Microbleed Status and 3-Month Outcome After Intravenous Thrombolysis in 717 Patients With Acute Ischemic Stroke

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1 Microbleed Status and 3-Month Outcome After Intravenous Thrombolysis in 717 Patients With Acute Ischemic Stroke Guillaume Turc, MD; Asmaa Sallem, MD; Solène Moulin, MD; Marie Tisserand, MD; Alexandre Machet, MD; Myriam Edjlali, MD; Jean-Claude Baron, ScD; Xavier Leclerc, PhD; Didier Leys, PhD; Jean-Louis Mas, MD; Charlotte Cordonnier, PhD; Catherine Oppenheim, PhD Background and Purpose Whether cerebral microbleeds (CMBs) detected on pretreatment magnetic resonance imaging increase the risks of symptomatic intracranial hemorrhage (sich) and, most importantly, poor outcome in patients treated by intravenous thrombolysis for acute ischemic stroke is still debated. We assessed the effect of CMB presence and burden on 3-month modified Rankin Scale and sich in a multicentric cohort. Methods We analyzed prospectively collected data of consecutive patients solely treated by intravenous thrombolysis for acute ischemic stroke, in 2 centers where magnetic resonance imaging is the first-line pretreatment imaging. Neuroradiologists blinded to clinical data rated CMBs on T2* sequence using a validated scale. Logistic regressions were used to assess relationships between CMBs and 3-month modified Rankin Scale or sich. Results Among 717 patients, 150 (20.9%) had 1 CMBs. CMB burden was associated with worse modified Rankin Scale in univariable shift analysis (odds ratio, 1.07; 95% confidence interval, per 1-CMB increase; P=0.049), but significance was lost after adjustment for age, hypertension, and atrial fibrillation (odds ratio, 1.03; 95% confidence interval, per 1-CMB increase; P=0.37). Results remained nonsignificant when taking into account CMB location or presumed underlying vasculopathy. The incidence of sich ranged from 3.8% to 9.1%, depending on the definition. Neither CMB presence, burden, location, nor presumed underlying vasculopathy was independently associated with sich. Conclusions Poor outcome or sich was not associated with CMB presence or burden on pre intravenous thrombolysis magnetic resonance imaging after adjustment for confounding factors. An individual patient data meta-analysis is needed to determine whether a subgroup of patients with CMBs carries an independent risk of poor outcome that might outweigh the expected benefit of intravenous thrombolysis. (Stroke. 2015;46: DOI: / STROKEAHA ) Key Words: cerebral hemorrhage magnetic resonance imaging stroke See related article, p Cerebral microbleeds (CMBs) are small areas of signal void on T2* or susceptibility-weighted imaging (SWI), which correspond to focal hemosiderin deposits presumably due to previous leakage from small vessels. 1,2 In patients with acute ischemic stroke (AIS), the reported prevalence of CMBs on pretreatment magnetic resonance imaging (MRI) ranges from 15% to 35%, depending on cohort characteristics and MRI sequences (T2* or SWI). 3 5 Whether preexisting CMBs increase the risks of intravenous thrombolysis (IVT) related symptomatic intracranial hemorrhage (sich) and, most importantly, of poor functional outcome is still uncertain. 6 Several studies have assessed the potential association between CMBs and post-ivt sich, with conflicting results, which prevented the American Heart Association Stroke Council from making specific recommendations on IVT in patients with CMBs. 7 In 2013, 2 independent systematic reviews and meta-analyses found an 2-fold increased risk of sich in patients with 1 CMB on pre-ivt MRI, but this association failed to reach statistical significance. 8,9 In view of the methodological limitations and heterogeneity of the included studies, namely different study designs, treatment modalities, and definitions of sich, authors acknowledged that good quality data from large, prospective cohorts were lacking at that time. 10 In 2014 and 2015, 3 additional studies reported results from prospectively collected data. Two found a significant association between CMB presence (or burden) and post- IVT sich, 5,11 whereas the last one did not. 4 Although post-ivt sich is an ominous event, a key clinical question remains whether the presence or burden of CMBs Continuing medical education (CME) credit is available for this article. Go to to take the quiz. Received March 12, 2015; final revision received April 23, 2015; accepted May 13, From the Departments of Neurology (G.T., J.