Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

Cerebrospinal Fluid CSF Flow Artifacts are Associated with Brain Pulsation in Patients with Severe Carotid Artery Stenoses.

OBJECTIVE: We investigated the factors associated with cerebrospinal fluid (CSF) flow artifacts on fluid-attenuated inversion recovery imaging in patients with carotid artery (CA) stenosis. METHODS: Each CSF artifact grade was defined by comparing the highest intensity in a given region of interest (ROI) to those in reference ROIs, as follows: higher than the intensity of normal white matter in the centrum semiovale = 2 points; equal to or less than the white matter, and higher than CSF = 1 point; and equal to CSF = 0. CSF flow scores in eight sites were measured and added to the total score (0 -16). The prevalences of each finding, specifically white matter lesions, CA stenoses and brain atrophy, were compared using multivariate logistic regression models. RESULTS: We evaluated the findings in 54 patients with CA stenosis treated by CA stenting (CAS) and 200 adults with no history of neurological disorders (control group). Adjusted by stroke risk factors, a CSF flow score ≤ 11 was positively associated with CA stenosis, heart rate > 70 / min, and brain atrophy, and negatively with the female gender. The score was 12.8 ± 1.8 in the control group and 12.0 ± 2.0 in CA stenosis group after CAS, which was significantly higher than before CAS (10.4 ± 2.8, p<0.001). CONCLUSION: The CSF flow score was associated with female gender, brain atrophy, heart rate, and severe CA stenosis, and was found to be elevated after revascularization.

Asymptomatic cerebral findings on 3-Tesla MRI in patients with severe carotid artery stenoses.

BACKGROUND AND PURPOSE: Small vessel diseases (SVDs) are often asymptomatic. However, SVDs significantly influence the prognosis in patients with large vessel diseases (LVDs). We investigated asymptomatic cerebral findings on 3-Tesla MRI in patients with severe carotid artery (CA) stenoses, compared to peoples without a past history of neurological disorders, including strokes. METHODS: We retrospectively analyzed the prevalences of various asymptomatic cerebral findings which were intracerebral hemorrhages (ICHs), cortical superficial siderosis, ventricular dilatation (Evans' index) and SVDs including cerebral microbleeds (CMBs), lacunar infarctions (LIs), deep white matter hyperintensities (WMHs), periventricular hyperintensities (PVHs). The prevalence of each finding was compared using multivariate logistic regression models with adjustment for stroke risk factors. RESULTS: We evaluated the findings in 54 patients with severe CA stenosis treated by stenting (CA stenosis group) and 200 adults with health screening tests of the brain and no past history of neurological disorders (control group). Multivariate analyses adjusted for age ≥ 65 years old, female gender, hypertension, hyperlipidemia, diabetes mellitus, alcohol consumption, and smoking index revealed that the prevalences of severe PVHs, severe deep WMHs, asymptomatic deep ICHs, and asymptomatic LIs were significantly higher in the CA stenosis group than the control group. However, there were no significant differences in the prevalences of CMBs, or the remaining asymptomatic findings described above. CONCLUSIONS: With pathological differences between SVD and LVD, asymptomatic SVDs except CMBs and deep ICHs often co-exists severe CA stenosis as a presentative LVD.

Elongated Internal Carotid Arteries in Patients with Severe Carotid Artery Stenosis.

OBJECTIVE: This study aimed to investigate the risk factors and asymptomatic cerebrovascular diseases associated with elongated internal carotid arteries (ICAs) and the relationship between ICA elongation and severe carotid artery (CA) stenosis. METHODS: We evaluated risk factors for stroke and magnetic resonance imaging (MRI) findings in patients with severe CA stenosis compared with people without neurological disorders who underwent brain screening (controls). On magnetic resonance angiography (MRA) images, we measured the longest distance, defined as the ICA distance, from the most distant anterior wall of the cervical ICA at the site of bending or kinking to the line between the origin of the external CA and the anterior protrusion of the ICA near the petrosal bone. We retrospectively compared various asymptomatic findings, including cerebral microbleeds, lacunar infarctions, and deep white matter hyperintensities (WMHs), between participants with an ICA distance ≥ 1.2 cm vs. < 1.2 cm. The prevalence of findings and stroke risk factors were compared using multivariate logistic regression models. RESULTS: We evaluated 53 patients (70.0 ± 8.1 years old, nine female) with severe CA stenosis treated by CA stenting and 400 controls (63.0 ± 9.2 years old, 227 females). Multivariate analyses showed that ICA distance ≥ 1.2 cm was associated with age ≥ 65 years (odds ratio (OR) = 1.8, p < 0.01), severe deep WMHs (OR = 2.0, p = 0.02), and severe CA stenosis (OR = 0.17, p < 0.01). CONCLUSION: ICA elongation, measured by ICA distance, was positively associated with age and deep WMHs and negatively associated with severe CA stenosis.

