Toshio Imaizumi

Antithrombotic Drug Use, Cerebral Microbleeds, and Intracerebral Hemorrhage A Systematic Review of Published and Unpublished Studies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 Methods— We performed a systematic review of published and unpublished data from cohorts with stroke or TIA to compare the presence of MB in: (1) antithrombotic users vs nonantithrombotic users with ICH; (2) antithrombotic users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 We also analyzed published and unpublished follow-up data to determine the risk of ICH in antithrombotic users with MB.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.

Detection of Hemosiderin Deposition by T2*-Weighted MRI After Subarachnoid Hemorrhage

Background and Purpose— Subarachnoid hemorrhage (SAH) is very difficult to diagnose several months after its onset. We thus investigated subarachnoid hemosiderin deposition well after SAH by T2*-weighted MRI, a sensitive method for hemosiderin detection. Methods— To investigate how hemosiderin deposition as confirmed by T2*-weighted MRI contributes to the determination of prior SAH and how the extent of hemosiderin deposition is associated with a number of clinical factors, we retrospectively analyzed 58 patients >3 months after SAH associated with ruptured aneurysms. We also investigated 209 healthy volunteers as controls. Results— T2*-weighted MRI demonstrated subarachnoid hemosiderin deposition in 72.4% of the SAH patients, whereas no deposition was seen in the healthy volunteer group. The hemosiderin was preferentially deposited in the subarachnoid space near a ruptured aneurysm. Odds ratios (ORs) were estimated from logistic regression analyses correlating hemosiderin deposition with other factors. Age (≥54 years) (OR, 5.1; 95% CI, 1.03 to 25.0; P =0.046), Fisher grade 3 on initial CT (OR, 8.0; 95% CI, 1.26 to 50.4; P =0.027), and Karnofsky Scale score ≤80% 6 months after onset of SAH (OR, 12.8; 95% CI, 1.97 to 83.3; P =0.0077) were all found to be independently associated with hemosiderin deposition levels. Conclusions— T2*-weighted MRI is an effective means of diagnosing prior SAH and may also reveal the location of a ruptured aneurysm. The extent of hemosiderin deposition was significantly associated with several factors, including age, CT findings, and poor prognosis.

Dot-like hemosiderin spots on gradient echo T2^*-weighted magnetic resonance imaging are associated with past history of small vessel disease in patients with intracerebral hemorrhage

Background and Purpose. Lipohyalinosis is considered an important cause of cerebral small vessel disease (SVD), including hypertensive intracerebral hematoma (ICH) and lacunar infarction. Dot‐like low‐intensity spots (dot‐like hemosiderin spots [dotHSs]) on gradient‐echo T2*‐weighted (T2*‐w) magnetic resonance imaging (MRI) have been histologically diagnosed as old microbleeds associated with microangiopathies (lipohyalinosis, amyloid angiopathy) and located in territories of perforating arteries (deep dotHSs) and subcortical regions (subcortical dotHSs). If dotHSs indicate the severity of lipohyalinosis, larger numbers of deep dotHSs may be associated with past history of SVD.Methods. The number of dotHSs was investigated in 213 patients with deep ICH (106 men, 107 women, 37 to 94 years old, mean age = 65.8 ± 11.2 years). Patients were divided into 2 subgroups according to past history of SVD. Odds ratio (OR) for the history was estimated from logistic regression analyses of the number of deep or subcortical dotHSs, as well as other factors.Results. Of 213 patients, 36 had a past history of SVD (symptomatic deep ICH in 18, symptomatic lacunar infarction in 17, and both in 1). An increased rate of history of SVD was found for patients with subcortical dotHSs. The OR per 1 subcortical dotHS was 1.09 (95% confidence internal (CI), 1.03–1.17;P= .005), and per deep dotHS, the OR was 1.07 (95% CI, 1.00–1.13;P= .039). Conclusions. The findings suggest that deep and subcortical dotHSs on T2*‐w MRI may indicate the severity of microangiopathy and may predict recurrence of SVD in patients with deep ICH.

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.

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.

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.

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.

Cerebral Blood Flow before and after Treatment with Amlodipine in Elderly Patients with Lacunar Infarction

ment of hypertension reduces the risk of ischaemic Patients were eligible for inclusion if they were stroke.[4-10] Moreover, a BP reduction in subacute admitted to Hakodate Municipal Hospital with and chronic stroke may also prevent lipohyalinosis symptomatic lacunar infarction from October 2000 and other vascular lesions associated with stroke. to September 2001. Infarctions were 90mm Hg or a systolic BP of >150mm Hg 3 weeks the lower limit of CBF autoregulation downwards in after the onset of lacunar infarction. Patients with spontaneously hypertensive rats.[16] Amlodipine lacunar infarction associated with embolism (exdoes not significantly affect relative indices of CBF cluding atrial fibrillation or ulcerations of the cerviin elderly hypertensive patients after BP lowering[17] cal internal carotid arteries) or lacunar infarction and it reduces the rate of carotid artery atherosclerorelated to the stenosis of a main trunk of a cerebral sis.[18] BP lowering with amlodipine has been shown artery, as determined by magnetic resonance angioto reduce stroke occurrence.[9] Such findings suggest graphy and/or digital subtraction angiography, were that amlodipine may be a suitable antihypertensive excluded. medication for elderly patients with acute stroke. Written informed consent was obtained from In our experience, reduction of systolic/diastolic either the patient or their closest relative. The study BP to normal (<140/85mm Hg) for lacunar infarcprotocol was approved by the Ethics Committee of tion is not harmful 2 weeks after the onset of stroke. Hakodate Municipal Hospital, Hokkaido, Japan. BP is reduced 2 weeks after stroke; the reduction Patients were treated medically with ozagrel for may be associated with normalisation of the sympa14 days after the onset of the infarction.[19] Rehabilithetic tone. At that time, further rehabilitation retation, including speech therapy, was started 2–3 quires stabilisation of BP. days after admission if the neurological deficit could