Publications by authors named "Keith W Muir"

169 Publications

Peripheral arteriopathy caused by Notch3 gain-of-function mutation involves ER and oxidative stress and blunting of NO/sGC/cGMP pathway.

Clin Sci (Lond) 2021 Mar;135(6):753-773

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K.

Notch3 mutations cause Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), which predisposes to stroke and dementia. CADASIL is characterised by vascular dysfunction and granular osmiophilic material (GOM) accumulation in cerebral small vessels. Systemic vessels may also be impacted by Notch3 mutations. However vascular characteristics and pathophysiological processes remain elusive. We investigated mechanisms underlying the peripheral vasculopathy mediated by CADASIL-causing Notch3 gain-of-function mutation. We studied: (i) small arteries and vascular smooth muscle cells (VSMCs) from TgNotch3R169C mice (CADASIL model), (ii) VSMCs from peripheral arteries from CADASIL patients, and (iii) post-mortem brains from CADASIL individuals. TgNotch3R169C vessels exhibited GOM deposits, increased vasoreactivity and impaired vasorelaxation. Hypercontractile responses were normalised by fasudil (Rho kinase inhibitor) and 4-phenylbutyrate (4-PBA; endoplasmic-reticulum (ER) stress inhibitor). Ca2+ transients and Ca2+ channel expression were increased in CADASIL VSMCs, with increased expression of Rho guanine nucleotide-exchange factors (GEFs) and ER stress proteins. Vasorelaxation mechanisms were impaired in CADASIL, evidenced by decreased endothelial nitric oxide synthase (eNOS) phosphorylation and reduced cyclic guanosine 3',5'-monophosphate (cGMP) levels, with associated increased soluble guanylate cyclase (sGC) oxidation, decreased sGC activity and reduced levels of the vasodilator hydrogen peroxide (H2O2). In VSMCs from CADASIL patients, sGC oxidation was increased and cGMP levels decreased, effects normalised by fasudil and 4-PBA. Cerebral vessels in CADASIL patients exhibited significant oxidative damage. In conclusion, peripheral vascular dysfunction in CADASIL is associated with altered Ca2+ homoeostasis, oxidative stress and blunted eNOS/sGC/cGMP signaling, processes involving Rho kinase and ER stress. We identify novel pathways underlying the peripheral arteriopathy induced by Notch3 gain-of-function mutation, phenomena that may also be important in cerebral vessels.
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http://dx.doi.org/10.1042/CS20201412DOI Listing
March 2021

Effect of intravenous alteplase on post-stroke depression in the WAKE UP trial.

Eur J Neurol 2021 Mar 3. Epub 2021 Mar 3.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

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.
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http://dx.doi.org/10.1111/ene.14797DOI Listing
March 2021

Cerebral Small Vessel Disease and Functional Outcome Prediction After Intracerebral Hemorrhage.

Neurology 2021 Apr 24;96(15):e1954-e1965. Epub 2021 Feb 24.

From the Stroke Research Centre (I.C.H., G.S., D.W., G.B., D.J.S., C.S., S.L., M.M.B., D.J.W.), University College London, Queen Square Institute of Neurology; Department of Neurology (G.S.), Stroke Unit, San Raffaele Hospital, Milan, Italy; Department of Statistical Science (G.A.), University College London, Gower Street, UK; Department of Neurology and Stroke Center (D.J.S.), Inselspital, Bern, Switzerland; Haemostasis Research Unit (H.C.), Department of Haematology, University College London, Chenies Mews; Lysholm Department of Neuroradiology and the Neuroradiological Academic Unit (T.A.Y., H.R.J.), Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London; Centre for Clinical Brain Sciences (R.A.-S.S.), School of Clinical Sciences, University of Edinburgh; Liverpool Centre for Cardiovascular Science (G.Y.H.L.), Liverpool Heart and Chest Hospital, University of Liverpool; Institute of Neuroscience & Psychology (K.W.M.), University of Glasgow, Queen Elizabeth University Hospital, Glasgow; and Department of Molecular Neuroscience (H.H.), UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London.

Objective: To determine whether CT-based cerebral small vessel disease (SVD) biomarkers are associated with 6-month functional outcome after intracerebral hemorrhage (ICH) and whether these biomarkers improve the performance of the preexisting ICH prediction score.

Methods: We included 864 patients with acute ICH from a multicenter, hospital-based prospective cohort study. We evaluated CT-based SVD biomarkers (white matter hypodensities [WMH], lacunes, brain atrophy, and a composite SVD burden score) and their associations with poor 6-month functional outcome (modified Rankin Scale score >2). The area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow test were used to assess discrimination and calibration of the ICH score with and without SVD biomarkers.

Results: In multivariable models (adjusted for ICH score components), WMH presence (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.12-2.06), cortical atrophy presence (OR 1.80, 95% CI 1.19-2.73), deep atrophy presence (OR 1.66, 95% CI 1.17-2.34), and severe atrophy (either deep or cortical) (OR 1.94, 95% CI 1.36-2.74) were independently associated with poor functional outcome. For the revised ICH score, the AUROC was 0.71 (95% CI 0.68-0.74). Adding SVD markers did not significantly improve ICH score discrimination; for the best model (adding severe atrophy), the AUROC was 0.73 (95% CI 0.69-0.76). These results were confirmed when lobar and nonlobar ICH were considered separately.

Conclusions: The ICH score has acceptable discrimination for predicting 6-month functional outcome after ICH. CT biomarkers of SVD are associated with functional outcome, but adding them does not significantly improve ICH score discrimination.

Trial Registration Information: ClinicalTrials.gov Identifier: NCT02513316.
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http://dx.doi.org/10.1212/WNL.0000000000011746DOI Listing
April 2021

Extent of FLAIR Hyperintense Vessels May Modify Treatment Effect of Thrombolysis: A Analysis of the WAKE-UP Trial.

Front Neurol 2020 4;11:623881. Epub 2021 Feb 4.

Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Fluid-attenuated inversion recovery (FLAIR) hyperintense vessels (FHVs) on MRI are a radiological marker of vessel occlusion and indirect sign of collateral circulation. However, the clinical relevance is uncertain. We explored whether the extent of FHVs is associated with outcome and how FHVs modify treatment effect of thrombolysis in a subgroup of patients with confirmed unilateral vessel occlusion from the randomized controlled WAKE-UP trial. One hundred sixty-five patients were analyzed. Two blinded raters independently assessed the presence and extent of FHVs (defined as the number of slices with visible FHV multiplied by FLAIR slice thickness). Patients were then separated into two groups to distinguish between few and extensive FHVs (dichotomization at the median <30 or ≥30). Here, 85% of all patients ( = 140) and 95% of middle cerebral artery (MCA) occlusion patients ( = 127) showed FHVs at baseline. Between MCA occlusion patients with few and extensive FHVs, no differences were identified in relative lesion growth ( = 0.971) and short-term [follow-up National Institutes of Health Stroke Scale (NIHSS) score; = 0.342] or long-term functional recovery [modified Rankin Scale (mRS) <2 at 90 days poststroke; = 0.607]. In linear regression analysis, baseline extent of FHV (defined as a continuous variable) was highly associated with volume of hypoperfused tissue (β = 2.161; 95% CI 0.96-3.36; = 0.001). In multivariable regression analysis adjusted for treatment group, stroke severity, lesion volume, occlusion site, and recanalization, FHV did not modify functional recovery. However, in patients with few FHVs, the odds for good functional outcome (mRS) were increased in recombinant tissue plasminogen activator (rtPA) patients compared to those who received placebo [odds ratio (OR) = 5.3; 95% CI 1.2-24.0], whereas no apparent benefit was observed in patients with extensive FHVs (OR = 1.1; 95% CI 0.3-3.8), -value for interaction was 0.11. While the extent of FHVs on baseline did not alter the evolution of stroke in terms of lesion progression or functional recovery, it may modify treatment effect and should therefore be considered relevant additional information in those patients who are eligible for intravenous thrombolysis. Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered February 2, 2012.
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http://dx.doi.org/10.3389/fneur.2020.623881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890254PMC
February 2021

Connecting Upper Limb Functional Stroke Recovery to Global Disability Measures: Finding the Forest in the Trees.

Neurology 2021 04 15;96(14):643-644. Epub 2021 Feb 15.

From the Institute of Neuroscience & Psychology (K.W.M.), University of Glasgow, Queen Elizabeth University Hospital, Scotland, UK; and Department of Neurology (J.J.M.), University of Utah, Salt Lake City.

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http://dx.doi.org/10.1212/WNL.0000000000011671DOI Listing
April 2021

Should Tenecteplase Replace Alteplase for Acute Thrombolysis?

Authors:
Keith W Muir

Stroke 2021 Mar 16;52(3):1091-1093. Epub 2021 Feb 16.

Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, Scotland, United Kingdom.

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http://dx.doi.org/10.1161/STROKEAHA.120.033593DOI Listing
March 2021

Safety and efficacy of intravenous thrombolysis in stroke patients on prior antiplatelet therapy in the WAKE-UP trial.

Neurol Res Pract 2020 20;2:40. Epub 2020 Nov 20.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

Background: One quarter to one third of patients eligible for systemic thrombolysis are on antiplatelet therapy at presentation. In this study, we aimed to assess the safety and efficacy of intravenous thrombolysis in stroke patients on prescribed antiplatelet therapy in the WAKE-UP trial.

Methods: WAKE-UP was a multicenter, randomized, double-blind, placebo-controlled clinical trial to study the efficacy and safety of MRI-guided intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time. The medication history of all patients randomized in the WAKE-UP trial was documented. The primary safety outcome was any sign of hemorrhagic transformation on follow-up MRI. The primary efficacy outcome was favorable functional outcome defined by a score of 0-1 on the modified Rankin scale at 90 days after stroke, adjusted for age and baseline stroke severity. Logistic regression models were fitted to study the association of prior antiplatelet treatment with outcome and treatment effect of intravenous alteplase.

Results: Of 503 randomized patients, 164 (32.6%) were on antiplatelet treatment. Patients on antiplatelet treatment were older (70.3 vs. 62.8 years,  <  0.001), and more frequently had a history of hypertension, atrial fibrillation, diabetes, hypercholesterolemia, and previous stroke or transient ischaemic attack. Rates of symptomatic intracranial hemorrhage and hemorrhagic transformation on follow-up imaging did not differ between patients with and without antiplatelet treatment. Patients on prior antiplatelet treatment were less likely to achieve a favorable outcome (37.3% vs. 52.6%,  = 0.014), but there was no interaction of prior antiplatelet treatment with intravenous alteplase concerning favorable outcome ( = 0.355). Intravenous alteplase was associated with higher rates of favorable outcome in patients on prior antiplatelet treatment with an adjusted odds ratio of 2.106 (95% CI 1.047-4.236).

Conclusions: Treatment benefit of intravenous alteplase and rates of post-treatment hemorrhagic transformation were not modified by prior antiplatelet intake among MRI-selected patients with unknown onset stroke. Worse functional outcome in patients on antiplatelets may result from a higher load of cardiovascular co-morbidities in these patients.
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http://dx.doi.org/10.1186/s42466-020-00087-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678217PMC
November 2020

Symptoms and probabilistic anatomical mapping of lacunar infarcts.

Neurol Res Pract 2020 3;2:21. Epub 2020 Aug 3.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

Background: The anatomical distribution of acute lacunar infarcts has mainly been studied for supratentorial lesions. In addition, little is known about the association with distinct stroke symptoms, not summarized as classical lacunar syndromes. We aimed to describe the spatial lesion distribution of acute supra- and infratentorial lacunar infarcts and their association with stroke symptoms in patients eligible for thrombolysis.

Methods: All patients enrolled in the WAKE-UP trial (efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in wake-up stroke) were screened for lacunar infarcts on diffusion-weighted imaging (DWI). The relationship between the anatomical distribution of supra- and infratentorial lacunar infarcts, their demographic characteristics and acute stroke symptoms, defined by the National Institutes of Health Stroke Scale (NIHSS) score, were correlated and compared.

Results: Maps of lesion distribution from 224 lacunar infarct patients (76 [33.9%] females, mean age [standard deviation] of 63.4 [11.5] years) were generated using computational image mapping methods. Median infarct volume was 0.73 ml (interquartile range [IQR] 0.37-1.15 ml). Median NIHSS sum score on hospital arrival was 4 (IQR 3-6). 165 (73.7%) patients had lacunar infarcts in the supratentorial deep white or grey matter, while 59 (26.3%) patients had infratentorial lacunar infarcts. Patients with supratentorial lacunar infarcts presented with a significantly lower occurrence of deficits in the NIHSS items gaze ( < 0.001) and dysarthria ( = 0.008), but had more often a paresis of the left arm ( = 0.009) and left leg ( = 0.068) compared to patients with infratentorial infarcts.

Conclusions: The anatomical lesion distribution of lacunar infarcts reveals a distinct pattern and supports an association of localization with different stroke symptoms.

Trial Registration: NCT01525290.
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http://dx.doi.org/10.1186/s42466-020-00068-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650076PMC
August 2020

Small Vessel Disease and Ischemic Stroke Risk During Anticoagulation for Atrial Fibrillation After Cerebral Ischemia.

Stroke 2021 01 7;52(1):91-99. Epub 2020 Dec 7.

Department of Brain Repair and Rehabilitation, UCL Stroke Research Center (H.D., D.W., G.B., C.S., M.M.B., D.J.W.), UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London.

