Martin Ebinger

Prehospital stroke management on mobile stroke units (MSUs) shortens time to IV thrombolysis (IVT) and improves functional outcomes. Because IVT effects are time-dependent, optimizing workflows and dispatch-related processes may enhance MSU benefits. The B_PROUD-2.0 study aimed to determine the effect of additional MSU dispatch on functional outcomes in acute stroke patients under optimized MSU organization and service delivery. In the nonrandomized, controlled B_PROUD-2.0 study (May 2019-April 2021) conducted in Berlin, Germany, MSUs were simultaneously dispatched with conventional care ambulances for suspected stroke emergency calls, whenever available. We compared outcomes and process parameters between dispatch groups (additional MSU dispatch vs conventional care only) among patients with cerebral ischemia with disabling neurologic symptoms and no contraindications to reperfusion treatments. We used data from the Berlin dispatch center and records from the B_SPATIAL registry, consisting of 15 Berlin hospitals with stroke units. We performed pooled analyses with the B_PROUD-1.0 primary population (February 2017-April 2021) and with an extended cohort that also included patients with reperfusion treatment contraindications. The primary and co-primary outcomes were 3-month modified Rankin Scale scores (0: no deficits to 6: death) and 3-tiered disability scale scores. Effect estimates for these outcomes were obtained from ordinal logistic regressions, adjusting for a priori selected covariates after multiple imputation for missing values. Coronavirus disease 2019 pandemic and limited funding hindered full implementation of procedural improvements. A total of 1,050 patients (mean age: 74 years, 46.7% female) were included in B_PROUD-2.0 (vs 1,500 planned). We found no statistically significant effect of MSU dispatch on primary (common odds ratio [cOR] 0.90, 95% CI 0.72-1.14) or co-primary (cOR 0.86, 95% CI 0.63-1.17) outcomes in B_PROUD-2.0, and higher odds of IVT ≤1 hour of dispatch in the MSU group (OR 10.15, 95% CI 7.10-14.51). In pooled B_PROUD-1.0+2.0 primary population analyses (N = 2,666, mean age: 73 years, 46.8% female), we found a beneficial effect on primary (cOR 0.80, 95% CI 0.67-0.96) and co-primary (cOR 0.79, 95% CI 0.64-0.97) outcomes. The average effect on all stroke/TIA patients in the extended cohort (N = 4,336, mean age 75 years, 47.6% female) was also favorable (primary cOR 0.85, 95% CI 0.75-0.95; co-primary cOR 0.86, 95% CI 0.75-0.99). While we did not observe statistically significant differences in functional outcomes in the underpowered B_PROUD-2.0 study, we found beneficial effects considering both B_PROUD study periods, also when including all stroke/TIA patients. ClinicalTrials.gov: NCT03931616. Registered: April 26, 2019. First patient enrolled: May 9, 2019. The B_PROUD-2.0 study provides Class III evidence that the addition of MSUs to conventional care ambulances did not improve functional outcomes at 3 months compared with conventional care ambulances alone in patients with acute ischemic stroke.

BACKGROUND: Blood-brain barrier (BBB) leakage measured with dynamic susceptibility contrast-enhanced magnetic resonance imaging (MRI) has been associated with hemorrhagic transformation in acute ischemic stroke. However, the influence of prethrombolysis BBB leakage on infarct growth has not been studied. Therefore, we aimed to characterize BBB integrity according to tissue state at admission and tissue fate on follow-up MRI. METHODS: This is a post hoc analysis of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke). Ischemic cores were segmented on diffusion-weighted imaging at baseline and on fluid-attenuated inversion recovery images at follow-up (22–36 hours). Dynamic susceptibility contrast-enhanced–MRI provided penumbra masks (time to maximum of the tissue residue function >6 s minus ischemic core) and BBB leakage (extraction fraction [EF], Z scored) maps via automated analysis. EF was averaged within the ischemic core, total penumbra, 2 penumbra subtypes (salvaged/infarcted penumbra), and normal tissue. Adjusted linear mixed-effects models tested for differences between tissue types and associations of EF with clinical/imaging outcomes. Complementary voxel-wise analyses were performed. RESULTS: Of 503 patients enrolled in the trial, 165 with suitable dynamic susceptibility contrast-enhanced–MRI data were included in this analysis (mean age 66 years, 38% women, median National Institutes of Health Stroke Scale score of 6; 53% receiving alteplase). EF was significantly increased in the ischemic core and penumbra relative to normally perfused tissue, while differences between total penumbra and ischemic core were statistically nonsignificant. Infarcted penumbra exhibited higher EF than salvaged penumbra, even after adjusting for hypoperfusion severity ( P <0.001, n=79 with baseline penumbral tissue and follow-up MRI). Voxel-wise analyses showed a significant association between EF and voxel-level infarction in the placebo group only. EF did not predict hemorrhagic transformation or functional outcomes. CONCLUSIONS: Penumbral BBB leakage may identify tissue at increased risk of infarction. Larger, prospective studies are needed to determine the clinical relevance of BBB leakage as an imaging marker of tissue fate. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01525290. URL: https://eudract.ema.europa.eu/ ; Unique identifier: 2011-005906-32.

