Dar Dowlatshahi

BACKGROUND: Restoring blood flow to ischemic tissue is the cornerstone of acute stroke therapy and is usually beneficial. However, when reperfusion is achieved for severely injured tissue, it is often futile and may occasionally cause harm. We aim to determine the prevalence and variables associated with clinical no improvement or acute worsening at 24 hours despite reperfusion in patients with large-vessel occlusion stroke treated with endovascular thrombectomy. METHODS: Data are from ESCAPE-NA1 (Safety and Efficacy of Nerinetide [NA-1] in Subjects Undergoing Endovascular Thrombectomy for Stroke), a randomized trial of nerinetide in patients with acute large-vessel occlusion stroke undergoing endovascular thrombectomy. Patients with unsuccessful recanalization (expanded Thrombolysis in Cerebral Infarction <2b), infarcts in new vascular territories, vessel perforation, or remote parenchymal hemorrhage were excluded. Clinical outcomes after reperfusion were classified by 24-hour National Institutes of Health Stroke Scale changes compared with baseline: improvement (≥4-point improvement), no improvement (±3-point from baseline), and worsening (≥4-point worsening). Baseline variables associated with worsening were identified using logistic regression. In the computed tomography perfusion subgroup, prevalence of parenchymal hemorrhage (any parenchymal hematoma) and infarct progression (final infarct volume exceeding the initial hypoperfused region) were evaluated. RESULTS: A total of 833 patients were included (median age, 70.9 years [interquartile range, 60.7–79.4]; 51.4% men). After reperfusion, 669 (80.3%) patients improved, 135 (16.2%) showed no improvement, and 29 (3.5%) worsened. Independent predictors of worsening were longer onset-to-reperfusion time (adjusted odds ratio, 1.02 [95% CI, 1.00–1.04] per 10-minute increase) and greater degree of sedation (adjusted odds ratio, 1.78 [95% CI, 1.29–2.46] per category of none, conscious sedation, and general anesthesia). In the computed tomography perfusion subgroup (n=414), among patients with worsening after reperfusion, parenchymal hemorrhage was seen in 5 patients (31.3%) and infarct progression in 4 patients (25%). CONCLUSIONS: Clinical worsening in the acute period (ie, early neurological deterioration) despite reperfusion and the absence of procedure-related complications was rare in this selected large-vessel occlusion stroke cohort (3.5%). Factors associated with worsening after reperfusion were a longer time from symptom onset-to-reperfusion and a higher degree of sedation.

Early hematoma expansion is a major determinant of outcome after intracerebral hemorrhage (ICH). The CTA spot sign predicts hematoma expansion and poor outcome but requires specialized expertise for interpretation. Automated detection facilitates imaging-based selection strategies for hemostatic therapies. We evaluated the diagnostic performance of an automated algorithm for spot sign detection using multiphase CTA. We analyzed patients presenting with spontaneous ICH within 4.5 h of symptom onset who underwent multiphase CTA. Fifty scans were randomly selected from a prospective registry. The automated algorithm independently classified each scan as spot sign positive or negative. An expert neuroradiologist served as reference standard. Sensitivity for spot sign detection was 95.7%, specificity was 74.1%. In this pilot study, automated detection of the CTA spot sign on dynamic CTA was feasible and demonstrated high sensitivity but moderate specificity, supporting further independent validation of CARL. Such tools may standardize spot sign identification, support clinical trial enrollment, and have the potential to facilitate rapid selection of patients at high risk of hematoma expansion.

