Background: Vasoregulatory autoantibodies including autoantibodies targeting G-protein-coupled receptors might play a functional role in vascular diseases. We investigated the impact of... Show moreBackground: Vasoregulatory autoantibodies including autoantibodies targeting G-protein-coupled receptors might play a functional role in vascular diseases. We investigated the impact of vasoregulatory autoantibodies on clinical outcome after ischemic stroke.Methods and results: Data were used from the PROSCIS-B (Prospective Cohort With Incident Stroke-Berlin). Autoantibody-targeting receptors such as angiotensin II type 1 receptor (AT1R), endothelin-1 type A receptor, complement factor-3 and -5 receptors, vascular endothelial growth factor receptor-1 and -2, vascular endothelial growth factor A and factor B were measured. We explored associations of high antibody levels with (1) poor functional outcome defined as modified Rankin Scale >2 or Barthel Index <60 at 1 year after stroke, (2) Barthel Index scores over time using general estimating equations, and (3) secondary vascular events (recurrent stroke, myocardial infarction) or death up to 3 years using Cox proportional hazard models. We included 491 patients with ischemic stroke with data on autoantibody levels and outcome. In models adjusted for demographics and vascular risk factors, high autoantibody concentrations (quartile 4) targeting complement factor C3a receptor, vascular endothelial growth factor receptor-2, and vascular endothelial growth factor B were associated with poor functional outcome at 1 year: (odds ratio, 2.0 [95% CI, 1.1-3.6]; odds ratio, 1.8 [95% CI, 1.1-3.2]; and odds ratio, 2.1 [95% CI, 1.2-3.6], respectively) and with lower Barthel Index scores over 3 years (complement factor C3a receptor: adjusted beta=-3.3 [95% CI, -5.7 to -0.5]; VEGF-B: adjusted beta=-2.4 [95% CI, -4.8 to -0.06]). Patients with high autoantibody levels were not at higher risk for secondary vascular events or death.Conclusions: High levels of autoantibodies against vascular endothelial growth factor receptor-2, vascular endothelial growth factor B, and complement factor C3a receptor measured are associated with poor functional outcome after stroke but not with recurrent vascular events or death. Show less
Background Anti-NMDA-receptor GluN1 antibodies (NMDAR1-abs) are present in an autoimmune encephalitis with severe neuropsychiatric symptoms. We aimed to estimate the impact of serum NMDAR1-abs on... Show moreBackground Anti-NMDA-receptor GluN1 antibodies (NMDAR1-abs) are present in an autoimmune encephalitis with severe neuropsychiatric symptoms. We aimed to estimate the impact of serum NMDAR1-abs on depressive symptoms years after first-ever ischemic stroke (IS).Methods Data were used from the PROSpective Cohort with Incident Stroke-Berlin (PROSCIS-B; NCT01363856). Serum NMDAR1-abs (IgM/IgA/IgG) were measured within 7 days after IS using cell-based assays. We defined seropositivity as titers >= 1:10, thereof low titers as <= 1:100 and high titers as >1:100. We used the Center for Epidemiological Studies-Depression (CES-D) scale to measure depressive symptoms at year one, two and three following IS. We calculated crude and confounder adjusted weighted generalized linear models to quantify the impact of NMDAR1-abs on CES-D assessed at three annual time-points.Results NMDAR1-abs were measured in 583 PROSCIS-B IS patients (mean age = 67 [SD = 13]; 42%female; median NIHSS = 2 [IQR = 1-4]) of whom 76 (13%; IgM: n = 49/IgA: n = 43/IgG: n = 2) were seropositive, 55 (9%) with low and 21 (4%) with high titers. CES-D regarded over all follow-up time-points was higher in seropositive patients (beta(crude) = 2.56 [95%CI = -0.34 to 5.45]; beta(adjusted) = 2.26 [95%CI = -0.68 to 5.20]) and effects were highest in patients with high titer (low titers: beta(crude) = 1.42 [95%CI = -1.79 to 4.62], beta(adjusted) = 0.53 [95%CI = -2.47 to 3.54]; high titers: beta(crude) = 5.85 [95%CI = 0.20 to 11.50]; beta(adjusted) = 7.20 [95%CI = 0.98 to 13.43]).Conclusion Patients with serum NMDAR1-abs (predominantly IgM&IgA) suffer more severe depressive symptoms after mild-to-moderate IS compared to NMDAR1-abs seronegative patients. Show less
Weber, J.E.; Ahmadi, M.; Boldt, L.H.; Eckardt, K.U.; Edelmann, F.; Gerhardt, H.; ... ; Pischon, T. 2023
