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Background: The MR-RESCUE trial failed to demonstrate improved outcome with reperfusion in patients with a favorable imaging profile, casting doubts on the penumbral hypothesis. We examined the effect of reperfusion on functional outcome in the EXTEND-IA randomized trial. Method(s): Patients receiving tPA < 4.5 h with major vessel occlusion were randomized (after written informed consent, IRB-approved) to thrombectomy versus tPA-only if CT-perfusion demonstrated mismatch ratio>1.2 between hypoperfused tissue (Tmax > 6 s) and irreversibly injured ischemic core (relative cerebral blood flow <30%), absolute mismatch > 10 mL and ischemic core <70 mL (RAPID software, Stanford University). Reperfusion was defined as >90% reduction in Tmax > 6 s hypoperfusion volume between baseline and 24 h perfusion imaging. Modified Rankin Scale (mRS) was assessed at 90 days. Result(s): There were 70 patients, 35 in each arm, mean age 69, median NIHSS 15. Reperfusion of >90% of the affected territory occurred in 89% endovascular patients and 34% tPA-only patients (p < 0.001).Reperfusion was associated with independence (mRS0-2) in 72% versus 30% nonreperfused patients (p < 0.001) and in ordinal analysis, unadjusted generalized odds ratio = 4.5, 95% CI 2.2-9.0, p < 0.001, number needed to treat = 1.6 (OR = 5.1, p < 0.001, adjusted for age and NIHSS, Figure). (Figure presented) Conclusion(s): In ischemic stroke patients with a proximal cerebral arterial occlusion and 'target mismatch' indicating salvageable tissue on CT-perfusion imaging, outcomes are usually unfavorable unless reperfusion is achieved. Differences in mismatch definition and reperfusion assessment likely underlie the incongruent MR-RESCUE findings.

Background: Trials of endovascular therapy for ischemic stroke have produced variable results. We conducted this study to test whether more advanced imaging selection, recently developed devices, and earlier intervention improve outcomes. Method(s): We randomly assigned patients with ischemic stroke who were receiving 0.9 mg of alteplase per kilogram of body weight less than 4.5 hours after the onset of ischemic stroke either to undergo endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever or to continue receiving alteplase alone. All the patients had occlusion of the internal carotid or middle cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 ml on computed tomographic (CT) perfusion imaging. The coprimary outcomes were reperfusion at 24 hours and early neurologic improvement (.8-point reduction on the National Institutes of Health Stroke Scale or a score of 0 or 1 at day 3). Secondary outcomes included the functional score on the modified Rankin scale at 90 days. Result(s): The trial was stopped early because of efficacy after 70 patients had undergone randomization (35 patients in each group). The percentage of ischemic territory that had undergone reperfusion at 24 hours was greater in the endovascular-therapy group than in the alteplase-only group (median, 100% vs. 37%; P<0.001). Endovascular therapy, initiated at a median of 210 minutes after the onset of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, P = 0.002) and improved the functional outcome at 90 days, with more patients achieving functional independence (score of 0 to 2 on the modified Rankin scale, 71% vs. 40%; P = 0.01). There were no significant differences in rates of death or symptomatic intracerebral hemorrhage. Conclusion(s): In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retrieve

Background: Optimal imaging selection for endovascular therapy for ischemic stroke remains controversial with a range of criteria used in the recent positive trials. Large volume severe hypoperfusion (Tmax > 10 s) is one such criterion, with optimal threshold > 82 mL ('malignant profile'), in a previous study. We examined whether this was associated with poor response to reperfusion in the EXTEND-IA randomized trial, which did not exclude patients on this basis. Method(s): Patients receiving tPA < 4.5 h with major vessel occlusion and favourable CT-perfusion (CTP) were randomised (after written informed consent, IRB-approved) to thrombectomy after tPA versus tPA-alone. CTP eligibility required mismatch ratio > 1.2 between hypoperfused tissue (Tmax > 6 s) and irreversibly injured ischemic core (relative cerebral blood flow <30%), absolute mismatch > 10 mL, ischemic core <70 mL (RAPID software, Stanford University). Tmax > 10 s volume was calculated and effect on clinical outcomes examined. Result(s): There were 70 patients, 35 in each arm, mean age = 69, median NIHSS = 15. In these patients with ischemic core <70 mL, median Tmax > 10 s volume was 41 mL with 12/70(17%) > 82 mL, 6/70(8.6%) > 100 mL. Of the 'malignant' patients(Tmax10s > 82 mL), 6/12(50%) had >90% reperfusion at 24 h (4 endovascular and 2 tPAonly), all of whom had 'early neurological recovery' (>=8 point NIHSS reduction or 0-1 by day 3) and 5/6(83%) had 90 day mRS0-1. No patient with <90% reperfusion had day 90 mRS < 3. Conclusion(s): In ischemic stroke patients <4.5 h after onset, large Tmax > 10 s volume in the absence of a large ischemic core was uncommon. Although the numbers in this study were small, the 83% rate of excellent functional outcome after reperfusion suggests that excluding such patients from therapy may not be justified.

