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Background: Long-term data showing the benefits of endovascular thrombectomy for stroke with large infarct are scarce. The TENSION trial showed the safety and efficacy of endovascular thrombectomy in patients with ischaemic stroke and large infarct at 90 days. We aimed to investigate the safety and efficacy at 12 months of endovascular thrombectomy in patients who were enrolled in the TENSION trial., Methods: TENSION was an open-label, blinded endpoint, randomised trial done at 40 hospitals across Europe and one hospital in Canada. We included patients (aged ≥18 years) with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and who had a large infarct, as indicated by an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) of 3-5 on standard-of-care stroke imaging. We randomly assigned patients (1:1) to receive either endovascular thrombectomy with medical treatment or medical treatment only up to 12 h from stroke onset. The primary outcome was functional outcome across the entire range of the modified Rankin Scale at 90 days. Here, we report the prespecified 12-month follow-up analyses for functional outcome (using the simplified modified Rankin Scale questionnaire), quality of life (using the Patient-Reported Outcomes Measurement Information System 10-item [PROMIS-10] and EQ-5D questionnaires), post-stroke anxiety and depression (using the Patient Health Questionnaire-4 [PHQ-4]), and overall survival. Outcomes (except survival) were assessed in the intention-to-treat population; the survival analysis was based on treatment received. This trial is registered with ClinicalTrials.gov, NCT03094715, and is completed., Findings: We enrolled patients between July 17, 2018, and Feb 21, 2023, when the trial was stopped early for efficacy. 253 patients were randomly assigned, 125 (49%) to endovascular thrombectomy and 128 (51%) to medical treatment only. Median follow-up was 8·36 months (IQR 0·02-12·00). Endovascular thrombectomy was associated with a shift in the distribution of scores on the modified Rankin Scale towards better functional outcome at 12 months (adjusted common odds ratio 2·39 [95% CI 1·47-3·90]). Endovascular thrombectomy was also associated with a better quality of life compared with medical treatment only, as reflected by median scores on the EQ-5D questionnaire index (0·7 [IQR 0·4-0·9] vs 0·4 [0·2-0·7]), median scores for health status on the EQ-5D questionnaire visual analogue scale (50 [IQR 35-70] vs 30 [5-60]), and median global physical health scores on the PROMIS-10 questionnaire (T-score 39·8 [IQR 37·4-50·8] vs 37·4 [32·4-44·9]); although there was not enough evidence to suggest a difference between groups in global mental health scores on PROMIS-10 (41·1 [IQR 36·3-48·3] vs 38·8 [31·3-44·7]) or the numbers of patients reporting anxiety (13 [22%] of 58 vs 15 [42%] of 36) and depression (18 [31%] vs 18 [50%]) on PHQ-4. Overall survival was slightly better in the endovascular thrombectomy group compared with medical treatment only (adjusted hazard ratio 0·70 [95% CI 0·50-0·99])., Interpretation: In patients with acute ischaemic stroke from large vessel occlusion with established large infarct, compared with medical treatment only, endovascular thrombectomy was associated at 12 months after stroke with better functional outcome, quality of life, and overall survival. These findings suggest that the benefits of endovascular thrombectomy in patients with an ischaemic stroke and a large infarct are sustained in the long term and support the use of endovascular thrombectomy in these patients., Funding: European Union Horizon 2020 Research and Innovation Programme., Competing Interests: Declaration of interests MB reports funding from the European Union Horizon 2020 and Deutsche Forschungsgemeinschaft (payments to the institution); honoraria for lectures from Novartis, Boehringer Ingelheim, and Seagen; consulting fees from NeuroScios and Boehringer Ingelheim; and a role as Editor-in-Chief of Clinical Neuroradiology (Springer), outside the submitted work. JF reports funding from the European Commission; personal consulting fees from Acandis, Cerenovus, Medtronic, Microvention, Phenox, Roche, and Stryker; consulting at Philips (no payments); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Penumbra and Tonbridge; support for attending meetings or travel from Medtronic and Penumbra; and stock or stock options from Tegus medical, eppdata, and Vastrax, outside the submitted work. JF also reports participation in a Data Safety Monitoring Board (DSMB) or Advisory Board at Phenox (personal fees) and Stryker (personal fees), and a role as past president of ESMINT. SB reports funding from the EU Horizon 2020 research and innovation programme (payments made to the institution; support for attending meetings or travel), outside the submitted work. AHA reports unrestricted research grants from Boehringer Ingelheim and honoraria for lectures from BMS/Pfizer, Teva, Roche, Abbvie, Lundbeck, Novartis, outside the submitted work. AHA also reports participation in Advisory Boards for MSD, BMS/Pfizer, Lundbeck, Lilly, and Abbvie. BF reports research grants from Carlos III Institute of Health (ISCIII), personal payment for educational lectures from Servicio Madrileño de Salud, payment to the institution for lectures from Euromedice, personal payment for educational lectures from Takeda, support for attending meetings from Daichii Sankyo, and receipt of materials for research from Abbot, outside the submitted work. MDH reports funding from Nil, a grant to the University of Calgary for the TEMPO-2 trial from Boehringer Ingelheim, a grant to the University of Calgary from Biogen, a grant to the University of Calgary for the ESCAPE-NA1 trial and ESCAPE-NEXT trial from NoNO, a grant to the University of Calgary for the ESCAPE-NA1 trial and ESCAPE-NEXT trial from the Canadian Institute for Health Research, a grant to the University of Calgary for the HERMES collaboration from Medtronic, and a grant to the University of Calgary for the QuICR Alberta Stroke Program; some of the funds were used for the ESCAPE-NA1 trial from Alberta Innovates. MDH also reports consulting fees from Sun Pharma Brainsgate (paid work for adjudication of clinical trial outcomes), US Patent 62/086,077 (licensed to Circle NVI), US Patent 10,916,346 (licensed to Circle NVI), and private stock ownership from Circle and PUreWeb, outside the submitted work. MDH reports participation as DSMC Chair of the RACECAT trial (end 2020), participation as DSMC Chair of the Oncovir Hiltonel trial (ongoing), participation as DSMC Chair of the DUMAS trial (ongoing), participation as DSMB member of the ARTESIA trial (ongoing), participation as DSMB member of the BRAIN-AF trial (ongoing), a role as President of the Canadian Neurological Sciences Federation (not for profit), and as Board Member of the Canadian Stroke Consortium (not for profit). AK reports grants from the European Commission for the TENSION study (payment to the institution), outside the submitted work. LP reports consulting fees from Balt, consulting fees from Microvention, consulting fees from Phenox, and support for attending meetings or travel for the TENSION investigator meeting (transport and accommodation was reimbursed by the organization), outside the submitted work. CZS reports grants from Health Research Foundation of Central Denmark Region, outside the submitted work. RAB reports speakers fees from Novo Nordisk and Beyer, outside the submitted work. HD reports financial compensation for the start-up fee and the obligatory payment to the hospital administration paid by the sponsor (Medical University Heidelberg) to the Clinical Division (no personal payments), personal consulting fees from Stryker, speakers honorary from Medtronic, and support for attending meetings or travel from Medtronic, outside the submitted work. HD also reports a role as past President of the Austrian Society of Interventional Radiology and past president Austrian Society of Neuroradiology. FD reports consulting fees from Cerenovus, Balt, Cerus Endovascular, and Microvention; payment for expert testimony from Cerenovus; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Cerenovus, Stryker, Acandis, Asahi, Penumbra, Medtronic, Tonbridge, Inspire, and Q'Apel, outside the submitted work. FD also reports participation in a DSMB or Advisory Board at Cerenovus and Microvention and previous roles as Associate Editor for Journal of Interventional Surgery, Journal of Clinical Medicine, and Clinical Neuroradiology. FF reports consulting fees from eppdata and support for attending meetings or travel from Microvention, Medtronic, Cerebrovascular Research and Education Foundation, and Acandis, outside the submitted work. SG reports consulting fees from eppdata, outside the submitted work. CH reports consulting fees from Brainomix and lecture fees from Stryker, outside the submitted work. SH-J reports funding for data collection and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Terumo, outside the submitted work. MG reports research grants from Medtronic and Cerenovus (payments to the University of Calgary); royalties or licenses from Microvention (systems of intracranial access); personal consulting fees from Microvention, Medtronic, Stryker, Mentice, Philips, and Penumbra; and stock or stock options from Circle Neurovascular, outside the submitted work. FCK was chair of the German Stroke Registry (unpaid). RM reports payments for stroke lecture from TMC Academy, outside the submitted work. MM reports grants from Balt, Medtronic, MicroVention, and Stryker; consulting fees from Siemens; and support for attending meetings or travel from Europa Group, outside the submitted work. SM-H reports consulting fees from Terumo and Boston Scientific Corporation and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Terumo and Boston Scientific Corporation, outside the submitted work. NM reports provision of study materials, outside the submitted work. PP reports support for attending meetings or travel for the TENSION investigator meeting (transport and accommodation was reimbursed by the organisation), outside the submitted work. MP reports grants from the German Research Foundation, speaker honoraria unrelated from Merck Serono and Bayer, and support for attending meetings or travel from Merck Serono (travel reimbursement) and Bayer (travel reimbursement), outside the submitted work. VP reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Boehringer Ingelheim, Daichii Sankyo, AstraZeneca and BMS, and support for attending meetings or travel from NoNo (travel reimbursement). PAR reports consulting fees to the institution from Boehringer Ingelheim and Bayer, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Boehringer Ingelheim, Bayer, Pfizer, and BMS (all made to the institution), outside the submitted work. ES reports grants from Hamburg Innovation and Hertie Foundation, outside the submitted work. DFV reports research grants from MicroVention, consulting fees from Medtronic, and paid lectures from Cerenovus/Johnson & Johnson, outside the submitted work. WW reports consulting fees to the institution from Abbvie, and consulting fees to the institution from BMS, GSK, and Servier, outside the submitted work. GT reports funding from the European Commission (EU Horizon 2020 research and innovation programme, payments to the institution); personal consulting fees from Acandis, AstraZeneca, Bayer, Boehringer Ingelheim, and Stryker; and personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Acandis, Alexion, Amarin, Bayer, Boehringer Ingelheim, BristolMyersSquibb/Pfizer, Daiichi Sankyo, Stryker, outside the submitted work. GT also reports participation as DSMB member for the TEA Stroke Trial (no payments) and ReSCInD trial (no payments), a role as speaker of the Commission for Cerebrovascular Diseases of the German Society of Neurology (no payments), and member of the Board of Directors of the European Stroke Organisation (no payments). All other declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Competing Interests: Dr Simonsen reports grants from the Health Research Foundation of Central Denmark Region and speaker fee from Pfizer, outside the submitted work. Dr Blauenfeldt reports speaker fee from Novo Nordisk, Pfizer, and Bayer, outside the submitted work.