Background And Purpose: The causes of recurrent ischemic stroke despite anticoagulation for atrial fibrillation are uncertain but might include small vessel occlusion. We investigated whether magnetic resonance imaging markers of cerebral small vessel disease (SVD) are associated with ischemic stroke risk during follow-up in patients anticoagulated for atrial fibrillation after recent ischemic stroke or transient ischemic attack.

Methods: We analyzed data from a prospective multicenter inception cohort study of ischemic stroke or transient ischemic attack anticoagulated for atrial fibrillation (CROMIS-2 [Clinical Relevance of Microbleeds in Stroke Study]). We rated markers of SVD on baseline brain magnetic resonance imaging: basal ganglia perivascular spaces (number ≥11); cerebral microbleeds (number ≥1); lacunes (number ≥1); and white matter hyperintensities (periventricular Fazekas grade 3 or deep white matter Fazekas grade ≥2). We investigated the associations of SVD presence (defined as presence of ≥1 SVD marker) and severity (composite SVD score) with the risk of ischemic stroke during follow-up using a Cox proportional hazards model adjusted for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65-74, female score.

Results: We included 1419 patients (mean age: 75.8 years [SD, 10.4]; 42.1% female). The ischemic stroke rate during follow-up in patients with any SVD was 2.20 per 100-patient years (95% CI, 1.60-3.02), compared with 0.98 per 100 patient-years (95% CI, 0.59-1.62) in those without SVD (=0.008). After adjusting for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65-74, female score, SVD presence remained significantly associated with ischemic stroke during follow-up (hazard ratio, 1.89 [95% CI, 1.01-3.53]; =0.046); the risk of recurrent ischemic stroke increased with SVD score (hazard ratio per point increase, 1.33 [95% CI, 1.04-1.70]; =0.023).

Conclusions: In patients anticoagulated for atrial fibrillation after ischemic stroke or transient ischemic attack, magnetic resonance imaging markers of SVD are associated with an increased risk of ischemic stroke during follow-up; improved stroke prevention treatments are required in this population. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02513316.
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http://dx.doi.org/10.1161/STROKEAHA.120.029474DOI Listing
January 2021

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

Lancet 2020 11 8;396(10262):1574-1584. Epub 2020 Nov 8.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers.

Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903.

Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024).

Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(20)32163-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734592PMC
November 2020

Microbleeds and the Effect of Anticoagulation in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Randomized Clinical Trial.

JAMA Neurol 2021 Jan;78(1):11-20

Division of Neurology, McMaster University / Population Health Research Institute, Hamilton, Ontario, Canada.

Importance: The reported associations of cerebral microbleeds with recurrent stroke and intracerebral hemorrhage have raised concerns regarding antithrombotic treatment in patients with a history of stroke and microbleeds on magnetic resonance imaging.

Objective: To characterize microbleeds in embolic strokes of undetermined source (ESUS) and report interactions between microbleeds and the effects of random assignment to anticoagulant vs antiplatelet therapy.

Design, Setting, And Participants: Subgroup analyses of the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) international, double-blind, randomized, event-driven phase 3 clinical trial. Participants were enrolled between December 2014 and September 2017 and followed up for a median of 11 months. The study setting included 459 stroke recruitment centers in 31 countries. Patients aged 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of these 7213 NAVIGATE ESUS participants, 3699 (51%) had information on cerebral microbleeds reported on their baseline clinical magnetic resonance imaging and were eligible for these analyses. Patients with a prior history of symptomatic intracerebral hemorrhage were excluded from the NAVIGATE ESUS trial.

Interventions: Rivaroxaban, 15 mg, compared with aspirin, 100 mg, daily.

Main Outcomes And Measures: The primary outcome was recurrent stroke. Secondary outcomes were ischemic stroke, intracerebral hemorrhage, and all-cause mortality.

Results: Microbleeds were present in 395 of 3699 participants (11%). Of patients with cerebral microbleeds, mean (SD) age was 69.5 (9.4) years, 241 were men (61%), and 201 were White (51%). Advancing age (odds ratio [OR] per year, 1.03; 95% CI, 1.01-1.04), East Asian race/ethnicity (OR, 1.57; 95% CI, 1.04-2.37), hypertension (OR, 2.20; 95% CI, 1.54-3.15), multiterritorial infarcts (OR, 1.95; 95% CI, 1.42-2.67), chronic infarcts (OR, 1.78; 95% CI, 1.42-2.23), and occult intracerebral hemorrhage (OR, 5.23; 95% CI, 2.76-9.90) were independently associated with microbleeds. The presence of microbleeds was associated with a 1.5-fold increased risk of recurrent stroke (hazard ratio [HR], 1.5; 95% CI, 1.0-2.3), a 4-fold risk of intracerebral hemorrhage (HR, 4.2; 95% CI, 1.3-13.9), a 2-fold risk of all-cause mortality (HR, 2.1; 95% CI, 1.1-4.3), and strictly lobar microbleeds with an approximately 2.5-fold risk of ischemic stroke (HR, 2.3; 95% CI, 1.3-4.3). There were no interactions between microbleeds and treatment assignments for recurrent stroke, ischemic stroke, or all-cause mortality. The HR of intracerebral hemorrhage on rivaroxaban was similar between persons with microbleeds (HR, 3.1; 95% CI, 0.3-30.0) and persons without microbleeds (HR, 3.0; 95% CI, 0.6-14.7; interaction P = .97).

Conclusions And Relevance: Microbleeds mark an increased risk of recurrent stroke, ischemic stroke, intracerebral hemorrhage, and mortality in ESUS but do not appear to influence effects of rivaroxaban on clinical outcomes.

Trial Registration: ClinicalTrials.gov Identifier: NCT02313909.
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http://dx.doi.org/10.1001/jamaneurol.2020.3836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573796PMC
January 2021

Prognostic value of acute CT in stroke thrombolysis.

Authors:
Keith W Muir

J Neurol Neurosurg Psychiatry 2020 12 14;91(12):1254. Epub 2020 Oct 14.

Neurology, University of Glasgow, Glasgow, Glasgow, UK

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http://dx.doi.org/10.1136/jnnp-2020-324808DOI Listing
December 2020

Clinical Characteristics and Outcome of Patients With Hemorrhagic Transformation After Intravenous Thrombolysis in the WAKE-UP Trial.