Introduction The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular ... Show moreIntroduction The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular (CV) disease progression by comprehensively investigating a high-risk patient population with different organ manifestations.Methods and analysis A total of 8000 adult patients will be recruited who have either suffered an acute CV event (CVE) requiring hospitalisation or who have not experienced a recent acute CVE but are at high CV risk. An initial study examination is performed during the acute treatment phase of the index CVE or after inclusion into the chronic high risk arm. Deep phenotyping is then performed after similar to 90 days and includes assessments of the patient's medical history, health status and behaviour, cardiovascular, nutritional, metabolic, and anthropometric parameters, and patient-related outcome measures. Biospecimens are collected for analyses including 'OMICs' technologies (e.g., genomics, metabolomics, proteomics). Subcohorts undergo MRI of the brain, heart, lung and kidney, as well as more comprehensive metabolic, neurological and CV examinations. All participants are followed up for up to 10 years to assess clinical outcomes, primarily major adverse CVEs and patient-reported (value-based) outcomes. State-of-the-art clinical research methods, as well as emerging techniques from systems medicine and artificial intelligence, will be used to identify associations between patient characteristics, longitudinal changes and outcomes.Ethics and dissemination The study was approved by the Charite-Universitatsmedizin Berlin ethics committee (EA1/066/17). The results of the study will be disseminated through international peer-reviewed publications and congress presentations.Clinical Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx? TrialID=DRKS00016852. Recruitment started on July 18, 2017.Second study phase: Approved WHO primary register: German Clinical Trials Register DRKS00023323, date of registration: November 4, 2020, URL: http://www.drks.de/DRKS00023323. Recruitment started on January 1, 2021. Show less
Wagner, L.; Mohrbach, D.; Ebinger, M.; Endres, M.; Nolte, C.H.; Harmel, P.; ... ; Siegerink, B. 2022
Background: Benefits of endovascular thrombectomy (ET) after intravenous thrombolysis (IVT) for patients with acute ischaemic stroke (AIS) have been demonstrated, but analyses of the relationship... Show moreBackground: Benefits of endovascular thrombectomy (ET) after intravenous thrombolysis (IVT) for patients with acute ischaemic stroke (AIS) have been demonstrated, but analyses of the relationship between IVT-ET time delay and functional outcomes among patients receiving both treatments are lacking. Methods: We used data from the "Berlin-Specific Acute Treatment in Ischaemic and haemorrhAgic stroke with Long-term outcome" (B-SPATIAL) registry. Between January 1st, 2016 and December 31st, 2019, we included patients who received both IVT and ET. The primary outcome was the 3-month ordinal modified Rankin scale (mRS) score. The IVT-ET time delay was analyzed in categories and continuously. We used adjusted ordinal logistic regression to estimate common odds ratios (cOR) and 95% confidence intervals (CI). Secondary analyses involved flexible modeling of IVT-ET delay and dichotomous outcomes. Results: Of 11,049 patients, 714 who received IVT followed by ET were included. Compared with having an IVT-ET window >120 min (reference), for an IVT-ET window < 30 min, we obtained adjusted cORs for mRS of 0.41 (95% CI: 0.22 to 0.78); and 0.52 (95% CI: 0.33 to 0.82) for 30 to 120 min. Secondary analyses also found protective effects of shorter time delays against "poor" functional outcomes at 3 months. Conclusions: In patients with AIS, shorter IVT-ET intervals were associated with better 3-month functional outcomes. While the time-to-IVT and time-to-ET include the time until medical attention is received, the IVT-ET time delays fall entirely within the domain of medical management and thus might be easier to optimize. Show less
Background Like other countries in sub-Saharan Africa, Madagascar has a high burden of stroke. The Malagasy population is unique in sharing both African and Asian ancestry. The proportion of... Show moreBackground Like other countries in sub-Saharan Africa, Madagascar has a high burden of stroke. The Malagasy population is unique in sharing both African and Asian ancestry. The proportion of ischemic and hemorrhagic stroke types is unknown for this population.Aim Our aim was to establish the proportion of stroke types and known risk factors for the Malagasy population.Methods We conducted a single-center, tertiary-level hospital-based case series. We included all patients with a CT-imaging confirmed stroke who presented at the emergency ward of the study hospital between January 1, 2017, and November 20, 2018.Results Of 223 patients with CT-confirmed stroke, 57.4% (128/223, 95% CI: 51-64%) had an ischemic stroke and 42.6% (95/223, 95% CI: 36-49%) had an intracranial hemorrhage. The majority (89.5%; 85/95, 95% CI: 