Small vessel disease is a disorder of cerebral microvessels that causes white matter hyperintensities and several other common abnormalities (eg, recent small subcortical infarcts and lacunes) seen ...on brain imaging. Despite being a common cause of stroke and vascular dementia, the underlying pathogenesis is poorly understood. Research in humans has identified several manifestations of cerebral microvessel endothelial dysfunction including blood–brain barrier dysfunction, impaired vasodilation, vessel stiffening, dysfunctional blood flow and interstitial fluid drainage, white matter rarefaction, ischaemia, inflammation, myelin damage, and secondary neurodegeneration. These brain abnormalities are more dynamic and widespread than previously thought. Relationships between lesions and symptoms are highly variable but poorly understood. Major challenges are the determination of which vascular dysfunctions are most important in pathogenesis, which abnormalities are reversible, and why lesion progression and symptomatology are so variable. This knowledge will help to identify potential targets for intervention and improve risk prediction for individuals with small vessel disease.
Summary The term cerebral small vessel disease (SVD) describes a range of neuroimaging, pathological, and associated clinical features. Clinical features range from none, to discrete focal ...neurological symptoms (eg, stroke), to insidious global neurological dysfunction and dementia. The burden on public health is substantial. The pathogenesis of SVD is largely unknown. Although the pathological processes leading to the arteriolar disease are associated with vascular risk factors and are believed to result from an intrinsic cerebral arteriolar occlusive disease, little is known about how these processes result in brain disease, how SVD lesions contribute to neurological or cognitive symptoms, and the association with risk factors. Pathology often shows end-stage disease, which makes identification of the earliest stages difficult. Neuroimaging provides considerable insights; although the small vessels are not easily seen themselves, the effects of their malfunction on the brain can be tracked with detailed brain imaging. We discuss potential mechanisms, detectable with neuroimaging, that might better fit the available evidence and provide testable hypotheses for future study.
Summary Background Recombinant tissue plasminogen activator (rt-PA, alteplase) improved functional outcome in patients treated soon after acute ischaemic stroke in randomised trials, but licensing is ...restrictive and use varies widely. The IST-3 trial adds substantial new data. We therefore assessed all the evidence from randomised trials for rt-PA in acute ischaemic stroke in an updated systematic review and meta-analysis. Methods We searched for randomised trials of intravenous rt-PA versus control given within 6 h of onset of acute ischaemic stroke up to March 30, 2012. We estimated summary odds ratios (ORs) and 95% CI in the primary analysis for prespecified outcomes within 7 days and at the final follow-up of all patients treated up to 6 h after stroke. Findings In up to 12 trials (7012 patients), rt-PA given within 6 h of stroke significantly increased the odds of being alive and independent (modified Rankin Scale, mRS 0–2) at final follow-up (1611/3483 46·3% vs 1434/3404 42·1%, OR 1·17, 95% CI 1·06–1·29; p=0·001), absolute increase of 42 (19–66) per 1000 people treated, and favourable outcome (mRS 0–1) absolute increase of 55 (95% CI 33–77) per 1000. The benefit of rt-PA was greatest in patients treated within 3 h (mRS 0–2, 365/896 40·7% vs 280/883 31·7%, 1·53, 1·26–1·86, p<0·0001), absolute benefit of 90 (46–135) per 1000 people treated, and mRS 0–1 (283/896 31·6% vs 202/883 22·9%, 1·61, 1·30–1·90; p<0·0001), absolute benefit 87 (46–128) per 1000 treated. Numbers of deaths within 7 days were increased (250/2807 8·9% vs 174/2728 6·4%, 1·44, 1·18–1·76; p=0·0003), but by final follow-up the excess was no longer significant (679/3548 19·1% vs 640/3464 18·5%, 1·06, 0·94–1·20; p=0·33). Symptomatic intracranial haemorrhage (272/3548 7·7% vs 63/3463 1·8%, 3·72, 2·98–4·64; p<0·0001) accounted for most of the early excess deaths. Patients older than 80 years achieved similar benefit to those aged 80 years or younger, particularly when treated early. Interpretation The evidence indicates that intravenous rt-PA increased the proportion of patients who were alive with favourable outcome and alive and independent at final follow-up. The data strengthen previous evidence to treat patients as early as possible after acute ischaemic stroke, although some patients might benefit up to 6 h after stroke. Funding UK Medical Research Council, Stroke Association, University of Edinburgh, National Health Service Health Technology Assessment Programme, Swedish Heart-Lung Fund, AFA Insurances Stockholm (Arbetsmarknadens Partners Forsakringsbolag), Karolinska Institute, Marianne and Marcus Wallenberg Foundation, Research Council of Norway, Oslo University Hospital.
