Publications by authors named "Robin Lemmens"

182 Publications

Impact of meningeal uptake and partial volume correction techniques on [F]MK-6240 binding in aMCI patients and healthy controls.

J Cereb Blood Flow Metab 2022 Jan 21:271678X221076023. Epub 2022 Jan 21.

Nuclear Medicine and Molecular Imaging, University Hospital and KU Leuven, Leuven, Belgium.

[F]MK-6240 is a second-generation tau PET-tracer to quantify neurofibrillary tangles in-vivo. However, individually variable levels of meningeal uptake induce spill-in-effects into the cortex, complicating [F]MK-6240 PET quantification. Group SUVR differences between age-matched HC subgroups with varying extracerebral uptake (EC-low/mixed/high), and between aMCI and each HC subgroup were assessed without and with partial volume correction (PVC). Both Müller-Gartner (MG-)PVC and region-based voxelwise (RBV-)PVC, with the latter also correcting for extracerebral spill-in-effects, were implemented. Between HC groups, where no differences are to be expected, HC EC-high showed spill-in differences compared to HC EC-low when no PVC was applied while for MG-PVC, differences were reduced and, for RBV-PVC, no statistically significant differences were observed. Between aMCI and HC, cortical SUVR differences were statistically significant, both without and with PVC, but modulated by the varying meningeal uptake in HC subgroups when no PVC was applied. After applying PVC, correlations to clinical parameters improved and effect sizes between HC and aMCI increased, independent of the HC-subgroup. Therefore, appropriate PVC with correction for extracerebral spill-in-effects is recommended to minimize the impact of varying meningeal uptake on cortical differences between HC and aMCI.
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http://dx.doi.org/10.1177/0271678X221076023DOI Listing
January 2022

Estimating nocturnal stroke onset times by magnetic resonance imaging in the WAKE-UP trial.

Int J Stroke 2021 Nov 18:17474930211059608. Epub 2021 Nov 18.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Fluid-attenuated inversion recovery (FLAIR) sequences have gained a role to guide treatment of patients with unknown time of stroke symptom onset. Evolution of signal intensities in FLAIR is associated with time since stroke onset with continuous linear increases.

Aims: Estimating symptom onset during night-sleep in patients from the WAKE-UP trial based on relative signal intensities FLAIR (FLAIR-rSI) from acute stroke lesions an independent dataset (PRE-FLAIR study).

Methods: FLAIR-rSI was quantified in stroke lesions in PRE-FLAIR and WAKE-UP. The PRE-FLAIR study was a multicenter observational trial establishing FLAIR as a surrogate parameter for time since stroke onset. WAKE-UP was a randomized controlled trial that revealed a benefit for alteplase in patients selected based on a DWI-FLAIR mismatch. Stroke onset times were recorded in PRE-FLAIR and used to fit a linear regression model with FLAIR-rSI, adjusted for patient age and lesion volume. The model was applied to FLAIR-rSI of stroke lesions to estimate onset times in those patients enrolled in WAKE-UP who had symptom onset during night-sleep.

Results: FLAIR-rSI was quantified in 399 patients from PRE-FLAIR. Linear regression indicated a significant association of age ( = 0.001), lesion volume ( = 0.005) and FLAIR-rSI ( < 0.001) with time since symptom onset (adjusted R= 0.179). In 813 patients from WAKE-UP, distribution of times of last seen well, symptom recognition and MRI examination were recorded. Median times of last seen well were 1 h before midnight (IQR 2.4 h) and symptom recognition 7 h after midnight (IRQ 2.2 h). Based on the FLAIR-rSI profiles, we estimated median stroke onset 6.1 h after midnight (IQR 2.7 h).

Conclusion: Nocturnal strokes during night-sleep may predominantly occur during the early morning hours. Our results are in line with evidence of characteristic diurnal patterns of cardiovascular events.
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http://dx.doi.org/10.1177/17474930211059608DOI Listing
November 2021

Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial.

Neurology 2022 Jan 15;98(3):e302-e314. Epub 2021 Nov 15.

From the Klinik und Hochschulambulanz für Neurologie (L.S., T.B.B., M. Endres, C.H.N.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humbold-Universität zu Berlin, and Berlin Institute of Health; Center for Stroke Research Berlin (L.S., T.B.B., I.G., J. Fiebach, M. Ebinger, M. Endres, C.H.N.), Charité-Universitätsmedizin; Berlin Institute of Health (L.S., T.B.B., M. Endres, C.H.N.), Germany; Hospices Civils de Lyon (F.B.), Service de Biostatistique; Université Lyon 1 and Centre National de la Recherche Scientifique (F.B.), UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France; Department of Neurology (J.V.), University Hospital Bern, Switzerland; Klinik und Poliklinik für Neurologie (M.J., B.C., G.T., C.G.), Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology (C.Z.S.), Aarhus University Hospital, Denmark; Department of Stroke Medicine (T.-H.C.), Université Claude Bernard Lyon 1, and Hospices Civils de Lyon, France; Department of Diagnostic and Interventional Neuroradiology (J. Fiehler), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Radiology (J.P., S.P.), Doctor Josep Trueta University Hospital, Department of Radiology (IDI) (J.P., S.P.), Girona Biomedical Research Institute (IDIBGI), Spain; Department of Neurology (V.T.), Austin Health, Heidelberg, Australia; Institute of Neuroscience and Psychology, University of Glasgow (K.M.), UK; Department of Stroke Medicine (N.N.), Université Claude Bernard Lyon 1, and Hospices Civils de Lyon, France; Department of Neurology (M. Ebinger), Medical Park Berlin Humboldtmühle; German Center for Cardiovascular Research (DZHK) (M. Endres, C.H.N.), Partner Site Berlin; German Center for Neurodegenerative Diseases (DZNE) (M. Endres, C.H.N.), Partner Site Berlin; ExcellenceCluster NeuroCure (M. Endres), Charité-Universitätsmedizin Berlin, Germany; Department of Neurology (R.L.), University Hospitals Leuven, Belgium; Department of Neurosciences (R.L.), Experimental Neurology, KU Leuven-University of Leuven; and VIB-KU Leuven Center for Brain and Disease Research (R.L.), Laboratory of Neurobiology, Leuven, Belgium.

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, = 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, = 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, = 0.022) without evidence of heterogeneity in relation to CMB presence ( 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.
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http://dx.doi.org/10.1212/WNL.0000000000013055DOI Listing
January 2022

A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke.

