Publications by authors named "Anke Wouters"

28 Publications

  • Page 1 of 1

Reversible Edema in the Penumbra Correlates With Severity of Hypoperfusion.

Stroke 2021 May 13:STROKEAHA120033071. 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 mm/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; =1.7×10; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; <1.0×10; 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; =7.1×10; 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; =1.5×10; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; =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
May 2021

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

Nat Commun 2021 May 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

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

Neurology 2021 Apr 9. Epub 2021 Apr 9.

Anke Wouters, Department of Neurology, University Hospitals Leuven, Leuven, Belgium - VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium - Department of Neurosciences, Experimental Neurology and Leuven Brain Institute, University of Leuven, Leuven, Belgium - Department of Neurology, Academic Medical Center, University of Amsterdam, The Netherlands; Lauranne Scheldeman, Department of Neurology, University Hospitals Leuven, Leuven, Belgium - VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium - Department of Neurosciences, Experimental Neurology and Leuven Brain Institute, University of Leuven, Leuven, Belgium; Sam Plessers, Department of Neurology, University Hospitals Leuven, Leuven, Belgium; Ronald Peeters, Department of Radiology, University Hospitals Leuven, Leuven, Belgium -Translational MRI, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium; Sarah Capelle, Department of Radiology, University Hospitals Leuven, Leuven, Belgium -Translational MRI, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium; Philippe Demaerel, Department of Radiology, University Hospitals Leuven, Leuven, Belgium -Translational MRI, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium; Wim Van Paesschen, Laboratory for Epilepsy Research, Department of Neurosciences, KU Leuven, Leuven, Belgium; Bert Ferdinande, Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium; Matthias Dupont, Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium; Jo Dens, Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium - Faculty of Medicine and Life Sciences, University Hasselt, Diepenbeek, Belgium; Stefan Janssens, Department of Cardiology, University Hospitals Leuven, Leuven, Belgium; Koen Ameloot, Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium - Faculty of Medicine and Life Sciences, University Hasselt, Diepenbeek, Belgium - Department of Cardiology, University Hospitals Leuven, Leuven, Belgium; Robin Lemmens, Department of Neurology, University Hospitals Leuven, Leuven, Belgium - VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium - Department of Neurosciences, Experimental Neurology and Leuven Brain Institute, University of Leuven, Leuven, Belgium.

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

Methods: In this trial brain MRI's were prospectively obtained. We calculated receiver operating characteristic curves for the average Apparent Diffusion Coefficient (ADC) value and percentage of brain voxels with an ADC value < 650 x 10 mm/s and < 450 x 10 mm/s. We constructed multivariable logistic regression models with clinical characteristics, electroencephalogram (EEG), somatosensory evoked potentials (SSEP) and ADC value as independent variables, to predict good neurological 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 neurological recovery. In univariable analysis of all tested MRI parameters, average ADC value in the postcentral cortex had the highest accuracy to predict good neurological recovery with an AUC of 0.78. In the most optimal multivariate model which also included corneal reflexes and EEG, this parameter remained an independent predictor of good neurological 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 (p=0.03).

Conclusion: Adding information on brain MRI in a multivariate model may improve the prediction of good neurological recovery in post-CA patients.

Classification Of Evidence: "This study provides Class III evidence that MRI ADC features predict neurological recovery in post-cardiac arrest patients."
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http://dx.doi.org/10.1212/WNL.0000000000011991DOI 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

Imaging Markers of Brain Frailty and Outcome in Patients With Acute Ischemic Stroke.

Stroke 2021 Mar 28;52(3):1004-1011. Epub 2021 Jan 28.

Stroke Division (V.T.), The Florey Institute of Neuroscience and Mental Health.

Background And Purpose: Functional outcome after stroke may be related to preexisting brain health. Several imaging markers of brain frailty have been described including brain atrophy and markers of small vessel disease. We investigated the association of these imaging markers with functional outcome after acute ischemic stroke.

Methods: We retrospectively studied patients with acute ischemic stroke enrolled in the AXIS-2 trial (AX200 in Ischemic Stroke Trial), a randomized controlled clinical trial of granulocyte colony-stimulating factor versus placebo. We assessed the ratio of brain parenchymal volume to total intracerebral volumes (ie, the brain parenchymal fraction) and total brain volumes from routine baseline magnetic resonance imaging data obtained within 9 hours of symptom onset using the unified segmentation algorithm in SPM12. Enlarged perivascular spaces, white matter hyperintensities, lacunes, as well as a small vessel disease burden, were rated visually. Functional outcomes (modified Rankin Scale score) at day 90 were determined. Logistic regression was used to test associations between brain imaging features and functional outcomes.

Results: We enrolled 259 patients with a mean age of 69±12 years and 46 % were female. Increased brain parenchymal fraction was associated with higher odds of excellent outcome (odds ratio per percent increase, 1.078 [95% CI, 1.008-1.153]). Total brain volumes and small vessel disease burden were not associated with functional outcome. An interaction between brain parenchymal fraction and large vessel occlusion on excellent outcome was not observed.

Conclusions: Global brain health, as assessed by brain parenchymal fraction on magnetic resonance imaging, is associated with excellent functional outcome after ischemic stroke. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00927836.
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http://dx.doi.org/10.1161/STROKEAHA.120.029841DOI 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

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

Review of Perfusion Imaging in Acute Ischemic Stroke: From Time to Tissue.

Stroke 2020 03 3;51(3):1017-1024. Epub 2020 Feb 3.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA (S.C., M.G.L.).

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http://dx.doi.org/10.1161/STROKEAHA.119.028337DOI Listing
March 2020

Quantitative Signal Intensity in Fluid-Attenuated Inversion Recovery and Treatment Effect in the WAKE-UP Trial.

