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Background and Purpose: Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year., Methods: We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020)., Results: There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths., Conclusions: During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT.

The treatment of stroke has significantly improved over the past two decades, resulting in reduced mortality and morbidity in high-income countries. However, strokes remain the third leading cause of mortality and disability worldwide. In addition to acute care and the prevention of risk factors, treatment of the various persisting disabilities that impact the daily activities and quality of life of patients also remain important. Motor and language deficits affect everyday life most obviously. Other deficits may involve complex movements, sensory, and cognitive functions. Patients also often suffer from anxiety, fatigue, and depression.Established ergotherapeutic, physiotherapeutic, and logopedic programs exist for motor and language deficits for in-patient treatment as well as in the ambulatory setting. The diagnosis and treatment of cognitive impairments and behavioral disorders, however, are largely confined to the early rehabilitation phase. Despite indications of a long-term impairment of quality of life due to cognitive deficits and behavioral disorders, previous study results speak against drug-based antidepressant therapy in in-patient rehabilitation. Individual patient-reported outcomes, supported by screening for cognitive deficits and consideration of individual risk factors and coping strategies, could further improve the treatment of stroke and its long-term burden., (© 2022. Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature.)

Objectives: The probability of recurring strokes in patients with atrial fibrillation is high. Within 1.8 years, 6.6 % of the patients suffered a new stroke. While effective secondary prevention options exist, low adherence challenges effective medical treatment. The aim of our study was to examine the risk understanding of acute stroke patients and to find the best way to communicate risk reduction., Materials and Methods: Risk communication had three formats: a text, a pictogram, and a cube diagram. All three were developed on the basis of the criteria of evidence-based patient information. Patients who were admitted to the stroke unit and diagnosed with acute stroke, assessed the information material. Data on secondary prevention using acetylsalicylic acid were taken as an example, with no reference to actual patient treatment. In a first step, we interviewed a focus group to check the feasibility of the questionnaire (qualitative study). In the second step, the information material was tested in a pilot randomized controlled trial., Results: Acute stroke patients (qualitative study, n=13) understood the information and were interested in numerical risk communication. The visualized representations were superior in terms of understandability of the numbers communicated (pilot randomized controlled trial, n=60, 50 % correct answers for question 1, p value of 0.502, and 55 % correct answers for question 2, p value of 0.338). Stroke-related neurologic deficits, measured with the National Institute of Health Stroke Scale (NIHSS) on admission, revealed a significant influence on the number of correct answers to stroke risk questions, whereas the type of stroke and education did not., Conclusions: Acute stroke patients were able to understand risk communication. Visualization helped them capture information on stroke risk., (Copyright © 2022. Published by Elsevier GmbH.)

Objective: The aim was to analyse whether the association between carotid atherosclerosis (CA) and atrial fibrillation (AF), heart function, and renal function is mediated by traditional risk factors., Methods: In the prospective, single centre, long term, population based Hamburg City Health Study citizens, between 45 and 74 years of age were studied by cross sectional analysis of the first cohort. Laboratory values, blood pressure, heart rhythm, and body mass index (BMI) were examined. Carotid intima media thickness (CIMT) and plaques were assessed by carotid ultrasound, and CA was defined as either CIMT ≥ 1 mm or presence of plaques or both. N-terminal pro-brain natriuretic peptide (NT-proBNP), and glomerular filtration rate (eGFR) were quantified as measures of heart and renal function. Association between CA and AF, NT-proBNP, and eGFR was analysed by multivariable linear and logistic regression., Results: Of the first 10 000 participants, carotid ultrasound was available for 9 466 (95%). Of these, 2 937 (31%) had carotid plaques, 643 (7%) had CIMT ≥ 1 mm, and 412 (4%) presented with both, so that 3 168 (34%) had CA. Participants with CA had AF more frequently (9.6% vs. 4.3%; p < .001), higher levels of NT-proBNP (median 100 vs. 73 pg/mL; p < .001), and lower eGFR (82.8 vs. 87.1 mL/min; p < .001) than those without CA. Adjusted for age and sex, CA was associated with AF (p = .01; OR 1.29) and higher NT-proBNP levels (p < .001; β = 0.12), but not with eGFR. After further adjustment for vascular risk factors and history of cardiovascular diseases, CA remained associated with NT-proBNP (p < .001; β = 0.10), but additionally adjusted for NT-proBNP (p < .001; OR 2.80) not with AF., Conclusion: CA is independently associated with higher levels of NT-proBNP, through common risk factors and NT-proBNP with AF, and not with renal function. CA's association with a marker of cardiac dysfunction beyond known common risk factors supports the value of carotid ultrasound in defining patients' cardiovascular risk profile. The measures of CA, i.e., CIMT and carotid plaque, had an equally directed and additive influence., (Copyright © 2022 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Background: Patient-reported outcome measures (PROMs) assess patient-relevant effects of medical treatments. We aimed to evaluate the implementation of the International Consortium for Health Outcomes Measurement Standard Set for Stroke (ICHOM-SSS) into routine inpatient care of a stroke unit., Methods: The ICHOM-SSS was administered in a certified stroke unit during and after inpatient care. Semi-structured interviews with medical staff (n = 5) and patients or their proxies (n = 19) about their experience were audio-recorded and analysed using thematic analyses. Implementation outcomes were chosen in advance and adhered to current standards of implementation science., Results: Patients perceived the ICHOM-SSS to be relevant and feasible. They reported limited understanding of why the assessment was introduced. The overall acceptance of using PROMs was high. While medical staff, too, perceived the assessment to be appropriate and relevant, their appraisal of feasibility, sustainability, and their acceptance of the implementation were low., Conclusions: For a sustainable implementation of PROMs in clinical practice, IT resources need to be adapted, medical care needs to be reorganized, and additional clinical resources are required. Future research should investigate benefits of the ICHOM-SSS and a simpler, automated implementation in stroke care., Trial Registration: ClinicalTrials.gov Identifier: NCT03795948 , retrospectively registered on 8 January 2019., (© 2022. The Author(s).)

Aims: Long-term sequelae may occur after SARS-CoV-2 infection. We comprehensively assessed organ-specific functions in individuals after mild to moderate SARS-CoV-2 infection compared with controls from the general population., Methods and Results: Four hundred and forty-three mainly non-hospitalized individuals were examined in median 9.6 months after the first positive SARS-CoV-2 test and matched for age, sex, and education with 1328 controls from a population-based German cohort. We assessed pulmonary, cardiac, vascular, renal, and neurological status, as well as patient-related outcomes. Bodyplethysmography documented mildly lower total lung volume (regression coefficient -3.24, adjusted P = 0.014) and higher specific airway resistance (regression coefficient 8.11, adjusted P = 0.001) after SARS-CoV-2 infection. Cardiac assessment revealed slightly lower measures of left (regression coefficient for left ventricular ejection fraction on transthoracic echocardiography -0.93, adjusted P = 0.015) and right ventricular function and higher concentrations of cardiac biomarkers (factor 1.14 for high-sensitivity troponin, 1.41 for N-terminal pro-B-type natriuretic peptide, adjusted P ≤ 0.01) in post-SARS-CoV-2 patients compared with matched controls, but no significant differences in cardiac magnetic resonance imaging findings. Sonographically non-compressible femoral veins, suggesting deep vein thrombosis, were substantially more frequent after SARS-CoV-2 infection (odds ratio 2.68, adjusted P < 0.001). Glomerular filtration rate (regression coefficient -2.35, adjusted P = 0.019) was lower in post-SARS-CoV-2 cases. Relative brain volume, prevalence of cerebral microbleeds, and infarct residuals were similar, while the mean cortical thickness was higher in post-SARS-CoV-2 cases. Cognitive function was not impaired. Similarly, patient-related outcomes did not differ., Conclusion: Subjects who apparently recovered from mild to moderate SARS-CoV-2 infection show signs of subclinical multi-organ affection related to pulmonary, cardiac, thrombotic, and renal function without signs of structural brain damage, neurocognitive, or quality-of-life impairment. Respective screening may guide further patient management., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Introduction: Revascularization procedures in carotid artery stenosis have shown a positive effect in the restoration of cerebral oxygen metabolism as assessed by T2' (T2 prime) imaging as well as capillary homeostasis by measurement of capillary transit time heterogeneity (CTH); however, data in patients with asymptomatic carotid stenosis without manifest brain lesions are scarce., Patients and Methods: The effect of revascularization on the hemodynamic profile and capillary homeostasis was evaluated in 13 patients with asymptomatic high-grade carotid stenosis without ischemic brain lesions using dynamic susceptibility contrast perfusion imaging and oxygenation-sensitive T2' mapping before and 6-8 weeks after revascularization by endarterectomy or stenting. The cognitive performance at both timepoints was further assessed., Results: Perfusion impairment at baseline was accompanied by an increased CTH (p = 0.008) in areas with a time to peak delay ≥ 2 s in the affected hemisphere compared to contralateral regions. Carotid intervention improved the overall moderate hemodynamic impairment at baseline by leading to an increase in normalized cerebral blood flow (p = 0.017) and a decrease in mean transit time (p = 0.027), oxygen extraction capacity (OEC) (p = 0.033) and CTH (p = 0.048). The T2' values remained unchanged., Conclusion: This study presents novel evidence of a state of altered microvascular function in patients with high-grade carotid artery stenosis in the absence of ischemic brain lesions, which shows sustained normalization after revascularization procedures., (© 2021. The Author(s).)