83-96%) of intracranial hemorrhages were intracerebral; 4.2% (4/95, 95% CI: 0-8%) had a subdural hematoma, 5.3% (5/95, 95% CI: 1-10%) had a subarachnoid hemorrhage, there was one isolated intraventricular hemorrhage (1.1%; 1/95, 95% CI: -1-3%). The prevalence of hypertension among stroke patients was high (86.6%; 187/216, 95% CI: 82-91%).Conclusions Our study is the first to report the proportion of stroke types and known risk factors in Madagascar. We find that the proportion of hemorrhagic strokes was unexpectedly higher than that reported from other countries in sub-Saharan Africa. Our findings highlight the need for a country-specific approach to stroke prevention, treatment, and rehabilitation and provide guidance on public health resource allocation in Madagascar. Show less
Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross... Show morePrevious genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries. Show less
Introduction: Low ankle-brachial index (ABI) <= 0. 9 is a marker for generalized atherosclerosis and a risk factor for cognitive decline in the general population. Objective: To evaluate the... Show moreIntroduction: Low ankle-brachial index (ABI) <= 0. 9 is a marker for generalized atherosclerosis and a risk factor for cognitive decline in the general population. Objective: To evaluate the impact of ABI <= 0.9 on cognitive function up to 3 years after first-ever ischemic stroke. Methods: Data was used from the "PROspective Cohort with Incident Stroke-Berlin" (PROSCIS-B; NCT01363856). ABI was measured at baseline and categorized into normal (1.4-0.9) vs. low (<= 0.9). Cognitive function was assessed with the Montreal Cognitive Assessment (MoCA) and the Mini-Mental-State-Examination (MMSE) at baseline and with the Telephone Interview for Cognitive Status-modified (TICS-m) at 1-3 years of follow-up. We performed confounder adjusted generalized linear models (GLM) to calculate relative risks (RR) for cognitive impairment at baseline (MMSE <= 26; MoCA <= 25) and linear mixed models (LMM) to estimate the impact of low ABI on TICS-m over time. Results: We included 325 patients [mean age: 66 (SD = 13); 38% female, median NIHSS = 2 (IQR = 1-4), ABI <= 0.9: 59 (18%)). Patients with tow ABI were at increased risk of cognitive impairment at baseline (adjusted RR for MoCA <= 25 = 1.98; 95%-CI:1.24 to 3.16). TICS-m scores were consistently lower over time in patients with low ABI (adjusted beta = -1.96; 95%-CI:-3.55 to -0.37). Independent of ABI, cognitive function did not decline over time (adjusted 95%-CI:-0.06 to 0.64). Conclusion: In patients with mild to moderate first-ever ischemic stroke, low ABI is associated with reduced cognitive function over a 3-year follow-up. Show less
Napierkowski, I.; Lorenz-Meyer, I.; Hille, A.; Ebinger, M.; Freitag, E.; Harmel, P.; ... ; Berlin-SPecific Acute Treatment Ischemic or hAemorrhagic Stroke With Long Term Follow-up 2022
Background and Objectives: Restricting follow-up assessment of both interventional and observational studies to patients who provide informed consent introduces relevant selection bias-particularly... Show moreBackground and Objectives: Restricting follow-up assessment of both interventional and observational studies to patients who provide informed consent introduces relevant selection bias-particularly by underrepresenting patients with neurologic communication deficits and impaired capacity to consent. Many patients who are initially unable to give consentmay be willing to do so after recovery. Informing patients on study purposes and procedures with offering them the option of nonparticipation but not requesting explicit consent is called "opt-out" approach. We investigated whether an opt-out strategy yields meaningful follow-up rates in an acute stroke registry with an embedded controlled study. Methods: The citywide Berlin-SPecific Acute Treatment in Ischemic or hAemorrhagic Stroke With Long Term Follow-up (B-SPATIAL) registry was designed to provide reliable information on process indicators and outcomes of specific acute stroke treatments to inform health care providers about quality of care and best practice strategies including the effects of a mobile stroke unit implementation. Because this information was regarded of high public interest, Berlin data protection authorities permitted data sampling without prior informed consent, using instead follow-up assessment on an "opt-out" basis. Patients were included if they had neurologic symptoms at ambulance or hospital arrival within 6 hours of onset and had a final diagnosis of stroke or TIA. Information on data collection and outcome assessment was sent by letter to patients 1 month before follow-up. Results: From February 1, 2017, to January 31, 2020, a total of 10,597 patients were assessed. Thirty-one (0.3%) patients declined any data use, whereas 578 (5.5%) opted out of follow-up assessment. Of those not opting out (n = 9,988), functional outcome (modified Rankin Scale) was collected in 8,330 patients (83.4%) and vital status in 9,741 patients (97.5%). We received no complaints regarding data collection procedures. Discussion: Opt-out-based follow-up collection offers a way to achieve high follow-up rates along with respecting patients' preferences. Show less