Front Neurol 2020 28;11:957. Epub 2020 Aug 28.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Hemorrhagic transformation (HT) is an important complication of intravenous thrombolysis with alteplase. HT can show a wide range from petechiae to parenchymal hematoma with mass effect with varying clinical impact. We studied clinical and imaging characteristics of patients with HT and evaluated whether different types of HT are associated with functional outcome. We performed a analysis of WAKE-UP, a multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in unknown onset stroke. HT was assessed on follow-up MRI or CT and diagnosed as hemorrhagic infarction type 1 and type 2 (HI1 and HI2, combined as HI), and parenchymal hemorrhage type 1 and type 2 (PH1 and PH2, combined as PH). Severity of stroke symptoms was assessed using the National Institutes of Health Stroke Scale (NIHSS) at baseline. Stroke lesion volume was measured on baseline diffusion weighted imaging (DWI). Primary endpoint was a favorable outcome defined as a modified Rankin Scale score 0-1 at 90 days. Of 483 patients included in the analysis, 95 (19.7%) showed HI and 21 (4.4%) had PH. Multiple logistic regression analysis identified treatment with alteplase (OR, 2.08 [95% CI, 1.28-3.40]), baseline NIHSS score (OR, 1.11 [95% CI, 1.05-1.17]), DWI lesion volume (OR, 1.03 [95% CI, 1.01-1.05]), baseline glucose levels (OR, 1.01 [95% CI, 1.00-1.01]) and atrial fibrillation (OR, 3.02 [95% CI, 1.57-5.80]) as predictors of any HT. The same parameters predicted HI. Predictors of PH were baseline NIHSS score (OR, 1.11 [95% CI, 1.01-1.22]) and as a trend treatment with alteplase (OR, 2.40 [95% CI, 0.93-6.96]). PH was associated with lower odds of favorable outcome (OR 0.25, 95% [CI 0.05-0.86]), while HI was not. Our results indicate that HI is associated with stroke severity, cardiovascular risk factors and thrombolysis. PH is a rare complication, more frequent in severe stroke and with thrombolysis. In contrast to HI, PH is associated with worse functional outcome. The impact of HT after MRI-guided intravenous alteplase for unknown onset stroke on clinical outcome is similar as in the trials of stroke thrombolysis within a known early time-window.
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http://dx.doi.org/10.3389/fneur.2020.00957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483750PMC
August 2020

Association between critical care admission and 6-month functional outcome after spontaneous intracerebral haemorrhage.

J Neurol Sci 2020 Nov 19;418:117141. Epub 2020 Sep 19.

Stroke Research Centre, University College London, Institute of Neurology, London, UK.

Background: There is uncertainty about the clinical benefit of admission to critical care after spontaneous intracerebral haemorrhage (ICH).

Purpose: We investigated factors associated with critical care admission after spontaneous ICH and evaluated associations between critical care and 6-month functional outcome.

Methods: We included 825 patients with acute spontaneous non-traumatic ICH, recruited to a prospective multicenter observational study. We evaluated the characteristics associated with critical care admission and poor 6-month functional outcome (modified Rankin Scale, mRS > 3) using univariable (chi-square test and Wilcoxon rank-sum test, as appropriate) and multivariable analysis.

Results: 286 patients (38.2%) had poor 6-month functional outcome. Seventy-seven (9.3%) patients were admitted to critical care. Patients admitted to critical care were younger (p < 0.001), had lower GCS score (p < 0.001), larger ICH volume (p < 0.001), more often had intraventricular extension (p = 0.008) and underwent neurosurgery (p < 0.001). Critical care admission was associated with poor functional outcome at 6 months (39/77 [50.7%] vs 286/748 [38.2%]; p = 0.034); adjusted OR 2.43 [95%CI 1.36-4.35], p = 0.003), but not with death (OR 1.29 [95%CI 0.71-2.35; p = 0.4). In ordinal logistic regression, patients admitted to critical care showed an OR 1.47 (95% CI 0.98-2.20; p = 0.07) for a shift in the 6-month modified Rankin Scale.

Conclusions: Admission to critical care is associated with poor 6-month functional outcome after spontaneous ICH but not with death. Patients admitted to critical care were a priori more severely affected. Although adjusted for main known predictors of poor outcome, our findings could still be confounded by unmeasured factors. Establishing the true effectiveness of critical care after ICH requires a randomised trial with clinical outcomes and quality of life assessments.
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http://dx.doi.org/10.1016/j.jns.2020.117141DOI Listing
November 2020

Sensitivity and specificity of blood-fluid levels for oral anticoagulant-associated intracerebral haemorrhage.

Sci Rep 2020 09 23;10(1):15529. Epub 2020 Sep 23.

Department of Brain Repair and Rehabilitation, UCL Stroke Research Centre, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Russell Square House, 10-12 Russell Square, London, WC1B 5EH, UK.

Intracerebral haemorrhage (ICH) is a life-threatening emergency, the incidence of which has increased in part due to an increase in the use of oral anticoagulants. A blood-fluid level within the haematoma, as revealed by computed tomography (CT), has been suggested as a marker for oral anticoagulant-associated ICH (OAC-ICH), but the diagnostic specificity and prognostic value of this finding remains unclear. In 855 patients with CT-confirmed acute ICH scanned within 48 h of symptom onset, we investigated the sensitivity and specificity of the presence of a CT-defined blood-fluid level (rated blinded to anticoagulant status) for identifying concomitant anticoagulant use. We also investigated the association of the presence of a blood-fluid level with six-month case fatality. Eighteen patients (2.1%) had a blood-fluid level identified on CT; of those with a blood-fluid level, 15 (83.3%) were taking anticoagulants. The specificity of blood-fluid level for OAC-ICH was 99.4%; the sensitivity was 4.2%. We could not detect an association between the presence of a blood-fluid level and an increased risk of death at six months (OR = 1.21, 95% CI 0.28-3.88, p = 0.769). The presence of a blood-fluid level should alert clinicians to the possibility of OAC-ICH, but absence of a blood-fluid level is not useful in excluding OAC-ICH.
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http://dx.doi.org/10.1038/s41598-020-72504-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511300PMC
September 2020

A Comparison of T Relaxation-Based MRI Stroke Timing Methods in Hyperacute Ischemic Stroke Patients: A Pilot Study.

J Cent Nerv Syst Dis 2020 12;12:1179573520943314. Epub 2020 Sep 12.

Faculty of Engineering, University of Bristol, Bristol, UK.

Background: T relaxation-based magnetic resonance imaging (MRI) signals may provide onset time for acute ischemic strokes with an unknown onset. The ability of visual and quantitative MRI-based methods in a cohort of hyperacute ischemic stroke patients was studied.

Methods: A total of 35 patients underwent 3T (3 Tesla) MRI (<9-hour symptom onset). Diffusion-weighted (DWI), apparent diffusion coefficient (ADC), T-weighted (Tw), T-weighted (Tw), and T relaxation time (T) images were acquired. T-weighted fluid attenuation inversion recovery (FLAIR) images were acquired for 17 of these patients. Image intensity ratios of the average intensities in ischemic and non-ischemic reference regions were calculated for ADC, DWI, Tw, T relaxation, and FLAIR images, and optimal image intensity ratio cut-offs were determined. DWI and FLAIR images were assessed visually for DWI/FLAIR mismatch.

