Vincent N. Thijs

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. 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. 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. 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. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://eudract.ema.europa.eu/; Unique identifier: 2011-005906-32.

The international trial AVERT (A Very Early Rehabilitation Trial) found that very early mobilization (VEM; commenced <24 hours after stroke) negatively affected functional outcome (modified Rankin Scale [mRS]). The drivers of this effect remain unclear. One plausible mechanism is that high-dose upright activity worsens cerebral perfusion in patients with cerebral large vessel occlusion (LVO). For this retrospective AVERT substudy, we collected brain imaging from participants from 8 AVERT sites (n=910) to explore the potential relationship between LVO, VEM, and mRS in ischemic stroke. We hypothesized that patients with evidence of LVO would be adversely affected by VEM compared with non-LVO patients. In this post hoc analysis of a randomized controlled trial, 2 neurologists independently classified patients with ischemic stroke as having LVO via direct (vessel truncation on computed tomography/magnetic resonance imaging angiography) or indirect evidence (hyperdense artery sign or established infarction of >2/3 of an arterial territory) from brain imaging obtained ≤7 days poststroke. The associations between LVO, VEM, and 3- and 12-month mRS was tested using logistic regression, adjusted for age, treatment with thrombolysis, and baseline National Institutes of Health Stroke Scale. Interrater reliability for LVO signs was high (weighted κ, 0.842 [95% CI, 0.631-0.969]). Of 689 participants (37.2% female; median age, 74.5 [interquartile range, 65.0-81.2] years) included in the primary analysis, 192 (28%) showed direct or indirect evidence of LVO. Computed tomography/magnetic resonance imaging angiography were available in 179 (26%) of those 689 participants. While LVO was associated with poor mRS (>2) at 3 months (adjusted odds ratio, 2.15 [95% CI, 1.29-3.64]) and 12 months (adjusted odds ratio, 1.76 [95% CI, 1.1-2.84]; P=0.02), there was no significant interaction between VEM, LVO, and mRS (P=0.16). We found no evidence that VEM was specifically harmful in patients with LVO. However, as arterial imaging was not consistently obtained before first mobilization, larger prospective studies with standardized measures of LVO are needed to fully address this question. URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=1266&isReview=true; Unique identifier: ACTRN12606000185561.

Tissue-level hypoperfusion (no-reflow) persists in 30% of patients with seemingly successful upstream angiographic recanalization at thrombectomy. We investigated the clinical impact of the no-reflow phenomenon by comparing patients with no-reflow versus patients with varying degrees of angiographic recanalization. In a post hoc pooled analysis of the EXTEND-IA (Endovascular Therapy for Ischemic Stroke With Perfusion-Imaging Selection) and EXTEND-IA TNK (Tenecteplase Versus Alteplase Before Thrombectomy for Ischemic Stroke) part 1 and 2 trials, clinical and radiological outcomes were compared between patients with (1) full angiographic recanalization with no-reflow (expanded Treatment in Cerebral Ischemia [eTICI] 2c3-NoReflow), defined as >15% reduction in relative cerebral blood flow or Volume within the infarct relative to a contralateral homolog on 24-hour-follow-up perfusion computed tomography or magnetic resonance imaging despite eTICI grade 2c-3 angiographic recanalization, (2) full angiographic recanalization and tissue reperfusion (eTICI 2c3-CompleteFlow), (3) partial angiographic recanalization (eTICI 2b), and (4) unsuccessful thrombectomy (eTICI 0-2a). The primary outcome, functional independence at 90 days, was investigated using a mixed effect logistic regression model, both unadjusted and adjusted for a priori-selected covariates, namely age, premorbid modified Rankin Scale, baseline National Institutes of Health Stroke Scale, and baseline core volume. Among 537 patients from the overall pooled cohort, 456 patients were included in the analysis. The mean age of the included patients was 71 years old, and 54% were male. A favorable outcome (90-day modified Rankin Scale score of 0-2 or return to baseline modified Rankin Scale) was observed in 43.33% (n=13/30) of patients with eTICI 2c3-NoReflow, 67.50% (n=81/120) of eTICI 2c3-CompleteFlow, 63.03% (n=150/238) of eTICI 2b, and 50.00% (n=34/68) of unsuccessful thrombectomy. In multivariable analysis, patients with eTICI 2c3-NoReflow had lower odds of favorable outcome compared with those with eTICI 2c3-CompleteFlow (adjusted odds ratio, 0.31 [95% CI, 0.12-0.77]; P=0.01) and eTICI 2b (adjusted odds ratio, 0.40 [95% CI, 0.17-0.96]; P=0.04) but not unsuccessful thrombectomy (adjusted odds ratio, 1.02 [95% CI, 0.38-2.73]; P=0.97). Patients with eTICI 2c3-NoReflow had similar follow-up infarct volume to unsuccessful thrombectomy (β=-8.26 [95% CI, -27.38 to 10.86]; P=0.40) and eTICI 2b (β=9.38 [95% CI, -7.33 to 26.09]; P=0.27) but had larger infarcts compared with eTICI 2c3-CompleteFlow (β=18.85 [95% CI, 1.16-36.54]; P=0.04). When no-reflow occurred, clinical and radiological outcomes in patients with full angiographic recanalization were similar to patients with unsuccessful thrombectomy. Preventing or reversing no-reflow has the potential to augment the clinical benefit of reperfusion treatment in ischemic stroke.