N Engl J Med 2021 11;385(20):1833-1844

From the Departments of Neurology (N.E.L., L.A.R., J.M.C., Y.B.W.E.M.R.), Radiology and Nuclear Medicine (M.K., K.M.T., A.E.B., O.A.B., H.V., M.L.T., R.B., L.F.M.B., B.J.E., C.B.L.M.M.), and Biomedical Engineering and Physics (O.A.B., H.V., M.L.T.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, the Departments of Radiology (K.M.T., G.J.L.N., I.R.W.) and Neurology (J.B., I.R.W.), The Hague Medical Center, and the Departments of Neurology (K.F.L.) and Radiology (L.C.D.), Haga Hospital, The Hague, the Departments of Radiology and Nuclear Medicine (O.A.B., L.W., A.L., P.-J.D.), Neurology (D.W.J.D., B.R.), and Public Health (D.N., H.F.L.), Erasmus MC University Medical Center, Rotterdam, the Department of Radiology, Leiden University Medical Center, Leiden (A.C.G.M.E.), the Departments of Neurology (K.K., R.A.R.G.) and Radiology (L.S.F.Y., G.M.K.), Catharina Hospital, Eindhoven, the Department of Neurology, Cardiovascular Research Institute Maastricht (R.J.O., I.R.R.), and the Department of Radiology and Nuclear Medicine (W.H.Z., A.A.P.), Maastricht University Medical Center, and the School for Mental Health and Sciences, Maastricht University (A.A.P.), Maastricht, the Department of Neurology and Neurosurgery, Brain Center (H.B.W.), and the Department of Radiology (R.T.H.L.), University Medical Center Utrecht, Utrecht, the Departments of Neurology (J.H.) and Radiology (J.M.M.), Rijnstate Hospital, Arnhem, the Departments of Neurology (W.J.S.) and Radiology (J.-A.V.), Sint Antonius Hospital, Nieuwegein, the Departments of Neurology (M.U.) and Radiology, Medical Imaging Center (R.P.H.B., A.H.), University Medical Center Groningen, Groningen, the Departments of Neurology (J.H.T.) and Radiology (H.K.), Elisabeth-TweeSteden Hospital, Tilburg, Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Department of Neurology (F.H.B.M.S.), and the Department of Neurosurgery, Radboud University Medical Center (H.D.B.), Nijmegen, the Departments of Neurology (H.M.H.) and Radiology and Nuclear Medicine (B.A.A.M.H.), Isala Hospital, Zwolle, the Departments of Neurology (P.J.A.M.B.) and Radiology (T.B.), Medisch Spectrum Twente, Enschede, the Departments of Neurology (M.J.M.R., A.N.) and Radiology (F.I.), Amphia Hospital, Breda, and the Departments of Neurology (A.D.R.) and Radiology (O.E.H.E.), Albert Schweitzer Hospital, Dordrecht - all in the Netherlands; the Departments of Neuroradiology (V.C.) and Neurology (C.A.), Centre Hospitalier Universitaire de Montpellier, Montpellier, and the Departments of Neurology (Y.S.) and Neuroradiology (F.C.), Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris Sorbonne Université, Paris - both in France; and the Department of Neurosciences, KU Leuven-University of Leuven, Experimental Neurology (R.L., J.D.), Vlaams Instituut voor Biotechnologie Center for Brain and Disease Research (R.L., J.D.), and University Hospitals Leuven, Department of Neurology (R.L., J.D.), Leuven, and the Departments of Neurology (P.D.) and Radiology (D.B.), Centre Hospitalier Chrétien, Liege - all in Belgium.

Background: The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations.

Methods: We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points.

Results: The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P = 0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81).

Conclusions: In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by the Collaboration for New Treatments of Acute Stroke consortium and others; MR CLEAN-NO IV ISRCTN number, ISRCTN80619088.).
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http://dx.doi.org/10.1056/NEJMoa2107727DOI Listing
November 2021

Imaging selection for reperfusion therapy in acute ischemic stroke beyond the conventional time window.

J Neurol 2021 Oct 31. Epub 2021 Oct 31.

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

Originally, the efficacy of acute ischemic stroke treatment with thrombolysis or thrombectomy was only proven in narrow time windows of, respectively, 4.5 and 6 h after onset. Introducing imaging-based selection beyond non-contrast enhanced computed tomography has expanded the treatment window, focusing on presumed tissue status rather than solely on time after stroke onset. Different mismatch concepts have been adopted in clinical practice to select patients in the extended and unknown time window based on findings from randomized controlled trials. Since various concepts exist that can identify patients likely to benefit from reperfusion strategies, clinicians may wonder which imaging modality may be preferred in the emergency setting. In this review, we will discuss the different mismatch concepts and their practical implementation for patient selection for thrombolysis or thrombectomy, beyond the conventional time window.
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http://dx.doi.org/10.1007/s00415-021-10872-4DOI Listing
October 2021

Cost-Effectiveness of Magnetic Resonance Imaging-Guided Thrombolysis for Patients With Stroke With Unknown Time of Onset.

Value Health 2021 11 31;24(11):1620-1627. Epub 2021 Jul 31.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objectives: Patients waking up with stroke symptoms are often excluded from intravenous thrombolysis with alteplase (IV-tpa). The WAKE-UP trial, a European multicenter randomized controlled trial, proved the clinical effectiveness of magnetic resonance imaging-guided IV-tpa for these patients. This analysis aimed to assess the cost-effectiveness of the intervention compared to placebo.

Methods: A Markov model was designed to analyze the cost-effectiveness over a 25-year time horizon. The model consisted of an inpatient acute care phase and a rest-of-life phase. Health states were defined by the modified Rankin Scale (mRS). Initial transition probabilities to mRS scores were based on WAKE-UP data and health state utilities on literature search. Costs were based on data from the University Medical Center Hamburg-Eppendorf, literature, and expert opinion. Incremental costs and effects over the patients' lifetime were estimated. The analysis was conducted from a formal German healthcare perspective. Univariate and probabilistic sensitivity analyses were performed.

Results: Treatment with IV-tpa resulted in cost savings of €51 009 and 1.30 incremental gains in quality-adjusted life-years at a 5% discount rate. Univariate sensitivity analysis revealed incremental cost-effectiveness ratio being sensitive to the relative risk of favorable outcome on mRS for placebo patients after stroke, the costs of long-term care for patients with mRS 4, and patient age at initial stroke event. In all cases, IV-tpa remained cost-effective. Probabilistic sensitivity analysis proved IV-tpa cost-effective in >95% of the simulations results.

