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Noninferiority trials aim to prove that the efficacy, defined in terms of a key clinical outcome, of a new treatment is not meaningfully worse than that of an established active control. Noninferiority trials are important when other aspects of care can be improved, such as convenience, toxicity, costs, and safety (nonefficacy benefits). While the motivation for a noninferiority trial is straightforward, the design, execution, and interpretation of these trials is not a trivial task. Several safeguards that protect superiority trials from incorrect conclusions do not apply or even work in reverse for noninferiority trials. This review aims to provide stroke clinicians and researchers with a general overview of noninferiority trials and a deeper understanding of 10 pitfalls they should consider when designing and interpreting such trials., Competing Interests: Dr Kaesmacher reports grants from Le Studium and grants from the Swiss National Science Foundation (SNSF) to other. Dr Saver reports stock options in Neuronics Medical; compensation from Biogen for consultant services; compensation from BrainQ for consultant services; compensation from Johnson & Johnson Health Care Systems, Inc, for consultant services; compensation from Roche for consultant services; stock options in MindRhythm; compensation from Stream Medical for consultant services; compensation from Bayer for consultant services; compensation from Medtronic USA, Inc, for consultant services; compensation from MIVI Neuroscience for data and safety monitoring services; compensation from CSL Behring for consultant services; compensation from Aeromics for consultant services; compensation from Boehringer Ingelheim (prevention only) for consultant services; compensation from Abbott Laboratories for consultant services; stock options in Rapid Medical; compensation from Occlutech for data and safety monitoring services; and compensation from BrainsGate for consultant services. Dr Gralla reports compensation from Johnson & Johnson Health Care Systems, Inc, for consultant services and compensation from Medtronic USA, Inc, for other services. Dr Fischer reports grants from Stryker to other; grants from Schweizerische Herzstiftung; grants from Penumbra, Inc, to other; grants from SNSF; compensation from phenox, Inc, for end point review committee services; grants from Medtronic to other; grants from phenox, Inc, to other; grants from Rapid Medical, Ltd, to other; grants from Boehringer Ingelheim; grants from Stryker to other; and grants from Medtronic to other. Dr Majoie reports grants from European Commission to other; grants from Health Evaluation Netherlands to other; grants from Stryker Corporation to other; stock holdings in Nicolab; grants from Dutch Heart Foundation to other; and grants from Boehringer Ingelheim to other. Dr Roos reports stock holdings in Nicolab. The other authors report no conflicts.

Background: Women with anterior circulation large vessel occlusion (LVO) have been reported to have worse outcomes after endovascular treatment (EVT) than men. Whether these disparities also exist in LVO of the posterior circulation is yet uncertain. We assessed sex differences in clinical, technical, and safety outcomes of EVT in posterior circulation LVO., Methods: We used data of patients with posterior circulation LVO included in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry (2014-2018). Primary outcome was the modified Rankin Scale (mRS) score at 90 days assessed with multivariable ordinal regression analysis. Secondary outcomes included favorable functional outcome (mRS ≤3), functional independence (mRS ≤2), death within 90 days, National Institutes of Health Stroke Scale (NIHSS) score 24-48 hours postintervention, complications, successful reperfusion (extended Thrombolysis in Cerebral Ischemia 2B-3), and procedure duration analyzed with multivariable logistic and linear regression analyses., Results: We included 264 patients (42% women). Compared with men, women were older (median age 68 vs 63 years), more often had prestroke disability (mRS ≥1: 37% vs 30%), and received intravenous thrombolytics less often (45% vs 56%). Clinical outcomes were similar between sexes (adjusted (common) OR (aOR) 0.82, 95% CI 0.51 to 1.34; favorable functional outcome 50% vs 43%, aOR 1.31, 95% CI 0.77 to 2.25; death 32% vs 29%, aOR 0.98, 95% CI 0.52 to 1.84). In addition, NIHSS score after 24-48 hours (median 7 vs 9), successful reperfusion (77% vs 73%), and complications did not differ between men and women., Conclusions: Outcomes in women treated with EVT for posterior circulation LVO were similar compared with men despite less favorable baseline characteristics in women. Therefore men and women may benefit equally from EVT., Competing Interests: Competing interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MJHW reports funding from NWO/ZonMw (VIDI 91717337 and Aspasia). JH reports funding from the Dutch Heart Foundation (CEI 2018T070). CBLMM reports funding from the TWIN Foundation, CVON/Dutch Heart Foundation, European Commission, Healthcare Evaluation Netherlands, and Stryker, all