Simone M. Gregoire

The Microbleed Anatomical Rating Scale (MARS): Reliability of a tool to map brain microbleeds

Objective: Brain microbleeds on gradient-recalled echo (GRE) T2*-weighted MRI may be a useful biomarker for bleeding-prone small vessel diseases, with potential relevance for diagnosis, prognosis (especially for antithrombotic-related bleeding risk), and understanding mechanisms of symptoms, including cognitive impairment. To address these questions, it is necessary to reliably measure their presence and distribution in the brain. We designed and systematically validated the Microbleed Anatomical Rating Scale (MARS). We measured intrarater and interrater agreement for presence, number, and anatomical distribution of microbleeds using MARS across different MRI sequences and levels of observer experience. Methods: We studied a population of 301 unselected consecutive patients admitted to our stroke unit using 2 GRE T2*-weighted MRI sequences (echo time [TE] 40 and 26 ms). Two independent raters with different MRI rating expertise identified, counted, and anatomically categorized microbleeds. Results: At TE = 40 ms, agreement for microbleed presence in any brain location was good to very good (intrarater κ = 0.85 [95% confidence interval (CI) 0.77–0.93]; interrater κ = 0.68 [95% CI 0.58–0.78]). Good to very good agreement was reached for the presence of microbleeds in each anatomical region and in individual cerebral lobes. Intrarater and interrater reliability for the number of microbleeds was excellent (intraclass correlation coefficient [ICC] = 0.98 [95% CI 0.97–0.99] and ICC = 0.93 [0.91–0.94]). Very good interrater reliability was obtained at TE = 26 ms (κ = 0.87 [95% CI 0.61–1]) for definite microbleeds in any location. Conclusion: The Microbleed Anatomical Rating Scale has good intrarater and interrater reliability for the presence of definite microbleeds in all brain locations when applied to different MRI sequences and levels of observer experience.

Antithrombotic Drug Use, Cerebral Microbleeds, and Intracerebral Hemorrhage A Systematic Review of Published and Unpublished Studies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.

Spectrum of transient focal neurological episodes in cerebral amyloid angiopathy: multicentre magnetic resonance imaging cohort study and meta-analysis.

Background and Purpose— Transient focal neurological episodes (TFNE) are recognized in cerebral amyloid angiopathy (CAA) and may herald a high risk of intracerebral hemorrhage (ICH). We aimed to determine their prevalence, clinical neuroimaging spectrum, and future ICH risk. Methods— This was a multicenter retrospective cohort study of 172 CAA patients. Clinical, imaging, and follow-up data were collected. We classified TFNE into: predominantly positive symptoms (“aura-like” spreading paraesthesias/positive visual phenomena or limb jerking) and predominantly negative symptoms (“transient ischemic attack–like” sudden-onset limb weakness, dysphasia, or visual loss). We pooled our results with all published cases identified in a systematic review. Results— In our multicenter cohort, 25 patients (14.5%; 95% confidence interval, 9.6%–20.7%) had TFNE. Positive and negative symptoms were equally common (52% vs 48%, respectively). The commonest neuroimaging features were leukoaraiosis (84%), lobar ICH (76%), multiple lobar cerebral microbleeds (58%), and superficial cortical siderosis/convexity subarachnoid hemorrhage (54%). The CAA patients with TFNE more often had superficial cortical siderosis/convexity subarachnoid hemorrhage (but not other magnetic resonance imaging features) compared with those without TFNE (50% vs 19%; P=0.001). Over a median period of 14 months, 50% of TFNE patients had symptomatic lobar ICH. The meta-analysis showed a risk of symptomatic ICH after TFNE of 24.5% (95% confidence interval, 15.8%–36.9%) at 8 weeks, related neither to clinical features nor to previous symptomatic ICH. Conclusions— TFNE are common in CAA, include both positive and negative neurological symptoms, and may be caused by superficial cortical siderosis/convexity subarachnoid hemorrhage. TFNE predict a high early risk of symptomatic ICH (which may be amenable to prevention). Blood-sensitive magnetic resonance imaging sequences are important in the investigation of such episodes.

Acute ischaemic brain lesions in intracerebral haemorrhage : multicentre cross-sectional magnetic resonance imaging study.

