Prolonged ischemic injury leads to capillary cell apoptosis, increased vascular permeability, inammation, and oxidative stress, enhancing the risk of hemorrhagic transformation [18]. Thus, treatment initiation beyond 4.5h is not recommended given the potential for higher rates of intracranial bleeding [7, 18]. However, advancements have been made in the subgroup of “wake-up” strokes, which were historically considered a contraindication to thrombolytic therapy given the unknown time of symptom onset and potential for a completed infarct. A series of trials evaluated the use of advanced imaging techniques using diffusion-weighted imaging MRI with uid-attenuated inversion recovery (FLAIR) sequence or CT perfusion to identify the presence of a salvageable penumbra amenable for interven­tion with thrombolysis and/or thrombectomy [7, 19, 20]. A meta-analysis of three randomized trials evaluating the use of thrombolysis in patients with AIS presenting within 4.5–9 h of LKW who underwent advanced imaging to identify perfusion mismatches revealed that a higher proportion of patients achieved an excellent func­tional outcome with alteplase compared to placebo, demonstrating that careful patient selection could extend the window of eligibility [20].