-C.B., J.-L.M.) and Radiology (M.T., A.M., C.O.), Hôpital Sainte-Anne, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR S894, DHU Neurovasc, Paris, France; and Departments of Neurology (S.M., D.L., C.C.) and Radiology (A.S., M.E., X.L.), Lille University Hospital and Université de Lille, UDSL, INSERM U1171, Lille, France. The online-only Data Supplement is available with this article at /-/DC1. Correspondence to Guillaume Turc, MD, Service de Neurologie, Hôpital Sainte-Anne, 1 rue Cabanis, Paris, France. g.turc@ch-sainte-anne.fr 2015 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 Turc et al Microbleed Status and 3-Month Outcome After IVT 2459 on-pretreatment MRI independently increases the risk of poor long-term outcome after IVT. Indeed, the benefit of IVT at 3 months may outweigh its harms even in some patients with initial sich. We aimed to determine whether the presence and burden of CMBs on pretreatment MRI were independently associated with 3-month outcome and sich. Materials and Methods Patients We analyzed prospectively collected data of consecutive patients who underwent IVT for AIS in 2 French centers where MRI is the first-line pretreatment imaging for AIS (Sainte-Anne, Paris, November 2003 to December 2013 and Lille, October 2009 to May 2014). Patients were included (1) if they had a pretreatment MRI, including diagnostic quality T2* sequence, and (2) if they were treated by IVT alone (alteplase, 0.9 mg/kg) for an AIS <4.5 hours or for a wake-up stroke with diffusion-weighted imaging fluid-attenuated inversion recovery mismatch. 12,13 High CMB burden was not an exclusion criterion for IVT in both centers. Sex, age, history of hypertension, diabetes mellitus, current smoking, atrial fibrillation, previous stroke/transient ischemic attack, baseline National Institute of Health Stroke Scale (NIHSS) score, serum glucose, blood pressure before IVT, and onsetto-treatment time were routinely collected. In accordance with the French legislation, the study did not need approval by an Ethics Committee nor written informed consent from patients because it implied only analysis of anonymized data collected prospectively as part of routine clinical care. The article was prepared in accordance with recently proposed recommendations for studies investigating the association between CMBs and sich or 3-month outcome. 6 Imaging Methods and Definition of CMBs In both centers, pretreatment MRI included diffusion-weighted imaging, fluid-attenuated inversion recovery, T2*-weighted gradient echo imaging, and intracranial MR angiography (total acquisition time, 10 minutes). The acquisition parameters of the T2* sequences remained unchanged throughout the study period: (1) Sainte-Anne center (1.5 Tesla GE Healthcare MR scanner): repetition time/echo time, 460/13 ms; flip angle, 25 ; field of view, cm 2 ; matrix, ; 6-mm contiguous slice thickness; duration, 1 minute 21 and (2) Lille center (1.5 Tesla Philips Achieva MR scanner): repetition time/echo time, 945/32 ms; flip angle, 18 ; field of view, cm 2 ; matrix, ; 5-mm slice thickness (gap, mm); duration, 2 minutes. 34 A follow-up imaging (MRI including T2* sequence or computed tomographic scanner) was scheduled 24 hours after IVT and in the case of neurological deterioration. Pretreatment T2* images were rated by neuroradiologists, blinded to clinical and follow-up imaging data, for the number of CMBs and their distribution, according to a validated scale. 14 CMBs were defined as small areas ( 10 mm) of signal void on T2* sequence with associated blooming and were classified as lobar, deep, or infratentorial. 14,15 All available MR sequences were analyzed to exclude potential CMB mimics (vascular structures, thrombus, calcifications, iron deposits, cavernous malformation, or hemorrhagic metastases). 15,16 Presumed underlying vasculopathy for CMBs was defined as cerebral amyloid angiopathy (CAA: strictly lobar distribution of CMBs in patients aged 55 years), 5,17 hypertensive vasculopathy (strictly deep or infratentorial distribution of CMBs in hypertensive patients), 4 or undetermined (all other situations). 