outside the submitted work (paid to institution). In addition, he is shareholder of Nicolab. IRvdW reports consulting fees from Philips, Medtronic, and Neurophyxia. DWJD reports funding from the Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences & Health, and unrestricted grants from Penumbra Inc, Stryker European Operations BV, Medtronic, Thrombolytic Science, LLC and Cerenovus, all paid to the institution. The other authors had no conflicting interests., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Although CT perfusion (CTP) is often incorporated in acute stroke workflows, it remains largely unclear what the associated costs and health implications are in the long run of CTP-based patient selection for endovascular treatment (EVT) in patients presenting within 6 hours after symptom onset with a large vessel occlusion., Methods: Patients with a large vessel occlusion were included from a Dutch nationwide cohort (n=703) if CTP imaging was performed before EVT within 6 hours after stroke onset. Simulated cost and health effects during 5 and 10 years follow-up were compared between CTP based patient selection for EVT and providing EVT to all patients. Outcome measures were the net monetary benefit at a willingness-to-pay of €80 000 per quality-adjusted life year, incremental cost-effectiveness ratio), difference in costs from a healthcare payer perspective (ΔCosts) and quality-adjusted life years (ΔQALY) per 1000 patients for 1000 model iterations as outcomes., Results: Compared with treating all patients, CTP-based selection for EVT at the optimised ischaemic core volume (ICV≥110 mL) or core-penumbra mismatch ratio (MMR≤1.4) thresholds resulted in losses of health (median ΔQALYs for ICV≥110 mL: -3.3 (IQR: -5.9 to -1.1), for MMR≤1.4: 0.0 (IQR: -1.3 to 0.0)) with median ΔCosts for ICV≥110 mL of -€348 966 (IQR: -€712 406 to -€51 158) and for MMR≤1.4 of €266 513 (IQR: €229 403 to €380 110)) per 1000 patients. Sensitivity analyses did not yield any scenarios for CTP-based selection of patients for EVT that were cost-effective for improving health, including patients aged ≥80 years CONCLUSION: In EVT-eligible patients presenting within 6 hours after symptom onset, excluding patients based on CTP parameters was not cost-effective and could potentially harm patients., Competing Interests: Competing interests: BJE reports grants from LtC (ZonMW and TKI-PPP of Health Holland). WHvZ reports speaker fees from Cerenovus, NicoLab and Stryker, and consulting fees from Philips, all paid to Institution. DWJD report grants from the Dutch Heart Foundation, Brain Foundation Netherlands, ZON MW, Stryker, Medtronic, Cerenovus, Thrombolytic Science, received by the Erasmus University Medical Center outside this project. AJY reports Research grants from Medtronic, Cerenovus, Penumbra, Stryker, and Genentech. Consultant for Penumbra, Cerenovus, Nicolab, Philips, Vesalio, Zoll Circulation, and NIH/NINDS. CBM: grants from Healthcare Evaluation Netherlands, CVON/Dutch Heart Foundation, TWIN foundation and Stryker during the conduct of the study and from European Commission outside this project (all paid to institution) and is shareholder of Nicolab. All other contributors report no other conflicts of interest., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Intravenous thrombolysis is recommended before endovascular treatment, but its value has been questioned in patients who are admitted directly to centres capable of endovascular treatment. Existing randomised controlled trials have indicated non-inferiority of endovascular treatment alone or have been statistically inconclusive. We formed the Improving Reperfusion Strategies in Acute Ischaemic Stroke collaboration to assess non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment., Methods: We conducted a systematic review and individual participant data meta-analysis to establish non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. We searched PubMed and MEDLINE with the terms "stroke", "endovascular treatment", "intravenous thrombolysis", and synonyms for articles published from database inception to March 9, 2023. We included randomised controlled trials on the topic of interest, without language restrictions. Authors of the identified trials agreed to take part, and individual participant data were provided by the principal investigators of the respective trials and collated centrally by the collaborators. Our primary outcome was the 90-day modified Rankin Scale (mRS) score. Non-inferiority of endovascular treatment alone was assessed using a lower boundary of 0·82 for the 95% CI around the adjusted common odds ratio (acOR) for shift towards improved outcome (analogous to 5% absolute difference in functional independence) with ordinal regression. We used mixed-effects models for all analyses. This study is registered with PROSPERO, CRD42023411986., Findings: We identified 1081 studies, and six studies (n=2313; 1153 participants randomly assigned to receive endovascular treatment alone and 1160 randomly assigned to receive intravenous thrombolysis and endovascular treatment) were eligible for analysis. The risk of bias of the included