Nave, A.H.; Kaynak, N.; Mai, K.; Siegerink, B.; Laufs, U.; Heuschmann, P.U.; ... ; Endres, M. 2022
Background: Elevated triglyceride and glucose levels are associated with an increased cardiovascular disease risk including ischemic stroke. It is not known whether the response to a combined oral... Show moreBackground: Elevated triglyceride and glucose levels are associated with an increased cardiovascular disease risk including ischemic stroke. It is not known whether the response to a combined oral triglyceride and glucose challenge after ischemic stroke improves identification of patients with increased risk for recurrent vascular events. Methods: The prospective, observational Berlin "Cream&Sugar" study was conducted at 3 different university hospital sites of the Charite-Universitatsmedizin Berlin, Germany, between January 24, 2009 and July 31, 2017. Patients with first-ever ischemic stroke were recruited 3 to 7 days after stroke. An oral triglyceride tolerance test (OTTT) and consecutive blood tests before (t(0)) as well as 3 (t(1)), 4 (t(2)), and 5 hours (t(3)) after OTTT were performed in fasting patients. An oral glucose tolerance test was performed in all nondiabetic patients 3 hours after the start of OTTT. Outcomes of the study were recurrent fatal or nonfatal stroke as well as a composite vascular end point including stroke, transient ischemic attack, myocardial infarction, coronary revascularization, and cardiovascular death assessed 1 year after stroke. Cox regression models were used to estimate hazard ratios and corresponding 95% CIs between patients with high versus low levels of triglyceride and glucose levels. Results: Overall 755 patients were included; 523 patients completed OTTT and 1-year follow-up. Patients were largely minor strokes patients with a median National Institutes of Health Stroke Scale score of 1 (0-3). Comparing highest versus lowest quartiles of triglyceride levels, neither fasting (adjusted hazard ratio(t0), 1.24 [95% CI, 0.45-3.42]) nor postprandial triglyceride levels (adjusted hazard ratio(t3), 0.44 [95% CI, 0.16-1.25]) were associated with recurrent stroke. With regard to recurrent vascular events, results were similar for fasting triglycerides (adjusted hazard ratio(t0), 1.09 [95% CI, 0.49-2.43]), however, higher postprandial triglyceride levels were significantly associated with a lower risk for recurrent vascular events (adjusted hazard ratio(t3), 0.42 [95% CI, 0.18-0.95]). No associations were observed between fasting and post-oral glucose tolerance test blood glucose levels and recurrent vascular risk. All findings were irrespective of the diabetic status of patients. Conclusions: In this cohort of patients with first-ever, minor ischemic stroke, fasting triglyceride or glucose levels were not associated with recurrent stroke at one year after stroke. However, higher postprandial triglyceride levels were associated with a lower risk of recurrent vascular events which requires further validation in future studies. Overall, our results do not support the routine use of a combined OTTT/oral glucose tolerance test to improve risk prediction for recurrent stroke. Show less
Objective We aimed to investigate whether serum anti-N-methyl-D-aspartate-receptor GluN1 (previously NR1) antibody (NMDAR1-abs) seropositivity impacts cognitive function (CF) in the long term... Show moreObjective We aimed to investigate whether serum anti-N-methyl-D-aspartate-receptor GluN1 (previously NR1) antibody (NMDAR1-abs) seropositivity impacts cognitive function (CF) in the long term following ischemic stroke. Methods Data were used from the PROSpective Cohort with Incident Stroke-Berlin. NMDAR1-abs (IgM/IgA/IgG) were measured with cell-based assays from serum obtained within 7 days after the first-ever stroke. Seropositivity was defined as titers >= 1:10, low titers as <= 1:100 and high titers as > 1:100. We assessed CF at 1, 2 and 3 years after stroke with the Telephone Interview for Cognitive Status-modified (TICS-m) and used crude and propensity score adjusted inverse probability weighted generalized linear models to estimate the impact of NMDAR1-abs serostatus