Stroke 2020 01 30;51(1):209-215. Epub 2019 Oct 30.

From the Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum (B.C., A.N., C.G., G.T.), University Medical Center Hamburg-Eppendorf, Germany.

Background and Purpose- Relative signal intensity of acute ischemic stroke lesions in fluid-attenuated inversion recovery (fluid-attenuated inversion recovery relative signal intensity [FLAIR-rSI]) magnetic resonance imaging is associated with time elapsed since stroke onset with higher intensities signifying longer time intervals. In the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke Trial), intravenous alteplase was effective in patients with unknown onset stroke selected by visual assessment of diffusion weighted imaging fluid-attenuated inversion recovery mismatch, that is, in those with no marked fluid-attenuated inversion recovery hyperintensity in the region of the acute diffusion weighted imaging lesion. In this post hoc analysis, we investigated whether quantitatively measured FLAIR-rSI modifies treatment effect of intravenous alteplase. Methods- FLAIR-rSI of stroke lesions was measured relative to signal intensity in a mirrored region in the contralesional hemisphere. The relationship between FLAIR-rSI and treatment effect on functional outcome assessed by the modified Rankin Scale (mRS) after 90 days was analyzed by binary logistic regression using different end points, that is, favorable outcome defined as mRS score of 0 to 1, independent outcome defined as mRS score of 0 to 2, ordinal analysis of mRS scores (shift analysis). All models were adjusted for National Institutes of Health Stroke Scale at symptom onset and stroke lesion volume. Results- FLAIR-rSI was successfully quantified in stroke lesions in 433 patients (86% of 503 patients included in WAKE-UP). Mean FLAIR-rSI was 1.06 (SD, 0.09). Interaction of FLAIR-rSI and treatment effect was not significant for mRS score of 0 to 1 (=0.169) and shift analysis (=0.086) but reached significance for mRS score of 0 to 2 (=0.004). We observed a smooth continuing trend of decreasing treatment effects in relation to clinical end points with increasing FLAIR-rSI. Conclusions- In patients in whom no marked parenchymal fluid-attenuated inversion recovery hyperintensity was detected by visual judgement in the WAKE-UP trial, higher FLAIR-rSI of diffusion weighted imaging lesions was associated with decreased treatment effects of intravenous thrombolysis. This parallels the known association of treatment effect and elapsing time of stroke onset.
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http://dx.doi.org/10.1161/STROKEAHA.119.027390DOI Listing
January 2020

Predictive value of JC virus PCR in cerebrospinal fluid in the diagnosis of PML.

Diagn Microbiol Infect Dis 2019 Nov 26;95(3):114859. Epub 2019 Jun 26.

Neurology Department, University Hospitals Leuven, Leuven, Belgium; Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium. Electronic address:

Objective: To assess the predictive value of JC virus (JCV) PCR in cerebrospinal fluid (CSF) in the diagnosis of progressive multifocal leukoencephalopathy (PML).

Methods: We conducted a retrospective database query to identify patients with positive CSF JCV PCR. Clinical features, final diagnosis and quantitative PCR results were obtained.

Results: A positive CSF JCV PCR had a PPV of 10.4% for the diagnosis of PML. A weakly positive PCR had a PPV of 1.6%, whereas a moderately to highly positive PCR had a PPV of 92.3%. A PPV of 0.0% was observed in immunocompetent patients and in patients without compatible clinical or radiological features.

Conclusions: A false-positive CSF JCV PCR is highly prevalent in our clinical practice. This test should be reserved for patients with a clinical suspicion of PML and the quantitative result of the PCR should be taken into account when making the diagnosis of PML.
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http://dx.doi.org/10.1016/j.diagmicrobio.2019.06.011DOI Listing
November 2019

Cerebrovascular events after surgery versus conservative therapy for moyamoya disease: a meta-analysis.

Acta Neurol Belg 2019 Sep 18;119(3):305-313. Epub 2019 Jun 18.

Department of Neurosciences, Experimental Neurology, KU Leuven, University of Leuven, Leuven, Belgium.

The background of this article is to determine the effect of a neurosurgical intervention in patients with moyamoya disease (MMD) on the risk of cerebrovascular events. We included studies with at least ten MMD patients in either intervention or control group which investigated cerebrovascular events during a minimal follow-up period of 1 year after neurosurgical intervention vs. conservative therapy. The primary outcome was all strokes; secondary outcome events were mortality, hemorrhagic, and ischemic stroke. Effects were evaluated for three prespecified subpopulations: adult, ischemic, and hemorrhagic moyamoya patients. We performed random-effects meta-analyses on odds ratios (ORs). We included 2,484 patients from 10 studies. The rate of all stroke was 14.1% in surgical treated compared to 30.0% in non-surgical-treated patients [pooled OR 0.38, 95%; confidence interval (CI) 0.23-0.64]. In subgroup analyses, we identified an association between surgery and all stroke in patients presenting with hemorrhagic, but not in patients with ischemic MMD. Hemorrhagic stroke during follow-up was less frequent in patients who underwent a surgical intervention, 4.6% compared to 18.6% of the conservatively treated patients (pooled OR 0.27, 95% CI 0.14-0.53). In addition, we observed a difference in mortality, 0.6% vs. 2.9% (pooled OR 0.32, 95% CI 0.13-0.77), but did not identify an association between surgical treatment and ischemic stroke (pooled OR 0.71, 95% CI 0.46-1.09). Surgical intervention in MMD is associated with a decreased risk of stroke most striking in patients presenting with hemorrhagic MMD. The relationship was present between surgical treatment and the outcome of hemorrhagic, but not ischemic stroke.
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http://dx.doi.org/10.1007/s13760-019-01165-9DOI Listing
September 2019

Clinical Characteristics and Outcome of Patients with Lacunar Infarcts and Concurrent Embolic Ischemic Lesions.