BACKGROUND: White matter hyperintensities of presumed vascular origin (WMH) are the most prominent imaging feature of cerebral small vessel disease (cSVD). Previous studies suggest a link between cSVD burden and intracerebral hemorrhage and worse functional outcome after thrombolysis in acute ischemic stroke. We aimed to determine the impact of WMH burden on efficacy and safety of thrombolysis in the MRI-based randomized controlled WAKE-UP trial of intravenous alteplase in unknown onset stroke. METHODS: The design of this post hoc study was an observational cohort design of a secondary analysis of a randomized trial. WMH volume was quantified on baseline fluid-attenuated inversion recovery images of patients randomized to either alteplase or placebo in the WAKE-UP trial. Excellent outcome was defined as score of 0-1 on the modified Rankin Scale after 90 days. Hemorrhagic transformation was assessed on follow-up imaging 24-36 hours after randomization. Treatment effect and safety were analyzed by fitting multivariable logistic regression models. RESULTS: Quality of scans was sufficient in 441 of 503 randomized patients to delineate WMH. Median age was 68 years, 151 patients were female, and 222 patients were assigned to receive alteplase. Median WMH volume was 11.4 mL. Independent from treatment, WMH burden was statistically significantly associated with worse functional outcome (odds ratio, 0.72 [95% CI, 0.57–0.92]), but not with higher chances of any hemorrhagic transformation (odds ratio, 0.78 [95% CI, 0.60–1.01]). There was no interaction of WMH burden and treatment group for the likelihood of excellent outcome ( P =0.443) or any hemorrhagic transformation ( P =0.151). In a subgroup of 166 patients with severe WMH, intravenous thrombolysis was associated with higher odds of excellent outcome (odds ratio, 2.40 [95% CI, 1.19–4.84]) with no significant increase in the rate of hemorrhagic transformation (odds ratio, 1.96 [95% CI, 0.80–4.81]). CONCLUSIONS: Although WMH burden is associated with worse functional outcome, there is no association with treatment effect or safety of intravenous thrombolysis in patients with ischemic stroke of unknown onset. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01525290.

Background: Reversibility of the diffusion-weighted imaging (DWI) lesion means that not all of the DWI lesion represents permanently injured tissue. We investigated DWI reversibility and the association with thrombolysis, reperfusion and functional outcome in patients from the WAKE-UP trial (Efficacy and Safety of Magnetic Resonance Imaging–Based Thrombolysis in Wake-Up Stroke). Methods: In this retrospective analysis of WAKE-UP, a randomized controlled trial (RCT) between September 2012 and June 2017 in Belgium, Denmark, France, Germany, Spain and United Kingdom, a convolutional neural network segmented the DWI lesions (b=1000 s/mm ² ) at baseline and follow-up (24 hours). We calculated absolute and relative DWI reversibility in 2 ways: first, a volumetric (baseline volume−24-hour volume >0) and second, a voxel-based (part of baseline lesion not overlapping with 24-hour lesion) approach. We additionally defined relative voxel-based DWI-reversibility >50% to account for coregistration inaccuracies. We calculated the odds ratio for reversibility according to treatment arm. We analyzed the association of reversibility with excellent functional outcome (modified Rankin Scale score of 0–1), in a multivariable model. Results: In 363 patients, the median DWI volume was 3 (1–10) mL at baseline and 6 (2–20) mL at follow-up. Volumetric DWI reversibility was present in 19% (69/363) with a median absolute reversible volume of 1 mL (0–2) or 28% (14–50) relatively. Voxel-based DWI reversibility was present in 358/363 (99%) with a median absolute volume of 1 mL (0–2), or 22% (9–38) relatively. In 18% of the patients (67/363), relative voxel-based DWI reversibility >50% was present. Volumetric DWI reversibility and relative voxel-based DWI reversibility >50% was more frequent in patients treated with alteplase versus placebo (OR, 1.86 [95% CI, 1.09–3.17] and OR, 2.03 [95% CI, 1.18–3.50], respectively). Relative voxel-based DWI reversibility >50% was associated with excellent functional outcome (OR, 2.30 [95% CI, 1.17–4.51]). Conclusions: Small absolute volumes of DWI reversibility were present in a large proportion of randomized patients in the WAKE-UP trial. Reversibility was more often present after thrombolysis.

