Peter John Mitchell

Suboptimal clinical outcomes are common after ischemic stroke with large vessel occlusion despite current reperfusion treatment with intravenous thrombolysis and mechanical thrombectomy. Targeting residual distal arterial and microvascular occlusions with intraarterial thrombolysis has recently gained substantial interest as an adjunct to improve cerebral tissue perfusion. While recent trials provide promise in selected patients with anterior-circulation stroke, further high-quality, large-scale studies and pooled individual-patient analyses are needed. This review summarizes the evolving role of intraarterial thrombolysis over the past 3 decades and projects potential developments.

Background: Lacunar stroke is a common and disabling cerebrovascular disease. Small-vessel vasculopathy is thought to be the most common underlying cause, but this has only been identified on histopathology. 7T MRI allows small vessels to be seen in vivo. This study aimed to investigate rates of small vessel vasculopathy in lacunar stroke using 7T MRI. Methods: Patients with lacunar stroke at an Australian tertiary stroke centre were prospectively screened and recruited to the study. Patients underwent 7T MRI with T1, T2, time-of-flight (TOF), diffusion-weighted imaging (DWI) and susceptibility-weighted imaging (SWI) sequences. Images were interpreted by two blinded neuroradiologists. Results: The likely symptomatic perforator could be identified in 16/19 (84%) of cases. Amongst cases where the symptomatic perforator was observed, 14/16 (88%) of the symptomatic perforator vessels had focal stenosis consistent with steno-occlusive vasculopathy. There were 3/19 (16%) of cases with associated large artery vasculopathy. There were 7/16 (44%) cases where an occluded perforator was seen. The majority of patients had at least one vascular risk factor (15/19, 79%) and there were no cases where non-atherosclerotic vasculopathy was suspected. Conclusions: Lacunar stroke is commonly associated with small vessel vasculopathy, likely due to atherosclerosis, which can be identified in vivo with 7T MRI time-of-flight imaging.

BACKGROUND: Extracranial internal carotid artery (ICA) stenosis is a common cause of ischemic stroke and transient ischemic attack. Cervical computed tomography (CT) angiography can rapidly diagnose carotid pathology but is not possible with current-generation CT scanners used in mobile stroke units. We assessed the diagnostic accuracy of the intracranial ICA contrast density ratio (CDR) to identify extracranial ICA stenosis. METHODS: We retrospectively reviewed consecutive patients at 3 comprehensive stroke centers in Melbourne, Victoria, who received CT angiography on the mobile stroke unit CereTom CT scanner, with reference standard in-hospital CT angiography or digital subtraction angiography in the Melbourne mobile stroke unit database. The mean Hounsfield units at 4 segments of the intracranial ICA, both ipsilateral and contralateral to the symptomatic hemisphere, were measured. The CDR was calculated using the formula: CDR=contralateral mean Hounsfield units/ipsilateral Hounsfield units. Statistical analysis was completed with univariate analysis of CDR, and leave-one-out cross-validation with receiver operating characteristic area under the curve to determine CDR thresholds associated with stenosis or occlusion, to determine sensitivity and specificity of the test. RESULTS: Of 151 patients included, 31 of 151 (20.5%) had extracranial ICA stenosis >50%, and the average CDR was higher in patients with >70% stenosis with threshold ratio of >1.24 (sensitivity, 80%; specificity, 88%; positive predictive value, 57%; and negative predictive value, 96%) or extracranial occlusion (sensitivity, 100; specificity, 82%; positive predictive value, 29%; and negative predictive value, 100%). The threshold of 1.18 for 50% to 99% and carotid occlusion had lower sensitivity (sensitivity, 78%; specificity, 95%; positive predictive value, 88%; and negative predictive value, 91%). CONCLUSIONS: Assessment of the intracranial ICA CDR may assist in ruling out high-grade extracranial stenosis in patients who are being considered for direct transfer for endovascular thrombectomy after head-only CT angiography.