Conclusions: Magnetic resonance imaging-guided IV-tpa compared to placebo is cost-effective in patients with ischemic stroke with unknown time of onset.
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http://dx.doi.org/10.1016/j.jval.2021.05.005DOI Listing
November 2021

Evidence in peroneal nerve entrapment: A scoping review.

Eur J Neurol 2022 Feb 31;29(2):665-679. Epub 2021 Oct 31.

Research Group Experimental Neurosurgery and Neuroanatomy and Leuven Brain Institute, Catholic University of Leuven, Leuven, Belgium.

Background And Purpose: Daily management of patients with foot drop due to peroneal nerve entrapment varies between a purely conservative treatment and early surgery, with no high-quality evidence to guide current practice. Electrodiagnostic (EDX) prognostic features and the value of imaging in establishing and supplementing the diagnosis have not been clearly established.

Methods: We performed a literature search in the online databases MEDLINE, Embase, and the Cochrane Library. Of the 42 unique articles meeting the eligibility criteria, 10 discussed diagnostic performance of imaging, 11 reported EDX limits for abnormal values and/or the value of EDX in prognostication, and 26 focused on treatment outcome.

Results: Studies report high sensitivity and specificity of both ultrasound (varying respectively from 47.1% to 91% and from 53% to 100%) and magnetic resonance imaging (MRI; varying respectively from 31% to 100% and from 73% to 100%). One comparative trial favoured ultrasound over MRI. Variable criteria for a conduction block (>20%-≥50) were reported. A motor conduction block and any baseline compound motor action potential response were identified as predictors of good outcome. Based predominantly on case series, the percentage of patients with good outcome ranged 0%-100% after conservative treatment and 40%-100% after neurolysis. No study compared both treatments.

Conclusions: Ultrasound and MRI have good accuracy, and introducing imaging in the standard diagnostic workup should be considered. Further research should focus on the role of EDX in prognostication. No recommendation on the optimal treatment strategy of peroneal nerve entrapment can be made, warranting future randomized controlled trials.
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http://dx.doi.org/10.1111/ene.15145DOI Listing
February 2022

Prediction of Stroke Infarct Growth Rates by Baseline Perfusion Imaging.

Stroke 2022 Feb 30;53(2):569-577. Epub 2021 Sep 30.

Department of Neurology, University Hospitals Leuven, Belgium (A.W., R.L.).

Background And Purpose: Computed tomography perfusion imaging allows estimation of tissue status in patients with acute ischemic stroke. We aimed to improve prediction of the final infarct and individual infarct growth rates using a deep learning approach.

Methods: We trained a deep neural network to predict the final infarct volume in patients with acute stroke presenting with large vessel occlusions based on the native computed tomography perfusion images, time to reperfusion and reperfusion status in a derivation cohort (MR CLEAN trial [Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands]). The model was internally validated in a 5-fold cross-validation and externally in an independent dataset (CRISP study [CT Perfusion to Predict Response to Recanalization in Ischemic Stroke Project]). We calculated the mean absolute difference between the predictions of the deep learning model and the final infarct volume versus the mean absolute difference between computed tomography perfusion imaging processing by RAPID software (iSchemaView, Menlo Park, CA) and the final infarct volume. Next, we determined infarct growth rates for every patient.

Results: We included 127 patients from the MR CLEAN (derivation) and 101 patients of the CRISP study (validation). The deep learning model improved final infarct volume prediction compared with the RAPID software in both the derivation, mean absolute difference 34.5 versus 52.4 mL, and validation cohort, 41.2 versus 52.4 mL (<0.01). We obtained individual infarct growth rates enabling the estimation of final infarct volume based on time and grade of reperfusion.

Conclusions: We validated a deep learning-based method which improved final infarct volume estimations compared with classic computed tomography perfusion imaging processing. In addition, the deep learning model predicted individual infarct growth rates which could enable the introduction of tissue clocks during the management of acute stroke.
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http://dx.doi.org/10.1161/STROKEAHA.121.034444DOI Listing
February 2022

Game-theoretical mapping of fundamental brain functions based on lesion deficits in acute stroke.

Brain Commun 2021 2;3(3):fcab204. Epub 2021 Sep 2.

Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Lesion analysis is a fundamental and classical approach for inferring the causal contributions of brain regions to brain function. However, many studies have been limited by the shortcomings of methodology or clinical data. Aiming to overcome these limitations, we here use an objective multivariate approach based on game theory, Multi-perturbation Shapley value Analysis, in conjunction with data from a large cohort of 394 acute stroke patients, to derive causal contributions of brain regions to four principal functional components of the widely used National Institutes of Health Stroke Score measure. The analysis was based on a high-resolution parcellation of the brain into 294 grey and white matter regions. Through initial lesion symptom mapping for identifying all potential candidate regions and repeated iterations of the game-theoretical approach to remove non-significant contributions, the analysis derived the smallest sets of regions contributing to each of the four principal functional components as well as functional interactions among the regions. Specifically, the factor 'language and consciousness' was related to contributions of cortical regions in the left hemisphere, including the prefrontal gyrus, the middle frontal gyrus, the ventromedial putamen and the inferior frontal gyrus. Right and left motor functions were associated with contributions of the left and right dorsolateral putamen and the posterior limb of the internal capsule, correspondingly. Moreover, the superior corona radiata and the paracentral lobe of the right hemisphere as well as the right caudal area 23 of the cingulate gyrus were mainly related to left motor function, while the prefrontal gyrus, the external capsule and the sagittal stratum fasciculi of the left hemisphere contributed to right motor function. Our approach demonstrates a practically feasible strategy for applying an objective lesion inference method to a high-resolution map of the human brain and distilling a small, characteristic set of grey and white matter structures contributing to fundamental brain functions. In addition, we present novel findings of synergistic interactions between brain regions that provide insight into the functional organization of brain networks.
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http://dx.doi.org/10.1093/braincomms/fcab204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473841PMC
September 2021

Excessive White Matter Hyperintensity Increases Susceptibility to Poor Functional Outcomes After Acute Ischemic Stroke.

Front Neurol 2021 10;12:700616. Epub 2021 Sep 10.

Centogene AG, Rostock, Germany.

