Nishita Singh

BACKGROUND: The ABCD ² score is widely used to stratify stroke risk after transient neurological events. We aimed to evaluate the association between the ABCD ² score and the risk of subsequent ischemic stroke among patients with diffusion-weighted imaging (DWI)–positive (DWI+) or DWI−negative (DWI−) findings for the index event. METHODS: We pooled individual participant data from 3 multicenter cohorts including patients presenting with transient or minor neurological events. Patients presenting with transient neurological symptoms, a normal neurological examination, and available DWI for the index event were included. Associations between the ABCD ² score and 90-day ischemic stroke risk were analyzed separately in the DWI+ and DWI− groups using logistic regression models adjusted for sex, atrial fibrillation, and study source. RESULTS: Among 2014 patients (1143 [56.8%] men; median age 67 years), the median ABCD ² score was 4 (interquartile range, 3–5), and 504 (25.0%) were DWI+. Ischemic stroke occurred within 90 days in 20 patients (4.0%) in the DWI+ group and 33 (2.2%) in the DWI− group. The ABCD ² score was associated with stroke risk in the DWI− group (per 1-point increase, odds ratio, 1.36 [95% CI, 1.04–1.79]), but this relationship was not significant in the DWI+ group (per 1-point increase, odds ratio, 1.08 [95% CI, 0.76–1.53]). When stratified ABCD ² score into 0 to 3, 4 to 5, and 6 to 7, the predicted 90-day stroke risks were 3.2%, 3.9%, and 4.5% in the DWI+ group (per 1-category increase, odds ratio, 1.23 [95% CI, 0.63–2.40]) and 1.0%, 2.3%, and 4.1% in the DWI− group (per 1-category increase, odds ratio, 1.88 [95% CI, 1.11–3.20]), respectively. CONCLUSIONS: The ABCD ² score was associated with 90-day stroke risk among patients with DWI− findings. Patients with both a low ABCD ² score and DWI− findings had a particularly low risk of subsequent stroke, which may inform risk stratification and clinical decision-making after transient neurological events.

Prehospital stroke trials enable assessments of ultraearly administration of treatments and management strategies, but face unique challenges in their design, conduct, and analysis. We outline important considerations and recommendations for planning prehospital stroke trials, focusing on patient identification, consent models, randomization strategies, end point selection, and statistical frameworks. As this field evolves, multidisciplinary collaboration, pragmatic study design, and scalable technology integration are critical to ensuring scientific rigor and equitable access. This framework is intended to inform and support future investigators in designing effective, ethically sound, and operationally feasible prehospital stroke trials in conventional emergency medical services settings.

Introduction: Patients with minor ischaemic stroke (NIHSS ≤ 5) and intracranial occlusion or focal perfusion abnormality ≤ 12 h of onset did not benefit from intravenous tenecteplase compared to non-thrombolytic standard care (control) in the Tenecteplase vs Standard of Care for Minor Ischaemic Stroke with Proven Occlusion (TEMPO-2) trial. We tested whether tenecteplase was associated with better outcomes in subgroups defined by baseline vessel occlusion status. Patients and methods: In this secondary analysis of the randomised, controlled, blinded TEMPO-2 trial, patients were divided into 3 subgroups: complete occlusion (revised arterial occlusive lesion score 0), near occlusion (score 1) and no visible occlusion (focal perfusion abnormality present). The primary outcome was return to pre-stroke neurological functioning or better, assessed with 90-day mRS. Outcomes were analysed using a generalised linear model adjusted for age, sex, onset-to-randomisation time and baseline stroke severity. Results: Of 881 patients, complete occlusion was present in 218 in the control and 216 in the tenecteplase arm, near occlusion in 102 and 92 and no visible occlusion in 130 and 123, respectively. At baseline, there were longer treatment delays in the control arm with near occlusion, and older age, more hypertension and higher creatinine levels in the tenecteplase arm with complete occlusion. We found no difference in the primary outcome between tenecteplase and control in any subgroup (no visible occlusion: adjusted RR 1.03 [95% CI, 0.90–1.18]; near occlusion: adjusted RR 0.85 [95% CI, 0.71–1.01]; complete occlusion: adjusted RR 1.00 [95% CI, 0.89–1.12]). Discussion and conclusion: There was no difference in outcome between tenecteplase and standard care for patients with mild stroke based on their baseline vessel occlusion status. Trial registration: Clinicaltrials.gov: NCT02398656.