5 Existence of ICH according to published radiological classification criteria (hemorrhagic infarct or parenchymal hematoma, type 1 or 2) 18 was rated on follow-up images by neuroradiologists blinded to clinical data and pretreatment CMB status. Outcomes Functional outcome (3-month modified Rankin Scale [mrs]) was considered as the primary end point and prospectively assessed by board-certified stroke neurologists, blinded to CMB rating, during face-to-face visits or structured telephone interviews. Occurrence of sich was considered as the secondary end point and assessed according to 4 definitions (Table I in the online-only Data Supplement): National Institute of Neurological Disorders and Stroke (NINDS), 19 European Cooperative Acute Stroke Studies 2 and 3 (ECASS-2 20 and ECASS-3 21 ), and Safe Implementation of Thrombolysis in Stroke- Monitoring Study (SITS-MOST 22 ). Statistical Analysis Continuous variables were expressed as mean±sd or median (interquartile range) and compared using the t test or Mann Whitney U test, as appropriate. Categorical variables were expressed as percentages and compared using the Pearson χ 2 test or Fisher's exact test, as appropriate. Associations between CMBs (presence or burden) and dependent variables (3-month mrs or sich according to the 4 above-mentioned definitions) were assessed by calculations of crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) in logistic regression models. Baseline variables associated with CMB presence at a level of P<0.20 in univariable analysis were considered for inclusion into multivariable models, taking into account potential multicollinearity. CMB burden was examined as a continuous variable (per 1-CMB increase) for the main analysis. In sensitivity analysis, CMB burden was examined using the following categorization: 0 versus 1 versus 2 to 4 versus 5. 5 Three-month mrs was dichotomized in binary logistic regression models (mrs score >1 versus 1 19 ; mrs score >2 versus 2 4 ). Because it may increase statistical power, 23 shift analysis over the whole range of the mrs was also performed in ordinal logistic regression models. For multivariable ordinal logistic regression, partial proportional odds models were used because 2 explanatory variables (age and hypertension) did not meet the assumption of proportional odds. 24 Statistical significance was set at P<0.05. Statistical analysis was performed using SAS version 9.4 (SAS Institute, Inc, Cary, NC). Results During the study period, 931 patients were treated by IVT for an ischemic stroke, of which 214 (23.0%) were excluded (Figure I in the online-only Data Supplement), leaving 717 patients for the analysis (Lille, n=375; Sainte-Anne, n=342). Included and excluded patients did not differ on baseline characteristics, except for NIHSS score (median, 11 versus 14; P=0.01). Patients characteristics are summarized in Table 1. Median (interquartile range) age and NIHSS score were 74 (60 83) and 11 (6 18), respectively. Ninety-one (12.7%) patients had a prestroke mrs score >1, including 62 (8.6%) patients with a prestroke mrs score >2. On pretreatment imaging, 150 (20.9%) patients had 1 CMB (maximum 26); 92 (12.8%) had precisely 1 CMB, 33 (4.6%) had 2 to 4 CMBs, and 25 (3.5%) had 5 CMBs. The prevalence of CMBs did not differ across centers (P=0.78). Among patients with CMBs, presumed underlying vasculopathy was CAA in 60 (40.0%), hypertensive vasculopathy in 34 (22.7%), and undetermined in 56 (37.3%) patients. Associations between the presence of CMBs and baseline characteristics are summarized in Table 2. Follow-up imaging modality was MRI in 674 (94.0%) patients. At 3 months, 329 (45.9%) patients had a mrs score >2 and 434 (60.5%) had a mrs score >1. With such dichotomizations of the mrs score, there was no significant association between CMB presence or burden and 3-month outcome in univariable and multivariable analyses (Table 3). Shift analysis over the entire range of the mrs showed a marginally significant association between CMB burden