To personalize the prognostication of post-stroke outcome using MRI-detected cerebrovascular pathology, we sought to investigate the association between the excessive white matter hyperintensity (WMH) burden unaccounted for by the traditional stroke risk profile of individual patients and their long-term functional outcomes after a stroke. We included 890 patients who survived after an acute ischemic stroke from the MRI-Genetics Interface Exploration (MRI-GENIE) study, for whom data on vascular risk factors (VRFs), including age, sex, atrial fibrillation, diabetes mellitus, hypertension, coronary artery disease, smoking, prior stroke history, as well as acute stroke severity, 3- to-6-month modified Rankin Scale score (mRS), WMH, and brain volumes, were available. We defined the unaccounted WMH (uWMH) burden modeling of expected WMH burden based on the VRF profile of each individual patient. The association of uWMH and mRS score was analyzed by linear regression analysis. The odds ratios of patients who achieved full functional independence (mRS < 2) in between trichotomized uWMH burden groups were calculated by pair-wise comparisons. The expected WMH volume was estimated with respect to known VRFs. The uWMH burden was associated with a long-term functional outcome (β = 0.104, < 0.01). Excessive uWMH burden significantly reduced the odds of achieving full functional independence after a stroke compared to the low and average uWMH burden [OR = 0.4, 95% CI: (0.25, 0.63), < 0.01 and OR = 0.61, 95% CI: (0.42, 0.87), < 0.01, respectively]. The excessive amount of uWMH burden unaccounted for by the traditional VRF profile was associated with worse post-stroke functional outcomes. Further studies are needed to evaluate a lifetime brain injury reflected in WMH unrelated to the VRF profile of a patient as an important factor for stroke recovery and a plausible indicator of brain health.
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http://dx.doi.org/10.3389/fneur.2021.700616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461233PMC
September 2021

Changes in synaptic density in the subacute phase after ischemic stroke: A C-UCB-J PET/MR study.

J Cereb Blood Flow Metab 2022 Feb 22;42(2):303-314. Epub 2021 Sep 22.

Department of Neurosciences, KU Leuven, Leuven, Belgium.

Functional alterations after ischemic stroke have been described with Magnetic Resonance Imaging (MRI) and perfusion Positron Emission Tomography (PET), but no data on synaptic changes exist. Recently, imaging of synaptic density became available by targeting synaptic vesicle protein 2 A, a protein ubiquitously expressed in all presynaptic nerve terminals. We hypothesized that in subacute ischemic stroke loss of synaptic density can be evaluated with C-UCB-J PET in the ischemic tissue and that alterations in synaptic density can be present in brain regions beyond the ischemic core. We recruited ischemic stroke patients to undergo C-UCB-J PET/MR imaging 21 ± 8 days after stroke onset to investigate regional C-UCB-J SUVR (standardized uptake value ratio). There was a decrease (but residual signal) of C-UCB-J SUVR within the lesion of 16 stroke patients compared to 40 healthy controls (ratio = 0.67 ± 0.28, p = 0.00023). Moreover, C-UCB-J SUVR was lower in the non-lesioned tissue of the affected hemisphere compared to the unaffected hemisphere (ΔSUVR = -0.17, p = 0.0035). The contralesional cerebellar hemisphere showed a lower C-UCB-J SUVR compared to the ipsilesional cerebellar hemisphere (ΔSUVR = -0.14, p = 0.0048). In 8 out of 16 patients, the asymmetry index suggested crossed cerebellar diaschisis. Future research is required to longitudinally study these changes in synaptic density and their association with outcome.
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http://dx.doi.org/10.1177/0271678X211047759DOI Listing
February 2022

Genome-Wide Association Study Identifies First Locus Associated with Susceptibility to Cerebral Venous Thrombosis.

Ann Neurol 2021 11 29;90(5):777-788. Epub 2021 Sep 29.

Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia, Italy.

Objective: Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood.

Methods: A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets.

Results: In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 × 10 ; odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 × 10 ). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 × 10 ) increased risk of CVT compared with individuals with blood group O.

Interpretation: We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021;90:777-788.
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http://dx.doi.org/10.1002/ana.26205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8666091PMC
November 2021

Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial.

Stroke 2021 12 26;52(12):3768-3776. Epub 2021 Aug 26.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Germany (I.L., M.J., E.S., F.Q., B.C., C.G., G.T.).

Background And Purpose: During the first days and weeks after an acute ischemic stroke, patients are prone to complications that can influence further treatment, recovery, and functional outcome. In clinical trials, severe complications are recorded as serious adverse events (SAE). We analyzed the effect of SAE on functional outcome and predictors of SAE in the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke).

Methods: We performed a post hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled clinical trial of magnetic resonance imaging-guided intravenous thrombolysis with alteplase in patients with acute ischemic stroke and unknown time of onset. Functional outcome was assessed by the modified Rankin Scale 90 days after the stroke. SAE were reported to a central safety desk and recorded and categorized by organ system using Medical Dictionary for Regulatory Activities terminology. We used logistic regression analysis to determine the effect of SAE on functional outcome and linear multiple regression analysis to identify baseline predictors of SAE.

Results: Among 503 patients randomized, 199 SAE were reported for n=110 (22%) patients. Of those patients who did suffer a SAE, 20 (10%) had a fatal outcome. Patients suffering from at least one SAE had a lower odds of reaching a favorable outcome (modified Rankin Scale score of 0-1) at 90 days (adjusted odds ratio, 0.36 [95% CI, 0.21-0.61], <0.001). Higher age (=0.04) and male sex (=0.01) were predictors for the occurrence of SAE.

Conclusions: SAEs were observed in about one in 5 patients, were more frequent in elderly and male patients and were associated with worse functional outcome. These results may help to assess the risk of SAE in future stroke trials and create awareness for severe complications after stroke in clinical practice. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://eudract.ema.europa.eu; Unique identifier: 2011-005906-32.
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http://dx.doi.org/10.1161/STROKEAHA.120.033425DOI Listing
December 2021

Colchicine for prevention of vascular inflammation in Non-CardioEmbolic stroke (CONVINCE) - study protocol for a randomised controlled trial.

Eur Stroke J 2021 Jun 18;6(2):222-228. Epub 2021 Jun 18.

Institute of Neuroscience, Newcastle University, Newcastle, UK.

Background: Inflammation contributes to unstable atherosclerotic plaque and stroke. In randomised trials in patients with coronary disease, canukinumab (an interleukin-1B antagonist) and colchicine (a tubulin inhibitor with pleiotropic anti-inflammatory effects) reduced recurrent vascular events.Hypothesis: Anti-inflammatory therapy with low-dose colchicine plus usual care will reduce recurrent vascular events in patients with non-severe, non-cardioembolic stroke and TIA compared with usual care alone.

