In patients with spontaneous intracerebral hemorrhage

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1 Incident Cerebral Microbleeds in a Cohort of Intracerebral Hemorrhage Marta Pasquini, MD; Marije R. Benedictus, MSc; Grégoire Boulouis, MD; Costanza Rossi, PhD; Nelly Dequatre-Ponchelle, MD; Charlotte Cordonnier, PhD Background and Purpose We aimed to identify prognostic and associated factors of incident cerebral microbleeds (CMBs) in intracerebral hemorrhage (ICH) survivors. Methods Observational prospective cohort of 168 ICH survivors who underwent 1.5T magnetic resonance imaging at ICH onset and during follow-up (median scan interval, 3.4; interquartile range, ) years. We used logistic regression adjusted for age, sex, and scan interval. Analyses were stratified according to the index ICH location (58 lobar ICH, 103 nonlobar ICH, excluding patients with multiple or unclassifiable ICH). Results Eighty-nine (53%) patients had CMBs at ICH onset, and 80 (48%) exhibited incident CMBs during follow-up. Predictors of incident CMBs at ICH onset were 1 CMBs (adjusted odds ratio [aor], 2.27; 95% confidence interval [CI], ), old radiological macrohemorrhage (aor, 6.78; 95% CI, ), and CMBs in mixed location (aor, 3.73; 95% CI, ). When stratifying by ICH location, incident CMBs were associated in nonlobar ICH with incident lacunes (aor, 2.86; 95% CI, ) and with the use of antiplatelet agents (aor, 2.89; 95% CI, ). In lobar ICH, incident CMBs were associated with incident radiological macrohemorrhage (aor, 9.76; 95% CI, ). Conclusions Prognostic and associated factors of incident CMBs differed according to the index ICH location. Whereas in lobar ICH, incident CMBs were associated with hemorrhagic biomarkers, in nonlobar ICH, ischemic burden also increased. CMBs may be interesting biomarkers to monitor in randomized trials on restarting antithrombotic drugs after ICH. (Stroke. 2016;47: DOI: /STROKEAHA ) Key Words: antithrombotic drugs cerebral hemorrhage cerebral microbleeds cohort studies magnetic resonance imaging In patients with spontaneous intracerebral hemorrhage (ICH), cerebral microbleeds (CMBs) are highly prevalent. 1 Their presence and number have been associated with a higher risk of recurrent ICH among ICH survivors 2,3 and with a higher risk of ICH among ischemic stroke survivors. 4 Furthermore, some evidence suggests that CMBs may increase the risk of antithrombotic-associated ICH: a systematic review of 1460 patients with ICH found that CMBs were almost twice as common at the time of ICH in people using warfarin versus those not using any type of antithrombotic drug. 5 This has led to consider CMBs as markers of bleeding-prone vasculopathies 6 and to avoid the use of antithrombotic drugs in patients with CMBs. 7 However, whether CMBs really increase the risk of antithrombotic-associated ICH remains uncertain. Before using CMBs as a surrogate marker of recurrent ICH, and avoiding therapies of proven benefit, prognostic and associated factors of incident CMBs should be better understood. Indeed, although incident CMBs have been associated with a higher risk of recurrent ICH in lobar ICH, 2 little is known about nonlobar ICH, and the influence of antithrombotic drugs may differ in these 2 groups of patients. Therefore, we studied prognostic factors of incident CMBs in an observational prospective ICH cohort with longterm follow-up, stratifying the analysis according to the index ICH location. Patients and Methods We included patients from The Prognosis of Intracerebral Hemorrhage (PITCH) cohort study, 8 an ongoing observational study that prospectively recruited consecutive adults admitted with ICH to the emergency department of Lille University Hospital from November 2004 to April 2009 in Lille, France (n=560). We excluded patients with purely intraventricular or extra-axial intracranial hemorrhage, with ICH attributable to a secondary cause of ICH (intracranial vascular malformation, head trauma, tumor or hemorrhagic transformation within a cerebral infarct, or congenital coagulopathies), and with no reliable data on ongoing treatment at presentation, discharge, or during follow-up. For this study, our inclusion criteria were (1) survival Received October 15, 2015; final revision received December 21, 2015; accepted December 24, From the Univ. Lille, Inserm, CHU Lille, U 1171, Degenerative and vascular cognitive disorders, Lille, France, (M.P., G.B., C.R., N.D.