BACKGROUND: There is a need for novel treatments that lower the risk of major adverse cardiovascular events and secondary inflammatory brain injury after an intracerebral hemorrhage (ICH). METHODS: We performed a double-blind, placebo-controlled, pilot randomized clinical trial at 11 centers across Canada to determine the feasibility of testing colchicine after an acute ICH. We recruited adults presenting within 48 hours of ICH onset with vascular neuroimaging evidence or risk factors for atherosclerosis. Participants were randomized to oral colchicine 0.5 mg daily or placebo and followed to a common study termination date. The primary feasibility outcome was the recruitment rate (participants/center per year). Secondary feasibility outcomes included retention of participants at 6 months and medication adherence at 12 months. This trial is registered (URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05159219). RESULTS: Between August 2022 and March 2024, 52 participants were allocated to colchicine 0.5 mg daily and 48 participants to placebo daily. Participants were, on average, 68 years old, and 60% were male. The mean time from ICH onset to randomization was 35 hours. The average recruitment rate was 8.9 participants/site per year. Retention at 6 months was 92% (colchicine 91% versus placebo 93%). Following randomization, 14 participants (27%) in the colchicine group and 13 participants (27%) in the placebo group permanently discontinued the study drug. Excluding participants who died or permanently discontinued the study intervention, 12-month medication adherence was 97%, with similar rates between the colchicine and placebo groups (100% versus 93%). We detected no difference in predefined exploratory efficacy or safety end points between the 2 groups over the median follow-up time of 364 days. CONCLUSIONS: It is feasible to test low-dose colchicine after an acute ICH. Future randomized clinical trials should account for the high rates of early permanent study drug discontinuation in this patient population. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05159219.

Background: To determine whether computed tomography (CT) thrombus characteristics modify the effect of intravenous (IV) thrombolysis type (tenecteplase vs alteplase) on outcomes. Methods: This is a secondary analysis of the Alteplase compared to Tenecteplase (AcT) trial. Patients with visible intracranial occlusions on thin-slice baseline imaging were included. Key thrombus characteristics assessed by CT imaging were hyperdense artery sign, thrombus length, residual flow, clot burden score, and occlusion site. Multivariable analyses were performed to test for interactions between thrombolysis type and thrombus characteristics on clinical and angiographic outcomes. Results: Of 1577 patients, 939 met inclusion criteria; 479 (51.0%) received tenecteplase and 460 (49.0%) alteplase. Among the 498 patients (53.0%) treated with endovascular thrombectomy (EVT), angiographic outcomes were comparable between treatment groups. A significant interaction was observed between thrombolysis type and thrombus length; longer thrombi were associated with reduced likelihood of modified Rankin Scale (mRS) 0–1 with alteplase (adjusted odds ratio (aOR) per 1 mm increase, 0.97 (95% confidence interval (CI): 0.95–1.00)), but not with tenecteplase (aOR: 1.00 (95% CI: 0.98–1.02); interaction p = 0.04). Similarly, the presence of residual flow within the thrombus was associated with higher odds of mRS 0–2 in the alteplase group (aOR: 2.00 (95% CI: 1.25–3.20)), but had no significant effect in the tenecteplase group (aOR: 0.93 (95% CI: 0.62–1.41); interaction p = 0.01). No other significant interactions between thrombus characteristics and thrombolysis type were identified. Conclusion: In the AcT trial, alteplase appeared less effective with longer thrombi and those lacking residual flow, whereas IV tenecteplase showed more consistent effectiveness across thrombus characteristics. These findings require confirmation in future prospective studies.

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.

