Differential impact of smoking on intracerebral haemorrhage based on cerebral microbleed status: a case-control study.

Background: Among patients with ischemic stroke, a link between chronic kidney disease (CKD) and presence of MRI-defined cerebral microbleeds (CMB), a harbinger of future hemorrhagic stroke, has been reported. However, the association of CKD with CMB among patients with intracerebral hemorrhage (ICH) has not been systematically investigated. The objective of this analysis was to evaluate the relationship between CKD and CMB in a biracial cohort of patients with ICH. Methods: Using data from subjects with a recent ICH enrolled in a NIH-sponsored observational study between September 2007, and June 2011, we evaluated the association between CKD (defined as estimated low glomerular filtration rate (GFR) <60 ml/min per 1.73 m 2 ) and CMB. The number and location of CMBs were identified on gradient-echo T2*-weighted magnetic resonance imaging. Multivariable models were generated to determine the contribution of CKD to the presence, number, and location of CMB after adjusting for confounders (age, sex, systolic BP, history of hypertension, antihypertensive drug use, and diabetes). Results: Of 162 subjects with complete data, mean age was 59 years, 44% were female, 74% were Black, 97 (60%) had 1 or more CMBs and 47 (29%) had CKD. In univariate analyses, subjects with CKD differed from those without CKD (p<0.1): history of hypertension (100% vs. 81%), history of diabetes (34% vs. 21%), on antihypertensive drug (74% vs. 51%), on renin-angiotensin system [RAS] modulator (44% vs. 26%), higher systolic BP (186 vs. 173 mmHg), presence of CMB (75% vs. 54%), number of deep located CMB (62% vs. 44%), number of deep located CMB (median, IQR: 2 {0, 3} vs. 0 {0, 2}), and size of index ICH (median, IQR: 7.5 {2.3, 29.7} vs. 13.8 {5.2, 34.2}). Overall, CKD was independently associated with presence of CMB (adjusted OR 2.29, 95% CI: 1.00-5.22, p=0.049) and number of CMB (adjusted RR 1.91, 95% CI: 1.08-3.38, p=0.027). There was also a borderline interaction between RAS drug use and CKD for number (i.e. fewer CMB) but not presence of CMB (p=0.09). In Black subjects CKD was associated with CMB presence (adjusted OR 3.11, 95% CI: 1.47-6.59) and number (adjusted RR 3.43, 95% CI:1.22-9.67), but not CMB presence (adjusted OR 2.00, 95% CI:0.37-10.92) or number (adjusted RR 1.56, 95% CI:0.25-9.78) in Non-Hispanic White subjects (interactions by race: p=0.84 and 0.74 respectively). Conclusions: CKD is associated with presence, number and location of CMB in ICH patients. These relationships are more pronounced in Black compared to Non-Hispanic White ICH patients. Low GFR may be a CMB risk marker or potential therapeutic target for mitigating the development of CMB. Further investigation is required to see if RAS modulators may have a role to play in ameliorating CMB occurrence.

Clinical Relevance of Cerebral Small Vessel Diseases.

Background: Cerebral microbleeds (CMBs) are associated with incident dementia, but the impact of specific CMB patterns is unclear. CMBs in lobar regions suggest cerebral amyloid angiopathy (CAA), which is sometimes accompanied by superficial siderosis (SS), while subcortical CMBs indicate hypertensive origins. This study investigates the association between CMB patterns and dementia risk in the community-based longitudinal Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Methods: All ARIC-NCS participants with a 3T research MRI at visit 5 (2011-13; aged 67-90) without intracerebral hemorrhage or dementia were included. CMB and SS presence and location were coded from T2* GRE sequences. Individuals were classified into one of four patterns: no CMBs, only subcortical, mixed (lobar and/or SS + subcortical), and only lobar and/or SS. Incident dementia diagnoses were defined by cognitive testing (in-person and telephone), informant interviews, and hospital discharge codes or death certificates. Cox proportional-hazards models assessed the association between the presence, patterns, and frequency of CMBs (0,1,2,3+), presence of SS, and incident dementia from visit 5 through 2020. Model covariates included demographics, vascular risk factors, and imaging markers of small vessel disease. Results: Among 1609 participants, 364 had CMBs (Table 1). Participants with CMBs tended to be older and female compared to those without CMBs. Compared to individuals with no CMBs, presence of any CMBs was associated with an increased risk of dementia (Table 2). Compared to individuals without CMBs, individuals with only lobar CMBs and/or SS had an increased risk of incident dementia, as did individuals with mixed CMBs, but individuals with subcortical-only did not. Participants with ≥3 CMBs of any variant had an increased risk of incident dementia vs no CMBs. Although SS was infrequent, its presence (vs no SS) was associated with an elevated risk of dementia. Conclusion: CMBs, particularly in a mixed or lobar and/or SS-only pattern, are linked to an increased risk of incident dementia. The number of recurrent CMBs and any SS also showed an increased dementia risk. These data support that dementia risk is high in individuals with a CAA-type CMB pattern, but also emphasize that a mixed pattern, not typical of CAA alone, is associated with a high risk of dementia. Further studies should evaluate mechanisms by which these different patterns contribute to dementia.

