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Title: Reduced Severity of Tissue Injury Within the Infarct May Partially Mediate the Benefit of Reperfusion in Ischemic Stroke.
Austin Authors: Ng, Felix C ;Churilov, Leonid ;Yassi, Nawaf;Kleinig, Timothy J;Thijs, Vincent N ;Wu, Teddy Y;Shah, Darshan G;Dewey, Helen M;Sharma, Gagan;Desmond, Patricia M;Yan, Bernard;Parsons, Mark W;Donnan, Geoffrey A ;Davis, Stephen M;Mitchell, Peter J;Leigh, Richard;Campbell, Bruce C V
Affiliation: Neurology..
The Florey Institute of Neuroscience and Mental Health..
Melbourne Medical School, The University of Melbourne, Heidelberg, Victoria, Australia..
Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Australia..
Department of Neurology, Princess Alexandra Hospital, Brisbane, Australia..
Department of Radiology, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia..
Department of Neurology, Royal Adelaide Hospital, Australia..
Eastern Health and Eastern Health Clinical School, Department of Neurosciences, Monash University, Clayton, Australia..
Department of Neurology, Christchurch Hospital, New Zealand..
Department of Neurology, John Hopkins University, Baltimore, MD..
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia..
Issue Date: Jun-2022 2022-02-09
Publication information: Stroke 2022; 53(6): 1915-1923
Abstract: Emerging data suggest tissue within the infarct lesion is not homogenously damaged following ischemic stroke but has a gradient of injury. Using blood-brain-barrier (BBB) disruption as a marker of tissue injury, we tested whether therapeutic reperfusion improves clinical outcome by reducing the severity of tissue injury within the infarct in patients with ischemic stroke. In a pooled analysis of patients treated for anterior circulation large vessel occlusion in the EXTEND-IA TNK (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke) and EXTEND-IA part-2 (Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischaemic Stroke) trials, post-treatment BBB permeability at 24 hours was calculated based on the extent of T1-brightening by extravascular gadolinium on T2* perfusion-weighted imaging and measured within the diffusion-weighted-imaging lesion. First, to determine the clinical significance of BBB disruption as a marker of severity of tissue injury, we examined the association between post-treatment BBB permeability and functional outcome. Second, we performed an exploratory (reperfusion, BBB permeability, functional outcome) mediation analysis to estimate the proportion of the reperfusion-outcome relationship that is mediated by change in BBB permeability. In the 238 patients analyzed, an increased BBB permeability measured within the infarct at 24 hours was associated with a reduced likelihood of favorable outcome (90-day modified Rankin Scale score of ≤2) after adjusting for age, baseline National Institutes of Health Stroke Scale, premorbid modified Rankin Scale, infarct topography, laterality, thrombolytic agent, sex, parenchymal hematoma, and follow-up infarct volume (adjusted odds ratio, 0.86 [95% CI, 0.75-0.98], P=0.023). Mediation analysis suggested reducing the severity of tissue injury (as estimated by BBB permeability) accounts for 18.2% of the association between reperfusion and favorable outcome, as indicated by a reduction in the regression coefficient of reperfusion after addition of BBB permeability as a covariate. In patients with ischemic stroke, reduced severity of tissue injury within the infarct, as determined by assessing the integrity of the BBB, is independently associated with improved functional outcome. In addition to reducing diffusion-weighted imaging-defined infarct volume, reperfusion may also improve clinical outcome by reducing tissue injury severity within the infarct.
DOI: 10.1161/STROKEAHA.121.036670
ORCID: 0000-0001-6973-8677
Journal: Stroke
PubMed URL: 35135319
PubMed URL:
Type: Journal Article
Subjects: blood-brain barrier
ischemic stroke
Appears in Collections:Journal articles

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