Cerebral microbleeds (CMBs) are detected on T2*-

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1 Cerebral Microbleeds and Recurrent Stroke Risk Systematic Review and Meta-Analysis of Prospective Ischemic Stroke and Transient Ischemic Attack Cohorts Andreas Charidimou, MSc; Puneet Kakar, MD; Zoe Fox, PhD; David J. Werring, PhD Background and Purpose To evaluate cerebral microbleeds (CMBs) and future stroke risk (including intracerebral hemorrhage [ICH]) in patients with ischemic stroke (IS) or transient ischemic attack. Materials and Methods A systematic review and meta-analysis of prospective cohorts with recent IS/transient ischemic attack. We critically appraised studies and calculated pooled odds ratios (ORs), using the Mantel Haenszel fixed-effects method, for ICH or recurrent IS, in patients with versus without CMBs. Results We pooled data from 10 cohorts, including 3067 patients. CMBs were associated with a significant increased risk of any recurrent stroke (OR, 2.25; 95% confidence interval [95% CI], ; P<0.0001), ICH (OR, 8.52; 95%CI, ; P=0.007), and IS (OR, 1.55; 95%CI, ; P<0.0001). When stratified by study population ethnicity (Asian versus Western [mainly white European]), the association of CMBs with ICH was significant for Asian cohorts (5 studies; n=1915; OR, 10.43; 95%CI, ; P<0.0001) but borderline and of lower magnitude for Western cohorts (4 studies; n=885; OR, 3.87; 95%CI, ; P=0.066). By contrast, there was a significant association of CMBs with recurrent IS in Western (3 studies; n=899) but not Asian cohorts (4 studies; n=1357; OR, 2.23; 95%CI, ; P=0.004 compared with OR, 1.30; 95%CI, ; P=0.192, respectively). Conclusions There is consistent evidence of an increased risk of recurrent stroke after IS or transient ischemic attack in patients with CMBs. The risk for spontaneous ICH appears to be greater than the risk for recurrent IS. Our findings also suggest that the balance of risk for ICH versus IS differs between Asian and Western cohorts. (Stroke. 2013;44: ) Key Words: cerebral amyloid angiopathy cerebral microbleeds intracerebral hemorrhage Cerebral microbleeds (CMBs) are detected on T2*- weighted gradient-recalled echo (T2*-GRE) and susceptibility-weighted imaging in an ever-increasing number of patients with ischemic stroke (IS), transient ischemic attack (TIA), and spontaneous intracerebral hemorrhage (ICH). 1 CMBs are a new MRI marker of cerebral small vessel disease, 1 which, by contrast with other manifestations (eg, lacunes or leukoaraiosis), are generally considered to provide direct evidence of blood leakage from pathologically fragile small vessels mainly affected by hypertensive arteriopathy (including arteriolosclerosis) or cerebral amyloid angiopathy (CAA). 2,3 It is hypothesized that CMBs may be a predictor of the future risk of spontaneous ICH in patients after either IS and TIAs 4,5 or ICH. 6 Since CMBs are also related to occlusive features of small vessel cerebrovascular disease (eg, lacunar infarcts), their presence might also confer an increased risk of future IS in some populations. 4,7 Accurate estimates of these risks are needed to inform clinical decisions, especially regarding whether to prescribe antithrombotic treatments in individuals with CMBs, an increasingly common clinical dilemma. Recently, a meta-analysis of patients with ICH and with IS or TIA showed that CMBs are more common in warfarin- or antiplatelet-related ICH than spontaneous ICH. 8 However, the studies included were mostly cross-sectional case control or case case comparisons so they could not be investigated for the predictive risk of CMBs and were subject to confounding by indication for antithrombotic treatment. Whether CMBs are a marker of increased future stroke risk (particularly ICH) remains a question of potentially major clinical significance. We therefore performed a systematic review and meta-analysis of published prospective cohorts. We hypothesized that the presence of CMBs is associated with an increased future risk of ICH and recurrent IS in patients after IS or TIA. Because the prevalence and severity of small vessel disease may differ between populations, we Received November 2, 2012; accepted December 17, From the Stroke Research Group, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK (A.C., D.J.W.); Department of Stroke Medicine, Imperial College Healthcare, NHS Trust, London, UK (P.K.); and Education Unit, UCL Institute of Neurology, Queen Square, London, UK (Z.F.). The online-only Data Supplement is available with this article at /-/DC1. Correspondence to David J. Werring, PhD, Reader in Clinical Neurology, National Hospital for Neurology and Neurosurgery, Box 6, Queen Square, London WC1N 3BG, United Kingdom. d.werring@ucl.ac.uk 2013 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 996 Stroke April 2013 also hypothesized that there may be differences in ICH and IS risk according to study population (Asian versus Western). 