Background: Hypertension and cerebral amyloid angiopathy are the most common causes of spontaneous intracerebral hemorrhage (ICH); however, these conditions do not imply macrovascular pathology. Still, computed tomography (CT) angiography (CTA) is often performed in the acute phase in patients with ICH., Purpose: To assess the diagnostic yield of CTA in the detection of secondary etiology in consecutive patients with spontaneous ICH., Material and Methods: We performed a retrospective analysis of data from a prospective single-center cohort study of 203 patients presenting with spontaneous ICH admitted to a comprehensive stroke center over a two-year period (15 October 2016 to 15 October 2018). The underlying vascular pathology was assessed using CTA., Results: CTA was performed in addition to non-contrast CT and/or magnetic resonance imaging (MRI). Vascular pathology was found in 11 of 203 (5.4%) patients and included arteriovenous malformations (n=4), aneurysms (n=4), vasospasms (n=1), cerebral venous thrombosis (n=1), and other vascular malformations (n=1). In eight cases, the finding was deemed symptomatic. Patients with vascular pathology on CTA more often had lobar located hemorrhages (63.6% vs. 36.4%, P  = 0.049). Numerically, patients with vascular pathology were younger, had smaller hematoma volumes, and lower mortality., Conclusion: Underlying macrovascular pathology was detected on CTA in only approximately 1 of 20 consecutive patients with ICH. The patients with vascular pathology more often had a hemorrhage with a lobar location and young age and the present study is supportive of a risk-based stratification approach in performing CTA., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objectives: Remote ischemic conditioning (RIC) is a low-cost, accessible, and noninvasive neuroprotective treatment strategy, but its efficacy and safety in acute ischemic stroke are controversial. With the publication of several randomized controlled trials (RCTs) and the recent results of the RESIST trial, it may be possible to identify the patient population that may (or may not) benefit from RIC. This systematic review and meta-analysis aims to evaluate the effectiveness and safety of RIC in patients with ischemic stroke receiving different treatments by pooling data of all randomized controlled studies to date., Methods: We searched the PubMed, Embase, Cochrane, Elsevier, and Web of Science databases to obtain articles in all languages from inception until May 25, 2023. The primary outcome was the modified Rankin Scale (mRS) score at the specified endpoint time in the trial. The secondary outcomes were change in NIH Stroke Scale (NIHSS) and recurrence of stroke events. The safety outcomes were cardiovascular events, cerebral hemorrhage, and mortality. The quality of articles was evaluated through the Cochrane risk assessment tool. This study was registered in PROSPERO (CRD42023430073)., Results: There were 7,657 patients from 22 RCTs included. Compared with the control group, patients who received RIC did not have improved mRS functional outcomes, regardless of whether they received medical management, reperfusion therapy with intravenous thrombolysis (IVT), or mechanical thrombectomy (MT). In the medical management group, patients who received RIC had decreased incidence of stroke recurrence (risk ratio 0.63, 95% CI 0.43-0.92, p = 0.02) and lower follow-up NIHSS score by 1.72 points compared with the control group ( p < 0.00001). There was no increased risk of adverse events including death or cerebral hemorrhage in the IVT or medical management group., Discussion: In patients with ischemic stroke who are not eligible for reperfusion therapy, RIC did not affect mRS functional outcomes but significantly improved the NIHSS score at the follow-up endpoint and reduced stroke recurrence, without increasing the risk of cerebral hemorrhage or death. In patients who received IVT or MT, the benefit of RIC was not observed.