-P., C.C.); Department of Neurology, Groupement des Hôpitaux de l Institut Catholique de Lille, Saint Philibert Hospital, Lille, France (M.P.); and Alzheimer Center and, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands (M.R.B.). Correspondence to Charlotte Cordonnier, PhD, Univ. Lille, Inserm, CHU Lille, U 1171, Degenerative and Vascular Cognitive Disorders, F Lille, France. charlotte.cordonnier@chru-lille.fr 2016 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 690 Stroke March 2016 for at least 6 months after ICH and (2) at least 2 brain magnetic resonance imaging (MRI). At baseline, we prospectively collected demographic characteristics, vascular risk factors (arterial hypertension, diabetes mellitus, smoking, excessive alcohol consumption, and atrial fibrillation), and past medical history (ischemic stroke or transient ischemic attack, ICH, ischemic heart disease, and dementia). Definitions were previously published. 8 We recorded antithrombotic drugs use according to type (antiplatelet agents, oral anticoagulants, or both) and assessed the use of these drugs at presentation and hospital discharge. Follow-up visit was scheduled for all survivors (first at 6 months, then every year). At each follow-up visit, we recorded the use of antithrombotic drugs, blood pressure lowering drugs, and statins. Blood pressure was measured manually at each visit. Brain MRI was performed at presentation and during follow-up unless contraindicated. Main variables of interest were available for all patients. The design of the PITCH cohort is in line with the Strengthening the Reporting of Observational Studies in Epidemiology statement. 9 Radiological Assessment All MRIs were rated by a study investigator with expertise in stroke and training in neuroradiology, blinded to clinical data and time points. For the present analysis, we considered the first MRI performed after the index ICH (median [interquartile range {IQR}] delay, 7 [4 14] days after ICH) and the MRI performed at the latest visit or the closest to time of death (follow-up MRI, median [IQR] scan interval, 3.4 [ ] years). At each time point, we performed an identical MRI protocol with identical acquisition parameters using a 1.5 Tesla scanner (GE Healthcare, Milwaukee, WI) including at least T1-weighted, Fluid-Attenuated Inversion Recovery, and T2* Gradient-Echo weighted sequences (echo time, 22.8 ms; repetition time, 700 ms; flip angle, 25 ; field of view, 250 mm; matrix ; slice thickness, 5 mm; and interslice gap, 1.5 mm). On each MRI, we recorded ICH location, classified as (1) lobar when exclusively involving the cerebral hemispheres superficial to the deep gray matter structures; (2) nonlobar when exclusively involving lenticular or caudate nuclei, thalamus, internal or external capsule, brain stem, or cerebellum; (3) unclassifiable when the origin of the bleeding could not be reliably identified, (4) multiple if there were >1 ICH at presentation. We assessed global cortical atrophy using a 4-point rating scale 10 (dichotomized: absent [0 1] or present [2 3]) and white matter hyperintensities using the Fazekas scale, 11 a 4-point rating scale (dichotomized: absent [0 1] or present [2 3]). The term lacune was used to describe scars of lacunar infarctions and referred to deep, subcortical, or pontine ovoid lesions (3 15 mm) with cerebrospinal fluid like signal with or without a hyperintense fluid-attenuated Inversion Recovery border 12 (pragmatic consensus was obtained to differentiate lacunes from dilated perivascular spaces in problematic cases). Lacunes were scored as present or absent. The presence, number, and location (lobar versus nonlobar) of old radiological macrohemorrhages (>10 mm) other than the index ICH were also recorded. CMBs were defined as round foci of hypointense signal, 10 mm in brain parenchyma on T2* Gradient-Echo weighted images and rated using the Brain Observer MicroBleed Scale. 