Background: Fluid-attenuated inversion recovery (FLAIR) sequences have gained a role to guide treatment of patients with unknown time of stroke symptom onset. Evolution of signal intensities in FLAIR is associated with time since stroke onset with continuous linear increases., Aims: Estimating symptom onset during night-sleep in patients from the WAKE-UP trial based on relative signal intensities FLAIR (FLAIR-rSI) from acute stroke lesions an independent dataset (PRE-FLAIR study)., Methods: FLAIR-rSI was quantified in stroke lesions in PRE-FLAIR and WAKE-UP. The PRE-FLAIR study was a multicenter observational trial establishing FLAIR as a surrogate parameter for time since stroke onset. WAKE-UP was a randomized controlled trial that revealed a benefit for alteplase in patients selected based on a DWI-FLAIR mismatch. Stroke onset times were recorded in PRE-FLAIR and used to fit a linear regression model with FLAIR-rSI, adjusted for patient age and lesion volume. The model was applied to FLAIR-rSI of stroke lesions to estimate onset times in those patients enrolled in WAKE-UP who had symptom onset during night-sleep., Results: FLAIR-rSI was quantified in 399 patients from PRE-FLAIR. Linear regression indicated a significant association of age ( p  = 0.001), lesion volume ( p  = 0.005) and FLAIR-rSI ( p  < 0.001) with time since symptom onset (adjusted R 2  = 0.179). In 813 patients from WAKE-UP, distribution of times of last seen well, symptom recognition and MRI examination were recorded. Median times of last seen well were 1 h before midnight (IQR 2.4 h) and symptom recognition 7 h after midnight (IRQ 2.2 h). Based on the FLAIR-rSI profiles, we estimated median stroke onset 6.1 h after midnight (IQR 2.7 h)., Conclusion: Nocturnal strokes during night-sleep may predominantly occur during the early morning hours. Our results are in line with evidence of characteristic diurnal patterns of cardiovascular events.

Aging is accompanied by structural brain changes that are thought to underlie cognitive decline and dementia. Yet little is known regarding the association between increasing age, structural brain damage, and alterations of functional brain connectivity. The aim of this study was to evaluate whether cortical thickness and white matter damage as markers of age-related structural brain changes are associated with alterations in functional connectivity in non-demented healthy middle-aged to older adults. Therefore, we reconstructed functional connectomes from resting-state functional magnetic resonance imaging (MRI) (rsfMRI) data of 976 subjects from the Hamburg City Health Study, a prospective population-based study including participants aged 45-74 years from the metropolitan region Hamburg, Germany. We performed multiple linear regressions to examine the association of age, cortical thickness, and white matter damage quantified by the peak width of skeletonized mean diffusivity (PSMD) from diffusion tensor imaging on whole-brain network connectivity and four predefined resting state networks (default mode, dorsal, salience, and control network). In a second step, we extracted subnetworks with age-related decreased functional connectivity from these networks and conducted a mediation analysis to test whether the effect of age on these networks is mediated by decreased cortical thickness or PSMD. We observed an independent association of higher age with decreased functional connectivity, while there was no significant association of functional connectivity with cortical thickness or PSMD. Mediation analysis identified cortical thickness as a partial mediator between age and default subnetwork connectivity and functional connectivity within the default subnetwork as a partial mediator between age and executive cognitive function. These results indicate that, on a global scale, functional connectivity is not determined by structural damage in healthy middle-aged to older adults. There is a weak association of higher age with decreased functional connectivity which, for specific subnetworks, appears to be mediated by cortical thickness., Competing Interests: The authors declare that this study received funding from Amgen, Astra Zeneca, Bayer, Badischen Anilin & Sodafabrik (BASF), Novartis, Pfizer, Schiller, Siemens, and Unilever. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication., (Copyright © 2022 Schulz, Mayer, Schlemm, Frey, Malherbe, Petersen, Gallinat, Kühn, Fiehler, Hanning, Twerenbold, Gerloff, Cheng and Thomalla.)

Analyses of alterations of brain networks have gained an increasing interest in stroke rehabilitation research. Compared with functional networks derived from resting-state analyses, there is limited knowledge of how structural network topology might undergo changes after stroke and, more importantly, if structural network information obtained early after stroke could enhance recovery models to infer later outcomes. The present work re-analysed cross-sectional structural imaging data, obtained within the first 2 weeks, of 45 acute stroke patients (22 females, 24 right-sided strokes, age 68 ± 13 years). Whole-brain tractography was performed to reconstruct structural connectomes and graph-theoretical analyses were employed to quantify global network organization with a focus on parameters of network integration and modular processing. Graph measures were compared between stroke patients and 34 healthy controls (15 females, aged 69 ± 10 years) and they were integrated with four clinical scores of the late subacute stage, covering neurological symptom burden (National Institutes of Health Stroke Scale), global disability (modified Rankin Scale), activity-related disability (Barthel Index) and motor functions (Upper-Extremity Score of the Fugl-Meyer Assessment). The analyses were employed across the complete cohort and, based on clustering analysis, separately within subgroups stratified in mild to moderate ( n  = 21) and severe ( n  = 24) initial deficits. The main findings were (i) a significant reduction of network's global efficiency, specifically in patients with severe deficits compared with controls ( P  = 0.010) and (ii) a significant negative correlation of network efficiency with the extent of persistent functional deficits at follow-up after 3-6 months ( P  ≤ 0.032). Specifically, regression models revealed that this measure was capable to increase the explained variance in future deficits by 18% for the modified Rankin Scale, up to 24% for National Institutes of Health Stroke Scale, and 16% for Barthel Index when compared with models including the initial deficits and the lesion volume. Patients with mild to moderate deficits did not exhibit a similar impact of network efficiency on outcome inference. Clustering coefficient and modularity, measures of segregation and modular processing, did not exhibit comparable structure-outcome relationships, neither in severely nor in mildly affected patients. This study provides empirical evidence that structural network efficiency as a graph-theoretical marker of large-scale network topology, quantified early after stroke, relates to recovery. Notably, this contribution was only evident in severely but not mildly affected stroke patients. This suggests that the initial clinical deficit might shape the dependency of recovery on global network topology after stroke., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Cerebral small vessel disease (CSVD) is a common cause of morbidity and cognitive decline in the elderly population. However, characterizing the disease pathophysiology and its association with potential clinical sequelae in early stages is less well explored. We applied fixel-based analysis (FBA), a novel framework of investigating microstructural white matter integrity by diffusion-weighted imaging, to data of 921 participants of the Hamburg City Health Study, comprising middle-aged individuals with increased cerebrovascular risk in early stages of CSVD. In individuals in the highest quartile of white matter hyperintensity loads (n = 232, median age 63 years; IQR 15.3 years), FBA detected significantly reduced axonal density and increased atrophy of transcallosal fiber tracts, the bilateral superior longitudinal fasciculus, and corticospinal tracts compared to participants in the lowest quartile of white matter hyperintensities (n = 228, mean age 55 years; IQR 10 years). Analysis of all participants (N = 921) demonstrated a significant association between reduced fiber density and worse executive functions operationalized by the Trail Making Test. Findings were confirmed by complementary analysis of diffusion tensor metrics., (© 2022. The Author(s).)

Background and Objectives: Cerebral microbleeds (CMBs) are common in patients with acute ischemic stroke and are associated with increased risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis. Whether CMBs modify the treatment effect of thrombolysis is unknown., Methods: We performed a prespecified analysis of the prospective randomized controlled multicenter Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial including patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch on MRI receiving alteplase or placebo. Patients were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). Patients were randomized to treatment with IV thrombolysis with alteplase at 0.9 mg/kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by 3 raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale (mRS) score ≤1, and symptomatic ICH according to National Institutes of Neurological Disease and Stroke trial criteria 22 to 36 hours after treatment., Results: Of 503 patients enrolled in the WAKE-UP trial, 459 (91.3%; 288 [63%] men) were available for analysis. Ninety-eight (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB; 37 (8.1%) had 2 to 4 CMBs; and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a nonsignificant increased risk of symptomatic ICH (11.2% vs 4.2%; adjusted odds ratio [OR] 2.32, 95% confidence interval [CI] 0.99-5.43, p = 0.052) but had no effect on functional outcome at 90 days (mRS score ≤1: 45.8% vs 50.7%; adjusted OR 0.99, 95% CI 0.59-1.64, p = 0.955). Patients receiving alteplase had better functional outcome (mRS score ≤1: 54.6% vs 44.6%, adjusted OR 1.61, 95% CI 1.07-2.43, p = 0.022) without evidence of heterogeneity in relation to CMB presence ( p of the interactive term = 0.546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy related) or not strictly lobar CMB distribution., Discussion: In the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in patients with acute ischemic stroke with ≥1 CMBs. Additional studies are needed to determine the treatment effect of alteplase and its benefit-harm ratio in patients with a larger number of CMBs., Trial Registration Information: ClinicalTrials.gov identifier NCT01525290; ClinicalTrialsRegister.EU identifier 2011-005906-32., Classification of Evidence: This study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Purpose: Rapid access to acute stroke treatment improves clinical outcomes in patients with ischemic stroke. We aimed to shorten the time to admission and to acute stroke treatment for patients with acute stroke in the Hamburg metropolitan area by collaborative multilevel measures involving all hospitals with stroke units, the Emergency Medical Services (EMS), and health-care authorities., Methods: In 2007, an area-wide stroke care quality project was initiated. The project included mandatory admission of all stroke patients in Hamburg exclusively to hospitals with stroke units, harmonized acute treatment algorithms among all hospitals, repeated training of the EMS staff, a multimedia educational campaign, and a mandatory stroke care quality monitoring system based on structured data assessment and quality indicators for procedural measures. We analyzed data of all patients with acute stroke who received inhospital treatment in the city of Hamburg during the evaluation period from the quality assurance database data and evaluated trends of key quality indicators over time., Results: From 2007 to 2016, a total of 83,395 patients with acute stroke were registered. During this period, the proportion of patients admitted within ≤3 h from symptom onset increased over time from 27.8% in 2007 to 35.2% in 2016 (p < 0.001). The proportion of patients who received rapid thrombolysis (within ≤30 min after admission) increased from 7.7 to 54.1% (p < 0.001)., Conclusions: Collaborative stroke care quality projects are suitable and effective to improve acute stroke care., (© 2021 S. Karger AG, Basel.)