Clin Neuroradiol 2020 Sep 3;30(3):511-516. Epub 2019 Jun 3.

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

Purpose: Lacunar infarcts are thought to result from occlusion of small penetrating arteries due to microatheroma and lipohyalinosis, pathognomonic for cerebral small vessel disease (CSVD). Concurrent embolic ischemic lesions indicate a different stroke mechanism. The purpose of this study was to examine the clinical characteristics and outcome of patients with lacunar infarcts and concurrent embolic infarcts on diffusion-weighted imaging (DWI).

Methods: All patients screened for the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290) were reviewed for acute lacunar infarcts and concurrent embolic lesions on baseline DWI. Clinical characteristics and outcome were compared between lacunar infarct patients with and without concurrent embolic lesions.

Results: Of 244 patients with an acute lacunar infarct, 20 (8.2%) had concurrent acute embolic infarcts. Compared to patients with a lacunar infarct only, patients with concurrent embolic infarcts were older (mean age 69 years vs. 63 years; p = 0.031), more severely affected (median National Institutes of Health Stroke Scale [NIHSS] score 5 vs. 4; p = 0.046), and-among those randomized-had worse functional outcome at 90 days (median modified Rankin Scale [mRS] 3 vs. 1; p = 0.011).

Conclusion: Approximately 8% of lacunar infarct patients show concurrent embolic lesions suggesting a stroke etiology other than CSVD. These patients are more severely affected and have a worse functional outcome illustrating the need for a thorough diagnostic work-up of possible embolic sources even in patients with an imaging-defined diagnosis of lacunar infarcts.
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http://dx.doi.org/10.1007/s00062-019-00800-5DOI Listing
September 2020

Froin Syndrome After Spinal Cord Injury.

World Neurosurg 2019 Jul 21;127:490-491. Epub 2019 May 21.

Department of Neurosurgery, University Hospitals, Leuven, Belgium.

Background: Froin syndrome is characterized by xanthochromia and hypercoagulability of the cerebrospinal fluid (CSF) due to elevated protein levels. This entity results from blockage of the spinal canal by a mass lesion leading to an isolated caudal CSF space.

Case Description: A 48-year-old male, who developed spasticity after a C6 spinal cord injury (SCI) 20 years earlier, presented with subobstruction of his intrathecal baclofen pump. A catheter access port aspiration revealed an extremely high protein concentration (38 g/L) with no signs of infection. Froin syndrome was confirmed when magnetic resonance imaging showed a complete obstruction of the spinal canal at the SCI level.

Conclusions: We report the first case of Froin syndrome after SCI. Froin syndrome can impact intrathecal drug delivery and CSF diagnostics.
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http://dx.doi.org/10.1016/j.wneu.2019.04.198DOI Listing
July 2019

Multimodal magnetic resonance imaging to identify stroke onset within 6 h in patients with large vessel occlusions.

Eur Stroke J 2018 Jun 1;3(2):185-192. Epub 2018 Feb 1.

Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven - University of Leuven, Leuven, Belgium.

Introduction: Mechanical thrombectomy within 6 h after stroke onset improves the outcome in patients with large vessel occlusions. The aim of our study was to establish a model based on diffusion weighted and perfusion weighted imaging to provide an accurate prediction for the 6 h time-window in patients with unknown time of stroke onset.

Patients And Methods: A predictive model was designed based on data from the DEFUSE 2 study and validated in a subgroup of patients with large vessel occlusions from the AXIS 2 trial.

Results: We constructed the model in 91 patients from DEFUSE 2. The following parameters were independently associated with <6 h time-window and included in the model: interquartile range and median relative diffusion weighted imaging, hypoperfusion intensity ratio, core volume and the interaction between median relative diffusion weighted imaging and hypoperfusion intensity ratio as predictors of the 6 h time-window. The area under the curve was 0.80 with a positive predictive value of 0.90 (95%CI 0.79-0.96). In the validation cohort (N = 90), the area under the curve was 0.73 ( for difference = 0.4) with a positive predictive value of 0.85 (95%CI 0.69-0.95).

Discussion: After validation in a larger independent dataset the model can be considered to select patients for endovascular treatment in whom stroke onset is unknown.

Conclusion: In patients with large vessel occlusion and unknown time of stroke onset an automated multivariate imaging model is able to select patients who are likely within the 6 h time-window.
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http://dx.doi.org/10.1177/2396987317753486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460412PMC
June 2018

Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial.

JAMA Neurol 2019 06;76(6):641-649

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

Importance: The rationale for intravenous thrombolysis in patients with lacunar infarcts is debated, since it is hypothesized that the microvascular occlusion underlying lacunar infarcts might not be susceptible to pharmacological reperfusion treatment.

Objective: To study the efficacy and safety of intravenous thrombolysis among patients with lacunar infarcts.

Design, Setting, And Participants: This exploratory secondary post hoc analysis of the WAKE-UP trial included patients who were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). The WAKE-UP trial was a multicenter, double-blind, placebo-controlled randomized clinical trial to study the efficacy and safety of intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time, guided by magnetic resonance imaging. All 503 patients randomized in the WAKE-UP trial were reviewed for lacunar infarcts. Diagnosis of lacunar infarcts was based on magnetic resonance imaging and made by consensus of 2 independent investigators blinded to clinical information.

Main Outcomes And Measures: The primary efficacy variable was favorable outcome defined by a score of 0 to 1 on the modified Rankin Scale at 90 days after stroke, adjusted for age and severity of symptoms.