studies was low to moderate. Variability between studies was small, and mainly related to the choice and dose of the thrombolytic drug and country of execution. The median mRS score at 90 days was 3 (IQR 1-5) for participants who received endovascular treatment alone and 2 (1-4) for participants who received intravenous thrombolysis plus endovascular treatment (acOR 0·89, 95% CI 0·76-1·04). Any intracranial haemorrhage (0·82, 0·68-0·99) occurred less frequently with endovascular treatment alone than with intravenous thrombolysis plus endovascular treatment. Symptomatic intracranial haemorrhage and mortality rates did not differ significantly., Interpretation: We did not establish non-inferiority of endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment in patients presenting directly at endovascular treatment centres. Further research could focus on cost-effectiveness analysis and on individualised decisions when patient characteristics, medication shortages, or delays are expected to offset a potential benefit of administering intravenous thrombolysis before endovascular treatment., Funding: Stryker and Amsterdam University Medical Centers, University of Amsterdam., Competing Interests: Declaration of interests CBM reports grants from CardioVasculair Onderzoek Nederland by the Dutch Heart Foundation, TWIN Foundation, the European Commission, Healthcare Evaluation Netherlands, and Stryker (all paid to institution); and is a minority interest shareholder of Nicolab. YBR reports being a minor shareholder of Nicolab. JG reports consultancy funds from Medtronic as Global Principal Investigator of STAR (NCT01327989) and Swift Direct (NCT03192332) and from Cerenovus (now part of Johnson & Johnson) and participation on a data safety monitoring board or advisory board (clinical ethics committee member of the Promise Study) for Penumbra. CC reports consulting fees from Microvention, Medtronic, Cerenovus, MIVI, and Stryker. TD reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Microvention. BJE reports institutional funding from HealthHolland Top Sector Life Sciences and Nicolab. RGN reports funding from Cerenovus as Principal Investigator of the ENDOLOW trial and from Stryker Neurovascular as Principal Investigator of the DUSK trial; consulting fees for advisory roles with Anaconda, Biogen, Cerenovus, Genentech, Philips, Hybernia, Imperative Care, Medtronic, Phenox, Philips, Prolong Pharmaceuticals, Stryker Neurovascular, Shanghai Wallaby, and Synchron; stock options for advisory roles with Astrocyte, Brainomix, Cerebrotech, Ceretrieve, Corindus Vascular Robotics, Vesalio, Viz-AI, RapidPulse, and Perfuze; and being an investor in Viz-AI, Perfuze, Cerebrotech, Reist–Q’Apel Medical, Truvic, Vastrax, and Viseon. UF reports funding from Medtronic, Stryker, Rapid Medical, Phenox, Penumbra, Swiss National Science Foundation, CSL Behring, Portola (now part of Alexion), Boehringer Ingelheim, and Biogen. SD reports institutional funding from the National Health and Medical Research Council and funding from Medtronic, Abbott, and CSL Behring for participation on data safety monitoring boards or advisory boards. PM reports institutional funding from Stryker and Medtronic. BY reports institutional research grants from Stryker and Medtronic. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: High systolic blood pressure (SBP) is associated with poor functional outcome. We analysed whether the association of SBP with outcomes after endovascular treatment (EVT) is modified by prior intravenous thrombolysis (IVT)., Patients and Methods: This was a post-hoc analysis of MR CLEAN-NO IV, a randomised trial of IVT with alteplase followed by EVT versus EVT alone, within 4.5 h from stroke onset. SBP was recorded on hospital admission. The primary outcome was 90-day modified Rankin Scale (mRS) score and secondary outcomes included symptomatic intracranial haemorrhage (sICH) and successful reperfusion (eTICI 2b-3), analysed with (ordinal) logistic regression. Estimates were calculated per 10 mmHg change in SBP. We assessed whether IVT modified the associations of SBP with these outcomes using multiplicative interaction terms., Results: Of 539 randomised patients, 266 received IVT. The association of SBP with mRS score was J-shaped, with an inflection point at 150 mmHg. Using 150 mmHg as a reference point, SBPs higher than 150 mmHg were associated with poor functional outcome (acOR: 1.23, 95% CI: 1.09-1.38), but lower SBPs were not (acOR: 1.14, 95% CI: 0.99-1.30). Higher SBP was not associated with the risk of sICH (aOR: 1.09, 95% CI: 0.93-1.27) nor with the probability of successful reperfusion (aOR: 1.00, 95% CI: 0.91-1.10). Our main result was that we found no effect modification by IVT ( p -values for interaction, mRS = 0.94; sICH = 0.26; successful reperfusion = 0.58)., Discussion and Conclusion: There was no effect modification of IVT with SBP for any of the clinical outcomes. Therefore, the level of SBP (if ⩽185/110 mmHg) should not guide IVT decisions in patients otherwise eligible for both IVT and EVT within the 4.5-h time window., Trial Registration: ISRCTN80619088, https://www.isrctn.com/ISRCTN80619088.