Since 2015 endovascular treatment has been an established treatment for intracranial large artery occlusion up to 6 h after symptom onset or when the patient was last known well.1 The effect of ...endovascular treatment within 6 h is strong; however, the timepoint when recanalisation therapy becomes ineffective varies between individuals, and some patients might benefit after 6 h. The DEFUSE-3 and DAWN trials tested endovascular treatment up to 16 h or 24 h after symptom onset in patients selected using clinical criteria and perfusion imaging (to identify ischaemic core and tissue-at-risk volumes within strict limits), and showed benefit within these strict criteria.2,3 On this basis, endovascular treatment was extended for clinical use beyond 6 h after stroke for patients meeting the DEFUSE-3 and DAWN clinical and perfusion imaging criteria. ...MR CLEAN-LATE showed the benefit of endovascular treatment in patients outside the Dutch endovascular treatment extended treatment guidelines based on DEFUSE-3 and DAWN criteria. ...MR CLEAN-LATE used pragmatic clinical patient selection criteria, and routine, widely available, easy-to-interpret brain imaging, without recourse to complex perfusion imaging or Alberta Stroke Program Early CT Score (ASPECTS) cutoff points.
To investigate the relationship between baseline white matter hyperintensities (WMH) in patients with ischemic stroke and long-term risk of dementia, functional impairment, recurrent stroke, and ...mortality.
Following the Meta-analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO protocol: CRD42018092857), we systematically searched Medline and Scopus for cohort studies of ischemic stroke patients examining whether MRI- or CT-assessed WMH at baseline are associated with dementia, functional impairment, recurrent stroke, and mortality at 3 months or later poststroke. We extracted data and evaluated study quality with the Newcastle-Ottawa scale. We pooled relative risks (RR) for the presence and severity of WMH using random-effects models.
We included 104 studies with 71,298 ischemic stroke patients. Moderate/severe WMH at baseline were associated with increased risk of dementia (RR 2.17, 95% confidence interval CI 1.72-2.73), cognitive impairment (RR 2.29, 95% CI 1.48-3.54), functional impairment (RR 2.21, 95% CI 1.83-2.67), any recurrent stroke (RR 1.65, 95% CI 1.36-2.01), recurrent ischemic stroke (RR 1.90, 95% CI 1.26-2.88), all-cause mortality (RR 1.72, 95% CI 1.47-2.01), and cardiovascular mortality (RR 2.02, 95% CI 1.44-2.83). The associations followed dose-response patterns for WMH severity and were consistent for both MRI- and CT-defined WMH. The results remained stable in sensitivity analyses adjusting for age, stroke severity, and cardiovascular risk factors, in analyses of studies scoring high in quality, and in analyses adjusted for publication bias.
Presence and severity of WMH are associated with substantially increased risk of dementia, functional impairment, stroke recurrence, and mortality after ischemic stroke. WMH may aid clinical prognostication and the planning of future clinical trials.
Background
Perivascular spaces, visible on brain magnetic resonance imaging, are thought to be associated with small vessel disease, neuroinflammation, and to be important for cerebral hemodynamics ...and interstitial fluid drainage.
Aims
To benchmark current knowledge on perivascular spaces associations with risk factors, neurological disorders, and neuroimaging lesions, using systematic review and meta-analysis.
Summary of review
We searched three databases for perivascular spaces publications, calculated odds ratios with 95% confidence interval and performed meta-analyses to assess adjusted associations with perivascular spaces. We identified 116 relevant studies (n = 36,108) but only 23 (n = 12,725) were meta-analyzable. Perivascular spaces assessment, imaging and clinical definitions varied. Perivascular spaces were associated (n; OR, 95%CI, p) with ageing (8395; 1.47, 1.28–1.69, p = 0.00001), hypertension (7872; 1.67, 1.20–2.31, p = 0.002), lacunes (4894; 3.56, 1.39–9.14, p = 0.008), microbleeds (5015; 2.26, 1.04–4.90, p = 0.04) but not WMH (4974; 1.54, 0.71–3.32, p = 0.27), stroke or cognitive impairment. There was between-study heterogeneity. Lack of appropriate data on other brain disorders and demographic features such as ethnicity precluded analysis.
Conclusions
Despite many studies, more are required to determine potential pathophysiological perivascular spaces involvement in cerebrovascular, neurodegenerative and neuroinflammatory disorders.
Cerebral small vessel disease (SVD) is highly prevalent and a common cause of ischemic and hemorrhagic stroke and dementia, yet the pathophysiology is poorly understood. Its clinical expression is ...highly varied, and prognostic implications are frequently overlooked in clinics; thus, treatment is currently confined to vascular risk factor management. Traditionally, SVD is considered the small vessel equivalent of large artery stroke (occlusion, rupture), but data emerging from human neuroimaging and genetic studies refute this, instead showing microvessel endothelial dysfunction impacting on cell-cell interactions and leading to brain damage. These dysfunctions reflect defects that appear to be inherited and secondary to environmental exposures, including vascular risk factors. Interrogation in preclinical models shows consistent and converging molecular and cellular interactions across the endothelial-glial-neural unit that increasingly explain the human macroscopic observations and identify common patterns of pathology despite different triggers. Importantly, these insights may offer new targets for therapeutic intervention focused on restoring endothelial-glial physiology.
