Time Is Brain.

See related article, p 645 The most recent American Heart Association guidelines recommend: “Because time from onset of symptoms to treatment has such a powerful impact on outcomes, treatment with IV alteplase should not be delayed to monitor for further improvement” with class III strength of recommendation (harm and strong), but the lowest level of evidence (consensus of expert opinion based on clinical evidence). The level of evidence is low because the interaction of stroke-onset-totreatment time (OTT) with clinical outcome after alteplase treatment has not been tested prospectively yet, and pathological conditions that might have interacted with OTT and clinical outcomes have not been explored in the randomized controlled trials of alteplase. Moreover, the results of controlled randomized trials do not unambiguously support the hypothesis that ischemic brain infarct growth progressively impairs neurological recovery during OTT. It is time to question, which conditions affect the chances for favorable outcome while patients are waiting for treatment. The NINDS Study Group (National Institute of Neurological Disorders and Stroke) r-tPA (recombinant tissue-type plasminogen activator) has observed favorable outcomes (modified Rankin Scale score, 0–1) at 3 months in 40% of patients treated within 90 minutes of symptom onset and in 45% of patients treated within 91 to 180 minutes of symptom onset. The odds ratio for the favorable outcome of alteplase versus placebo increased from 1.7 for early treatment to 2.4 for delayed treatment. In a post hoc analysis, the NINDSinvestigators identified an imbalance in the baseline National institutes of Health Stroke Score severity in the 2 treatment groups at different OTT confounding a better response to early alteplase treatment compared with later treatment initiation. Their analysis suggested no significant favorable treatment effect of alteplase after 2.5 hours. Treatment with alteplase administered between 3 and 4.5 hours (median 3 hours 59 minutes) achieved, however, favorable outcomes in 52% of patients compared to 45% of placebo treated patients. A similar result was observed in patients with unknown OTT and a time that had elapsed since the patient was last known to be well exceeding 4.5 hours. Favorable outcome was reported in 53% of alteplase treated patients compared with 42% of placebo-treated patients. A meta-analysis of individual patient data from 6756 patients in 9 randomized trials compared favorable functional outcomes after alteplase and placebo in 3 cohorts being treated within 3 hours (N=1549), between 3 and 4.5 hours (N=2812), and after 4.5 hours (N=2395). In the alteplase group OTT had no impact on the percentage of patients with favorable outcomes in 33%, 35%, and 33% of patients in the 3 OTT-cohorts, whereas this percentage increased with increasing OTT from 23% to 30% and 31% in the placebo group. This observation suggests that ischemic stroke patients presenting early have more brain tissue to loose because of major artery occlusion than have late-presenting patients. Late-presenting patients’ brain circulation pathology allows more often spontaneous recovery. The proportion of patients with favorable outcomes after placebo treatment was even more impressive in both late time-window trials. The condition that increases the chances for a favorable outcome in the placebo group with increasing OTT has not been identified yet. The NINDS rt-PA study group has recruited patients with less severe strokes in their late time-window. Less severe strokes may be associated with minor artery occlusion, better collateral capacity, smaller volumes of ischemia, spontaneous recanalization and reperfusion, or ischemia of less eloquent brain regions, conditions that may facilitate neuronal recovery. Remarkably, the DEFUSE (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) 2 investigators observed favorable clinical outcomes in 42% of ischemic stroke patients without reperfusion. Other conditions beside tissue reperfusion may facilitate neurological recovery, for example, small vessel ischemia compensated by brain plasticity. If time was brain, however, and the volume of salvageable ischemic brain tissue would steadily shrink since symptom onset, the chances to recover with and without reperfusion therapy would decrease with increasing OTT. Endovascular treatment of major artery occlusion stroke provides the opportunity to study stroke pathology in more detail. The HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) investigators present in this issue a meta-analysis of the interaction between OTT and favorable outcomes using the pooled individual data of 601 major artery occlusion stroke patients treated with IV alteplase alone randomized in 7 controlled trials on thrombectomy. On the average, 20% of patients achieved favorable functional outcomes (modified Rankin Scale score, 0–1) at 3 months in contrast to the 34% of alteplase treated patients with undefined vascular pathology. In contrast to the randomized alteplase trials, the probability for favorable functional outcome declined with increasing OTT in these major artery The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Institute and Policlinic of Diagnostic and Interventional Neuroradiology, University Hospital Carl Gustav Carus, Dresden,Germany. Guest Editor for this article was Markku Kaste, MD, PhD. Correspondence to Rüdiger von Kummer, Prof Dr Med, Institute and Policlinic of Diagnostic and Interventional Neuroradiology, University Hospital Carl Gustav Carus, Fetscherstraße 74, 01307 Dresden, Germany. Email ruediger.vonkummer@uniklinikum-dresden.de Time Is Brain Fact or Fiction