LAUSR

From the outset, given that the beneficial effect has been shown only in patients treated during this short time-window, treatment of ischemic stroke with IV recombinant tissue plasminogen activator (rt-PA) has been restricted to patients who present within the first 3 hours of symptom onset and thus is not available to approximately 90% of stroke victims. [1] Importantly, the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study investigators provided an explanatory analysis showing that stroke onset-totreatment time (OTT) is associated with a progressive decline of beneficial treatment response, but not with an increasing risk of symptomatic brain hemorrhage. [2] The authors correctly state that they cannot draw conclusions regarding the OTT-treatment relationship beyond 3 hours. Moreover, even though there is no data to suggest that IVrt-PA therapy beyond 3 hours is either unsafe or ineffective, the United States Food and Drug Administration (FDA) still does not approve ischemic stroke treatment with IV rt-PA beyond the 3-hour window. Infarct growth and disappearance of penumbra at a steady pace of neural circuitry loss in human ischemic stroke became a popular theory explaining the progressive decline of beneficial response to reperfusion therapy. [3–5] Old observations and, in particular, recent controlled randomized trials, challenge this theory and favor the view that brain infarct growth may happen, but is not the rule in individual stroke patients. Time does not mean progressive loss of brain tissue after each ischemic stroke, and there is a stroke population that can recover with arterial recanalization and restoration of blood supply far beyond 3 hours. [6, 7] The pathological conditions that enable or inhibit benefit from reperfusion therapy are still widely unknown, and the question which major artery occlusion strokes should not be treated remains unanswered. [8] Neuronal recovery of cortical neurons is related to the degree and duration of ischemia. [9] Neurons can tolerate cerebral blood flow (CBF) below 10 ml/100g ×min for a maximum of 30 minutes, and can survive ischemic CBF values above 18 ml/ 100g ×min for an indeterminate period of time. Ischemic brain tissue with electrical failure but no neuronal damage was first observed lasting for hours after experimental MCA occlusion in non-human primates and was subsequently named Bpenumbra.^ [10] In fact, researchers found Bpenumbra^ even years after MCA occlusion. [11] Modern brain imaging with diffusionweighted and perfusion magnetic resonance imaging confirmed these findings in ischemic stroke patients showing no infarct growth and persistence of penumbra over 24 hours. [12–14] Additionally, autopsies performed weeks and months after middle cerebral artery (MCA) strokes have shown infarct volumes varying from small to large. [15] Corresponding to these autopsy findings, cerebral blood flowmeasurements after proximalMCA occlusion in 36 ischemic stroke patients showed a variation of ischemic core volumes between 7 and 70% of theMCA territory volume. Ischemic core volume, however, was not associated with time from onset to imaging. [16] Controlled randomized trials have now clearly demonstrated that thrombolytics and thrombectomy can facilitate neuronal recovery if applied 3 to 24 hours after stroke onset in well-selected patients and thus proved that general exclusion of stroke patients from reperfusion therapy-based on OTT estimates is not justified. [6, 7, 17, 18] If OTT is not associated with increasing loss of brain tissue, how can we explain the decline in treatment response to thrombolysis and thrombectomy with prolonged OTT? [19, 20]. The most recent meta-analysis of individual patient data from randomized trials on IV rt-PA showed excellent functional outcomes (modified Rankin score—mRS 0–1) after ischemic stroke in 259/787 patients (32.9%) treated with IV rtPA within 3 hours and in 401/1229 patients (32.6%) treated beyond 4.5 hours. Excellent functional outcomes were observed after placebo in 176/762 patients (23.1%) with treatment within 3 hours and in 357/1166 patients (30.6%) treated * Rüdiger von Kummer [email protected]