Background: Remote ischemic conditioning (RIC) is a simple and noninvasive procedure that has proved to be safe and feasible in numerous smaller clinical trials. Mixed results have been found in recent large randomized controlled trials. This is a post hoc subgroup analysis of the RESIST trial (Remote Ischemic Conditioning in Patients With Acute Stroke), investigating the effect of RIC in different acute ischemic stroke etiologies, and whether an effect was modified by treatment adherence., Methods: Eligible patients were adults (aged ≥18 years), independent in activities of daily living, who had prehospital stroke symptoms with a duration of less than 4 hours. They were randomized to RIC or sham. The RIC treatment protocol consisted of 5 cycles with 5 minutes of cuff inflation alternating with 5 minutes with a deflated cuff. Acceptable treatment adherence was defined as when at least 80% of planned RIC cycles were received. The analysis was performed using the entire range (shift analysis) of the modified Rankin Scale (ordinal logistic regression)., Results: A total of 698 had acute ischemic stroke, 253 (36%) were women, and the median (interquartile range) age was 73 (63-80) years. Median (interquartile range) overall adherence to RIC/sham was 91% (68%-100%). In patients with a stroke due to cerebral small vessel disease, who were adherent to treatment, RIC was associated with improved functional outcome, and the odds ratio for a shift to a lower score on the modified Rankin Scale was 2.54 (1.03-6.25); P =0.042. The association remained significant after adjusting for potential confounders. No significant associations were found with other stroke etiologies, and the overall test for interaction was not statistically significant (χ 2 , 4.33, P =0.23)., Conclusions: In patients with acute ischemic stroke due to cerebral small vessel disease, who maintained good treatment adherence, RIC was associated with improved functional outcomes at 90 days. These results should only serve as a hypothesis-generating for future trials., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481777., Competing Interests: Disclosures Dr Blauenfeldt received lecture fees from Bayer, Pfizer, and Novo Nordisk, unrelated to the submitted work. Dr Hess was supported by a research grant from the National Institutes of Health. Dr Simonsen was supported by research grants from the Health Research Foundation of the Central Denmark Region. The other authors report no conflicts.

Objectives: An increased risk of stroke has been reported among patients with COVID-19 caused by SARS-CoV-2. We aimed to investigate the nationwide prevalence of SARS-CoV-2 among patients with acute ischaemic stroke and to study the impact on stroke severity, quality of care and mortality on an individual patient level., Design: This was a nationwide register-based cohort study., Setting: We used data from several Danish registers which were linked at an individual patient level using the unique civil registration number assigned to all Danish citizens. Patients were identified from the Danish Stroke Registry and information on SARS-CoV-2 infection status was collected from the Danish National COVID-19 Registry. Concurrent SARS-CoV-2 infection was defined as a positive PCR test within 31 days prior to, and 1 day after, stroke admission. Information on comorbidity was collected from the Danish National Patient Registry and information on vital status was collected from the Danish Civil Registration System., Participants: A total of 11 502 patients admitted with acute ischaemic stroke from 10 March 2020 to 31 May 2021 were included in the study., Results: Among the included patients, the majority (84.6%) were tested for SARS-CoV-2, but only 68 had a positive test. These patients were more prone to have atrial fibrillation and were more often treated with reperfusion therapy. They had a significantly increased risk of severe stroke (adjusted relative risk (aRR) 1.93, 95% CI: 1.22 to 3.04) and a significantly increased 30-day mortality risk (aRR 2.29, 95% CI: 1.19 to 4.39). There was no difference in the proportion of patients fulfilling relevant performance measures on quality of care., Conclusion: In this nationwide study, only 0.6% of patients with acute ischaemic stroke were tested positive for a concurrent SARS-CoV-2 infection. The patients with SARS-CoV-2 presented with more severe strokes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Recent evidence suggests a beneficial effect of endovascular thrombectomy in acute ischaemic stroke with large infarct; however, previous trials have relied on multimodal brain imaging, whereas non-contrast CT is mostly used in clinical practice., Methods: In a prospective multicentre, open-label, randomised trial, patients with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and a large established infarct indicated by an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) of 3-5 were randomly assigned using a central, web-based system (using a 1:1 ratio) to receive either endovascular thrombectomy with medical treatment or medical treatment (ie, standard of care) alone up to 12 h from stroke onset. The study was conducted in 40 hospitals in Europe and one site in Canada. The primary outcome was functional outcome across the entire range of the modified Rankin Scale at 90 days, assessed by investigators masked to treatment assignment. The primary analysis was done in the intention-to-treat population. Safety endpoints included mortality and rates of symptomatic intracranial haemorrhage and were analysed in the safety population, which included all patients based on the treatment they received. This trial is registered with ClinicalTrials.gov, NCT03094715., Findings: From July 17, 2018, to Feb 21, 2023, 253 patients were randomly assigned, with 125 patients assigned to endovascular thrombectomy and 128 to medical treatment alone. The trial was stopped early for efficacy after the first pre-planned interim analysis. At 90 days, endovascular thrombectomy was associated with a shift in the distribution of scores on the modified Rankin Scale towards better outcome (adjusted common OR 2·58 [95% CI 1·60-4·15]; p=0·0001) and with lower mortality (hazard ratio 0·67 [95% CI 0·46-0·98]; p=0·038). Symptomatic intracranial haemorrhage occurred in seven (6%) patients with thrombectomy and in six (5%) with medical treatment alone., Interpretation: Endovascular thrombectomy was associated with improved functional outcome and lower mortality in patients with acute ischaemic stroke from large vessel occlusion with established large infarct in a setting using non-contrast CT as the predominant imaging modality for patient selection., Funding: EU Horizon 2020., Competing Interests: Declaration of interests MB reports funding from EU Horizon 2020 and Deutsche Forschungsgemeinschaft (payments to the institution); honoraria for lectures from Novartis, Boehringer Ingelheim, and Seagen; and consulting fees from NeuroScios and Boehringer Ingelheim and is an editor in chief of Clinical Neuroradiology (Springer). JF reports funding from the European Commission; personal consulting fees from Acandis, Cerenovus, Medtronic, Microvention, Phenox, Stryker, and Roche; consulting at Philips (no payments); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Penumbra and Tonbridge; support for attending meetings or travel from Medtronic and Penumbra; stock or stock options from Tegus Medical, Eppdata, and Vastrax; and participation in a Data Safety Monitoring Board or Advisory Board at Phenox (personal fees) and Stryker (personal fees) and is a past president of ESMINT. SB reports funding from the EU Horizon 2020 research and innovation programme (754640; payments made to the institution); and support for attending meetings or travel from Medtronic and Penumbra; AHA reports unrestricted research grants from Boehringer Ingelheim; honoraria for lectures from BMS/Pfizer, Teva, Roche, Abbvie, Lundbeck, and Novartis; and participation in Advisory Boards for MSD, BMS/Pfizer, Lundbeck, Lilly, and Abbvie. BF reports research grants from Carlos III Institute of Health; personal payment for educational lectures from Servicio Madrileño de Salud; payment for lectures from Euromedice to the institution; personal payment for educational lectures from Takeda; support for attending meetings from Daiichi Sankyo; receipt of materials for research from Abbot. MDH reports funding from Nil; grants to the University of Calgary for the TEMPO-2 trial from Boehringer Ingelheim, Biogen, NoNO (ESCAPE-NA1 trial and ESCAPE-NEXT trial), Canadian Institute for Health Research (ESCAPE-NA1 trial and ESCAPE-NEXT trial), Medtronic (HERMES collaboration), Alberta Innovates (QuICR Alberta Stroke Program); that some of the funds were used for the ESCAPE-NA1 trial from Alberta Innovates; consulting fees from Sun Pharma Brainsgate (paid work for adjudication of clinical trial outcomes); US patents 62/086,077 (licensed to Circle NVI) and 10,916,346 (licensed to Circle NVI); private stock ownership from Circle and PUreWeb; participation as data and safety monitoring committee chair of the RACECAT trial (end 2020), the Oncovir Hiltonel trial (ongoing), and the DUMAS trial (ongoing); participation as a data and safety monitoring committee member of the ARTESIA trial (ongoing), and the BRAIN-AF trial (ongoing); and is president of the Canadian Neurological Sciences Federation (not for profit) and a Board member of the Canadian Stroke Consortium (not for profit). AK reports grants from the European Commission for the TENSION study (payment to the institution). LP reports consulting fees from Balt, Microvention, and Phenox; and support for attending meetings or travel for the TENSION investigator meeting (transport and accommodation was reimbursed by the organization). CZS reports grants from Novo Nordisk Foundation and Health Research Foundation of Central Denmark Region. RAB reports speakers fees from Novo Nordisk and Beyer. HD reports financial compensation for the start-up fee and the obligatory payment to the hospital administration paid by the sponsor (Medical University Heidelberg) to the clinical division (no personal payments); personal consulting fees from Stryker; speakers honorary from Medtronic; support for attending meetings or travel from Medtronic; and past presidency of the Austrian Society of Interventional Radiology and past presidency Austrian Society of Neuroradiology. FD reports consulting fees from Cerenovus, Phenox, Balt, Cerus Endovascular, Stryker; payment for expert testimony from Cerenovus; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Cerenovus, Stryker, Acandis, Asahi, and Penumbra; participation in a Data Safety Monitoring Board or Advisory Board at Cerenovus; and previously work as an associate editor for Journal of NeuroInterventional Surgery and Journal of Clinical Medicine. FF reports consulting fees from Eppdata and support for attending meetings or travel from Microvention, Medtronic, Cerebrovascular Research and Education Foundation (CREF), and Acandis. SG reports consulting fees from Eppdata. CH reports consulting fees from Brainomix and lecture fees from Stryker. SH-J reports funding for data collection, payment, or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Terumo. MG reports research grants from Medtronic and Cerenovus (payments to the University of Calgary); royalties or licenses from Microvention (systems of intracranial access); personal consulting fees from Microvention, Medtronic, Stryker, Mentice, Philips, and Penumbra; and stock or stock options from Circle Neurovascular. CFK was chair of the German stroke registry (unpaid). RM reports payments for a stroke lecture from TMC Academy. MM reports grants from Balt, Medtronic, MicroVention, and Stryker; consulting fees from Siemens; and support for attending meetings or travel from Europa Group. SM-H reports consulting fees from Terumo and Boston Scientific Corporation; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Terumo and Boston Scientific Corporation. NM reports the provision of study materials. PP reports support for attending meetings or travel for the TENSION investigator meeting (transport and accommodation was reimbursed by the organisation). MP reports grants from the German Research Foundation (DFG SFB 1158 A10, DFG KFO 5001 P02, DFG KFO 5001 Z, and DFG SFB TR 240 B02); speaker honoraria unrelated from Merck Serono and Bayer; and support for attending meetings or travel from Merck Serono (travel reimbursement) and Bayer (travel reimbursement). PAR reports consulting fees to the institution from Boehringer Ingelheim and Bayer; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Boehringer Ingelheim, Bayer, Pfizer, and BMS (all made to the institution). ES reports grants from Hamburg Innovation and Hertie Foundation. DFV reports research grants from MicroVention; consulting fees from Medtronic; and paid lectures from Cerenovus and Johnson & Johnson. WW reports consulting fees to the institution from Abbvie, BMS, GSK, and Servier. GT reports funding from the European Commission (EUHorizon 2020 research and innovation programme, 754640; payments to the institution); personal consulting fees from Acandis, AstraZeneca, Bayer, Boehringer Ingelheim, and Stryker; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Acandis, Alexion, Marin, Bayer, Boehringer Ingelheim, BristolMyersSquibb/Pfizer, Daiichi Sankyo, and Stryker; participation as DSMB member for the TEA Stroke Trial (no payments) and ReSCInD trial (no payments); work as a speaker of the Commission for Cerebrovascular Diseases of the German Society of Neurology (DGN; no payments); and membership of the Board of Directors of the European Stroke Organisation (ESO; no payments). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: When patients with acute ischemic stroke present with suspected large vessel occlusion in the catchment area of a primary stroke center (PSC), the benefit of direct transport to a comprehensive stroke center (CSC) has been suggested. Equipoise remains between transport strategies and the best transport strategy is not well established., Methods: We conducted a national investigator-driven, multicenter, randomized, assessor-blinded clinical trial. Patients eligible for intravenous thrombolysis (IVT) who were suspected for large vessel occlusion were randomized 1:1 to admission to the nearest PSC (prioritizing IVT) or direct CSC admission (prioritizing endovascular therapy). The primary outcome was functional improvement at day 90 for all patients with acute ischemic stroke, measured as shift towards a lower score on the modified Rankin Scale score., Results: From September 2018 to May 2022, we enrolled 171 patients of whom 104 had acute ischemic stroke. The trial was halted before full recruitment. Baseline characteristics were well balanced. Primary analysis of shift in modified Rankin Scale (ordinal logistic regression) revealed an odds ratio for functional improvement at day 90 of 1.42 (95% CI, 0.72-2.82, P =0.31). Onset to groin time for patients with large vessel occlusion was 35 minutes ( P =0.007) shorter when patients were transported to a CSC first, whereas onset to needle (IVT) was 30 minutes ( P =0.012) shorter when patients were transported to PSC first. IVT was administered in 67% of patients in the PSC group versus 78% in the CSC group and EVT was performed in 53% versus 63% of the patients, respectively., Conclusions: This trial investigated the benefit of bypassing PSC. We included only IVT-eligible patients presenting <4 hours from onset and with suspected large vessel occlusion. Lack of power prevented the results from showing effect on functional outcome for patients going directly to CSC., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03542188., Competing Interests: Disclosures Dr Fisher reports employment by Beth Israel Deaconess Medical Center and compensation from Lumosa for consultant services. Dr Blauenfeldt reports compensation from Bayer and Novo Nordisk AS for other services. Dr Johnsen reports compensation from TrygFonden, Phizer, and Bristol Meyers Squibb for consultant services. Dr Simonsen reports employment by Aarhus University Hospital. The other authors report no conflicts.

