We searched PubMed, Google Scholar, ClinicalTrials.gov, Cochrane Library, from Dec 1, 2012, to Dec 31, 2018, using search terms “lacunar”, “stroke”, “dementia”, “small vessel disease” and its terminologies (“white matter hyperintensities”, “white matter lesions”, “leukoaraiosis”, “lacune”, “microbleed”, “perivascular space”, “Virchow-Robin space”), “meta-analysis”, “systematic review”, and “randomised controlled trial”, restricting to human studies published in English, German, Spanish, French,
ReviewSmall vessel disease: mechanisms and clinical implications
Introduction
Small vessel disease is a disorder of the brain's small perforating arterioles, capillaries, and probably venules1 that causes various lesions that are seen on pathological examination or brain imaging with MRI or CT. Typical small vessel disease lesions are white matter hyperintensities of presumed vascular origin, lacunes, microbleeds, superficial siderosis, perivascular spaces, and microinfarcts (panel).2, 3 These lesions might be clinically silent individually, and many affected people do not have symptoms, but increasing numbers of individual lesion types and combinations of lesion types are associated with cognitive impairment, dementia, depression, mobility problems, increased risk of stroke,4 and worse outcome after stroke.5 Other typical small vessel disease lesions are recent small subcortical (or lacunar) infarcts and intracerebral haemorrhage, which typically present with stroke.2 These varied clinical presentations have usually been considered separately in research and in the clinic, and patients have been referred to separate stroke, cognition, or mobility clinics. However, small vessel disease causes about a quarter of ischaemic strokes and most haemorrhagic strokes, is the commonest cause of vascular dementia, often occurs with Alzheimer's disease, and worsens the resulting cognitive impairment,6, 7 thus contributing to about 50% of dementias worldwide, a massive health burden of stroke and dementia.4, 7
Small vessel disease-related brain damage is not confined to the visible lesions. More sensitive MRI methods show that pathological changes occur in the so-called normal appearing white matter and grey matter, which worsen as the small vessel disease lesions increase,8, 9 and that white matter fibres passing through visible lesions can die back, leading to secondary degeneration in distant cortex or the brain stem and resulting in global brain effects.8, 9, 10 Some MRI methods are exquisitely sensitive to small changes in fluid content, and studies8, 11 suggest that white matter hyperintensities, at least partly or in their early stages, represent areas of increased interstitial fluid, not just demyelination.
Small vessel disease is recognised as being increasingly diverse, including rare familial and common sporadic (ie, non-familial) forms, with apparently different subtypes, even among sporadic forms. For example, cerebral amyloid angiopathy with microbleeds and superficial siderosis has different pathology to predominantly non-haemorrhagic small vessel diseases.12
In this Review, we discuss sporadic (ie, non-familial) small vessel disease, the commonest clinically recognised form, focusing on causes and implications of white matter hyperintensities, lacunes, recent small subcortical infarcts, and subvisible findings. Microinfarcts and haemorrhagic small vessel diseases (cerebral amyloid angiopathy, microbleeds, and superficial siderosis) have been reviewed elsewhere.3, 12, 13 We review the evidence that sporadic small vessel disease starts in the endothelium, and discuss how it causes focal lesions that are more dynamic than traditionally thought, and how it affects the whole brain. We consider potential explanations for the different clinical effects of small vessel disease and highlight potential therapeutic targets and interventions.
Section snippets
Small vessel disease as a dynamic, whole-brain disorder
Pathology studies of small vessel disease mechanisms describe abnormalities in arterioles, such as arteriolosclerosis, lipohyalinosis, or fibrinoid necrosis,1, 12, 14 and risk factors, particularly hypertension.1 In arteriolosclerosis and fibrinoid necrosis, the arteriolar wall is thickened and the lumen can be narrowed, occluded, or dilated. Capillaries and venules can also be abnormal and arteriolar abnormalities and small vessel disease lesions can occur in individuals without hypertension.12
Clinical implications
Many of the clinical manifestations of small vessel disease, including stroke, cognitive decline,65 gait problems,66 apathy,67 depression,68 and extrapyramidal symptoms,69 relate to functions with structural and functional underpinnings in widely distributed neuronal networks, consistent with diffuse effects of small vessel disease on the brain, and are important when considering mechanisms and interventions. The presenting symptoms and clinical course of small vessel disease are highly
Pharmacological and lifestyle interventions
Evidence on prevention and treatment of small vessel disease comes from randomised controlled trials of vascular risk modifying agents, drugs used in other fields with relevant modes of action,84 and modifiable lifestyle factors (table).
In the Secondary Prevention of Small Subcortical Stroke (SPS3) trial of 3020 patients with lacunar ischaemic stroke (mean age 63 years, trial duration 3 years),85 long-term dual versus single antiplatelet therapy increased bleeding and death without reducing
Conclusions and future directions
Small vessel disease causes a fifth to a quarter of all strokes, age-related cognitive, physical, and mood decline, and about half of all dementias.3, 4, 5, 6, 7 Despite this high burden of disease, understanding of the pathophysiology is incomplete. Much understanding of pathophysiological mechanisms in humans derives from advanced neuroimaging methods, such as diffusion tensor imaging and imaging of the blood–brain barrier, cerebrovascular reactivity, and cerebral blood flow, which
Search strategy and selection criteria
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