on TICS-m. Results Data on NMDAR1-abs (median day of sampling = 4[IQR = 2-5]) were available in 583/621 PROSCIS-B patients (39% female; median NIHSS = 2[IQR = 1-4]; median MMSE = 28[IQR:26-30]), of whom 76(13%) were seropositive (IgM: n = 48/IgA: n = 43/IgG: n = 2). Any NMDAR1-abs seropositivity had no impact on TICS-m compared to seronegative patients (beta crude = 0.69[95%CI = - 0.84 to 2.23]; beta adjusted = 0.65[95%CI = - 1.00 to 2.30]). Patients with low titers scored better on TICS-m compared to seronegative patients (beta crude = 2.33[95%CI = 0.76 to 3.91]; beta adjusted = 2.47[95%CI = 0.75 to 4.19]); in contrast, patients with high titers scored lower on TICS-m (beta crude = -2.82[95%CI = - 4.90 to - 0.74], beta adjusted = - 2.96[95%CI = - 5.13 to - 0.80]), compared to seronegative patients. Conclusion In our study, NMDAR1-abs seropositivity did not affect CF over 3 years after a first mild to moderate ischemic stroke. CF differed according to NMDAR1-abs serum titer, with patients with high NMDAR1-abs titers having a less favorable cognitive outcome compared to seronegative patients. Show less
Background The smoking-paradox of a better outcome in ischemic stroke patients who smoke may be due to increased efficacy of thrombolysis. We investigated the effect of smoking on outcome following... Show moreBackground The smoking-paradox of a better outcome in ischemic stroke patients who smoke may be due to increased efficacy of thrombolysis. We investigated the effect of smoking on outcome following endovascular therapy (EVT) with mechanical thrombectomy alone versus in combination with intra-arterial (IA-) thrombolysis.Methods The primary endpoint was defined by three-month modified Rankin Scale (mRS). We performed a generalized linear model and reported relative risks (RR) for smoking (adjustment for age, sex, hypertension, atrial fibrillation, stroke severity, time to EVT) in patient data stemming from the Virtual International Stroke Trials Archive-Endovascular database.Results Among 1,497 patients, 740(49.4%) were randomized to EVT; among EVT patients, 524(35.0%) received mechanical thrombectomy alone and 216(14.4%) received it in combination with IA-thrombolysis. Smokers (N = 396) had lower mRS scores (mean 2.9 vs. 3.2; p = 0.02) and mortality rates (10% vs. 17.3%; p<0.001) in univariate analysis. In all patients and in patients treated with mechanical thrombectomy alone, smoking had no effect on outcome in regression analyses. In patients who received IA-thrombolysis (N = 216;14%), smoking had an adjusted RR of 1.65 for an mRS1 (95%CI 0.77-3.55). Treatment with IA-thrombolysis itself led to reduced RR for favorable outcome (adjusted RR 0.30); interaction analysis of IA-thrombolysis and smoking revealed that non-smokers with IA-thrombolysis had mRS <= 2 in 47 cases (30%, adjusted RR 0.53 [0.41-0.69]) while smokers with IA-thrombolysis had mRS <= 2 in 23 cases (38%, adjusted RR 0.61 [0.42-0.87]).Conclusions Smokers had no clear clinical benefit from EVT that incorporates IA-thrombolysis. Show less
BackgroundRecent evidence suggests cardiac troponin levels to be a marker of increased vascular risk. We aimed to assess whether levels of high-sensitivity cardiac troponin T (hs-cTnT) are... Show moreBackgroundRecent evidence suggests cardiac troponin levels to be a marker of increased vascular risk. We aimed to assess whether levels of high-sensitivity cardiac troponin T (hs-cTnT) are associated with recurrent vascular events and death in patients with first-ever, mild to moderate ischemic stroke.Methods and ResultsWe used data from the PROSCIS-B (Prospective Cohort With Incident Stroke Berlin) study. We computed Cox proportional hazards regression analyses to assess the association between hs-cTnT levels upon study entry (Roche Elecsys, upper reference limit, 14 ng/L) and the primary outcome (composite of recurrent stroke, myocardial infarction, and all-cause death). A total of 562 patients were analyzed (mean age, 67 years [SD 13]; 38.6% women; median National Institutes of Health Stroke Scale=2; hs-cTnT above upper reference limit, 39.2%). During a mean follow-up of 3 years, the primary outcome occurred in 89 patients (15.8%), including 40 (7.1%) recurrent strokes, 4 (0.7%) myocardial infarctions, and 51 (9.1%) events of all-cause death. The primary outcome occurred more often in patients with hs-cTnT above the upper reference limit (27.3% versus 10.2%; adjusted hazard ratio, 2.0; 95% CI, 1.3-3.3), with a dose-response relationship when the highest and lowest hs-cTnT quartiles were compared (15.2 versus 1.8 events per 100 person-years; adjusted hazard ratio, 4.8; 95% CI, 1.9-11.8). This association remained consistent in sensitivity analyses, which included age matching and stratification for sex.ConclusionsHs-cTnT is dose-dependently associated with an increased risk of recurrent vascular events and death within 3 years after first-ever, mild to moderate ischemic stroke. These findings support further studies of the utility of hs-cTnT for individualized risk stratification after stroke.RegistrationURL: ; Unique identifier: NCT01363856. Show less