Association of Ultrasonography and MRI Findings with Stroke Recurrence: Differences Between Patients with Past Histories of Atherothrombotic Versus Lacunar Infarctions.

OBJECTIVE: This study investigated the association of MRI and ultrasonography findings with stroke recurrence in patients with past histories of atherothrombotic infarctions (ATIs) or lacunar infarctions (LIs). METHODS: We prospectively analyzed the incidence of stroke recurrence. Deep and lobar cerebral microbleeds (MBs), asymptomatic lacunae, asymptomatic intracerebral hemorrhages (ICHs), severe white matter lesions (WML), and intima-media thickness (IMT) were investigated on enrollment. Stroke recurrence rates were compared by using the log-rank test. The odds ratios for recurrent strokes were derived using multivariate logistic regression models, adjusted for risk factors. RESULTS: We evaluated the stroke recurrence rate in 362 ATI patients and 309 LI patients. The log-rank test and multivariate analyses revealed that the incidence of recurrent stroke was significantly higher in ATI patients with mean IMT greater than or equal to 1.1 mm, asymptomatic ICHs, or lobar MBs than in those without. The incidence was significantly higher in LI patients with asymptomatic ICHs, asymptomatic LIs, and severe WMLs than in those without. In ATI patients, those with strictly lobar MBs or mixed MBs (deep and lobar MBs) had significantly higher recurrence rates than those without MB. In LI patients, those with strictly deep MBs or mixed MBs had higher recurrence rates than those without MB, and the incidences of those with mixed MBs was larger than those with strictly deep MBs. CONCLUSIONS: There were differences between ATI and LI patients in terms of the association of MRI and ultrasonography findings, in particularly strictly lobar or deep MBs, with the incidence of stroke recurrence.

Distribution of cerebral microbleeds in the East and West: Individual participant meta-analysis.

OBJECTIVE: We investigated differences in the anatomical distribution of cerebral microbleeds (CMBs) on MRI, hypothesized to indicate the type of underlying cerebral small vessel disease (SVD), between Eastern and Western general populations. METHODS: We analyzed data from 11 studies identified by a PubMed search between 1996 and April 2014 according to the Preferred Reporting Items for a Systematic Review and Meta-analysis of Individual Participant Data. Study quality measures indicated low or medium risk of bias. We included stroke-free participants from populations aged between 55 and 75 years, categorized by geographic location (Eastern or Western). We categorized CMB distribution (strictly lobar, deep and/or infratentorial [D/I], or mixed [i.e., CMBs located in both lobar and D/I regions]). We tested the hypothesis that Eastern and Western populations have different anatomical distributions of CMBs using multivariable mixed effects logistic regression analyses adjusted for age, sex, and hypertension and clustering by institution. RESULTS: Among 8,595 stroke-free individuals (mean age [SD] 66.7 [5.6] years; 48% male; 42% from a Western population), 624 (7.3%) had CMBs (strictly lobar in 3.1%; D/I or mixed in 4.2%). In multivariable mixed effects models, Eastern populations had higher odds of D/I or mixed CMBs (adjusted odds ratio 2.78, 95% confidence interval [CI] 1.77-4.35) compared to Western populations. Eastern populations had a higher number of D/I or mixed CMBs (adjusted prevalence ratio 2.83, 95% CI 1.27-6.31). CONCLUSIONS: Eastern and Western general populations have different anatomical distributions of CMBs, suggesting differences in the spectrum of predominant underlying SVDs, with potential implications for SVD diagnosis and treatment.

Clinical significance of cerebral microbleeds on MRI: A comprehensive meta-analysis of risk of intracerebral hemorrhage, ischemic stroke, mortality, and dementia in cohort studies (v1).