9 Methods Search Strategy, Selection Criteria, and Data Extraction PubMed and Embase were searched between January 1, 1999, and July 1, 2012, using medical subject heading (MESH) terms and text words: [ microbleed* OR microh(a)emorrhage* OR h(a)emorrhagic lacune AND [ stroke OR TIA ]. Reference lists from all included articles, relevant review articles, and the authors own files were also searched. Studies were eligible for inclusion if they: included patients with symptomatic IS or TIA; had a prospective design, with 3 months of follow-up; assessed the risk of symptomatic spontaneous ICH or recurrent symptomatic IS (outcomes) during followup; quantified these risks in relation to the presence of CMBs on baseline T2*-GRE MRI; and were published in English. We excluded case control and cross-sectional studies, case reports or case series, population-based studies, and studies in other patient populations (eg, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL], spontaneous or thrombolysis-related ICH, etc.). Prospective cohorts were excluded if the risks of ICH and IS after the baseline event were not described separately. We classified each study population as Asian or Western (white) based on published information describing the dominant ethnicity of subjects included in each cohort. We contacted the corresponding author of publications without adequate published details of population ethnicity. Data Extraction For each study, we extracted data on the country of the study, time period, clinical setting, population size, demographic data (including mean age and sex), use of antithrombotic agents, T2*-GRE MRI parameters, outcome events of interest (spontaneous symptomatic ICH or symptomatic IS, clearly defined according to defined criteria) stratified by CMBs presence. Critical Appraisal and Risk of Bias All included studies were critically appraised against a checklist of key quality indicators that we developed, with reference to the STROBE statement (online-only reference 1), the PRISMA guidelines (online-only reference 2), and the ideal characteristics for a study of CMBs (Table I in the online-only Data Supplement). Statistical Analysis In a fixed-effects meta-analysis, we used the Mantel-Haenszel method to combine the odds ratios (ORs) of ICH or recurrent IS across studies in patients with versus without CMBs. As a sensitivity analysis, we repeated our analyses using random-effects models, but because of the small number of studies (n=10), the estimate of heterogeneity would have had poor precision, and because the results of the fixed-effects models were consistent with the results of the random-effects model, we present the results for the fixed-effects meta-analysis (Table III in the online-only Data Supplement). We assessed heterogeneity using I 2 and x 2 statistics and also visually through inspection of the forest plot and checking for overlapping confidence intervals (CIs). We explored publication bias with funnel plots and the Harbord regression tests for funnel plot asymmetry. Analyses were further stratified by study population ethnic origin (Asian versus Western [white populations]) to see whether the relationships between CMBs and recurrent stroke differed. All analyses were performed using Stata 11.2 (StataCorp LP, TX). We prepared this report with reference to the PRISMA guidelines. Results Ten studies, including a total of 3067 patients (884 with CMBs), met our predefined inclusion criteria and were pooled in meta-analyses (Figure 1). 4,5,7,10 16 The characteristics and methodology of the studies included in this review and key quality indicators are summarized in Table 1 and online-only Tables II and III. Five of the cohorts recruited their patients from Asian populations (China and Japan), 5,12 15 whereas the remaining 5 cohorts were completed in Western (European and North American) centers, mainly including patients of white origin. 4,7,10,11,16 One study included only patients with lacunar infarcts, 12 and one study only patients with TIA. 10 The remaining studies included either patients with IS 5,11,13 15 or with IS and TIA. 4,7,16 In particular, all of the Asian cohorts only included patients with IS, whereas 3 of the Western cohorts included patients with TIA as well as IS (Table 1 and onlineonly Table III). All studies used T2*-GRE MRI to detect CMBs, although imaging parameters, including field strength, echo time, and slice thickness, varied slightly (Table I). The basic demographic and clinical characteristics of the patient cohort in each study are summarized in Table 2. The CMB (+) versus CMB ( ) groups were not significantly different in demographic, clinical, and imaging variables in 2 studies. 7,10 In 5 studies, 4,5,11,13,16 these 2 groups were different in mean age, prevalence of hypertension, previous history of stroke, and burden of white matter changes: in general, patients with CMBs were older, 11,13,16 more often hypertensive, 5,13,16 and with a previous history of stroke, 4,5,13 and more severe white matter changes 4,11,13,16 (Table 2). Only 4 studies provided Figure 1. Flow chart of study selection. Thirty articles were identified for full-text review. Three studies were excluded because they provided insufficient data to quantify the numbers of patients with ischemic stroke or transient ischemic attack with and without cerebral microbleeds (CMBs).

