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Background: In the ESCAPE-NA1 trial, treatment with nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, was associated with improved functional outcome among patients with acute ischaemic stroke due to large vessel occlusion undergoing endovascular thrombectomy without co-treatment with an intravenous thrombolytic agent. There was no benefit when intravenous thrombolytic agent co-treatment was used. We sought to confirm the clinical benefit of nerinetide in the absence of previous intravenous thrombolytic drug treatment., Methods: In this multicentre, randomised, double-blind, placebo-controlled study, done in 77 centres in Canada (16), the USA (16), Germany (21), Italy (four), the Netherlands (three), Norway (four), Switzerland (three), Australia (eight), and Singapore (two), we enrolled patients with acute ischaemic stroke due to anterior circulation large vessel occlusion within 12 h from onset. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation (baseline National Institutes of Health Stroke Scale [NIHSS] score >5), who had been functioning independently in the community (Barthel Index score >90) before the stroke, had Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and who were not treated with a plasminogen activator. Patients were randomly allocated (1:1) to receive intravenous infusion of nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, based upon estimated or actual weight (if known) or saline placebo using a real-time, dynamic, internet-based, stratified randomised minimisation procedure. All patients underwent endovascular thrombectomy. The primary outcome was a favourable functional outcome 90 days from randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. The analysis was by intention to treat and adjusted for time from stroke onset to randomisation (≤4·5 h [yes or no]), age, sex, baseline NIHSS score, occlusion location, time from qualifying imaging to randomisation, baseline ASPECTS, and region. Secondary outcomes were measures of mortality, worsening of stroke, improved functional independence, and measures of neurological disability. This trial is registered with ClinicalTrials.gov, NCT04462536., Findings: From Dec 6, 2020, to Jan 31, 2023, 850 patients were assigned to receive nerinetide (n=454) or placebo (n=396). 206 (45%) participants in the nerinetide group and 181 (46%) participants in the placebo group achieved an mRS score of 0-2 at 90 days (odds ratio 0·97, 95% CI 0·72-1·30; p=0·82). Serious adverse events occurred equally between groups., Interpretation: While nerinetide did not improve outcomes in patients with acute ischaemic stroke, it was not associated with excess adverse events. Further study is needed to identify the ideal timing of treatment and the sub-population of stroke patients who might benefit from treatment combined with current reperfusion therapies., Funding: Canadian Institutes for Health Research and NoNO., Competing Interests: Declaration of interests AHA reports an unrestricted grant from Boehringer-Ingelheim for the TenCRAOS trial. DJG reports share ownership in NoNO. MAA reports Advisory Board membership for Fluid Biomed and Palmera Medical. NA reports salary support from the American Heart Association for her role as section editor in Stroke and from the Florida Stroke Registry. JMC reports grants from Bayer and AstraZeneca and is a co-founder and shareholder of TrianecT. AMD reports a grant from Medtronic, DSMC membership for the WE TRUST study (sponsored by Phillips), DSMC chairman for the LT 3001-203 and LT3001-205 studies (sponsored by Lumosa), and board chairmanship for the Canadian Stroke Consortium (non-profit sector). DWJD reports grants from Stryker Neurovascular, Medtronic, Cerenovus, Penumbra, and Thrombolytic Science, DSMC chairmanship for the ACT-Global and LATE-MT studies, and past chairmanship of the CONTRAST Consortium. AE reports board membership of the Norwegian Stroke Organization. TSF reports payment for advisory board roles for Bayer, Novartis, HLS Therapeutics, and AstraZeneca and board membership for Destine Health and the Vancouver General Hospital–University of British Columbia Foundation. SF reports consulting fees and honoria from Microvention, Rapid Medical,and Stryker Neurovascular. DG reports grants from Microvention and consulting fees from Navigantis. MG reports grants from Medtronic and Cerenovus; consulting fees from Microvention, Stryker Neurovascular, Medronic, Mentice, Phillips, and Penumbra; and stock ownership in Circle Neurovascular. JG reports consulting fees from Medtronic and Johnson & Johnson/Cerenovus. AEH reports grants from GE Healthcare and Viz.ai, consulting fees or honoraria from Medtronic, Microvention, Stryker Neurovascular, Penumbra, Cerevonus, Xcath, Imperative Care, Perfuze, Route 92, Genentech, GE Healthcare, Scientia, Balt, Viz.ai, Insera Therapeutics, Proximie, NovaSignal, and Vesalio, DSMC membership for the COMMAND study, and is the past-president of the Society of Vascular and Interventional Neurology. KJH reports share ownership in NoNO. VH reports grants and consulting fees from Wallaby/Phenox. MDH reports grants from NoNO and Canadian Institutes of Health Research (CIHR) which directly supported the ESCAPE-NEXT study, past grants from NoNO, Medtronic, Boehringer-Ingelheim, CIHR, and Heart & Stroke Foundation; consulting fees from Sun Pharma and Brainsgate, patents licensed to Circle Neurovascular, DSMC charimanship for the DUMAS and Oncover Hiltonel trials, DSMC membership for the ARTESIA, BRAIN-AF and LAAOS-4 trials, stock ownership in Circle Neurovascular, and is the current president of the Canadian Neurological Sciences Federation (non-profit sector). MH reports consulting fees or honoraria from Balt, Medtronic, Stryker Neurovascular, Microvention, Phenox, Cerenovus, Siemens, and Rapid Medical. MEK reports consulting fees from Medtronic and Penumbra and stock or stock options from Basecamp Vascular, Radical Catheter Technology, and Endostream. TL reports grants from Cerus, Stryker Neurovascular, and Phenox and DSMC membership in the CLOT OUT study. NL reports consulting fees from Medtronic and honoraria from Medtronic, Penumbra, Balt, Cerenovus, Microvention, and Stryker Neurovascular. JLM reports advisory board membership for the SECRET study and board membership for the Canadian Stroke Consortium (non-profit sector). BKM reports grants for the CIHR. MM reports consulting fees from Stryker Neurovascular. MP reports grants from German Research Foundation and honoraria from Merck. SP reports grants from BMS/Pfizer, Boehringer-Ingelheim, Danichi-Sankyo, EU, German Federal Joint Committee Innovation Fund, German Federal Ministry of Education of Research, Helena Laboratories, and Werfen; consulting fees from Alexion, AstraZeneca, Daichi-Sankyo, and Werfen; and honoraria from Alexion, Bayer, Boehringer-Ingelheim, BMS/Pfizer, and Portola. AYP reports grants from Brain Canada, Heart & Stroke Foundation Canada, and CIHR, honoraria from Roche Canada, safety committee chairmanship for the ACT trial, and fellowship certification committee chairmanship for the Canadian Stroke Consortium (non-profit sector). M-NP reports grants from Swiss National Science Foundation, Bangerter-Rhyner Stiftung, Stryker Neurovascular, Phenox, Medtronic, Penumbra, and Siemens Healthineers and honoraria from Stryker Neurovascular, Medtronic, Pneumbra, Acandis, and Siemens Healthineers. ASP reports DSMC membership for Cerevasc and Keep, stock or stock options in NTI, Galaxy, Agile, and Perfuse, and a consultancy role for Cerenovus, Agile, Arsenal, Route 92, Stryker Neurovascular, Rapid, and Spryte. MR reports grants from the National Institutes of Health (NIH). RHS reports grants from the NIH, CIHR, and Ontario Brain Institute, DSMC membership for Hoffman La Roche, and stock or stock options in FollowMD. JWT reports consulting fees from Medtronic, Stryker Neurovascular, and Qure.ai. MT reports stock and CEO role in NoNO. PJvD reports consulting fees from Stryker Neurovascular, Phillips, Medtronic, and Siemens. WvZ reports consulting fees or honoraria from Phillips, Bayer, Stryker Neurovascular, Medtronic, Nico Lab, Cerenovus, and DSMC membership in the WeTrust, Athena, and InExtremis trials. MW reports grants from Ab medica, Acandis, Cerenovus, Kaneka Pharmaceuticals, Medtronic, Microvention, Phenox, Siemens Healthcare, and Stryker Neurovascular, consulting fees from Stryker Neurovascular, honoraria from Bracco Imaging, Medtronic, Siemens Healthcare, and Stryker Neurovascular. LLLY reports grants from National Medical Research Council (Singapore) and the Ministry of Education, advisory board membership for AstraZeneca, vice-president role for the Society of Neurointerventional Surgery, stock or stock options in Cereflo and medical advisor roles for Sunbird-bio, Cortirio, and See-mode. All other authors declare no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies. Published by Elsevier Ltd.. All rights reserved.)