Background and Purpose: Cardiac ultrasound to identify sources of cardioembolism is part of the diagnostic workup of acute ischemic stroke. Recommendations on whether transesophageal echocardiography (TEE) should be performed in addition to transthoracic echocardiography (TTE) are controversial. We aimed to determine the incremental diagnostic yield of TEE in addition to TTE in patients with acute ischemic stroke with undetermined cause., Methods: In a prospective, observational, pragmatic multicenter cohort study, patients with acute ischemic stroke or transient ischemic attack with undetermined cause before cardiac ultrasound were studied by TTE and TEE. The primary outcome was the rate of treatment-relevant findings in TTE and TEE as defined by a panel of experts based on current evidence. Further outcomes included the rate of changes in the assessment of stroke cause after TEE., Results: Between July 1, 2017, and June 30, 2019, we enrolled 494 patients, of whom 492 (99.6%) received TTE and 454 (91.9%) received TEE. Mean age was 64.7 years, and 204 (41.3%) were women. TEE showed a higher rate of treatment-relevant findings than TTE (86 [18.9%] versus 64 [14.1%], P <0.001). TEE in addition to TTE resulted in 29 (6.4%) additional patients with treatment-relevant findings. Among 191 patients ≤60 years additional treatment-relevant findings by TEE were observed in 27 (14.1%) patients. Classification of stroke cause changed after TEE in 52 of 453 patients (11.5%), resulting in a significant difference in the distribution of stroke cause before and after TEE ( P <0.001)., Conclusions: In patients with undetermined cause of stroke, TEE yielded a higher number of treatment-relevant findings than TTE. TEE appears especially useful in younger patients with stroke, with treatment-relevant findings in one out of seven patients ≤60 years., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03411642.

Background and Purpose: Patients presenting in the extended time window may benefit from mechanical thrombectomy. However, selection for mechanical thrombectomy in this patient group has only been performed using specialized image processing platforms, which are not widely available. We hypothesized that quantitative lesion water uptake calculated in acute stroke computed tomography (CT) may serve as imaging biomarker to estimate ischemic lesion progression and predict clinical outcome in patients undergoing mechanical thrombectomy in the extended time window., Methods: All patients with ischemic anterior circulation stroke presenting within 4.5 to 24 hours after symptom onset who received initial multimodal CT between August 2014 and March 2020 and underwent mechanical thrombectomy were analyzed. Quantitative lesion net water uptake was calculated from the admission CT. Prediction of clinical outcome was assessed using univariable receiver operating characteristic curve analysis and logistic regression analyses., Results: One hundred two patients met the inclusion criteria. In the multivariable logistic regression analysis, net water uptake (odds ratio, 0.78 [95% CI, 0.64-0.95], P =0.01), age (odds ratio, 0.94 [95% CI, 0.88-0.99]; P =0.02), and National Institutes of Health Stroke Scale (odds ratio, 0.88 [95% CI, 0.79-0.99], P =0.03) were significantly and independently associated with favorable outcome (modified Rankin Scale score ≤1), adjusted for degree of recanalization and Alberta Stroke Program Early CT Score. A multivariable predictive model including the above parameters yielded the highest diagnostic ability in the classification of functional outcome, with an area under the curve of 0.88 (sensitivity 92.3%, specificity 82.9%)., Conclusions: The implementation of quantitative lesion water uptake as imaging biomarker in the diagnosis of patients with ischemic stroke presenting in the extended time window might improve clinical prognosis. Future studies could test this biomarker as complementary or even alternative tool to CT perfusion.

Introduction: Chronic cerebral hypoperfusion caused by asymptomatic high-grade stenosis of the internal carotid artery (ICA) has been associated with impaired cognitive function. Only few studies exist on underlying changes of functional connectivity (FC)., Methods: 20 patients with unilateral high-grade ICA stenosis without MRI lesions and 25 aged-match controls underwent resting-state functional MRI (rsfMRI) and neuropsychological assessment. Patients were examined within ten days before and 6-10 weeks after surgical or interventional revascularization of carotid stenosis. We examined mean resting-state FC ipsi- and contralateral to stenosis and network topology using graph-theoretical measures., Results: At baseline, intrahemispheric FC was similar for patients and healthy controls. After revascularization mean FC increased moderately without an effect on network topology. Patients performed worse in TMT B and Stroop test, while performance in global screening tests for dementia (Mini Mental Status Examination, DemTect) were comparable. Test results did not improve after revascularization., Conclusion: In our study population, we find no effect of chronic hypoperfusion on FC and global cognitive function, although we observe minor impairments in processing speed and mental flexibility. The subtle increase of FC after revascularization could indicate excessive upregulation after restoration of perfusion. However, it might as well be a coincidental finding due to the limited sample size., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Impaired motor functions after stroke are common and negatively affect patients' activities of daily living and quality of life. In particular, hand motor function is essential for daily activities, but often returns slowly and incompletely after stroke. However, few data are available on the long-term dynamics of motor recovery and self-reported health status after stroke. The Interdisciplinary Platform for Rehabilitation Research and Innovative Care of Stroke Patients (IMPROVE) project aims to address this knowledge gap by studying the clinical course of recovery after inpatient rehabilitation., Methods: In this prospective observational longitudinal multicenter study, patients were included towards the end of inpatient rehabilitation after ischemic or hemorrhagic stroke. Follow-up examination was performed at three, six, and twelve months after enrollment. Motor function was assessed by the Upper Extremity Fugl-Meyer Assessment (FMA), grip and pinch strength, and the nine-hole peg test. In addition, Patient-Reported Outcomes Measurement Information System 10-Question Short Form (PROMIS-10) was included. Linear mixed effect models were fitted to analyze change over time. To study determinants of hand motor function, patients with impaired hand function at baseline were grouped into improvers and non-improvers according to hand motor function after twelve months., Results: A total of 176 patients were included in the analysis. Improvement in all motor function scores and PROMIS-10 was shown up to 1 year after inpatient rehabilitation. FMA scores improved by an estimate of 5.0 (3.7-6.4) points per year. In addition, patient-reported outcome measures increased by 2.5 (1.4-3.6) and 2.4 (1.4-3.4) per year in the physical and mental domain of PROMIS-10. In the subgroup analysis non-improvers showed to be more often female (15% vs. 55%, p = 0.0155) and scored lower in the Montreal Cognitive Assessment (25 [23-27] vs. 22 [20.5-24], p = 0.0252)., Conclusions: Continuous improvement in motor function and self-reported health status is observed up to 1 year after inpatient stroke rehabilitation. Demographic and clinical parameters associated with these improvements need further investigation. These results may contribute to the further development of the post-inpatient phase of stroke rehabilitation., Trial Registration: The trial is registered at ClinicalTrials.gov (NCT04119479)., (© 2021. The Author(s).)

Background and Purpose: The aim of this study was to examine whether sphingosine-1-phosphate (S1P) levels in patients with acute stroke are associated with stroke severity and outcome., Methods: In a prospective stroke cohort (MARK-STROKE), 374 patients with acute ischemic stroke or transient ischemic attack were enrolled (mean age: 67.9±13.0 years, sex: 64.7% male), and serum-S1P at admission was analyzed with tandem mass spectrometry. In addition to cross-sectional analyses, 79 adverse events (death, stroke, myocardial infarction, rehospitalization) were recorded in 270 patients during follow-up. Regression analyses were adjusted for age, sex, low-density lipoprotein cholesterol, and vascular risk factors. Results were validated in an independent stroke cohort with 219 patients with acute ischemic stroke (CIRCULAS)., Results: Low serum-S1P was associated with higher National Institutes of Health Stroke Scale score at admission and with anterior circulation nonlacunar infarcts determined by multivariate regression analyses. During a follow-up of 294±170 days, patients with S1P in the lowest tertile (<1.33 µmol/L) had more adverse events (Kaplan-Meier analysis, P =0.048 for trend). In adjusted Cox regression analysis, the lowest S1P tertile was associated with a worse outcome after stroke (hazard ratio, HR 0.51 [95% confidence interval 0.28-0.92]). Results were confirmed in an independent cohort, ie, low S1P levels were associated with higher National Institutes of Health Stroke Scale, larger infarct volumes and worse outcome after 90 days (β-coefficient: -0.03, P =0.026; β-coefficient: -0.099, P =0.009 and odds ratio 0.52 [0.28-0.96], respectively)., Conclusions: Our findings imply a detrimental role of low S1P levels in acute stroke and therefore underpin the therapeutic potential of S1P-mimics.

Purpose: The aim of this study was to analyze sex differences in outcome after thrombectomy for acute ischemic stroke in clinical practice in a large prospective multicenter registry., Methods: Data of consecutive stroke patients treated with thrombectomy (June 2015-April 2018) derived from an industry-independent registry (German Stroke Registry-Endovascular Treatment) were prospectively analyzed. Multivariable binary logistic regression analyses were applied to determine whether sex is a predictor of functional independence outcome (defined as a modified Rankin scale [mRS] 0-2) 90 days after stroke., Results: In total, 2316 patients were included in the analysis, 1170 (50.5%) were female and 1146 (49.5%) were male. Women were older (median age 78 vs. 72 years; p < 0.001) and more frequently had a prestroke functional impairment defined by mRS >1 (24.8% vs. 14.1%; p < 0.001). In unadjusted analyses, independent outcome at 90 days was less frequent in women (33.2%) than men (40.6%; p < 0.001). Likewise, mortality was higher in women than in men (30.7% vs. 26.4%; p = 0.024). In adjusted regression analyses, however, sex was not associated with outcome. Lower age, a lower baseline National Institutes of Health Stroke Scale score, a higher Alberta Stroke Program Early CT score, prestroke functional independence, successful reperfusion, and concomitant intravenous thrombolysis therapy predicted independent outcome., Conclusion: Women showed a worse functional outcome after thrombectomy for acute ischemic stroke in clinical practice; however, after adjustment for crucial confounders sex was not a predictor of outcome. The difference in outcome thus appears to result from differences in confounding factors such as age and prestroke functional status., (© 2020. The Author(s).)

