Mapping the ischaemic penumbra with PET: a new approach

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Abstract
After decades of nihilism, recent evidence indicates that neurological outcome after acute stroke can be improved through three types of measures (Brott and Bogousslavsky, 2000): (i) restoring perfusion in the ischaemic tissue with the thrombolytic agent recombinant tissue plasminogen activator (rt-PA) given intravenously within 3 h of clinical onset; (ii) preventing secondary deleterious events such as hyperglycaemia, pyrexia, hypoxia, systemic hypotension, stroke recurrence and pulmonary embolism, best achieved in specialized stroke units; and (iii) providing appropriate rehabilitation. The reperfusion strategy is based on experimental evidence in the nonhuman primate with middle cerebral artery (MCA) occlusion that, surrounding the profoundly ischaemic core of already irreversible damage, there exists an area of brain tissue (the `penumbra') which, though severely ischaemic and functionally silent, can still escape infarction if perfusion is restored before a certain time has elapsed (Lassen, 1990); the penumbra has been documented in man (Baron, 1999; Heiss, 2000). Although beneficial when considering cohorts, i.v. rt-PA is hazardous in individual patients owing to the several-fold increased risk of symptomatic haemorrhagic transformation (Brott and Bogousslavsky, 2000). In addition, it is an expensive treatment which should only be used when necessary. Because of this, it would appear sensible to reserve rt-PA for those patients still having an area of critically ischaemic tissue at the time of assessment, i.e. excluding those with already completed irreversible damage due to rapid deterioration of the ischaemic tissue beyond reversibility or with already established spontaneous reperfusion (Baron et al., 1995). Interestingly, one trial (in need of replication) found that in patients selected for the presence of proximal MCA occlusion, the intra-arterial administration of another thrombolytic agent, pro-urokinase, resulted in significant and large clinical benefits even if given as late as 6 h after stroke (Furlan et al., 1999). This indicates that a proportion of the penumbra was still there long after the 3-h window in such patients, consistent with imaging studies (Marchal et al., 1996; Read et al., 2000). Clearly, if i.v. thrombolysis is to be tested beyond the 3-h time-point, the idea of selecting the appropriate patients becomes even more compelling.