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Robert C. Griggs, MD

Editors’ Note: Commenting on “Natural course of total mismatch and predictors for tissue infarction,” Dr. Shamy points out that mismatch on CT perfusion is an incomplete predictor of benefit following revascularization and may be better used to exclude stroke patients with a matched defect. Authors Hotter and Fiebach agree and stress that the absence of imaging proof of infarction is not, per se, an exclusion criterion for IV thrombolysis. Drs. Cappellari and Bovi critique the meta-analysis on cerebral microbleeds and postthrombolysis intracerebral hemorrhage risk, pointing out several limitations. Authors Charidimou and Werring respond and explain that their results are preliminary and do not support withholding tissue plasminogen activator or using MRI to screen for cerebral microbleeds in acute stroke. —Chafic Karam, MD, and Robert C. Griggs, MD

NATURAL COURSE OF TOTAL MISMATCH AND PREDICTORS FOR TISSUE INFARCTION

Michel C. Shamy, Ottawa, Canada: Mismatch on CT perfusion (CTP) has been suggested as a means of differentiating penumbra from core, with the aim of identifying patients most likely to benefit from revascularization and potentially extending the therapeutic window in acute ischemic stroke. The recent study by Hotter et al. demonstrated how this logic may be reversed, in that CTP is potentially better at excluding rather than including patients for revascularization.1 CTP is intended to provide a snapshot of penumbra vs core at the time of imaging. However, patient outcome is determined by the state of penumbra vs core at the time reperfusion occurs. CTP mismatch cannot predict if or when reperfusion may occur, or the rate of progression from penumbra to core for any given patient. Therefore, mismatch will always be an incomplete predictor of benefit, with some patients progressing to infarction despite best therapy. CTP may be better used to exclude patients with a matched defect.2 If reliable parameters for infarcted tissue can be established, CTP may be used to identify those patients least likely to benefit from revascularization. Until that time, it should remain a research tool. Author Response: Benjamin Hotter, Jochen B. Fiebach, Berlin: We thank Dr. Shamy for the comments 880

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on our article1 and agree that our approach differed from a typical mismatch interpretation. The high rate of infarctions on follow-up scans were the most important message of our study, especially since magnetic resonance mismatch studies have been disappointing in recent clinical application studies and in terms of infarct size prediction. Some studies even excluded patients for not showing an infarction3 or a minimum infarction size4 on initial MRI. Our findings justify an approach to treatment similar to a process from CT-based screening.5 For instance, missing imaging proof of infarction is not, per se, an exclusion criterion for IV thrombolysis. Key differences between PCT and stroke MRI include whole brain coverage in MRI and sensitivity to very small hyperintensities with high-resolution diffusion-weighted imaging (DWI). Therefore, patients presenting with negative DWI should not necessarily be interpreted as stroke mimics. We hope our findings help with the clinical problem of how to treat apparent acute cerebrovascular events without DWI findings. Regarding clinical trials, it might be preferable to exclude those patients if the selection criteria are designed to include a majority of severely affected patients. © 2016 American Academy of Neurology 1.

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Hotter B, Ostwaldt AC, Levichev-Connolly A, et al. Natural course of total mismatch and predictors for tissue infarction. Neurology 2015;85:770–775. Campbell BCV, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion imaging selection. N Engl J Med 2015;372:1009–1018. Thomalla G, Fiebach JB, Ostergaard L, et al. A multicenter, randomized, double-blind, placebo-controlled trial to test efficacy and safety of magnetic resonance imaging-based thrombolysis in wake-up stroke (WAKE-UP). Int J Stroke 2014;9:829–836. Schabitz WR, Laage R, Vogt G, et al. AXIS: a trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke. Stroke 2010;41:2545–2551. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317–1329.