Antiplatelet therapy and future intracerebral hemorrhage in hemodialysis patients with cerebral microbleeds

Background and Purpose: Cerebral microbleed (CMB) in the lobar region is regarded as an image marker for cerebral amyloid angiopathy (CAA), but it is sometimes encountered in patients with intracerebral hemorrhage (ICH) owing to hypertension or other small vessel disease (SVD). Recently, enlarged perivascular space (EPVS) in white matter and deep region was suggested to be another potential marker for SVD. Knowledge of CMB location and EPVS in patients with ICH in relation to amyloid deposition might help us understand its heterogeneous pathophysiology. Methods: Fifty-seven primary, spontaneous ICH patients underwent magnetic resonance imaging (MRI) with susceptibility-weighted imaging (SWI) to analyze the CMB, the EPVS in basal ganglia (BG) and centrum semiovale (CSO), and the overall white matter hyperintensity (WMH). 11 C-Pittsburgh Compound B (PiB) positron emission tomography was also performed to measure the global amyloid deposition and was quantified as standardized uptake value ratio (SUVR) using cerebellum as the reference. Results: Twenty-six patients with lobar ICH and 31 patients with deep ICH were included. Positive PiB scan (SUVR >1.13) was found in 37% of patients (11 lobar ICH, 10 deep ICH). Presence of lobar CMB was found in 65% of patients irrespective of PiB scan status (p=0.084), but PiB (+) had higher number of lobar CMB (14.6 ± 16.9 vs. 5.4± 10.1, p=0.014) compared with PiB (-) patients. In PiB (-) patients, the number of lobar CMB is positively correlated with the number of deep CMB (p<0.001, r=0.773). The presence of lobar CMB in PiB (-) patients is also associated with severe EPVS in BG (70% vs. 31%, p=0.042), but not in CSO (p=0.073). Conclusions: Lobar CMB can be found in more than half of ICH patients irrespective of PiB scan status, but higher number of lobar CMB is seen in PiB (+) ICH patients. In PiB (-) patients, the presence of lobar CMB is associated with higher deep CMB number and EPVS in BG, suggesting the contribution of hypertensive angiopathy instead of amyloid angiopathy.

Background: Markers of cerebral small vessel disease (cSVD) severity and prognosis in strictly lobar or strictly deep intracerebral hemorrhages (ICH)/cerebral microbleeds (CMB) are well defined but data are scarce for mixed-location ICH/CMB. We aimed to compare neuroimaging features and outcomes between deep ICH patients with and without lobar CMBs. Methods: Patients with first-ever deep ICH from a prospectively maintained single-center registry were analyzed. Demographics, risk factors and neuroimaging markers of cSVD including CMBs, cortical superficial siderosis, enlarged perivascular spaces (EPVS), white matter hyperintensity volumes (WMH) and brain atrophy scores (range 0-15) were compared between deep ICH patients with lobar CMBs and those without lobar CMBs. The follow-up data were analyzed for ICH recurrence, ischemic stroke (IS) and all-cause mortality. Results: Of 208 patients, 98 (47.1%) had lobar CMBs. Patients with L-CMBs were older (65.3±12.1 vs. 57.4±12.5, p<0.001) and more likely to be hypertensive (98% vs. 90.9%, p=0.037) than those without L-CMBs. Deep CMBs (83.7% vs 56.4%, p<0.001), lacunes (53.1% vs 31.8%, p=0.003) and severe basal ganglia EPVS (40.8% vs 17.3%, p<0.001) were more common in patients with L-CMBs. Patients with L-CMBs had higher volumes of WMH (17.4 ml [IQR 9-38] vs 4.8 ml [IQR 1-13], p<0.001) and atrophy scores (4 [IQR 2-7] vs 3 [IQR 0-6], p=0.007) as compared to patients without L-CMBs. During a median follow-up of 21 months, the ICH recurrence rate was similar between groups (p=0.2), but higher incident IS (3.0 vs 0.0 per 1000-person-months, p=0.016) and all-cause mortality (4.9 vs 1.5 per 1000-person-months, p=0.026) were observed in patients with L-CMBs. In a cox regression model, the presence of lobar CMBs was independently associated with a composite outcome measure (ICH/IS/mortality) after adjusting for age, hypertension, WMH volume, lacune, BG-EPVS and atrophy scores (odds ratio: 2.9, 95%CI:1.01-8.4 p=0.046). Conclusions: Presence of lobar CMBs in patients with deep ICH is associated with parenchymal markers of more severe cSVD and poor prognosis, suggesting a more advanced vasculopathy compared to patients with strictly deep ICH.