Aims: To distinguish between the genuine cellular impact of the ischemic cascade by leukocytes and unspecific effects of edema and humoral components, two knock-in mouse lines were utilized. Mouse lines Y731F and Y685F possess point mutations in VE-cadherin, which lead to a selective inhibition of transendothelial leukocyte migration or impaired vascular permeability., Methods: Ischemic stroke was induced by a model of middle cerebral artery occlusion. Analysis contained structural outcomes (infarct volume and extent of brain edema), functional outcomes (survival analysis, rotarod test, and neuroscore), and the extent and spatial distribution of leukocyte migration (heatmaps and fluorescence-activated cell sorting (FACS) analysis)., Results: Inhibition of transendothelial leukocyte migration as in Y731F mice leads to smaller infarct volumes (52.33 ± 4719 vs. 70.43 ± 6483 mm 3 , p = .0252) and improved motor skills (rotarod test: 85.52 ± 13.24 s vs. 43.06 ± 15.32 s, p = .0285). An impaired vascular permeability as in Y685F mice showed no effect on structural or functional outcomes. Both VE-cadherin mutations did not influence the total immune cell count or spatial distribution in ischemic brain parenchyma., Conclusion: Selective inhibition of transendothelial leukocyte migration by VE-cadherin mutation after ischemic stroke in a mouse model leads to smaller infarct volumes and improved motor skills., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Purpose: This study aimed to evaluate the effectiveness and safety of the NeVa TM stent retriever as first- and second-line device for mechanical thrombectomy in acute ischemic stroke., Methods: In this retrospective single-center study, all consecutive patients that underwent mechanical thrombectomy with NeVa TM stent retriever as first- or second-line device due to intracranial vessel occlusion with acute ischemic stroke between March and November 2022 were included., Results: Thirty-nine patients (m=18, f=21) with a mean age of 69.9 ± 13.3 years were treated with the NeVa TM stent retriever. NeVa TM stent retriever was used as first-line device in 24 (61.5%) of patients and in 15 (38.5%) as second-line device. First-pass rate (≥mTICI 2c) of NeVa TM stent retriever was both 66.7% when used as first- or second-line device. Final recanalization rate including rescue strategies was 92.3% for ≥mTICI2c and 94.9% for ≥mTICI2b. No device-related minor or major adverse events were observed. A hemorrhage was detected in 33.3% of patients at 24h post-thrombectomy dual-energy CT, of which none was classified as symptomatic intracerebral hemorrhage. NIHSS and mRS improved significantly at discharge compared to admission (p<0.05)., Conclusion: The NeVa TM stent retriever has a high effectivity and good safety profile as first- and second-line device for mechanical thrombectomy in acute ischemic stroke., (© 2023. The Author(s).)