Importance: Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke., Objective: To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke., Design, Setting, and Participants: This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023)., Intervention: The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants., Main Outcomes and Measures: The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke., Results: Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group., Conclusions and Relevance: RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke., Trial Registration: ClinicalTrials.gov Identifier: NCT03481777.

Background: We present a case illustrating evolution of symptoms and brain magnetic resonance imaging in cortical superficial siderosis., Case Presentation: A 74-year-old man with no prior medical history presented with transient focal neurological episodes with subtle imaging changes. There was no evidence of cortical superficial siderosis. Two weeks later, the patient was readmitted with new episodes, and had developed cortical superficial siderosis adjacent to a cerebral microbleed. Transient focal neurological episode secondary to cortical superficial siderosis was diagnosed together with probable cerebral amyloid angiopathy., Conclusion: Clinical symptoms may precede the development of cortical superficial siderosis prior to being detectable on brain MRI. This case highlights the temporal development of cortical superficial siderosis., (© 2023. The Author(s).)

Objectives: We observed a decrease in the number of patients who were offered reperfusion therapy. We aimed to investigate if whether hospital system pressure measured as the percentage of stroke bed occupancy influenced decisions on treatment and disposition., Design: Data from a regional quality of stroke care database were obtained and linked to the organizational data monitoring of the hourly inpatient stroke bed occupancy rate. Logistic regression was used to analyze the relationship., Results: A total of 15,025 admissions were included from 1 January 2019 to 24 August 2022. Of these, 5,659 (38%) had an acute ischemic stroke. The rates of reperfusion therapy treatment were the highest in 2019 (36.2%) and 2020 (34.1%) and declined afterward (30.0% in 2021). In the logistic regression analysis, an occupancy rate of ≥85% in the hour of the first admission was associated with reduced odds of admission at the stroke unit within 3 h from the symptom onset [adjusted odds ratio: 0.80, 95% confidence interval: (0.71-0.90), p < 0.001] and a reduced odds of receiving reperfusion therapy (adjusted odds ratio: 0.83 (0.73-0.95), p = 0.007)., Conclusion: An increased bed occupancy level in the hour of the first hospital admission for stroke patients was strongly associated with decreased odds of receiving reperfusion therapy., Competing Interests: The 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., (Copyright © 2023 Blauenfeldt, Damgaard and Simonsen.)