Background Cerebral microbleeds can confer a high risk of intracerebral hemorrhage, ischemic stroke, death and dementia, but estimated risks remain imprecise and often conflicting. We investigated the association between cerebral microbleeds presence and these outcomes in a large meta-analysis of all published cohorts including: ischemic stroke/TIA, memory clinic, "high risk" elderly populations, and healthy individuals in population-based studies. Methods Cohorts (with > 100 participants) that assessed cerebral microbleeds presence on MRI, with subsequent follow-up (≥3 months) were identified. The association between cerebral microbleeds and each of the outcomes (ischemic stroke, intracerebral hemorrhage, death, and dementia) was quantified using random effects models of (a) unadjusted crude odds ratios and (b) covariate-adjusted hazard rations. Results We identified 31 cohorts ( n = 20,368): 19 ischemic stroke/TIA ( n = 7672), 4 memory clinic ( n = 1957), 3 high risk elderly ( n = 1458) and 5 population-based cohorts ( n = 11,722). Cerebral microbleeds were associated with an increased risk of ischemic stroke (OR: 2.14; 95% CI: 1.58-2.89 and adj-HR: 2.09; 95% CI: 1.71-2.57), but the relative increase in future intracerebral hemorrhage risk was greater (OR: 4.65; 95% CI: 2.68-8.08 and adj-HR: 3.93; 95% CI: 2.71-5.69). Cerebral microbleeds were an independent predictor of all-cause mortality (adj-HR: 1.36; 95% CI: 1.24-1.48). In three population-based studies, cerebral microbleeds were independently associated with incident dementia (adj-HR: 1.35; 95% CI: 1.00-1.82). Results were overall consistent in analyses stratified by different populations, but with different degrees of heterogeneity. Conclusions Our meta-analysis shows that cerebral microbleeds predict an increased risk of stroke, death, and dementia and provides up-to-date effect sizes across different clinical settings. These pooled estimates can inform clinical decisions and trials, further supporting cerebral microbleeds role as biomarkers of underlying subclinical brain pathology in research and clinical settings.

Brain microbleeds, anticoagulation, and hemorrhage risk: Meta-analysis in stroke patients with AF.

OBJECTIVES: To assess the association between cerebral microbleeds (CMBs) and future spontaneous intracerebral hemorrhage (ICH) risk in ischemic stroke patients with nonvalvular atrial fibrillation (AF) taking oral anticoagulants. METHODS: This was a meta-analysis of cohort studies with >50 patients with recent ischemic stroke and documented AF, brain MRI at baseline, long-term oral anticoagulation treatment, and ≥6 months of follow-up. Authors provided summary-level data on stroke outcomes stratified by CMB status. We estimated pooled annualized ICH and ischemic stroke rates from Poisson regression. We calculated odds ratios (ORs) of ICH by CMB presence/absence, ≥5 CMBs, and CMB topography (strictly lobar, mixed, and strictly deep) using random-effects models. RESULTS: We established an international collaboration and pooled data from 8 centers including 1,552 patients. The crude CMB prevalence was 30% and 7% for ≥5 CMBs. Baseline CMB presence (vs no CMB) was associated with ICH during follow-up (OR 2.68, 95% confidence interval [CI] 1.19-6.01, p = 0.017). Presence of ≥5 CMB was related to higher future ICH risk (OR 5.50, 95% CI 2.07-14.66, p = 0.001). The pooled annual ICH incidence increased from 0.30% (95% CI 0.04-0.55) among CMB-negative patients to 0.81% (95% CI 0.17-1.45) in CMB-positive patients (p = 0.01) and 2.48% (95% CI 1.2-6.2) in patients with ≥5 CMBs (p = 0.001). There was no association between CMBs and recurrent ischemic stroke. CONCLUSIONS: The presence of CMB on MRI and the dichotomized cutoff of ≥5 CMBs might identify subgroups of ischemic stroke patients with AF with high ICH risk and after further validation could help in risk stratification, in anticoagulation decisions, and in guiding randomized trials and ongoing large observational studies.

Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: A meta-analysis.