Background and purpose intracranial hemorrhage risk in patients with cerebral microbleeds (CMBs) after mechanical thrombectomy for acute ischemic stroke (AIS) was investigated. We searched PubMed and Embase from inception to 29 August 2023 for relevant studies, calculated pooled odds ratio (ORs) of intracerebral hemorrhage (ICH) subtypes in AIS patients with CMB presence, 1-4 or ≥ 5 CMBs versus CMB absence, and with different CMB locations after mechanical thrombectomy. ICH subtypes included any ICH, symptomatic and asymptomatic ICH, hemorrhage outside infarct (including subarachnoid hemorrhage), hemorrhagic infarction, and parenchymal hemorrhage after mechanical thrombectomy. Five eligible studies enrolling 2051 patients were included. No significant association was shown between CMB locations (lobar, deep, infratentorial or mixed) and ICH risk. CMB presence or 1-4 CMBs did not significantly increase the risk of any ICH, symptomatic or asymptomatic ICH, ICH outside infarct, subarachnoid hemorrhage, hemorrhagic infarction, or parenchymal hemorrhage. CMBs ≥ 5 increased the risk of any ICH (OR 2.58, 95% CI 1.16-5.72), parenchymal hemorrhage (OR 3.38, 95% CI 1.43-7.97) and parenchymal hemorrhage-2 (OR 5.33, 2.05-13.86), without increasing hemorrhagic infarction or parenchymal haemorrhage-1 risk. After adjusted for possible confounding factors, increases in CMB burden were associated with hemorrhagic complications but not with symptomatic ICH. In AIS patients who received mechanical thrombectomy, no association was shown between CMB location and ICH risk. ICH risk was not significantly increased by CMB presence or 1-4 CMBs. ICH risk in patients with ≥ 5 CMBs requires further study.

<i>Stroke</i> : Highlights of Selected Articles

Association between cerebral microbleeds and prior primary intracerebral hemorrhage in ischemic stroke patients

Background: Cerebral microbleeds (CMBs) are reported to predict recurrent stroke and antithrombotic-related intracerebral hemorrhage (ICH). We characterize CMBs in a well-defined population of embolic strokes of undetermined source (ESUS). Notably, we report for the first time interactions between CMBs and effects of random assignment to anticoagulant therapy. Methods: Subgroup analyses of the NAVIGATE ESUS randomized trial comparing rivaroxaban 15 mg vs. aspirin 100 mg daily were performed. CMBs were rated on T2*-GRE sequences obtained at baseline MRI in 3699 participants (mean age 67y). Multivariable regression analyses were used to identify variables independently associated with CMBs. Cox proportional hazards models were used to estimate the contribution of CMBs to risk of recurrent stroke, ischemic stroke, ICH and all-cause mortality. Analyses followed the intent-to-treat paradigm. Results: CMBs were present in 11% of participants. CMBs were strictly deep in 55%, lobar in 26%, and mixed in 19% of cases. Most (68%) had 1-2 CMBs, 27% had 3-10, and 5% &gt;10. Advancing age (OR per yr 1.0, 95% CI 1.01-1.04), East Asian ethnicity (1.6, 1.0-2.4), hypertension (2.2, 1.5-3.2), multi-territorial ESUS (2.0, 1.4-2.7), chronic infarcts (1.8, 1.4-2.2), and occult ICH (5.2, 2.8-9.9) were independently associated with CMBs. During a median follow-up of 11 months, 5.1% of participants had recurrent stroke (4.8% ischemic stroke; 0.3% ICH) and 1.3% died. The presence of CMBs was associated with a 50% increased risk of recurrent stroke (HR 1.5, 95% CI 1.0-2.3), four-fold risk of ICH (4.2, 1.3-13.9), and two-fold risk of all-cause mortality (2.1, 1.1-4.3), and strictly lobar CMBs with a ~2.5-fold risk of ischemic stroke (2.3, 1.3-4.3). There were no interactions between CMBs and treatment assignments for recurrent stroke (p-value for interaction=0.2), ischemic stroke (p=0.3), or all-cause mortality (p=0.6). The hazard ratio (HR) of ICH on rivaroxaban was similar between persons with CMBs (HR 3.1, 95% CI 0.3 - 30.0) and persons without CMBs (HR 3.0, 95% CI 0.6 - 14.7; interaction p=1.0). Conclusions: CMBs mark an increased risk of recurrent ischemic stroke, ICH and mortality in ESUS, but do not appear to influence effects of rivaroxaban, particularly on the outcome of ICH.