Objective To determine the role of circulating microvesicles (MV) on long-term cardiovascular outcomes after stroke, we measured them in patients with first-ever stroke with a 3-year follow-up.... Show moreObjective To determine the role of circulating microvesicles (MV) on long-term cardiovascular outcomes after stroke, we measured them in patients with first-ever stroke with a 3-year follow-up. Methods In the Prospective Cohort With Incident Stroke Berlin (PROSCIS-B), patients with first-ever ischemic stroke were followed up for 3 years. The primary combined endpoint consisted of recurrent stroke, myocardial infarction, and all-cause mortality. Citrate-blood levels of endothelial MV (EMV), leukocyte-derived MV (LMV), monocytic MV (MMV), and platelet-derived MV (PMV) were measured with flow cytometry. Kaplan-Meier curves and adjusted Cox proportional hazards models were used to estimate the effect of MV levels on the combined endpoint. Results Five hundred seventy-one patients were recruited (median age 69 years, 39% female, median NIH Stroke Scale score 2, interquartile range 1-4), and 95 endpoints occurred. Patients with levels of EMV (adjusted hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.2-4.9) or LMV (HR 3.1, 95% CI 1.4-6.8) in the highest quartile were more likely to experience an event than participants with lower levels with the lowest quartile used as the reference category. The association was less pronounced for PMV (HR 1.7, 95% CI 0.9-3.2) and absent for MMV (HR 1.1, 95% CI 0.6-1.8). Conclusion High levels of EMV and LMV after stroke were associated with worse cardiovascular outcome within 3 years. These results reinforce that endothelial dysfunction and vascular inflammation affect the long-term prognosis after stroke. EMV and LMV might play a role in risk prediction for stroke patients. ClinicalTrials.gov Identifier NCT01363856. Classification of Evidence This study provides Class II evidence of the effect of MV levels on subsequent stroke, myocardial infarction, or all-cause mortality in survivors of mild stroke. Show less
Ebinger, M.; Siegerink, B.; Kunz, A.; Wendt, M.; Weber, J.E.; Schwabauer, E.; ... ; Audebert, H.J. 2021
Importance Effects of thrombolysis in acute ischemic stroke are time-dependent. Ambulances that can administer thrombolysis (mobile stroke units [MSUs]) before arriving at the hospital have been... Show moreImportance Effects of thrombolysis in acute ischemic stroke are time-dependent. Ambulances that can administer thrombolysis (mobile stroke units [MSUs]) before arriving at the hospital have been shown to reduce time to treatment. Objective To determine whether dispatch of MSUs is associated with better clinical outcomes for patients with acute ischemic stroke. Design, Setting, and Participants This prospective, nonrandomized, controlled intervention study was conducted in Berlin, Germany, from February 1, 2017, to October 30, 2019. If an emergency call prompted suspicion of stroke, both a conventional ambulance and an MSU, when available, were dispatched. Functional outcomes of patients with final diagnosis of acute cerebral ischemia who were eligible for thrombolysis or thrombectomy were compared based on the initial dispatch (both MSU and conventional ambulance or conventional ambulance only). Exposure Simultaneous dispatch of an MSU (computed tomographic scanning with or without angiography, point-of-care laboratory testing, and thrombolysis capabilities on board) and a conventional ambulance (n = 749) vs conventional ambulance alone (n = 794). Main Outcomes and Measures The primary outcome was the distribution of modified Rankin Scale (mRS) scores (a disability score ranging from 0, no neurological deficits, to 6, death) at 3 months. The coprimary outcome was a 3-tier disability scale at 3 months (none to moderate disability; severe disability; death) with tier assignment based on mRS scores if available or place of residence if mRS scores were not available. Common odds ratios (ORs) were used to quantify the association between exposure and outcome; values less than 1.00 indicated a favorable shift in the mRS distribution and lower odds of higher levels of disability. Results Of the 1543 patients (mean age, 74 years; 723 women [47%]) included in the adjusted primary