OBJECTIVE: We evaluated recurrent intracerebral hemorrhage (ICH) risk in ICH survivors, stratified by the presence, distribution, and number of cerebral microbleeds (CMBs) on MRI (i.e., the presumed causal underlying small vessel disease and its severity). METHODS: This was a meta-analysis of prospective cohorts following ICH, with blood-sensitive brain MRI soon after ICH. We estimated annualized recurrent symptomatic ICH rates for each study and compared pooled odds ratios (ORs) of recurrent ICH by CMB presence/absence and presumed etiology based on CMB distribution (strictly lobar CMBs related to probable or possible cerebral amyloid angiopathy [CAA] vs non-CAA) and burden (1, 2-4, 5-10, and >10 CMBs), using random effects models. RESULTS: We pooled data from 10 studies including 1,306 patients: 325 with CAA-related and 981 CAA-unrelated ICH. The annual recurrent ICH risk was higher in CAA-related ICH vs CAA-unrelated ICH (7.4%, 95% confidence interval [CI] 3.2-12.6 vs 1.1%, 95% CI 0.5-1.7 per year, respectively; p = 0.01). In CAA-related ICH, multiple baseline CMBs (versus none) were associated with ICH recurrence during follow-up (range 1-3 years): OR 3.1 (95% CI 1.4-6.8; p = 0.006), 4.3 (95% CI 1.8-10.3; p = 0.001), and 3.4 (95% CI 1.4-8.3; p = 0.007) for 2-4, 5-10, and >10 CMBs, respectively. In CAA-unrelated ICH, only >10 CMBs (versus none) were associated with recurrent ICH (OR 5.6, 95% CI 2.1-15; p = 0.001). The presence of 1 CMB (versus none) was not associated with recurrent ICH in CAA-related or CAA-unrelated cohorts. CONCLUSIONS: CMB burden and distribution on MRI identify subgroups of ICH survivors with higher ICH recurrence risk, which may help to predict ICH prognosis with relevance for clinical practice and treatment trials.

Cerebral microbleeds and white matter hyperintensities in cardioembolic stroke patients due to atrial fibrillation: single-centre longitudinal study.

Cerebral microbleeds (CMBs) are a potential predictor of future stroke risk with clinical relevance for antithrombotic treatments, especially in ischaemic stroke patients with atrial fibrillation. However, prospective data on CMBs and risk of stroke in this particular stroke population remain scarce. We therefore performed a single centre longitudinal study to investigate CMBs and white matter hyperintensities (WMH) and the risk of future stroke. Consecutive acute stroke patients, admitted during 2008-2012 for presumed cardioembolic stroke due to non-valvular atrial fibrillation with available follow-up for the occurrence of recurrent stroke were included in our study. The rate of future stroke between patients with vs. without CMBs and moderate to severe WMH at baseline MRI was compared in separate survival and multivariable Cox regression analyses. A total of 119 cardioembolic stroke patients (49% female, median age: 76; IQR: 68-82years) were included. CMBs were found at baseline in 26/119 (21.8%; 95% CI: 14.8-30.4%) patients. Moderate to severe WMH were present in 27/119 (22.7%; 95% CI: 15.5-31.3%) cases. During a median follow-up time of 17months (IQR: 3-50months), 17 of 119 patients experienced a symptomatic stroke: 14 patients had an ischaemic stoke and 3 had intracerebral haemorrhage. The overall incidence rate for ischaemic stroke and intracerebral haemorrhage was 4.2 (95% CI: 2.3-7.1) and 0.9 (95% CI: 0.5-2.6) per 1000 patient-year of follow-up respectively. In multivariable Cox regression analysis the hazard ratio for total CMB number and the risk of stroke during follow-up was 1.05 (95% CI: 0.99-1.11; p=0.137, per each additional CMB increase), after adjusting for CHAD2S. A similar regression analysis demonstrated that moderate to severe WMHs were independently associated with increased risk of symptomatic stroke at follow-up, after adjusting for CHAD2S (HR: 2.99; 95% CI: 1.01-8.30; p=0.036). Despite the small sample size, our study provides useful data to guide power calculations and likely effect sizes relevant for ongoing and future larger studies and clinical trials.

Recurrent stroke risk and cerebral microbleed burden in ischemic stroke and TIA: A meta-analysis.