Background: The effects of thrombus imaging characteristics on procedural and clinical outcomes after ischemic stroke are increasingly being studied. These thrombus characteristics - for eg, size, location, and density - are commonly analyzed as separate entities. However, it is known that some of these thrombus characteristics are strongly related. Multicollinearity can lead to unreliable prediction models. We aimed to determine the distribution, correlation and clustering of thrombus imaging characteristics based on a large dataset of anterior-circulation acute ischemic stroke patients., Methods: We measured thrombus imaging characteristics in the MR CLEAN Registry dataset, which included occlusion location, distance from the intracranial carotid artery to the thrombus (DT), thrombus length, density, perviousness, and clot burden score (CBS). We assessed intercorrelations with Spearman's coefficient (ρ) and grouped thrombi based on 1) occlusion location and 2) thrombus length, density and perviousness using unsupervised clustering., Results: We included 934 patients, of which 22% had an internal carotid artery (ICA) occlusion, 61% M1, 16% M2, and 1% another occlusion location. All thrombus characteristics were significantly correlated. Higher CBS was strongly correlated with longer DT (ρ=0.67, p<0.01), and moderately correlated with shorter thrombus length (ρ=-0.41, p<0.01). In more proximal occlusion locations, thrombi were significantly longer, denser, and less pervious. Unsupervised clustering analysis resulted in four thrombus groups; however, the cohesion within and distinction between the groups were weak., Conclusions: Thrombus imaging characteristics are significantly intercorrelated - strong correlations should be considered in future predictive modeling studies. Clustering analysis showed there are no distinct thrombus archetypes - novel treatments should consider this thrombus variability., Competing Interests: Competing interests: This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 777072 (INSIST project), and the AMC medical Research BV, Amsterdam UMC, location AMC, under project No 21937. The MR CLEAN registry is partially funded by unrestricted grants from the Applied Scientific Institute for Neuromodulation (Toegepast Wetenschappelijk Instituut voor Neuromodulatie), Erasmus Medical Center, Amsterdam University Medical Center and Maastricht University Medical Center. HAM reports being a co-founder and shareholder of Nicolab, a company that focuses on the use of artificial intelligence for medical image analysis. CBLMM reports grants from European Commission during the conduct of the study; grants from CVON/Dutch Heart Foundation, TWIN Foundation, Health Evaluation Netherlands, and Stryker, outside the submitted work; and shareholder of Nicolab. DWJD reports unrestricted grants from Stryker, Penumbra, Medtronic, Cerenovus, Thrombolytic Science, LLC, Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences and Health, and Thrombolytic Science, LLC for research, paid to institution. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cardiac thrombi are a major risk factor for ischemic stroke, but are rarely diagnosed in the acute phase. We examined characteristics and functional outcome of patients with ischemic stroke and a concomitant cardiac thrombus detected on cardiac CT performed in the acute phase., Patients and Methods: We used data from "Mind the Heart," a prospective cohort study in which consecutive adult patients with acute ischemic stroke underwent prospective ECG-gated cardiac CT during their acute stroke imaging protocol. We compared characteristics, functional outcome (modified Rankin scale) and stroke recurrence rate at 90 days of patients with a cardiac thrombus on CT (defined as filling defect <100 Hounsfield Units) to those without a cardiac thrombus., Results: Among 452 included patients, cardiac CT detected 41 thrombi in 38 (8%) patients. Thrombi were most often located in the left atrial appendage (31/38 [82%]). Patients with a cardiac thrombus more frequently had intracranial occlusions in multiple vascular territories (5% vs 0.5%, p  = 0.04) and a higher baseline NIHSS score (17 [IQR 6-22] vs 5 [IQR 2-3], p  < 0.001) compared to patients without a cardiac thrombus. In 13/38 (34%) patients with a cardiac thrombus, no atrial fibrillation was detected. A cardiac thrombus was associated with worse functional outcome (adjusted common odds ratio 3.18 95%CI 1.68-6.00). Recurrence rate was not significantly different (8% vs 4%, aOR 1.50 (0.39-5.82)., Discussion and Conclusion: Cardiac CT detected a cardiac thrombus in one in every 12 patients with acute ischemic stroke, and these patients had more severe deficits, multivessel occlusions, and a worse functional outcome., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CBLMM has received research grants from CVON/Dutch Heart Foundation, European Commission, TWIN Foundation Dutch Health Evaluation program and Stryker (paid to institution). CBLMM, HAM and YBWEMR are shareholders of Nico.lab, a company that focuses on the use of artificial intelligence for medical image analysis. JMC reports grants from Medtronic, Boehringer Ingelheim, and Bayer outside the submitted work. (paid to institution). The other authors have no financial conflicts of interest., (© European Stroke Organisation 2022.)

Introduction: Little is known about the timing of occurrence of symptomatic intracranial hemorrhage (sICH) after endovascular therapy (EVT) for acute ischemic stroke. A better understanding could optimize in-hospital surveillance time points and duration. The aim of this study was to delineate the probability of sICH over time and to identify factors associated with its timing., Patients and Methods: We retrospectively analyzed data from the Dutch MR CLEAN trial and MR CLEAN Registry. We included adult patients who underwent EVT for an anterior circulation large vessel occlusion within 6.5 h of stroke onset. In patients with sICH (defined as ICH causing an increase of ⩾4 points on the National Institutes of Health Stroke Scale [NIHSS]), univariable and multivariable linear regression analysis was used to identify factors associated with the timing of sICH. This was defined as the time between end of EVT and the time of first CT-scan on which ICH was seen as a proxy., Results: SICH occurred in 205 (6%) of 3391 included patients. Median time from end of EVT procedure to sICH detection on NCCT was 9.0 [IQR 2.9-22.5] hours, with a rapidly decreasing incidence after 24 h. None of the analyzed factors, including baseline NIHSS, intravenous alteplase treatment, and poor reperfusion at the end of the procedure were associated with the timing of sICH., Conclusion: SICHs primarily occur in the first hours after EVT, and less frequently beyond 24 h. Guidelines that recommend to perform frequent neurological assessments for at least 24 h after intravenous alteplase treatment can be applied to ischemic stroke patients treated with EVT., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DD and AvdL report funding from the Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organisation for Health Research and Development, Health Holland Top Sector Life Sciences & Health, and unrestricted grants from Penumbra Inc., Stryker, Medtronic, Thrombolytic Science, LLC and Cerenovus for research, all paid to institution. CM: received funds from TWIN Foundation (related to this project, paid to institution); and from CVON/Dutch Heart Foundation, Stryker, European Commission, Health Evaluation Netherlands (unrelated; all paid to institution). CM is shareholder of Nicolab, a company that focuses on the use of artificial intelligence for medical imaging analysis. WvZ reports speaker fees from Stryker, Nicolab and Cerenovus, both paid to institution. BR reports funding from the Dutch Heart Foundation, and The Netherlands Organisation for Health Research and Development, all paid to institution., (© European Stroke Organisation 2022.)