Background and Hypothesis: Thrombolysis with tissue plasminogen activator is proven to reduce disability when given within 4.5h of ischemic stroke onset. However, tissue plasminogen activator only succeeds in recanalizing large vessel arterial occlusion in a minority of patients. We hypothesized that anterior circulation ischemic stroke patients, selected with 'dual target' vessel occlusion and evidence of salvageable brain using computed tomography or magnetic resonance imaging 'mismatch' within 4.5h of onset, would have improved reperfusion and early neurological improvement when treated with intra-arterial clot retrieval after intravenous tissue plasminogen activator compared with intravenous tissue plasminogen activator alone. Study Design: EXTEND-IA is an investigator-initiated, phase II, multicenter prospective, randomized, open-label, blinded-endpoint study. Ischemic stroke patients receiving standard 0.9mg/kg intravenous tissue plasminogen activator within 4.5h of stroke onset who have good prestroke functional status (modified Rankin Scale <2, no upper age limit) will undergo multimodal computed tomography or magnetic resonance imaging. Patients who also meet dual target imaging criteria: vessel occlusion (internal carotid or middle cerebral artery) and mismatch (perfusion lesion:ischemic core mismatch ratio >1.2, absolute mismatch >10ml, ischemic core volume <70ml) will be randomized to either clot retrieval with the Solitaire FR device after full dose intravenous tissue plasminogen activator, or tissue plasminogen activator alone. Study Outcomes: The coprimary outcome measure will be reperfusion at 24h and favorable clinical response (reduction in National Institutes of Health Stroke Scale by >=8 points or reaching 0-1) at day 3. Secondary outcomes include modified Rankin Scale at day 90, death, and symptomatic intracranial hemorrhage. © 2013 World Stroke Organization.

Objective: To examine hemodynamic changes following endovascular embolization in newborn infants with vein of Galen malformation and severe cardiac failure in the first week of life. Study design: Over a recent 5-year period, nine such infants were identified. In seven of these infants, changes in arterial blood pressure were analyzed in relation to the timing of embolization procedures. Result(s): A significant increase in arterial blood pressure was noted after most embolizations. In two infants, this systemic hypertension was severe and treated using intravenous antihypertensive drugs. Both infants subsequently developed complete infarction of both cerebral hemispheres with sparing of the brainstem and cerebellum. Mortality in the nine infants was 33%, and 83% of the survivors were neurologically normal or near normal at follow-up. Conclusion(s): The systemic hypertension observed following endovascular embolizations may provide a protective mechanism to maintain cerebral blood flow after reperfusion injury. Lowering blood pressure in this situation may therefore be detrimental. © 2006 Nature Publishing Group. All rights reserved.

Objective: Higher latitude, lower ultraviolet exposure, and lower serum 25-hydroxyvitamin D (25OHD) correlate with higher multiple sclerosis (MS) prevalence, relapse rate, and mortality. We therefore evaluated the effects of high-dose vitamin D2 (D2) in MS. Method(s): Adults with clinically active relapsing-remitting MS (RRMS) were randomized to 6 months' double-blind placebo-controlled high-dose vitamin D2, 6,000 IU capsules, dose adjusted empirically aiming for a serum 25OHD 130-175 nM. All received daily low-dose (1,000 IU) D2 to prevent deficiency. Brain MRIs were performed at baseline, 4, 5, and 6 months. Primary endpoints were the cumulative number of new gadolinium-enhancing lesions and change in the total volume of T2 lesions. Secondary endpoints were Expanded Disability Status Scale (EDSS) score and relapses. Result(s): Twenty-three people were randomized, of whom 19 were on established interferon or glatiramer acetate (Copaxone) treatment. Median25OHDrose from54to69nM(low-dose D2) vs59to120 nM (high-dose D2) (p = 0.002). No significant treatment differences were detected in the primary MRI endpoints. ExitEDSS,after adjustment for entryEDSS,washigher following high-doseD2than following low-doseD2(p=0.05). There were4relapses with high-doseD2vs none with low-doseD2(p=0.04). Conclusion(s): We did not find a therapeutic advantage in RRMS for high-dose D2 over low-dose D2 supplementation. Classification of evidence: This study provides Class I evidence that high-dose vitamin D2 (targeting 25OHD 130-175 nM), compared to low-dose supplementation (1,000 IU/d), was not effective in reducing MRI lesions in patients with RRMS. Copyright © 2011 by AAN Enterprises, Inc.

Shifts in rainfall patterns and increasing temperatures associated with climate change are likely to cause widespread forest decline in regions where droughts are predicted to increase in duration and severity. One primary cause of productivity loss and plant mortality during drought is hydraulic failure. Drought stress creates trapped gas emboli in the water transport system, which reduces the ability of plants to supply water to leaves for photosynthetic gas exchange and can ultimately result in desiccation and mortality. At present we lack a clear picture of how thresholds to hydraulic failure vary across a broad range of species and environments, despite many individual experiments. Here we draw together published and unpublished data on the vulnerability of the transport system to drought-induced embolism for a large number of woody species, with a view to examining the likely consequences of climate change for forest biomes. We show that 70% of 226 forest species from 81 sites worldwide operate with narrow (,1 megapascal) hydraulic safety margins against injurious levels of drought stress and therefore potentially face long-term reductions in productivity and survival if temperature and aridity increase as predicted for many regions across the globe. Safety margins are largely independent of mean annual precipitation, showing that there is global convergence in the vulnerability of forests to drought, with all forest biomes equally vulnerable to hydraulic failure regardless of their current rainfall environment. These findings provide insight into why drought-induced forest decline is occurring not only in arid regions but also in wet forests not normally considered at drought risk.