The Ischemic Penumbra: Correlates in Imaging and Implications for Treatment of Ischemic Stroke. The Johann Jacob Wepfer Award 2011

The concept of the ischemic penumbra was formulated 30 years ago based on experiments in animal models showing functional impairment and electrophysiological disturbances with decreasing flow to the brain below defined values (the threshold for function) and irreversible tissue damage with the blood supply further decreased (the threshold for infarction). The perfusion range between these thresholds was termed 'penumbra', and restitution of flow above the functional threshold was able to reverse the deficits without permanent damage. However, in further experiments, the dependency of the development of irreversible lesions on the interaction of the severity and duration of critically reduced blood flow was established - proving that the lower the flow, the shorter the time for efficient reperfusion. Therefore, infarction develops from the core of ischemia to the areas of less severe hypoperfusion. The propagation of irreversible tissue damage is characterized by a complex cascade of interconnected electrophysiological, molecular, metabolic and perfusional disturbances. Waves of depolarizations, the peri-infarct spreading depression-like depolarizations, inducing activation of ion pumps and liberation of excitatory transmitters, have dramatic consequences as drastically increased metabolic demand cannot be satisfied in regions with critically reduced blood supply. The translation of experimental concept into the basis for efficient treatment of stroke requires non-invasive methods by which regional flow and energy metabolism can be repeatedly investigated to demonstrate penumbra tissue that can benefit from therapeutic interventions. Positron emission tomography (PET) allows the quantification of regional cerebral blood flow, the regional metabolic rate for oxygen and the regional oxygen extraction fraction. From these variables, clear definitions of irreversible tissue damage and critically perfused but potentially salvageable tissue (i.e. the penumbra) can be achieved in animal models and stroke patients. Additionally, further tracers can be used for early detection of irreversible tissue damage, e.g. by the central benzodiazepine receptor ligand flumazenil. However, PET is a research tool and its complex logistics limit clinical routine applications. As a widely applicable clinical tool, perfusion/diffusion-weighted (PW/DW) MRI is used, and the 'mismatch' between the PW and the DW abnormalities serve as an indicator of the penumbra. However, comparative studies of PW/DW-MRI and PET have pointed to an overestimation of the core of irreversible infarction as well as of the penumbra by MRI modalities. Some of these discrepancies can be explained by unselective application of relative perfusion thresholds, which might be improved by more complex analytical procedures. Heterogeneity of the MRI signatures used for the definition of the mismatch are also responsible for disappointing results in the application of PW/DW-MRI for the selection of patients for clinical trials. As long as a validation of the mismatch selection paradigm is lacking, its use as a surrogate marker of outcome is limited.