Background: To evaluate the association of age with long-term outcome after thrombectomy., Methods: In a retrospective cohort study based on routine healthcare data from Germany between 2010 and 2018, we included 18 506 patients with acute ischaemic stroke treated with mechanical thrombectomy. Association between age and mortality, disability, and level of care at 1 year was assessed., Results: The median age was 76 years, 36.3% were aged ≥80 years and 55.8% were women. Patients aged ≥80 compared with those <80 years had a higher mortality (55.4% vs 28.5%; adjusted HR 1.13; 95% CI 1.05 to 1.31), more often had moderate/severe disability (35.5% vs 33.2%, adjusted HR 1.14; 95% CI 1.06 to 1.23) and less frequently had no/slight disability (17.4% vs 41.0%) at 1 year. Older age was associated with a higher likelihood of living in a nursing home (13.4% vs 9.2%, adjusted HR 1.09; 95% CI 0.97 to 1.22) and a lower likelihood of living at home (33.8% vs 62.8%) at 1 year. These associations were also robust when analysed in patients with no disability prior to stroke. Factors most strongly associated with worse 1-year outcomes in elderly patients were chronic limb-threatening ischaemia (67.9% vs 56.4%; HR 1.59, 95% CI 1.38 to 1.82), dementia at baseline (65.2% vs 47.3%; HR 1.29, 95% CI 1.17 to 1.44) and ventilation >48 hours (79.3% vs 52.2%; HR 2.91, 95% CI 2.66 to 3.18)., Conclusions: In this large 'real-world' cohort, outcomes after mechanical thrombectomy were strongly associated with age. Of patients aged ≥80 years more than half were dead and less than one-fifth were functionally independent at 1 year. Certain comorbidities and ventilation >48 hours were associated with even worse outcomes., Competing Interests: Competing interests: CB has received speaking fees from Chugai Pharma. HW receives honoraria for acting as a member of Scientific Advisory Boards from Abbvie, Alexion, Argenx, Bristol Myers Squibb/Celgene, Janssen, Merck, Novartis and Sandoz. Speaker honoraria and travel support from Alexion, Biogen, Bristol Myers Squibb, Genzyme, Merck, Neurodiem, Novartis, Ology, Roche, TEVA and WebMD Global. HW is acting as a paid consultant for Abbvie, Actelion, Argenx, BD, Biogen, Bristol Myers Squibb, EMD Serono, Fondazione Cariplo, Gossamer Bio, Idorsia, Immunic, Immunovant. Janssen. Lundbeck, Merck, NexGen, Novartis, PSI CROl, Roche, Sanofi, Swiss Multiple Sclerosis Society, UCB and Worldwide Clinical Trials. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Deutsche Myasthenie Gesellschaft e.V., Alexion. Amicus Therapeutics Inc., Argenx, Biogen, CSL Behring, F. Hoffmann - La Roche, Genzyme, Merck KgaA, Novartis, Roche Pharma and UCB Biopharma. HR received Consulting fees from PLURISTEM, NEOVASC; Payment honoraria for lectures, presentations from DAICHI SANKYIO, DIAPLAN, MEDUPDATE, STREAMEDUP, CORVIA; Participation in Advisory Boards from BMS, PFIZER, NOVONORDISK; the department received research grants from BARD, PFIZER, BMS. JM has received grants from Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung (BMBF), Else Kröner-Fresenius-Stiftung, EVER Pharma Jena, and Ferrer International, travel grants from Boehringer Ingelheim, and speaking fees from Bayer Vital and Chugai Pharma., (© 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.)