There is currently no single resource for UI/UX guidelines and design standards that encapsulates all the requirements for young stroke survivors (<55 years) and their carers. We reviewed 25 studies to provide a summary of recommendations for designing stroke rehabilitation and self-management apps and digital platforms for young stroke survivors. The findings highlight the need for participatory codesign and research to build consensus on UI/UX guidelines and design standards.

Background and Objectives: Data from randomized trials on the treatment effect of pure thrombolysis in patients with vessel occlusion are lacking. We examined data from a corresponding subsample of patients from the multicenter, randomized, placebo-controlled WAKE-UP trial to determine whether MRI-guided IV thrombolysis with alteplase in unknown-onset ischemic stroke benefits patients presenting with vessel occlusion. Methods: Patients with an acute ischemic lesion visible on MRI diffusion-weighted imaging but no marked parenchymal hyperintensity on fluid-attenuated inversion recovery images were randomized to treatment with IV alteplase or placebo. The primary end point was a favorable outcome defined by a modified Rankin Scale score of 0-1 at 90 days after stroke. We investigated the interaction between vessel status and treatment effect using an unconditional logistic regression model. Treatment effects (adjusted odds ratio [aOR]) and their 95% CI were compared in patients with and without any vessel occlusion (AVO) and large vessel occlusion (LVO). Results: 185 patients (mean age 64.5 years, 46% female, median NIH Stroke Scale score 9, median time between last seen well and MRI 10.26 hours) received treatment and presented with an occlusion. 98 (20%) had LVO (defined as occlusion of the internal carotid artery, middle cerebral artery trunk, or combination). A favorable outcome was observed in 30 of 94 patients with AVO (31.9%) in the alteplase group and in 18 of 91 (19.8%) in the placebo group (aOR 2.04, 95% CI 1.00-4.18). In the subgroup of patients with LVO, a favorable outcome was observed in 16 of 53 (30.2%) in the alteplase group and in 7 of 44 (15.9%) in the placebo group (aOR 2.08, 95% CI 0.71-6.10). Treatment with alteplase was associated with higher odds of favorable outcomes with no heterogeneity of treatment effect between patients with AVO and patent vessel (p = 0.56), or between patients with and without LVO (p = 0.69). Discussion: Although the WAKE-UP study was not powered to demonstrate treatment efficacy in patient subpopulations, this subgroup analysis points to a benefit of MRI-guided thrombolysis in patients with unknown-onset ischemic stroke, independent of vessel occlusion. Clinical trial registration: Registered at ClinicalTrials.gov with unique identifier NCT01525290 (clinicaltrials.gov/study/NCT01525290). The study was first posted on February 2, 2012; the first patient was enrolled on September 24, 2012. Classification of evidence: This study provides Class II evidence that for patients with unknown-onset ischemic stroke with AVO, MRI-guided treatment with IV tissue plasminogen activator improves outcomes.

STOP-MSU: Stopping Haemorrhage With Tranexamic Acid for Hyperacute Onset Presentation Including Mobile Stroke Units. A Phase II Randomised, Placebo-controlled, Investigator-driven Trial of Tranexamic Acid Within 2 Hours of Intracerebral Haemorrhage

A Multicentre, Randomised Controlled Trial of Exenatide Versus Standard Care in Acute Ischemic Stroke (TEXAIS)

Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial