mortality was similar between DOACs and VKAs in RCTs (RR, 1.15 [95% CI, 0.28–4.68]) and in the pooled analysis. When direct thrombin inhibitors were compared with factor Xa inhibitors, there were no significant differences in outcomes. CONCLUSIONS: DOACs demonstrated comparable efficacy and safety to VKAs in the treatment of cerebral venous thrombosis. These findings support the use of DOACs as a reasonable alternative.

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). ESUS was categorized into 3 groups: (1) established mechanism after further workup (ESUS‐E), (2) comprehensive diagnostic workup without an identified cause (ESUS 2.0), and (3) no advanced workup. The primary outcome of recurrent ischemic stroke was compared between ESUS with established mechanism and ESUS 2.0 versus ESUS with no advanced workup and was assessed using adjusted Cox proportional hazards models. Results: Among 2281 patients, the mean age was 65 years, and 50.1% were men. 694 (30.4%) classified as ESUS‐E, 1,243 (54.5%) classified as ESUS‐NAW, and 344 (15.1%) as ESUS 2.0. The ESUS 2.0 group had a significantly lower risk of recurrent stroke than both the group with ESUS with no advanced workup (adjusted hazard ratio [aHR], 0.31 [95% CI, 0.13–0.76]) and the group with ESUS with established mechanism (aHR, 0.35 [95% CI, 0.15–0.85]). Within the group with ESUS with established mechanism, cancer (aHR, 5.33 [95% CI, 2.09–13.63]) and nonstenosing atherosclerotic disease or arch atheroma (aHR, 3.40 [95% CI, 1.18–9.83]) were associated with significantly increased risk of recurrence when compared with the group with ESUS 2.0. Conclusions: These findings demonstrate a lower risk of recurrent stroke in patients classified as ESUS 2.0 than reported in prior ESUS trials and highlight the importance of age‐appropriate advanced diagnostic evaluation. Registration: URL: https://www.clinicaltrials.gov . Identifier: NCT06398366.

Background: Perioperative ischemic stroke is uncommon overall but frequent in cardiac, major vascular, and neurosurgical procedures. Existing calculators often exclude these settings and rarely incorporate cerebrovascular disease markers available in routine electronic health record data. Methods: We assembled a retrospective cohort of adults undergoing procedures at 3 hospitals (January 2016–June 2024). The model was derived at Rhode Island Hospital (255 850 procedures) and externally validated at 2 affiliated hospitals (The Miriam Hospital/Newport Hospital; 189 095 procedures). Candidate predictors included age, vascular comorbidities, documented carotid stenosis and intracranial atherosclerosis, procedure setting (ambulatory versus inpatient/emergency), and procedural service (including vascular versus nonvascular neurosurgery and open versus interventional cardiovascular procedures). We fit a multivariable logistic regression model with internal validation using 1000 bootstrap resamples and assessed calibration by observed versus predicted risk across deciles. External validation applied locked derivation coefficients without refitting. Results: Strokes occurred in 1235/255 850 derivation procedures (0.48%) and 418/189 095 validation procedures (0.22%). Independent predictors included older age, prior stroke or transient ischemic attack (adjusted odds ratio [aOR], 6.66), inpatient/emergency setting (aOR, 4.25 versus ambulatory), vascular neurosurgery (aOR, 6.70 versus general surgery), and open cardiovascular procedures (aOR, 4.14). Discrimination was high (derivation area under the curve, 0.87 [95% CI, 0.87–0.88]; optimism‐corrected area under the curve, 0.87; validation area under the curve, 0.86 [95% CI, 0.84–0.87]) with good calibration. Prespecified risk strata (5%) separated observed event rates in both cohorts. Conclusion: A pragmatic, electronic health record‐derived model integrating procedural category and cerebrovascular disease accurately predicts 30‐day periprocedural ischemic stroke across diverse procedures and is available as a web‐based calculator to support counseling and targeted prevention.

Background and ObjectivesCarotid artery web (CW) is an underrecognized cause of ischemic stroke that promotes blood stasis and embolization despite non–flow-limiting stenosis. The clot phenotype of...

Background: Cervical artery dissection (CeAD) is a common cause of stroke in young adults but is frequently misdiagnosed due to its nonspecific symptoms. This study examines factors associated with possible diagnostic error in CeAD and evaluates its impact on patient outcomes. Methods: We conducted a secondary analysis of the STOP‐CAD (Antithrombotic Therapy for Stroke Prevention in Cervical Artery Dissection) study, which is a multicenter international study of adult patients admitted with CeAD. Possible diagnostic error was defined as the presence of CeAD symptoms within 30 days before the index CeAD diagnosis. The comparison group included patients diagnosed on their first medical encounter. Multivariable regression was used to identify factors associated with possible diagnostic error. Primary and secondary outcomes included ischemic stroke, death, and modified Rankin Scale score P P =0.007), and more likely to present with headaches (OR, 1.43, P P P =0.86), 90‐day modified Rankin Scale score P =0.80), or death (adjusted OR, 0.58, P =0.34). Conclusions: One in 6 patients with CeAD experienced a possible diagnostic error, particularly those who were younger, had migraines, or presented with headaches and nonfocal symptoms.