Results: Of the 503 patients randomized in the WAKE-UP trial, 108 patients (including 74 men [68.5%]) had imaging-defined lacunar infarcts, whereas 395 patients (including 251 men [63.5%]) had nonlacunar infarcts. Patients with lacunar infarcts were younger than patients with nonlacunar infarcts (mean age [SD], 63 [12] years vs 66 [12] years; P = .003). Of patients with lacunar infarcts, 55 (50.9%) were assigned to treatment with alteplase and 53 (49.1%) to receive placebo. Treatment with alteplase was associated with higher odds of favorable outcome, with no heterogeneity of treatment outcome between lacunar and nonlacunar stroke subtypes. In patients with lacunar strokes, a favorable outcome was observed in 31 of 53 patients (59%) in the alteplase group compared with 24 of 52 patients (46%) in the placebo group (adjusted odds ratio [aOR], 1.67 [95% CI, 0.77-3.64]). There was 1 death and 1 symptomatic intracranial hemorrhage according to Safe Implementation of Thrombolysis in Stroke-Monitoring Study criteria in the alteplase group, while no death and no symptomatic intracranial hemorrhage occurred in the placebo group. The distribution of the modified Rankin Scale scores 90 days after stroke also showed a nonsignificant shift toward better outcomes in patients with lacunar infarcts treated with alteplase, with an adjusted common odds ratio of 1.94 (95% CI, 0.95-3.93).

Conclusions And Relevance: While the WAKE-UP trial was not powered to demonstrate the efficacy of treatment in subgroups of patients, the results indicate that the association of intravenous alteplase with functional outcome does not differ in patients with imaging-defined lacunar infarcts compared with those experiencing other stroke subtypes.
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http://dx.doi.org/10.1001/jamaneurol.2019.0351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563546PMC
June 2019

Alberta Stroke Program Early CT Score Versus Computed Tomographic Perfusion to Predict Functional Outcome After Successful Reperfusion in Acute Ischemic Stroke.

Stroke 2018 10;49(10):2361-2367

From the Division of Experimental Neurology, Department of Neurosciences (J.D., A.W., R.L.), Catholic University (KU) Leuven-University of Leuven, Belgium.

Background and Purpose- We aimed to compare the ability of conventional Alberta Stroke Program Early CT Score (ASPECTS), automated ASPECTS, and ischemic core volume on computed tomographic perfusion to predict clinical outcome in ischemic stroke because of large vessel occlusion ≤18 hours after symptom onset. Methods- We selected patients with acute ischemic stroke from the CRISP study (Computed Tomographic Perfusion to Predict Response to Recanalization in Ischemic Stroke Project) with successful reperfusion (modified treatment in cerebral ischemia score 2b or 3). We used e-ASPECTS software to calculate automated ASPECTS and RAPID software to estimate ischemic core volumes. We studied associations between these imaging characteristics and good outcome (modified Rankin Scale score, 0-2) or poor outcome (modified Rankin Scale score, 4-6) in univariable and multivariable analysis, after adjustment for relevant clinical confounders. Results- We included 156 patients. Conventional and automated ASPECTS was not associated with good or poor outcome in univariable analysis ( P=nonsignificant for all). Automated ASPECTS was associated with good outcome in multivariable analysis ( P=0.02) but not with poor outcome. Ischemic core volume was associated with good ( P<0.01) and poor outcome ( P=0.04) in univariable and multivariable analysis ( P=0.03 and P=0.02, respectively). Computed tomographic perfusion predicted good outcome with an area under the curve of 0.62 (95% CI, 0.53-0.71) and optimal cutoff core volume of 15 mL. Conclusions- Ischemic core volume assessed on computed tomographic perfusion is a predictor of clinical outcome among patients in whom endovascular reperfusion is achieved ≤18 hours after symptom onset. In this population, conventional or automated ASPECTS did not predict outcome.
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http://dx.doi.org/10.1161/STROKEAHA.118.021961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207080PMC
October 2018

Prediction of Outcome in Patients With Acute Ischemic Stroke Based on Initial Severity and Improvement in the First 24 h.

Front Neurol 2018 7;9:308. Epub 2018 May 7.

Department of Neurosciences, Experimental Neurology, KU Leuven - University of Leuven, Leuven, Belgium.

Introduction: Stroke severity measured by the baseline National Institutes of Health Stroke Scale (NIHSS) is a strong predictor of stroke outcome. Early change of baseline severity may be a better predictor of outcome. Here, we hypothesized that the change in NIHSS in the first 24 h after stroke improved stroke outcome prediction.

Materials And Methods: Patients from the Leuven Stroke Genetics Study were included when the baseline NIHSS (B-NIHSS) was determined on admission in the hospital and NIHSS after 24 h could be obtained from patient files. The delta NIHSS, relative reduction NIHSS, and major neurological improvement (NIHSS of 0-1 or ≥8-point improvement at 24 h) were calculated. Good functional outcome (GFO) at 90 days was defined as a modified Rankin Scale of 0-2. Independent predictors of outcome were identified by multivariate logistic regression. We performed a secondary analysis after excluding patients presenting with a minor stroke (NIHSS 0-5) since the assessment of change in NIHSS might be more reliable in patients presenting with a moderate to severe deficit.

Results: We analyzed the outcome in 369 patients. B-NIHSS was associated with GFO (odds ratio: 0.82; 95% CI 0.77-0.86). In a multivariate model with B-NIHSS and age as predictors, the accuracy [area under the curve (AUC): 0.82] improved by including the delta NIHSS (AUC: 0.86;  < 0.01). In 131 patients with moderate to severe stroke, the predictive multivariate model was more accurate when including the RR NIHSS (AUC: 0.83) to the model which included B-NIHSS, age and ischemic heart disease (AUC: 0.77;  = 0.03).