Design: CONVINCE is a multi-centre international (in 17 countries) Prospective, Randomised Open-label, Blinded-Endpoint assessment (PROBE) controlled Phase 3 clinical trial in 3154 participants. The intervention is colchicine 0.5 mg/day and usual care versus usual care alone (antiplatelet, lipid-lowering, antihypertensive treatment, lifestyle advice). Included patients are at least 40 years, with non-severe ischaemic stroke (modified Rankin score ≤3) or high-risk TIA (ABCD2 > 3, or positive DWI, or cranio-cervical artery stenosis) within 72 hours-28 days of randomisation, with qualifying stroke/TIA most likely caused by large artery stenosis, lacunar disease, or cryptogenic embolism. Exclusions are stroke/TIA caused by cardio-embolism or other defined cause (e.g. dissection), contra-indication to colchicine (including potential drug interactions), or incapacity for participation in a clinical trial. The anticipated median follow-up will be 36 months. The primary analysis will be by intention-to-treat.

Outcome: The primary outcome is time to first recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation with unstable angina (non-fatal or fatal).

Summary: CONVINCE will provide high-quality randomised data on the efficacy and safety of anti-inflammatory therapy with colchicine for secondary prevention after stroke.

Schedule: First-patient first-visit was December 2016. Recruitment to complete in 2021, follow-up to complete in 2023.
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http://dx.doi.org/10.1177/2396987320972566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370082PMC
June 2021

24-hour blood pressure variability and treatment effect of intravenous alteplase in acute ischaemic stroke.

Eur Stroke J 2021 Jun 18;6(2):168-175. Epub 2021 Jun 18.

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

Introduction: To assess the association between 24 h blood pressure variability (BPV) on functional outcome and treatment effect of intravenous alteplase in acute ischaemic stroke.

Patients And Methods: In all patients with acute ischaemic stroke of unknown onset randomised in the WAKE-UP (Efficacy and Safety of magnetic resonance imaging [MRI]-based Thrombolysis in Wake-Up Stroke) trial, blood pressure (BP) was measured before randomisation and after initiation of treatment at regular intervals up to 24 hours. Individual BPV was measured by coefficient of variation (CV) of all BP values. Primary outcome measure was favourable outcome defined by a modified Rankin Scale (mRS) score 0 or 1 at 90 days after stroke.

Results: BP measurements were available for 498 of 503 patients randomised (177 women [35.5%], mean age [SD] of 65.2 [11.5] years). Systolic BPV was not associated with the treatment effect of thrombolysis (test for interaction, p = 0.46). The adjusted odds ratio (aOR) for favourable outcome with alteplase, adjusted for age, stroke severity and baseline BP on admission, did not show an association across the quintiles of increasing systolic BPV with an aOR 1.89 (95% confidence interval [CI], 0.76-4.70) in the lowest quintile to aOR 1.05 (95% CI, 0.43-2.56) in the highest quintile. Higher mean systolic BP was associated with a smaller treatment effect of thrombolysis with a significant interaction (p = 0.033). The aOR for favourable outcome with alteplase decreased with quintiles of increasing mean systolic BP from aOR 3.16 (95% CI, 1.26-7.93) in the lowest quintile to aOR 0.84 (95% CI, 0.34-2.10) in in the highest quintile.

Conclusions: There was a significant interaction between mean systolic BP and treatment effect of thrombolysis with higher mean systolic BP being associated with poorer outcome. BPV was not associated with outcome after thrombolysis.ClinicalTrials.gov identifier NCT01525290.
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http://dx.doi.org/10.1177/23969873211014758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370068PMC
June 2021

Hyperintense acute reperfusion marker associated with hemorrhagic transformation in the WAKE-UP trial.

Eur Stroke J 2021 Jun 12;6(2):128-133. Epub 2021 Jun 12.

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

Introduction: Hyperintense acute reperfusion marker (HARM) is an indicator of early disruption of the blood-brain-barrier. Our aim was to investigate the incidence of HARM in patients with a diffusion weighted imaging (DWI) - fluid attenuated inversion recovery (FLAIR) mismatch and determine the association between this marker and hemorrhagic complications as well as clinical outcome.

Patients And Methods: We included patients from the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial who underwent baseline perfusion weighted imaging (PWI). HARM was defined as a hyperintense signal in the cerebrospinal fluid space on FLAIR imaging at 24 h after baseline imaging. We compared baseline characteristics in patients with and without HARM and investigated the association between HARM and any hemorrhagic transformation (HT) and parenchymal hematoma (PH) in a multivariate logistic regression. We also explored HARM as an independent predictor of poor outcome, defined as a modified Rankin Scale of 3-6 at 90 days.

Results: HARM was present in 14 of 223 (6%) patients with a DWI-FLAIR mismatch and baseline characteristics were similar in patients with vs without HARM. HARM showed an independent relationship with any HT (OR 6.67; 95%CI 1.72-26.58) and any PH (OR 6.92; 95%CI 1.34-29.49). The rate of HARM was similar in patients with good and poor outcome (5%, p = 0.90).

Conclusion: In the WAKE-UP trial, the incidence of HARM was only 6% at 24 h. An association was present between HARM and hemorrhagic complications, but no relationship with functional outcome was observed.
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http://dx.doi.org/10.1177/23969873211007686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370087PMC
June 2021

A survey of functional dyspepsia in 361,360 individuals: Phenotypic and genetic cross-disease analyses.

Neurogastroenterol Motil 2021 Aug 11:e14236. Epub 2021 Aug 11.

Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, San Sebastian, Spain.

Background: Functional dyspepsia (FD) is a common gastrointestinal condition of poorly understood pathophysiology. While symptoms' overlap with other conditions may indicate common pathogenetic mechanisms, genetic predisposition is suspected but has not been adequately investigated.

Methods: Using healthcare, questionnaire, and genetic data from three large population-based biobanks (UK Biobank, EGCUT, and MGI), we surveyed FD comorbidities, heritability, and genetic correlations across a wide spectrum of conditions and traits in 10,078 cases and 351,282 non-FD controls of European ancestry.

Key Results: In UK Biobank, 281 diagnoses were detected at increased prevalence in FD, based on healthcare records. Among these, gastrointestinal conditions (OR = 4.0, p < 1.0 × 10 ), anxiety disorders (OR = 2.3, p < 1.4 × 10 ), ischemic heart disease (OR = 2.2, p < 2.3 × 10 ), and infectious and parasitic diseases (OR = 2.1, p = 1.5 × 10 ) showed strongest association with FD. Similar results were obtained in an analysis of self-reported conditions and use of medications from questionnaire data. Based on a genome-wide association meta-analysis of genotypes across all cohorts, FD heritability was estimated close to 5% (  = 0.047, p = 0.014). Genetic correlations indicate FD predisposition is shared with several other diseases and traits (r  > 0.344), mostly overlapping with those also enriched in FD patients. Suggestive (p < 5.0 × 10 ) association with FD risk was detected for 13 loci, with 2 showing nominal replication (p < 0.05) in an independent cohort of 192 FD patients.