Rabenosyn (RBSN) is a conserved endosomal protein necessary for regulating internalized cargo. Here, we present clinical, genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability. Using exome sequencing, we identified recessively acting germline alleles p.Arg180Gly and p.Gly183Arg, which are both situated in the FYVE domain of RBSN. We find that these variants abrogate binding to its cognate substrate phosphatidylinositol 3-phosphate (PI3P) and thus prevent its translocation to early endosomes. Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts show accumulation of cargo tagged for lysosomal degradation. Our results suggest that these variants are separation-of-function alleles, which cause a delay in endosomal maturation without affecting cargo recycling. We conclude that distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Hyperglycemia is highly prevalent in patients with acute ischemic stroke and is associated with increased risk of symptomatic intracranial hemorrhage, larger infarct size and unfavorable outcome. Furthermore, glucose may modify the effect of endovascular treatment (EVT) in patients with ischemic stroke. Hyperglycemia might lead to accelerated conversion of penumbra into infarct core. However, it remains uncertain whether hyperglycemia on admission is associated with the size of penumbra or infarct core in acute ischemic stroke. In this study, we aimed to assess the association between hyperglycemia and Computed Tomographic Perfusion (CTP) derived parameters in patients who underwent EVT for acute ischemic stroke., Methods: We used data from the MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). Hyperglycemia was defined as admission serum glucose of >7.8 mmol/L. Dichotomized and quantiles of glucose levels were related to size of core, penumbra and core penumbra ratio. Hypoperfused area is mean transient time 45% higher than that of the contralateral hemisphere. Core is the area with cerebral blood volume of <2 mL/100 g and penumbra is the area with cerebral blood volume > 2 mL/100 g. Core-penumbra ratio is the ischemic core divided by the total volume of hypoperfused tissue (core plus penumbra) multiplied by 100. Adjustments were made for age, sex, NIHSS on admission, onset-imaging time and diabetes mellitus., Results: Hundred seventy-three patients were included. Median glucose level on admission was 6.5 mmol/L (IQR 5.8-7.5 mmol/L) and thirty-five patients (20%) were hyperglycemic. Median core volume was 33.3 mL (IQR 13.6-62.4 mL), median penumbra volume was 80.2 mL (IQR 36.3-123.5 mL) and median core-penumbra ratio was 28.5% (IQR 18.6-45.8%). Patients with hyperglycemia on admission had larger core volumes and core penumbra ratio than normoglycemic patients with a regression coefficient of 15.1 (95% confidence interval (CI), 1.8 to 28.3) and 11.5 (95% confidence interval (CI), 3.4 to 19.7) respectively., Conclusion: Hyperglycemia on admission was associated with larger ischemic core volume and larger core-penumbra ratio in patients with acute ischemic stroke who underwent endovascular treatment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: The optimal anaesthesia approach for endovascular treatment (EVT) in acute ischaemic stroke is currently unknown. In stroke due to medium vessel occlusions (MeVO), the occluded vessels are particularly small and more difficult to access, especially in restless or uncooperative patients. In these patients, general anaesthesia (GA) may be preferred by physicians to prevent complications due to patient movement. We investigated physicians' approaches to anaesthesia during EVT for MeVO stroke., Methods: In a worldwide, case-based, online survey, physicians' preferred anaesthesia approach during EVT for MeVO stroke was categorized as "initial GA", "initial GA if necessary" (depending on patient cooperation), "no initial GA, but conversion if necessary" (start with local anaesthesia or conscious sedation), and "no GA". Preferred anaesthesia approaches were reported overall and stratified by physician and patient characteristics., Results: A total of 366 survey participants provided 1464 responses to 4 primary MeVO EVT case-scenarios. One-third of responses (489/1464 [33%]) favoured no initial GA, but conversion if necessary. Both initial GA and initial GA if necessary were preferred in 368/1464 (25%) of responses respectively. No GA was favoured in 244/1464 (17%). Occlusion location, respondent specialization (interventional neuroradiology), higher age, and female respondent sex were significantly associated with GA preference. GA was more often used in Europe than in other parts of the world ( p  < 0.001)., Conclusions: Anaesthesia approaches in MeVO EVT vary across world regions and patient and physician factors. Most physicians in this survey preferred to start with local anaesthesia or conscious sedation and convert to GA if necessary.