Conclusion: B-NIHSS is a predictor of stroke outcome. In this cohort, the prediction of GFO was improved by adding change in stroke severity after 24 h to the model.
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http://dx.doi.org/10.3389/fneur.2018.00308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5950843PMC
May 2018

MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset.

N Engl J Med 2018 08 16;379(7):611-622. Epub 2018 May 16.

From Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf (G.T., B. Cheng, S.G., A.G., C.G.), the Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf (J.F.), and ZytoService Deutschland (E.S.), Hamburg, Universitätsklinik für Neurologie, Medizinische Universität Graz, Graz (F.F.), Centrum für Schlaganfallforschung Berlin (I.G., K.G.H., K.V., M. Ebinger, M. Endres, J.B.F.) and Klinik und Hochschulambulanz für Neurologie (K.G.H., L.N., M. Endres), Charité-Universitätsmedizin Berlin, and Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin, Mediri (J. Gregori, M.G.), the Department of Neurology, Medical Faculty Mannheim, University of Heidelberg (M.H.), and Neurologische Klinik, Universitätsklinikum Heidelberg (P. Ringleb), Heidelberg, Fraunhofer MEVIS and University of Bremen, Bremen (M.G.), and Institut für Neuroradiologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck (A.K.) - all in Germany; the Department of Neurology, Aarhus University Hospital, Aarhus (C.Z.S., G.A.), the Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen (J.M.), and Department of Neurology, Stroke Unit, Aalborg University Hospital, Aalborg (B.M.) - all in Denmark; Hospices Civils de Lyon, Service de Biostatistique (F.B., P. Roy), the Neuroradiology Department, Neurological Hospital, University Lyon (Y.B.), and the Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon (T.-H.C., N.N.), Lyon, and Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne (F.B., P. Roy) - all in France; the Institute of Neuroscience and Psychology (B. Cheripelli, K.W.M.) and the Robertson Centre for Biostatistics (I.F.), University of Glasgow, Glasgow, United Kingdom (I.F.); Fundació Salut Empordà Hospital, Figueres (J. Guibernau), Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Barcelona (N.P.O.), and the Department of Radiology (J.P., S.P.) and the Stroke Unit (J.S.), Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona - all in Spain; the Department of Neurology, St. Antonius Hospital, Nieuwegein, and University Medical Center Utrecht, Utrecht (W.S.) - both in the Netherlands; the Department of Imaging and Pathology, University of Leuven (S.S.), the Department of Neurology, University Hospitals Leuven (A.W., R.L.), KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology (A.W., R.L.), and the VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology (A.W., R.L.), Leuven, Belgium; and Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia (V.T.).

Background: Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase.

Methods: In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis).

Results: The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15).

Conclusions: In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .).
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http://dx.doi.org/10.1056/NEJMoa1804355DOI Listing
August 2018

Automated DWI analysis can identify patients within the thrombolysis time window of 4.5 hours.

Neurology 2018 05 4;90(18):e1570-e1577. Epub 2018 Apr 4.

From the Departments of Neurosciences (A.W., R. Lemmens), Cognitive Neurology (P.D.), and Electrical Engineering (D.R.), KU Leuven, University of Leuven; VIB Center for Brain & Disease Research (A.W., R. Lemmens); Department of Neurology (A.W., R. Lemmens), University Hospitals Leuven, Leuven, Belgium; Department of Neurology (B.C., G.T.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Stanford Stroke Center (S.C., G.W.A.), Stanford University Medical Center, Palo Alto, CA; Department of Neurology (B.N.), Lund University, Sweden; Guided Development GmbH (R. Laage), Heidelberg, Germany; and Florey Institute of Neuroscience and Mental Health (V.N.T.), Heidelberg, Australia.

Objective: To develop an automated model based on diffusion-weighted imaging (DWI) to detect patients within 4.5 hours after stroke onset and compare this method to the visual DWI-FLAIR (fluid-attenuated inversion recovery) mismatch.

Methods: We performed a subanalysis of the "DWI-FLAIR mismatch for the identification of patients with acute ischemic stroke within 4.5 hours of symptom onset" (PRE-FLAIR) and the "AX200 for ischemic stroke" (AXIS 2) trials. We developed a prediction model with data from the PRE-FLAIR study by backward logistic regression with the 4.5-hour time window as dependent variable and the following explanatory variables: age and median relative DWI (rDWI) signal intensity, interquartile range (IQR) rDWI signal intensity, and volume of the core. We obtained the accuracy of the model to predict the 4.5-hour time window and validated our findings in an independent cohort from the AXIS 2 trial. We compared the receiver operating characteristic curve to the visual DWI-FLAIR mismatch.

Results: In the derivation cohort of 118 patients, we retained the IQR rDWI as explanatory variable. A threshold of 0.39 was most optimal in selecting patients within 4.5 hours after stroke onset resulting in a sensitivity of 76% and specificity of 63%. The accuracy was validated in an independent cohort of 200 patients. The predictive value of the area under the curve of 0.72 (95% confidence interval 0.64-0.80) was similar to the visual DWI-FLAIR mismatch (area under the curve = 0.65; 95% confidence interval 0.58-0.72; for difference = 0.18).

Conclusions: An automated analysis of DWI performs at least as good as the visual DWI-FLAIR mismatch in selecting patients within the 4.5-hour time window.
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http://dx.doi.org/10.1212/WNL.0000000000005413DOI Listing
May 2018

A Comparison of Relative Time to Peak and Tmax for Mismatch-Based Patient Selection.

Front Neurol 2017 13;8:539. Epub 2017 Oct 13.

Stanford Stroke Center, Stanford University Medical Center, Palo Alto, CA, United States.

