Editorial: The Ischemic Penumbra: Still the Target for Stroke Therapies?

The ischemic penumbra refers to tissue at risk of infarction where perfusion is inadequate to support neuronal function, but just adequate to maintain cell viability (1).This dysfunctional, but salvageable tissue has been the target of all acute stroke therapies (2), and this concept underpinned the successful trials of intravenous thrombolysis using t-PA (3).Advanced imaging, including diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) MR and CT perfusion (CTp), was developed to rapidly identify stroke patients with still present penumbra, who were thought to be the best candidates for reperfusion therapies.However, early studies, using different methods for identifying penumbra, different measures of outcome, and different time-windows have not consistently confirmed the benefit of selecting treatment candidates on the basis of imaged penumbra.Therefore, some outstanding questions surround the optimal modality for imaging the penumbra, the most reliable thresholds in each modality, how long the penumbra can be maintained under what subject-specific circumstances, and the functional significance of persistent penumbra.These questions have taken on particular importance in light of the results of five recently completed randomized clinical trials showing benefit of endovascular treatment of stroke, when patients are carefully selected and treated on a timely basis.These trials include MR CLEAN (4), ESCAPE (5); EXTEND-IA (6), and two trials that have not been published, but the results of which have been presented at the International Stroke Conference [SWIFT PRIME (7) and REVASCAT 1 ].These trials have used different criteria to select patients for treatment, including different modalities of imaging (CT vs. MRI), but those that have shown the highest odds of favorable functional outcome have selected patients on the basis of having both a small core infarct, and either large volume of penumbral tissue ("tissue at risk") (6, 7) or the presence of moderate-good collateral circulation (5) that would support penumbral tissue in the face of proximal occlusion.These recent studies, together with an earlier successful pilot trial of another thrombolytic agent that used MR-based selection of target penumbral patients (8) have shown the importance of selecting patients on the basis of the presence of penumbral tissue, but underscore the urgency of defining appropriate thresholds with imaging that can be obtained swiftly in order to maximize the efficiency of intervention.While the gold standard for both irreversibly ischemic core and penumbra has been defined by PET (2), PET cannot be obtained rapid enough to provide a practical guide for acute stroke treatment.Some centers are able to obtain rapid MRI, while most will rely likely on multiphase CT angiogram and/or CTp to guide intervention.It is critical that the stroke field adopts valid and reliable thresholds using any of these modalities to select candidates for intervention.Toward this goal, two MR vs. PET back-to-back studies have proposed validated MR-perfusion thresholds, based on small samples (9, 10).This Research Topic consists of a set of papers that addresses some of the controversies and intriguing questions that remain.Kaesemann and colleagues (11) evaluated the impact of severe extracranial ICA stenosis on MRI measures of penumbra in patients with middle cerebral artery occlusion who were