3 Charidimou et al Cerebral Microbleeds and Recurrent Stroke 997 Table 1. Basic Characteristics and Study Design of Included Studies Study Country Ethnicity Type of Patients Follow-Up Time Asian cohorts Mok et al 12 China Chinese Lacunar stroke 5 y Soo et al 13 China Chinese IS 26.6 mo (mean) Huang et al., China Chinese IS mo*** Naka et al 15 Japan Japanese IS 1.54 y Fan et al 5 China Chinese IS 27.5 mo (mean) Western cohorts Fluri et al 10 Switzerland European (white) TIA 3 mo* Thijs et al 4 Belgium European (white) IS/TIA (27%) 2.2 y (median) Gregoire et al 7 UK European (white) IS/TIA (5%) 5.6 y** (mean) Orken et al 11 Turkey European (Turkish) IS 3.94 y (mean) Boulanger et al 16 Canada Canada (90-95% white) IS/TIA (34.3%) 14 mo** (median) ICH indicates intracerebral hemorrhage; IS, ischemic stroke; mo, months; NA, not available; TIA, transient ischemic attack; and y, years. For detailed characteristics, see Table III in the online-only Data Supplement. *Excluded from ICH risk analysis (0 events in both CMB and non-cmb groups). **Excluded from IS risk analysis (0 events in both CMB and non-cmb groups). ***Excluded from IS risk analysis (results not stratified according to CMBs). additional details on CMBs apart from prevalence; only Soo et al 13 and Thijs et al 4 (the largest Asian and Western cohorts, respectively) reported data on the distribution of CMBs (Table IV in the online-only Data Supplement). The overall prevalence of CMBs in all studies was 28.8%. Among patients with CMBs, 99 out of 884 (11.2%) experienced any form of stroke during follow-up, compared with 132 of 2183 (6.1%) patients without CMBs. The pooled OR of any stroke was 2.25 (95%CI, ; P<0.0001) for those with CMBs compared with those without CMBs (Figure 2A). The results were consistent from study to study (test for heterogeneity; P=0.524). Nine studies provided data on the incidence of spontaneous ICH (n=2891; CMBs prevalence, 29.7%): 4,5,7,11 16 among patients with CMBs, 34 of 858 (4%) experienced spontaneous ICH compared with 10 of 2033 (0.5%) patients without CMBs. The pooled OR of spontaneous ICH was 8.52 (95%CI, ; P=0.007) for those with CMBs compared with those without CMBs (Figure 2B). Seven studies provided data on recurrent IS (n=2207; CMBs prevalence, 24.3%). Three studies were excluded from the analysis of IS risk: 1 study 14 did not stratify recurrent IS according to the presence of CMBs; and 2 studies had no events in either the CMB or non-cmb group. In one of these, all patients (most of whom had a cardioembolic source of ischemic stroke) were anticoagulated with warfarin, 11 whereas the other included only 21 patients, factors that likely account for the low IS event rates. 7 Among patients with CMBs, 65 of 573 (11.3%) experienced recurrent IS compared with 122 of 1634 (7.5%) patients without CMBs. The pooled OR of recurrent IS was 1.55 (95%CI, ; P<0.0001) for those with CMBs compared with those without CMBs (Figure 2C). There was no evidence of publication bias for either the spontaneous ICH outcome or IS outcome (Harbord test for bias; P=0.58 and P=0.36, respectively). However, there was evidence of publication bias for data on all strokes combined (Harbord test for bias; P=0.006). Even though no heterogeneity was detected overall, we used meta-regression on studies with sufficient information to see whether certain confounders could have affected our results. No significant heterogeneity was noted according to age, sex, hypertension, previous stroke, or white matter changes for any of the outcomes. To explore the influence of patient ethnic origin on the odds of stroke according to presence of CMBs, we stratified the meta-analysis based on where the cohorts were completed: Asian (mainly Chinese and Japanese populations) versus