3 2460 Stroke September 2015 Table 1. Population Characteristics (n=717) Baseline characteristics Male sex 351 (48.9) Age, y, median (IQR) 74 (60 83) Hypertension 452 (63.0) Diabetes mellitus 113 (15.8) Current smoking 128 (17.8) Atrial fibrillation 166 (23.1) Previous stroke 71 (9.9) Before IVT NIHSS, median (IQR) 11 (6 18) OTT, min, median (IQR) 152 ( ) Serum glucose, mmol/l, mean±sd 7.1±2.5 Systolic BP, mm Hg, mean±sd 154.9±21.4 Diastolic BP, mm Hg, mean±sd 82.3±15.2 CMB(s) on baseline MRI No CMB 567 (79.1) 1 CMB 92 (12.8) 2 4 CMBs 33 (4.6) 5 CMBs 25 (3.5) Deep/infratentorial CMB(s) only 70 (9.8) Lobar CMB(s) only 45(6.3) Lobar and deep/infratentorial CMB(s) 35 (4.9) Outcomes 3-month mrs, median (IQR) 2 (1 4) 3-month mrs score, >1 434 (60.5) 3-month mrs score, >2 329 (45.9) sich definition NINDS 65 (9.1) ECASS-2 64 (8.9) ECASS-3 27 (3.8) SITS-MOST 27 (3.8) Numbers in parentheses are percentages, unless indicated. BP indicates blood pressure; CMB, cerebral microbleed; ECASS, European Cooperative Acute Stroke Study; IQR, interquartile range; IVT, intravenous thrombolysis; MRI, magnetic resonance imaging; mrs, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; NINDS, National Institute of Neurological Disorders and Stroke; OTT, onset-to-treatment time; sich, symptomatic intracranial hemorrhage; and SITS-MOST, Safe Implementation of Thrombolysis in Stroke-Monitoring Study. and worse outcome in univariable analysis (OR, 1.07; 95% CI, per 1-CMB increase; P=0.049) but not in multivariable analysis (OR, 1.03; 95% CI, per 1-CMB increase; P=0.37; Table 3). Results remained nonsignificant when (1) considering CMB burden as a categorical variable, (2) taking into account CMB location or presumed underlying vasculopathy, and (3) an alternative model, including all baseline variables, associated with mrs score >2 was considered 25 (data not shown). The rates of sich ranged from 3.8% (ECASS-3 and SITS- MOST definitions) to 9.1% (NINDS definition). There was no significant association between CMB presence or burden (considered as a continuous variable) and sich in univariable or multivariable analysis, irrespective of the sich definition (Table 3). In sensitivity analyses, CMB burden, considered as a categorical variable, was only marginally associated in univariable analysis with sich according to the NINDS definition (P=0.046). CMB location or presumed underlying vasculopathy were not significantly associated with sich (data not shown). Discussion Capitalizing on a large sample of patients with AIS to address the clinical relevance of CMBs on pre-ivt MRI, we observed a marginally significant association between CMB burden and worse 3-month outcome in univariable ordinal logistic regression, which lost significance after adjustment for confounding factors. We found no independent association between CMB burden at baseline and sich, irrespective of the definition used. Most researchers assessing the clinical significance of pre-ivt CMBs have focused on sich, 3,8 as this association has pathophysiological plausibility 10 and because sich is a determinant cause of poor long-term functional outcome. 26 Although our findings on the relationship between sich and CMB burden were similar to those of the previous reports, 3,4 they stand in clear distinction to those of 2 recent studies. 5,11 Using the ECASS-3 definition, both studies found a significant association between sich and a high CMB burden. We could not replicate these findings, except in univariable analysis for sich according to the NINDS definition, when using the specific categorization proposed by Dannenberg et al. 5 Table 2. Baseline Characteristics Associated With CMB Presence in Univariable Analysis CMB Presence OR (95% CI) P Value Male sex 1.09 ( ) 0.64 Age, per 10-year increase 1.29 ( ) Hypertension 1.37 ( ) 0.11 Diabetes mellitus 0.78 ( ) 0.36 Current smoking 0.85 ( ) 0.51 Atrial fibrillation 1.33 ( ) 0.17 Previous stroke 1.21 ( ) 0.51 Prestroke mrs score, > ( ) 0.32 NIHSS, per 1-point increase 1.00 ( ) 0.96 OTT, per 10-min increase 1.04 ( ) 0.05 Serum glucose, per 1-mmol/L increase 0.96 ( ) 0.31 Systolic BP, per 10-mm Hg increase 1.12 ( ) 0.01 Diastolic BP, per 10-mm Hg increase 1.09 ( ) 0.15 Lille center 1.05 ( ) 0.78 Sainte-Anne center 1.00 Antithrombotic medication before stroke* 1.41 ( ) 0.21 BP indicates blood pressure; CI, confidence interval; CMB, cerebral microbleed; mrs, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; OR, odds ratio; and OTT, onset-to-treatment time. *Sainte-Anne cohort only, n=342.

