Extension of therapeutic window in ischemic stroke by selective mismatch imaging
Authors: Heiss Wolf-Dieter , Zaro-Weber Olivier 
Published: April 2019

The concept of the ischemic penumbra was formulated on the basis of animal experiments showing functional impairment and electrophysiologic disturbances with decreasing flow to the brain below defined values (the threshold for function) and irreversible tissue damage with blood supply further decreased (the threshold for infarction). The perfusion range between these thresholds was termed the “penumbra,” and restitution of flow above the functional threshold was able to reverse the deficits without permanent damage. In further experiments, the dependency of the development of irreversible lesions on the interaction of the severity and the duration of critically reduced blood flow was established, proving that the lower the flow, the shorter the time for efficient reperfusion. As a consequence, infarction develops from the core of ischemia to the areas of less severe hypoperfusion. The translation of this experimental concept as the basis for the efficient treatment of stroke requires methods by which regional flow and energy metabolism can be repeatedly investigated to demonstrate penumbra tissue, which can benefit from therapeutic interventions. Positron emission tomography allows the quantification of regional cerebral blood flow, the regional oxygen extraction fraction, and the regional metabolic rate for oxygen. With these variables, clear definitions of irreversible tissue damage and of critically hypoperfused but potentially salvageable tissue (i.e. the penumbra) in stroke patients can be achieved. However, positron emission tomography is a research tool, and its complex logistics limit clinical routine applications. Perfusion-weighted or diffusion-weighted magnetic resonance imaging is a widely applicable clinical tool, and the “mismatch” between perfusion-weighted and diffusion-weighted abnormalities serves as an indicator of the penumbra. Also computed tomography angiography and computed tomography perfusion imaging can be used to detect areas suspicious of penumbra. The findings with both methods should be validated by positron emission tomography measurements. Several studies included the selection of patients for intravenous thrombolysis on the basis of a perfusion-weighted imaging–diffusion-weighted imaging mismatch or computed tomography perfusion studies. A meta-analysis of several mismatch-based thrombolysis studies of delayed treatment from the DIAS, DIAS-2, DEDAS, EPITHET, and DEFUSE trials revealed increased recanalization. However, this analysis did not confirm an improvement in clinical outcome with delayed thrombolysis. Randomized controlled trials that did enroll patients based on the presence of a target mismatch on multimodal imaging demonstrated a higher benefit of revascularization treatment by comparison with those who did not and demonstrated for the first time that revascularization treatment for occlusion of an internal carotid artery (ICA) or a proximal middle cerebral artery (MCA) was still beneficial from 6 to 24 h after onset among patients in whom the clinical examination and the multimodal brain imaging indicate a persistent penumbra. On this background, the yield of imaging for the selection of patients for a revascularization therapy will be discussed.