In stroke patients directly admitted to thrombectomy-capable centers, the value of intravenous thrombolysis (IVT) with alteplase before thrombectomy is time dependent. While early IVT may improve outcomes, delayed IVT administration lowers the likelihood of benefit. To date, no previous cost-effectiveness study has considered onset-to-treatment time. This study evaluated the cost-effectiveness of intravenous (IV) alteplase plus thrombectomy vs thrombectomy alone in patients admitted directly to thrombectomy-capable centers across 16 countries, stratified by onset-to-IVT time. A decision tree integrated with a Markov model estimated costs, quality-adjusted life years (QALYs), and incremental net monetary benefit (INMB) over 15 years. A willingness-to-pay threshold of one gross domestic product per capita was applied for each country. Effectiveness data were derived from individual patient data from 6 trials including patients with anterior circulation large-vessel occlusion eligible for both IVT and thrombectomy who presented directly to thrombectomy-capable centers. Costs were obtained from a literature review. Onset-to-IVT time was categorized as <140, 140-169, 170-199, and ≥200 minutes. One-way sensitivity and probabilistic sensitivity analyses were performed to check robustness of results. Ninety-day functional outcome distributions from 2,268 patients (median age 71 years; 44% female) were used to model cost-effectiveness in a hypothetical cohort of 10,000 patients. Without accounting for onset-to-IVT time, IV alteplase plus thrombectomy seemed cost-effective in 13 countries (INMB: $85-$3,618; 50-65% probability of cost-effectiveness) and not cost-effective in the United States, China, and Vietnam, with modest health gains (0.06-0.08 QALYs per patient). Time-stratified analyses revealed that IVT plus thrombectomy was cost-effective in 16 countries when onset-to-IVT time was <140 minutes (INMB: $615-$30,645; 82%-98% probability) and at 140-169 minutes (INMB: $86-$16,918; 51%-77% probability). However, IV alteplase plus thrombectomy was no longer cost-effective in 8 countries at 170-199 minutes. Universally, the INMB was negative for onset-to-IVT times exceeding 200 minutes. Cost-effectiveness of IV alteplase plus thrombectomy varies per country and onset-to-IVT time. IV alteplase plus thrombectomy is cost-effective when IVT can be administered within 170 minutes from symptom onset. Cost-effectiveness of IV alteplase plus thrombectomy diminishes progressively with longer onset-to-IVT times and becomes detrimental after 200 minutes.

The no-reflow phenomenon, observed in up to 30% of patients with ischemic stroke despite technically successful thrombectomy, is associated with poor outcomes. However, its temporal evolution remains uncharacterized. Understanding its progression is essential to inform the development of adjunctive therapies aimed at improving outcomes after recanalization. The objective of this study was to characterize the temporal dynamics of no-reflow using serial post-thrombectomy MR perfusion imaging. In a multicenter prospective observational study, 67 consecutive adult patients with acute anterior large vessel occlusion underwent serial post-thrombectomy perfusion MRI at 2 hours (time point 1, TP1) and 24-48 hours (time point 2, TP2) after the procedure. Key exclusions were inability to tolerate MRI, expanded Treatment in Cerebral Ischemia (eTICI) scores 15% interside median relative cerebral blood volume or flow reduction after eTICI 2c-3 angiographic reperfusion. No-reflow was assessed globally (across the entire diffusion-weighted imaging-positive lesion at TP2) and within 2 subregions (early ischemic core and infarct growth). The associations between no-reflow patterns, infarct growth, and favorable clinical outcome (modified Rankin Scale [mRS] scores 0-1 at 3 months) were examined as exploratory analyses. Among 29 patients with eTICI 2c-3 (median age, 73 years; 48% female), 6 (21%) showed no-reflow changes at TP1 and 7 (24%) showed global no-reflow at TP2. Between TP1 and TP2, no-reflow persisted in 3 patients, progressed in 1, resolved in 2, and newly developed in 3. Global no-reflow at TP1 was associated with greater infarct growth at TP2 (median difference 25.02 mL, 95% CI 5.60-44.43, p = 0.01). Global no-reflow at TP2 was associated with lower odds of good clinical outcome (mRS score 0-1: odds ratio 0.14, 95% CI 0.02-0.84, p = 0.03). No-reflow manifests early after technically successful thrombectomy and frequently persists, possibly contributing to infarct growth and worse patient outcomes. Cases of resolution and progression suggest a dynamic and reversible pathology, potentially amenable to timely treatment. ACTRN12624000629538.

Background: Repeat thrombectomy for recurrent large vessel occlusion (LVO) is uncommon but clinically consequential. Although previous studies have described general causes of recurrent LVO, the association between recurrence timing and underlying aetiology—particularly atrial fibrillation—remains poorly characterised. Methods: We performed a retrospective study of consecutive patients who underwent repeat thrombectomy for recurrent LVO at a tertiary comprehensive stroke centre between January 2020 and December 2024. Recurrence timing was stratified into early (≤1 day) versus delayed (≥2 days). Clinical characteristics, aetiology and procedural variables were compared between early versus delayed group. Results: Among 1116 thrombectomy procedures, 16 patients (1.4%) had recurrent LVO requiring thrombectomy. Eight patients (50.0%) had early recurrence, and eight (50.0%) had delayed recurrence. Early events demonstrated a consistent same-vessel pattern (8/8, 100%) and were exclusively associated with non-atrial fibrillation mechanisms, including intracranial atherosclerotic disease and arterial dissection. In contrast, delayed recurrence was strongly associated with atrial fibrillation (7/8, 87.5%; p<0.001). Notably, four of seven atrial fibrillation–related cases (57.1%) were not on appropriate anticoagulation at the time of recurrence. Functional outcomes at 90 days did not differ significantly between groups (median modified Rankin Scale 5 vs 5; p=0.704). Conclusions: Recurrent LVO after thrombectomy appeared to display distinct time-dependent patterns in this cohort. These findings suggest that recurrence timing may serve as a practical clinical marker to guide targeted evaluation—vascular imaging and plaque assessment for early recurrence cases, and intensified rhythm monitoring for delayed cases. Larger studies are needed to validate these time-specific patterns.