13 CMBs presence was defined as the presence of at least 1 CMB, and their location was classified as strictly lobar (when involving the cortex, the gray white matter junction, and the subcortical white matter), nonlobar (when involving the basal ganglia, internal capsule, or posterior fossa), or mixed when involving both lobar and nonlobar structures. Incident CMBs were defined as a difference of 1 in the number of CMBs between the 2 MRIs. The same definition was used for incident lacunes. We found less CMBs at follow-up when compared with the MRI at ICH onset in 15 patients. These patients were added to the group of no incident CMBs. 14 We defined global cortical atrophy and white matter hyperintensities progression as any change in category from MRI at ICH onset to follow-up MRI. We recorded the appearance of new radiological macrohemorrhage. Statistical Analysis To determine whether survivors at 6 months with follow-up MRI differed from those for whom follow-up MRI was not available, we compared the main baseline characteristics and initial clinical severity between those 2 groups, using χ 2 test for categorical variables and Mann Whitney U test for continuous variables (data not shown). We investigated characteristics associated with the incidence of CMBs during follow-up using bivariate logistic regression analysis, then adjusted for age, sex, and scan interval. Then, we stratified our analyses according to the index ICH location (lobar/nonlobar) because of the potential influence of the underlying vasculopathy (mostly cerebral amyloid angiopathy in lobar ICH and mostly deep perforating vasculopathy in nonlobar ICH). We performed statistical analyses with the SPSS 22.0 (windows). Ethics The study protocol was considered as observational by the internal review board of the Lille University Hospital. No written consent was requested. The database was declared to the ad hoc commission protecting personal data. Results From the original PITCH cohort, 264 patients were alive 6 months after ICH onset. Eighty-two patients were excluded because they could not undergo MRI (Figure 1). Of the remaining 182 patients, 168 had at least 2 MRIs of good quality and were included in our study. The excluded patients were more likely to be older, to have a history of previous ICH, and to be demented at the time of ICH onset when compared with patients in the follow-up group (data not shown). Baseline severity of neurological deficit was similar in the 2 groups of patients. Baseline Characteristics Among 168 patients (median age, 64 years; IQR, 53 76), 89 patients (53%) had at least 1 CMBs at baseline (median number of CMBs in patients with at least 1 CMBs [IQR], 4 [ ]), of whom 18 (20%) had strictly lobar CMBs, 25 (28%) had strictly nonlobar CMBs, and 46 (52%) had CMBs in mixed location. The number of CMBs in the whole brain area ranged from 0 to 53. The anatomic distribution and number of CMBs were similar in patients with lobar and nonlobar ICH (P=0.83 and P=0.36, respectively; Table 1). Incidence of CMBs Incident CMBs appeared in 80 patients (48%; 95% confidence interval [CI], 40% 55%) in a median delay of 3.4 (IQR, Figure 1. Flowchart of the study population. ICH indicates intracerebral hemorrhage; and MRI, magnetic resonance imaging.

3 Pasquini et al Incident Microbleeds After ICH ) years (including 29 patients without CMBs at ICH onset), with a total number of 285 new CMBs, leading to an incidence rate of 14.2 per 100 person-years. The rate of increase in the number of CMBs was 0.5 lesions per year in the overall cohort, a number which increased to 0.7 lesions per year in patients with CMBs at baseline. Among patients with lobar ICH (n=58), 26 patients (45%; 95% CI, 32 58) had incident CMBs, of whom 8 (31%; 95% CI, 12 50) had strictly lobar incident CMBs, 11 (42%; 95% CI, 22 63) strictly nonlobar CMBs, and 7 (27%; 95% CI, 9 45) had incident CMBs in mixed location. Among patients with nonlobar ICH (n=103), 50 (48%; 95% CI, 39 58) had incident CMBs, of whom 10 (20%; 95% CI, 8 31) had strictly lobar incident CMBs, 24 (48%; 95% CI, 34 62) had strictly nonlobar CMBs, and 16 (32%; 95% CI, 19 45) had incident CMBs in mixed location. Prognostic Factors of Incident CMBs The results of the bivariate and multivariable analyses comparing patients with and without incident CMBs are summarized in Table 1. Patients with CMBs at ICH onset had a 2.5-fold increased risk of developing incident CMBs