A systematic review of dynamic cerebral and peripheral endothelial function in lacunar stroke versus controls

Background: The aetiology of cerebral small vessel disease is unknown. An association with endothelial dysfunction has been suggested. We systematically assessed all relevant studies of dynamic endothelial function in patients with lacunar stroke, as a marker of small vessel disease. Methods: We searched for studies of cerebral or peripheral vascular reactivity in patients with lacunar or cortical (i.e. large artery atheromatous) ischaemic stroke or non-stroke controls. We calculated standardised mean difference (SMD) in vascular reactivity, +/- 95% confidence intervals (CI) between small vessel disease and control groups. Results: Sixteen publications (974 patients) were included. In lacunar stroke: cerebrovascular reactivity (n=534) was reduced compared with age-matched normal (SMD -0.94, 95%CI -1.17, -0.70), but not age+risk factor-matched controls (SMD 0.08, 95%CI -0.36, 0.53) or cortical strokes (SMD -0.29, 95%CI -0.69, 0.11); forearm flow mediated dilatation (n=401) was reduced compared with age-matched normal controls (SMD -1.04, 95%CI -1.33, -0.75) and age+risk factor-matched controls (SMD -0.94, 95%CI -1.26, -0.61), but not cortical strokes (SMD -0.23, 95%CI -0.55, 0.08). Conclusions: Endothelial dysfunction is present in patients with lacunar stroke but may simply reflect exposure to vascular risk factors and having a stroke, as a similar degree of dysfunction is found in cortical (large artery atheromatous) stroke. Current data do not confirm that endothelial dysfunction is specific to small vessel stroke. Future studies should include controls with non-lacunar stroke

Potential recruitment into a clinical trial of vascular secondary prevention medications in cerebral small vessel disease, based on concomitant medication use

This research has been conducted using the UK Biobank resource. The authors are grateful to UK Biobank participants. UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government, and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government and the British Heart Foundation.Peer reviewedPublisher PD

The key challenges of discussing end-of life stroke care with patients and families: a mixed-methods electronic survey of hospital and community healthcare professionals

Background: Communication between professionals, patients and families about palliative and end-of-life care after stroke is complex and there is a need for educational resources in this area. Methods: To explore the key learning needs of healthcare professionals, a multidisciplinary, expert group developed a short electronic survey with open and closed questions, and then distributed it to six UK multiprofessional networks and two groups of local clinicians. Results: A total of 599 healthcare professionals responded. Educational topics that were either definitely or probably needed were: ensuring consistent messages to families and patients (88%); resolving conflicts among family members (83%); handling unrealistic expectations (88%); involving families in discussions without them feeling responsible for decisions (82%); discussion of prognostic uncertainties (79%); likely mode of death (72%); and oral feeding for 'comfort' in patients at risk of aspiration (71%). The free-text responses (n = 489) and 82 'memorable' cases identified similar themes. Conclusion: Key topics of unmet need for education in end-of-life care in stroke have been identified and these have influenced the content of an open access, web-based educational resource

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

Small vessel disease and dietary salt intake: cross sectional study and systematic review

Background: Higher dietary salt intake increases the risk of stroke and may increase white matter hyperintensity (WMH) volume. We hypothesized that a long-term higher salt intake may be associated with other features of small vessel disease (SVD). Methods: We recruited consecutive patients with mild stroke presenting to the Lothian regional stroke service. We performed brain magnetic resonance imaging, obtained a basic dietary salt history, and measured the urinary sodium/creatinine ratio. We also carried out a systematic review to put the study in the context of other studies in the field. Results: We recruited 250 patients, 112 with lacunar stroke and 138 with cortical stroke, with a median age of 67.5 years. After adjustment for risk factors, including age and hypertension, patients who had not reduced their salt intake in the long term were more likely to have lacunar stroke (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.10-3.29), lacune(s) (OR, 2.06; 95% CI, 1.09-3.99), microbleed(s) (OR, 3.4; 95% CI, 1.54, 8.21), severe WMHs (OR, 2.45; 95% CI 1.34-4.57), and worse SVD scores (OR, 2.17; 95% CI, 1.22-3.9). There was limited association between SVD and current salt intake or urinary sodium/creatinine ratio. Our systematic review found no previously published studies of dietary salt and SVD. Conclusion: The association between dietary salt and background SVD is a promising indication of a potential neglected contributory factor for SVD. These results should be replicated in larger, long-term studies using the recognized gold-standard measures of dietary sodium