BackgroundIntravenous tissue plasminogen activator (IV tPA) after acute ischemic stroke carries the risk of symptomatic intracerebral hemorrhage (sICH). Cerebral microbleeds (CMBs) may indicate increased risk of hemorrhage and can be seen on magnetic resonance imaging (MRI). In this study, we examined the association between CMBs and sICH, focusing on the predictive value of their presence, burden, and location.MethodsRecords from all patients presenting to two academic stroke centers with acute ischemic stroke treated with IV tPA over a 5-year period were retrospectively reviewed. Demographic, medical, and imaging variables were evaluated. The presence, number, and location (lobar vs nonlobar) of CMBs were noted on gradient echo MRI sequences obtained during the admission. Univariable and multivariable statistical models were used to determine the relationship between CMBs and hemorrhagic (symptomatic and asymptomatic) transformation.ResultsOf 292 patients (mean age 62.8 years (SD 15.3), 49% African-American, 52% women), 21% (n = 62) had at least one CMB, 1% (n = 3) had > 10 CMBs, and 1% (n = 3) were diagnosed with probable cerebral amyloid angiopathy. After treatment, 16% (n = 46) developed hemorrhagic transformation, of which 6 (2%) were sICH. There was no association between CMB presence (p = .135) or location (p = .325) with sICH; however, those with a high CMB burden (> 10 CMB) were more likely to develop sICH (OR 37.8; 95% CI: 2.7–539.3; p = .007).ConclusionsOur findings support prior findings that a high CMB burden (> 10) in patients with acute stroke treated with IV tPA are associated with a higher risk of sICH. However, the overall rate of sICH in the presence of CMB is very low, indicating that the presence of CMBs by itself should not dictate the decision to treat with thrombolytics.

Previous studies indicate a potential link between elevated serum lipid levels and an increased risk of cerebral microbleeds (CMBs). Since multiple CMBs can elevate the risk of future intracerebral hemorrhage (ICH), it is important to explore the relationship between lipid profiles and CMBs in ICH patients. However, data on this specific correlation in ICH populations are currently limited. This study retrospectively enrolled 223 consecutive patients from a spontaneous ICH cohort. We collected comprehensive clinical, demographic, and laboratory data, with a focus on lipid levels and the presence of CMBs. Using a multivariate logistic regression model, we investigated the association between lipid parameters and CMB occurrence. Among the 223 patients, 111 (49.8%) had CMBs. Univariate analysis showed that individuals without lobar CMBs tended to have higher levels of serum total cholesterol (TC), low-density lipoprotein (LDL), and non-high-density lipoprotein (Non-HDL). After adjusting for potential confounders, TC [odds ratio (OR), 0.989; 95% confidence interval (CI), 0.979-0.999; p = 0.028] and Non-HDL (OR, 0.989; 95% CI, 0.979-1.000; p = 0.043) were identified as independent predictors of lobar CMBs. Our findings suggest an inverse correlation between TC and Non-HDL levels and the presence of lobar CMBs in ICH patients. Further prospective studies are needed to clarify the causal relationship between statin use and CMBs in ICH patients and to evaluate the prognostic significance of CMB presence and severity in statin-treated individuals.