during the followup period when compared with patients without CMBs at ICH onset (adjusted odds ratio [aor], 2.27; 95% CI, ). This was especially true for patients with multiple CMBs at baseline (Figure 2). Patients with incident CMBs were more likely to exhibit CMBs in mixed location (aor, 3.73; 95% CI, ) and old radiological macrohemorrhages (aor, 6.78; 95% CI, ) at ICH onset. Although the use of antiplatelet agents during follow-up was associated with incident CMBs in bivariate analysis (OR, 2.11; 95% CI, ), this result failed to reach significance (aor, 1.80; 95% CI, ) when adjusted with age, sex, and scan interval. When stratifying patients according to the index ICH location (lobar and nonlobar), some differences emerged (Tables 2 and 3). The influence of antiplatelet agent use during followup for incident CMBs was significant in patients with nonlobar ICH (aor, 2.89; 95% CI, ), but not in patients with lobar ICH (aor, 0.89; 95% CI, ). Of note, the proportion of antiplatelet agent use was similar in lobar and nonlobar ICH (31% and 32%, respectively; P=0.89). In patients with nonlobar ICH, incident CMBs were associated with incidence of new lacunes (aor, 2.86; 95% CI, ), whereas in patients with lobar ICH, incident CMBs were associated with the appearance of new radiological Table 1. Factors Associated With the Incidence of CMBs in ICH Patients No Incident CMBs (n=88) Incident CMBs (n=80) OR aor (Age, Sex, and Scan Interval) Past medical history History of arterial hypertension 55 (62) 50 (62) 1.00 ( ) 0.96 ( ) ICH 3 (3) 4 (5) 1.49 ( ) 1.60 ( ) Dementia 9 (10) 4 (5) 0.47 ( ) 0.43 ( ) Ischemic stroke or TIA 8 (9) 12 (15) 1.76 ( ) 1.78 ( ) Median (IQR) SBP during follow-up 130 ( ) 133 ( ) 0.99 ( ) 1.00 ( ) Median (IQR) DBP during follow-up 70 (60 75) 72 (69 77) 1.02 ( ) 1.02 ( ) Medication during follow-up Statins 37 (42) 41 (51) 1.45 ( ) 1.10 ( ) Antiplatelets 22 (25)* 33 (41)* 2.11 ( )* 1.80 ( ) Oral anticoagulants 13 (15) 12 (15) 1.02 ( ) 0.81 ( ) Radiological characteristics WMH severity at ICH onset 1.87 ( )* 2.13 ( )* (57)* 33 (41)* (43)* 47 (59)* WMH progression 14 (16) 14 (17) 1.11 ( ) 0.87 ( ) GCA severity at ICH onset 0.93 ( ) 0.98 ( ) (56) 46 (57) (44) 34 (43) GCA progression 15 (17)* 24 (30)* 2.09 ( )* 1.61 ( ) Presence of lacunes at ICH onset 28 (32) 37 (46) 1.84 ( ) 2.02 ( )* Incident lacunes on follow-up MRI 18 (20) 21 (26) 1.38 ( ) 1.40 ( ) Presence of CMBs at ICH onset 38 (43)* 51 (64)* 2.31 ( )* 2.27 ( )* Presence of old macrohemorrhage at ICH onset 8 (9)* 30 (37)* 6.00 ( )* 6.78 ( )* New macrohemorrhage on follow-up MRI 3 (3) 9 (11) 3.64 ( ) 3.56 ( ) Results from bivariate and multivariate analyses. Values in the second and third columns represent number of patients (%) unless specified. aor indicates adjusted odds ratio; CMBs, cerebral microbleeds; DBP, diastolic blood pressure; GCA, global cortical atrophy; ICH, intracerebral hemorrhage; IQR, interquartile range; MRI, magnetic resonance imaging; OR, odds ratio; SBP, systolic blood pressure; TIA, transient ischemic attack; and WMH, white matter hyperintensities.

4 692 Stroke March 2016 Figure 2. Proportion of patients with incident cerebral microbleeds (CMBs) according to number of CMBs at intracerebral hemorrhage (ICH) onset. macrohemorrhage (aor, 9.76; 95% CI, ), which occurred only in lobar location. Discussion In our longitudinal observational ICH cohort, 48% (95% CI, 40 55) of patients exhibited incident CMBs over a 3.4-year interval between MRIs. Prognostic and associated factors of incident CMBs differed according to the index ICH location. In nonlobar ICH, incident CMBs were associated with incident lacunes (aor, 2.86; 95% CI, ) and with the use of antiplatelet agents during follow-up (aor, 2.89; 95% CI, ), whereas in lobar ICH, incident CMBs were associated with incident radiological macrohemorrhages (aor, 9.76; 95% CI, ). These results suggest an implication of the nature of the underlying vessel disease that eventually led to the index ICH. The strength of our study was to provide long-term MRI follow-up data in a large cohort of ICH survivors. Data were collected prospectively, with rigorous information on treatment and standardized predefined MRI analyses. Although our cohort is hospital based, the baseline