Objective: The purpose of this study was to characterize patients with ischemic stroke due to bacterial meningitis., Methods: In a single-center retrospective study, we analyzed 102 patients with bacterial meningitis of which 19 had an ischemic stroke. Clinical characteristics, cerebrospinal fluid (CSF) analyses, and spatiotemporal distribution of infarcts were assessed. In addition, we searched PubMed from database inception to August 2021 for observational studies on ischemic stroke in patients with bacterial meningitis, and performed a meta-analysis to investigate the frequency and timing of stroke as well as its effect on mortality., Results: In our cohort, 15 (78.9%) patients with stroke had an modified Rankin scale (mRS)  ≥  3 at discharge compared to 33 (39.8%) in patients without stroke (p < 0.01). Of 1,692 patients with bacterial meningitis from 15 cohort studies included in our meta-analysis, cerebral infarcts were found in 332 (16%, 95% confidence interval [CI] = 0.13-0.20) patients. The occurrence of stroke was strongly associated with a higher mortality (odds ratio [OR] = 2.38, 95% CI = 1.70-3.34, p < 0.0001). There was no association of any specific causative pathogen with the occurrence of stroke. Infarcts were mainly distributed in territories of arteries located in the vicinity to the infection focus and peaked at 3 to -7 days and at 2 weeks after onset of meningitis. In patients with ischemic stroke, vasculopathy was found in 63.2% and additional intracerebral hemorrhage in 15.8%., Interpretation: This study found that ischemic stroke due to bacterial meningitis is caused by cerebral vasculopathy located in the vicinity of the infection focus, and that the time course of infarctions might enable a therapeutic intervention. ANN NEUROL 2023;93:1094-1105., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Rag1 -/- mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1 -/- mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1 null IL2rg null (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1 -/- and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1 -/- NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1 -/- were comparable in number and function to those in WT mice. Rag1 -/- mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1 -/- controls. Our results indicate that NK cells from Rag1 -/- mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke., (© 2021. The Author(s).)

Although several studies have suggested that anti-inflammatory strategies reduce secondary infarct growth in animal stroke models, clinical studies have not yet demonstrated a clear benefit of immune modulation in patients. Potential reasons include systematic differences of post-ischemic neuroinflammation between humans and rodents. We here performed a systematic review and meta-analysis to summarize and compare the spatial and temporal distribution of immune cell infiltration in human and rodent stroke. Data on spatiotemporal distribution of immune cells (T cells, macrophages, and neutrophils) and infarct volume were extracted. Data from all rodent studies were pooled by means of a random-effect meta-analysis. Overall, 20 human and 188 rodent stroke studies were included in our analyses. In both patients and rodents, the infiltration of macrophages and neutrophils preceded the lymphocytic influx. Macrophages and neutrophils were the predominant immune cells within 72 h after infarction. Although highly heterogeneously across studies, the temporal profile of the poststroke immune response was comparable between patients and rodents. In rodent stroke, the extent of the immune cell infiltration depended on the duration and location of vessel occlusion and on the species. The density of infiltrating immune cells correlated with the infarct volume. In summary, we provide the first systematic analysis and comparison of human and rodent post-ischemic neuroinflammation. Our data suggest that the inflammatory response in rodent stroke models is comparable to that in patients with stroke. However, the overall heterogeneity of the post-ischemic immune response might contribute to the translational failure in stroke research., (© 2021. The Author(s).)

Background and Objectives: To test the hypothesis that CT hypoperfusion-hypodensity mismatch identifies patients with ischemic stroke within 4.5 hours of symptom onset., Methods: We therefore performed the Retrospective Multicenter Hypoperfusion-Hypodensity Mismatch for The identification of Patients With Stroke Within 4.5 Hours study of patients with acute ischemic stroke and known time of symptom onset. The predictive values of hypoperfusion-hypodensity mismatch for the identification of patients with symptom onset within 4.5 hours were the main outcome measure., Results: Of 666 patients, 548 (82.3%) had multimodal CT within 4.5 hours and 118 (17.7%) beyond 4.5 hours. Hypoperfusion-hypodensity mismatch was visible in 516 (94.2%) patients with symptom onset within and in 30 (25.4%) patients beyond 4.5 hours. CT hypoperfusion-hypodensity mismatch identified patients within 4.5 hours of stroke onset with 94.2% (95% confidence interval [CI] 91.9%-95.8%) sensitivity, 74.6% (95% CI 66.0%-81.6%) specificity, 94.5% (95% CI 92.3%-96.1%) positive predictive value, and 73.3% (95% CI 64.8%-80.4%) negative predictive value. Interobserver agreement for hypoperfusion-hypodensity mismatch was substantial (κ = 0.61, 95% CI 0.53-0.69)., Discussion: Patients with acute ischemic stroke with absence of a hypodensity on native CT (NCCT) within the hypoperfused core lesion on perfusion CT (hypoperfusion-hypodensity mismatch) are likely to be within the time window of thrombolysis. Applying this method may guide the decision to use thrombolysis in patients with unknown time of stroke onset., Trial Registration Information: ClinicalTrials.gov Identifier: NCT04277728., Classification of Evidence: This study provides Class III evidence that CT hypoperfusion-hypodensity mismatch identifies patients with stroke within 4.5 hours of onset., (© 2021 American Academy of Neurology.)