CEREBRAL MICROBLEEDS AND POSTTHROMBOLYSIS INTRACEREBRAL HEMORRHAGE RISK: UPDATED META-ANALYSIS

Manuel Cappellari, Paolo Bovi, Verona, Italy: Charidimou et al.1 indicated that the pooled odds

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ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

ratio (OR) for the presence of cerebral microbleeds (CMBs) and risk of symptomatic intracerebral hemorrhage (sICH) was 2.87 (95% confidence interval 1.76–4.69) in patients treated with IV thrombolysis only. The methodologic limitations reported by Charidimou et al.2 require a critical revision. First, current consensus MRI criteria for CMB identification define strategy for their differential diagnosis with mimics and artefacts. Second, the incidence of sICH following IV thrombolysis varies considerably according to the clinical, radiologic, and time criteria used to define sICH.3 Third, time from stroke onset to IV thrombolysis is significantly associated with a higher OR for sICH in patients treated within 6 hours of symptoms onset.4 Fourth, since CMBs are general markers of small vessel fragility and vulnerability to bleeding and underlying mechanisms of thrombolysis-associated ICH are different, rating of number and anatomical distribution of CMBs according to a valid scale is an essential prerequisite to assess a possible association between severity of small vessel disease marked by CMB and risk of different postthrombolysis ICH subtypes. However, a recent large prospective study showed that sICH was not associated with CMB presence, burden, location, or presumed underlying vasculopathy on pre-IV thrombolysis MRI after adjustment for confounding factors.5 Currently, there is no evidence to support routine use of pre-IV thrombolysis MRI to detect CMBs or restriction on access to IV thrombolysis based on presence of CMBs. Author Response: Andreas Charidimou, David Werring, London: We thank Drs. Cappellari and Bovi for their interest in our meta-analysis1 and the insightful comments on the methodologic limitations of included studies. We agree that distinguishing CMBs from mimics is important: 8/10 pooled studies used clear criteria to define CMBs, including awareness of .2 CMB mimics (table 21), according to current consensus guidelines.6 We also agree that the incidence of ICH depends on follow-up imaging modality and timing, which slightly differed across centers (table 11), causing some heterogeneity. However, the main outcome in

our meta-analysis was symptomatic ICH with significant clinical deterioration prompting brain imaging, which is likely similar across centers. We acknowledged that our estimates were unadjusted for established sICH risk factors, including stroke severity or time from symptom onset to tissue plasminogen activator (tPA).7 Turc et al.5 did not find an association between CMBs and sICH. The only way to fully explore the effect of CMBs with adjustment for confounding factors is an individual patient meta-analysis, incorporating CMB burden,8 location, and presumed underlying microangiopathy. Our results are preliminary and do not support withholding tPA or using MRI to screen for CMBs in acute stroke. © 2016 American Academy of Neurology 1.

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Charidimou A, Shoamanesh A, Wilson D, et al. Cerebral microbleeds and postthrombolysis intracerebral hemorrhage risk: updated meta-analysis. Neurology 2015;85:927–934. Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009;8:165–174. Seet RC, Rabinstein AA. Symptomatic intracranial hemorrhage following intravenous thrombolysis for acute ischemic stroke: a critical review of case definitions. Cerebrovasc Dis 2012;34:106–114. Ahmed N, Kellert L, Lees KR, et al. Results of intravenous thrombolysis within 4.5 to 6 hours and updated results within 3 to 4.5 hours of onset of acute ischemic stroke recorded in the Safe Implementation of Treatment in Stroke International Stroke Thrombolysis Register (SITSISTR): an observational study. JAMA Neurol 2013;70: 837–844. Turc G, Sallem A, Moulin S, et al. Microbleed Status and 3-month outcome after intravenous thrombolysis in 717 patients with acute ischemic stroke. Stroke 2015;46: 2458–2463. Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013;12:822–838. Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384:1929–1935. Shoamanesh A, Kwok CS, Lim PA, Benavente OR. Postthrombolysis intracranial hemorrhage risk of cerebral microbleeds in acute stroke patients: a systematic review and meta-analysis. Int J Stroke 2013;8:348–356.

Author disclosures are available upon request ([email protected]). Neurology 86

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ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Cerebral microbleeds and postthrombolysis intracerebral hemorrhage risk: Updated meta-analysis Manuel Cappellari, Andreas Charidimou, Paolo Bovi, et al. Neurology 2016;86;880-881 DOI 10.1212/01.wnl.0000481473.14013.c8 This information is current as of February 29, 2016 Updated Information & Services

including high resolution figures, can be found at: http://www.neurology.org/content/86/9/880.2.full.html

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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2016 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

Cerebral microbleeds and postthrombolysis intracerebral hemorrhage risk: Updated meta-analysis.

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