Background: Location‐specific hematoma‐volume thresholds are potentially important for prognostication and surgical decisions in acute intracerebral hemorrhage. We aimed to define this metric in relation to poor functional outcome in a pooled individual patient‐level data analysis of 2 large intracerebral hemorrhage clinical trials: ATACH II (Antihypertensive Treatment of Acute Cerebral Hemorrhage) and INTERACT2 (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial). Methods: Final hematoma volumes were measured using planimetric analysis of 24‐hour computed tomography in relation to hematoma location stratified by basal ganglia, thalamus, and lobar regions. Volume thresholds in 5‐mL increments to >50 mL and Youden's index were used to identify optimal thresholds associated with poor outcome (modified Rankin Scale scores, 4–6) and death at 3 months. Multivariable logistic regression was used to estimate adjusted odds ratio models within each location. Results: There were 1691 patients included in these analyses, with 919 (54.3%), 551 (32.6%), and 221 (13.1%) located in the basal ganglia, thalamus, and lobar regions, respectively. Using Youden's index, location‐specific hematoma volume thresholds (mL) that were most predictive of poor outcome were: 22.24 for basal ganglia (sensitivity, 0.57; specificity, 0.84; adjusted odds ratio, 4.82 [95% CI, 3.19–7.27]), 8.13 for thalamus (sensitivity, 0.68; specificity, 0.75; adjusted odds ratio, 2.73 [95% CI, 1.62–4.59]), and 21.99 for lobar (sensitivity, 0.82; specificity, 0.64; adjusted odds ratio, 6.31 [95% CI, 2.53–15.74]). Hematoma volume thresholds predictive of death were 19.72 for basal ganglia, 10.06 for thalamic, and 51.94 for lobar intracerebral hemorrhage. Conclusions: Hematoma volumes associated with poor outcomes and death vary by anatomic location, indicating that each brain region has a distinct volume tolerance. Location‐specific volume thresholds may guide surgical intervention to reduce hematoma burden.

Collateral status at CT angiography was the baseline imaging variable associated with 90-day ordinal modified Rankin Scale score in participants with acute stroke due to medium-vessel occlusion in the ESCAPE-MeVO trial.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is thought to increase the risk of postthrombolytic intracranial bleeding, yet CAA neuroimaging markers and magnetic resonance imaging criteria have not been systematically evaluated in large acute stroke trials. We, therefore, examined the association of radiological Boston CAA criteria and their constituent markers with hemorrhagic risks and functional outcomes after intravenous thrombolysis in the AcT trial (Alteplase Compared to Tenecteplase). METHODS: Blinded raters recorded lobar cerebral microbleeds, cortical superficial siderosis, white matter hyperintensity multispot sign, and centrum semiovale enlarged perivascular spaces, and classified possible and probable CAA according to radiological Boston criteria iterations, versions 1.0, 1.5, and 2.0. Multivariable logistic or ordinal regressions, adjusted for age, sex, baseline stroke severity, diabetes, hypertension, onset-to-needle time, thrombolytic agent, and endovascular therapy, assessed associations of these features/criteria with safety end points: symptomatic intracerebral hemorrhage (ICH), any ICH, Heidelberg hemorrhage grade, 90-day mortality, and functional outcomes (modified Rankin Scale score of 0–1 and ordinal modified Rankin Scale score shift). RESULTS: Among 1600 patients in the trial, 482 had suitable magnetic resonance imaging (mean age, 71 years; 47.1% female). Cortical superficial siderosis burden emerged as the dominant harmful marker: each increment was associated with increased risk of symptomatic ICH (adjusted odds ratio [aOR] per additional affected sulcus, 3.88 [95% CI, 2.87–5.26]), any ICH (aOR, 1.91 [95% CI, 1.22–2.98]), hemorrhage severity, 90-day mortality (aOR, 1.42 [95% CI, 1.18–1.71]), worse modified Rankin Scale scores (adjusted common odds ratio, 1.74 [95% CI, 1.58–1.91]), and lower odds of excellent functional recovery (aOR, 0.70 [95% CI, 0.64–0.77]). Fulfilling probable radiological Boston criteria, versions 1.0 and 1.5, increased odds of any ICH (aOR, 2.57 and 2.39 [95% CI, 2.05–3.23]; aOR, 2.39 [95% CI, 1.71–3.34], respectively), whereas fulfilling possible Boston criteria, version 1.5, was associated with worse modified Rankin Scale scores (adjusted common odds ratio, 2.34 [95% CI, 1.30–4.22]). Boston criteria, version 2.0, were not significantly associated with any hemorrhagic outcomes. CONCLUSIONS: In thrombolyzed patients with acute ischemic stroke, cortical superficial siderosis burden is strongly and consistently associated with higher risk of severe hemorrhage, disability, and death, making it a particularly relevant CAA marker when weighing thrombolytic risk versus benefit. Meeting radiological Boston criteria, versions 1.0 or 1.5, increases hemorrhagic risk, but meeting the latest 2.0 criteria does not.

