Time is Penumbra: Imaging, Selection and Outcome. The Johann Jacob Wepfer Award 2014

The foundation of modern therapy for ischaemic stroke involves reperfusion of the ischaemic penumbra and salvage of threatened but potentially viable brain tissue. Work on imaging of the penumbra and clinical trials using penumbral evaluation or selection have been a major focus of our collaborative work over several decades. We review the original description of the ischaemic penumbra, its measurement using a variety of imaging techniques, the duration of the penumbra and its potential salvage up to 48 h after stroke onset. The penumbra can now be accurately measured using automated thresholded techniques in real time with MRI or CT perfusion (CTP). Particular advances include more precise definitions of mismatch with validation of the measures for the ischaemic core and exclusion of benign oligaemia. While there has been greater trial experience with MRI perfusion/diffusion mismatch, CTP mismatch using a similar thresholded perfusion metric (Tmax 6 s) and relative blood flow (around 31%) to estimate the ischaemic core is generally more available and practicable in our experience. We review the completed clinical trials, which generally demonstrate the clinical benefits of acute reperfusion in penumbral patients, provided that large ischaemic cores are excluded. Our EPITHET trial was the first randomized controlled trial of tissue plasminogen activator (tPA) versus placebo at delayed times to test the concept of penumbral selection. We showed that in patients with a penumbra receiving thrombolysis, there was substantially increased reperfusion. Major reperfusion times were associated with reduced growth of the ischaemic core and improved clinical outcomes. Our current trial programme involves the application of penumbral imaging to attempt to extend the time window for intravenous tPA and treat wake-up strokes, to test the benefits of endovascular therapy in patients who have already received tPA but still have both substantial penumbra and an occluded vessel, and, finally, to use penumbral imaging to define a responder population in a phase III trial testing intravenous tenecteplase versus tPA within the current 4.5-hour time window. We believe that confirmation of these trial hypotheses will substantiate the role of multimodal imaging of the penumbra as a routine part of acute stroke management.