Acute ischemic stroke is the leading cause of permanent disability and second leading cause of death worldwide. Over the past 10 years, mechanical thrombectomy has become a powerful technique for improving outcomes after large-vessel occlusion in patients with a small baseline infarct. Reperfusion in patients with extensive infarction has historically been considered futile or harmful. However, a recent series of trials showed that endovascular therapy benefits patients who present with extensive baseline infarction. These new data represent a paradigm shift in the approach to stroke therapy, leading to an expansion of indications. Therefore, more patients will benefit from mechanical thrombectomy. Furthermore, these data challenge current definitions of infarct and ischemia as seen on imaging. The data suggest a new era of reperfusion therapy that focuses on optimizing patient-specific approaches and developing adjunctive neuroprotectants and neurorestorative therapies.

Background: and Purpose Cardioembolic sources account for 20%–30% of acute ischemic strokes (AIS), often with high morbidity. Conventional imaging confirms etiology retrospectively but lacks insight into the dynamic behavior of embolic transport. We aimed to predict stroke laterality by integrating patient-specific computational fluid dynamics (CFD) simulations with robust Bayesian logistic regression modeling. Methods: Eight patients (median age 77.5 years; 2 females) with anterior circulation AIS of confirmed cardiac origin underwent high-resolution computed tomography angiography. Vascular geometries were segmented to generate CFD models simulating physiologic pulsatile flow. In each cardiac cycle, 1,000 massless particles were released at the aortic inlet. Two features were derived: x1 (long-term embolic bias over 10 seconds) and x2 (short-term embolic bias during the first cardiac cycle). These were used as predictors in a robust Bayesian logistic regression model. Results: The right internal carotid artery (ICA) received more embolic particles (mean 34/s) than the left ICA (mean 28/s). Patients with right-sided strokes had higher x1 (median 0.27 vs. -0.44) and lower x2 (median -0.82 vs. 0.56) than those with left-sided strokes. The model yielded posterior mean coefficients of 1.51 (95% credible interval [CrI]: -0.46 to 4.11) for x1 and -1.96 (95% CrI: -4.88 to 0.20) for x2, achieving complete separation of stroke patients by laterality in this pilot cohort. Conclusions The combination of CFD-based embolic modeling and Bayesian analysis accurately predicted stroke laterality in cardioembolic AIS, exposing distinct patient-specific embolic transport dynamics.

Background: and Purpose Whether perfusion-diffusion mismatch modifies treatment effect of mechanical thrombectomy (MT) for large strokes is poorly known. To address this question, we conducted a post hoc secondary analysis of the Large Stroke Therapy Evaluation (LASTE) randomized controlled trial (RCT). Methods: The LASTE RCT compared MT plus best medical treatment (BMT) to BMT alone in patients with large infarct (Alberta Stroke Program Early CT Score 0–5) in the 0–7-hour timewindow. This secondary analysis was restricted to patients with available baseline MR perfusionweighted imaging. We investigated the potential heterogeneity of MT treatment according to the presence of perfusion-diffusion mismatch, defined as a mismatch ratio ≥1.2, calculated as the time-to-maximum >6 seconds cerebral volume divided by ischemic core volume. The primary outcome was better functional outcome (favorable shift in the distribution of modified Rankin Scale [mRS] at 90 days, analyzed using generalized odds ratio [GenOR]). Results: A total of 102/324 patients were included, among whom 55 (54%) had a perfusiondiffusion mismatch. No significant treatment effect heterogeneity by diffusion-perfusion mismatch was observed for the primary outcome (GenOR for better functional outcome: 1.70 [95% confidence interval, CI, 0.95 to 3.05] and 1.04 [95% CI, 0.57 to 1.87] in patients with and without mismatch, respectively; ratio of GenORs: 1.63 [95% CI, 0.71 to 3.74]; P for heterogeneity=0.24) or for the secondary efficacy and safety outcomes. Conclusions Our study found no evidence of heterogeneity of treatment effect with respect to benefit or safety in patients with unrestricted infarct size at baseline treated with MT by presence of perfusion-diffusion mismatch. An individual participant-data meta-analysis of RCT is needed for definitive conclusions.