Background and Objectives: In acute stroke, early ischemic lesion hypodensity on CT is considered the imaging hallmark of brain infarction, representing a state of irreversible tissue damage with a continual increase of net water uptake. This dogma, however, is challenged by rare cases of apparently reversed early lesion hypodensity after complete reperfusion. The purpose of this study was to investigate the occurrence of reversible ischemic edema after endovascular treatment., Methods: One hundred eighty-four patients with acute ischemic anterior circulation stroke were included after consecutive screening. Ischemic brain edema was determined with quantitative lesion net water uptake (NWU) in admission CT and follow-up CT based on CT densitometry, and ΔNWU was calculated as the difference. The association of edema progression to imaging and clinical parameters was investigated. Clinical outcome was assessed with the modified Rankin Scale (mRS) scores at day 90., Results: Of 184 patients, 27 (14.7%) showed edema arrest and 3 (1.6%) exhibited significant edema reversibility. Higher degree of recanalization (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.46-6.01, p < 0.01) and shorter time from imaging to recanalization (OR per hour 0.32, 95% CI 0.18-0.54, p < 0.0001) were significantly associated with edema arrest or reversibility. Clinical outcome was significantly better in patients without edema progression (median mRS score 2 vs 5, p = 0.004)., Discussion: Although rare, lesion hypodensity considered to be representative of early infarct in acute stroke CT may be reversible after complete recanalization. Arrest of edema progression of acute brain infarct lesions may occur after successful rapid vessel recanalization, resulting in improved functional outcome. Future research is needed to investigate conditions in which early revascularization may halt or even reverse vasogenic edema of ischemic tissue., (© 2021 American Academy of Neurology.)

Background: Different imaging characteristics such as clot burden score, collaterals, and pre-interventional thrombus migration are associated with functional outcome in patients with acute ischemic stroke. Moreover, histological thrombus composition is associated with pre-interventional thrombus migration. We hypothesized that smaller clots may more likely migrate and that collateral status in ischemic stroke patients may mediate this tendency of the clot to migrate., Methods: In this prospective cohort of consecutive ischemic stroke patients, clot burden scores and collateral scores were rated and the retrieved thrombi were histologically analyzed. We then investigated the relationship between clot burden score, probability for thrombus migration, and collateral scores using mediation analysis., Results: 163 patients are included of which 36 (22.1%) had a clot migration. Probability of thrombus migration was significantly associated with lower collateral scores (P<0.01), higher clot burden scores (P<0.01), shorter thrombi (P<0.01), and higher RBC count (P<0.01). In the mediator pathway, higher collateral scores were significantly associated with higher clot burden scores (P<0.01) and younger age (P=0.029). The total effect of an increase in clot burden score by one grade on thrombus migration is composed of the direct effect (+18%, P<0.01) and the collateral score-mediated indirect effect (-5%, P<0.01)., Conclusions: Smaller, erythrocyte-rich thrombi tend to migrate more often. Good collaterals seem to have a considerable effect on limiting migration. This supports the hypothesis that larger clots have stronger adherence with the vessel wall and that good collaterals increase the counter pressure distal of the clot., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine whether thrombectomy is safe in children up to 24 hours after onset of symptoms when selected by mismatch between clinical deficit and infarct., Methods: A secondary analysis of the Save ChildS Study (January 2000-December 2018) was performed, including all pediatric patients (<18 years) diagnosed with arterial ischemic stroke who underwent endovascular recanalization at 27 European and United States stroke centers. Patients were included if they had a relevant mismatch between clinical deficit and infarct., Results: Twenty children with a median age of 10.5 (interquartile range [IQR] 7-14.6) years were included. Of those, 7 were male (35%), and median time from onset to thrombectomy was 9.8 (IQR 7.8-16.2) hours. Neurologic outcome improved from a median Pediatric NIH Stroke Scale score of 12.0 (IQR 8.8-20.3) at admission to 2.0 (IQR 1.2-6.8) at day 7. Median modified Rankin Scale (mRS) score was 1.0 (IQR 0-1.6) at 3 months and 0.0 (IQR 0-1.0) at 24 months. One patient developed transient peri-interventional vasospasm; no other complications were observed. A comparison of the mRS score to the mRS score in the DAWN and DEFUSE 3 trials revealed a higher proportion of good outcomes in the pediatric compared to the adult study population., Conclusions: Thrombectomy in pediatric ischemic stroke in an extended time window of up to 24 hours after onset of symptoms seems safe and neurologic outcomes are generally good if patients are selected by a mismatch between clinical deficit and infarct., Classification of Evidence: This study provides Class IV evidence that for children with acute ischemic stroke with a mismatch between clinical deficit and infarct size, thrombectomy is safe., (© 2020 American Academy of Neurology.)