Purpose: Evaluating the extent of cerebral ischemic infarction is essential for treatment decisions and assessment of possible complications in patients with acute ischemic stroke. Patients are often triaged according to image-based early signs of infarction, defined by Alberta Stroke Program Early CT Score (ASPECTS). Our aim was to evaluate interrater reliability in a large group of readers., Methods: We retrospectively analyzed 100 investigators who independently evaluated 20 non-contrast computed tomography (NCCT) scans as part of their qualification program for the TENSION study. Test cases were chosen by four neuroradiologists who had previously scored NCCT scans with ASPECTS between 0 and 8 and high interrater agreement. Percent and interrater agreements were calculated for total ASPECTS, as well as for each ASPECTS region., Results: Percent agreements for ASPECTS ratings was 28%, with interrater agreement of 0.13 (95% confidence interval, CI 0.09-0.16), at zero tolerance allowance and 66%, with interrater agreement of 0.32 (95% CI: 0.21-0.44), at tolerance allowance set by TENSION inclusion criteria. ASPECTS region with highest level of agreement was the insular cortex (percent agreement = 96%, interrater agreement = 0.96 (95% CI: 0.94-0.97)) and with lowest level of agreement the M3 region (percent agreement = 68%, interrater agreement = 0.39 [95% CI: 0.17-0.61])., Conclusion: Interrater agreement reliability for total ASPECTS and study enrollment was relatively low but seems sufficient for practical application. Individual region analysis suggests that some are particularly difficult to evaluate, with varying levels of reliability. Potential impairment of the supraganglionic region must be examined carefully, particularly with respect to the decision whether or not to perform mechanical thrombectomy., (© 2021. The Author(s).)

Background and Purpose: During the first days and weeks after an acute ischemic stroke, patients are prone to complications that can influence further treatment, recovery, and functional outcome. In clinical trials, severe complications are recorded as serious adverse events (SAE). We analyzed the effect of SAE on functional outcome and predictors of SAE in the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke)., Methods: We performed a post hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled clinical trial of magnetic resonance imaging-guided intravenous thrombolysis with alteplase in patients with acute ischemic stroke and unknown time of onset. Functional outcome was assessed by the modified Rankin Scale 90 days after the stroke. SAE were reported to a central safety desk and recorded and categorized by organ system using Medical Dictionary for Regulatory Activities terminology. We used logistic regression analysis to determine the effect of SAE on functional outcome and linear multiple regression analysis to identify baseline predictors of SAE., Results: Among 503 patients randomized, 199 SAE were reported for n=110 (22%) patients. Of those patients who did suffer a SAE, 20 (10%) had a fatal outcome. Patients suffering from at least one SAE had a lower odds of reaching a favorable outcome (modified Rankin Scale score of 0-1) at 90 days (adjusted odds ratio, 0.36 [95% CI, 0.21-0.61], P <0.001). Higher age ( P =0.04) and male sex ( P =0.01) were predictors for the occurrence of SAE., Conclusions: SAEs were observed in about one in 5 patients, were more frequent in elderly and male patients and were associated with worse functional outcome. These results may help to assess the risk of SAE in future stroke trials and create awareness for severe complications after stroke in clinical practice. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://eudract.ema.europa.eu; Unique identifier: 2011-005906-32.

Background and Purpose: Cortical beta oscillations are reported to serve as robust measures of the integrity of the human motor system. Their alterations after stroke, such as reduced movement-related beta desynchronization in the primary motor cortex, have been repeatedly related to the level of impairment. However, there is only little data whether such measures of brain function might directly relate to structural brain changes after stroke., Methods: This multimodal study investigated 18 well-recovered patients with stroke (mean age 65 years, 12 males) by means of task-related EEG and diffusion-weighted structural MRI 3 months after stroke. Beta power at rest and movement-related beta desynchronization was assessed in 3 key motor areas of the ipsilesional hemisphere that are the primary motor cortex (M1), the ventral premotor area and the supplementary motor area. Template trajectories of corticospinal tracts (CST) originating from M1, premotor cortex, and supplementary motor area were used to quantify the microstructural state of CST subcomponents. Linear mixed-effects analyses were used to relate tract-related mean fractional anisotropy to EEG measures., Results: In the present cohort, we detected statistically significant reductions in ipsilesional CST fractional anisotropy but no alterations in EEG measures when compared with healthy controls. However, in patients with stroke, there was a significant association between both beta power at rest ( P =0.002) and movement-related beta desynchronization ( P =0.003) in M1 and fractional anisotropy of the CST specifically originating from M1. Similar structure-function relationships were neither evident for ventral premotor area and supplementary motor area, particularly with respect to their CST subcomponents originating from premotor cortex and supplementary motor area, in patients with stroke nor in controls., Conclusions: These data suggest there might be a link connecting microstructure of the CST originating from M1 pyramidal neurons and beta oscillatory activity, measures which have already been related to motor impairment in patients with stroke by previous reports.

We hypothesized that imaging-only-based machine learning algorithms can analyze non-enhanced CT scans of patients with acute intracerebral hemorrhage (ICH). This retrospective multicenter cohort study analyzed 520 non-enhanced CT scans and clinical data of patients with acute spontaneous ICH. Clinical outcome at hospital discharge was dichotomized into good outcome and poor outcome using different modified Rankin Scale (mRS) cut-off values. Predictive performance of a random forest machine learning approach based on filter- and texture-derived high-end image features was evaluated for differentiation of functional outcome at mRS 2, 3, and 4. Prediction of survival (mRS ≤ 5) was compared to results of the ICH Score. All models were tuned, validated, and tested in a nested 5-fold cross-validation approach. Receiver-operating-characteristic area under the curve (ROC AUC) of the machine learning classifier using image features only was 0.80 (95% CI [0.77; 0.82]) for predicting mRS ≤ 2, 0.80 (95% CI [0.78; 0.81]) for mRS ≤ 3, and 0.79 (95% CI [0.77; 0.80]) for mRS ≤ 4. Trained on survival prediction (mRS ≤ 5), the classifier reached an AUC of 0.80 (95% CI [0.78; 0.82]) which was equivalent to results of the ICH Score. If combined, the integrated model showed a significantly higher AUC of 0.84 (95% CI [0.83; 0.86], P value <0.05). Accordingly, sensitivities were significantly higher at Youden Index maximum cut-offs (77% vs. 74% sensitivity at 76% specificity, P value <0.05). Machine learning-based evaluation of quantitative high-end image features provided the same discriminatory power in predicting functional outcome as multidimensional clinical scoring systems. The integration of conventional scores and image features had synergistic effects with a statistically significant increase in AUC., (© 2021. The Author(s).)

Background Randomized controlled clinical trials (RCT) have demonstrated the efficacy of endovascular treatment in anterior circulation large vessel occlusions. However, outcome of patients treated in daily practice differs from the results of the clinical trials. We hypothesize that this is attributable to the study criteria and that application of the criteria on patients undergoing endovascular therapy in daily routine would improve their outcome. Methods and Results Data from a multicenter prospective registry of GSR-ET (German Stroke Registry - Endovascular Treatment) was used. Inclusion criteria and selectivity of SWIFT-PRIME (Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment trial), MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands trial), ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times trial), DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo trial) and DEFUSE-3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke trial) trials were analyzed. Baseline characteristics, procedural and outcome data of patients from GSR-ET before and after selection were compared with the results of the RCTs. Furthermore, outcome of patients who underwent endovascular treatment despite not fulfilling the RCT criteria was analyzed. A total of 2611 patients were included (median age, 75 years; 49.6% women; median National Institute of Health Stroke Scale, 16). A minority of patients met all inclusion criteria, ranging from 3% (DEFUSE-3 criteria) to 35% (MR CLEAN criteria). Of the patients fulfilling the MR CLEAN criteria, 41% of patients had a good clinical outcome, compared with 34% of patients that did not fulfill MR CLEAN criteria. Conclusions The RCTs represent a selected population with higher rates of good clinical outcome compared with daily practice. The good outcomes of RCTs can be reproduced in clinical routine in patients who fulfill the RCT inclusion criteria. Furthermore, patients who did not meet the criteria of the RCT still had substantial rates of good clinical outcome.

Importance: Some patients have poor outcomes despite small infarcts after endovascular therapy (EVT), while others with large infarcts do well. Understanding why these discrepancies occur may help to optimize EVT outcomes., Objective: To validate exploratory findings from the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial regarding pretreatment, treatment-related, and posttreatment factors associated with discrepancies between follow-up infarct volume (FIV) and 90-day functional outcome., Design, Setting, and Participants: This cohort study is a post hoc analysis of the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, a double-blind, randomized, placebo-controlled, international, multicenter trial conducted from March 2017 to August 2019. Patients who participated in ESCAPE-NA1 and had available 90-day modified Rankin Scale (mRS) scores and 24-hour to 48-hour posttreatment follow-up parenchymal imaging were included., Exposures: Small FIV (volume ≤25th percentile) and large FIV (volume ≥75th percentile) on 24-hour computed tomography/magnetic resonance imaging. Baseline factors, outcomes, treatments, and poststroke serious adverse events (SAEs) were compared between discrepant cases (ie, patients with 90-day mRS score ≥3 despite small FIV or those with mRS scores ≤2 despite large FIV) and nondiscrepant cases., Main Outcomes and Measures: Area under the curve (AUC) and goodness of fit of prespecified logistic models, including pretreatment (eg, age, cancer, vascular risk factors) and treatment-related and posttreatment (eg, SAEs) factors, were compared with stepwise regression-derived models for ability to identify small FIV with higher mRS score and large FIV with lower mRS score., Results: Among 1091 patients (median [IQR] age, 70.8 [60.8-79.8] years; 549 [49.7%] women; median [IQR] FIV, 24.9 mL [6.6-92.2 mL]), 42 of 287 patients (14.6%) with FIV of 7 mL or less (ie, ≤25th percentile) had an mRS score of at least 3; 65 of 275 patients (23.6%) with FIV of 92 mL or greater (ie, ≥75th percentile) had an mRS score of 2 or less. Prespecified models of pretreatment factors (ie, age, cancer, vascular risk factors) associated with low FIV and higher mRS score performed similarly to models selected by stepwise regression (AUC, 0.92 [95% CI, 0.89-0.95] vs 0.93 [95% CI, 0.90-0.95]; P = .42). SAEs, specifically infarct in new territory, recurrent stroke, pneumonia, and congestive heart failure, were associated with low FIV and higher mRS scores; stepwise models also identified 24-hour hemoglobin as treatment-related/posttreatment factor (AUC, 0.92 [95% CI, 0.90-0.95] vs 0.94 [95% CI, 0.91-0.96]; P = .14). Younger age was associated with high FIV and lower mRS score; stepwise models identified absence of diabetes and higher baseline hemoglobin as additional pretreatment factors (AUC, 0.76 [95% CI, 0.70-0.82] vs 0.77 [95% CI, 0.71-0.83]; P = .82). Absence of SAEs, especially stroke progression, symptomatic intracerebral hemorrhage, and pneumonia, was associated with high FIV and lower mRS score2; stepwise models also identified 24-hour hemoglobin level, glucose, and diastolic blood pressure as posttreatment factors associated with discrepant cases (AUC, 0.80 [95% CI, 0.74-0.87] vs 0.79 [95% CI, 0.72-0.86]; P = .92)., Conclusions and Relevance: In this study, discrepancies between functional outcome and post-EVT infarct volume were associated with differences in pretreatment factors, such as age and comorbidities, and posttreatment complications related to index stroke evolution, secondary prevention, and quality of stroke unit care. Besides preventing such complications, optimization of blood pressure, glucose levels, and hemoglobin levels are potentially modifiable factors meriting further study.