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 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 Charité–Universitätsmedizin 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.

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.

Purpose of review: The earlier the treatment, the better the outcomes after acute ischemic stroke. Optimizing prehospital care bears potential to shorten treatment times. We here review the recent literature on mothership vs. drip-and-ship as well as mobile stroke unit concepts. Recent findings: Mobile stroke units result in the shortest onset-to-treatment times in mostly urban settings. Summary: Future research should focus on further streamlining processes around mobile stroke units, especially improving dispatch algorithms and improve referral for endovascular therapy.

Background and aim: To report the six-month safety analyses among patients enrolled in the “Physical Fitness Training in Subacute Stroke—PHYS-STROKE” trial and identify underlying risk factors associated with serious adverse events. Methods: We performed a pre-specified safety analysis of a multicenter, randomized controlled, endpoint-blinded trial comprising 200 patients with moderate to severe subacute stroke (days 5–45 after stroke) that were randomly assigned (1:1) to receive either aerobic, bodyweight supported, treadmill-based training (n = 105), or relaxation sessions (n = 95, control group). Each intervention session lasted for 25 min, five times weekly for four weeks, in addition to standard rehabilitation therapy. Serious adverse events defined as cerebro- and cardiovascular events, readmission to hospital, and death were assessed during six months of follow-up. Incident rate ratios (IRR) were calculated, and Poisson regression analyses were conducted to identify risk factors for serious adverse events and to test the association with aerobic training. Results: Six months after stroke, 50 serious adverse events occurred in the trial with a higher incidence rate (per 100 patient-months) in the training group compared to the relaxation group (6.31 vs. 3.22; IRR 1.70, 95% CI 0.96 to 3.12). The association of aerobic training with serious adverse events incidence rates were modified by diabetes mellitus (IRR for interaction: 7.10, 95% CI 1.56 to 51.24) and by atrial fibrillation (IRR for interaction: 4.37, 95% CI 0.97 to 31.81). Conclusions: Safety analysis of the PHYS-STROKE trial found a higher rate of serious adverse events in patients randomized to aerobic training compared to control within six months after stroke. Exploratory analyses found an association between serious adverse events occurrence in the aerobic training group with pre-existing diabetes mellitus and atrial fibrillation which should be further investigated in future trials. Data access statement: The raw data and analyses scripts are provided by the authors on a secure online repository for reproduction of reported findings.

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 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 hours 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 three months post-stroke depending on risk of the exposure variables (smoking yes/no, thrombolysis yes/no). The following confounders were adjusted for: smoking, hypertension, atrial fibrillation, stroke severity, and stroke etiology. Results: Out of 468 patients, 30.6% 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 0.97 (95%CI 0.87-1.01) 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 0.93-1.33]). 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 hours of symptom onset, smoking did not modify treatment effect of thrombolysis.

Objective: To explore the prevalence of the perfusion‐weighted imaging (PWI)–diffusion‐weighted imaging (DWI) mismatch and response to intravenous thrombolysis in the WAKE‐UP trial.Methods: We performed a prespecified post hoc analysis of ischemic stroke patients screened for DWI–fluid‐attenuated inversion recovery (FLAIR) mismatch in WAKE‐UP who underwent PWI. We defined PWI‐DWI mismatch as ischemic core volume < 70ml, mismatch volume > 10ml, and mismatch ratio > 1.2. Primary efficacy end point was a modified Rankin Scale score of 0–1 at 90 days, adjusted for age and symptom severity.Results: Of 1,362 magnetic resonance imaging–screened patients, 431 underwent PWI. Of these, 57 (13%) had a double mismatch, 151 (35%) only a DWI‐FLAIR mismatch, and 54 (13%) only a PWI‐DWI mismatch. DWI‐FLAIR mismatch was more prevalent than PWI‐DWI mismatch (48%, 95% confidence interval [CI] = 43–53% vs 26%, 95% CI = 22–30%; p < 0.0001). Screening for either one of the mismatch profiles resulted in a yield of 61% (95% CI = 56–65%). Prevalence of PWI‐DWI mismatch was similar in patients with (27%) or without (24%) DWI‐FLAIR mismatch (p = 0.52). In an exploratory analysis in the small subgroup of 208 randomized patients with PWI, PWI‐DWI mismatch status did not modify the treatment response (p for interaction = 0.73).Interpretation: Evaluating both the DWI‐FLAIR and PWI‐DWI mismatch patterns in patients with unknown time of stroke onset will result in the highest yield of thrombolysis treatment. The treatment benefit of alteplase in patients with a DWI‐FLAIR mismatch seems to be driven not merely by the presence of a PWI‐DWI mismatch, although this analysis was underpowered. ANN NEUROL 2020;87:931–938