Background: A dietary supplementation with conjugated linoleic acid (CLA) was shown to attenuate inflammation and increase the proportions of circulating regulatory T cells (Tregs) and M2-type macrophages in disease models such as autoimmune encephalitis and arteriosclerosis. Since Tregs and anti-inflammatory (M2-type) macrophages were found to enhance stroke recovery, we hypothesized that CLA-supplementation might improve stroke recovery via immune modulatory effects. Methods: Functional assessment was performed over 90 days after induction of experimental photothrombotic stroke in wild type mice (n = 37, sham n = 10). Subsequently, immunological characterization of different immunological compartments (n = 16), ex vivo magnetic resonance (MR, n = 12) imaging and immunohistochemical staining (n = 8) was performed. Additionally, we tested the effect of CLA in vitro on peripheral blood mononuclear cells from human stroke patients and healthy controls (n = 12). Results: MR diffusion tensor imaging (DTI) demonstrated enhanced microstructural reorganization of interhemispheric white matter tracts, dependent on lesion size. Functional recovery over 90 days remained unaffected. Detailed immunological analyses across various compartments revealed no significant long-term immunological alterations due to CLA. However, analyses of human blood samples post-stroke showed reduced levels of pro-inflammatory interferon-γ (IFN-γ) and tumor necrosis factor alpha (TNF-α) release by T-lymphocytes following in vitro treatment with CLA. Conclusion: We aimed to explore the efficacy of a dietary intervention with minimal known side effects that could be accessible to human stroke patients, regardless of the degree of disability, and without the risks associated with aggressive immunomodulatory therapies. Our main findings include improved microstructural reorganization in small infarcts and a reduced inflammatory response of human T cells in vitro. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the effectiveness and safety of the NeVaTM stent retriever as first- and second-line device for mechanical thrombectomy in acute ischemic stroke. Methods: In this retrospective single-center study, all consecutive patients that underwent mechanical thrombectomy with NeVaTM stent retriever as first- or second-line device due to intracranial vessel occlusion with acute ischemic stroke between March and November 2022 were included. Results: Thirty-nine patients (m=18, f=21) with a mean age of 69.9 ± 13.3 years were treated with the NeVaTM stent retriever. NeVaTM stent retriever was used as first-line device in 24 (61.5%) of patients and in 15 (38.5%) as second-line device. First-pass rate (≥mTICI 2c) of NeVaTM stent retriever was both 66.7% when used as first- or second-line device. Final recanalization rate including rescue strategies was 92.3% for ≥mTICI2c and 94.9% for ≥mTICI2b. No device-related minor or major adverse events were observed. A hemorrhage was detected in 33.3% of patients at 24h post-thrombectomy dual-energy CT, of which none was classified as symptomatic intracerebral hemorrhage. NIHSS and mRS improved significantly at discharge compared to admission (p<0.05). Conclusion: The NeVaTM stent retriever has a high effectivity and good safety profile as first- and second-line device for mechanical thrombectomy in acute ischemic stroke. [ABSTRACT FROM AUTHOR]