Objectives: Patients waking up with stroke symptoms are often excluded from intravenous thrombolysis with alteplase (IV-tpa). The WAKE-UP trial, a European multicenter randomized controlled trial, proved the clinical effectiveness of magnetic resonance imaging-guided IV-tpa for these patients. This analysis aimed to assess the cost-effectiveness of the intervention compared to placebo., Methods: A Markov model was designed to analyze the cost-effectiveness over a 25-year time horizon. The model consisted of an inpatient acute care phase and a rest-of-life phase. Health states were defined by the modified Rankin Scale (mRS). Initial transition probabilities to mRS scores were based on WAKE-UP data and health state utilities on literature search. Costs were based on data from the University Medical Center Hamburg-Eppendorf, literature, and expert opinion. Incremental costs and effects over the patients' lifetime were estimated. The analysis was conducted from a formal German healthcare perspective. Univariate and probabilistic sensitivity analyses were performed., Results: Treatment with IV-tpa resulted in cost savings of €51 009 and 1.30 incremental gains in quality-adjusted life-years at a 5% discount rate. Univariate sensitivity analysis revealed incremental cost-effectiveness ratio being sensitive to the relative risk of favorable outcome on mRS for placebo patients after stroke, the costs of long-term care for patients with mRS 4, and patient age at initial stroke event. In all cases, IV-tpa remained cost-effective. Probabilistic sensitivity analysis proved IV-tpa cost-effective in >95% of the simulations results., Conclusions: Magnetic resonance imaging-guided IV-tpa compared to placebo is cost-effective in patients with ischemic stroke with unknown time of onset., (Copyright © 2021 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Recent developments of higher-order diffusion-weighted imaging models have enabled the estimation of specific white matter fiber populations within a voxel, addressing limitations of traditional imaging markers of white matter integrity. We applied fixel based analysis (FBA) to investigate the evolution of fiber-specific white matter changes in a prospective study of stroke patients and upper limb motor deficit over 1 year after stroke. We studied differences in fiber density and macrostructural changes in fiber cross-section. Motor function was assessed by grip strength. We conducted a whole-brain analysis of fixel metrics and predefined corticospinal tract (CST) region of interest in relation to changes in motor functions. In 30 stroke patients (mean age 62.3 years, SD ±16.9; median NIHSS 4, IQR 2-5), whole-brain FBA revealed progressing loss of fiber density and cross-section in the ipsilesional corticospinal tract and long-range fiber tracts such as the superior longitudinal fascicle and trans-callosal tracts extending towards contralesional white matter tracts. Lower FBA metrics measured at the brainstem section of the CST 1 month after stroke were significantly associated with lower grip strength 3 months (p = .009, adjusted R 2  = 0.259) and 1 year (T4: p < .001, adj. R 2  = 0.515) after stroke. Compared to FA, FBA metrics showed a comparably strong association with grip strength at later time points. Using FBA, we demonstrate progressive fiber-specific white matter loss after stroke and association with functional motor outcome. Our results promote the application of fiber-specific analysis to detect secondary neurodegeneration after stroke in relation to clinical recovery., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: Thrombus microfragmentation causing peripheral emboli (PE) during mechanical thrombectomy (MT) may modulate treatment effects, even in cases with successful reperfusion. This study aims to investigate whether intravenous alteplase is of potential benefit in reducing PE after successful MT., Methods: Patients from a prospective study treated at a tertiary care stroke center between 08/2017 and 12/2019 were analyzed. The main inclusion criterion was successful reperfusion after MT (defined as expanded thrombolysis in cerebral infarction (eTICI) scale ≥ 2b50) of large vessel occlusion anterior circulation stroke. All patients received a high-resolution diffusion-weighted imaging (DWI) follow-up 24 h after MT for PE detection. Patients were grouped as "direct MT" (no alteplase) or as MT plus additional intravenous alteplase. The number and volume of ischemic core lesions and PE were then quantified and analyzed., Results: Fifty-six patients were prospectively enrolled. Additional intravenous alteplase was administered in 46.3% (26/56). There were no statistically significant differences of PE compared by groups of direct MT and additional intravenous alteplase administration regarding mean numbers (12.1, 95% CI 8.6-15.5 vs. 11.1, 95% CI 7.0-15.1; p = 0.701), and median volume (0.70 mL, IQR 0.21-1.55 vs. 0.39 mL, IQR 0.10-1.62; p = 0.554). In uni- and multivariable linear regression analysis, higher eTICI scores were significantly associated with reduced PE, while the administration of alteplase was neither associated with numbers nor volume of peripheral emboli. Additional alteplase did not alter reperfusion success., Conclusions: Intravenous alteplase neither affects the number nor volume of sub-angiographic DWI-PE after successful endovascular reperfusion. In the light of currently running randomized trials, further studies are warranted to validate these findings., Key Points: • Thrombus microfragmentation during endovascular stroke treatment may cause peripheral emboli that are only detectable on diffusion-weighted imaging and may directly compromise treatment effects. • In this prospective study, the application of intravenous alteplase did not influence the occurrence of peripheral emboli detected on high-resolution diffusion-weighted imaging. • A higher degree of recanalization was associated with a reduced number and volume of peripheral emboli and better functional outcome, while contrariwise, peripheral emboli did not modify the effect of recanalization on modified Rankin Scale scores at day 90., (© 2021. The Author(s).)

Background: Ischemic water uptake in acute stroke is a reliable indicator of lesion age. Nevertheless, inter-individually varying edema progression has been observed and elevated water uptake has recently been described as predictor of malignant infarction., Aims: We hypothesized that early-elevated lesion water uptake indicates accelerated "tissue clock" desynchronized with "time clock" and therefore predicts poor clinical outcome despite successful recanalization., Methods: Acute middle cerebral artery stroke patients with multimodal admission-CT who received successful thrombectomy (TICI 2b/3) were analyzed. Net water uptake (NWU), a quantitative imaging biomarker of ischemic edema, was determined in admission-CT and tested as predictor of clinical outcome using modified Rankin Scale (mRS) after 90 days. A binary outcome was defined for mRS 0-4 and mRS 5-6., Results: Seventy-two patients were included. The mean NWU (SD) in patients with mRS 0-4 was lower compared to patients with mRS 5-6 (5.0% vs. 12.1%; p  < 0.001) with similar time from symptom onset to imaging (2.6 h vs. 2.4 h; p  = 0.7). Based on receiver operating curve analysis, NWU above 10% identified patients with very poor outcome with high discriminative power (AUC 0.85), followed by Alberta Stroke Program Early CT Score (ASPECTS) (AUC: 0.72) and National Institutes of Health Stroke Scale (NIHSS) (AUC: 0.72)., Conclusions: Quantitative NWU may serve as an indicator of "tissue clock" and pronounced early brain edema with elevated NWU might suggest a desynchronized "tissue clock" with real "time clock" and therefore predict futile recanalization with poor clinical outcome.

Background and Purpose: This study evaluates the benefit of endovascular treatment (EVT) for patients with extensive baseline stroke compared with best medical treatment., Methods: This retrospective, multicenter study compares EVT and best medical treatment for computed tomography (CT)–based selection of patients with extensive baseline infarcts (Alberta Stroke Program Early CT Score ≤5) attributed to anterior circulation stroke. Patients were selected from the German Stroke Registry and 3 tertiary stroke centers. Primary functional end points were rates of good (modified Rankin Scale score of ≤3) and very poor outcome (modified Rankin Scale score of ≥5) at 90 days. Secondary safety end point was the occurrence of symptomatic intracerebral hemorrhage. Angiographic outcome was evaluated with the modified Thrombolysis in Cerebral Infarction Scale., Results: After 1:1 pair matching, a total of 248 patients were compared by treatment arm. Good functional outcome was observed in 27.4% in the EVT group, and in 25% in the best medical treatment group (P=0.665). Advanced age (adjusted odds ratio, 1.08 [95% CI, 1.05–1.10], P<0.001) and symptomatic intracerebral hemorrhage (adjusted odds ratio, 6.35 [95% CI, 2.08–19.35], P<0.001) were independently associated with very poor outcome. Mortality (43.5% versus 28.9%, P=0.025) and symptomatic intracerebral hemorrhage (16.1% versus 5.6%, P=0.008) were significantly higher in the EVT group. The lowest rates of good functional outcome (≈15%) were observed in groups of failed and partial recanalization (modified Thrombolysis in Cerebral Infarction Scale score of 0/1–2a), whereas patients with complete recanalization (modified Thrombolysis in Cerebral Infarction Scale score of 3) with recanalization attempts ≤2 benefitted the most (modified Rankin Scale score of ≤3:42.3%, P=0.074) compared with best medical treatment., Conclusions: In daily clinical practice, EVT for CT–based selected patients with low Alberta Stroke Program Early CT Score anterior circulation stroke may not be beneficial and is associated with increased risk for hemorrhage and mortality, especially in the elderly. However, first- or second-pass complete recanalization seems to reveal a clinical benefit of EVT highlighting the vulnerability of the low Alberta Stroke Program Early CT Score subgroup., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03356392.

