The effect of different combinations of vascular, dependency and cognitive endpoints on the sample size required to detect a treatment effect in trials of treatments to improve outcome after lacunar and non-lacunar ischaemic stroke

Background Endpoints that are commonly used in trials of moderate/severe stroke may be less frequent in patients with minor, non-disabling stroke thus inflating sample sizes. We tested whether trial efficiency might be improved with composite endpoints. Methods We prospectively recruited patients with lacunar and minor non-lacunar ischaemic stroke (NIHSS ≤ 7) and assessed recurrent vascular events (stroke, transient ischaemic attack (TIA), ischemic heart disease (IHD)), modified Rankin Score (mRS) and cognitive testing with the Addenbrooke’s Cognitive Examination (ACE-R) one year post-stroke. For a potential secondary prevention randomised controlled trial (RCT), we estimated sample sizes using individual or combined outcomes, at power 80% (and 90%), alpha 5%, required to detect a relative 10% risk reduction. Results Amongst 264 patients (118 lacunar, 146 non-lacunar), at one year, 30/264 (11%) patients had a recurrent vascular event, 5 (2%) had died, 3 (1%) had clinically-diagnosed dementia, 53/264 (20%) had mRS ≥ 3 and 29/158 (19%) had ACE-R ≤ 82 (57 could not attend for cognitive testing). For a potential trial, at 80% power, using mRS ≥ 3 alone would require n > 5000 participants, recurrent vascular events alone n = 9908 participants, and a composite of any recurrent vascular event, ACE-R ≤ 82, dementia or mRS ≥ 2 (present in 56% of patients) n = 2224 patients. However, including cognition increased missing data. Results were similar for lacunar and non-lacunar minor ischaemic stroke. Conclusions Composite outcomes including vascular events, dependency, and cognition reduce sample size and increase efficiency, feasibility, and relevance to patients of RCTs in minor ischaemic stroke. Efficiency might be improved further with more practical cognitive test strategies

Characteristics of patients with minor ischaemic strokes and negative MRI: a cross-sectional study

International audienceAbstract Background: Diffusion weighted (DWI) MRI is recommended in UK guidelines to evaluate minor strokes, yet can produce negative results. Objective: We determined the rate of negative MRI (including DWI) and associated features in patients presenting to hospital with minor strokes. Methods: We performed a prospective observational cross sectional study in a teaching hospital of patients with a clinical diagnosis of ischaemic lacunar or minor cortical stroke. We performed MRI (DWI, T2, FLAIR, T2* and T1) as soon as possible after presentation. We used multivariate analysis to determine predictors of negative DWI and MRI (all sequences). Gold standard for clinical diagnosis of stroke was the opinion of an expert panel. Results: We recruited 246 patients, mean age 68.1 years (SD 11.6 years), 162 were males (66%) and the median NIHSS was 2 (range 0-8). The median time from stroke onset to MR scan was 12 days (IQR 4-27 days). Eighty-one patients (33%) did not show any ischaemia on DWI. Sixty patients (24%) did not show the recent infarct on MRI (DWI/T2/FLAIR). With multivariate analysis, less severe stroke, younger age, female gender and increased time from stroke onset to scan were associated with negative DWI. With multivariate analysis, younger age and female gender were associated with negative MRI (DWI or T2 or FLAIR) scans. Conclusions: There is a high rate of negative MRI and DWI amongst patients with minor stroke (a third) which has important management and research implications. A negative MRI or DWI does not exclude the diagnosis of stroke

Retinopathy in ischemic stroke subtypes

BACKGROUND AND PURPOSE: Lacunar stroke is associated with an intrinsic cerebral small vessel disorder of unknown aetiology although possible causes include increased blood brain barrier permeability. Retinal arterioles are similar to cerebral small vessels and retinopathy occurs secondary to increased blood retinal barrier permeability. We hypothesized that there would be higher rates of retinopathy in patients with acute lacunar versus cortical stroke. METHODS: We prospectively recruited patients presenting with acute lacunar and cortical ischaemic stroke. An experienced stroke physician diagnosed and subtyped the stroke based on clinical features and cerebral magnetic resonance imaging. We performed 6 dilated digital retinal photographs of each eye in all patients. A carefully trained physician graded retinopathy (one or more of hard or soft exudates, microaneurysms or haemorrhages) blind to stroke type as definitely present/absent or uncertain. RESULTS: We recruited 220 patients; 6 were excluded with ungradeable photographs leaving 214 patients for analysis (105 lacunar and 109 cortical strokes). Mean age was 68 years (SD 11 years) and median NIHSS 2. Similar proportions of each group had diabetes (17% lacunar v 10 % cortical) and hypertension (56% lacunar and 66% cortical). 18% of lacunar and 19% of cortical patients had any retinopathy. After adjusting for baseline differences in age, hypertension and diabetes, retinopathy was not associated with ischaemic stroke subtype. CONCLUSIONS: We have not demonstrated a strong association between retinopathy and ischaemic stroke subtype. However larger samples or assessment of other retinal vascular abnormalities may yield positive associations