Cerebral small vessel disease (CSVD) is a very common neurological disease in older people. It causes stroke and dementia, mood disturbance and gait problems. Since it is difficult to visualise CSVD ...pathologies in vivo, the diagnosis of CSVD has relied on imaging findings including white matter hyperintensities, lacunar ischaemic stroke, lacunes, microbleeds, visible perivascular spaces and many haemorrhagic strokes. However, variations in the use of definition and terms of these features have probably caused confusion and difficulties in interpreting results of previous studies. A standardised use of terms should be encouraged in CSVD research. These CSVD features have long been regarded as different lesions, but emerging evidence has indicated that they might share some common intrinsic microvascular pathologies and therefore, owing to its diffuse nature, CSVD should be regarded as a ‘whole-brain disease’. Single antiplatelet (for acute lacunar ischaemic stroke) and management of traditional risk factors still remain the most important therapeutic and preventive approach, due to limited understanding of pathophysiology in CSVD. Increasing evidence suggests that new studies should consider drugs that target endothelium and blood–brain barrier to prevent and treat CSVD. Epidemiology of CSVD might differ in Asian compared with Western populations (where most results and guidelines about CSVD and stroke originate), but more community-based data and clear stratification of stroke types are required to address this.
Background: Perivascular spaces (PVS) are an important component of cerebral small vessel disease (SVD), several inflammatory disorders, hypertension and blood-brain barrier breakdown, but are ...difficult to quantify. A recent international collaboration of SVD experts has highlighted the need for a robust, easy-to-use PVS rating scale for the effective investigation of the diagnostic and prognostic significance of PVS. The purpose of the current study was to develop and extend existing PVS scales to provide a more comprehensive scale for the measurement of PVS in the basal ganglia, centrum semiovale and midbrain, and to test its intra- and inter-rater agreement, assessing reasons for discrepancy. Methods: We reviewed previously published PVS scales, including site of PVS assessed, rating method, and size and morphological criteria. Retaining key features, we devised a more comprehensive scale in order to improve the reliability of PVS rating. Two neuroradiologists tested the new scale in MRI brain scans of 60 patients from two studies (stroke, ageing population), chosen to represent a full range of PVS, and demonstrating concomitant features of SVD such as lacunes and white matter hyperintensities. We rated basal ganglia, centrum semiovale, and midbrain PVS. Basal ganglia and centrum semiovale PVS were rated 0 (none), 1 (1-10), 2 (11-20), 3 (21-40) and 4 (>40), and midbrain PVS were rated 0 (none visible) or 1 (visible). We calculated kappa statistics for rating, assessed consistency in use of PVS categories (Bhapkar test) and reviewed sources of discrepancy. Results: Intra- and inter-rater kappa statistics were highest for basal ganglia PVS (range 0.76-0.87 and 0.8-0.9, respectively) than for centrum semiovale PVS (range 0.68-0.75 and 0.61-0.8, respectively) or midbrain PVS (inter-rater range 0.51-0.52). Inter-rater consistency was better for basal ganglia compared to centrum semiovale PVS (Bhapkar statistic 2.49-3.72, compared to 6.79-21.08, respectively). Most inter-rater disagreements were due to very faint PVS, coexisting extensive white matter hyperintensities (WMH) or the presence of lacunes. Conclusions: We developed a more inclusive and robust visual PVS rating scale allowing rating of all grades of PVS severity on structural brain imaging. The revised PVS rating scale has good observer reliability for basal ganglia and centrum semiovale PVS, best for basal ganglia PVS, and moderate reliability for midbrain PVS. Agreement is influenced by PVS severity and the presence of background features of SVD. The current scale can be used in further studies to assess the clinical implications of PVS.
Abstract
Small vessel diseases (SVDs) are a group of disorders that result from pathological alteration of the small blood vessels in the brain, including the small arteries, capillaries and veins. ...Of the 35-36 million people that are estimated to suffer from dementia worldwide, up to 65% have an SVD component. Furthermore, SVD causes 20-25% of strokes, worsens outcome after stroke and is a leading cause of disability, cognitive impairment and poor mobility. Yet the underlying cause(s) of SVD are not fully understood. Magnetic resonance imaging has confirmed enlarged perivascular spaces (PVS) as a hallmark feature of SVD. In healthy tissue, these spaces are proposed to form part of a complex brain fluid drainage system which supports interstitial fluid exchange and may also facilitate clearance of waste products from the brain. The pathophysiological signature of PVS and what this infers about their function and interaction with cerebral microcirculation, plus subsequent downstream effects on lesion development in the brain has not been established. Here we discuss the potential of enlarged PVS to be a unique biomarker for SVD and related brain disorders with a vascular component. We propose that widening of PVS suggests presence of peri-vascular cell debris and other waste products that form part of a vicious cycle involving impaired cerebrovascular reactivity, blood-brain barrier dysfunction, perivascular inflammation and ultimately impaired clearance of waste proteins from the interstitial fluid space, leading to accumulation of toxins, hypoxia, and tissue damage. Here, we outline current knowledge, questions and hypotheses regarding understanding the brain fluid dynamics underpinning dementia and stroke through the common denominator of SVD.
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