Subclinical acute ischaemic lesions on brain magnetic resonance imaging have recently been described in spontaneous intracerebral haemorrhage, and may be important to understand pathophysiology and guide treatment. The underlying mechanisms are uncertain. We tested the hypothesis that ischaemic lesions are related to magnetic resonance imaging markers of the severity and type of small-vessel disease (hypertensive arteriopathy or cerebral amyloid angiopathy) in a multicentre, cross-sectional study. We studied consecutive patients with intracerebral haemorrhage from four specialist stroke centres, and age-matched stroke service referrals without intracerebral haemorrhage. Acute ischaemic lesions were assessed on magnetic resonance imaging (<3 months after intracerebral haemorrhage) using diffusion-weighted imaging. White matter changes and cerebral microbleeds were rated with validated scales. We investigated associations between diffusion-weighted imaging lesions, clinical and radiological characteristics. We included 114 patients with intracerebral haemorrhage (39 with clinically probable cerebral amyloid angiopathy) and 47 age-matched controls. The prevalence of diffusion-weighted imaging lesions was 9/39 (23%) in probable cerebral amyloid angiopathy-related intracerebral haemorrhage versus 6/75 (8%) in the remaining patients with intracerebral haemorrhage (P = 0.024); no diffusion-weighted imaging lesions were found in controls. Diffusion-weighted imaging lesions were mainly cortical and were associated with mean white matter change score (odds ratio 1.14 per unit increase, 95% confidence interval 1.02-1.28, P = 0.024) and the presence of strictly lobar cerebral microbleeds (odds ratio 3.85, 95% confidence interval 1.15-12.93, P = 0.029). Acute, subclinical ischaemic brain lesions are frequent but previously underestimated after intracerebral haemorrhage, and are three times more common in cerebral amyloid angiopathy-related intracerebral haemorrhage than in other intracerebral haemorrhage types. Ischaemic brain lesions are associated with white matter changes and cerebral microbleeds, suggesting that they result from an occlusive small-vessel arteriopathy. Diffusion-weighted imaging lesions contribute to the overall burden of vascular-related brain damage in intracerebral haemorrhage, and may be a useful surrogate marker of ongoing ischaemic injury from small-vessel damage.

Cerebral microbleeds and vascular cognitive impairment

MRI manifestations of small vessel diseases including white matter hyperintensities and lacunes have been recognized as potential substrates of vascular cognitive impairment for many years. Cerebral microbleeds (CMBs)--small, perviascular haemorrhages seen as small, well-demarcated, hypointense, rounded lesions on MRI sequences sensitive to magnetic susceptibility effects--are also now recognized as an imaging marker for small vessel pathology, but their clinical impact on cognition remains uncertain. CMBs are present in about a third of patients with ischaemic stroke, and in a high proportion of patients with Alzheimers disease, cerebral amyloid angiopathy, and vascular dementia. They have also been increasingly found in normal elderly populations, particularly using sequences optimized for their detection. Some recent studies have suggested an effect of CMBs on cognition, which could relate directly to focal damage to or dysfunction of adjacent brain tissues; alternatively, CMBs may be a more general marker for the severity of small vessel pathology related to hypertension or cerebral amyloid angiopathy. CMBs may therefore play a role in understanding the underlying mechanisms of vascular cognitive impairment, in diagnosis, and in assessing its severity and prognosis; this review considers recent evidence on this topic.

Brain microbleeds as a potential risk factor for antiplatelet-related intracerebral haemorrhage: hospital-based, case–control study

Background Intracerebral haemorrhage (ICH) is an uncommon but devastating complication of regular antiplatelet use: identifying high-risk patients before treatment could potentially reduce this hazard. Brain microbleeds on gradient-recalled echo (GRE) T2*-weighted MRI are considered a biomarker for bleeding-prone small-vessel diseases. The authors hypothesised that microbleeds are a risk factor for antiplatelet-related ICH, and investigated this in a hospital-based matched case–control study. Methods Cases of spontaneous ICH were ascertained, using overlapping methods, from a prospective database of 1017 consecutive unselected patients referred to our stroke unit and associated clinics. For each case of antiplatelet-related ICH, two controls matched for age, sex and hypertension without history of ICH on antiplatelet therapy were selected. Microbleeds were identified by a trained observer blinded to clinical details. Results Microbleeds were more frequent in antiplatelet users with ICH than in matched antiplatelet users without ICH (13/16 (81%) vs 6/32 (19%), p=0.004) and patients with non-antiplatelet-related ICH (13/16 (81%) vs 15/33 (45%), p=0.03). The frequency of lobar microbleeds was 11/16 (69%) in antiplatelet-related ICH versus 11/33 (33%) in non antiplatelet-related ICH (p=0.032). Microbleeds were more numerous in antiplatelet users with ICH compared with controls (p=0.016). The number of microbleeds was associated with the risk of antiplatelet-related ICH (adjusted OR 1.33 per additional microbleed, 95% CI 1.06 to 1.66, p=0.013). Conclusions Brain microbleeds are associated with antiplatelet-related ICH. In patients with a large number of lobar microbleeds, the risk of ICH could outweigh the benefits of antiplatelet therapy. Larger prospective studies to investigate the prognostic significance of microbleeds in regular antiplatelet users are warranted.