OBJECTIVE: To determine associations between cerebral microbleed (CMB) burden with recurrent ischemic stroke (IS) and intracerebral hemorrhage (ICH) risk after IS or TIA. METHODS: We identified prospective studies of patients with IS or TIA that investigated CMBs and stroke (ICH and IS) risk during ≥3 months follow-up. Authors provided aggregate summary-level data on stroke outcomes, with CMBs categorized according to burden (single, 2-4, and ≥5 CMBs) and distribution. We calculated absolute event rates and pooled risk ratios (RR) using random-effects meta-analysis. RESULTS: We included 5,068 patients from 15 studies. There were 115/1,284 (9.6%) recurrent IS events in patients with CMBs vs 212/3,781 (5.6%) in patients without CMBs (pooled RR 1.8 for CMBs vs no CMBs; 95% confidence interval [CI] 1.4-2.5). There were 49/1,142 (4.3%) ICH events in those with CMBs vs 17/2,912 (0.58%) in those without CMBs (pooled RR 6.3 for CMBs vs no CMBs; 95% CI 3.5-11.4). Increasing CMB burden increased the risk of IS (pooled RR [95% CI] 1.8 [1.0-3.1], 2.4 [1.3-4.4], and 2.7 [1.5-4.9] for 1 CMB, 2-4 CMBs, and ≥5 CMBs, respectively) and ICH (pooled RR [95% CI] 4.6 [1.9-10.7], 5.6 [2.4-13.3], and 14.1 [6.9-29.0] for 1 CMB, 2-4 CMBs, and ≥5 CMBs, respectively). CONCLUSIONS: CMBs are associated with increased stroke risk after IS or TIA. With increasing CMB burden (compared to no CMBs), the risk of ICH increases more steeply than that of IS. However, IS absolute event rates remain higher than ICH absolute event rates in all CMB burden categories.

The Severity of White Matter Lesions Possibly Influences Stroke Recurrence in Patients with Histories of Lacunar Infarctions.

BACKGROUND: To investigate the recurrent stroke types associated with white matter lesions (WMLs), we prospectively observed recurrences in patients with histories of lacunar infarctions (LIs). METHODS: We prospectively analyzed the types of stroke recurrences in 305 patients (138 women, 70.2 ± 11.7 years old) consecutively admitted to our hospital with LIs from April 2004 to December 2011. WMLs were graded using Fazekas' grades (Gr). Recurrence-free rate curves were generated by the Kaplan-Meier method using the log-rank test. RESULTS: The follow-up period was 50.7 ± 32.8 (.25-114) months. During this period, 62 strokes recurred. The incidences of strokes (all types), LIs, and deep intracerebral hemorrhages (ICHs) presenting as recurrences in 112 patients with Gr 2-3 were 6.2, 2.0, and 1.5 %/year, respectively, values that were significantly greater than those seen in 79 patients with Gr 0 (2.1 [P = .0001], .6 [P = .014], and .5 %/year [P = .016], respectively), and in 114 patients with Gr 1 (2.8 [P = .003], .9 [P = .009], and .6 %/year [P = .043], respectively). There was no significant difference among Gr 0, 1, and 2-3 in incidences of recurrences presenting as lobar ICHs, atherothrombotic infarctions, or cardioembolic infarctions. Multivariate analyses demonstrated that Gr 2-3 significantly and independently elevated the rate of deep ICHs or LIs presenting as recurrences after adjustment for risk factors. CONCLUSIONS: The presence of high-grade WMLs elevated the rate of stroke recurrences presenting as LIs and deep ICHs, but not other types.

Contribution of Deep Microbleeds to Stroke Recurrence: Differences between Patients with Past Deep Intracerebral Hemorrhages and Lacunar Infarctions.