Objectives: To investigate the association between prestroke physical activity and depressive symptoms up to 6 months after stroke and examine if citalopram treatment modified the association., Design: A secondary analysis of data from the multicentre randomised controlled trial The Efficacy of Citalopram Treatment in Acute Ischemic Stroke (TALOS)., Setting and Participants: TALOS was conducted at multiple stroke centres in Denmark from 2013 to 2016. It enrolled 642 non-depressed patients with first-ever acute ischaemic stroke. Patients were eligible for this study if a prestroke physical activity level was assessed by the Physical Activity Scale for the Elderly (PASE)., Interventions: All patients were randomised to citalopram or placebo for 6 months., Outcomes: Depressive symptoms 1 and 6 months after stroke measured on the Major Depression Inventory (MDI) ranging from 0 to 50., Results: A total of 625 patients were included. Median (IQR) age was 69 (60-77) years, 410 (65.6%) were men, 309 (49.4 %) received citalopram and median (IQR) prestroke PASE score was 132.5 (76-197). Higher prestroke PASE quartile, compared with the lowest PASE quartile, was associated with fewer depressive symptoms both after 1 month (mean difference third quartile -2.3 (-4.2, -0.5), p=0.013, mean difference fourth quartile -2.4 (-4.3, -0.5), p=0.015) and 6 months after stroke (mean difference third quartile -3.3 (-5.5, -1.2), p=0.002, mean difference fourth quartile -2.8 (-5.2, -0.3), p=0.027). There was no interaction between citalopram treatment and prestroke PASE score on poststroke MDI scores (p=0.86)., Conclusions: A higher prestroke physical activity level was associated with fewer depressive symptoms 1 and 6 months after stroke. Citalopram treatment did not seem to modify this association., Trial Registration Numbers: NCT01937182 (ClinicalTrials.gov) and 2013-002253-30 (EUDRACT)., Competing Interests: Competing interests: None declared., (© 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.)

Introduction: Evidence-based early stroke care as reflected by fulfillment of process performance measures, is strongly related to better patient outcomes after stroke and transient ischemic attack (TIA). Detailed data on the resilience of stroke care services during the COVID-19 pandemic are limited. We aimed to examine the quality of early stroke care at Danish hospitals during the early phases of the COVID-19 pandemic., Materials and Methods: We extracted data from Danish national health registries in five time periods (11 March, 2020-27 January, 2021) and compared these to a baseline pre-pandemic period (13 March, 2019-10 March, 2020). Quality of early stroke care was assessed as fulfilment of individual process performance measures and as a composite measure (opportunity-based score)., Results: A total of 23,054 patients were admitted with stroke and 8153 with a TIA diagnosis in the entire period. On a national level, the opportunity-based score (95% confidence interval [CI]) at baseline for ischemic patients was 81.1% (80.8-81.4), for intracerebral hemorrhage (ICH) 85.5% (84.3-86.6), and for TIA 96.0% (95.3-96.1). An increase of 1.1% (0.1-2.2) and 1.5% (0.3-2.7) in the opportunity-based score was observed during the first national lockdown period for AIS and TIA followed by a decline of -1.3% (-2.2 to -0.4) in the gradual reopening phase for AIS indicators. We found a significant negative association between regional incidence rates and quality-of-care in ischemic stroke patients implying that quality decreases when admission rates increase., Conclusion: The quality of acute stroke/TIA care in Denmark remained high during the early phases of the pandemic and only minor fluctuations occurred., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RAB is supported by National Institute of Health (1R01NS112511-01A1). CK is supported from Novo Nordisk Foundation (NNF18OC0031840). DG is supported by Novo Nordisk Foundation (NNF20OC0064637). GA is supported by Novo Nordisk Foundation (NNF18OC0052924, NNF20OC0060998) Trygfoundation (120636), Lundbeck Foundation (349-2020-907), and National Institute of Health (1R01NS112511-01A1). CZS is supported by a research grant from Novo Nordisk Foundation (NNF17OC0029520) and Health Research Foundation of Central Denmark Region. Authors DD, TWS, JNH, BM, and SPJ reports no conflict of interest., (© European Stroke Organisation 2022.)

Introduction: Rapid identification and treatment of stroke is crucial for the outcome of the patient. We aimed to determine the performance of glial fibrillary acidic protein (GFAP) independently and in combination with the Prehospital Stroke Score (PreSS) for identification and differentiation of acute stroke within 4.5 h after symptom onset., Patients and Methods: Clinical data and serum samples were collected from the Treat-Norwegian Acute Stroke Prehospital Project (Treat-NASPP). Patients with suspected stroke and symptoms lasting ≤ 4.5 h had blood samples collected and were evaluated with the National Institutes of Health Stroke Scale prospectively. In this sub study, NIHSS was retrospectively translated into PreSS and GFAP was measured using the sensitive single molecule array (SIMOA)., Results: A total of 299 patients with suspected stroke were recruited from Treat-NASPP and included in this study (44% acute ischemic stroke (AIS), 10% intracranial hemorrhage (ICrH), 7% transient ischemic attack (TIA), and 38% stroke mimics). ICrH was identified with a cross-fold validated area under the receiver-operating characteristic curve (AUC) of 0.73 (95% CI 0.62-0.84). A decision tree with PreSS and GFAP combined, first identified patients with a low probability of stroke. Subsequently, GFAP detected patients with ICrH with a 25.0% sensitivity (95% CI 11.5-43.4) and 100.0% specificity (95% CI 98.6-100.0). Lastly, patients with large-vessel occlusion (LVO) were detected with a 55.6% sensitivity (95% CI 35.3-74.5) and 82.4% specificity (95% CI 77.3-86.7)., Conclusion: In unselected patients with suspected stroke, GFAP alone identified ICrH. Combined in a decision tree, GFAP and PreSS identified subgroups with high proportions of stroke mimics, ICrH, LVO, and AIS (non-LVO strokes)., (© 2023. The Author(s).)

Background: Despite effective treatments, many patients are still not offered reperfusion therapy for acute ischemic stroke., Methods: We present a single-center observational study on acute ischemic stroke patients, who presented as candidates for reperfusion therapy but were deemed ineligible after work-up. Reasons for non-treatment were obtained by studying patient files and subsequently grouped into "too risky" (e.g., anticoagulant use, comorbidities), "too large" (large infarct), "too late" (late presentation of stroke and wake-up strokes), or "too mild" (clinically mild/remitting symptoms). Modified Rankin scale (mRS) score was prospectively collected in all patients by a structured telephone interview. All non-treated patients with a National Institute of Health Stroke Scale (NIHSS) score of 0-5 were compared with a similar cohort that was treated., Results: Of 529 patients with acute ischemic stroke arriving as reperfusion therapy candidates, 198 (37.4%) were not treated. The majority (42%) were not treated due to admission outside the treatment window (too late) and 24% had absolute contraindications (too risky). Only 8% was excluded because their infarct was too large [median Alberta Stroke Program Early CT score 3 (2-4)]. In the "too mild" group (14%) the percentage of patients not being independent at 90 days was 30%. The adjusted odds ratio for a better outcome (lower mRS) among treated patients with NIHSS 0-5 compared with non-treated was 1.93 (95% confidence interval 1.15-3.23)., Conclusion: Presenting outside the treatment window is still the most common reason for not receiving therapy. Our study suggests a benefit of thrombolysis for patients with mild symptoms., Competing Interests: The 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., (Copyright © 2022 Behrndtz, Damsbo, Blauenfeldt, Andersen, Speiser and Simonsen.)