Background: and Purpose The management of acute ischemic stroke (AIS) due to distal medium vessel occlusion (DMVO) remains uncertain, particularly in comparing the effectiveness of intravenous thrombolysis (IVT) plus mechanical thrombectomy (MT) versus IVT alone. This study aimed to evaluate the safety and efficacy in DMVO patients treated with either MT-IVT or IVT alone. Methods: This multinational study analyzed data from 37 centers across North America, Asia, and Europe. Patients with AIS due to DMVO were included, with data collected from September 2017 to July 2023. The primary outcome was functional independence, with secondary outcomes including mortality and safety measures such as types of intracerebral hemorrhage. Results: The study involved 1,057 patients before matching, and 640 patients post-matching. Functional outcomes at 90 days showed no significant difference between groups in achieving good functional recovery (modified Rankin Scale 0–1 and 0–2), with adjusted odds ratios (OR) of 1.21 (95% confidence interval [CI] 0.81 to 1.79; P=0.35) and 1.00 (95% CI 0.66 to 1.51; P>0.99), respectively. Mortality rates at 90 days were similar between the two groups (OR 0.75, 95% CI 0.44 to 1.29; P=0.30). The incidence of symptomatic intracerebral hemorrhage was comparable, but any type of intracranial hemorrhage was significantly higher in the MT-IVT group (OR 0.43, 95% CI 0.29 to 0.63; P<0.001). Conclusion The results of this study indicate that while MT-IVT and IVT alone show similar functional and mortality outcomes in DMVO patients, MT-IVT presents a higher risk of hemorrhagic complications, thus MT-IVT may not routinely offer additional benefits over IVT alone for all DMVO stroke patients. Further prospective randomized trials are needed to identify patient subgroups most likely to benefit from MT-IVT treatment in DMVO.

Background: and Purpose Various mechanisms are involved in the etiology of stroke caused by atherosclerosis of the middle cerebral artery (MCA). Here, we compared differences in plaque nature and hemodynamic parameters according to stroke mechanism in patients with MCA atherosclerosis. Methods: Consecutive patients with asymptomatic and symptomatic MCA atherosclerosis (≥50% stenosis) were enrolled. MCA plaque characteristics (location and plaque enhancement) and wall shear stress (WSS) were measured using high-resolution vessel wall and four-dimensional flow magnetic resonance imaging, respectively, at five points (initial, upstream, minimal lumen, downstream, and terminal). These parameters were compared between patients with asymptomatic and symptomatic MCA atherosclerosis with infarctions of different mechanisms (artery-to-artery embolism vs. local branch occlusion). Results: In total, 110 patients (46 asymptomatic, 32 artery-to-artery embolisms, and 32 local branch occlusions) were investigated. Plaques were evenly distributed in the MCA of patients with asymptomatic MCA atherosclerosis, more commonly observed in the distal MCA of patients with artery-to-artery embolism, and in the middle MCA of patients with local branch occlusion. Maximum WSS and plaque enhancement were more prominent in the minimum lumen area of patients with asymptomatic MCA atherosclerosis or those with local branch occlusion, and were more prominent in the upstream area in those with artery-to-artery embolism. The elevated variability in the maximum WSS was related to stroke caused by artery-to-artery embolism. Conclusion Stroke caused by artery-to-artery embolism was related to plaque enhancement and the highest maximum WSS at the upstream point of the plaque, and was associated with elevated variability of maximum WSS.