Background And Purpose: The perfusion-weighted imaging (PWI)/diffusion-weighted imaging (DWI) mismatch profile is used to select patients for endovascular treatment. A PWI map of Tmax is commonly used to identify tissue with critical hypoperfusion. A time to peak (TTP) map reflects similar hemodynamic properties with the added benefit that it does not require arterial input function (AIF) selection and deconvolution. We aimed to determine if TTP could substitute Tmax for mismatch categorization.

Methods: Imaging data of the DEFUSE 2 trial were reprocessed to generate relative TTP (rTTP) maps. We identified the rTTP threshold that yielded lesion volumes comparable to Tmax > 6 s and assessed the effect of reperfusion according to mismatch status, determined based on Tmax and rTTP volumes.

Results: Among 102 included cases, the Tmax > 6 s lesion volumes corresponded most closely with rTTP > 4.5 s lesion volumes: median absolute difference 6.9 mL (IQR: 2.3-13.0). There was 94% agreement in mismatch classification between Tmax and rTTP-based criteria. When mismatch was assessed by Tmax criteria, the odds ratio (OR) for favorable clinical response associated with reperfusion was 7.4 (95% CI 2.3-24.1) in patients with mismatch vs. 0.4 (95% CI 0.1-2.6) in patients without mismatch. When mismatch was assessed with rTTP criteria, these ORs were 7.2 (95% CI 2.3-22.2) and 0.3 (95% CI 0.1-2.2), respectively.

Conclusion: rTTP yields lesion volumes that are comparable to Tmax and reliably identifies the PWI/DWI mismatch profile. Since rTTP is void of the problems associated with AIF selection, it is a suitable substitute for Tmax that could improve the robustness and reproducibility of mismatch classification in acute stroke.
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http://dx.doi.org/10.3389/fneur.2017.00539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645507PMC
October 2017

Prediction of Stroke Onset Is Improved by Relative Fluid-Attenuated Inversion Recovery and Perfusion Imaging Compared to the Visual Diffusion-Weighted Imaging/Fluid-Attenuated Inversion Recovery Mismatch.

Stroke 2016 10 6;47(10):2559-64. Epub 2016 Sep 6.

From the Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, B-3000 Leuven, Belgium (A.W., R. Lemmens); VIB, Vesalius Research Center, Laboratory of Neurobiology, B-3000 Leuven, Belgium (A.W., R. Lemmens); Department of Neurology, University Hospitals Leuven, B-3000 Leuven, Belgium (A.W., R. Lemmens); Laboratory for Cognitive Neurology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium (P.D.); Department of Clinical Sciences, Section of Neurology, Lund University, Sweden (B.N.); Guided Development GmbH, Heidelberg, Germany (R. Laage); Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurologie, Kopf-und Neurozentrum, Hamburg, Germany (G.T.); Stroke Center, Stanford University, Palo Alto, CA (G.W.A.); and Department of Neurology Austin Health, and Melbourne Brain Center, Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.).

Background And Purpose: Acute stroke patients with unknown time of symptom onset are ineligible for thrombolysis. The diffusion-weighted imaging and fluid-attenuated inversion recovery (FLAIR) mismatch is a reasonable predictor of stroke within 4.5 hours of symptom onset, and its clinical usefulness in selecting patients for thrombolysis is currently being investigated. The accuracy of the visual mismatch rating is moderate, and we hypothesized that the predictive value of stroke onset within 4.5 hours could be improved by including various clinical and imaging parameters.

Methods: In this study, 141 patients in whom magnetic resonance imaging was obtained within 9 hours after symptom onset were included. Relative FLAIR signal intensity was calculated in the region of nonreperfused core. Mean Tmax was calculated in the total region with Tmax >6 s. Mean relative FLAIR, mean Tmax, lesion volume with Tmax >6 s, age, site of arterial stenosis, core volume, and location of infarct were analyzed by logistic regression to predict stroke onset time before or after 4.5 hours.

Results: Receiver-operating characteristic curve analysis revealed an area under the curve of 0.68 (95% confidence interval 0.59-0.78) for the visual diffusion-weighted imaging/FLAIR mismatch, thereby correctly classifying 69% of patients with an onset time before or after 4.5 hours. Age, relative FLAIR, and Tmax increased the accuracy significantly (P<0.01) to an area under the curve of 0.82 (95% confidence interval 0.74-0.89). This new predictive model correctly categorized 77% of patients according to stroke onset before versus after 4.5 hours.

Conclusions: In patients with unknown stroke onset, the accuracy of predicting time from symptom onset within 4.5 hours is improved by obtaining relative FLAIR and perfusion imaging.
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http://dx.doi.org/10.1161/STROKEAHA.116.013903DOI Listing
October 2016

Association Between Time From Stroke Onset and Fluid-Attenuated Inversion Recovery Lesion Intensity Is Modified by Status of Collateral Circulation.

Stroke 2016 Apr 25;47(4):1018-22. Epub 2016 Feb 25.

From the Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven-University of Leuven, Leuven, Belgium (A.W., R.L.); Laboratory of Neurobiology, VIB, Vesalius Research Center, Leuven, Belgium (A.W., R.L.); Department of Neurology, University Hospitals Leuven, Leuven, Belgium (A.W., R.L.); Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium (P.D.); Department of Neurology, Stroke Center, Stanford University, Palo Alto, CA (S.C., G.A.); Section of Neurology, Department of Clinical Sciences, Lund University, Lund, Sweden (B.N.); Guided Development GmbH, Heidelberg, Germany (R.L.); Uinversitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurologie, Kopf-und Neurozentrum, Hamburg, Germany (G.T.); and Department of Neurology Austin Health, Melbourne Brain Center, Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia (V.T.).