To investigate the relationship between chronic kidney disease (CKD) and MRI-defined cerebral microbleeds (CMB), a harbinger of future intracerebral hemorrhage (ICH), among patients with a recent history of primary ICH. Using data from a predominantly black cohort of patients with a recent ICH-enrolled in an observational study between September 2007 and June 2011, we evaluated the association between CKD (defined as estimated low glomerular filtration rate<60 mL/min per 1.73 m(2)) and CMB on gradient-echo MRI. Multivariable models were generated to determine the contribution of CKD to the presence, number, and location of CMB. Of 197 subjects with imaging data, mean age was 59 years, 48% were women, 73% were black, 114 (58%) had ≥1 CMBs, and 52 (26%) had CKD. Overall, CKD was associated with presence of CMB (adjusted odds ratio, 2.70; 95% confidence interval [CI], 1.10-6.59) and number of CMB (adjusted relative risk, 2.04; 95% CI, 1.27-3.27). CKD was associated with CMB presence (adjusted odds ratio, 3.44; 95% CI, 1.64-7.24) and number (adjusted relative risk, 2.46; 95% CI, 1.11-5.42) in black patients, but not CMB presence (adjusted odds ratio, 3.00; 95% CI, 0.61-14.86) or number (adjusted relative risk, 1.03; 95% CI: 0.22-4.89) in non-Hispanic white patients (interactions by race were statistically not significant). CKD is associated with a greater presence and number of CMB in ICH patients, particularly in patients of black race. Future studies should assess whether low estimated glomerular filtration rate may be a CMB risk marker or potential therapeutic target for mitigating the development of CMB.

ObjectivesAim of this study was to evaluate the association between cerebral microbleeds (CMBs) and white matter disease (WMD) with intracerebral hemorrhage (ICH) after intravenous thrombolysis (IVT) with rt-PA. We also evaluated whether CMBs characteristics and WMD burden correlate with symptomatic ICH and outcome.MethodsWe included acute ischemic stroke (AIS) patients treated with IVT. The number and location of CMBs as well as severity of WMD were rated analyzing pre- or post-treatment MRI. Multivariable regression analysis was used to determine the impact of CMB and WMD on ICH subgroups and outcome measures.Results434 patients were included. CMBs were detected in 23.3% of them. ICH occurred in 34.7% of patients with CMBs. Independent predictors of parenchymal hemorrhage were the presence of CMBs (OR 2.724, 95% CI 1.360–5.464, p = 0.005) as well as cortical-subcortical stroke (OR 3.629, 95% CI 1.841–7.151, p < 0.001) and atherothrombotic stroke subtype (OR 3.381, 95% CI 1.335–8.566, p = 0.010). Either the presence, or number, and location of CMBs, as well as WMD, was not independently associated with the development of SICH. No independent association between the presence, number, or location of CMBs or WMD and outcome measures was observed.ConclusionsThe results of our study suggest that the exclusion of eligible candidates to administration of IV rt-PA only on the basis of CMBs presence is not justified. The clinical decision should be weighed with a case-by-case approach. Additional data are needed to evaluate the benefit-risk profile of rt-PA in patients carrying numerous microbleeds.

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic cause of stroke. In addition to ischemic stroke, CADASIL predisposes to development of cerebral microbleeds (CMB). CMB and hypertension are known to be associated with intracerebral hemorrhage (ICH). The purpose of this study was to analyze the relationships among CMB, hypertension, and ICH in CADASIL. We enrolled 94 genetically confirmed CADASIL patients from 76 unrelated families at Jeju National University Hospital (Korea) between March 2012 and February 2015. We analyzed CMB presence, number, and distribution on susceptibility-weighted imaging MRI using the microbleed anatomical rating scale. Multiple logistic regression was used to determine factors associated with the presence of CMB and ICH. CMB were observed in 62 patients (66%), median number of CMB per patient was 4 (range 0-121). Twenty-two ICHs were found in 16 patients (17%). There was incongruence between the most common site of CMB (thalamus) and that of ICH (basal ganglia). Hypertension was independently associated with the presence of CMB (multiple regression OR, 2.71; 95% CI 1.02-7.18, p < 0.05), and CMB ≥ 9 (highest third) was significantly associated with the presence of ICH (multiple regression OR = 9.50, 95% CI 1.08-83.71, p < 0.05). In this CADASIL sample, presence of hypertension was independently associated with CMB presence, and CMB burden was independently associated with ICH. Incongruence of sites for CMB and ICH is currently unexplained and requires further study.