characteristics of our population were similar to those of a population-based registry, consistent with recommendations on observational studies, 9 providing reassurance on the external validity of our results. Because of the longitudinal, observational design of this study, the time point of last follow-up MRI was not standardized. A possible limitation of the study is that selective dropout may have influenced our results. People who participated were younger and healthier than Table 2. Factors Associated With the Incidence of CMBs in the 103 Patients With Nonlobar ICH No Incident CMBs (n=53) Incident CMBs (n=50) OR aor (Age, Sex, and Scan Interval) Past medical history History of arterial hypertension 35 (66) 33 (66) 1.00 ( ) 0.91 ( ) ICH 1 (2) 2 (4) 2.17 ( ) 1.60 ( ) Dementia 3 (6) 3 (6) 1.09 ( ) 0.96 ( ) Ischemic stroke or TIA 3 (6)* 10 (20)* 4.17 ( )* 3.74 ( ) Median (IQR) SBP during follow-up 130 ( ) 133 ( ) 0.99 ( ) 0.99 ( ) Median (IQR) DBP during follow-up 79 (72 85) 78 (74 85) 1.01 ( ) 1.01 ( ) Medication during follow-up Statins 19 (36)* 30 (60)* 2.68 ( )* 1.92 ( ) Antiplatelets 10 (19)* 23 (46)* 3.66 ( )* 2.89 ( )* Oral anticoagulants 6 (11) 9 (18) 1.72 ( ) 1.71 ( ) Radiological characteristics WMH severity at ICH onset 1.65 ( ) 1.67 ( ) (58) 23 (46) (42) 27 (54) WMH progression 9 (17) 8 (16) 0.91 ( ) 0.61 ( ) GCA severity at ICH onset 1.19 ( ) 0.71 ( ) (62) 29 (58) (38) 21 (42) GCA progression 7 (13)* 16 (32)* 3.09 ( )* 2.17 ( ) Presence of lacunes at ICH onset 20 (38) 27 (54) 1.94 ( ) 2.17 ( ) Incident lacunes on follow-up MRI 8 (15)* 16 (32)* 2.65 ( )* 2.86 ( )* Presence of CMBs at ICH onset 21 (40) 29 (58) 2.10 ( ) 1.88 ( ) Presence of old macrohemorrhage at ICH onset 4 (7)* 18 (36)* 6.89 ( )* 6.96 ( )* New macrohemorrhage on follow-up MRI 2 (4) 2 (4) 1.08 ( ) 1.24 ( ) Results from bivariate and multivariable analyses. Values in the second and third columns represent number of patients (%) unless specified. aor indicates adjusted odds ratio; CMBs, cerebral microbleeds; DBP, diastolic blood pressure; GCA, global cortical atrophy; ICH, intracerebral hemorrhage; IQR, interquartile range; MRI, magnetic resonance imaging; OR, odds ratio; SBP, systolic blood pressure; TIA, transient ischemic attack; and WMH, white matter hyperintensities.

5 Pasquini et al Incident Microbleeds After ICH 693 Table 3. Factors Associated With the Incidence of CMBs in the 58 Patients With Lobar ICH No Incident CMBs (n=32) those who were ineligible for a follow-up MRI scan. In this case, we may have slightly underestimated the true incidence of CMBs in our cohort. In our subgroup analyses on lobar and nonlobar ICH, we dealt with smaller numbers of patients; therefore, our results should be interpreted with caution. Finally, this study was observational, so conclusions cannot be drawn on the causal relationship between antiplatelet drugs and incident CMBs. In our cohort of ICH survivors, the incidence of new CMBs reached 48% over 3.4 years of follow-up when compared with 18% over 2 years in patients with lacunar strokes. 15 In the general population, cumulative incidences of CMBs ranged from 6.9% over a 4-year period 16 to 10% over a 3-year period, 14 whereas in a memory clinic population, an incidence of 12% was reported (follow-up interval, 1.9 years). 17 The higher incidence in our study probably reflects the manifest small-vessel pathology present in all our ICH patients. In small series of patients with primary ICH, with a shorter follow-up, similar incidence rates (30% 50%) were reported. 2,3,18,19 Higher blood pressure levels were considered as prognostic factors of incident CMBs in ischemic stroke survivors 15,20 and in a cohort of essential hypertensive patients. 