BACKGROUND: With the increasing use of tenecteplase for acute ischemic stroke, it is important to determine its safety in young adults. We aimed to characterize the clinical characteristics and imaging findings of young adults (≤45 years) in the AcT trial (Intravenous Tenecteplase Compared With Alteplase for Acute Ischaemic Stroke in Canada) and to compare their safety and efficacy outcomes. METHODS: This is a secondary analysis of the AcT trial, a phase 3 pragmatic multicenter registry-linked randomized controlled trial. We describe clinical and imaging characteristics of young adults with acute ischemic stroke. Logistic regression adjusted for sex and stroke severity was performed to assess safety and efficacy outcomes between the tenecteplase and alteplase arms. RESULTS: Of the 1577 enrolled patients, 68 (4.31%) were ≤45 years. Of 53 patients with available comorbidity data, 33 (62.26%) had no comorbidities. Hypertension was the most common comorbidity (n=8, 15%), whereas cardiac pathologies were observed in a smaller proportion (n=4, 7.5%). Intracranial atherosclerosis was identified in 7 patients (10%) and carotid or vertebral artery dissection in 6 patients (9%). Safety outcomes, including mortality, intracranial hemorrhage, and serious adverse events, were similar between the tenecteplase and alteplase arms. Excellent functional outcome (modified Rankin Scale score 0–1) at 90 days was better in the tenecteplase arm (84.72% versus 45%; adjusted odds ratio, 6.55 [95% CI, 1.89–22.71]). CONCLUSIONS: The majority of young adults presenting with acute ischemic stroke did not have any traditional risk factors for stroke at presentation. Safety outcomes were similar between the tenecteplase and alteplase arms. Although functional outcomes were observed to be better in the tenecteplase arm, these findings are exploratory and should be interpreted cautiously, given the study’s limited sample size and lack of adjustment for key confounders. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03889249.

Background: Symptomatic nonstenotic (<50% stenosis) carotid disease in the presence of high‐risk plaque features is a potential cause of ischemic stroke. We assessed stroke risk associated with symptomatic nonstenotic carotid disease. Methods: This cross‐sectional secondary analysis of the AcT (Alteplase Compared to Tenecteplase) randomized controlled trial evaluated baseline computed tomography angiograms for degree of internal carotid artery stenosis, plaque features and the presence of intraluminal thrombi, webs, dissection, and rim sign. Stroke location was evaluated on 24‐hour follow‐up imaging. At a carotid level, mixed‐effects logistic regression models adjusted for age and sex, with patient identity as a random effect, examined associations between “concordant stroke” (ipsilateral acute stroke in the internal carotid artery territory) and symptomatic nonstenotic carotid disease. Results: Of 1577 patients enrolled, 1407 (89.2%) with interpretable imaging were included: 329 (23.4%) had no carotid disease, 869 (61.8%) had nonstenotic carotid disease, and 209 (14.9%) had stenotic (≥50%) carotid disease in either the left or right internal carotid artery. Median age was 73 years (interquartile range, 63–83), with 48% female patients. Among 2519 (89.5%) internal carotid arteries with nonstenotic disease, 689 (27.4%) concordant strokes were identified. Intraluminal thrombi, carotid webs, carotid dissections, and carotid rim sign were significantly associated with concordant stroke (adjusted odds ratio, 8.11 [95% CI, 1.60–41.08]; adjusted odds ratio, 3.58 [95% CI, 1.53–8.35]; adjusted odds ratio, 6.77 [95% CI, 1.72–26.75]; and adjusted odds ratio, 3.17 [95% CI, 1.39–7.23], respectively). Results remained unchanged after excluding patients with atrial fibrillation and lacunar infarctions. Conclusions: Features other than the degree of stenosis should be considered when evaluating patients with carotid disease.