The penumbra, therapeutic time window and acute ischaemic stroke

There is a great deal of evidence that an ischaemic penumbra exists in animals and humans after the occurrence of focal brain ischaemia (Hossmann, 1994). The concept of the penumbra leads to the idea of a therapeutic time window. Because, if the region of irreversible injury (infarction) after focal ischaemia evolves in time and space, then the possibility of therapy to interfere becomes a tenable hypothesis. All of the acute stroke therapies given after onset have their basis from this hypothesis of a therapeutic time window (Fisher, 1995). As previously alluded to, a more apt term might be a window-shade, because this metaphor suggests a more dynamic event. The time and location of potentially salvageable ischaemic brain tissue after ischaemic stroke is a moving target and many unanswered questions remain. The data from animal stroke models support 2-3 hours as the time when intervention is likely to be beneficial in rats. Non-human primate data are scarce, but the few studies available do imply that at 3-4 hours after stroke onset some ischaemic tissue remains potentially salvageable. In humans, we really do not know what the time window is and we must remember that it is likely to be highly variable among individuals. This variability relates to many factors including the status of collateral flow, patient age, coexistent metabolic abnormalities (i.e. hyperglycaemia), premorbid medications and many other confounding variables. All acute stroke intervention trials are trying to initiate therapy within 6-8 hours after onset and the earlier, presumably the better. However, this approach is based upon population averaging, since we have had no convenient and reliable mechanism to determine, if an individual patient has viable tissue when therapy can be started. The availability of an imaging modality that could distinguish the presence and extent of salvageable ischaemic tissue would greatly facilitate stroke therapy trials and ultimately the selection of patients when proven therapies are available. The new MRI techniques might afford this possibility. As we enter the exciting era of effective therapy for acute ischaemic stroke, the issues surrounding the therapeutic time window(shade) will become more critical, because it is this critical time that will define the success or failure of our interventions. Therefore it is incumbent upon basic stroke researchers and clinicians to continue to define the ischaemic penumbra and to develop readily applicable mechanisms to identify and treat this moving target.