Results: The T relaxation time image intensity ratio was the only parameter with significant correlation with stroke duration ( = 0.49,  = .003), an area under the receiver operating characteristic curve (AUC = 0.77,  < .0001), and an optimal cut-off (T ratio = 1.072) that accurately identified patients within the 4.5-hour thrombolysis treatment window with sensitivity of 0.74 and specificity of 0.74. In the patients with the additional FLAIR, areas under the precision-recall-gain curve (AUPRG) and F scores showed that the T relaxation time ratio (AUPRG = 0.60, F = 0.73) performed considerably better than the FLAIR ratio (AUPRG = 0.39, F = 0.57) and the visual DWI/FLAIR mismatch (F = 0.25).

Conclusions: Quantitative T relaxation time is the preferred MRI parameter in the assessment of patients with unknown onset for treatment stratification.
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http://dx.doi.org/10.1177/1179573520943314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488882PMC
September 2020

Blood pressure excursions in acute ischemic stroke patients treated with intravenous thrombolysis.

J Hypertens 2021 Feb;39(2):266-272

Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.

Objective: To investigate the association of blood pressure BP excursions, defined as greater than 185 SBP or greater than 105 DBP, with the probability of intracranial hemorrhage (ICH) and worse functional outcomes in patients with acute ischemic stroke (AIS) treated with tissue plasminogen activator (tPA).

Methods: We performed a post hoc analysis of the CLOTBUST-ER trial. Serial BP measurements were conducted using automated cuff recording according to the recommended BP protocol guidelines for tPA administration. The outcomes were prespecified efficacy and safety endpoints of CLOTBUST-ER.

Results: The mean number of serial BP recordings per patient was 37. Of the 674 patients, 227 (34%) had at least one BP excursion (>185/105 mmHg) during the first 24 h following tPA-bolus. The majority of BP excursions (46%) occurred within the first 75 min from tPA-bolus. Patients with at least one BP excursion in the first 24 h following tPA bolus had significantly lower rates of independent functional outcome at 90 days (31 vs. 40.1%, P = 0.028). The total number of BP excursions was associated with decreased odds of 24-h clinical recovery (OR = 0.88, 95% CI:0.80-0.96), 24-h neurological improvement (OR = 0.87, 95% CI: 0.81-0.94), 7-day functional improvement (common OR = 0.92, 95% CI: 0.87-0.97), 90-day functional improvement (common OR = 0.94, 95% CI: 0.88-0.98) and 90-day independent functional outcome (OR = 0.90, 95% CI: 0.82-0.98) in analyses adjusted for potential confounders. DBP excursions were independently associated with increased odds of any intracranial hemorrhage (OR = 1.26, 95% CI: 1.04-1.53).

Conclusion: BP excursions above guideline thresholds during the first 24 h following tPA administration for AIS are common and are independently associated with adverse clinical outcomes.
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http://dx.doi.org/10.1097/HJH.0000000000002628DOI Listing
February 2021

Public health and cost consequences of time delays to thrombectomy for acute ischemic stroke.

Neurology 2020 11 17;95(18):e2465-e2475. Epub 2020 Sep 17.

From the University of Calgary (W.G.K., M.A.A., B.K.M., A.M.D., M.D.H., M.G.), Alberta, Canada; Department of Radiology (W.G.K.), University Hospital, LMU Munich, Germany; Harvard T.H. Chan School of Public Health (M.G.H.), Boston, MA; Erasmus MC (M.G.H., D.W.J.D.), University Medical Center Rotterdam, the Netherlands; Faculty of Medicine (M.A.A.), King Abdulaziz University, Jeddah, Saudi Arabia; David Geffen School of Medicine (J.L.S.), University of California-Los Angeles; Academic Medical Center (C.B.L.M.M.), Amsterdam, the Netherlands; University of Pittsburgh Medical Center (T.G.J.), PA; Hospital Germans Trias i Pujol (A.D.), Barcelona, Spain; University Hospital of Nancy (S. Bracard, F.G.), France; University of Melbourne (B.C.V.C., P.J.M.), Australia; Newcastle University (P.W.), UK; University of Glasgow (K.W.M.), UK; and Altair Biostatistics (S. Brown), St. Louis Park, MN.

Objective: To determine public health and cost consequences of time delays to endovascular thrombectomy (EVT) for patients, health care systems, and society, we estimated quality-adjusted life-years (QALYs) of EVT-treated patients and associated costs based on times to treatment.

Methods: The Markov model analysis was performed from US health care and societal perspectives over a lifetime horizon. Contemporary data from 7 trials within the Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES) collaboration served as data source. Aside from cumulative lifetime costs, we calculated the net monetary benefit (NMB) to determine the economic value of care. We used a contemporary willingness-to-pay threshold of $100,000 per QALY for NMB calculations.

Results: Every 10 minutes of earlier treatment resulted in an average gain of 39 days (95% prediction interval 23-53 days) of disability-free life. Overall, the cumulative lifetime costs for patients with earlier or later treatment were similar. Patients with later treatment had higher morbidity-related costs but over a shorter time span due to their shorter life expectancy, resulting in similar lifetime costs as in patients with early treatment. Regarding the economic value of care, every 10 minutes of earlier treatment increased the NMB by $10,593 (95% prediction interval $5,549-$14,847) and by $10,915 (95% prediction interval $5,928-$15,356) taking health care and societal perspectives, respectively.

Conclusions: Any time delay to EVT reduces QALYs and decreases the economic value of care provided by this intervention. Health care policies to implement efficient prehospital triage and to accelerate in-hospital workflow are urgently needed.
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http://dx.doi.org/10.1212/WNL.0000000000010867DOI Listing
November 2020

Association of enlarged perivascular spaces and anticoagulant-related intracranial hemorrhage.

Neurology 2020 10 15;95(16):e2192-e2199. Epub 2020 Sep 15.

From the Stroke Research Center (J.G.B., C.B., H.D., G.B., D.W., C.S., M.M.B., D.J.W.) and Lysholm Department of Neuroradiology and the Neuroradiological Academic Unit (T.A.Y., H.R.J.), Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology; Department of Statistical Science (G.A.), Haemostasis Research Unit, Department of Haematology (H.C.), University College London, UK; Stroke Research Center, Department of Neurology (H.D.), Fujian Medical University Union Hospital, Fuzhou, China; Center for Clinical Brain Sciences, School of Clinical Sciences (R.A.-S.S.), University of Edinburgh; Liverpool Center for Cardiovascular Science (G.Y.H.L.), University of Liverpool and Liverpool Heart and Chest Hospital, UK; Aalborg Thrombosis Research Unit, Department of Clinical Medicine (G.Y.H.L.), Aalborg University, Denmark; Department of Molecular Neuroscience (H.H.), UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London; and Institute of Neuroscience & Psychology (K.W.M.), University of Glasgow, Queen Elizabeth University Hospital, UK.