4 Turc et al Microbleed Status and 3-Month Outcome After IVT 2461 Table 3. Association Between CMBs on Pretreatment Imaging and Outcome CMB(s) Presence CMB Burden Univariable Analysis Multivariable Analysis* Univariable Analysis Multivariable Analysis* OR (95% CI) P Value OR (95% CI) P Value OR (95% CI) P Value OR (95% CI) P Value 3-month mrs score, > ( ) ( ) ( ) ( ) month mrs score, > ( ) ( ) ( ) ( ) 0.72 Worse 3-month mrs (shift analysis) 1.18 ( ) ( ) ( ) ( ) 0.37 sich NINDS definition 1.26 ( ) ( ) ( ) ( ) 0.20 ECASS-2 definition 0.86 ( ) ( ) ( ) ( ) 0.63 ECASS-3 definition 1.08 ( ) ( ) ( ) ( ) 0.83 SITS-MOST definition 1.08 ( ) ( ) ( ) ( ) 0.49 CI indicates confidence interval; CMB, cerebral microbleed; ECASS, European Cooperative Acute Stroke Study; mrs, modified Rankin Scale; OR, odds ratio; sich, symptomatic intracranial hemorrhage; and SITS-MOST, Safe Implementation of Thrombolysis in Stroke-Monitoring Study. *Adjusted for age, hypertension, and atrial fibrillation. Per 1-microbleed increase. Exclusion of 62 patients with prestroke mrs score of >2. Exclusion of 91 patients with prestroke mrs score of >1. This discrepancy is unlikely to be due to a lack of statistical power in our study, given its sample size and the prevalence of sich, CMB presence, and proportion of patients with a high CMB burden, which were similar to those of the literature. 3 5,8 Yet, differences in population characteristics could possibly explain the discrepancy across studies. Compared with our population, patients included in the study by Dannenberg et al 5 were slightly older and more frequently had a presumed CAA, which might carry a higher risk of post-ivt sich, including remote parenchymal hematoma. 27 Although the proportion of presumed CAA in the subgroup of patients with 5 CMBs is not mentioned in the publication by Dannenberg et al, 5 it might have been higher than ours. Patients included in the study by Yan et al 11 had a high proportion of patients with 1 CMBs (39.9%) and an important CMB burden (742 CMBs in 133 patients), which is consistent with a previous report from another Asian cohort 28 but much higher than expected in a white one (401 CMBs in 150 patients in our study, in line with others 3 ). It remains to be determined whether Asian patients carry a higher risk of post-ivt sich in the presence of CMBs than Western patients. 27 Although sich is an important end point for patients with CMBs treated by IVT, our main end point was 3-month mrs, for several reasons. First, the incidence of sich varies greatly depending on its definition, 22 none being optimal. 29,30 By contrast, 3-month mrs is a consensual, reproducible, and widely used measure of long-term functional outcome. Second, the clinical relevance of CMB burden on pretreatment MRI should be assessed taking into account the long-term outcome, as the benefit of IVT at 3 months may outweigh its harms even in patients with initial sich. To date, 4 studies (including the present one) assessed the relationship between pre-ivt CMBs and 3-month outcome (Table II in the online-only Data Supplement). 4,5,11 We found an association between CMB burden and worse outcome in univariable shift analysis, in line with findings from the 3 other above-mentioned studies. However, this unadjusted association could be because of confounding factors, such as older age 3 5 or hypertension. 4,31 Indeed, in multivariable shift analysis, the association between CMB burden and worse outcome was no longer significant in our population, in line with previous findings. 4,5 To date, only Yan et al 11 have observed a significant association between a high CMB burden and poor outcome in multivariable analysis. These conflicting results stress the need for an individual patient data meta-analysis to determine whether CMB burden is an independent predictor of 3-month poor outcome and to estimate the effect size of the association. Such a meta-analysis could yield sufficient statistical power to identify whether there is a subgroup of patients with CMBs, which seems to have an independent risk of poor 3-month outcome so important that it might outweigh the expected benefit of IVT. If such a subgroup exists, such findings would support a widespread use of MRI for AIS and could lead to a randomized controlled trial to determine the best acute treatment for these high-risk patients. However, to date, detecting CMBs on pretreatment MRI should not prevent IVT based on current evidence, given the uncertainty about the independence of the association between CMBs and poor outcome, and the lack of a control (placebo) group in the available observational studies. Strengths of our study include its sample size, the prospective data collection involving 2 centers, the systematic implementation of MRI as first-line pretreatment imaging in both centers, the use of a validated scale for CMBs rating, 14 and the homogeneity of the cohort, as only patients solely treated by IVT were included. Our study has several potential limitations. First, 23% of the patients treated by IVT during the study period were excluded from the final analysis. However, included and excluded patients did not differ on baseline characteristics except for NIHSS score, which was not associated with CMB presence or burden in our or in previous studies. 