Infarct volume (FIV) on follow-up diffusion-weighted imaging (FU-DWI) is only moderately associated with functional outcome in acute ischemic stroke patients. However, FU-DWI may contain other imaging biomarkers that could aid in improving outcome prediction models for acute ischemic stroke. We included FU-DWI data from the HERMES, ISLES, and MR CLEAN-NO IV databases. Lesions were segmented using a deep learning model trained on the HERMES and ISLES datasets. We assessed the performance of three classifiers in predicting functional independence for the MR CLEAN-NO IV trial cohort based on: (1) FIV alone, (2) the most important features obtained from a trained convolutional autoencoder (CAE), and (3) radiomics. Furthermore, we investigated feature importance in the radiomic-feature-based model. For outcome prediction, we included 206 patients: 144 scans were included in the training set, 21 in the validation set, and 41 in the test set. The classifiers that included the CAE and the radiomic features showed AUC values of 0.88 and 0.81, respectively, while the model based on FIV had an AUC of 0.79. This difference was not found to be statistically significant. Feature importance results showed that lesion intensity heterogeneity received more weight than lesion volume in outcome prediction. This study suggests that predictions of functional outcome should not be based on FIV alone and that FU-DWI images capture additional prognostic information.

Introduction: Computed tomography perfusion (CTP) is variably considered to assess eligibility for endovascular thrombectomy (EVT) in acute ischemic (AIS) stroke patients. Although CTP is recommended for patient selection in later (6-24 h) time window, it is currently not recommended in the earlier (0-6 h) time window and the costs and health effects of including CTP for EVT selection remain unknown. We aim to estimate the costs and health effects of using CTP for EVT selection in AIS patients compared to conventional selection., Patients and Methods: CLEOPATRA is a healthcare evaluation study using clinical and imaging data from multiple, prospective EVT trials and registries in both the earlier and later time windows. To study the long-term health and cost effects, we will construct a ("Markov") health state transition model simulating the clinical outcome over a 5-year follow-up period for CTP-based and conventional selection for EVT. Clinical data acquired within the current study and estimates from the literature will be used as input for probabilities of events, costs, and Quality-Adjusted Life Years (QALYs) per modified Rankin Scale (mRS) subscore. Primary outcome for the cost-effectiveness analysis will be the Incremental Cost-Effectiveness Ratio (ICER) in terms of costs per QALY gained over the simulated follow-up period., Study Outcomes: Outcome measures will be reported as cumulative values over a 5-year follow-up period., Discussion: This study will provide preliminary insight into costs and health effects of including CTP in the selection for EVT for AIS patients, presenting between 0 and 24 h after time last known well. The results may be used to develop recommendations and inform further implementation projects and studies., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BJE reports grants from LtC (ZonMW and TKI-PPP of Health Holland). WHvZ reports personal fees from Codman and from Stryker. DWJD and AvdL report grants from the Dutch Heart Foundation, AngioCare, Medtronic/Covidien/EV3, MEDAC/LAMEPRO, Penumbra, Top Medical/Concentric, Stryker, and Cerenovus; consultation fees from Stryker, Bracco Imaging, and Servier, received by the Erasmus University Medical Centre outside this project. CBLMM reports grants from TWIN, during the conduct of the study and grants from CVON/Dutch Heart Foundation, European Commission, Dutch Health Evaluation Program, and from Stryker outside this project (paid to institution) and is shareholder of Nicolab. HAM is co-founder and shareholder of Nicolab. All other contributors report no conflicts of interest., (© European Stroke Organisation 2022.)

Introduction: Vascular anatomy might affect endovascular treatment success in acute ischemic stroke patients with large vessel occlusion. We investigated the prognostic value of extracranial vascular characteristics on procedural time and revascularization success in patients with large vessel occlusion in the anterior cerebral circulation., Patients and Methods: We included 828 patients endovascularly treated within 6.5 hours of symptom onset from the Dutch MR CLEAN-Registry. We evaluated aortic arch configuration, stenosis and tortuosity of supra-aortic arteries, and internal carotid arteries (ICAs) on pre-intervention CTA. We constructed logistic prediction models for outcome variables procedural duration (≥60 minutes) and non-successful revascularization (extended thrombolysis in cerebral infarction (eTICI) of 0-2A) using baseline characteristics and assessed the effect of extracranial vascular characteristics on model performance., Results: Cervical ICA tortuosity and stenosis ≥99% improved prediction of long procedural duration compared with baseline characteristics from area under the curve of 0.61 (95% CI: 0.57-0.65) to 0.66 (95% CI: 0.62-0.70) ( P < 0.001). Cervical ICA tortuosity was significantly associated with non-successful recanalization. Prediction of non-successful revascularization did not improve after including aortic arch elongation, acute take-off angle, aortic variant, origin stenosis of supra-aortic arteries, and cervical ICA tortuosity, with an area under the curve of 0.63 (95% CI: 0.59-0.67) compared with 0.59 (95% CI: 0.55-0.63) ( P = 0.11)., Conclusion: Extracranial vascular characteristics have additional prognostic value for procedural duration, but not for revascularization success, compared with baseline characteristics. Performance of both prediction models is limited in patients treated for large vessel occlusion., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AL received grants from: Cerenovus, Penumbra, Stryker, Medtronic, Dutch Heart Foundation, The Netherlands Organisation for Health Research and Development, Health Holland Top Sector Life Sciences & Health and from Dutch Brain Foundation. CBLMM received grants during the conduct of the study (paid to institution) from TWIN Foundation and outside of the submitted work (paid to institution) from CVON/Dutch Heart Foundation, European Commission, Dutch Health Evaluation Program and from Stryker; and is shareholder of Nico.Lab. HAM is co-founder and shareholder of Nico.Lab. GH, MPMES, TD, NDK, JJG, WJS, GJLN, LSFY, FJAM, MJHW and MAAW declared no conflict interest., (© European Stroke Organisation 2022.)