Western (mainly white; European and North American populations). Among patients with CMBs versus patients without CMBs, the pooled OR of any form of stroke (either spontaneous ICH or IS) during follow-up was 2.19 (95%CI, ; P<0.0001) in 5 Asian cohorts 5,12 15 (n=1915; CMBs prevalence, 33.7%) versus 2.42 (95%CI, ; P=0.001) in 5 Western cohorts (n=1061; CMBs prevalence, 22.5%; Figure 3). The pooled OR of spontaneous ICH observed in Asian cohorts 5,12 15 (n=1915; CMBs prevalence, 33.7%) was (95%CI, ; P<0.0001; Figure 4A). By contrast, there was only weak evidence of an association with future spontaneous ICH in Western cohorts (n=885; CMBs prevalence, 24.1%): pooled OR 3.87 (95%CI, ; P=0.066; Figure 4B). 4,7,11,16 The pooled OR for recurrent IS in Asian cohorts 5,12,13,15 (n=1357; CMBs prevalence, 26.9%) was 1.30 (95%CI, ; P=0.192) compared with 2.23 (95%CI, ; P=0.004) in Western cohorts 4,10,16 (n=899; CMBs prevalence, 22.3%; Figure 4C and 4D). Discussion In our systematic review and meta-analysis of 10 prospective cohorts involving >3000 IS or TIA patients, we found consistent evidence of a significant association between the presence of CMBs at baseline and the risk of any recurrent stroke. The pooled estimates suggest that among all subjects included, the risk is greater for subsequent spontaneous ICH than for recurrent IS.

4 998 Stroke April 2013 Table 2. Characteristics of Patients by Study Study Patient Number (% Men) Mean Age (Years) Major Vascular Risk Factors CMBs reflect previous small areas of blood leakage from pathologically fragile small vessels, 2,3 and it is hypothesized that they may be a potentially powerful marker of future ICH risk. Although some evidence supports this hypothesis, 8 this is largely derived from cross-sectional case control and case case comparisons. The association we found between the presence of CMBs and subsequent ICH risk in our meta-analysis of prospective cohorts provides new and stronger evidence for this hypothesis. Recent studies show that CMBs develop dynamically over time in a significant proportion of patients and healthy elderly individuals. 7,17 Most new CMBs in these studies developed in those patients with CMBs at baseline. It is, thus, possible that in certain circumstances (eg, with the use of antithrombotic drugs), CMBs, rather than being sealed off by normal hemostatic mechanisms and surrounding tissue, may enlarge into a symptomatic ICH. 5 This hypothesis is supported by some data describing incident symptomatic ICH occurring at the site of a previous microbleed. 5,14 Alternatively, CMBs may simply be a general marker of increased small vessel fragility and vulnerability to bleeding. Several lines of evidence support the hypothesis that CMB distribution in the brain reflects the underlying small vessel disease: strictly lobar CMBs reflect CAA, whereas deep CMBs reflect hypertensive arteriopathy. 1,18 The risk of recurrent bleeding after symptomatic ICH seems to be higher for lobar ICH (presumed often because of CAA). 19,20 Lobar CMBs, as HTN AF Hx of IS/TIA Hx of ICH Antithrombotic Users Antiplatelet Users Warfarin Users CMBs Prevalence Significant Differences CMBs (+) vs CMBs ( ) Groups CMBs Independent Predictor of Stroke Risk (IS/ICH)* Asian cohorts Mok et al (52%) % NA 22.7% 96% NA 22.7% NA NA Soo et al (57.7%) NA 68% 73.8% 18.4% 1.3% 92.5% 4.3% 27.8% Mean age: 71.2 vs 67.3; P<0.001 NA/Yes HTN: 79.4% vs 63.7%; P<0.001 Hx of ICH: 3.2% vs 0.65%; P=0.005 Hx IS: 29.8% vs 14%; P<0.001 WMC: 3.6% vs 2.1%; P<0.001 WMC severity (P<0.001) Huang et al (68.7%) % NA NA 0% 100% 0% 38.9% NA NA Naka et al (..) NA NA NA NA NA NA NA 29% NA No/Yes Fan et al (67.8%) % 5% 31.4% 4.1% 80% 5.8% 35.5% Hx of stroke: 62.8% vs 28.2%; P=0.000 NA Hx ICH: 11.6% vs 0%; P=0.005 Hx of ICH+IS: 