Background And Purpose: In patients with acute stroke, the intensity of a fluid-attenuated inversion recovery (FLAIR) lesion in the region of diffusion restriction is associated with time from symptom onset. We hypothesized that collateral status as assessed by the hypoperfusion intensity ratio could modify the association between time from stroke onset and FLAIR lesion intensity.

Methods: From the AX200 for ischemic stroke trial, 141 patients had appropriate FLAIR, diffusion-weighted imaging, and perfusion-weighted imaging. In the region of nonreperfused core, we calculated voxel-based relative FLAIR (rFLAIR) signal intensity. The hypoperfusion intensity ratio was defined as the ratio of the Tmax >10 s lesion over the Tmax >6 s lesion volume. A hypoperfusion intensity ratio threshold of ≤0.4 was used to dichotomize good versus poor collaterals. We studied the interaction between collateral status on the association between time from symptom onset and FLAIR intensity.

Results: Time from symptom onset was associated with the rFLAIR intensity in the region of nonreperfused core (B=1.05; 95% confidence interval, 1.0-1.1). We identified an interaction between this association and collateral status; an association was present between time and rFLAIR intensity in patients with poor collaterals (r=0.53), but absent in patients with good collaterals (r=0.17; P=0.04).

Conclusions: Our findings show that the relationship between time from symptom onset and rFLAIR lesion intensity depends on collateral status. In patients with good collaterals, the development of an rFLAIR-positive lesion is less dependent on time from symptom onset compared with patients with poor collaterals.
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http://dx.doi.org/10.1161/STROKEAHA.115.012010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811703PMC
April 2016

Magnetic resonance imaging-based endovascular versus medical stroke treatment for symptom onset up to 12 h.

Int J Stroke 2016 Jan;11(1):127-33

KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium VIB, Vesalius Research Center, Laboratory of Neurobiology, Leuven, Belgium University Hospitals Leuven, Department of Neurology, Leuven, Belgium.

Background: Recent trials have shown a clear benefit of endovascular therapy for stroke patients presenting within 6 h after stroke onset. Imaging-based selection may identify a cohort with a favorable response to endovascular therapy, in an even later time window.

Aims: We performed an indirect comparison between outcomes seen in DEFUSE 2, a prospective cohort study of patients who received a baseline MRI before endovascular therapy, and a control group from AXIS 2 receiving standard medical care up to 12 h after symptom onset.

Methods: Patients from AXIS 2 with a confirmed large vessel occlusion were selected as a control group for DEFUSE 2-patients. The primary endpoint was good functional outcome at day 90 (Modified Rankin Score 0-2). We performed a stratified analysis based on the presence of the target mismatch for both studies and reperfusion status in DEFUSE 2.

Results: We compared good functional outcome in 108 patients from AXIS 2 and 99 patients from DEFUSE 2. In DEFUSE 2-patients with the target mismatch profile in whom reperfusion was achieved, the rate of good functional outcome was increased compared to target mismatch patients in AXIS 2, 54% versus 29% (OR 3.2, 95% CI 1.1-9.4). In target mismatch patients treated between 6 and 12 h after stroke onset, this association between study and good functional outcome remained present (OR 9.0, 95% CI 1.1-75.8).

Conclusions: This indirect comparison suggests that endovascular treatment resulting in substantial reperfusion is associated with improved outcome in target mismatch patients even beyond 6 h after stroke onset. Confirmation is needed from future clinical trials that randomize patients beyond the 6 h time window.
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http://dx.doi.org/10.1177/1747493015607503DOI Listing
January 2016

Association between the perfusion/diffusion and diffusion/FLAIR mismatch: data from the AXIS2 trial.

J Cereb Blood Flow Metab 2015 Oct 3;35(10):1681-6. Epub 2015 Jun 3.

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

The perfusion-/diffusion-weighted imaging (PWI/DWI) mismatch and the diffusion/fluid attenuated inversion recovery (DWI/FLAIR) mismatch are magnetic resonance imaging (MRI) markers of evolving brain ischemia. We examined whether the DWI/FLAIR mismatch was independently associated with the PWI/DWI mismatch. Furthermore, we determined whether the presence of the DWI/FLAIR mismatch in patients with the PWI/DWI mismatch would provide additional information regarding last seen normal time (LTM). We used data from the 'AX200 for ischemic stroke' trial (AXIS 2 study NCT00927836). We studied the association between the presence of the DWI/FLAIR and PWI/DWI mismatch, baseline National Institute of Health Stroke Scale (NIHSS), age, ischemic-core volume, gender, intravenous (IV) tissue plasminogen activator (tPA), and perfusion-mismatch volume in univariate analysis. Significant variables (P<0.05) were added into the final multivariate model. We analyzed 197 patients. Seventy-two (37%) had both the PWI/DWI and the DWI/FLAIR mismatch. Patients with the double mismatch pattern had a shorter LTM than patients with the PWI/DWI mismatch alone (Median difference 90 minutes, P<0.01). Multivariate analysis confirmed the independent association between the two mismatch patterns (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.2 to 5.4). Our study implies that the DWI/FLAIR mismatch and PWI/DWI mismatch are strongly associated, independent from LTM. Furthermore, in the presence of the PWI/DWI mismatch, the DWI/FLAIR pattern indicates a shorter LTM. This could have implications in selecting patients for reperfusion therapy.
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http://dx.doi.org/10.1038/jcbfm.2015.108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640316PMC
October 2015

Reperfusion of very low cerebral blood volume lesion predicts parenchymal hematoma after endovascular therapy.

Stroke 2015 May 31;46(5):1245-9. Epub 2015 Mar 31.

