We used systematic reviews where available, searched Medline and Embase (from inception to September 2012) extensively for papers on lacunar stroke, for all small vessel disease components in imaging or pathology studies, on the role of reduced blood flow and inflammation, the endothelium, other potential mechanisms, risk factors, in human and animal studies, population-based, cohort studies, and clinical trials. We used the key words “lacunar”, “small vessel disease”, “white matter lesions”,
ReviewMechanisms of sporadic cerebral small vessel disease: insights from neuroimaging
Introduction
Cerebral small vessel disease (SVD) is the term commonly used to describe a syndrome of clinical, cognitive, neuroimaging, and neuropathological findings thought to arise from disease affecting the perforating cerebral arterioles, capillaries, and venules, and the resulting brain damage in the cerebral white and deep grey matter.1 These perforating vessels are essential to maintain optimum functioning of the brain's most metabolically active nuclei and complex white matter networks.2
In the past 15 years, SVD has been recognised as a serious problem. The disease is very common and causes substantial cognitive,3 psychiatric,4 and physical disabilities,5, 6 is responsible for about a fifth of all strokes worldwide,7 more than doubles the future risk of stroke,8, 9 and contributes to up to 45% of dementias.10 The cost to society is huge. Because the cause of disease is unknown, prevention and treatment (still mostly empirical) are probably suboptimum11, 12 or even dangerous.13 This unawareness could have resulted from attention being given to other stroke mechanisms (ie, cortical atherothromboembolic and cardioembolic stroke), the cognitive component being overshadowed by Alzheimer's disease, and because most research has focused on individual features of SVD and did not recognise the combined components as one disorder.
Why is so little known about such an important disease? Small vessels are difficult to image and investigate in vivo.14 The clinical manifestations are diverse and include: sudden-onset stroke symptoms or syndromes; covert neurological symptoms that include mild, largely ignored, neurological symptoms and signs;15 self-reported cognitive difficulties;16 progressive cognitive decline;6 dementia; depression;4 and physical disabilities.5 Reliance on clinical features and CT scanning to differentiate between lacunar and non-lacunar stroke is imprecise and has probably confounded epidemiological and observational studies of risk factor associations.17 Many trials have not explicitly differentiated ischaemic stroke subtypes, and might have overlooked any differences in treatment responses between patients with different subtypes of stroke.18 Death resulting directly from lacunar stroke is rare, so most pathology shows late-stage disease.19 Only a few studies of human lacunar stroke pathology have been done19 and few studies compared imaging and pathology findings.20 To backtrack from a late-stage scar to the initial pathology is difficult. Much of SVD is clinically silent and late, and experimental models are limited by lack of a mechanism to mimic.21, 22 Terminology for clinical features, imaging,23 and the pathology24 of SVD is highly varied. Standardisation of terminology for imaging features is the subject of an international collaboration of experts; their report is due in 2013.25 Until the terminology has been standardised, we use some traditional terms because these were used in the reports that formed the basis of this Review. We focus on common sporadic SVD and do not discuss any of the rare hereditary forms of SVD (eg, CADASIL, CARASIL, COL4AI, Fabry's, and HERNS) except where these diseases have immediate relevance to sporadic SVD. For space reasons, we do not discuss details of amyloid-associated angiopathy (ie, cerebral amyloid angiopathy) because this has been the subject of recent reviews.26
In this Review, we will discuss traditional perceived mechanisms for SVD and then focus on a novel pathway that may provide a better fit with available data and testable predictions for future study. To achieve this, we will focus on the pathogenesis of the microvascular and brain abnormality, which is undetermined in most cases of SVD. We define SVD as a sporadic intrinsic process affecting small cerebral arterioles, capillaries, and sometimes venules. Features of SVD probably develop over many years before they become clinically evident. The main mechanism underlying SVD-related brain injury is usually assumed to be ischaemia, which acts through narrowed arteries or structural or functional occlusion (eg, vasospasm, impaired autoregulation, or hypotension). However, arteriolar occlusion might be a late-stage phenomenon and does not explain the early pathology of the disease. We discuss specific SVD imaging features to help put the commonest suspected mechanisms into perspective, then focus on what we consider to be a key problem: diffuse cerebrovascular endothelial failure. We summarise evidence suggesting that endothelial damage leads to increased permeability with leakage of material into the vessel wall and perivascular tissue, damage to the vessel wall, inflammation, demyelination, glial scarring, thickening and stiffness of the vessel wall, impaired autoregulation, and at a late stage, luminal narrowing and occlusion, precipitating discrete focal brain parenchymal ischaemia and infarction.