11.6% vs 6.41%; P=0.021 Western cohorts Fluri et al (60.8%) % 69.9% 0% 0% NA NA 14.8% None NA Thijs et al (61%) 72 64% 21% 13% 32% 26.5% Stroke history: 19% vs 10%; P=0.02 Severe WMC: 63% vs 34%; P< Yes lobar/mixed CMBs and stroke Gregoire et al 7 21 (62%) % NA 23.8% 90% 5% 38.1% None NA Orken et al (57.5%) % NA 18.4% NA 100% 22% Mean age: vs 64.70; P=0.04 WMC: 23% vs 58%; P=0.008 NA Boulanger et al (54%) NA 60.2% 18.2% 23.3% 96.2% 19.1% Age >75 y: 68.9 vs 39.8; P<0.001 HTN: 80% vs 55.5%; P=0.003 Diabetes mellitus: vs 13.6%; P=0.01 Confluent WMC: 68.9% vs 30.4; P<0.001 Yes stroke AF indicates atrial fibrillation; CMBs, cerebral microbleeds; HTN, hypertension; ICH, intracerebral hemorrhage; IS, ischemic stroke; NA, not available; and WMC, white matter changes. *After adjusting for baseline variables likely to affect the risk of ischemic stroke and intracerebral hemorrhage. a putative CAA marker, may thus be a stronger risk factor for ICH than deep CMBs, at least in some populations, but definitive data are lacking. We were not able to investigate this question in the current study because of a lack of published data reporting the effect of CMB distribution on stroke risk. Our meta-analysis showed that the presence of CMBs is also associated with an increased risk of future IS, although the patient numbers and the magnitude of the effect size were lower compared with ICH risk (OR, 1.55; 95%CI, ; P<0.0001). CMBs are associated with risk factors for small vessel disease, including hypertension, aging, lacunar infarcts, and leukoaraiosis, 1 which are themselves risk factors for both spontaneous ICH and IS. The association of CMBs with both future symptomatic ICH and IS creates a clinical dilemma concerning the use of antithrombotic agents in patients with CMBs. Further studies evaluating the relative effects of CMB burden on future ICH and IS risk are needed to determine whether a certain CMB load might tip the risk benefit balance in favor of avoiding antithrombotic treatment. Lovelock et al demonstrated an excess of CMBs in warfarin users compared with nonantithrombotic users (OR, 8.0; 95%CI, ; P=0.01) and in warfarin-related ICH versus spontaneous ICH (OR, 2.7; 95%CI, ; P<0.001). 8 However, our systematic review found no large prospective studies of CMBs in IS cohorts treated with anticoagulants for atrial fibrillation. Recent indirect evidence implicates CAA as a risk for anticoagulation-related ICH, 21,22 so multiple lobar

5 Charidimou et al Cerebral Microbleeds and Recurrent Stroke 999 Figure 2. Meta-analysis of effect of cerebral microbleeds (CMBs) on the risk of all stroke (A), spontaneous intracerebral hemorrhage (ICH; B), and ischemic stroke (C). CMBs merit particular investigation as a means of refining anticoagulation treatment decisions. Our analysis stratified by Asian and Western cohorts raises the possibility that the relative risks of ICH and IS in the presence of CMBs might vary across ethnic subgroups. The risk of ICH associated with CMBs was higher in Asian compared with Western cohorts (Figure 4). By contrast, the increased risk of IS was statistically significant only in Western cohorts (Figure 4). Of note, all Asian cohorts included patients with IS only, whereas 3 of the Western cohorts included patients with IS as well as TIA. Nevertheless, IS patients constituted the majority of patients in these Western cohorts 4,7,16 ( 70%), so it is unlikely that this difference substantially influenced our results. Because of the limited number of patients and