analysis, 1337 (87%) had available mRS scores (primary outcome) and 1506 patients (98%) had available the 3-tier disability scale assessment (coprimary outcome). Patients with an MSU dispatched had lower median mRS scores at month 3 (1; interquartile range [IQR], 0-3) than did patients without an MSU dispatched (2; IQR, 0-3; common OR for worse mRS, 0.71; 95% CI, 0.58-0.86; P < .001). Similarly, patients with an MSU dispatched had lower 3-month coprimary disability scores: 586 patients (80.3%) had none to moderate disability; 92 (12.6%) had severe disability; and 52 (7.1%) had died vs patients without an MSU dispatched: 605 (78.0%) had none to moderate disability; 103 (13.3%) had severe disability; and 68 (8.8%) had died (common OR for worse functional outcome, 0.73, 95% CI, 0.54-0.99; P = .04). Conclusions and Relevance In this prospective, nonrandomized, controlled intervention study of patients with acute ischemic stroke in Berlin, Germany, the dispatch of mobile stroke units, compared with conventional ambulances alone, was significantly associated with lower global disability at 3 months. Clinical trials in other regions are warranted.This cohort study compares global disability at 3 months among Berlin patients with out-of-hospital ischemic stroke brought to care via a mobile stroke unit ambulance (with prehospital CT scanning with or without angiography, point-of-care laboratory testing, prehospital thrombolysis) vs conventional ambulance alone.Question Is the dispatch of mobile stroke units in the out-of-hospital setting before arriving at the hospital associated with better functional outcomes among patients with acute ischemic stroke eligible for thrombolysis or thrombectomy? Findings In this prospective nonrandomized controlled intervention study involving 1543 patients in Berlin, Germany, the dispatch of mobile stroke units in addition to conventional ambulances vs conventional ambulances alone was significantly associated with lower levels of global disability at 3 months (common odds ratio for higher modified Rankin Scale scores [ie, worse outcome], 0.71). Meaning Among patients with acute ischemic stroke in Berlin, Germany, dispatch of a mobile stroke unit was associated with lower global disability at 3 months; further research in diverse settings is needed. Show less
Background: Many regions worldwide reported a decline of stroke admissions during the early phase of the coronavirus disease 2019 (COVID-19) pandemic. It remains unclear whether urban and rural... Show moreBackground: Many regions worldwide reported a decline of stroke admissions during the early phase of the coronavirus disease 2019 (COVID-19) pandemic. It remains unclear whether urban and rural regions experienced similar declines and whether deviations from historical admission numbers were more pronounced among specific age, stroke severity or treatment groups.Methods: We used registry datasets from (a) nine acute stroke hospitals in Berlin, and (b) nine hospitals from a rural TeleNeurology network in Northeastern Germany for primary analysis of 3-week-rolling average of stroke/TIA admissions before and during the COVID-19 pandemic. We compared course of stroke admission numbers with regional cumulative severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) infections. In secondary analyses, we used emergency department logs of the Berlin Charite University hospital to investigate changes in age, stroke severity, and thrombolysis/thrombectomy frequencies during the early regional Sars-CoV-2 spread (March and April 2020) and compared them with preceding years.Results: Compared to past years, stroke admissions decreased by 20% in urban and 20-25% in rural hospitals. Deviations from historical averages were observable starting in early March and peaked when numbers of regional Sars-CoV-2 infections were still low. At the same time, average admission stroke severity and proportions of moderate/severe strokes (NIHSS >5) were 20 and 20-40% higher, respectively. There were no relevant deviations observed in proportions of younger patients (<65 years), proportions of patients with thrombolysis, or number of thrombectomy procedures. Stroke admissions at Charite subsequently rebounded and reached near-normal levels after 4 weeks when the number of new Sars-CoV-2 infections started to decrease.Conclusions: During the early pandemic, deviations of stroke-related admissions from historical averages were observed in both urban and rural regions of Northeastern Germany and appear to have been mainly driven by avoidance of admissions of mildly affected stroke patients. Show less