BACKGROUND: This study investigated the contribution of deep cerebral microbleeds (MBs) to stroke recurrences in patients with histories of deep intracerebral hemorrhages (ICHs) or lacunar infarctions (LIs). METHODS: We prospectively analyzed stroke recurrences in patients admitted to our hospital who were treated for deep ICHs or LIs between April 2004 and December 2011. The number of deep MBs was counted on admission. Stroke recurrence-free rate curves were generated with the Kaplan-Meier method using the log-rank test. The odds ratios (ORs) for recurrent strokes were derived using multivariate logistic regression models, based on deep MBs and risk factors. RESULTS: We evaluated magnetic resonance images or the recurrences of 231 deep-ICH patients (92 women, 68.0 ± 12.0 years old) and 309 LI patients (140 women, 70.7 ± 11.7 years old). The incidences of deep ICHs (1.5%/year) and LIs (2.1%/year) presenting as stroke recurrences were significantly larger in LI patients with deep MBs than in those without (.01 [P = .0001] and .08%/year [P = .005], respectively). However, there was no significant difference between deep-ICH patients with and without MBs in terms of incidence of recurrences. Multivariate analyses revealed that deep MBs independently and significantly elevated the rate of deep ICHs (OR, 19.0; P = .007) or LIs (OR, 3.62; P = .008) presenting as recurrences in LI patients, but not in deep-ICH patients, when adjusted for stroke risk factors. CONCLUSIONS: There may be differences between patients with deep ICHs and those with LIs in terms of the contribution of deep MBs to stroke recurrence.

The severities of white matter lesions possibly influence the recurrences of several stroke types.

BACKGROUND: White matter lesions (WML) have been reported to be a surrogate marker of stroke occurrences. To investigate the recurrent stroke types associated with WML, we prospectively observed recurrences in stroke patients. METHODS: We prospectively analyzed the types of stroke recurrence in 807 patients (351 women, 69.8 ± 12.0 years old) consecutively admitted to our hospital with strokes from April 2004 to October 2009. WML were graded using Fazekas grades. Recurrence-free rate curves were generated by the Kaplan-Meier method using the log-rank test. RESULTS: The follow-up period was 31.6 ± 22.2 (range .5-71) months. During this period, 111 strokes recurred. The incidence of all stroke recurrences in 223 patients with grades 2 and 3 was 6.0% per year, which was significantly higher than that seen in 287 patients with grade 0 (2.1% per year, P = .006) and 297 patients with grade 1 (4.3% per year, P < .0001). The incidences of intracerebral hemorrhages (ICHs), lacunar infarctions, and atherothrombotic infarctions in patients with grades 2 and 3 were 1.2, 1.4, and 2.4% per year, respectively, which were higher than those seen in patients with grade 0 (.3%, P = .004; .2%, P = .002; and .9% per year, P = .010) but not similar to those in patients with grade 1 (.9%, P = .180; .9%, P = .161; and 1.4% per year, P = .249). There was no significant difference among grades 0, 1, 2, and 3 in incidence of stroke recurrences presenting as cardioembolic infarctions. CONCLUSIONS: The presence of high-grade WML elevated the rate of stroke recurrences presenting as ICHs, lacunar infarctions, and atherothrombotic infarctions but not as cardioembolic infarctions.

Nascent lobar microbleeds and stroke recurrences.

BACKGROUND: Lobar microbleeds (MBs) are occasionally visible on gradient-echo T2*-weighted (T2*-w) magnetic resonance imagings (MRIs) in patients with deep intracerebral hemorrhages (ICHs). This study investigated the contribution of nascent lobar MBs to occurrences of deep ICHs. METHODS: We prospectively analyzed nascent lobar MBs in patients admitted to our hospital who were treated with index strokes between April 2004 and November 2009. Numbers of nascent lobar MBs were counted on T2*-w MRI scans around 1 year after index strokes and compared with previous MRIs on admission. Deep ICH occurrence-free rate curves were generated by the Kaplan-Meier method using the log-rank test. The odds ratio (OR) for deep ICH occurrence was derived from a multivariate logistic regression model using nascent lobar MBs and risk factors. RESULTS: We investigated MRIs (interscan interval: 14.6 ± 5.9 months) of 508 patients (207 women, 68.9 ± 11.5 years), with a follow-up period of 44.1 ± 15.4 months. Repeated T2*-w MRIs demonstrated 157 nascent lobar MBs in 62 of 508 patients. The occurrence rate of deep ICHs (1.9% per year) was significantly higher in patients with nascent lobar MBs than in those without (.5% per year, P = .012). Multivariate analyses revealed that the rate of nascent lobar MBs was significantly elevated in patients with deep ICH-type stroke recurrences (OR: 3.85, P = .020), adjusted by the presence of hypertension, diabetes mellitus, use of antithrombotic drugs, severity of white matter lesions, age, and gender. CONCLUSIONS: Though a cohort study limited the power of analyses, our findings suggested that lobar MBs might be associated with deep ICH.