Conclusions & Inferences: FD has a weak heritable component that shows commonalities with multiple conditions across a wide spectrum of pathophysiological domains. This new knowledge contributes to a better understanding of FD etiology and may have implications for improving its treatment.
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http://dx.doi.org/10.1111/nmo.14236DOI Listing
August 2021

MRI Radiomic Signature of White Matter Hyperintensities Is Associated With Clinical Phenotypes.

Front Neurosci 2021 12;15:691244. Epub 2021 Jul 12.

Department of Neurology, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO, United States.

Objective: Neuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of quantitatively describing conventional images, radiomic analyses hold potential for evaluating brain health. We sought to: (1) evaluate radiomics to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and (2) uncover associations between predictive radiomic features and clinical phenotypes.

Methods: We analyzed a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images with total brain and WMH segmentations. Radiomic features were extracted from normal-appearing brain tissue (brain mask-WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with stable selected features predictive of WMH burden and then related this signature to clinical variables using canonical correlation analysis (CCA).

Results: Radiomic features were predictive of WMH burden ( = 0.855 ± 0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected -values < 0.001, -value = 0.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and diabetes, CV4 by hypertension, CV5 by atrial fibrillation (AF) and diabetes, CV6 by coronary artery disease (CAD), and CV7 by CAD and diabetes.

Conclusion: Radiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes, suggesting different radiographical textural abnormalities per cardiovascular risk profile. Further research could evaluate radiomics to predict the progression of WMH and for the follow-up of stroke patients' brain health.
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http://dx.doi.org/10.3389/fnins.2021.691244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312571PMC
July 2021

Technology-supported sitting balance therapy versus usual care in the chronic stage after stroke: a pilot randomized controlled trial.

J Neuroeng Rehabil 2021 07 28;18(1):120. Epub 2021 Jul 28.

Department of Rehabilitation Sciences, KU Leuven - University of Leuven, Leuven, Belgium.

Background: Technology development for sitting balance therapy and trunk rehabilitation is scarce. Hence, intensive one-to-one therapist-patient training is still required. We have developed a novel rehabilitation prototype, specifically aimed at providing sitting balance therapy. We investigated whether technology-supported sitting balance training was feasible and safe in chronic stroke patients and we determined whether clinical outcomes improved after a four-week programme, compared with usual care.

Methods: In this parallel-group, assessor-blinded, randomized controlled pilot trial, we divided first-event chronic stroke participants into two groups. The experimental group received usual care plus additional therapy supported by rehabilitation technology, consisting of 12 sessions of 50 min of therapy over four weeks. The control group received usual care only. We assessed all participants twice pre-intervention and once post-intervention. Feasibility and safety were descriptively analysed. Between-group analysis evaluated the pre-to-post differences in changes in motor and functional outcomes.

Results: In total, 30 participants were recruited and 29 completed the trial (experimental group: n = 14; control group: n = 15). There were no between-group differences at baseline. Therapy was evaluated as feasible by participants and therapist. There were no serious adverse events during sitting balance therapy. Changes in clinical outcomes from pre- to post-intervention demonstrated increases in the experimental than in the control group for: sitting balance and trunk function, evaluated by the Trunk Impairment Scale (mean points score (SD) 7.07 (1.69) versus 0.33 (2.35); p < 0.000); maximum gait speed, assessed with the 10 Metre Walk Test (mean gait speed 0.16 (0.16) m/s versus 0.06 (0.06) m/s; p = 0.003); and functional balance, measured using the Berg balance scale (median points score (IQR) 4.5 (5) versus 0 (4); p = 0.014).

Conclusions: Technology-supported sitting balance training in persons with chronic stroke is feasible and safe. A four-week, 12-session programme on top of usual care suggests beneficial effects for trunk function, maximum gait speed and functional balance.

Trial Registration: ClinicalTrials.gov identifier: NCT04467554, https://clinicaltrials.gov/ct2/show/NCT04467554 , date of Registration: 13 July 2020.
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http://dx.doi.org/10.1186/s12984-021-00910-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316712PMC
July 2021

Genetic Variation Is Associated with Post-Reperfusion Therapy Parenchymal Hematoma. A GWAS Meta-Analysis.

J Clin Med 2021 Jul 16;10(14). Epub 2021 Jul 16.

Department of Neurology, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08025 Barcelona, Spain.

Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing genetic background. We performed a GWAS and meta-analysis, following standard quality controls and association analysis (fastGWAS), adjusting age, NIHSS, and principal components. FUMA was used to annotate, prioritize, visualize, and interpret the meta-analysis results. The total number of patients in the meta-analysis was 2034 (216 cases and 1818 controls). We found rs79770152 having a genome-wide significant association (beta 0.09, -value 3.90 × 10) located in the gene and a suggestive variant (rs13297983: beta 0.07, -value 6.10 × 10) located in associated with PH occurrence. The genetic correlation showed a shared genetic background of PH with Alzheimer's disease and white matter hyperintensities. In addition, genes containing the ten most significant associations have been related to aggregated amyloid-β, tau protein, white matter microstructure, inflammation, and matrix metalloproteinases.
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http://dx.doi.org/10.3390/jcm10143137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305811PMC
July 2021

An Updated Meta-Analysis of RCTs of Colchicine for Stroke Prevention in Patients with Coronary Artery Disease.

J Clin Med 2021 Jul 14;10(14). Epub 2021 Jul 14.

Second Department of Neurology, School of Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, 45701 Athens, Greece.

Emerging evidence from randomized controlled clinical trials (RCTs) suggests that colchicine has cardiovascular benefits for patients with coronary disease, including benefits for stroke prevention. We performed an updated systematic review and meta-analysis of all RCTs reporting on stroke outcomes during the follow-up of patients with a history of cardiovascular disease randomized to colchicine treatment or control (placebo or usual care). We identified 6 RCTs including a total of 11,870 patients (mean age 63 years, 83% males) with a mean follow-up of 2 years. Colchicine treatment was associated with a lower risk of stroke during follow-up, compared to that of placebo or usual care (risk ratio = 0.49, 95% confidence interval: 0.31-0.80; = 0.004), without heterogeneity across the included studies (I = 0%, for Cochran's Q = 0.52). In the subgroup analysis, no heterogeneity ( = 0.77) was identified in the effect of colchicine on stroke prevention between patients with recent acute (RR = 0.55, 95% CI: 0.15-2.05) or chronic stable (RR = 0.43, 95% CI: 0.21-0.89) coronary artery syndromes. In conclusion, we found that colchicine treatment decreases the stroke risk in patients with a history of atherosclerotic cardiovascular disease.
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http://dx.doi.org/10.3390/jcm10143110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307322PMC
July 2021

Influence of stroke infarct location on quality of life assessed in a multivariate lesion-symptom mapping study.