Stroke is a leading cause of death and disability. Some patients may present with atypical symptoms. One of the very rare presentations of stroke is initial neurogenic pain. Rare painful presentations include, amongst others, acute trigeminal neuralgia, atypical facial pain, hemi-sensory pain, and episodic pain. Based on the available literature, the pain at presentation may be episodic, transient, or persistent, and it may herald other debilitating stroke symptoms such as hemiparesis. Pain quality is often described as burning; less often as sharp. Patients often have accompanying focal symptoms and findings on neurological examination. However, in several of the reviewed cases, these were discrete or non-existent. In patients with pain located in the trunk and/or extremities, lesions may involve the thalamus, lateral medulla oblongata, insula, or parietal lobe. In patients with atypical facial or orbital pain (including the burning "salt and pepper" sensation), the stroke lesions are typically located in the pons. In this narrative review, we included studies/case series of patients who had pain at the time of onset, shortly before or within 24 h of stroke symptoms (on the day of admission). Cases with pain related to aortic or cervical vessel dissection, cerebral venous sinus thrombosis, subarachnoid hemorrhage, reversible cerebral vasoconstriction syndrome, and CNS vasculitis were excluded. With this review, we aim to summarize the current knowledge on stroke presenting with acute pain., (© 2022 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

The aging process leads to subtle decline in cognitive function, and in some overt dementia. Like physical activity Remote Ischemic Conditioning (RIC) may ameliorate these changes on cognitive impairment in humans. The purpose of this study was to compared the effects of single, repeated short-term and long-term treatment RIC, and analyze its effect registered as immediate vs. long-term on cognitive performance in humans. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and was registered with PROSPERO, number (CRD42021285668). A systematic review was conducted to identify relevant studies through six healthcare science databases (Cochrane, PubMed, EMBASE, EBSCO, Scopus, and Web of Science) up to December 2021. Eligibility criteria included (1) a study sample of participants aged ≥18 years, (2) post-intervention changes on cognitive performance in humans, and (3) this systematic review included only randomized controlled trials of RIC in humans. The quality of the included studies was assessed by GRADEpro tool. A total of 118 articles were initially identified, 35 of which met the inclusion criteria. Based on title/abstract, age and RIC protocol, 14 articles were included in this review: 5 studies investigated the immediate and long-term effect of a single RIC (n = 370 patients), 4 studies examined intermittent short-term RIC (n = 174 patients) and 5 studies evaluated repeated long-term RIC (n = 228 patients). A single pre-operative RIC treatment had an immediate effect that disappeared at one week. Short-term RIC showed either a positive or no effects on cognitive function. The majority of studies examining long-term RIC treatment showed improvements in cognitive performance, particularly in very old adults and older patients with cognitive impairments. Single RIC treatment did not show any persisting effect on cognition. However, repeated short term RIC showed some improvement and long-term RIC may improve cognitive performance after stroke or enhance neuropsychological tests in patients diagnosed with vascular dementia. The mixed results might be explained by different RIC treatment protocols and populations investigated., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The risk of thrombosis increases in infectious diseases, yet observational studies from single centers have shown a decrease in admission of acute ischemic stroke patients during the COVID-19 pandemic. To investigate unselected stroke admission rates we performed a nationwide study in Denmark., Methods: We extracted information from Danish national health registries. The following mutually exclusive time periods were compared to the year before the lockdown: (1) first national lockdown, (2) gradual reopening, (3) few restrictions, (4) regional lockdown, and (5) second national lockdown., Results: Generally, admission rates were unchanged during the pandemic. In the unadjusted data, we observed a small decrease in the admission rate for all strokes under the first lockdown (incidence rate ratio: 0.93, confidence interval [CI]: 0.87-0.99) and a slight increase during the periods with gradual reopening, few restrictions, and the regional lockdown driven by ischemic strokes. We found no change in the rate of severe strokes, mild strokes, or 30-day mortality. An exception was the higher mortality for all strokes during the first lockdown (risk ratio: crude 1.30 [CI: 1.03-1.59]; adjusted 1.17 [CI: 0.93-1.47]). The quality of care remained unchanged., Conclusion: Stroke admission rates remained largely unchanged during the pandemic, while an increased short-term mortality rate in patients admitted with stroke observed during the first lockdown was seen, probably reflecting that the more frail patients constituted a higher proportion of admitted patients at the beginning of the pandemic., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objectives: The main aim of the study is to investigate the performance of a two-part stroke scale for screening and subsequent severity assessment combined with a telephone conference (teleconference)., Materials and Methods: During a 6-month period, we prospectively tested the Prehospital Stroke Score (PreSS). PreSS part 1 is designed to identify stroke or TIA in a prehospital setting. PreSS part 2 is a stroke severity scale designed to identify large-vessel occlusion (LVO). PreSS was performed by emergency medical service (EMS) providers prior to a teleconference with a stroke neurologist., Results: Combined teleconference and PreSS part 1 were performed on 79.3% of all patients diagnosed with stroke/TIA, and 99.1% of the patients with positive scores were subsequently PreSS part 2 scored. PreSS part 1 and teleconference had a sensitivity to identify stroke/TIA of 89.3% (95% CI 85.7-92.2), specificity of 64.5% (95% CI 59.3-69.5), and an area under the curve (AUC) of 0.80 (95% CI 0.77-0.83). Regarding LVO, PreSS part 1 with teleconference recognized 96.7% (95% CI 88.7-99.6) of all cases as stroke. PreSS part 2 had a sensitivity of 55.7% (95% CI 42.4-68.5), specificity of 91.5% (95% CI 89.0-93.6), and AUC of 0.86 (95% CI 0.82-0.90) for identification of LVO., Conclusions: PreSS was feasible and the sensitivity for stroke/TIA and LVO was high to moderate providing an overall high precision. Almost all LVO cases were ensured acute stroke admission. The high specificity for LVO could be useful for determining transfers strategies., Classification of Evidence: This study provides Class I evidence when evaluating PreSS combined with teleconference., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Prehospital delay is the main reason why only a limited number of stroke patients receive reperfusion therapy. We aimed to investigate help-seeking behaviour in patients and bystanders after onset of stroke and subsequent patient and system delay., Materials & Methods: We conducted a cross-sectional study of 332 patients with stroke. We performed structured interviews and used data from the medical records and the Danish Stroke Registry. Primary outcomes were patient delay and system delay., Results: The median patient delay was 280 min, and the median system delay was 97 min. For a patient delay of <3 h, an additional non-significant system delay of median 30 min was seen for a first contact to a general practitioner (GP), and an additional significant delay of median 490 min was seen for the small group of patients with a first contact to 'other' healthcare professionals compared to the Emergency Medical Services (EMS). For a patient delay of more than 3 h, an additional system delay of median 78 min was found when the first contact was directed to the out-of-hours primary care (OOH-PC). A total of 17% of patients were admitted to another hospital or department before arrival at the stroke centre; this resulted in a substantially prolonged system delay of a median of 431 min., Conclusions: Patient delay remains the main reason for delayed arrival at the stroke centre. Appropriate help-seeking behaviour and efficient pre-hospital triage are essential for reducing the prehospital delay and increasing the proportion of patients receiving reperfusion therapy., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Stroke is a leading cause of death and disability. Intravenous thrombolysis and mechanical thrombectomy have greatly improved outcomes in acute ischemic stroke (AIS). However, only a minority of patients receive reperfusion therapies, highlighting the need for novel neuroprotective therapies. Remote ischemic conditioning (RIC), consisting of brief, intermittent extremity occlusion and reperfusion induced with an inflatable cuff, is a potential neuroprotective therapy in acute stroke. The objective of this narrative review is to describe the effect of RIC on endogenous fibrinolysis and, from this perspective, investigate the potential of RIC in the prevention and treatment of stroke. A systematic literature search was performed in PubMed, and human studies in English were included. Seven studies had investigated the effect of RIC on fibrinolysis in humans. Long-term daily administration of RIC increased endogenous fibrinolysis, whereas a single RIC treatment did not acutely influence endogenous fibrinolysis. Fifteen studies had investigated the effect of RIC as a neuroprotective therapy in the prevention and treatment of stroke. Long-term RIC administration proved effective in reducing new cerebral vascular lesions in patients with established cerebrovascular disease. In patients with acute stroke, RIC was safe and feasible, though its clinical efficacy as a neuroprotectant is yet unproven. In conclusion, a single RIC treatment does not affect fibrinolysis in the acute phase, whereas long-term RIC administration may increase endogenous fibrinolysis. Increased endogenous fibrinolysis is unlikely to be the mediator of the acute neuroprotective effect of RIC in stroke patients, whereas it may partly explain the reduced stroke recurrence associated with long-term RIC treatment., Competing Interests: None declared., (Thieme. All rights reserved.)