Nascent deep microbleeds and stroke recurrences.

BACKGROUND: Cerebral microbleeds (MBs) on gradient echo T2*-weighted magnetic resonance imaging (MRI) scans are associated with the severity of cerebral microangiopathies. This study investigated the contributions of nascent deep MBs to stroke recurrence. METHODS: We prospectively analyzed nascent deep MBs in patients admitted to our hospital who were treated for index strokes between April 2004 and November 2009. The number of nascent deep MBs was counted on T2*-weighted MRI scans around 1 year after the index strokes, and compared to previous MRIs on admission. Stroke recurrence-free rate curves were generated using the Kaplan-Meier method using the log-rank test. The odds ratio for nascent deep MBs was derived using a multivariate logistic regression model that was based on recurrent strokes and other risk factors. RESULTS: We evaluated the MRIs (interval between MRIs 14.6 ± 5.9 months) of 508 patients (207 women; 68.9 ± 11.5 years), with a follow-up period of 44.1 ± 15.4 months. Repeated T2*-weighted MRI scans revealed 256 nascent deep MBs in 116 of 508 patients. The incidence of deep intracerebral hemorrhage was significantly greater in patients with nascent deep MBs than those without (2.0% vs 0.4% per year, respectively; P < .0001). Multivariate analyses revealed that the rate of nascent deep MBs was significantly elevated in patients whose stroke recurrences took the form of deep intracerebral hemorrhages (odds ratio 5.41; P = .007), when adjusted for hypertension, preexisting MBs, and other risk factors. CONCLUSIONS: Our findings suggested that nascent deep MBs might be associated with stroke recurrence, in particular with deep intracerebral hemorrhage.

Antithrombotic drug uses and deep intracerebral hemorrhages in stroke patients with deep cerebral microbleeds.

BACKGROUND: It has been suggested that antiplatelet or anticoagulant drugs elevate the rate of intracerebral hemorrhage (ICH) in patients with cerebral microbleeds (MBs). To investigate the mechanism by which antiplatelet drugs or warfarin may contribute to deep ICH occurrences in patients with deep MBs, we prospectively analyzed deep ICH occurrences in 807 consecutive patients (351 females and 456 males; mean age ± standard deviation 69.8 ± 12.0 years) who were admitted to our hospital with strokes. METHODS: Occurrence-free rate curves were generated using the Kaplan-Meier method; deep ICH occurrence-free rates were compared using the log-rank test. The follow-up period was 0.5 to 71 months (mean ± standard deviation 31.6 ± 22.2 months). RESULTS: In patients with deep MBs, the rates (1.0%/year; 6 ICHs in 180 patients) of deep ICH occurrence associated with antiplatelet drugs were not significantly greater than that without the drugs (1.0%/year; 6 ICHs in 167 patients; P = .977). The incidence of deep ICHs associated with warfarin use was not significantly greater than that without warfarin use. CONCLUSIONS: Multivariate analysis revealed that the use of antiplatelet drugs or warfarin did not significantly influence the occurrence of deep ICH in patients with deep MBs. Antiplatelet drugs or warfarin did not significantly elevate the rate of deep ICHs in stroke patients with pre-existing deep MBs.

The difference in location between traumatic cerebral microbleeds and microangiopathic microbleeds associated with stroke.

BACKGROUND AND PURPOSE: Microbleeds (MBs) are low-intensity spots on gradient echo T2*-weighted MRI frequently associated with cerebral microangiopathies resulting in stroke. MBs can also be caused by cerebral axonal injuries. We compared the location of MBs associated with cerebral microangiopathies with those associated with trauma. METHODS: T2*-weighted MRI identified traumatic MBs (t-MBs) in 23 (6 females; 38.7 ± 25.8 years old) of the 312 patients with head trauma consecutively admitted to our hospital between March 2003 and March 2009. We prospectively examined for the presence of microangiopathic MBs (m-MBs) in the 131 patients (59 females; 65.2 ± 9.2 years old) admitted consecutively for stroke (May -December 2004) as controls. RESULTS: We identified a total of 145 t-MBs and 504 m-MBs. t-MBs were frequently located in the mid portion of the subcortical area of the cerebrum, above the corpus callosum in axial slices, and were absent from the basal ganglia. In contrast, m-MBs were frequently located within the basal ganglia or thalamus. CONCLUSION: There are substantial differences in locations of MB development in trauma patients in comparison to stroke patients.