Background: and Purpose High-grade carotid artery stenosis may alter hemodynamics in the ipsilateral hemisphere, but consequences of this effect are poorly understood. Cortical thinning is associated with cognitive impairment in dementia, head trauma, demyelination, and stroke. We hypothesized that hemodynamic impairment, as represented by a relative time-to-peak (TTP) delay on MRI in the hemisphere ipsilateral to the stenosis, would be associated with relative cortical thinning in that hemisphere. Methods: We used baseline MRI data from the NINDS-funded Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis–Hemodynamics (CREST-H) study. Dynamic contrast susceptibility MR perfusion-weighted images were post-processed with quantitative perfusion maps using deconvolution of tissue and arterial signals. The protocol derived a hemispheric TTP delay, calculated by subtraction of voxel values in the hemisphere ipsilateral minus those contralateral to the stenosis. Results: Among 110 consecutive patients enrolled in CREST-H to date, 45 (41%) had TTP delay of at least 0.5 seconds and 9 (8.3%) subjects had TTP delay of at least 2.0 seconds, the maximum delay measured. For every 0.25-second increase in TTP delay above 0.5 seconds, there was a 0.006-mm (6 micron) increase in cortical thickness asymmetry. Across the range of hemodynamic impairment, TTP delay independently predicted relative cortical thinning on the side of stenosis, adjusting for age, sex, hypertension, hemisphere, smoking history, low-density lipoprotein cholesterol, and preexisting infarction (P=0.032). Conclusions Our findings suggest that hemodynamic impairment from high-grade asymptomatic carotid stenosis may structurally alter the cortex supplied by the stenotic carotid artery.

Background: and Purpose Intracranial arterial stenosis (ICAS)-related stroke occurs due to three primary mechanisms with distinct infarct patterns: (1) borderzone infarcts (BZI) due to impaired distal perfusion, (2) territorial infarcts due to distal plaque/thrombus embolization, and (3) plaque progression occluding perforators. The objective of the systematic review is to determine whether BZI secondary to ICAS is associated with a higher risk of recurrent stroke or neurological deterioration. Methods: As part of this registered systematic review (CRD42021265230), a comprehensive search was performed to identify relevant papers and conference abstracts (with ≥20 patients) reporting initial infarct patterns and recurrence rates in patients with symptomatic ICAS. Subgroup analyses were performed for studies including any BZI versus isolated BZI and those excluding posterior circulation stroke. The study outcome included neurological deterioration or recurrent stroke during follow-up. For all outcome events, corresponding risk ratios (RRs) and 95% confidence intervals (95% CI) were calculated. Results: A literature search yielded 4,478 records with 32 selected during the title/abstract triage for full text; 11 met inclusion criteria and 8 studies were included in the analysis (n=1,219 patients; 341 with BZI). The meta-analysis demonstrated that the RR of outcome in the BZI group compared to the no BZI group was 2.10 (95% CI 1.52–2.90). Limiting the analysis to studies including any BZI, the RR was 2.10 (95% CI 1.38–3.18). For isolated BZI, RR was 2.59 (95% CI 1.24–5.41). RR was 2.96 (95% CI 1.71–5.12) for studies only including anterior circulation stroke patients. Conclusion This systematic review and meta-analysis suggests that the presence of BZI secondary to ICAS may be an imaging biomarker that predicts neurological deterioration and/or stroke recurrence.

Background: and Purpose Vessel recanalization after cerebral venous thrombosis (CVT) is associated with favorable outcomes and lower mortality. Several studies examined the timing and predictors of recanalization after CVT with mixed results. We aimed to investigate predictors and timing of recanalization after CVT. Methods: We used data from the multicenter, international AntiCoagulaTION in the Treatment of Cerebral Venous Thrombosis (ACTION-CVT) study of consecutive patients with CVT from January 2015 to December 2020. Our analysis included patients that had undergone repeat venous neuroimaging more than 30 days after initiation of anticoagulation treatment. Prespecified variables were included in univariate and multivariable analyses to identify independent predictors of failure to recanalize. Results: Among the 551 patients (mean age, 44.4±16.2 years, 66.2% women) that met inclusion criteria, 486 (88.2%) had complete or partial, and 65 (11.8%) had no recanalization. The median time to first follow-up imaging study was 110 days (interquartile range, 60–187). In multivariable analysis, older age (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.03–1.07), male sex (OR, 0.44; 95% CI, 0.24–0.80), and lack of parenchymal changes on baseline imaging (OR, 0.53; 95% CI, 0.29–0.96) were associated with no recanalization. The majority of improvement in recanalization (71.1%) occurred before 3 months from initial diagnosis. A high percentage of complete recanalization (59.0%) took place within the first 3 months after CVT diagnosis. Conclusion Older age, male sex, and lack of parenchymal changes were associated with no recanalization after CVT. The majority recanalization occurred early in the disease course suggesting limited further recanalization with anticoagulation beyond 3 months. Large prospective studies are needed to confirm our findings.