Background: Insight in differences in patient outcomes between endovascular thrombectomy (EVT) centers can help to improve stroke care. We assessed between-center variation in functional outcome of patients with acute ischemic stroke who were treated with EVT. We analyzed to what extent this variation may be explained by modifiable center characteristics., Methods: We used nationwide registry data of patients with stroke treated with EVT in the Netherlands and in the Czech Republic. Primary outcome was modified Rankin Scale score at 90 days as an indicator of disability. We used multilevel ordinal logistic regression to quantify the between-center variation in outcomes and the impact of patient and center characteristics. Between-center variation was expressed as the relative difference in odds of a more favorable modified Rankin Scale score between a relatively better performing center (75th percentile) and a relatively worse performing center (25th percentile)., Results: We included a total of 4518 patients treated in 33 centers. Adjusted for patient characteristics, the odds of a more favorable outcome in a center at the 75th percentile of the outcome distribution were 1.46 times higher (95% CI, 1.31-1.70) than the odds in a center at the 25th percentile. Adjustment for center characteristics, including the median time between stroke onset and reperfusion per center, decreased this relative difference in odds to 1.30 (95% CI, 1.18-1.50, P =0.01). This translates into an absolute difference in likelihood of good functional outcome of 8% after adjustment for patient characteristics and to 5% after further adjustment for modifiable center characteristics., Conclusions: The considerable between-center variation in patient outcomes after EVT for acute ischemic stroke could be largely explained by center-specific characteristics, such as time to reperfusion. Improvement of these parameters may likely result in a decrease in center-specific differences, and an overall improvement in outcome of patients with acute ischemic stroke.

Residual blood flow distal to an arterial occlusion in patients with acute ischemic stroke (AIS) is associated with favorable patient outcome. Both collateral flow and thrombus permeability may contribute to such residual flow. We propose a method for discriminating between these two mechanisms, based on determining the direction of flow in multiple branches distal to the occluding thrombus using dynamic Computed Tomography Angiography (dynamic CTA). We analyzed dynamic CTA data of 30 AIS patients and present patient-specific cases that identify typical blood flow patterns and velocities. We distinguished patterns with anterograde (N = 10), retrograde (N = 9), and both flow directions (N = 11), with a large variability in velocities for each flow pattern. The observed flow patterns reflect the interplay between permeability and collaterals. The presented method characterizes distal flow and provides a tool to study patient-specific distal tissue perfusion.

Background and Purpose: Acute ischemic stroke due to large vessel occlusion is uncommon in young adults. We assessed stroke cause in young patients and compared their outcomes after endovascular thrombectomy with older patients., Methods: We used data (March 2014 until November 2017) of patients with an anterior circulation large vessel occlusion stroke from the MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry, a nationwide, prospective study on endovascular thrombectomy in the Netherlands. We compared young patients (18-49 years) with older patients (≥50 years). Outcomes included modified Rankin Scale score after 90 days (both shift and dichotomized analyses), expanded Thrombolysis in Cerebral Infarction score, and symptomatic intracranial hemorrhage. Analyses were adjusted for confounding., Results: We included 3256 patients, 310 (10%) were 18 to 49 years old. Young patients had lower median National Institutes of Health Stroke Scale scores (14 versus 16, P <0.001) and less cardiovascular comorbidities than older patients. Stroke etiologies in young patients included carotid dissection (16%), cardio-embolism (15%), large artery atherosclerosis (10%), and embolic stroke of undetermined source (31%). Clinical outcome was better in young than older patients (acOR for modified Rankin Scale shift: 1.8 [95% CI, 1.5-2.2]; functional independence [modified Rankin Scale score 0-2] 61 versus 39% [adjusted odds ratio, 2.1 [95% CI, 1.6-2.8]); mortality 7% versus 32%, adjusted odds ratio, 0.2 [95% CI, 0.1-0.3]). Symptomatic intracranial hemorrhage occurred less frequently in young patients (3% versus 6%, adjusted odds ratio, 0.5 [95% CI, 0.2-1.00]). Successful reperfusion (expanded Thrombolysis in Cerebral Infarction Score 2b-3) did not differ between groups. Onset to reperfusion time was shorter in young patients (253 versus 255 minutes, adjusted B in minutes 12.4 [95% CI, 2.4-22.5])., Conclusions: Ten percent of patients with acute ischemic stroke undergoing endovascular thrombectomy were younger than 50. Cardioembolism and carotid dissection were common underlying causes in young patients. In one-third of cases, no cause was identified, indicating the need for more research on stroke cause in young patients. Young patients had better prognosis and lower risk of symptomatic intracranial hemorrhage than older patients.