Section snippets
History of ideas about SVD pathophysiology
Modern ideas about aetiology and pathogenesis come from the seminal post-mortem work of C Miller Fisher done between 1955 and 1973. His work was based on detailed clinicopathological and vascular post-mortem examinations of 20 patients in whom he studied between one and 50 individual lesions (lacunes, lacunar infarcts, and perforating arterioles).27, 28, 29, 30, 31 After the introduction of CT scanning in 1973, pathological examination of the brain in patients with lacunar stroke almost
Features of SVD on MRI
The main imaging features of SVD (now recognised to be inter-related) visible on conventional MRI at 1·5T or 3T include acute lacunar (or small subcortical) infarcts or haemorrhages, lacunes (fluid-filled cavities thought to show old infarcts, many clinically silent),9 white matter hyperintensities (in which many investigators include small deep grey matter hyperintensities, mostly clinically silent),32 visible perivascular spaces,33 microbleeds,34 and brain atrophy (figure 1).35 Other emerging
Mechanisms underlying lacunar infarcts, lacunes, and white matter hyperintensities
The commonest abnormality described pathologically19, 27, 30, 31 is a diffuse, intrinsic disease of the small (40–200 μm diameter) arterioles, referred to by Fisher as arteriolosclerosis, lipohyalinosis, or fibrinoid necrosis (depending on severity of the abnormality), which he thought largely to result from hypertension. The vessel wall changes include infiltration of plasma components and inflammatory cells into the vessel wall and perivascular tissue with resulting vessel wall and
Other mechanisms
Some years ago, we observed that an abnormal perforating arteriole could sometimes be seen in the centre of an acute symptomatic lacunar infarct.14 The arteriolar wall appeared thickened as it passed through the infarct not proximal to it (as might be expected with a typical cortical atherothromboembolic infarct), with a signal that indicated thrombus in the lumen and blood products in and around the arteriole wall. This led to scrutiny of Fisher's original descriptions of the microvascular
Proposed role of early endothelial failure
Since first postulated, more evidence has accumulated for the hypothesis that early endothelial failure is a main precipitant of sporadic SVD. At the capillary level, the endothelium forms a key part of the blood–brain barrier,110 a phylogenetically important structure for conservation of neuronal function that is present in drosophila to human beings.111 Because the blood–brain barrier impedes the passage of many drugs into the brain, and thereby limits potential therapeutic approaches, this
Why does the endothelium fail?
The cerebrovascular endothelium becomes increasingly permeable with age:123 patients aged 70–80 years have an almost two times more permeable blood–brain barrier compared with patients younger than 70 years. Up to the age of 60 years, the increase in permeability of the blood–brain barrier per decade is probably less marked than in people older than 60 years, suggesting that, as with many ageing-related features, loss of endothelial integrity can start in different people at different ages and
Insights from pathology of SVD
In the study of SVD so far, pathology has had a minor although pivotal role. Patients rarely die in the acute phase of SVD, and the disease pathology is often observed at post mortem almost as an incidental finding (figure 5). Subacute lesions are rarely observed (appendix), on the basis of size and in the absence of any substantial relevant clinical dysfunction in life, are assumed to be asymptomatic lacunes (appendix). Imaging correlation is rarely available. The need for a unified approach
Other mechanisms suspected from imaging
Few studies have measured cerebral blood flow in patients with SVD, and those that have have produced conflicting results. Cerebral blood flow and blood flow velocities decrease as people get older. Reduced cerebral blood flow was observed with MRI in patients with more white matter hyperintensities in some,160 but not other161 studies; both studies found associations between cerebral blood flow and atrophy suggesting that a fall in cerebral blood flow might happen secondary to tissue loss. Old
Future directions and conclusions
Until more is known about the mechanism of SVD, we should continue with careful clinical management of vascular risk factors, particularly hypertension.142 Many combined antiplatelet agents should be used cautiously in patients with pure SVD without other large-artery risk factors.18 Until we understand the cause of white matter hyperintensities, instead of being referred to as ischaemic, perhaps these intensities should be called white matter hyperintensities, ageing-related white matter
Search strategy and selection criteria
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