BACKGROUND: Equipoise persists whether patients with stroke with carotid tandem lesions undergoing endovascular treatment (EVT) should undergo acute carotid stenting, and whether intravenous thrombolysis (IVT) before EVT should influence this decision. We assessed functional and safety outcomes of acute carotid stenting in patients with carotid tandem lesions randomized to IVT plus EVT or EVT alone. METHODS: Individual participant data meta-analysis of 6 randomized clinical trials conducted in Asia, Europe, and Oceania between 2017 and 2021 investigating IVT plus EVT versus EVT alone in patients with carotid tandem lesions presenting directly to EVT-capable centers. The primary outcome was the 90-day modified Rankin Scale score, assessed with mixed-effect ordinal regression models. Safety outcomes were any intracranial hemorrhage and symptomatic intracranial hemorrhage. A secondary analysis used inverse probability of treatment weighting. Treatment effect heterogeneity between IVT plus EVT and EVT alone was assessed in a 2-step meta-analysis. RESULTS: Overall, 340 of 2267 (15%) patients had carotid tandem lesions with 113 of 329 (34%) undergoing acute carotid stenting. Stenting was associated with better 90-day functional outcomes (adjusted common odds ratio, 1.60 [95% CI, 1.03–2.47]), confirmed in inverse probability of treatment weighting analysis (adjusted common odds ratio, 1.66 [95% CI, 1.08–2.54]). Patients undergoing stenting had no statistically significant higher rates of any intracranial hemorrhage (44% versus 35%; adjusted odds ratio, 1.30 [95% CI, 0.79–2.15]) and symptomatic intracranial hemorrhage (6.3% versus 3.7%; adjusted odds ratio, 2.09 [95% CI, 0.78–5.59]). No heterogeneity in treatment effect was observed in patients randomized to IVT plus EVT (adjusted common odds ratio, 2.07 [95% CI, 1.06–4.07]) or EVT alone (1.21 [95% CI, 0.59–2.50]; P interaction=0.81). CONCLUSIONS: In this international individual participant data meta-analysis of patients with carotid tandem lesions randomized to EVT alone or IVT followed by EVT, acute carotid stenting during EVT was associated with better functional outcomes, and this association was not modified by prior treatment with IVT.

Background: To rapidly predict outcomes of candidate for endovascular thrombectomy in time‐sensitive situations with limited clinical information, we propose a simple but balanced approach, integrating National Institutes of Health Stroke Scale (NIHSS) and Alberta Stroke Program Early CT Score (ASPECTS). Methods: This study utilized data from 2 independent registries to investigate the associations of NIHSS scores and ASPECTS with clinical outcomes of patients with stroke with large vessel occlusion in the anterior circulation who underwent endovascular thrombectomy and to evaluate the accuracy of a novel clinical‐imaging equation in predicting these outcomes. The primary outcome was functional independence. Results: A total of 2128 patients were included. Of these, 1052 (49.4%) achieved functional independence. ASPECTS, NIHSS scores, and age were identified as key predictors across all basic parameters. Clinical‐imaging equations (with and without age adjustment, defined as ASPECTS−0.5×NIHSS−age×0.2 and ASPECTS−NIHSS×0.5) were developed. These equations exhibited superior discriminative ability (C statistic, 0.71 [95% CI, 0.68–0.74], 0.68 [95% CI, 0.65–0.70]) compared with traditional methods in the validation cohort. The prediction probability of functional independence by quartiles of clinical‐imaging equation with age adjustment (≤−15.5, −15.5 to −12, −15.5 to −12, >−9.5) was 32% (95% CI, 17%–47%), 51% (95% CI, 43%–59%), 63% (95% CI, 58%–69%), and 77% (95% CI, 65%–90%) in the validation cohort. Conclusions: By integrating ASPECTS and NIHSS scores, our clinical‐imaging equations improved rapid prediction of endovascular thrombectomy outcomes in time‐sensitive situations such as patient transfers from primary stroke centers or in mobile stroke units, where clinical information is limited.