Lesion analysis is a fundamental and classical approach for inferring the causal contributions of brain regions to brain function. However, many studies have been limited by the shortcomings of methodology or clinical data. Aiming to overcome these limitations, we here use an objective multivariate approach based on game theory, Multi-perturbation Shapley value Analysis, in conjunction with data from a large cohort of 394 acute stroke patients, to derive causal contributions of brain regions to four principal functional components of the widely used National Institutes of Health Stroke Score measure. The analysis was based on a high-resolution parcellation of the brain into 294 grey and white matter regions. Through initial lesion symptom mapping for identifying all potential candidate regions and repeated iterations of the game-theoretical approach to remove non-significant contributions, the analysis derived the smallest sets of regions contributing to each of the four principal functional components as well as functional interactions among the regions. Specifically, the factor 'language and consciousness' was related to contributions of cortical regions in the left hemisphere, including the prefrontal gyrus, the middle frontal gyrus, the ventromedial putamen and the inferior frontal gyrus. Right and left motor functions were associated with contributions of the left and right dorsolateral putamen and the posterior limb of the internal capsule, correspondingly. Moreover, the superior corona radiata and the paracentral lobe of the right hemisphere as well as the right caudal area 23 of the cingulate gyrus were mainly related to left motor function, while the prefrontal gyrus, the external capsule and the sagittal stratum fasciculi of the left hemisphere contributed to right motor function. Our approach demonstrates a practically feasible strategy for applying an objective lesion inference method to a high-resolution map of the human brain and distilling a small, characteristic set of grey and white matter structures contributing to fundamental brain functions. In addition, we present novel findings of synergistic interactions between brain regions that provide insight into the functional organization of brain networks., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: Prolonged transfer times between the primary stroke center (PSC) and the comprehensive stroke center (CSC) are one of the major causes of treatment delay for endovascular stroke treatment. We aimed to analyze the effect of the diurnal variations in traffic rates at weekdays and weekends on the catchment area size of three transportation paradigms, i.e. mothership, drip-and-ship (DS) and drip-and-drive (DD)., Methods: A conditional probability model that predicts the probability of good outcome for patients with suspected large vessel occlusion was used to analyze the prehospital stroke triage in northwest Germany and produce catchment area maps. Transportation times were calculated during each hour of a weekday and a Sunday using Google Maps. For comparison, real DD transportation times from our CSC in Hamburg-Eppendorf (blinded for review) to a PSC in Lüneburg were prospectively recorded., Result: On weekdays, the mothership catchment area was the largest (≥40,000 km 2 , 63%) except for a decrease during morning rush hours, when the DD catchment area was highest (30,879 km 2 , 48%). The DS catchment area was higher than the DD catchment area during the afternoon rush hours both during the week as well as on Sundays., Conclusion: Our study showed a considerable impact of the diurnal variations in traffic rate and direction of travel on optimal stroke transportation. Stroke systems of care should take real time traffic information into account., (© 2020. The Author(s).)

Maintaining optimal cognitive functioning throughout the lifespan is a public health priority. Evaluation of cognitive outcomes following interventions to promote and preserve brain structure and function in older adults, and associated neural mechanisms, are therefore of critical importance. In this randomized controlled trial, we examined the behavioral and neural outcomes following mindfulness training ( n = 72), compared to a cognitive fitness program ( n = 74) in healthy, cognitively normal, older adults (65-80 years old). To assess cognitive functioning, we used the Preclinical Alzheimer Cognitive Composite (PACC), which combines measures of episodic memory, executive function, and global cognition. We hypothesized that mindfulness training would enhance cognition, increase intrinsic functional connectivity measured with magnetic resonance imaging (MRI) between the hippocampus and posteromedial cortex, as well as promote increased gray matter volume within those regions. Following the 8-week intervention, the mindfulness training group showed improved performance on the PACC, while the control group did not. Furthermore, following mindfulness training, greater improvement on the PACC was associated with a larger increase in intrinsic connectivity within the default mode network, particularly between the right hippocampus and posteromedial cortex and between the left hippocampus and lateral parietal cortex. The cognitive fitness training group did not show such effects. These findings demonstrate that mindfulness training improves cognitive performance in cognitively intact older individuals and strengthens connectivity within the default mode network, which is particularly vulnerable to aging affects. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT02628548], identifier [NCT02628548]., 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 © 2021 Sevinc, Rusche, Wong, Datta, Kaufman, Gutz, Schneider, Todorova, Gaser, Thomalla, Rentz, Dickerson and Lazar.)

Background: We aimed to identify groups of patients with similar health status after stroke, assessed by patient reported outcome measures (PROMs), to improve initial risk stratification., Methods: In a prospective study, inpatients were recruited during acute stroke treatment. Demographics, history, and cardio-vascular risk factors were assessed at baseline. Self-reported functional status, physical and mental health as well as anxiety and depressive symptoms were assessed 3 and 12 months after stroke and used to identify latent classes. The association of patient characteristics with latent class membership was investigated with multinomial logistic regression., Results: Of the 650 patients included with a mean age of 75 years and 48% female, 70% had ischemic, 6% hemorrhagic strokes, and 24% transient ischemic attacks. Median NIHSS on admission was 2 (IQR:0,5). Values of PROMs remained comparable at 3 and 12 months. A three-class model was developed, differentiating between patients with mildly (75%), moderately (17%), and severely (8%) impaired self-reported health status. Adjusted for univariately significant baseline characteristics, initial NIHSS distinguished mild- from moderate-, and moderate- from severe-class-membership (p < 0.001). Length of inpatient stay (p < 0.001;OR = 1.1), diabetes (p = 0.021;OR = 1.91), and atrial fibrillation (p = 0.004;OR = 2.20) predicted allocation to the moderately vs. mildly affected class., Conclusions: Grading stroke patients by a standard set of PROMs up to 1 year after stroke allows to distinguish the diverse impact of baseline characteristics on differently affected groups. In addition to initial stroke severity, longer inpatient stay, presence of diabetes and atrial fibrillation correlate with greater impairment of self-reported health in the less affected groups., Trial Registration: http://www.ClinicalTrials.gov ; Unique identifier: NCT03795948 ., (© 2021. The Author(s).)

Objectives: Impairments after stroke may affect multiple domains of health-related quality of life (HRQoL). Patient-reported outcome measures (PROMs) have proven valuable in measuring patients' well-being. We examine the psychometric properties of a standard set of PROMs assessing global health, anxiety, and depression, and functioning in a German health care setting., Method: We included inpatients at the Department of Neurology at the University Medical Center Hamburg-Eppendorf, diagnosed with stroke. Following the stroke-specific standard set of the International Consortium for Health Outcome Measurement, we collected demographic and clinical information at baseline, and PROMs for global health (PROMIS-10), three items for self-reported functioning, anxiety, and depression (PHQ-4) at 90 days follow-up. We calculated confirmatory factor analyses to test factorial validity and correlation analyses to test construct validity. We further conducted item and reliability analyses., Results: In a sample of 487 patients (mean age, SD: 71.1, 12.6; 47% female) with mild and moderate symptoms, model fit for the PROMIS-10 was acceptable for the two-factor and single-factor models. Factor loadings ranged from 0.52 to 0.94. The postulated single-factor model for functioning was saturated with zero degrees of freedom. Factor loadings ranged from 0.90 to 0.96. For the PHQ-4, the two-factor model showed excellent model fit. Factor loadings ranged from 0.78 to 0.87. Internal consistency was acceptable to good. Construct validity was generally confirmed., Conclusions: The PROMIS-10 is a valid and reliable instrument to measure HRQoL among German stroke patients. While the PHQ-4 was confirmed as a screening measure for mental disorders, further research is needed on items assessing self-reported functioning. Results are limited to patients showing minimal functional deficits., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background and Aims: We aimed to determine the association of carotid intima media thickness (CIMT), carotid plaques, and heart function with peak systolic velocity (PSV) of the common (CCA) and internal carotid artery (ICA) in a cross-sectional study., Methods: In the population-based Hamburg-City-Health-Study participants between 45 and 74 years were recruited. Cardio-vascular risk factors were assessed by history, blood samples, and clinical examination. CIMT, plaques, and PSV were determined by carotid ultrasound. Serum N-terminal brain natriuretic peptide (NT-proBNP) was determined as a biomarker for cardiac dysfunction, and left ventricular ejection fraction (LVEF) was quantified by echocardiography. Participants with carotid stenosis were excluded. Data were analyzed by multivariate linear regression., Results: We included 8567 participants, median age was 62 years, 51.8% were women. Median CIMT was 0.75 mm, NT-proBNP 80 pg/ml, LVEF 58.5%, and 30.4% had carotid plaques. For women PSV decreased in decades from 89 to 73 cm/s in CCAs and 78 to 66 cm/s in ICAs, and for men from 91 to 76 cm/s in CCAs and from 70 to 66 cm/s in ICAs. Corrected for age, sex, red blood cell count, and blood pressure, in CCAs lower PSV was associated with carotid plaques (p < 0.001; β = -0.03), lower CIMT (p = 0.005; β = 0.007), higher levels of log-transformed NT-proBNP (p < 0.001; β = -0.01), and lower LVEF (p < 0.001; β = 0.01). In ICAs, lower PSV was independently associated with lower CIMT (p < 0.001; β = 0.02) and lower EF (p = 0.001; β = 0.007)., Conclusions: Markers of cardiac dysfunction and plaques are associated with lower and CIMT with higher flow velocities in the carotid arteries., Clinical Trial Registration: http://www.clinicaltrials.gov, NCT03934957., Competing Interests: DLR, KB, JPW, MJ, CAB, CW, TZ, and ESD have nothing to report. RBS has received speaker honoraria from Bristol-Myers Squibb/Pfizer. RBS has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 648131), from the European Union's Horizon 2020 research and innovation programme under the grant agreement No 847770 (AFFECT-EU) and German Center for Cardiovascular Research (DZHK e.V.) (81Z1710103); German Ministry of Research and Education (BMBF 01ZX1408A) and ERACoSysMed3 (031L0239). SB has received research funding from Abbott Diagnostics, Bayer, SIEMENS, Singulex and Thermo Fisher. He received honoraria for lectures from Abbott, Abbott Diagnostics, Astra Zeneca, Bayer, AMGEN, Medtronic, Pfizer, Roche, SIEMENS, Thermo Fisher and as member of Advisory Boards for consulting for Bayer, Novartis and Thermo Fisher. CG reports personal fees from Amgen, Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi Aventis, Abbott, and Prediction Biosciences outside the submitted work. GT reports receiving consulting fees from Acandis, grant support, and lecture fees from Bayer, lecture fees from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo, and consulting fees and lecture fees from Stryker outside the submitted work., (© 2021 The Authors.)