Sex Differences in Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis

Background: Cerebral small vessel disease (SVD) is a common cause of stroke, mild cognitive impairment, dementia and physical impairments. Differences in SVD incidence or severity between males and females are unknown. We assessed sex differences in SVD by assessing the male-to-female ratio (M:F) of recruited participants and incidence of SVD, risk factor presence, distribution, and severity of SVD features. Methods: We assessed four recent systematic reviews on SVD and performed a supplementary search of MEDLINE to identify studies reporting M:F ratio in covert, stroke, or cognitive SVD presentations (registered protocol: CRD42020193995). We meta-analyzed differences in sex ratios across time, countries, SVD severity and presentations, age and risk factors for SVD. Results: Amongst 123 relevant studies (n = 36,910 participants) including 53 community-based, 67 hospital-based and three mixed studies published between 1989 and 2020, more males were recruited in hospital-based than in community-based studies [M:F = 1.16 (0.70) vs. M:F = 0.79 (0.35), respectively; p < 0.001]. More males had moderate to severe SVD [M:F = 1.08 (0.81) vs. M:F = 0.82 (0.47) in healthy to mild SVD; p < 0.001], and stroke presentations where M:F was 1.67 (0.53). M:F did not differ for recent (2015–2020) vs. pre-2015 publications, by geographical region, or age. There were insufficient sex-stratified data to explore M:F and risk factors for SVD. Conclusions: Our results highlight differences in male-to-female ratios in SVD severity and amongst those presenting with stroke that have important clinical and translational implications. Future SVD research should report participant demographics, risk factors and outcomes separately for males and females. Systematic Review Registration: [PROSPERO], identifier [CRD42020193995]

Blood-Brain Barrier Permeability and Long-Term Clinical and Imaging Outcomes in Cerebral Small Vessel Disease

BACKGROUND AND PURPOSE: Increased blood-brain barrier (BBB) permeability occurs in cerebral small vessel disease (SVD). It is not known if BBB changes predate progression of SVD. METHODS: We followed up patients with non-disabling lacunar or cortical stroke and BBB permeability MR imaging following their original stroke. About three years later, we assessed functional outcome (Oxford Handicap Score, OHS, poor outcome defined as 3-6), recurrent neurological events and white matter hyperintensity (WMH) progression on MRI. RESULTS: Amongst 70 patients, mean age 68 (SD±11) years, median time to clinical follow up was 39 months (IQR 30-45), median OHS was 2 (IQR 1-3); poor functional outcome was associated with higher baseline WMH score (p<0.001) and increased basal ganglia BBB permeability (p=0.046). Amongst 48 patients with follow-up MRI, WMH progression at follow-up was associated with baseline WMH (ANCOVA p<0.0001) and age (ANCOVA p=0.032). CONCLUSIONS: Further long term studies to evaluate the role of BBB dysfunction in progression of SVD are required in studies that are large enough to account for key prognostic influences such as baseline WMH and age

Vascular risk factors, large-artery atheroma, and brain white matter hyperintensities

OBJECTIVE: To determine the magnitude of potentially causal relationships among vascular risk factors (VRFs), large-artery atheromatous disease (LAD), and cerebral white matter hyperintensities (WMH) in 2 prospective cohorts. METHODS: We assessed VRFs (history and measured variables), LAD (in carotid, coronary, and leg arteries), and WMH (on structural MRI, visual scores and volume) in: (a) community-dwelling older subjects of the Lothian Birth Cohort 1936, and (b) patients with recent nondisabling stroke. We analyzed correlations, developed structural equation models, and performed mediation analysis to test interrelationships among VRFs, LAD, and WMH. RESULTS: In subjects of the Lothian Birth Cohort 1936 (n = 881, mean age 72.5 years [SD ±0.7 years], 49% with hypertension, 33% with moderate/severe WMH), VRFs explained 70% of the LAD variance but only 1.4% to 2% of WMH variance, of which hypertension explained the most. In stroke patients (n = 257, mean age 74 years [SD ±11.6 years], 61% hypertensive, 43% moderate/severe WMH), VRFs explained only 0.1% of WMH variance. There was no direct association between LAD and WMH in either sample. The results were the same for all WMH measures used. CONCLUSIONS: The small effect of VRFs and LAD on WMH suggests that WMH have a large “nonvascular,” nonatheromatous etiology. VRF modification, although important, may be limited in preventing WMH and their stroke and dementia consequences. Investigation of, and interventions against, other suspected small-vessel disease mechanisms should be addressed

Retinal microvasculature and cerebral small vessel disease in the Lothian Birth Cohort 1936 and Mild Stroke Study

Abstract Research has suggested that the retinal vasculature may act as a surrogate marker for diseased cerebral vessels. Retinal vascular parameters were measured using Vessel Assessment and Measurement Platform for Images of the Retina (VAMPIRE) software in two cohorts: (i) community-dwelling older subjects of the Lothian Birth Cohort 1936 (n = 603); and (ii) patients with recent minor ischaemic stroke of the Mild Stroke Study (n = 155). Imaging markers of small vessel disease (SVD) (white matter hyperintensities [WMH] on structural MRI, visual scores and volume; perivascular spaces; lacunes and microbleeds), and vascular risk measures were assessed in both cohorts. We assessed associations between retinal and brain measurements using structural equation modelling and regression analysis. In the Lothian Birth Cohort 1936 arteriolar fractal dimension accounted for 4% of the variance in WMH load. In the Mild Stroke Study lower arteriolar fractal dimension was associated with deep WMH scores (odds ratio [OR] 0.53; 95% CI, 0.32–0.87). No other retinal measure was associated with SVD. Reduced fractal dimension, a measure of vascular complexity, is related to SVD imaging features in older people. The results provide some support for the use of the retinal vasculature in the study of brain microvascular disease