Sci Rep 2021 06 29;11(1):13490. Epub 2021 Jun 29.

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

Stroke has a deleterious impact on quality of life. However, it is less well known if stroke lesions in different brain regions are associated with reduced quality of life (QoL). We therefore investigated this association by multivariate lesion-symptom mapping. We analyzed magnetic resonance imaging and clinical data from the WAKE-UP trial. European Quality of Life 5 Dimensions (EQ-5D) 3 level questionnaires were completed 90 days after stroke. Lesion symptom mapping was performed using a multivariate machine learning algorithm (support vector regression) based on stroke lesions 22-36 h after stroke. Brain regions with significant associations were explored in reference to white matter tracts. Of 503 randomized patients, 329 were included in the analysis (mean age 65.4 years, SD 11.5; median NIHSS = 6, IQR 4-9; median EQ-5D score 90 days after stroke 1, IQR 0-4, median lesion volume 3.3 ml, IQR 1.1-16.9 ml). After controlling for lesion volume, significant associations between lesions and EQ-5D score were detected for the right putamen, and internal capsules of both hemispheres. Multivariate lesion inference analysis revealed an association between injuries of the cortico-spinal tracts with worse self-reported quality of life 90 days after stroke in comparably small stroke lesions, extending previous reports of the association of striato-capsular lesions with worse functional outcome. Our findings are of value to identify patients at risk of impaired QoL after stroke.
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http://dx.doi.org/10.1038/s41598-021-92865-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241844PMC
June 2021

Inflammation and Stroke Risk: A New Target for Prevention.

Stroke 2021 08 24;52(8):2697-2706. Epub 2021 Jun 24.

Second Department of Neurology, "Attikon" University Hospital, National & Kapodistrian University of Athens, Greece (G.T.).

New therapeutic approaches are required for secondary prevention of residual vascular risk after stroke. Diverse sources of evidence support a causal role for inflammation in the pathogenesis of stroke. Randomized controlled trials of anti-inflammatory agents have reported benefit for secondary prevention in patients with coronary disease. We review the data from observational studies supporting a role for inflammation in pathogenesis of stroke, overview randomized controlled trials of anti-inflammatory therapy in cardiac disease and discuss the potential implications for stroke prevention therapy.
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http://dx.doi.org/10.1161/STROKEAHA.121.034388DOI Listing
August 2021

The impact of COVID-19 on acute stroke care in Belgium.

Acta Neurol Belg 2021 Oct 19;121(5):1251-1258. Epub 2021 Jun 19.

Department of Neurology, Groeninge Hospital, Kortrijk, Belgium.

A worldwide decline in stroke hospitalizations during the COVID-19 pandemic has been reported. Information on stroke care during the pandemic in Belgium is lacking. This study aims to analyze the impact of COVID-19 on acute stroke care in eight Belgian stroke centers. This Belgian study is part of an international observational and retrospective study in 70 countries and 457 stroke centers. We compared volumes of COVID-19 and stroke hospitalizations, intravenous thrombolysis and endovascular treatment rates, acute treatment time intervals and functional outcome at 90 days during the first wave of the pandemic to two control intervals (March-May 2019 and December-February 2020). From March 2020 to May 2020, 860 stroke patients were hospitalized. In the same time period, 2850 COVID-19 patients were admitted, of which 37 (1.3%) were diagnosed with a stroke. Compared to the months prior to the pandemic and the same time epoch one year earlier, stroke hospitalizations were reduced (relative difference 15.9% [p = 0.03] and 14.5% [p = 0.05], respectively). Despite a reduction in absolute volumes, there was no difference in the monthly proportion of thrombolysis or endovascular treatment provided to the overall stroke hospitalizations. Acute treatment time metrics did not change between COVID-19 pandemic and control time epochs. We found no difference in 90-day functional outcomes nor in mortality after stroke between patients admitted during the pandemic versus control periods. We found a decline in the volume of stroke hospitalizations during the first wave of the COVID-19 pandemic in Belgium. Stroke care quality parameters remained unchanged.
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http://dx.doi.org/10.1007/s13760-021-01726-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214455PMC
October 2021

Outcome after acute ischemic stroke is linked to sex-specific lesion patterns.

Nat Commun 2021 06 2;12(1):3289. Epub 2021 Jun 2.

Department of Neurology, Washington University School of Medicine & Barnes-Jewish Hospital, St Louis, MO, USA.

Acute ischemic stroke affects men and women differently. In particular, women are often reported to experience higher acute stroke severity than men. We derived a low-dimensional representation of anatomical stroke lesions and designed a Bayesian hierarchical modeling framework tailored to estimate possible sex differences in lesion patterns linked to acute stroke severity (National Institute of Health Stroke Scale). This framework was developed in 555 patients (38% female). Findings were validated in an independent cohort (n = 503, 41% female). Here, we show brain lesions in regions subserving motor and language functions help explain stroke severity in both men and women, however more widespread lesion patterns are relevant in female patients. Higher stroke severity in women, but not men, is associated with left hemisphere lesions in the vicinity of the posterior circulation. Our results suggest there are sex-specific functional cerebral asymmetries that may be important for future investigations of sex-stratified approaches to management of acute ischemic stroke.
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http://dx.doi.org/10.1038/s41467-021-23492-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172535PMC
June 2021

Reversible Edema in the Penumbra Correlates With Severity of Hypoperfusion.

Stroke 2021 07 13;52(7):2338-2346. Epub 2021 May 13.

Department of Neurology, University Hospitals Leuven, Belgium (L.S., A.W., R. Lemmens).

Background And Purpose: We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra.

Methods: We determined core and perfusion lesions in subjects from the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) and AXIS 2 trial (Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke) with perfusion- and diffusion-weighted imaging at baseline. Only subjects with a mismatch volume >15 mL and ratio >1.2 were included. We created voxel-based relative fluid-attenuated inversion recovery signal intensity (rFLAIR SI) maps at baseline and follow-up. We studied rFLAIR SI in 2 regions of interest: baseline penumbra (baseline perfusion lesion−[core lesion+voxels with apparent diffusion coefficient <620 10−6 mm2/s]) and noninfarcted penumbra (baseline perfusion lesion−follow-up fluid-attenuated inversion recovery lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). We analyzed the association between rFLAIR SI and severity of hypoperfusion, defined as time to maximum of the residue function.