We examined the relationship between white matter hyperintensities (WMH) and cortical neurodegeneration in cerebral small vessel disease (CSVD) by investigating whether cortical thickness is a remote effect of WMH through structural fiber tract connectivity in a population at increased risk of CSVD. We measured cortical thickness on T1-weighted images and segmented WMH on FLAIR images in 930 participants of a population-based cohort study at baseline. DWI-derived whole-brain probabilistic tractography was used to define WMH connectivity to cortical regions. Linear mixed-effects models were applied to analyze the relationship between cortical thickness and connectivity to WMH. Factors associated with cortical thickness (age, sex, hemisphere, region, individual differences in cortical thickness) were added as covariates. Median age was 64 [IQR 46-76] years. Visual inspection of surface maps revealed distinct connectivity patterns of cortical regions to WMH. WMH connectivity to the cortex was associated with reduced cortical thickness ( p  = 0.009) after controlling for covariates. This association was found for periventricular WMH ( p  = 0.001) only. Our results indicate an association between WMH and cortical thickness via connecting fiber tracts. The results imply a mechanism of secondary neurodegeneration in cortical regions distant, yet connected to subcortical vascular lesions, which appears to be driven by periventricular WMH.

Background and Purpose: We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra., Methods: We determined core and perfusion lesions in subjects from the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) and AXIS 2 trial (Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke) with perfusion- and diffusion-weighted imaging at baseline. Only subjects with a mismatch volume >15 mL and ratio >1.2 were included. We created voxel-based relative fluid-attenuated inversion recovery signal intensity (rFLAIR SI) maps at baseline and follow-up. We studied rFLAIR SI in 2 regions of interest: baseline penumbra (baseline perfusion lesion−[core lesion+voxels with apparent diffusion coefficient <620 10−6 mm2/s]) and noninfarcted penumbra (baseline perfusion lesion−follow-up fluid-attenuated inversion recovery lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). We analyzed the association between rFLAIR SI and severity of hypoperfusion, defined as time to maximum of the residue function., Results: In the baseline penumbra, rFLAIR SI was elevated (ratio, 1.04; P=1.7×10−13; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; P<1.0×10−4; n=126). In WAKE-UP, imaging at 24 hours revealed a further increase of rFLAIR SI in the noninfarcted penumbra (ratio, 1.05 at 24 hours versus 1.03 at baseline; P=7.1×10−3; n=43). In AXIS 2, imaging at 30 days identified reversibility of the rFLAIR SI (ratio, 1.02 at 30 days versus 1.04 at baseline; P=1.5×10−3; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; P=0.099; n=26)., Conclusions: Penumbral rFLAIR SI increases appear early after stroke onset, correlate with severity of hypoperfusion, further increase at 24 hours, and are reversible by 30 days., Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://clinicaltrials.gov; Unique identifier: NCT00927836.

Background: The COVID-19 pandemic led to profound changes in the organization of health care systems worldwide., Aims: We sought to measure the global impact of the COVID-19 pandemic on the volumes for mechanical thrombectomy, stroke, and intracranial hemorrhage hospitalizations over a three-month period at the height of the pandemic (1 March-31 May 2020) compared with two control three-month periods (immediately preceding and one year prior)., Methods: Retrospective, observational, international study, across 6 continents, 40 countries, and 187 comprehensive stroke centers. The diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases at participating centers., Results: The hospitalization volumes for any stroke, intracranial hemorrhage, and mechanical thrombectomy were 26,699, 4002, and 5191 in the three months immediately before versus 21,576, 3540, and 4533 during the first three pandemic months, representing declines of 19.2% (95%CI, -19.7 to -18.7), 11.5% (95%CI, -12.6 to -10.6), and 12.7% (95%CI, -13.6 to -11.8), respectively. The decreases were noted across centers with high, mid, and low COVID-19 hospitalization burden, and also across high, mid, and low volume stroke/mechanical thrombectomy centers. High-volume COVID-19 centers (-20.5%) had greater declines in mechanical thrombectomy volumes than mid- (-10.1%) and low-volume (-8.7%) centers (p < 0.0001). There was a 1.5% stroke rate across 54,366 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.9% (784/20,250) of all stroke admissions., Conclusion: The COVID-19 pandemic was associated with a global decline in the volume of overall stroke hospitalizations, mechanical thrombectomy procedures, and intracranial hemorrhage admission volumes. Despite geographic variations, these volume reductions were observed regardless of COVID-19 hospitalization burden and pre-pandemic stroke/mechanical thrombectomy volumes.

Objective: A previous study revealed a preliminary trend towards higher in hospital mortality in patients admitted as an emergency with acute stroke during the COVID-19 pandemic in Germany. The current study aimed to further examine the possible impact of a confirmed SARS-CoV-2 infection on in hospital mortality., Methods: This was a retrospective analysis of health insurance claims data from the second largest insurance fund in Germany, BARMER. Patients hospitalised for ST elevation (STEMI) and non-ST elevation (NSTEMI) myocardial infarction, acute limb ischaemia (ALI), aortic rupture, acute stroke, or transient ischaemic attack (TIA) between 1 January 2017, and 31 October 2020, were included. Admission rates per 10 000 insured and mortality were compared between March - June 2017 - 2019 (pre-COVID) and March - June 2020 (COVID). Mortality rates were determined by the occurrence of a confirmed SARS-CoV-2 infection., Results: A total of 316 718 hospitalisations were included (48.7% female, mean 72.5 years), and 21 191 (6.7%, 95% CI 6.6% - 6.8%) deaths occurred. In hospital mortality increased during the COVID-19 pandemic when compared with the three previous years for patients with acute stroke from 8.3% (95% CI 8.0 - 8.5) to 9.6% (95% CI 9.1 - 10.2), while no statistically significant changes were observed for STEMI, NSTEMI, ALI, aortic rupture, and TIA. When comparing patients with confirmed SARS-CoV-2 infection (2.4%, 95% CI 2.3 - 2.5) vs. non-infected patients, a higher in hospital mortality was observed for acute stroke (12.4% vs. 9.0%), ALI (14.3% vs. 5.0%), and TIA (2.7% vs. 0.3%), while no statistically significant differences were observed for STEMI, NSTEMI, and aortic rupture., Conclusion: This retrospective analysis of claims data has provided hints of an association between the COVID-19 pandemic and increased in hospital mortality in patients with acute stroke. Furthermore, confirmed SARS-CoV-2 infection was associated with increased mortality in patients with stroke, TIA, and ALI. Future studies are urgently needed to better understand the underlying mechanism and relationship between the new coronavirus and acute stroke., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

This expert opinion paper on cardiac imaging after acute ischemic stroke or transient ischemic attack (TIA) includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. The Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork (AFNET) endorsed this paper. Cardiac imaging is a key component of etiological work-up after stroke. Enhanced echocardiographic tools, constantly improving cardiac computer tomography (CT) as well as cardiac magnetic resonance imaging (MRI) offer comprehensive non- or less-invasive cardiac evaluation at the expense of increased costs and/or radiation exposure. Certain imaging findings usually lead to a change in medical secondary stroke prevention or may influence medical treatment. However, there is no proof from a randomized controlled trial (RCT) that the choice of the imaging method influences the prognosis of stroke patients. Summarizing present knowledge, the German Heart and Brain consortium proposes an interdisciplinary, staged standard diagnostic scheme for the detection of risk factors of cardio-embolic stroke. This expert opinion paper aims to give practical advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on expert opinion, reported case series, and clinical experience.

Stroke has a deleterious impact on quality of life. However, it is less well known if stroke lesions in different brain regions are associated with reduced quality of life (QoL). We therefore investigated this association by multivariate lesion-symptom mapping. We analyzed magnetic resonance imaging and clinical data from the WAKE-UP trial. European Quality of Life 5 Dimensions (EQ-5D) 3 level questionnaires were completed 90 days after stroke. Lesion symptom mapping was performed using a multivariate machine learning algorithm (support vector regression) based on stroke lesions 22-36 h after stroke. Brain regions with significant associations were explored in reference to white matter tracts. Of 503 randomized patients, 329 were included in the analysis (mean age 65.4 years, SD 11.5; median NIHSS = 6, IQR 4-9; median EQ-5D score 90 days after stroke 1, IQR 0-4, median lesion volume 3.3 ml, IQR 1.1-16.9 ml). After controlling for lesion volume, significant associations between lesions and EQ-5D score were detected for the right putamen, and internal capsules of both hemispheres. Multivariate lesion inference analysis revealed an association between injuries of the cortico-spinal tracts with worse self-reported quality of life 90 days after stroke in comparably small stroke lesions, extending previous reports of the association of striato-capsular lesions with worse functional outcome. Our findings are of value to identify patients at risk of impaired QoL after stroke.