21 In our ICH cohort, Incident CMBs (n=26) OR aor (Age, Sex, and Scan Interval) Past medical history History of arterial hypertension 19 (60) 15 (58) 0.93 ( ) 0.87 ( ) ICH 2 (6) 1 (4) 0.60 ( ) 0.69 ( ) Dementia 6 (19) 1 (4) 0.17 ( ) 0.14 ( ) Ischemic stroke or TIA 5 (16) 2 (8) 0.45 ( ) 0.46 ( ) Median (IQR) SBP during follow-up 127 ( ) 134 ( ) 1.01 ( ) 1.02 ( ) Median (IQR) DBP during follow-up 73 (67 75) 75 (70 85) 1.04 ( ) 1.05 ( ) Medication during follow-up Statins 16 (50) 10 (38) 0.62 ( ) 0.49 ( ) Antiplatelets 10 (31) 8 (30) 0.98 ( ) 0.89 ( ) Oral anticoagulants 7 (21) 3 (11) 0.47 ( ) 0.35 ( ) Radiological characteristics WMH severity at ICH onset 2.25 ( ) 2.82 ( ) (50) 8 (31) (50) 18 (69) WMH progression 5 (16) 6 (23) 1.62 ( ) 1.53 ( ) GCA severity at ICH onset 1.70 ( ) 1.86 ( ) (41) 14 (54) (59) 12 (46) GCA progression 8 (25) 7 (27) 1.10 ( ) 1.08 ( ) Presence of lacunes at ICH onset 8 (25) 9 (35) 1.59 ( ) 1.61 ( ) Incident lacunes on follow-up MRI 10 (31) 3 (11) 0.29 ( ) 0.28 ( ) Presence of CMBs at ICH onset 16 (50) 19 (73) 2.71 ( ) 2.70 ( ) Presence of old macrohemorrhage at ICH onset 3 (9)* 11 (42)* 7.09 ( )* 9.36 ( )* New macrohemorrhage on follow-up MRI 1 (3)* 6 (23)* 9.30 ( )* 9.76 ( )* Results from bivariate and multivariable analyses. Values in the second and third columns represent number of patients (%) unless specified. aor indicates adjusted odds ratio; CMBs, cerebral microbleeds; DBP, diastolic blood pressure; GCA, global cortical atrophy; ICH, intracerebral hemorrhage; IQR, interquartile range; MRI, magnetic resonance imaging; OR, odds ratio; SBP, systolic blood pressure; TIA, transient ischemic attack; and WMH, white matter hyperintensities. we did not report such a prognostic factor. Our larger study sample 15,20 with higher incidence of CMBs 21 could explain this difference. Moreover, we used mean values of blood pressure measured during each follow-up visit, which may better reflect blood pressure control during follow-up, whereas other studies mainly focused on blood pressure levels at baseline. Because of the regular follow-up by a stroke neurologist, we achieved a relatively good blood pressure control, which could also explain the lack of association. The presence and number of CMBs, and the presence of old radiological macrohemorrhages at ICH onset, predicted incident CMBs. This is consistent with results from previous studies. 2,14,15,19,21 Interestingly, prognostic and associated factors differed according to the ICH location, suggesting an impact of the nature of the underlying vessel disease. In lobar ICH, incident CMBs were associated with incident new radiological macrohemorrhage, which confirms previous result 2 and suggests that incident CMBs are markers of a bleedingprone vasculopathy when associated with lobar ICH, although the small numbers of events must lead to caution. By contrast, in nonlobar ICH, incident CMBs were associated with incident lacunes, suggesting that ischemic and hemorrhagic

6 694 Stroke March 2016 burden both increased. In the overall cohort, we found a trend for the association with antiplatelet use during follow-up and incident CMBs, which was significant only in nonlobar ICH. However, no inference can be made about a causal relationship because incident CMBs may reflect the evolution of the underlying vessel disease requiring antiplatelet agents. In conclusion, incident CMBs frequently appeared during follow-up. Prognostic and associated factors of incident CMBs differed according to the index ICH location. Although in patients with lobar ICH, incident CMBs were associated with hemorrhagic-prone biomarkers, in patients with nonlobar ICH, the meaning of CMBs progression is not as straightforward because ischemic burden also increased. Therefore, CMBs may be interesting surrogate biomarkers to monitor in future randomized clinical trial addressing the question of restarting, or not, antithrombotic drugs after ICH. Sources of Funding M.R. Benedictus was supported by a fellowship of Alzheimer Nederland (WE ). Disclosures Drs Rossi and Dequatre-Ponchelle were investigators in clinical trials (Pfizer, Pierre Fabre). Dr Cordonnier was investigator in clinical trials (Pfizer, Pierre Fabre, and Astra-Zeneca). She serves on scientific boards for Bayer. She is a member of the Institut Universitaire de France. There was no personal funding for any of the authors. The other authors report no conflicts. References 1. 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 Greenberg SM, Eng JA, Ning M, Smith EE, Rosand J. Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage. Stroke. 2004;35: doi: /01. STR e. 3. Jeon SB, Kang DW, Cho AH, Lee EM, Choi CG, Kwon SU, et al. Initial microbleeds at MR imaging can predict recurrent intracerebral hemorrhage. 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