Objective: To investigate whether enlarged perivascular spaces (PVS) within the basal ganglia or deep cerebral white matter are risk factors for intracranial hemorrhage in patients taking oral anticoagulants (OACs), independent of established clinical and radiologic risk factors, we conducted a post hoc analysis of Clinical Relevance of Microbleeds in Stroke (CROMIS-2) (atrial fibrillation [AF]), a prospective inception cohort study.

Methods: Patients with atrial fibrillation and recent TIA or ischemic stroke underwent standardized MRI prior to starting OAC. We rated basal ganglia PVS (BGPVS) and centrum semiovale PVS (CSOPVS), cerebral microbleeds (CMBs), white matter hyperintensities, and lacunes. We dichotomized the PVS rating using a threshold of >10 PVS in the relevant region of either cerebral hemisphere. The primary outcome was symptomatic intracranial hemorrhage (sICH). We identified risk factors for sICH using Cox regression.

Results: A total of 1,386 participants with available clinical and imaging variables were followed up for a mean of 2.34 years; 14 sICH occurred (11 intracerebral). In univariable analysis, diabetes, CMB presence, lacune presence, and >10 BGPVS, but not CSOPVS, were associated with sICH. In a multivariable model incorporating all variables with significant associations in univariable analysis, >10 BGPVS (hazard ratio [HR] 8.96, 95% [CI] 2.41-33.4, = 0.001) and diabetes (HR 3.91, 95% CI 1.34-11.4) remained significant risk factors for sICH.

Conclusion: Enlarged BGPVS might be a novel risk factor for OAC-related ICH. The strength of this association and potential use in predicting ICH in clinical practice should be investigated in larger cohorts.
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http://dx.doi.org/10.1212/WNL.0000000000010788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713790PMC
October 2020

Multi-centre, multi-vendor reproducibility of 7T QSM and R* in the human brain: Results from the UK7T study.

Neuroimage 2020 12 9;223:117358. Epub 2020 Sep 9.

Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Box 65, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom.

Introduction: We present the reliability of ultra-high field T* MRI at 7T, as part of the UK7T Network's "Travelling Heads" study. T*-weighted MRI images can be processed to produce quantitative susceptibility maps (QSM) and R* maps. These reflect iron and myelin concentrations, which are altered in many pathophysiological processes. The relaxation parameters of human brain tissue are such that R* mapping and QSM show particularly strong gains in contrast-to-noise ratio at ultra-high field (7T) vs clinical field strengths (1.5-3T). We aimed to determine the inter-subject and inter-site reproducibility of QSM and R* mapping at 7T, in readiness for future multi-site clinical studies.

Methods: Ten healthy volunteers were scanned with harmonised single- and multi-echo T*-weighted gradient echo pulse sequences. Participants were scanned five times at each "home" site and once at each of four other sites. The five sites had 1× Philips, 2× Siemens Magnetom, and 2× Siemens Terra scanners. QSM and R* maps were computed with the Multi-Scale Dipole Inversion (MSDI) algorithm (https://github.com/fil-physics/Publication-Code). Results were assessed in relevant subcortical and cortical regions of interest (ROIs) defined manually or by the MNI152 standard space.

Results And Discussion: Mean susceptibility (χ) and R* values agreed broadly with literature values in all ROIs. The inter-site within-subject standard deviation was 0.001-0.005 ppm (χ) and 0.0005-0.001 ms (R*). For χ this is 2.1-4.8 fold better than 3T reports, and 1.1-3.4 fold better for R*. The median ICC from within- and cross-site R* data was 0.98 and 0.91, respectively. Multi-echo QSM had greater variability vs single-echo QSM especially in areas with large B inhomogeneity such as the inferior frontal cortex. Across sites, R* values were more consistent than QSM in subcortical structures due to differences in B-shimming. On a between-subject level, our measured χ and R* cross-site variance is comparable to within-site variance in the literature, suggesting that it is reasonable to pool data across sites using our harmonised protocol.

Conclusion: The harmonized UK7T protocol and pipeline delivers on average a 3-fold improvement in the coefficient of reproducibility for QSM and R* at 7T compared to previous reports of multi-site reproducibility at 3T. These protocols are ready for use in multi-site clinical studies at 7T.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480266PMC
December 2020

Characteristics of Recurrent Ischemic Stroke After Embolic Stroke of Undetermined Source: Secondary Analysis of a Randomized Clinical Trial.

JAMA Neurol 2020 Jul 6. Epub 2020 Jul 6.

Population Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Importance: The concept of embolic stroke of undetermined source (ESUS) unifies a subgroup of cryptogenic strokes based on neuroimaging, a defined minimum set of diagnostic tests, and exclusion of certain causes. Despite an annual stroke recurrence rate of 5%, little is known about the etiology underlying recurrent stroke after ESUS.

Objective: To identify the stroke subtype of recurrent ischemic strokes after ESUS, to explore the interaction with treatment assignment in each category, and to examine the consistency of cerebral location of qualifying ESUS and recurrent ischemic stroke.

Design, Setting, And Participants: The NAVIGATE-ESUS trial was a randomized clinical trial conducted from December 23, 2014, to October 5, 2017. The trial compared the efficacy and safety of rivaroxaban and aspirin in patients with recent ESUS (n = 7213). Ischemic stroke was validated in 309 of the 7213 patients by adjudicators blinded to treatment assignment and classified by local investigators into the categories ESUS or non-ESUS (ie, cardioembolic, atherosclerotic, lacunar, other determined cause, or insufficient testing). Five patients with recurrent strokes that could not be defined as ischemic or hemorrhagic in absence of neuroimaging or autopsy were excluded. Data for this secondary post hoc analysis were analyzed from March to June 2019.

Interventions: Patients were randomly assigned to receive rivaroxaban, 15 mg/d, or aspirin, 100 mg/d.

Main Outcomes And Measures: Association of recurrent ESUS with stroke characteristics.

Results: A total of 309 patients (205 men [66%]; mean [SD] age, 68 [10] years) had ischemic stroke identified during the median follow-up of 11 (interquartile range [IQR], 12) months (annualized rate, 4.6%). Diagnostic testing was insufficient for etiological classification in 39 patients (13%). Of 270 classifiable ischemic strokes, 156 (58%) were ESUS and 114 (42%) were non-ESUS (37 [32%] cardioembolic, 26 [23%] atherosclerotic, 35 [31%] lacunar, and 16 [14%] other determined cause). Atrial fibrillation was found in 27 patients (9%) with recurrent ischemic stroke and was associated with higher morbidity (median change in modified Rankin scale score 2 [IQR, 3] vs 0 (IQR, 1]) and mortality (15% vs 1%) than other causes. Risk of recurrence did not differ significantly by subtype between treatment groups. For both the qualifying and recurrent strokes, location of infarct was more often in the left (46% and 54%, respectively) than right hemisphere (40% and 37%, respectively) or brainstem or cerebellum (14% and 9%, respectively).