Competing Interests: Competing interests: WH reports consultancy fees from Neuravi and fees for DSMB work by Phenox. DWJD reports funding from the Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organisation for Health Research and Development, Health Holland Top Sector Life Sciences & Health, and unrestricted grants from Penumbra, Stryker European Operations BV, Medtronic, Thrombolytic Science, LLC and Cerenovus for research, all paid to institution. CZS reports research grants from Novo Nordisk Foundation and Health Research Foundation of Central Denmark Region. JF reports research support from the German Ministry of Science and Education (BMBF and BMWi), German Research Foundation (DFG), European Union (EU), Hamburgische Investitions- und Förderbank (IFB), Medtronic, Microvention, Philips, Stryker, and consultancy fees from Acandis, Boehringer Ingelheim, Cerenovus, Covidien, Evasc Neurovascular, MD Clinicals, Medtronic, Medina, Microvention, Penumbra, Route92, Stryker, Transverse Medical. GT reports personal fees from Acandis, grants and personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers-Squibb/Pfizer, personal fees from Portola, and personal fees from Stryker outside the submitted work, and is Neurological Co-Principal Investigator of the TENSION study, which receives funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 754640. TA reports consultancy fees from Amnis Therapeutics, Anaconda, Cerenovus/Neuravi, Rapid Medical and Stryker. MM is a member of the TESLA steering committee and local principal investigator. He reports research support from the NIH and consultancy fees from Medtronic and Cerenovus as well as stock options in Serenity Medical, Synchron and Endostream. AJY is the co-Principal Investigator for TESLA and reports research funding from Medtronic, Cerenovus, Penumbra and Stryker. He reports consultancy fees from Penumbra, Cerenovus, Vesalio and Zoll Circulation. He has equity interests in Insera Therapeutics. SAS reports research support from the NIH, American Academy of Neurology and Society for Vascular and Interventional Neurology, and consultancy fees from Penumbra and Cerenovus. OOZ is the co-Principal Investigator for TESLA and reports consultancy fees from Cerenovus, Stryker, Penumbra and Medtronic. TGJ reports consultancy fees from Cerenovus and Contego, and research support from Stryker. DL reports consultancy fees from Cerenovus, Genentech, Medtronic, and Stryker outside the submitted work.

Introduction: To assess the association between 24 h blood pressure variability (BPV) on functional outcome and treatment effect of intravenous alteplase in acute ischaemic stroke., Patients and Methods: In all patients with acute ischaemic stroke of unknown onset randomised in the WAKE-UP (Efficacy and Safety of magnetic resonance imaging [MRI]-based Thrombolysis in Wake-Up Stroke) trial, blood pressure (BP) was measured before randomisation and after initiation of treatment at regular intervals up to 24 hours. Individual BPV was measured by coefficient of variation (CV) of all BP values. Primary outcome measure was favourable outcome defined by a modified Rankin Scale (mRS) score 0 or 1 at 90 days after stroke., Results: BP measurements were available for 498 of 503 patients randomised (177 women [35.5%], mean age [SD] of 65.2 [11.5] years). Systolic BPV was not associated with the treatment effect of thrombolysis (test for interaction, p = 0.46). The adjusted odds ratio (aOR) for favourable outcome with alteplase, adjusted for age, stroke severity and baseline BP on admission, did not show an association across the quintiles of increasing systolic BPV with an aOR 1.89 (95% confidence interval [CI], 0.76-4.70) in the lowest quintile to aOR 1.05 (95% CI, 0.43-2.56) in the highest quintile. Higher mean systolic BP was associated with a smaller treatment effect of thrombolysis with a significant interaction (p = 0.033). The aOR for favourable outcome with alteplase decreased with quintiles of increasing mean systolic BP from aOR 3.16 (95% CI, 1.26-7.93) in the lowest quintile to aOR 0.84 (95% CI, 0.34-2.10) in in the highest quintile., Conclusions: There was a significant interaction between mean systolic BP and treatment effect of thrombolysis with higher mean systolic BP being associated with poorer outcome. BPV was not associated with outcome after thrombolysis.ClinicalTrials.gov identifier NCT01525290., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EB, BC, ME, MEn, JBF, AN, VT, KWM, PR, SP, CG and GT report grants from European Union 7th Framework Program during the conduct of the study. FB reports grants from University Medical Center Hamburg-Eppendorf during the conduct of the study. MEn reports grants from Bayer and fees paid to the Charité from Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Amgen, GlaxoSmithKlineGSK, Sanofi, Covidien, Novartis, all outside the submitted work. JBF reports personal fees from Bioclinica, Artemida, Cerevast, and Nicolab outside the submitted work. RL reports fees paid to VIB/KU Leuven from Bayer, Boehringer Ingelheim, Medtronic, Ischemiaview and Genentec all outside the submitted work. VT reports personal fees and non-financial support from Boehringer Ingelheim, Pfizer/BMS, Bayer, Sygnis, Amgen and Allergan outside the submitted work. KWM reports personal fees and non-financial support from Boehringer Ingelheim outside the submitted work. CZS reports grants from Novo Nordisk Foundation and personal fees from Bayer outside the submitted work. CG reports personal fees from AMGEN, Bayer Vital, BMS, Boehringer Ingelheim, Sanofi Aventis, Abbott, and Prediction Biosciences outside the submitted work. GT reports personal fees from Acandis, Boehringer Ingelheim, BMS/Pfizer, Stryker, Daiichi Sankyo, grants and personal fees from Bayer, grants from Corona Foundation, German Innovation Fonds and Else Kroener Fresenius Foundation outside the submitted work. All remaining authors declare no competing interests., (© European Stroke Organisation 2021.)

Space-occupying brain oedema is a potentially life-threatening complication in the first days after large hemispheric or cerebellar infarction. Several treatment strategies for this complication are available, but the size and quality of the scientific evidence on which these strategies are based vary considerably. The aim of this Guideline document is to assist physicians in their management decisions when treating patients with space-occupying hemispheric or cerebellar infarction. These Guidelines were developed based on the European Stroke Organisation (ESO) standard operating procedure and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. A working group identified 13 relevant questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and wrote evidence-based recommendations. An expert consensus statement was provided if not enough evidence was available to provide recommendations based on the GRADE approach. We found high-quality evidence to recommend surgical decompression to reduce the risk of death and to increase the chance of a favourable outcome in adult patients aged up to and including 60 years with space-occupying hemispheric infarction who can be treated within 48 hours of stroke onset, and low-quality evidence to support this treatment in older patients. There is continued uncertainty about the benefit and risks of surgical decompression in patients with space-occupying hemispheric infarction if this is done after the first 48 hours. There is also continued uncertainty about the selection of patients with space-occupying cerebellar infarction for surgical decompression or drainage of cerebrospinal fluid. These Guidelines further provide details on the management of specific subgroups of patients with space-occupying hemispheric infarction, on the value of monitoring of intracranial pressure, and on the benefits and risks of medical treatment options. We encourage new high-quality studies assessing the risks and benefits of different treatment strategies for patients with space-occupying brain infarction., (© European Stroke Organisation 2021.)

Introduction: The initiation and conduct of randomised clinical trials are complicated by multiple barriers, including delays in obtaining regulatory approvals. Quantitative data on the extent of the delays due to national or local review in randomised clinical trials is scarce., Materials and Methods: We assessed the times needed to obtain regulatory approval and to initiate a trial site for an academic, EU-funded, phase III, randomised clinical trial of pharmacological prevention of complications in patients with acute stroke in over 80 sites in nine European countries. The primary outcome was the time from the first submission to a regulatory authority to initiation of a trial site. Secondary outcomes included time needed to complete each individual preparatory requirement and the number of patients recruited by each site in the first 6 and 12 months., Results: The median time from the first submission to a regulatory authority to initiation of a trial site was 784 days (IQR: 586-1102). The single most time-consuming step was the conclusion of a clinical trial agreement between the national coordinator and the trial site, which took a median of 194 days (IQR: 93-293). A longer time to site initiation was associated with a lower patient recruitment rate in the first six months after initiation (B = -0.002; p  = 0.02)., Conclusion: In this EU-funded clinical trial, approximately 26 months were needed to initiate a trial site for patient recruitment. The conclusion of a contract with a trial site was the most time-consuming activity. To simplify and speed up the process, we suggest that the level of detail of contracts for academic trials should be proportional to the risks and commercial interests of these trials., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: HBvdW served as a consultant to Boehringer Ingelheim, Bayer and LivaNova. PMB is Stroke Association Professor of Stroke Medicine and an emeritus NIHR Senior Investigator. He has received grant funding from British Heart Foundation and EU FP7 funding, and honoraria from DiaMedica, Moleac and Phagenesis. GT was coordinating investigator of the WAKE-UP trial and is neurological principal investigator of the TENSION study. He is the National Coordinator in Germany for the PRECIOUS trial. He has received fees as consultant or lecturer from Acandis, Bayer, Bristol-Myers-Squibb/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Portola and Stryker outside the submitted work., (© European Stroke Organisation 2021.)

Background and Purpose: The aim was to study the effect of intravenous alteplase on the development of post-stroke depression (PSD) in acute stroke patients, and to identify predictors of PSD., Methods: This post hoc analysis included patients with unknown onset stroke randomized to treatment with alteplase or placebo in the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290), in whom a composite end-point of PSD was defined as a Beck Depression Inventory ≥10, medication with an antidepressant, or depression recorded as an adverse event. Multiple logistic regression was used to identify predictors of PSD at 90 days. Structural equation modelling was applied to assess the indirect effect of thrombolysis on PSD mediated by the modified Rankin Scale., Results: Information on the composite end-point was available for 438 of 503 randomized patients. PSD was present in 96 of 224 (42.9%) patients in the alteplase group and 115 of 214 (53.7%) in the placebo group (odds ratio 0.63; 95% confidence interval 0.43-0.94; p = 0.022; adjusted for age and National Institutes of Health Stroke Scale at baseline). Prognostic factors associated with PSD included baseline medication with antidepressants, higher lesion volume, history of depression and assignment to placebo. While 65% of the effect of thrombolysis on PSD were caused directly, 35% were mediated by an improvement of the mRS., Conclusions: Treatment with alteplase in patients with acute stroke resulted in lower rates of depression at 90 days, which were only partially explained by reduced functional disability. Predictors of PSD including history and clinical characteristics may help in identifying patients at risk of PSD., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)