From the Stanford Stroke Center, Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA (N.K.M., S.C., M.S., M.M., S.K., C.W.C., G.W.A., M.G.L.); Department of Experimental Neurology, KU Leuven, Leuven, Belgium (A.W.); Department of Medicine and Neurology, Royal Melbourne Hospital, University of Melbourne, Victoria, Australia (B.C.V.C.); Stroke Center, Department of Neurology, Neurocenter (EOC) of Southern Switzerland, Lugano, Switzerland (C.W.C.); and Department of Radiology, Stanford University Medical Center, CA (R.B., M.P.M.).

Background And Purpose: Ischemic stroke patients with regional very low cerebral blood volume (VLCBV) on baseline imaging have increased risk of parenchymal hemorrhage (PH) after intravenous alteplase-induced reperfusion. We developed a method for automated detection of VLCBV and examined whether patients with reperfused-VLCBV are at increased risk of PH after endovascular reperfusion therapy.

Methods: Receiver operating characteristic analysis was performed to optimize a relative CBV threshold associated with PH in patients from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 2 (DEFUSE 2) study. Regional reperfused-VLCBV was defined as regions with low relative CBV on baseline imaging that demonstrated normal perfusion (Tmax <6 s) on coregistered early follow-up magnetic resonance imaging. The association between VLCBV, regional reperfused-VLCBV and PH was assessed in univariate and multivariate analyses.

Results: In 91 patients, the greatest area under the curve for predicting PH occurred at an relative CBV threshold of <0.42 (area under the curve, 0.77). At this threshold, VLCBV lesion volume ≥3.55 mL optimally predicted PH with 94% sensitivity and 63% specificity. Reperfused-VLCBV lesion volume was more specific (0.74) and equally sensitive (0.94). In total, 18 patients developed PH, of whom 17 presented with VLCBV (39% versus 2%; P=0.001), all of them had regional reperfusion (47% versus 0%; P=0.01), and 71% received intravenous alteplase. VLCBV lesion (odds ratio, 33) and bridging with intravenous alteplase (odds ratio, 3.8) were independently associated with PH. In a separate model, reperfused-VLCBV remained the single independent predictor of PH (odds ratio, 53).

Conclusions: These results suggest that VLCBV can be used for risk stratification of patients scheduled to undergo endovascular therapy in trials and routine clinical practice.
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http://dx.doi.org/10.1161/STROKEAHA.114.008171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414872PMC
May 2015

Infarct volume-based subgroup selection in acute ischemic stroke trials.

Stroke 2015 May 12;46(5):1368-70. Epub 2015 Mar 12.

From the Department of Neurology, Center for Stroke Research Berlin, Charité University Hospital Berlin, Germany (A.K., J.B.F.); Experimental Neurology, Department of Neurosciences, KU Leuven-University of Leuven, Leuven, Belgium (A.W., V.T.); Department of Neurology, BioClinica Bio-Imaging Technologies, Lyon France (L.B.); Department of Neurology, Sygnis Bioscience, Im Neuenheimer Feld 515, Heidelberg, Germany (R.L., A.S.); Department of Neurology, Evangelisches Krankenhaus Bielefeld, Germany (W.-R.S.); Department of Neuroradiology, Hospices Civils de Lyon, France (M.H.); VIB, Vesalius Research Center, Laboratory of Neurobiology, B-3000 Leuven, Belgium (V.T.); and Department of Neurology, University Hospitals Leuven, Leuven, Belgium (V.T.).

Background And Purpose: We investigated whether hyperintensities with a diameter of at least 3, 3.5, and 4 cm and visible on at least 3 slices on diffusion-weighted imaging enables patient selection with an infarct volume of ≥15 mL.

Methods: Consecutive acute stroke patients were screened for the AXIS2 trial and examined according to a standardized magnetic resonance imaging protocol in 65 sites. Diffusion-weighted lesion diameters were measured and compared with volumetric assessments.

Results: Out of 238 patients, 86.2% (N=206) had infarct diameter of at least 3 cm. Volumetric assessments showed infarct volume of ≥15 mL in 157 patients. A cut-off value of 3 cm led to 96.8% sensitivity and 33.3% specificity for predicting lesion volume of ≥15 mL. Analogously, a 3.5 cm cut-off led to 96.8% sensitivity and 50.6% specificity and a 4 cm cut-off led to 91.7% sensitivity and 61.7% specificity.

Conclusions: Lesion diameter measures may enable multicentric patient recruitment with a prespecified minimal infarct volume.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927836.
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http://dx.doi.org/10.1161/STROKEAHA.114.008115DOI Listing
May 2015

Wake-up stroke and stroke of unknown onset: a critical review.

Front Neurol 2014 12;5:153. Epub 2014 Aug 12.

KU Leuven Department of Neurosciences and Experimental Neurology, KU Leuven , Leuven , Belgium ; Department of Neurology, University Hospital Leuven , Leuven , Belgium ; Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven , Leuven , Belgium ; Laboratory of Neurobiology, Vesalius Research Center , Leuven , Belgium.

Patients, who wake up with an ischemic stroke, account for a large number of the total stroke population, due to circadian morning predominance of stroke. Currently, this subset of patients is excluded from revascularization-therapy since no exact time of onset is known. A large group of these patients might be eligible for therapy. In this review, we assessed the current literature about the hypothesis that wake-up-strokes occur just prior on awakening and if this subgroup differs in characteristics compared to the overall stroke population. We looked at the safety and efficacy of thrombolysis and interventional techniques in the group of patients with unknown stroke-onset. We performed a meta-analysis of the diagnostic accuracy of the diffusion-FLAIR mismatch in identifying stroke within 3 and 4.5 h. The different imaging-selection criteria that can be used to treat these patients are discussed. Additional research on imaging findings associated with recent stroke and penumbral imaging will eventually lead to a shift from a rigid time-frame based therapy to a tissue-based individualized treatment approach.
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http://dx.doi.org/10.3389/fneur.2014.00153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4129498PMC
August 2014