Conclusions And Relevance: In this secondary analysis of randomized clinical trial data, most recurrent strokes after ESUS were embolic and of undetermined source. Recurrences associated with atrial fibrillation were a minority but were more often disabling and fatal. More extensive investigation to identify the embolic source is important toward an effective antithrombotic strategy.

Trial Registration: ClinicalTrials.gov Identifier: NCT02313909.
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http://dx.doi.org/10.1001/jamaneurol.2020.1995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550970PMC
July 2020

Longer term stroke risk in intracerebral haemorrhage survivors.

J Neurol Neurosurg Psychiatry 2020 08 17;91(8):840-845. Epub 2020 Jun 17.

Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, United Kingdom

Objective: To evaluate the influence of intracerebral haemorrhage (ICH) location on stroke outcomes.

Methods: We included patients recruited to a UK hospital-based, multicentre observational study of adults with imaging confirmed spontaneous ICH. The outcomes of interest were occurrence of a cerebral ischaemic event (either stroke or transient ischaemic attack) or a further ICH following study entry. Haematoma location was classified as lobar or non-lobar.

Results: All 1094 patients recruited to the CROMIS-2 (Clinical Relevance of Microbleeds in Stroke) ICH study were included (mean age 73.3 years; 57.4% male). There were 45 recurrent ICH events (absolute event rate (AER) 1.88 per 100 patient-years); 35 in patients presenting with lobar ICH (n=447, AER 3.77 per 100 patient-years); and 9 in patients presenting with non-lobar ICH (n=580, AER 0.69 per 100 patient-years). Multivariable Cox regression found that lobar ICH was associated with ICH recurrence (HR 8.96, 95% CI 3.36 to 23.87, p<0.0001); similar results were found in multivariable completing risk analyses. There were 70 cerebral ischaemic events (AER 2.93 per 100 patient-years); 29 in patients presenting with lobar ICH (AER 3.12 per 100 patient-years); and 39 in patients with non-lobar ICH (AER 2.97 per 100 patient-years). Multivariable Cox regression found no association with ICH location (HR 1.13, 95% CI 0.66 to 1.92, p 0.659). Similar results were seen in completing risk analyses.

Conclusions: In ICH survivors, lobar ICH location was associated with a higher risk of recurrent ICH events than non-lobar ICH; ICH location did not influence risk of subsequent ischaemic events.

Trial Registration Number: NCT02513316.
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http://dx.doi.org/10.1136/jnnp-2020-323079DOI Listing
August 2020

Diagnosis and management of acute ischaemic stroke.

Pract Neurol 2020 Aug 7;20(4):304-316. Epub 2020 Jun 7.

Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK

Acute ischaemic stroke is a major public health priority and will become increasingly relevant to neurologists of the future. The cornerstone of effective stroke care continues to be timely reperfusion treatment. This requires early recognition of symptoms by the public and first responders, triage to an appropriate stroke centre and efficient assessment and investigation by the attending stroke team. The aim of treatment is to achieve recanalisation and reperfusion of the ischaemic penumbra with intravenous thrombolysis and/or endovascular thrombectomy in appropriately selected patients. All patients should be admitted directly to an acute stroke unit for close monitoring for early neurological deterioration and prevention of secondary complications. Prompt investigation of the mechanism of stroke allows patients to start appropriate secondary preventative treatment. Future objectives include improving accessibility to endovascular thrombectomy, using advanced imaging to extend therapeutic windows and developing neuroprotective agents to prevent secondary neuronal damage.
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http://dx.doi.org/10.1136/practneurol-2020-002557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577107PMC
August 2020

Non-invasive brain stimulation in Stroke patients (NIBS): A prospective randomized open blinded end-point (PROBE) feasibility trial using transcranial direct current stimulation (tDCS) in post-stroke hemispatial neglect.

Neuropsychol Rehabil 2020 Jun 5:1-27. Epub 2020 Jun 5.

School of Psychology, University of Glasgow, Glasgow, UK.

Up to 80% of people who experience a right-hemisphere stroke suffer from hemispatial neglect. This syndrome is debilitating and impedes rehabilitation. We carried out a clinical feasibility trial of transcranial direct current stimulation (tDCS) and a behavioural rehabilitation programme, alone or in combination, in patients with neglect. Patients >4 weeks post right hemisphere stroke were randomized to 10 sessions of tDCS, 10 sessions of a behavioural intervention, combined intervention, or a control task. Primary outcomes were recruitment and retention rates, with secondary outcomes effect sizes on measures of neglect and quality of life, assessed directly after the interventions, and at 6 months follow up. Of 288 confirmed stroke cases referred (representing 7% of confirmed strokes), we randomized 8% (0.6% of stroke cases overall). The largest number of exclusions (91/288 (34%)) were due to medical comorbidities that prevented patients from undergoing 10 intervention sessions. We recruited 24 patients over 29 months, with 87% completing immediate post-intervention and 67% 6 month evaluations. We established poor feasibility of a clinical trial requiring repeated hospital-based tDCS within a UK hospital healthcare setting, either with or without behavioural training, over a sustained time period. Future trials should consider intensity, duration and location of tDCS neglect interventions. ClinicalTrials.gov identifier: NCT02401724.
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http://dx.doi.org/10.1080/09602011.2020.1767161DOI Listing
June 2020

Different Mismatch Concepts for Magnetic Resonance Imaging-Guided Thrombolysis in Unknown Onset Stroke.

Ann Neurol 2020 06 20;87(6):931-938. Epub 2020 Apr 20.

Department of Neurology, University Hospitals Leuven, Leuven, Belgium.

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.
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http://dx.doi.org/10.1002/ana.25730DOI Listing
June 2020

Ischemic Stroke despite Oral Anticoagulant Therapy in Patients with Atrial Fibrillation.

Ann Neurol 2020 Feb 12. Epub 2020 Feb 12.

Stroke Research Center, Department of Brain Repair and Rehabilitation, University College London Queen Square Institute of Neurology, and the National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom.

Objective: It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed.

Methods: We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OAC ) with those without prior oral anticoagulation (OAC ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OAC ) with those who continued the same anticoagulation as secondary prevention (OAC ). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine-Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71-84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2-12]). The median CHA DS -Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) was 5 (IQR = 4-6) and was similar for OAC (n = 1,195) and OAC (n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2-5.3%). OAC was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OAC (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OAC (n = 585).

Interpretation: Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA DS -Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group. ANN NEUROL 2020.
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http://dx.doi.org/10.1002/ana.25700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383617PMC
February 2020

Intracerebral implantation of human neural stem cells and motor recovery after stroke: multicentre prospective single-arm study (PISCES-2).

J Neurol Neurosurg Psychiatry 2020 04 10;91(4):396-401. Epub 2020 Feb 10.