Background Though risk for recurrent vascular events is high following ischemic stroke, little knowledge about risk factors for secondary events post-stroke exists. Objectives Coagulation factors... Show moreBackground Though risk for recurrent vascular events is high following ischemic stroke, little knowledge about risk factors for secondary events post-stroke exists. Objectives Coagulation factors XII, XI, and VIII (FXII, FXI, and FVIII) have been implicated in first thrombotic events, and our aim was to estimate their effects on vascular outcomes within 3 years after first stroke. Patients/Methods In the Prospective Cohort with Incident Stroke Berlin (PROSCIS-B) study, we followed participants aged 18 and older for 3 years after first mild to moderate ischemic stroke event or until occurrence of recurrent stroke, myocardial infarction, or all-cause mortality. We compared high coagulation factor activity levels to normal and low levels and also analyzed activities as continuous variables. We used Cox proportional hazards models adjusted for age, sex, and cardiovascular risk factors to estimate hazard ratios (HRs) for the combined endpoint. Results In total, 94 events occurred in 576 included participants, resulting in an absolute rate of 6.6 events per 100 person-years. After confounding adjustment, high FVIII activity showed the strongest relationship with the combined endpoint (HR = 2.05, 95% confidence interval [CI] 1.28-3.29). High FXI activity was also associated with a higher hazard (HR = 1.80, 95% CI 1.09-2.98), though high FXII activity was not (HR = 0.86, 95% CI 0.49-1.51). Continuous analyses yielded similar results. Conclusions In our study of mild to moderate ischemic stroke patients, high activity levels of FXI and FVIII but not FXII were associated with worse vascular outcomes in the 3-year period after first ischemic stroke. Show less
Background We compared two simple and rapid diameter-based methods (ABC/2, od-value) in terms of their accuracy in predicting lesion volume >70 ml and >100 ml. Methods In 238 DWI images of... Show moreBackground We compared two simple and rapid diameter-based methods (ABC/2, od-value) in terms of their accuracy in predicting lesion volume >70 ml and >100 ml. Methods In 238 DWI images of ischemic stroke patients from the AXIS2 trial, maximum lesion diameter and corresponding maximum orthogonal diameter were measured. Estimation of infarct volume based on od-value and ABC/2 calculation was compared to volumetric assessments. Results Accuracy of od-value and ABC/2 was similar for >70 ml (92.0 vs. 87.4) and >100 ml (92.9 vs. 93.3). ABC/2 overestimated lesion volume by 29.9%, resulting in a lower specificity. Conclusions Od-value is a robust tool for patient selection in trials. Show less
Kufner, A.; Ebinger, M.; Luijckx, G.J.; Endres, M.; Siegerink, B.; Dutch String Pearls Stroke Study 2020
Background:The smoking-thrombolysis paradox refers to a better outcome in smokers who suffer from acute ischemic stroke (AIS) following treatment with thrombolysis. However, studies on this subject... Show moreBackground:The smoking-thrombolysis paradox refers to a better outcome in smokers who suffer from acute ischemic stroke (AIS) following treatment with thrombolysis. However, studies on this subject have yielded contradictory results and an interaction analysis of exposure to smoking and thrombolysis in a large, multicenter database is lacking. Methods:Consecutive AIS patients admitted within 12 h of symptom onset between 2009 and 2014 from the prospective, multicenter stroke registry (Dutch String-of-Pearls Stroke Study) were included for this analysis. We performed a generalized linear model for functional outcome 3 months post-stroke depending on risk of the exposure variables (smoking yes/no, thrombolysis yes/no). The following confounders were adjusted for: age, smoking, hypertension, atrial fibrillation, diabetes mellitus, stroke severity, and stroke etiology. Results:Out of 468 patients, 30.6% (N= 143) were smokers and median baseline NIHSS was 3 (interquartile range 1-6). Smoking alone had a crude and adjusted relative risk (RR) of 0.99 (95% CI 0.89-1.10) and 0.96 (95% CI 0.86-1.01) for good outcome (modified Rankin Score <= 2), respectively. A combination of exposure variables (smoking and thrombolysis) did not change the results significantly [crude RR 0.87 (95% CI 0.74-1.03], adjusted RR 1.1 (95%CI 0.90-1.30)]. Smoking alone had an adjusted RR of 1.2 (95% CI 0.6-2.7) for recanalization following thrombolysis (N= 88). Conclusions:In patients with mild to moderate AIS admitted within 12 h of symptom onset, smoking did not modify treatment effect of thrombolysis. Show less
Klok, F.A.; Boon, G.J.A.M.; Barco, S.; Endres, M.; Geelhoed, J.J.M.; Knauss, S.; ... ; Siegerink, B. 2020
