Stroke of unknown onset accounts for up to 20% of all acute ischemic stroke. Prior to the successful completion of the Efficacy and Safety of MRI-Based Thrombolysis in WAKE UP Stroke (WAKE UP) trial, these patients were typically excluded from treatment with IV tPA as this therapy was only approved for cases within 4.5 hours of known symptom onset. WAKE UP utilized a novel imaging biomarker of lesion age, the DWI-FLAIR mismatch (acute stroke visible on DWI but not yet visible on FLAIR), to allocate patients into the early time window for which thrombolysis has been proven safe and efficient; a concept which became known as “tissue clocking”. As a multicenter and imaging-heavy trial, WAKE UP relied upon a homogeneous understanding and interpretation of its imaging criteria by all of its many investigators, a process that was safeguarded by dedicated training developed especially for the study’s purposes. The study was successful and, upon its completion in 2017, together with two smaller and similar trials that were completed at comparable time points, WAKE UP generated enough high quality evidence to influence a change in official guidelines, now recommending thrombolysis for patients with stroke of unknown onset who satisfy WAKE UP criteria. Various sub-analyses conducted since on the WAKE UP cohort further cemented the credibility of tissue clocking as a patient selection paradigm. But it is not the only such model. In addition to tissue clocking another concept, dubbed penumbral imaging and used as a biomarker of tissue at risk of infarction, has also been investigated in large clinical trials such as EXTEND and ECASS-4, as a way to offer treatment to patients with unknown symptom onset. Both of these methods fall under the umbrella of advanced imaging because they necessitate hardware and/or software as well as expertise in image interpretation that is not routinely available in the majority of the world’s hospitals. Tissue clocking (using magnetic resonance imaging and the DWI-FLAIR mismatch) as well as penumbral imaging (using MR or CT based perfusion imaging) offer a lot of additional information, and through it, assurance to the treating physician that potential risks have been minimized and possible benefits of therapy enhanced. In this sense, advanced brain imaging should definitely be considered as part of state of the art, evidence based stroke treatment. Especially in the unknown time window, and due to its ability to perform both tissue clocking and penumbral imaging, MRI as a modality has been proposed as the most inclusive approach to screening ischemic stroke patients in hopes of identifying those still eligible for thrombolytic treatment. However, this approach clearly suffers the drawback of limited availability in everyday clinical practice. Further, well-designed and well-conducted prospective, randomized, controlled trials should be performed to evaluate the exact scope of (advanced) imaging needed for an as-inclusive-as-possible and successful patient selection in the unknown time window