Background: Venous thrombosis and venous thromboembolism (VTE) are important causes and complications of stroke. They may complicate acute stroke as deep venous thrombosis or pulmonary embolism (DVT/PE), contribute causally to ischemic stroke through paradoxical embolism from a patent foramen ovale (PFO), or present directly as cerebral venous thrombosis (CVT). Despite shared pathophysiological features and overlapping antithrombotic strategies, these conditions are typically considered separately, fragmenting evidence and limiting the exchange of concepts. Purpose: We therefore convened experts across both stroke neurology and thrombosis medicine fields to examine these conditions under a unifying venous theme and define priorities for future clinical trials. Methods: Thirty-two stroke and thrombosis clinicians and researchers identified research priorities across three domains: prevention of VTE after stroke, secondary prevention after PFO-related stroke, and acute and long-term management of CVT. Structured discussions were guided by the PICO (Population, Intervention, Comparison, Outcome) framework, followed by a Delphi survey to establish consensus. Priority questions centered on the balance between thrombosis prevention and bleeding risk and the optimal timing, duration, and choice of DVT/PE prophylaxis after stroke; the optimal antithrombotic strategy for patients awaiting or forgoing PFO closure; and, for CVT, the role of endovascular therapy in severe disease and the optimal duration of secondary prevention (Graphical Abstract). Across domains, the group prioritized pragmatic and platform trial designs, integration with international registries to address the rarity of CVT, and patient-oriented outcomes that extend beyond functional recovery. Conclusions: By considering these venous conditions together and bridging stroke and thrombosis disciplines, this work defines priority questions to address persistent evidence gaps, harmonize practice, and improve patient-centered outcomes.

Stroke has become the single leading neurological illness that results in neurological disability and is the second most common cause of death worldwide. Approximately 85% of strokes are ischemic, whereas the remaining 15% are hemorrhagic. With the advent of increasingly effective treatment modalities, such as intravenous thrombolytics and endovascular mechanical thrombectomy, there has been a growing disparity in the ability to provide standard of care, despite substantial efforts made in lower- and middle-income countries. substantial effort in high-income countries to provide the current standard of care to patients with stroke, with the hope of improving outcomes. Extensive research has shown that the disparities in treatment among various countries stem from multiple sociocultural barriers and the lack of robust healthcare infrastructure. The societal influences in play include the lack of knowledge of stroke symptoms, cultural beliefs, health, and spiritual fatalism, which are then associated with delayed healthcare-seeking behaviors. As a result, it is imperative to increase access to treatment for patients with stroke to address inequities in stroke care and diminish the global burden of stroke. This narrative review highlights causes of major gaps in stroke treatment infrastructure in several global communities and examines the pertinent sociocultural factors that impede progress in stroke treatment.

During acute ischemic stroke, cerebral tissue undergoes different stages of ischemic damage and evolves towards irreversible injury at a varying pace depending on local perfusion and metabolic factors. This complex ischemic pathological process represents a dynamic continuum that has been historically conceptualized as a binary ischemic core-penumbra model. Although this simplification has proven useful for explaining the evolution of tissue damage in acute stroke, important nuances with clinical implications might be underappreciated. In this review, we critically appraise the pathophysiology and conventional clinical concepts adopted to explain infarct evolution in the early phases of ischemic stroke. We discuss recent mounting evidence that challenges the traditional compartmentalization of the ischemic core, penumbra, and oligemia, calling for more nuanced pathophysiological tissue concepts. For example, clinical benefits and the harmful hemorrhagic transformation associated with reperfusion therapies are observed across a spectrum of core volumes, challenging the deterministic assumptions of the core-penumbra hypothesis. Automated image processing systems reinforce this simplification of stroke pathophysiology, leading to misinterpretation of the range of truth in human imaging. We propose a modified definition of the core-penumbra-oligemia continuum that includes 6 levels of ischemic progression and their corresponding clinical implications: (1) benign oligemia, (2) vulnerable oligemia, (3) durable penumbra, (4) critical penumbra, (5) nonleaky core, and (6) leaky core. This more granular classification could better reflect the continuum of pathological ischemic changes and vulnerability. The proposed 6 levels can provide a framework for future neuroimaging efforts to better understand tissue fate and infarct evolution in ischemic stroke, ultimately informing treatment decision-making and refining targeting for new therapeutic approaches.