6 1000 Stroke April 2013 Figure 3. Meta-analysis of the risk of all stroke (A and B) stratified by the dominant ethnicity of subjects included in each cohort as Asian or Western (white), with and without cerebral microbleeds (CMBs). outcome events for these subanalyses, the CIs for effects were wide. Our findings are thus hypothesis-generating, and suggest this as an important topic for further study. The differences between Asian and Western cohorts may reflect differences in the type or severity of small vessel disease. In a European hospital cohort of 487 patients with TIA or IS, patients with CMBs had a higher risk of future IS, but not ICH; 4 only strictly lobar or mixed CMBs increased the risk of recurrent stroke (P=0.018). 4 Moreover, CMBs were more often found in a mixed or strictly lobar distribution, indicating a high prevalence of CAA. 4,22 By contrast, in the largest Asian study, CMBs were most commonly deep suggesting that hypertensive arteriopathy was the predominant small vessel pathology (Table IV). 13 Another large-scale prospective study (mean follow-up, 3.6 years) of 2102 healthy elderly individuals in Japan found that CMBs were more strongly associated with ICH (hazard ratio, 50.2; 95%CI, ) than IS (hazard ratio, 4.48; 95%CI, ); 23 all ICHs were deep and were associated with deep CMBs. 23 These findings are in line with the higher prevalence of hypertensive arteriopathy rather than CAA in Asia. 9 Figure 4. Meta-analysis of the risk of spontaneous intracerebral hemorrhage (ICH; A and B) and ischemic stroke (C and D) stratified by the dominant ethnicity of subjects included in each cohort as Asian or Western (white), with and without cerebral microbleeds (CMBs).

7 Charidimou et al Cerebral Microbleeds and Recurrent Stroke 1001 Our systematic review and meta-analysis has limitations. Some studies were not specifically designed to answer our study question, 14 and some had a small sample size, variable follow-up, and few outcome events, leading to wide CIs around risk estimates. Studies used varied imaging parameters, for example the echo time, potentially affecting the detection of CMBs, 18 although the prevalence of CMBs was fairly consistent across studies. Furthermore, studies are subject to selection bias because not all stroke patients undergo T2*-GRE. Most studies to date have not used standardized rating scales for CMBs. Few studies have reported on recurrent stroke risk in relation to CMB number and anatomic location. We found evidence of possible publication bias in the included studies for overall stroke risk, but not for future ICH and IS, when considered separately; the latter result may reflect limited sample sizes for the individual end points. Finally, a potentially important limitation is possible confounding because of lack of adjustment for other baseline variables related to future stroke risk (eg, antithrombotic drug use, hypertension, age) in some studies. Nevertheless, all studies showed a consistent direction of association between CMBs and recurrent stroke, even when adjusted for these potential confounders. Furthermore, CMB (+) and CMB ( ) groups had similar antithrombotic profiles on discharge, making use of these drugs unlikely to be a sufficient explanation for the increased ICH risk associated with CMBs. Sources of Funding This work was supported by the Greek State Scholarship Foundation (A.C.), Stroke Association, British Heart Foundation, and the Department of Health/Higher Education Funding Council for England (A.C., D.J.W.). This work was undertaken at UCLH/UCL, which received a portion of funding from the Department of Health NIHR Biomedical Research Centres funding scheme. None. Disclosures References 1. 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: Shoamanesh A, Kwok CS, Benavente O. Cerebral microbleeds: histopathological correlation of neuroimaging. Cerebrovasc Dis. 2011;32: Fazekas F, Kleinert R, Roob G, Kleinert G, Kapeller P, Schmidt R, et al. 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