Antithrombotic drug use, cerebral microbleeds, and intracerebral hemorrhage: a systematic review of published and unpublished studies.

BACKGROUND AND PURPOSE: Cerebral microbleeds (MB) are potential risk factors for intracerebral hemorrhage (ICH), but it is unclear if they are a contraindication to using antithrombotic drugs. Insights could be gained by pooling data on MB frequency stratified by antithrombotic use in cohorts with ICH and ischemic stroke (IS)/transient ischemic attack (TIA). METHODS: We performed a systematic review of published and unpublished data from cohorts with stroke or TIA to compare the presence of MB in: (1) antithrombotic users vs nonantithrombotic users with ICH; (2) antithrombotic users vs nonusers with IS/TIA; and (3) ICH vs ischemic events stratified by antithrombotic use. We also analyzed published and unpublished follow-up data to determine the risk of ICH in antithrombotic users with MB. RESULTS: In a pooled analysis of 1460 ICH and 3817 IS/TIA, MB were more frequent in ICH vs IS/TIA in all treatment groups, but the excess increased from 2.8 (odds ratio; range, 2.3-3.5) in nonantithrombotic users to 5.7 (range, 3.4-9.7) in antiplatelet users and 8.0 (range, 3.5-17.8) in warfarin users (P difference=0.01). There was also an excess of MB in warfarin users vs nonusers with ICH (OR, 2.7; 95% CI, 1.6-4.4; P<0.001) but none in warfarin users with IS/TIA (OR, 1.3; 95% CI, 0.9-1.7; P=0.33; P difference=0.01). There was a smaller excess of MB in antiplatelet users vs nonusers with ICH (OR, 1.7; 95% CI, 1.3-2.3; P<0.001), but findings were similar for antiplatelet users with IS/TIA (OR, 1.4; 95% CI, 1.2-1.7; P<0.001; P difference=0.25). In pooled follow-up data for 768 antithrombotic users, presence of MB at baseline was associated with a substantially increased risk of subsequent ICH (OR, 12.1; 95% CI, 3.4-42.5; P<0.001). CONCLUSIONS: The excess of MB in warfarin users with ICH compared to other groups suggests that MB increase the risk of warfarin-associated ICH. Limited prospective data corroborate these findings, but larger prospective studies are urgently required.

Impaired spinal cord remyelination by long-term cultured adult porcine olfactory ensheathing cells correlates with altered in vitro phenotypic properties.

BACKGROUND: Extensive studies in rodents have identified olfactory ensheathing cells (OECs) as promising candidates for cell-based therapies of spinal cord and peripheral nerve injury. Previously, we demonstrated that short-term cultured adult porcine OECs can remyelinate the rodent and non-human primate spinal cord. Here, we studied the impact of the culturing interval on the remyelinating capacity of adult porcine OECs. METHODS: Cells were maintained for 1, 2, and 4 to 6 weeks in vitro prior to transplantation into the demyelinated rat spinal cord. Parallel to this, the in vitro phenotypic properties of the OEC preparations used for transplantation were analyzed with regard to morphology, low affinity nerve growth factor receptor (p75(NTR)) expression and proliferation. RESULTS: We report that prolonged culturing of adult porcine OECs resulted in impaired remyelination of the adult rat spinal cord. Animals receiving transplants of OECs maintained in vitro for 2 weeks displayed significantly less remyelinated axons than those animals that received OEC transplants cultured for 1 week. There was virtually no remyelination after transplantation of OECs cultured for 4 to 6 weeks. The adult porcine OECs displayed a progressive lost of p75(NTR)-expression as determined by immunostaining and flow cytometry with time in culture. CONCLUSIONS: Taken together, the results indicate that porcine OECs undergo systematic changes with time in culture that result in reduced p75(NTR)-expression, decreased proliferation, and reduced remyelinating capability with time in vitro indicating that relatively short term cultures with limited expansion would be required for transplantation studies.