ReNeuron Ltd, Bridgend, UK.

Background: Human neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute-chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study.

Methods: We undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2-13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation.

Findings: Twenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures.

Interpretation: Administration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials.

Funding: ReNeuron, Innovate UK (application no 32074-222145).

Trial Registration Number: EudraCT Number: 2012-003482-18.
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http://dx.doi.org/10.1136/jnnp-2019-322515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147186PMC
April 2020

Public Health and Cost Benefits of Successful Reperfusion After Thrombectomy for Stroke.

Stroke 2020 03 22;51(3):899-907. Epub 2020 Jan 22.

From the University of Calgary, Alberta, Canada (W.G.K., M.A.A., B.K.M., A.M.D., M.D.H., M.G.).

Background and Purpose- The benefit that endovascular thrombectomy offers to patients with stroke with large vessel occlusions depends strongly on reperfusion grade as defined by the expanded Thrombolysis in Cerebral Infarction (eTICI) scale. Our aim was to determine the lifetime health and cost consequences of the quality of reperfusion for patients, healthcare systems, and society. Methods- A Markov model estimated lifetime quality-adjusted life years (QALY) and lifetime costs of endovascular thrombectomy-treated patients with stroke based on eTICI grades. The analysis was performed over a lifetime horizon in a United States setting, adopting healthcare and societal perspectives. The reference case analysis was conducted for stroke at 65 years of age. National health and cost consequences of improved eTICI 2c/3 reperfusion rates were estimated. Input parameters were based on best available evidence. Results- Lifetime QALYs increased for every grade of improved reperfusion (median QALYs for eTICI 0/1: 2.62; eTICI 2a: 3.46; eTICI 2b: 5.42; eTICI 2c: 5.99; eTICI 3: 6.73). Achieving eTICI 3 over eTICI 2b reperfusion resulted on average in 1.31 incremental QALYs as well as healthcare and societal cost savings of $10 327 and $20 224 per patient. A 10% increase in the eTICI 2c/3 reperfusion rate of all annually endovascular thrombectomy-treated patients with stroke in the United States is estimated to yield additional 3656 QALYs and save $21.0 million and $36.8 million for the healthcare system and society, respectively. Conclusions- Improved reperfusion grants patients with stroke additional QALYs and leads to long-term cost savings. Procedural strategies to achieve complete reperfusion should be assessed for safety and feasibility, even when initial reperfusion seems to be adequate.
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http://dx.doi.org/10.1161/STROKEAHA.119.027874DOI Listing
March 2020

Observer Agreement on Computed Tomography Perfusion Imaging in Acute Ischemic Stroke.

Stroke 2019 11 25;50(11):3108-3114. Epub 2019 Sep 25.

From the Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, Scotland (S.E.-T., K.W.M.).

Background and Purpose- Computed tomography (CT) perfusion (CTP) provides potentially valuable information to guide treatment decisions in acute stroke. Assessment of interobserver reliability of CTP has, however, been limited to small, mostly single center studies. We performed a large, internet-based study to assess observer reliability of CTP interpretation in acute stroke. Methods- We selected 24 cases from the IST-3 (Third International Stroke Trial), ATTEST (Alteplase Versus Tenecteplase for Thrombolysis After Ischaemic Stroke), and POSH (Post Stroke Hyperglycaemia) studies to illustrate various perfusion abnormalities. For each case, observers were presented with noncontrast CT, maps of cerebral blood volume, cerebral blood flow, mean transit time, delay time, and thresholded penumbra maps (dichotomized into penumbra and core), together with a short clinical vignette. Observers used a structured questionnaire to record presence of perfusion deficit, its extent compared with ischemic changes on noncontrast CT, and an Alberta Stroke Program Early CT Score for noncontrast CT and CTP. All images were viewed, and responses were collected online. We assessed observer agreement with Krippendorff-α. Intraobserver agreement was assessed by inviting observers who reviewed all scans for a repeat review of 6 scans. Results- Fifty seven observers contributed to the study, with 27 observers reviewing all 24 scans and 17 observers contributing repeat readings. Interobserver agreement was good to excellent for all CTP. Agreement was higher for perfusion maps compared with noncontrast CT and was higher for mean transit time, delay time, and penumbra map (Krippendorff-α =0.77, 0.79, and 0.81, respectively) compared with cerebral blood volume and cerebral blood flow (Krippendorff-α =0.69 and 0.62, respectively). Intraobserver agreement was fair to substantial in the majority of readers (Krippendorff-α ranged from 0.29 to 0.80). Conclusions- There are high levels of interobserver and intraobserver agreement for the interpretation of CTP in acute stroke, particularly of mean transit time, delay time, and penumbra maps.
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http://dx.doi.org/10.1161/STROKEAHA.119.026238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824508PMC
November 2019

Cognitive Impairment Before Atrial Fibrillation-Related Ischemic Events: Neuroimaging and Prognostic Associations.

J Am Heart Assoc 2020 01 4;9(1):e014537. Epub 2020 Jan 4.

Department of Brain Repair and Rehabilitation Stroke Research Centre UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery London United Kingdom.

Background It is likely that a proportion of poststroke cognitive impairment is sometimes attributable to unidentified prestroke decline; prestroke cognitive function is also clinically relevant because it is associated with poor functional outcomes, including death. We investigated the radiological and prognostic associations of preexisting cognitive impairment in patients with ischemic stroke or transient ischemic attack associated with atrial fibrillation. Methods and Results We included 1102 patients from the prospective multicenter observational CROMIS-2 (Clinical Relevance of Microbleeds in Stroke 2) atrial fibrillation study. Preexisting cognitive impairment was identified using the 16-item Informant Questionnaire for Cognitive Decline in the Elderly. Functional outcome was measured using the modified Rankin scale. Preexisting cognitive impairment was common (n=271; 24.6%). The presence of lacunes (odds ratio [OR], 1.50; 95% CI, 1.03-1.05; =0.034), increasing periventricular white matter hyperintensity grade (per grade increase, OR, 1.38; 95% CI, 1.17-1.63; <0.0001), deep white matter hyperintensity grade (per grade increase, OR, 1.26; 95% CI, 1.05-1.51; =0.011), and medial temporal atrophy grade (per grade increase, OR, 1.61; 95% CI, 1.34-1.95; <0.0001) were independently associated with preexisting cognitive impairment. Preexisting cognitive impairment was associated with poorer functional outcome at 24 months (mRS >2; adjusted OR, 2.43; 95% CI, 1.42-4.20; =0.001). Conclusions Preexisting cognitive impairment in patients with atrial fibrillation-associated ischemic stroke or transient ischemic attack is common, and associated with imaging markers of cerebral small vessel disease and neurodegeneration, as well as with longer-term functional outcome. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02513316.
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http://dx.doi.org/10.1161/JAHA.119.014537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988157PMC
January 2020