Cerebral Microbleeds and Long-Term Cognitive Outcome: Longitudinal Cohort Study of Stroke Clinic Patients

Background: Vascular cognitive impairment causes significant disability in the elderly and is common following ischaemic stroke. Although the underlying mechanisms and prognostic factors remain unclear, small vessel diseases are known to contribute. Cerebral microbleeds (CMBs) are a magnetic resonance imaging (MRI) manifestation of small vessel diseases and may contribute to vascular cognitive impairment, particularly frontal-executive functions. We hypothesized that baseline CMBs would predict long-term cognitive outcome, specifically frontal-executive function. Methods: A cohort of consecutive patients found to have CMBs when first referred to a stroke clinic, together with a CMB-free control group matched for age, gender and clinicoradiological characteristics, were invited for follow-up cognitive assessment a median of 5.7 years later. MRI and detailed cognitive assessment (including current intellectual function, verbal memory, visual memory, naming skills, perceptual functions, frontal-executive functions; and speed and attention) were performed at baseline and follow-up. Patients were classified (blinded to MRI and clinical data) as impaired or unimpaired in each domain using predefined criteria. We compared the prevalence of cognitive impairments in each domain at baseline and follow-up and investigated clinical and radiological predictors [including baseline CMBs and white matter changes (WMCs)] of frontal-executive cognitive impairment. Results: Of the original cohort of 55 patients, 13 died without follow-up. Twenty-six of the surviving patients (9 with, 17 without baseline CMBs) agreed to follow-up neuropsychological assessment; 21 of these patients had a repeat MRI scan. The median number of cognitive domains impaired increased, regardless of the presence of baseline CMBs (with baseline CMBs: median 3, range 0–5 at follow-up vs. median 2, range 0–2 at baseline, p = 0.016; without CMBs: median 1.0, range 0–5 at follow-up vs. median 0, range 0–5 at baseline, p = 0.035). Frontal-executive impairment at follow-up was more prevalent in patients with baseline CMBs than in those without (78 vs. 29%, p = 0.038). The presence of baseline CMBs predicted frontal-executive impairment at follow-up (OR 8.40, 95% CI 1.27–55.39, p = 0.027). Fifty percent of patients with CMBs versus 8% of patients without baseline CMBs developed new CMBs (p = 0.047). The severity of WMCs increased; the difference was statistically significant only in patients without baseline CMBs (p = 0.027). There were no new cortical infarcts. Conclusion: In stroke clinic patients, CMBs are consistently associated with frontal-executive impairment; baseline CMBs are associated with frontal-executive impairment at follow-up after 5.7 years. The presence of CMBs has prognostic relevance for long-term cognitive outcome in stroke clinic patients, and may help to optimally target preventive strategies in individuals at highest risk of cognitive decline.

MRI Detection of New Microbleeds in Patients With Ischemic Stroke. Five-Year Cohort Follow-Up Study

Background and Purpose— Little is known about the development of cerebral microbleeds in patients with ischemic stroke. We studied the incidence of new microbleeds in a cohort of patients with ischemic stroke or transient ischemic attack screened for microbleeds at baseline. Methods— Twenty-one surviving patients with ischemic stroke or transient ischemic attack were followed up after a mean interval of 5.5 years with repeat MRI and clinical assessment. Predictors of new microbleeds were tested in logistic regression. Results— Of patients with microbleeds at baseline, 50% had new microbleeds at follow-up compared with 8% of those without baseline microbleeds (P=0.047). The presence of microbleeds at baseline predicted new microbleeds (OR, 12; 95% CI, 1.02 to 141.34; P=0.048), as did mean systolic blood pressure (OR, 1.28 per unit increase; 95% CI, 1.23 to 1.33; P<0.001). One patient had a stroke (intracerebral hemorrhage) during follow-up. Conclusions— Patients with ischemic stroke or transient ischemic attack are at risk of developing new microbleeds over 5.5 years, despite most surviving patients remaining clinically stable. Systolic blood pressure is the strongest predictor of microbleed development; better control of hypertension may help prevent new microbleed formation.