BACKGROUND: Complete recanalization of cerebral arteries is strongly associated with good functional outcome in ischemic stroke. We hypothesize that successful recanalization results in better functional outcomes. METHODS: This is a secondary observational cohort analysis of TEMPO-2 (Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion), a randomized controlled trial comparing tenecteplase with standard of care (control) in minor stroke (National Institutes of Health Stroke Scale score ≤5) with intracranial occlusion/focal perfusion abnormality ≤12 hours of onset. Among those enrolled based on computed tomography angiography with visible occlusion, a follow-up computed tomography angiography was done at 4 to 8 hours after randomization. The primary outcome was return to baseline functional outcomes using the modified Rankin Scale score at 90 days. Safety outcomes included stroke progression (National Institutes of Health Stroke Scale score ≥2 worsening), bleeding events, and mortality. Patients with successful recanalization, defined as revised Arterial Occlusive Lesion score ≥2b/3, were compared with those with unsuccessful recanalization on follow-up computed tomography angiography. Regression analysis was used to assess the association of successful recanalization with outcomes after adjusting for age, sex, baseline stroke severity, and onset-to-randomization time. RESULTS: Of the 886 enrolled patients, 517 (58.3%) with follow-up computed tomography angiography were included. Of these, 178 (34.6%) had successful recanalization (122 [68.5%]: tenecteplase, 56 (31.5%): control), and 336 (65.4%) did not achieve successful recanalization (unsuccessful recanalization; 134: tenecteplase, 202: control). Baseline characteristics were similar between patients with and without successful recanalization. Successful recanalization was significantly associated with the primary outcome as compared with unsuccessful recanalization (adjusted risk ratio, 1.21 [95% CI, 1.07–1.34]). Patients with successful recanalization had significantly lower rates of stroke progression as compared with unsuccessful recanalization (2.8% versus 13.1%, adjusted risk ratio, 0.21 [95% CI, 0.08–0.52]). Multivariable analysis showed that tenecteplase treatment was the strongest independent predictor of successful recanalization (odds ratio, 3.48 [95% CI, 2.33–5.18]). CONCLUSIONS: Successful recanalization is a critical determinant of early and 90-day functional recovery in patients with minor stroke with intracranial occlusion, regardless of treatment modality. Tenecteplase significantly increases the odds of achieving successful recanalization compared with standard care. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02398656.

Background: With the increasing use of tenecteplase, it is important to understand its safety compared with alteplase. We aimed to determine the incidence, predictors, and functional impact of serious adverse events (SAEs) in patients treated with alteplase versus tenecteplase. Methods: This is a post hoc analysis of the AcT (Alteplase Compared to Tenecteplase) trial, a phase 3 multicenter randomized controlled trial that randomized 1577 ischemic patients with stroke (2019–2022) into tenecteplase versus alteplase presenting P =0.002) and higher endovascular treatment rates (50.2% versus 29.2%; P <0.001) than those without SAEs. Nervous system disorders were the most common SAE (58.2%), including stroke worsening (26.7%) and intracranial hemorrhage (25%). No significant differences were observed in SAE distribution by thrombolytic. Patients with SAEs had higher 90‐day modified Rankin Scale scores (median, 4 versus 2; odds ratio [OR], 3.93 [95% CI, 2.78–5.56]). Independent predictors of SAEs included baseline National Institutes of Health Stroke Scale (per SD increase: OR, 1.2 [95% CI, 1.0–1.5]), large‐vessel occlusion (OR, 1.6 [95% CI, 1.1–2.5]), Alberta Stroke Program Early Computed Tomography Score (per point increase: OR, 0.9 [95% CI, 0.8–1.0]), and cerebral atrophy (per point increase: OR, 1.5 [95% CI, 1.1–1.9]). Conclusions: Our study found no difference between rate or type of SAEs by thrombolytic type, supporting the safety of tenecteplase. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT03889249.

Background: The final infarct volume has been historically considered the most critical radiological outcome in ischemic stroke. Yet, discrepancies between final infarct volume and functional outcomes occur frequently. We aim to evaluate whether 24‐hour computed tomography (CT) infarct density modifies the relationship between 24‐hour CT infarct volume and functional outcomes and is associated with outcomes in acute ischemic stroke. Methods: Data are from the AcT (Alteplase Versus Tenecteplase in AIS [Acute Ischemic Stroke] Within 4.5 Hours) trial. Patients with detected 24‐hour CT infarct and no parenchymal hematoma were included. To capture within‐lesion heterogeneity, “24‐hour CT standardized infarct density” was calculated as mean Hounsfield Unit/SD for every patient. Primary outcome was the 90‐day ordinal modified Rankin Scale score. We assessed effect modification using interaction terms and performed adjusted regression analyses. Results: Of 1577 patients, 839 (53.2%) were included (median age 75 years [interquartile range, 64–84], 414 [9.3%] female). Median infarct volume was 7.5 mL (interquartile range, 1.6–28.0), and median standardized infarct density was 4.8 standardized‐Hounsfield Units (interquartile range, 4.0–5.8). Standardized infarct density significantly modified the effect of infarct volume on modified Rankin Scale score ( P ‐interaction=0.001) and mortality ( P ‐interaction=0.014). Higher standardized infarct density (ie, less severe infarct degree) was associated with better 90‐day modified Rankin Scale score (adjusted common odds ratio [acOR], 0.87 [95% CI, 0.80–0.96] per 1‐standardized‐Hounsfield Unit increase), whereas infarct volume was not (acOR, 0.96 [95% CI, 0.90–1.01] per 5‐mL increase). Conclusions: CT infarct density modifies the effect of infarct volume on outcomes and is independently associated with better outcomes. These findings suggest that 24‐hour CT infarct volume and density may provide complementary information on the infarct burden.