BACKGROUND: Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. METHODS: We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. RESULTS: Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21–1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97–1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10–0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83–1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04–0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15–0.73]). CONCLUSIONS: After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06398366.

Background: Ischemic stroke in deep brain regions is commonly attributed to small vessel ischemic disease (SVID) or branch atheromatous disease (BAD). Differentiating these mechanisms is clinically important, as BAD is associated with progressive symptoms, early neurological deterioration, and poorer outcomes, whereas SVID typically follows a more stable course. Conventional imaging is limited in distinguishing these entities. High‐resolution vessel wall imaging enables direct visualization of intracranial vessel wall pathology and may refine risk stratification. Methods: We conducted a prospective, single‐center study of patients with acute subcortical infarcts admitted between 2023 and 2025. Eligible patients underwent magnetic resonance imaging with high‐resolution vessel wall imaging within 1 week of admission. SVID was defined as lacunar infarction without evidence of parent artery plaque or vessel wall enhancement. BAD was defined as infarction in the territory of a penetrating artery with associated parent artery enhancement. The primary outcome was differentiation of BAD from SVID based on vessel wall enhancement. Secondary outcomes included 90‐day functional outcomes. Results: Of 23 patients enrolled, 10 underwent magnetic resonance imaging with high‐resolution vessel wall imaging. Vessel wall enhancement was observed in 5 patients (50%). Patients with enhancement were more often male (100% versus 40%) and had a higher prevalence of hyperlipidemia (100% versus 20%) compared with those without enhancement. Functional outcomes at 90 days were similar between the 2 groups. Conclusions: High‐resolution vessel wall imaging can identify parent artery pathology not evident on conventional imaging, helping to distinguish BAD from SVID. This differentiation is clinically meaningful, as BAD may require more intensive secondary prevention. Larger studies are needed to validate these findings.

BACKGROUND: Pregnancy-associated stroke may present with nonfocal symptoms, leading to missed diagnostic opportunities (MDO). METHODS: We conducted a retrospective study including patients aged 18 to 50 years and pregnant or within 1 year of delivery, treated at 5 US comprehensive stroke centers from 2012 to 2021 for confirmed arterial ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, or cerebral venous thrombosis. Vascular neurologists at each site reviewed cases using a validated tool, Safer Stroke-Dx. We determined the proportion of cases with MDO and estimated 95% CIs based on a binomial distribution. RESULTS: We identified 135 patients with pregnancy-related stroke (mean age, 32.4 [SD, 6.0] years), of whom 37 (27%) had MDO (95% CI, 20.6%–35.5%). Presenting symptoms included focal neurological deficits (57%; n=77), headache (53%; n=71), systemic symptoms (26%; n=35), and altered mental status (19%; n=25). More patients with MDO had hemorrhagic strokes (22 of 37 [59%] versus 34 of 79 [43%] patients with no MDO, and 10 of 19 [53%] with insufficient information to determine [ P =0.05]). Among patients with MDO, 34 of 37 (92%) had ≥1 documented medical encounter in the month preceding stroke diagnosis compared with 47 of 79 (59%) individuals without MDO and 9 of 19 (47%) with insufficient information to determine ( P 1 in 4 pregnant or postpartum patients with acute stroke experienced MDO. Our results suggest a need for enhanced clinician education, particularly for nonneurologists, in diagnosing stroke during pregnancy and the postpartum period.

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.

Over the last 30 years, several classification systems have been proposed or used to aid in patients with subtyping ischemic stroke based on its likely etiology. Since these classification systems have been published, the field has gained more knowledge about newly reported mechanisms (eg, carotid artery web), new treatments being effective (eg, patent foramen ovale closure), and new diagnostic testing (eg, prolonged outpatient cardiac monitoring). Therefore, an updated ischemic stroke classification system is needed to integrate these advancements, enabling a more targeted workup and potentially improving treatment strategies. We propose a more comprehensive but practical and generalizable diagnostic evaluation and checklist for patients with ischemic stroke to help identify definite, probable, or possible mechanisms related to cardioembolism, large artery atherosclerosis, small vessel disease, or other determined causes (eg, hypercoagulable disorders, genetic disorders, cancer, or dissection). This expands the minimum diagnostic evaluation, leading to reclassification of patients and possibly improving secondary stroke prevention strategies. This will also create a new framework for targeted treatments and randomized trials for various ischemic stroke subtypes.