3 5,28 Second, the lack of a control group without IVT prevented us from drawing conclusions on the benefit/risk ratio of IVT in subgroups of interest. However, withholding IVT in patients otherwise eligible for this treatment may be ethically questionable. 3 Third, the statistical power of our study was limited for

5 2462 Stroke September 2015 specific subgroup analyses, for instance to assess the effect of presumed CAA underlying vasculopathy in patients with 5 CMBs. Fourth, we did not control for potentially interesting variables, such as current antithrombotic medication, volume of pretreatment diffusion-weighted imaging lesion, or leukoaraiosis. However, the 2 first variables, available in the Sainte- Anne cohort, did not reach the prespecified P<0.20 threshold for the univariable association with CMB presence, making them unlikely to be strong confounding factors. Moreover, the inclusion of >4 explanatory variables could have led to overfitting in models with a limited number of events (eg, sich according to ECASS-3). Fifth, one may argue that potentially relevant differences between the 2 studies showing an increased risk of sich in patients with CMBs and the present work include the imaging modalities (present study: T2*/1.5 T; Dannenberg et al 5 : T2*/3T; Yan et al 11 : SWI/3T). However, other researchers, using SWI (1.5T and 3T) did not find such an association. 4 The magnetic field strength does not greatly modify the detection of CMBs, 4 but SWI is more sensitive than T2* for detecting CMBs. 32 Using the T2* instead of SWI sequence, we may have underestimated the global number of CMBs, which only plausible consequence would be a loss of statistical power. Of note, despite using different T2* parameters, the prevalence of CMBs was similar across our centers. In conclusion, we found that CMB burden on pre-ivt MRI was not associated with an increased risk of poor 3-month outcome after adjustment for confounding factors, such as age and hypertension. An individual patient data metaanalysis is needed to determine whether a subgroup of patients with CMBs carries an independent risk of 3-month poor outcome that might outweigh the expected benefit of reperfusion therapies. Sources of Funding M. Tisserand was supported by the Société Française de Radiologie. None. Disclosures References 1. Fazekas F, Kleinert R, Roob G, Kleinert G, Kapeller P, Schmidt R, et al. Histopathologic analysis of foci of signal loss on gradient-echo T2*- weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. AJNR Am J Neuroradiol. 1999;20: Cordonnier C, Al-Shahi Salman R, Wardlaw J. Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain. 2007;130(pt 8): doi: / brain/awl Fiehler J, Albers GW, Boulanger JM, Derex L, Gass A, Hjort N, et al; MR STROKE Group. Bleeding risk analysis in stroke imaging before thrombolysis (BRASIL): pooled analysis of T2*-weighted magnetic resonance imaging data from 570 patients. Stroke. 2007;38: doi: /STROKEAHA Gratz PP, El-Koussy M, Hsieh K, von Arx S, Mono ML, Heldner MR, et al. Preexisting cerebral microbleeds on susceptibility-weighted magnetic resonance imaging and post-thrombolysis bleeding risk in 392 patients. Stroke. 2014;45: doi: /STROKEAHA Dannenberg S, Scheitz JF, Rozanski M, Erdur H, Brunecker P, Werring DJ, et al. Number of cerebral microbleeds and risk of intracerebral hemorrhage after intravenous thrombolysis. Stroke. 2014;45: doi: /STROKEAHA Charidimou A, Fox Z, Werring DJ. Do cerebral microbleeds increase the risk of intracerebral hemorrhage after thrombolysis for acute ischemic stroke? Int J Stroke. 2013;8:E1 E2. doi: /ijs Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, et al; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44: doi: /STR.0b013e a. 8. Charidimou A, Kakar P, Fox Z, Werring DJ. Cerebral microbleeds and the risk of intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2013;84: doi: /jnnp 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: doi: /j x. 10. Charidimou A, Werring DJ. Cerebral microbleeds as a predictor of macrobleeds: what is the evidence? Int J Stroke. 