Time is Brain”- ' The diagnosis needs to be confirmed fast' - The proven Thrombolytic therapy works only if given within 3 hrs. of stroke onset (studies would later extend it to 4.5 hrs.). With the introduction of Thrombolytic's as a proven treatment for Ischemic Stroke, terms like LKW (Last Known Well), LKN (Last Known Normal) were drilled into us. “The diagnosis needs to be confirmed fast' -





As thrombolytic therapy for Ischemic Stroke within 4.5 hr's of onset became ‘A standard of Care’. The problem faced was – what to do with patients who wake up with stroke or presented after a family members found them with stroke symptoms (no idea when they suffered the stroke).





Did this patient have a stroke an hour prior to waking up or as soon as he went to sleep'? – 'Guess we will never know' – was a common taking point. Someone would suggest - 'If only we could go back in time or maybe in patient’s brain aka DiCaprio in Inception' – wouldn’t that be great! '? –– was a common taking point. Someone would suggest - '– wouldn’t that be great!





2 recent studies appeared to have solved this conundrum. Both literally dive into the Brain Tissue (Real Life following Hollywood).





' WAKE UP’ Trial in NEJM August 16th 2018, Vol 379; pp 611-622, used a difference in MRI Imaging – lesion seen in DWI (diffusion weighted Imaging),but not in FLAIR portion (Fluid Attenuated Inversion Recovery). This finding was used to signify recent stroke (<4.5 hrs). ‘WAKE UP’ Trial was a multicenter trial across Europe. It randomized 503 patients with unknown time of stroke (89% - woke up with stroke symptoms) and a mismatch on MRI Imaging to thrombolytic therapy (254) or Placebo (249). Favorable outcome (Full recovery to minimal symptoms) was more common in Thrombolytic therapy arm (53.3% vs 41.8%).





EXTEND Trial in NEJM May 9 th 2019;380; pp 1795-1803, used CT & MRI Perfusion imaging to show a mismatch between the Core (infarcted area) & the At-Risk area (old Umbra & penumbra) as evidence of Salvageable tissue.The

'EXTEND Trial' randomized 225 patients presenting between 4.5 hrs. to 9 hrs. or those waking up with stroke to thrombolytic therapy (113) vs Placebo (112). The patients needed to have hypoperfused but salvageable brain on imaging by CT & MRI Perfusion. Therapy with thrombolytic was associated with a favorable outcome (35.4% vs 29.5%).





Symptomatic ICH was more in thrombolytic arm in both studies but not outside the norm. Surprisingly both studies were stopped early due to different reasons.Wake-Up due to lack of funding and Extend due to benefit showed by the earlier study..





So What now: ‘Time is Brain’ still applies, try to get the thrombolytic therapy started within 4.5 hours for Ischemic Stroke. For patient's presenting beyond 4.5 hours or after waking up with Stroke, there needs to be a robust Radiology / Neurology department, with protocols in place – to get Imaging studies completed, interpreted in a timely manner - and to provide guidance for thrombolytic therapy. still applies, try to get the thrombolytic therapy started within 4.5 hours for Ischemic Stroke. For patient's presenting beyond 4.5 hours or after waking up with Stroke, there needs to be a robust Radiology / Neurology department, with protocols in place – to get Imaging studies completed, interpreted in a timely manner - and to provide guidance for thrombolytic therapy.





Then there is the option of Thrombectomy - to be discussed later.