Fractal Analysis Reveals Reduced Complexity of Retinal Vessels in CADASIL

The Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) affects mainly small cerebral arteries and leads to disability and dementia. The relationship between clinical expression of the disease and progression of the microvessel pathology is, however, uncertain as we lack tools for imaging brain vessels in vivo. Ophthalmoscopy is regarded as a window into the cerebral microcirculation. In this study we carried out an ophthalmoscopic examination in subjects with CADASIL. Specifically, we performed fractal analysis of digital retinal photographs. Data are expressed as mean fractal dimension (mean-D), a parameter that reflects complexity of the retinal vessel branching. Ten subjects with genetically confirmed diagnosis of CADASIL and 10 sex and age-matched control subjects were enrolled. Fractal analysis of retinal digital images was performed by means of a computer-based program, and the data expressed as mean-D. Brain MRI lesion volume in FLAIR and T1-weighted images was assessed using MIPAV software. Paired t-test was used to disclose differences in mean-D between CADASIL and control groups. Spearman rank analysis was performed to evaluate potential associations between mean-D values and both disease duration and disease severity, the latter expressed as brain MRI lesion volumes, in the subjects with CADASIL. The results showed that mean-D value of patients (1.42±0.05; mean±SD) was lower than control (1.50±0.04; p = 0.002). Mean-D did not correlate with disease duration nor with MRI lesion volumes of the subjects with CADASIL. The findings suggest that fractal analysis is a sensitive tool to assess changes of retinal vessel branching, likely reflecting early brain microvessel alterations, in CADASIL patients

Perivascular Spaces Segmentation in Brain MRI Using Optimal 3D Filtering

Perivascular Spaces (PVS) are a recently recognised feature of Small Vessel Disease (SVD), also indicating neuroinflammation, and are an important part of the brain's circulation and glymphatic drainage system. Quantitative analysis of PVS on Magnetic Resonance Images (MRI) is important for understanding their relationship with neurological diseases. In this work, we propose a segmentation technique based on the 3D Frangi filtering for extraction of PVS from MRI. Based on prior knowledge from neuroradiological ratings of PVS, we used ordered logit models to optimise Frangi filter parameters in response to the variability in the scanner's parameters and study protocols. We optimized and validated our proposed models on two independent cohorts, a dementia sample (N=20) and patients who previously had mild to moderate stroke (N=48). Results demonstrate the robustness and generalisability of our segmentation method. Segmentation-based PVS burden estimates correlated with neuroradiological assessments (Spearman's $\rho$ = 0.74, p $<$ 0.001), suggesting the great potential of our proposed metho

Retinal arteriolar geometry is associated with cerebral white matter hyperintensities on MRI

Background. Cerebral small vessel disease (lacunar stroke and cerebral white matter hyperintensities) is caused by vessel abnormalities of unknown aetiology. Retinal vessels show developmental and pathophysiological similarities to cerebral small vessels and microvessel geometry may influence vascular efficiency. Hypothesis. We hypothesized that retinal arteriolar branching angles or co-efficients (the ratio of the sum of the cross sectional areas of the two daughter vessels to the cross sectional area of the parent vessel at an arteriolar bifurcation) may be associated with cerebral small vessel disease. Methods. We performed a cross-sectional observational study in a tertiary referral hospital, United Kingdom. An experienced stroke physician recruited consecutive patients presenting with lacunar ischaemic stroke with a control group consisting of patients with minor cortical ischaemic stroke. We performed brain magnetic resonance imaging to assess the recent infarct and periventricular and deep white matter hyperintensities. We subtyped stroke with clinical and radiological findings. We took digital retinal photography to assess retinal arteriolar branching co-efficients and branching angles using a semi-automated technique. Results. We recruited 205 patients (104 lacunar stroke, 101 cortical stroke), mean age 68 (Standard Deviation 12) years. With multivariate analysis, increased branching coefficient was associated with periventricular white matter hyperintensities (p=0.006) and ischaemic heart disease (p<0.001); decreased branching co-efficient with deep white matter hyperintensities (p=0.003) but not with lacunar stroke subtype (p=0.96). We found no associations with retinal branching angles. Conclusions. Retinal arteriolar geometry differs between cerebral small vessel phenotypes. More research is needed to ascertain the clinical significance of these findings