2014;9: doi: /ijs Yan S, Jin X, Zhang X, Zhang S, Liebeskind DS, Lou M. Extensive cerebral microbleeds predict parenchymal haemorrhage and poor outcome after intravenous thrombolysis [published online ahead of print January 28, 2015]. J Neurol Neurosurg Psychiatry. early/2015/01/28/jnnp long. Accessed May 14, Thomalla G, Cheng B, Ebinger M, Hao Q, Tourdias T, Wu O, et al; STIR and VISTA Imaging Investigators. DWI-FLAIR mismatch for the identification of patients with acute ischaemic stroke within 4.5 h of symptom onset (PRE-FLAIR): a multicentre observational study. Lancet Neurol. 2011;10: doi: /S (11) Petkova M, Rodrigo S, Lamy C, Oppenheim G, Touzé E, Mas JL, et al. MR imaging helps predict time from symptom onset in patients with acute stroke: implications for patients with unknown onset time. Radiology. 2010;257: doi: /radiol Gregoire SM, Chaudhary UJ, Brown MM, Yousry TA, Kallis C, Jäger HR, et al. The Microbleed Anatomical Rating Scale (MARS): reliability of a tool to map brain microbleeds. Neurology. 2009;73: doi: /WNL.0b013e3181c34a7d. 15. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al; STandards for ReportIng Vascular changes on neuroimaging (STRIVE v1). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12: doi: /S (13) Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, et al; Microbleed Study Group. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol. 2009;8: doi: /S (09) Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology. 2001;56: Trouillas P, von Kummer R. Classification and pathogenesis of cerebral hemorrhages after thrombolysis in ischemic stroke. Stroke. 2006;37: doi: /01.STR The National Institute of Neurological Disorders and Stroke rt-pa Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333: Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352: Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359: doi: /NEJMoa Wahlgren N, Ahmed N, Dávalos A, Ford GA, Grond M, Hacke W, et al; SITS-MOST Investigators. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke- Monitoring Study (SITS-MOST): an observational study. Lancet. 2007;369: doi: /S (07)

6 Turc et al Microbleed Status and 3-Month Outcome After IVT Saver JL, Gornbein J. Treatment effects for which shift or binary analyses are advantageous in acute stroke trials. Neurology. 2009;72: doi: /01.wnl b Ananth CV, Kleinbaum DG. Regression models for ordinal responses: a review of methods and applications. Int J Epidemiol. 1997;26: Turc G, Apoil M, Naggara O, Calvet D, Lamy C, Tataru AM, et al. Magnetic Resonance Imaging-DRAGON score: 3-month outcome prediction after intravenous thrombolysis for anterior circulation stroke. Stroke. 2013;44: doi: / STROKEAHA Strbian D, Sairanen T, Meretoja A, Pitkäniemi J, Putaala J, Salonen O, et al; Helsinki Stroke Thrombolysis Registry Group. Patient outcomes from symptomatic intracerebral hemorrhage after stroke thrombolysis. Neurology. 2011;77: doi: /WNL. 0b013e b8c. 27. Charidimou A, Kakar P, Fox Z, Werring DJ. Cerebral microbleeds and recurrent stroke risk: systematic review and meta-analysis of prospective ischemic stroke and transient ischemic attack cohorts. Stroke. 2013;44: doi: /STROKEAHA Kakuda W, Thijs VN, Lansberg MG, Bammer R, Wechsler L, Kemp S, et al; DEFUSE Investigators. Clinical importance of microbleeds in patients receiving IV thrombolysis. Neurology. 2005;65: doi: /01.wnl f. 29. Turc G, Tisserand M, Seners P, Oppenheim C, Baron JC. Letter by Turc et al regarding article, Defining clinically relevant cerebral hemorrhage after thrombolytic therapy for stroke: analysis of the national institute of neurological disorders and stroke tissue-type plasminogen activator trials. Stroke. 2015;46:e43 e44. doi: / STROKEAHA Rao NM, Levine SR, Saver JL. Response to letter regarding article, Defining clinically relevant cerebral hemorrhage after thrombolytic therapy for stroke: analysis of the national institute of neurological disorders and stroke tissue-type plasminogen activator trials. Stroke. 2015;46:e45. doi: /STROKEAHA Kim HS, Lee DH, Ryu CW, Lee JH, Choi CG, Kim SJ, et al. Multiple cerebral microbleeds in hyperacute ischemic stroke: impact on prevalence and severity of early hemorrhagic transformation after thrombolytic treatment. AJR Am J Roentgenol. 2006;186: doi: / AJR Cheng AL, Batool S, McCreary CR, Lauzon ML, Frayne R, Goyal M, et al. Susceptibility-weighted imaging is more reliable than T2*- weighted gradient-recalled echo MRI for detecting microbleeds. Stroke. 2013;44: doi: /STROKEAHA