Remote ischemic conditioning (RIC) is a promising safe, feasible, and inexpensive treatment for acute stroke, both ischemic and hemorrhagic. It is applied with a blood pressure cuff on the limbs and is ideal for the prehospital setting. RIC is a form of preconditioning with similarities to physical exercise. Its mechanisms of action are multiple and include improvement of collateral cerebral blood flow (CBF) and RIC acts as a "collateral therapeutic". The increased CBF is likely related to nitric oxide synthase 3 in the endothelium and more importantly in circulating blood cells like the red blood cell. The RESIST clinical trial is a 1500 subject multicenter, randomized, sham-controlled trial of RIC in the prehospital setting in Denmark and should address the questions of whether RIC is safe and effective in acute stroke and whether the effect is mediated by an effect on nitric oxide/nitrite metabolism.

Introduction: Only a minority of patients with acute ischaemic stroke receive reperfusion treatment, primarily due to prehospital delay. We aimed to investigate predictors of a primary contact to the emergency medical services, arrival at stroke centre within 3 h of symptom onset and initiation of reperfusion therapy in patients with acute stroke., Patients and Methods: We conducted a cross-sectional study of consecutive patients with acute ischaemic stroke, intracerebral haemorrhage or transient ischaemic attack. Structured interviews of patients and bystanders were performed and combined with clinical information from the Danish Stroke Registry. Eligible patients were aged ≥18 years and were independent in activities of daily living before the stroke., Results: We included 435 patients. Presence of a bystander at symptom onset and knowledge of ≥2 core symptoms of stroke were associated with a primary emergency medical services contact. Higher stroke severity and patients or bystanders perceiving the situation as very serious were associated with a primary emergency medical services contact (OR patients 2.10; 95% CI 1.12-3.95 and OR bystanders 22.60; 95% CI 4.98-102.67), <3 h from onset to arrival (OR patients 3.01; 95% CI 1.46-6.21 and OR bystanders 4.44; 95% CI 1.37-14.39) and initiation of reperfusion therapy (OR patients 3.08; 95% CI 1.23-7.75 and OR bystanders 4.70; 95% CI 1.14-19.5). Conclusion: Having a bystander, knowledge of ≥2 core symptoms and understanding that stroke is a serious event are associated with appropriate help-seeking behaviour, shorter prehospital delay and higher chance of reperfusion therapy in acute stroke patients., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© European Stroke Organisation 2020.)

There is a large unmet need for fast and reliable diagnostics in several diseases. One such disease is stroke, where the efficacy of modern reperfusion therapies is highly time-dependent. Diagnosis of stroke and treatment initiation should be performed as soon as possible, and preferably before arrival at the stroke center. In recent years, several potential blood biomarkers for stroke have been evaluated, but without success. In this review, we will go into detail on the possibility of utilizing extracellular vesicles (EVs) released into the blood as novel biomarkers for stroke diagnostics. EVs are known to reflect the immediate state of the secreting cells and to be able to cross the blood-brain barrier, thus making them attractive as diagnostic biomarkers of brain diseases. Indeed, several studies have reported EV markers that enable differentiation between stroke patients and controls and, to a lesser extent, the ability to correctly classify the different stroke types. Most of the studies rely on the use of sophisticated and time-consuming methods to quantify specific subpopulations of the nanosized EVs. As these methods cannot be easily implemented in a rapid point of care (POC) test, technical developments followed by prospective clinical studies are needed.

Rationale: Remote ischaemic conditioning, applied in the prehospital setting and continued in-hospital, may improve functional outcome in patients with acute ischaemic stroke and intracerebral haemorrhage., Aims: To evaluate whether combined remote ischaemic per- and postconditioning can improve long-term functional outcome in acute ischaemic stroke and intracerebral haemorrhage patients., Methods and Design: Danish multicentre, prospective, randomised, patient-assessor blinded, sham-controlled study. Adult patients with a putative stroke identified prehospital with symptom duration <4 h, who are independent in daily activities will be randomised 1:1 to remote ischaemic conditioning or Sham-remote ischaemic conditioning. The treatment protocol will be five cycles, each consisting of 5 min with a blood pressure cuff inflation and 5 min with a deflated cuff placed on the upper extremity. The cuff pressure for remote ischaemic conditioning will be 200 mmHg-285 mmHg according to the individual systolic blood pressure and 20 mmHg sham-remote ischaemic conditioning during inflation. The study is approved as an acute study and consent is waived in the acute phase. Sample size estimation: For a 7% increased odds for a beneficial shift on the modified Rankin Scale at a significance level of 5% and power of 90%, 1000 patients with a target diagnosis of acute ischaemic stroke and intracerebral haemorrhage and a total of 1500 patients with a prehospital presumed stroke will be included. Study outcomes: The primary outcome will be the modified Rankin Scale score measured at three-month follow-up (analysed using ordinal logistic regression). ClinicalTrials.gov Identifier: NCT03481777., (© European Stroke Organisation 2019.)

Introduction: Physical activity (PA) is associated with a lower risk of stroke and stroke mortality as well as a favorable stroke outcome. PA may also prevent general cognitive decline. Poststroke cognitive impairment is both common and disabling, and focusing on all possible preventive measures is important. Studies on the effect of PA on poststroke cognitive performance are sparse, however. We therefore aimed to examine the association between prestroke PA and poststroke cognitive performance., Methods: We studied the correlation between prestroke PA and poststroke cognitive performance in a prespecified analysis in The Efficacy of Citalopram Treatment in Acute Ischemic Stroke (TALOS) trial. We used the Physical Activity Scale for the Elderly (PASE) to collect information on PA during the 7-day period before stroke. PA was quantified, and patients were stratified into quartiles based on their PASE score. Cognitive performance was measured using the Symbol Digit Modalities Test (SDMT) at 1 and 6 months and the Mini-Mental State Examination (MMSE) at 6 months. The functional outcome was assessed using the modified Rankin Scale (mRS)., Results: In total, 625 of 642 patients (97%) completed the PASE questionnaire. The median age was 69 (interquartile range [IQR]: 60-77), and the median PASE score was 137 (82-205). Higher prestroke PASE quartiles (2nd, 3rd, and 4th, each compared to the 1st) were independently associated with a higher SDMT score at 1 month in the both the univariable and multivariable analyses (2nd: 3.99 points, 95% confidence interval [CI]: 1.01-6.97; 3rd: 3.6, CI: 0.6-6.61; 4th: 4.1, CI: 0.95-7.24). This association remained at 6 months. PA was not statistically associated with the MMSE score or mRS., Conclusion: Higher prestroke PA was associated with a better cognitive performance as measured by the SDMT at 1 and 6 months poststroke. We found no significant association between prestroke PA and functional outcome. Our results are encouraging and support further investigations of PA as a protective measure against poststroke cognitive impairment., (© 2020 S. Karger AG, Basel.)