Results: In the baseline penumbra, rFLAIR SI was elevated (ratio, 1.04; P=1.7×10−13; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; P<1.0×10−4; n=126). In WAKE-UP, imaging at 24 hours revealed a further increase of rFLAIR SI in the noninfarcted penumbra (ratio, 1.05 at 24 hours versus 1.03 at baseline; P=7.1×10−3; n=43). In AXIS 2, imaging at 30 days identified reversibility of the rFLAIR SI (ratio, 1.02 at 30 days versus 1.04 at baseline; P=1.5×10−3; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; P=0.099; n=26).

Conclusions: Penumbral rFLAIR SI increases appear early after stroke onset, correlate with severity of hypoperfusion, further increase at 24 hours, and are reversible by 30 days.

Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://clinicaltrials.gov; Unique identifier: NCT00927836.
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http://dx.doi.org/10.1161/STROKEAHA.120.033071DOI Listing
July 2021

Preserved structural connectivity mediates the clinical effect of thrombolysis in patients with anterior-circulation stroke.

Nat Commun 2021 05 10;12(1):2590. Epub 2021 May 10.

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

Thrombolysis with recombinant tissue plasminogen activator in acute ischemic stroke aims to restore compromised blood flow and prevent further neuronal damage. Despite the proven clinical efficacy of this treatment, little is known about the short-term effects of systemic thrombolysis on structural brain connectivity. In this secondary analysis of the WAKE-UP trial, we used MRI-derived measures of infarct size and estimated structural network disruption to establish that thrombolysis is associated not only with less infarct growth, but also with reduced loss of large-scale connectivity between grey-matter areas after stroke. In a causal mediation analysis, infarct growth mediated a non-significant 8.3% (CI [-8.0, 32.6]%) of the clinical effect of thrombolysis on functional outcome. The proportion mediated jointly through infarct growth and change of structural connectivity, especially in the border zone around the infarct core, however, was as high as 33.4% (CI [8.8, 77.4]%). Preservation of structural connectivity is thus an important determinant of treatment success and favourable functional outcome in addition to lesion volume. It might, in the future, serve as an imaging endpoint in clinical trials or as a target for therapeutic interventions.
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http://dx.doi.org/10.1038/s41467-021-22786-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110812PMC
May 2021

Horizontal Saccadic Palsy as a Prominent Symptom of Anti-NMDAR Encephalitis.

Neurol Clin Pract 2021 Feb;11(1):e20-e21

Department of Neurology (KD, TC, BD, MS, RL), University Hospitals Leuven, Leuven, Belgium; University Hospitals Leuven (KP), Laboratory Medicine, Leuven, Belgium; KU Leuven (KP), Department of Neurosciences, Laboratory for Molecular Neurobiomarker Research, Leuven, Belgium; KU Leuven (BD), Department of Neurosciences, Laboratory for Neuroimmunology, Leuven, Belgium; Department of Neurology (JD), Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Neurology (JD), University of Pennsylvania, Philadelphia, PA; Institució Catalana de Recerca i Estudis Avançats (ICREA) (JD), Barcelona, Spain; Department of Neurosciences (RL), KU Leuven-University of Leuven, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium; and VIB (RL), Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium.

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http://dx.doi.org/10.1212/CPJ.0000000000000750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101314PMC
February 2021

Reversible cerebral vasoconstriction syndrome triggered by ondansetron.

Acta Neurol Belg 2021 Aug 27;121(4):1061-1063. Epub 2021 Apr 27.

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

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http://dx.doi.org/10.1007/s13760-021-01678-2DOI Listing
August 2021

Added Value of Quantitative Apparent Diffusion Coefficient Values for Neuroprognostication After Cardiac Arrest.

Neurology 2021 05 9;96(21):e2611-e2618. Epub 2021 Apr 9.

From the Departments of Neurology (A.W., L.S., S.P., R.L.), Radiology (R.P., S.C., P.D.), and Cardiology (S.J., K.A.), University Hospitals Leuven; Laboratory of Neurobiology (A.W., L.S., R.L.), Center for Brain & Disease Research, VIB; Department of Neurosciences (A.W., L.S., R.L.), Experimental Neurology and Leuven Brain Institute, University of Leuven, Belgium; Department of Neurology (A.W.), Academic Medical Center, University of Amsterdam, the Netherlands; Translational MRI, Department of Imaging and Pathology (R.P., S.C., P.D.), and Laboratory for Epilepsy Research, Department of Neurosciences (W.V.P.), KU Leuven, Belgium; Department of Cardiology (B.F., M.D., J.D., K.A.), Ziekenhuis Oost-Limburg, Genk; and Faculty of Medicine and Life Sciences (J.D., K.A.), Faculty of Medicine and Life Sciences, University Hasselt, Diepenbeek, Belgium.

Objective: To test the prognostic value of brain MRI in addition to clinical and electrophysiologic variables in patients post-cardiac arrest (CA), we explored data from the randomized Neuroprotect Post-CA trial (NCT02541591).

Methods: In this trial, brain MRIs were prospectively obtained. We calculated receiver operating characteristic (ROC) curves for the average apparent diffusion coefficient (ADC) value and percentage of brain voxels with an ADC value <650 × 10 mm/s and <450 × 10 mm/s. We constructed multivariable logistic regression models with clinical characteristics, EEG, somatosensory evoked potentials (SSEP), and ADC value as independent variables to predict good neurologic recovery.

Results: In 79/102 patients, MRI data were available and in 58/79 patients all other data were available. At 180 days post-CA, 25/58 (43%) patients had good neurologic recovery. In univariable analysis of all tested MRI measures, average ADC value in the postcentral cortex had the highest accuracy to predict good neurologic recovery, with an area under the ROC curve (AUC) of 0.78. In the most optimal multivariable model, which also included corneal reflexes and EEG, this measure remained an independent predictor of good neurologic recovery (AUC 0.96, false-positive 27%). This model provided a more accurate prediction compared to the most optimal combination of EEG, corneal reflexes, and SSEP ( = 0.03).

Conclusions: Adding information on brain MRI in a multivariable model may improve the prediction of good neurologic recovery in patients post-CA.

Classification Of Evidence: This study provides Class III evidence that MRI ADC features predict neurologic recovery in patients post-CA.
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http://dx.doi.org/10.1212/WNL.0000000000011991DOI Listing
May 2021
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