Expanding the concept of neuroprotection for acute ischemic stroke: The pivotal roles of reperfusion and the collateral circulation.

This review surveys the efforts taken to achieve clinically efficacious protection of the ischemic brain and underscores the necessity of expanding our purview to include the essential role of cerebral perfusion and the collateral circulation. We consider the development of quantitative strategies to measure cerebral perfusion at the regional and local levels and the application of these methods to elucidate flow-related thresholds of ischemic viability and to characterize the ischemic penumbra. We stress that the modern concept of neuroprotection must consider perfusion, the necessary substrate upon which ischemic brain survival depends. We survey the major mechanistic approaches to neuroprotection and review clinical neuroprotection trials, focusing on those phase 3 multicenter clinical trials for acute ischemic stroke that have been completed or terminated. We review the evolution of thrombolytic therapies; consider the lessons learned from the initial, negative multicenter trials of endovascular therapy; and emphasize the highly successful positive trials that have finally established a clinical role for endovascular clot removal. As these studies point to the brain's collateral circulation as key to successful reperfusion, we next review the anatomy and pathophysiology of collateral perfusion as it relates to ischemic infarction, as well as the molecular and genetic influences on collateral development. We discuss the current MR and CT-based diagnostic methods for assessing the collateral circulation and the prognostic significance of collaterals in ischemic stroke, and we consider past and possible future therapeutic directions.