Polymerase chain reaction analysis and oligoclonal antibody in the cerebrospinal fluid from 34 patients with varicella-zoster virus infection of the nervous system.

Objective: To study cerebrospinal fluid (CSF) and serum samples from 34 consecutive patients suspected of having varicella-zoster virus (VZV) infection of the central nervous system (CNS). Population and methods: The patients were divided into three groups. The first group consisted of 27 patients with a rash in one to three dermatomes and clinical suspicion of meningitis and radiculitis; among them, three subgroups were distinguished according to the affected dermatome: ophthalmicus (n = 9), oticus (n = 11) and cervico-thoraco-lumbar zoster (n = 7). Four cases of zoster sine herpete (ZSH) were included in the second group: these patients presented with either radiculitis (n = 2) or meningoencephalitis (n = 2), without cutaneous eruption. The third group consisted of three patients with a generalised rash and encephalitis. A polymerase chain reaction (PCR) for VZV DNA and antigen-driven immunoblots for oligoclonal anti-VZV antibodies were carried out on all CSF samples. Results: PCR of the CSF was positive in 44% of the patients from the first group, mainly within the first 7 days after eruption. In addition, intrathecal synthesis of anti-VZV antibodies was detected in 37% of patients, always after an interval of 7 days (p<0.0001). Among the four patients with ZSH, a positive VZV PCR was detected in three patients and CSF-specific oligoclonal anti-VZV antibodies in two. PCR was also positive in the CSF of two of the three patients with generalised rash and encephalitis; local production of anti-VZV antibodies was seen in a second CSF sample in one patient, and was also present in the third patient. Conclusion: Amplification of VZV DNA by PCR in the CSF and antigen-driven immunoblots have important diagnostic value in suspected VZV infection, although their presence depends on the timing of the CSF sampling. VZV is thought to be a causative agent in unexplained cases of meningitis associated with radiculitis or focal CNS symptoms, even in the absence of skin manifestations. In such patients, rapid diagnosis by this combined approach permits early antiviral treatment.

Strictly Lobar Microbleeds Are Associated With Executive Impairment in Patients With Ischemic Stroke or Transient Ischemic Attack

Background and Purpose— Cerebral microbleeds (CMBs) are a marker of small vessel diseases, including hypertensive arteriopathy and cerebral amyloid angiopathy, and may be associated with cognitive impairment. The relationship between CMBs and cognitive function in ischemic cerebrovascular disease remains uncertain. We, therefore, investigated the cognitive impact of CMBs in a cohort of patients with ischemic stroke or transient ischemic attack. Methods— All patients underwent detailed and comprehensive neuropsychological testing and standardized MRI, including fluid attenuation inversion recovery, T1, T2, and gradient-recalled echo T2*-weighted sequences. CMBs, white matter changes, lacunes, and territorial cortical infarcts (defined by standardized criteria) were identified, and associations with cognition assessed. Results— Three hundred twenty patients with a diagnosis of ischemic stroke or transient ischemic attack were included. Of these, 72 (22.5%) had at least 1 CMB. Of all the cognitive domains tested, only executive impairment was more prevalent in patients with CMBs than without (38% versus 25%; P=0.039). In univariate analysis, the presence of strictly lobar (but not deep) CMBs was associated with executive impairment (odds ratio, 2.49; 95% confidence interval, 1.16–5.36; P=0.019). In adjusted multivariate analyses, the presence (OR, 2.34; 95% confidence interval, 1.08–5.09; P=0.031) and number (OR, 1.33; 95% confidence interval, 1.04–1.69; P=0.022) of strictly lobar CMBs were significantly associated with executive impairment. CMBs were not associated with impairment in other cognitive domains. Conclusions— Strictly lobar CMBs are independently associated with executive dysfunction in patients with ischemic stroke or transient ischemic attack. Our findings suggest that a microangiopathy related to strictly lobar CMBs (eg, cerebral amyloid angiopathy) contributes to cognitive impairment in this population.