Rationale: For patients with acute ischemic stroke and large vessel occlusions, intravenous thrombolysis and endovascular therapy are standard of care, but the effect of endovascular therapy is superior to intravenous thrombolysis. If a severe stroke with symptoms indicating large vessel occlusions occurs in the catchment area of a primary stroke center, there is equipoise regarding optimal transport strategy., Aim: For patients presenting with suspected large vessel occlusions (PASS ≥ 2) and a final diagnosis of acute ischemic stroke, we hypothesize that bypassing the primary stroke center will result in an improved 90-day functional outcome., Sample Size: We aim to randomize 600 patients, 1:1., Design: A national investigator-driven, multi-center, randomized assessor-blinded clinical trial. The Prehospital Acute Stroke Severity Scale has been developed. It identifies most patients with large vessel occlusions in the pre-hospital setting. Patients without a contraindication for intravenous thrombolysis are randomized to either transport directly to a comprehensive stroke centers for intravenous thrombolysis and of endovascular therapy or to a primary stroke center for intravenous thrombolysis and subsequent transport to a comprehensive stroke centers for of endovascular therapy, if needed., Outcomes: The primary outcome will be the 90-day modified Rankin Scale score (mRS) for all patients with acute ischemic stroke. Secondary outcomes include 90-day mRS for all randomized patients, all patients with ischemic stroke but without large vessel occlusions, and patients with hemorrhagic stroke. The safety outcomes include severe dependency or death and time to intravenous thrombolysis for ischemic stroke patients., Discussion: Study results will influence decision making regarding transport strategy for patients with suspected large vessel occlusions.

Background: A high prestroke physical activity (PA) level is associated with reduced stroke rate, stroke mortality, better functional outcome, and possible neuroprotective abilities. The aim of the present study was to examine the possible neuroprotective effect of prestroke PA on 24-h cerebral infarct growth in a cohort of acute ischemic stroke patients treated with intravenous tPA and randomized to remote ischemic perconditioning., Methods: In this predefined subanalysis, data from a randomized clinical trial investigating the effect of remote ischemic perconditioning (RIPerC) on AIS was used. Prestroke (7 days before admission) PA was quantified using the PA Scale for the Elderly (PASE) questionnaire at baseline. Infarct growth was evaluated using MRI (acute, 24-h, and 1-month)., Results: PASE scores were obtained from 102 of 153 (67%) patients with a median (interquartile range) age of 66 (58-73) years. A high prestroke PA level correlated significantly with reduced acute infarct growth (24 h) in the linear regression model (4th quartile prestroke PA level compared with the 1st quartile), β4th quartile = -0.82 (95% CI -1.54 to -0.10). However, the effect of prestroke PA was present mainly in patients randomized to RIPerC, β4th quartile = -1.14 (95% CI -2.04 to -0.25). In patients randomized to RIPerC, prestroke PA was a predictor of final infarct size (1-month infarct volume), β4th quartile = -1.78 (95% CI -3.15 to -0.41)., Conclusion: In AIS patients treated with RIPerC, as add-on to intravenous thrombolysis, the level of PA the week before the stroke was associated with decreased 24-h infarct growth and final infarct size. These results are highly encouraging and stress the need for further exploration of the potentially protective effects of both PA and remote ischemic conditioning., (© 2017 S. Karger AG, Basel.)

Remote ischaemic conditioning (RIC) triggers endogenous protective pathways in distant organs such as the kidney, heart and brain, and represents an exciting new paradigm in neuroprotection. RIC involves repetitive inflation and deflation of a blood pressure cuff on the limb, and is safe and feasible. The exact mechanism of signal transmission from the periphery to the brain is not known, but both humoral factors and an intact nervous system seem to have critical roles. Early-phase clinical trials have already been conducted to test RIC in the prehospital setting in acute ischaemic stroke, and in subarachnoid haemorrhage for the prevention of delayed cerebral ischaemia. Furthermore, two small randomized clinical trials in patients with symptomatic intracranial atherosclerosis have shown that RIC can reduce recurrence of stroke and have neuroprotective activity. RIC represents a highly practical and translatable therapy for acute, subacute, and chronic neurological diseases with an ischaemic or inflammatory basis. In this Review, we consider the principles and mechanisms of RIC, evidence from preclinical models and clinical trials that RIC is beneficial in neurological disease, and how the procedure might be used in the future in disorders such as vascular cognitive impairment and traumatic brain injury.

Objective: Alterations of the electroencephalogram (EEG) have been reported in patients with hepatic encephalopathy (HE). However, previous methods have not assessed transient phenomena in the EEG signal (dynamics) and associations to psychometric test performance have in general been poor. The aims were to quantify spectral and dynamic EEG abnormalities in patients with HE and to correlate putative findings to psychometric test performances., Methods: Multichannel EEG (64 electrodes) was recorded in 24 cirrhotic patients with various grades of HE and 26 healthy volunteers. Spectral and dynamic EEG indices were quantified by continues wavelet analysis. In addition, the psychometric hepatic encephalopathy score (PHES), continues reaction time, and biochemical profile were assessed., Results: Compared with healthy volunteers, patients had progressively slowing of the EEG (all p ≤ 0.004) (spectral EEG indices) and increased variability in the alpha [7.5-13.5 Hz] (p = 0.001) and beta bands [13.5-32 Hz] (p = 0.02) (dynamic EEG indices). In addition, anteriorization and dissociation of the basic posterior alpha rhythm, along with dissociation of frontal delta activities [1-3.5 Hz] were seen with worsening of HE. Spectral EEG indices (all frequency bands) as well as dynamic EEG indices (alpha and beta bands) were correlated to PHES scores (all p < 0.05)., Conclusion: EEG analysis, based on continues wavelet transform, provides quantifiable information on static as well as dynamic features of the EEG in patients with HE. EEG abnormalities were correlated to psychometric test performance and may provide valuable clinical biomarkers for surveillance, prognostication and treatment of this entity.

Background and Aims: Autonomic neuropathy seems to play a central role in the development of gastrointestinal symptoms in diabetes. In order to explore the neuronal mechanisms behind the symptoms we evaluated the brain processing of painful visceral stimuli., Methods: Evoked brain potentials were recorded to assess the response to painful oesophageal electrical stimuli in 15 healthy volunteers and 14 type-1 diabetes patients with autonomic neuropathy and related gastrointestinal symptoms. Source reconstruction analysis (fixed Multiple Signal Classification (MUSIC) algorithm) was applied to estimate the location of the evoked electrical activity in the brain., Results: The patients had increased oesophageal sensory thresholds compared to the controls (P=0.004). The latencies of the evoked brain potentials at vertex (Cz) were increased (P=0.007) and amplitudes reduced (P=0.011) in diabetics. Compared with controls the patients had a posterior shift of the electrical sources in the anterior cingulate cortex at 54 ms, and additional sources close to the posterior insula at 95 ms and in medial frontal gyrus at 184 ms., Conclusions: There is evidence of altered central processing to visceral stimulation, and both peripheral and central mechanisms seem involved. Central neuronal reorganisation may contribute to our understanding of the gastrointestinal symptoms in patients with diabetic autonomic neuropathy and this may guide development and evaluation of new treatment modalities., (Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)