Thrombus perviousness is strongly associated with functional outcome and intravenous alteplase treatment success in patients with acute ischemic stroke. Accuracy of thrombus attenuation increase (TAI) assessment may be compromised by a heterogeneous thrombus composition and interobserver variations of currently used manual measurements. We hypothesized that TAI is more strongly associated with clinical outcomes when evaluated on the entire thrombus. In 195 patients, five TAI measures were performed: one manual by placing three regions of interest (TAI manual ) and four automated ones assessing densities from the entire thrombus. The automated TAI measures were calculated by comparing quartiles; Q1, Q2, and Q3 of the non-contrast and contrast enhanced thrombus density distribution and using the lag of the maximum of the cross correlations (MCC). Associations with functional outcome (mRS at 90 days) were assessed with univariate and multivariable analyses. All entire TAI measures were significantly associated with functional outcome with odd ratios (OR) of 1.63(95 %CI:1.19-2.25, p = 0.003) for Q1, 1.56(95 %CI:1.16-2.10, p = 0.003) for Q2, 1.24(95 %CI:1.00-1.54, p = 0.045) for Q3, and 1.70(95 %CI:1.24-2.34, p = 0.001) for MCC per 10 HU increase in univariate models. TAI manual was not significantly associated with functional outcome (p = 0.055). In the multivariable logistic regression models including age, NIHSS, and recanalization, only TAI measures derived from the entire thrombus were independently associated with favorable outcome; OR of 1.64(95 %CI:1.01-2.66, p = 0.048) for Q2 and 1.82(1.13-2.95, p = 0.014) for MCC per 10 HU increase of thrombus attenuation. The novel perviousness measures of the entire thrombus are more strongly associated with functional outcome than the traditional manual perviousness assessments., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Brain atrophy is suggested to impair the potential for functional recovery after acute ischemic stroke. We assessed whether the effect of endovascular treatment is modified by brain atrophy in patients with acute ischemic stroke due to large vessel occlusion., Methods: We used data from MR CLEAN, a multicenter trial including patients with acute ischemic stroke due to anterior circulation large vessel occlusion randomized to endovascular treatment plus medical care (intervention) versus medical care alone (control). We segmented total brain volume (TBV) and intracranial volume (ICV) on baseline non-contrast computed tomography (n = 410). Next, we determined the degree of atrophy as the proportion of brain volume in relation to head size (1 - TBV/ICV) × 100%, analyzed as continuous variable and in tertiles. The primary outcome was a shift towards better functional outcome on the modified Rankin Scale expressed as adjusted common odds ratio. Treatment effect modification was tested using an interaction term between brain atrophy (as continuous variable) and treatment allocation., Results: We found that brain atrophy significantly modified the effect of endovascular treatment on functional outcome (P for interaction = 0.04). Endovascular treatment led to larger shifts towards better functional outcome in the higher compared to the lower range of atrophy (adjusted common odds ratio, 1.86 [95% CI: 0.97-3.56] in the lowest tertile vs. 1.97 [95% CI: 1.03-3.74] in the middle tertile vs. 3.15 [95% CI: 1.59-6.24] in the highest tertile)., Conclusion: Benefit of endovascular treatment is larger in the higher compared to the lower range of atrophy, demonstrating that advanced atrophy should not be used as an argument to withhold endovascular treatment.

Objective: In patients presenting within 6 hours after signs and symptoms of suspected subarachnoid hemorrhage (SAH), CSF examination is judged to be no longer necessary if a noncontrast CT (NCCT) scan rules out SAH. In this study, the authors evaluated the performance of NCCT to rule out SAH in patients with positive CSF findings., Methods: Between January 2006 and April 2018, 1657 patients were admitted with a nontraumatic SAH. Of these patients, 1546 had positive SAH findings on the initial NCCT and 111 patients had an NCCT scan that was reported as negative in the acute setting, but with positive CSF examination for subarachnoid blood. Demographic data, World Federation of Neurosurgical Societies grade, and SAH time points (ictus, time of NCCT, and time of lumbar puncture) were collected. All 111 NCCT scans were reevaluated by an experienced neuroradiologist., Results: Of the 111 patients with positive CSF findings, SAH was initially missed on NCCT in 25 patients (23%). Reevaluation of 21 patients presenting within 6 hours of symptom onset confirmed NCCT negative findings in 12 (5 aneurysms), an aneurysmal SAH (aSAH) pattern in 8 (7 aneurysms), and a perimesencephalic pattern in 1 patient. Reevaluation of 90 patients presenting after 6 hours confirmed negative NCCT findings in 74 patients (37 aneurysms), aSAH pattern in 10 (4 aneurysms), and a perimesencephalic pattern in 6 (2 aneurysms)., Conclusions: CSF examination is still mandatory to rule out SAH as NCCT can fail to show blood, even within 6 hours after symptom onset. In addition, the diagnosis SAH was frequently missed during initial reporting.