Objective: In rare cases, Lyme neuroborreliosis (LNB) can induce cerebral vasculitis leading to severe stenosis of the cerebral vasculature and consecutive ischemia. Therapy is based on anti-biotic treatment of the tick-borne disease, whereas interventional therapeutic options have not been assessed yet. Material and Methods: We report on a patient with LNB and concomitant stenoses and progressive and fatal vasculitis of the cerebral vessels despite all therapeutic efforts by the departments of neurology and interventional neuroradiology. In this context, we also conducted a literature review on endovascular treatment of LNB-associated cerebral ischemia. Results: A 52-year-old female presented with transient neglect and psychomotor slowdown (initial NIHSS = 0). MRI and serology led to the diagnosis of basal meningitis due to LNB with vasculitis of cerebral arteries. Despite immediate treatment with antibiotics and steroids, neurologic deterioration (NIHSS 8) led to an emergency angiography on day 2 after admission. Hemodynamically relevant stenoses of the MCA were treated via spasmolysis and PTA, leading to almost complete neurological recovery. Despite intensified medical treatment, the vasculitis progressed and could only be transiently ameliorated via repetitive spasmolysis. On day 19, she again presented with significant neurologic deterioration (NIHSS 9), and PTA and stenting of the nearly occluded MCA were performed with a patent vessel, initially without hemorrhagic complications. Despite all therapeutic efforts and preserved stent perfusion, vasculitis worsened and the concurrent occurrence of subdural hemorrhage led to the death of the patient. Conclusion: Neuroradiological interventions, i.e., spasmolysis, PTA, and, if necessary, stenting, can and should be considered in cases of LNB-induced vasculitis and stroke that are refractory to best medical treatment alone. Key point: Neuroradiological interventions can be considered in patients with vascular complications of Lyme neuroborreliosis as an additional extension of the primary drug therapy. [ABSTRACT FROM AUTHOR]

Inflammation triggers secondary brain damage after stroke. The meninges and other CNS border compartments serve as invasion sites for leukocyte influx into the brain thus promoting tissue damage after stroke. However, the post-ischemic immune response of border compartments compared to brain parenchyma remains poorly characterized. Here, we deeply characterize tissue-resident leukocytes in meninges and brain parenchyma and discover that leukocytes respond differently to stroke depending on their site of residence. We thereby discover a unique phenotype of myeloid cells exclusive to the brain after stroke. These stroke-associated myeloid cells partially resemble neurodegenerative disease-associated microglia. They are mainly of resident microglial origin, partially conserved in humans and exhibit a lipid-phagocytosing phenotype. Blocking markers specific for these cells partially ameliorates stroke outcome thus providing a potential therapeutic target. The injury-response of myeloid cells in the CNS is thus compartmentalized, adjusted to the type of injury and may represent a therapeutic target. How ischaemic stroke affects the brain borders is not fully understood. Here the authors show that a stroke-associated myeloid cell population occurs exclusively in brain parenchyma that shares features with neurodegenerative microglia and blockade of proteins on these cells can ameliorate stroke symptoms. [ABSTRACT FROM AUTHOR]

Sodium chloride promotes vascular fibrosis, arterial hypertension, pro-inflammatory immune cell polarization and endothelial dysfunction, all of which might influence outcomes following stroke. But despite enormous translational relevance, the functional importance of sodium chloride in the pathophysiology of acute ischemic stroke is still unclear. In the current study, we show that high-salt diet leads to significantly worse functional outcomes, increased infarct volumes, and a loss of astrocytes and cortical neurons in acute ischemic stroke. While analyzing the underlying pathologic processes, we identified the migrasome as a novel, sodium chloride-driven pathomechanism in acute ischemic stroke. The migrasome was previously described in vitro as a migrating organelle, which incorporates and dispatches cytosol of surrounding cells and plays a role in intercellular signaling, whereas a pathophysiological meaning has not been elaborated. We here confirm previously reported characteristics of the migrasome in vivo. Immunohistochemistry, electron microscopy and proteomic analyses further demonstrate that the migrasome incorporates and dispatches cytosol of surrounding neurons following stroke. The clinical relevance of these findings is emphasized by neuropathological examinations, which detected migrasome formation in infarcted brain parenchyma of human stroke patients. In summary, we demonstrate that high-salt diet aggravates stroke outcomes, and we characterize the migrasome as a novel mechanism in acute stroke pathophysiology. [ABSTRACT FROM AUTHOR]

Large artery atherosclerotic stroke (LAS) shows substantial heritability not explained by previous genome-wide association studies. Here, we explore the role of coding variation in LAS by analyzing variants on the HumanExome BeadChip in a total of 3,127 cases and 9,778 controls from Europe, Australia, and South Asia. We report on a nonsynonymous single-nucleotide variant in serpin family A member 1 (SERPINA1) encoding alpha-1 antitrypsin [AAT; p.V213A; P = 5.99E-9, odds ratio (OR) = 1.22] and confirm histone deacetylase 9 (HDAC9) as a major risk gene for LAS with an association in the 3'-UTR (rs2023938; P = 7.76E-7, OR = 1.28). Using quantitative microscale thermophoresis, we show that M1 (A213) exhibits an almost twofold lower dissociation constant with its primary target human neutrophil elastase (NE) in lipoprotein-containing plasma, but not in lipid-free plasma. Hydrogen/deuterium exchange combined with mass spectrometry further revealed a significant difference in the global flexibility of the two variants. The observed stronger interaction with lipoproteins in plasma and reduced global flexibility of the Val-213 variant most likely improve its local availability and reduce the extent of proteolytic inactivation by other proteases in atherosclerotic plaques. Our results indicate that the interplay between AAT, NE, and lipoprotein particles is modulated by the gate region around position 213 in AAT, far away from the unaltered reactive center loop (357-360). Collectively, our findings point to a functionally relevant balance between lipoproteins, proteases, and AAT in atherosclerosis. [ABSTRACT FROM AUTHOR]

