Response to Letter Regarding Article, “Time and Diffusion Lesion Size in Major Anterior Circulation Ischemic Strokes”
Dai et al suggest that our findings may be explained, in part, by the tendency of patients with less severe symptoms to present later and those with more severe symptoms to present earlier is attractive and plausible. If true, it would be expected that there would be an inverse relationship between patient National Institutes of Health Stroke Scale score and time of presentation at the hospital. To test this hypothesis, we performed a regression analysis between National Institutes of Health Stroke Scale and time that the patient was imaged after stroke onset in the 139 patients of the prospective cohort. No significant correlation was found between National Institutes of Health Stroke Scale and time (P=0.88 and R2=0.00). Although we cannot completely exclude this possibility, it is not supported by the data.
We agree with Dai et al that caution is necessary before treating patients outside traditional time windows. In considering this possibility, one of the following is probably true of these patients who present with small infarcts outside the traditional time window:
They have a persistent arterial occlusion, but good collateral circulation.
They have a persistent distal arterial occlusion, with poor or no collateral circulation, such that all of the downstream tissue has already suffered infarction.
Their brain has reperfused, leaving only a small infarct.
In theory, thrombolysis would not help the patients in groups (2) and (3), and could entail a significant risk of causing hemorrhage in tissue that has already undergone infarction. However, thrombolysis might help the patients in group (1), for 2 reasons. First, collateral circulation may not preserve tissue viability indefinitely. Second, if intra-arterial emboli remain present, pieces of them may break off and travel to more distal branches, causing infarction that cannot be prevented by collaterals.
Distinguishing among these groups of patients requires advanced imaging, which takes extra time. We suggest that our data make the point that, in these patients, we have the time. Patients who present later with small diffusion weighted imaging lesions probably have infarcts that are growing at a slower rate, so that only a small amount of tissue would be lost while advanced imaging is performed. That extra imaging time potentially could be helpful in selecting the appropriate patients who might benefit from recanalization therapy, or from other therapies.
We wish to reiterate that we agree with Dai et al that administration of thrombolytic therapy outside of established time windows should be undertaken carefully, and only to that subgroup of patients who may be shown to benefit by clinical trials. We are currently studying the safety and efficacy of intravenous alteplase in subjects beyond the traditional time windows in a multicenter trial of advanced imaging to identify subjects with a favorable MRI profile that is consistent with a pattern early ischemic injury (MR WITNESS Trial; http://clinicaltrials.gov/show/NCT01282242).
Our evolving understanding of stroke physiology suggests that advanced imaging might be able to identify patients who are in that likely to benefit subgroup. The data in our study suggest that the cost of identifying those patients, in terms of the volume of tissue lost while advanced imaging is being performed, is low, so that such trials are worth pursuing.
Reza Hakimelahi, MD
Lee H. Schwamm, MD
R. Gilberto González, MD, PhD
Neuroradiology Division and Stroke Service
Massachusetts General Hospital
Harvard Medical School
Dr Schwamm receives research funding from National Institute of Neurological Disorders and Stroke for a trial of MRI-based patient selection for IV Thrombolysis in an extended window (MR WITNESS). Genentech provides alteplase at no cost and supplementary site financial support. Dr Schwamm is on the international steering committee for Desmoteplase In Acute Ischemic Stroke 2,3 and Data and Safety Monitoring Board for Penumbra 3D trial. The other authors report no conflicts.
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