Introduction: Patients with large vessel occlusion (LVO) stroke are often transferred from primary to tertiary stroke centres for endovascular thrombectomy (EVT). We previously showed that ≥33% improvement in National Institute of Health Stroke Scale (NIHSS) score correlated with early recanalization, obviating the need for EVT. We aimed to validate this correlation and assess cost savings if non-invasive imaging was performed prior to digital subtraction angiography (DSA). Methods: Patients transferred to an Australian tertiary stroke centre for possible EVT between January 2023 and April 2024 and underwent DSA with or without EVT were included. Changes in NIHSS between transfer and arrival, demographic, treatment, and anatomical factors were collected. NIHSS changes were correlated with early recanalization. Real-time costs of in- and out-of-hours neuroimaging and DSA were calculated. Results: A total of 257 transferred patients with LVO were included (30% female, median age 71 [IQR 61–79]). The median presentation NIHSS was 14 (IQR 10–19). A total of 129 (50%) patients received intravenous thrombolytics. Twenty-seven (11%) patients demonstrated early recanalization and did not require EVT. Threshold of ≥33% NIHSS improvement remained the best trade-off between sensitivity (74%) and specificity (88%) for recanalization. The hyperacute investigation and treatment costs in/out-of-hours per patient were AUD 1,491 and AUD 3,591. Costs if patients with ≥33% NIHSS improvement were non-invasively imaged prior to DSA were AUD 1,471 and AUD 3,548 – savings of AUD 34 per patient overall. Conclusion: We validated that ≥33% neurological recovery between primary and tertiary stroke centre had the best sensitivity-specificity profile for predicting early recanalization. Modest cost savings occurred using this threshold, but in resource-poor settings, this may be more significant.

The association of anesthesia approach during endovascular thrombectomy (EVT) with clinical outcomes in large strokes is unexplored. We aimed to evaluate whether general anesthesia (GA), compared with non-GA, was associated with better functional outcomes in the SELECT2 trial. In a prespecified secondary analysis of the SELECT2 trial that enrolled patients with large strokes on noncontrast CT (Alberta Stroke Program Early CT Score [ASPECTS] 3-5), CT perfusion/MRI (core volume ≥50 mL), or both, functional outcomes were compared in EVT-treated patients who received GA or non-GA and whether this association was modified by stroke severity (NIH Stroke Scale score), ischemic injury estimates, and collateral status was evaluated. The primary outcome was 90-day functional status (ordinal modified Rankin Scale [mRS]). Secondary outcomes were functional independence (mRS scores 0-2), independent ambulation (mRS scores 0-3), complete dependence or death (mRS scores 5-6), and mortality. Of 178 EVT patients (median [interquartile range] age 66 [58-75] years, stroke severity 19 [15-23], CT-ASPECTS 4 [3-5], and core volume 101.5 [70-138] mL, 71 women [39.9%]), 104 (58%) received GA. Time from randomization to arterial puncture was longer with GA (40 [23-59] minutes) vs non-GA (27 [18-47] minutes), but procedural duration (GA: 57 [31.5-77] minutes vs non-GA: 49.5 [30-71] minutes) was similar. Successful reperfusion (modified treatment in cerebral infarction [mTICI] score 2b-3) rates were similar (GA 81 (78%) vs non-GA 62 (84%), adjusted relative risk [aRR] 0.91, 95% CI 0.79-1.06). In addition, mRS distribution did not differ between GA and non-GA groups (adjusted generalized odds ratio 1.21, 95% CI 0.86-1.70), as well as independent ambulation (GA: 41% vs non-GA: 34%, aRR 1.22, 95% CI 0.86-1.74) and functional independence (GA: 22% vs non-GA: 18%, aRR 1.32, 95% CI 0.75-2.35). Stroke severity, ASPECTS, ischemic core volume, or collaterals did not modify the association between anesthesia and functional outcome (all p-interaction >0.05). Patients experienced systolic blood pressure (SBP) variability ≥40 mm Hg and minimum intraprocedural SBP (p-interaction = 0.77 and 0.89, respectively). In patients with large core strokes randomized in SELECT2, EVT outcomes did not differ significantly based on anesthesia approach (GA or non-GA) without heterogeneity across stroke severity and size. While GA was associated with higher SBP variability and lower minimum SBP, this did not modify GA association with functional outcomes. While allocation to anesthesia approach was nonrandomized, our findings suggest that optimizing institutional protocols for preferred anesthesia technique, whether GA or non-GA, may enhance EVT procedural outcomes. ClinicalTrials.gov ID: NCT03876457. This study provides Class II evidence that in patients presenting within 24 hours with large vessel occlusion strokes undergoing EVT, the 90-day mRS score is comparable in those with or without GA.