Background and aims: Sleep related breathing disorders (SRBD) are common in patients with ischemic stroke and are associated with poor outcome. SRBD after stroke were assumed to be a direct consequence of injury of specific central nervous system structures. However, whether specific locations of ischemic infarcts cause SRBD is yet unknown. We therefore investigated the association of ischemic lesion location with SRBD. Methods: Patients with acute ischemic stroke treated on our stroke unit were included in a prospective observational study. All patients underwent magnetic resonance imaging (MRI) and polygraphy in the acute phase after stroke. SRBD was defined by an apnea—hypopnea index (AHI) ≥10. MRI were evaluated using standardized maps to depict voxel-wise probability distribution of infarction for patients with and without SRBD. Groups were compared using logistic regression analysis. Results: Of 142 patients included, 86 (59%) had a SRBD. Age, body mass index and prevalence of arterial hypertension were significantly higher in patients with SRBD. There was no statistically significant association between any lesion location and SRBD. Conclusion: We found no association of lesion location and SRBD in stroke patients, whereas established risk factors for SRBD, known from general population, were significantly associated with SRBD. Given the high prevalence of SRBD in stroke patients, these findings suggest that cerebral ischemia facilitates the occurrence of SRBD in patients with pre-existing risk factors rather than causing it by damaging specific central nervous system structures. Our findings can be used to identify stroke patients who might benefit from polygraphy screening. [ABSTRACT FROM AUTHOR]

Over recent decades, experimental and clinical stroke studies have identified a number of neurorestorative treatments that stimulate neural plasticity and promote functional recovery. In contrast to the acute stroke treatments thrombolysis and endovascular thrombectomy, neurorestorative treatments are still effective when initiated days after stroke onset, which makes them applicable to virtually all stroke patients. In this article, selected physical, pharmacological and cell-based neurorestorative therapies are discussed, with special emphasis on interventions that have already been transferred from the laboratory to the clinical setting. We explain molecular and structural processes that promote neural plasticity, discuss potential limitations of neurorestorative treatments, and offer a speculative viewpoint on how neurorestorative treatments will evolve. [ABSTRACT FROM PUBLISHER]

Neuroprotection aims to prevent salvageable neurons from dying. Despite showing efficacy in experimental stroke studies, the concept of neuroprotection has failed in clinical trials. Reasons for the translational difficulties include a lack of methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to homogeneous strokes in animal models. Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY-059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria. However, there are a number of neuroprotective treatments under investigation in clinical trials such as hypothermia and ebselen. Moreover, promising neuroprotective treatments based on a deeper understanding of the complex pathophysiology of ischemic stroke such as inhibitors of NADPH oxidases and PSD-95 are currently evaluated in preclinical studies. Further concepts to improve translation include the investigation of neuroprotectants in multicenter preclinical Phase III-type studies, improved animal models, and close alignment between clinical trial and preclinical methodologies. Future successful translation will require both new concepts for preclinical testing and innovative approaches based on mechanistic insights into the ischemic cascade. [ABSTRACT FROM AUTHOR]

• Permanent ischemic stroke is marked by temporarily and repetitively occurring stalls in the peri -infarct capillary network. • Neutrophil granulocytes are involved in perfusion derangement following focal ischemia. • dtTomato expressing neutrophils are a suitable model to analyze vascular dynamics in stroke. Flow stagnation of peri -ischemic capillaries due to dynamic leukocyte stalls has been described to be a contributor to ongoing penumbral injury in transient brain ischemia, but has not been investigated in permanent experimental stroke so far. Moreover, it is discussed that obstructing neutrophils are involved in this process; however, their contribution has not yet been proven. Here, we characterize the dynamics of neutrophil granulocytes in two models of permanent stroke (photothrombosis and permanent middle cerebral artery occlusion) using intravital two-photon fluorescence microscopy. Different to previous studies on LysM-eGFP+ cells we additionally apply a transgenic mouse model with tdTomato-expressing neutrophils to avoid interference from additional immune cell subsets. We identify repetitively occurring capillary stalls of varying duration promoted by neutrophils in both models of permanent cerebral ischemia, validating the suitability of our new transgenic mouse model in determining neutrophil occlusion formation in vivo. Flow cytometric analysis of peripheral blood (PB) and brain tissue from mice subjected to photothrombosis reveal an increase in the total proportion of neutrophils, with selective upregulation of endothelial adherence markers in the PB. In conclusion, the dynamic microcirculatory stall phenomenon that is described after transient ischemia followed by reperfusion also occurs after permanent small- or large-vessel stroke and is clearly attributable to neutrophils. [ABSTRACT FROM AUTHOR]