Elsevier

The Lancet Neurology

Volume 9, Issue 7, July 2010, Pages 689-701
The Lancet Neurology

Review
Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges

https://doi.org/10.1016/S1474-4422(10)70104-6Get rights and content

Summary

The term cerebral small vessel disease refers to a group of pathological processes with various aetiologies that affect the small arteries, arterioles, venules, and capillaries of the brain. Age-related and hypertension-related small vessel diseases and cerebral amyloid angiopathy are the most common forms. The consequences of small vessel disease on the brain parenchyma are mainly lesions located in the subcortical structures such as lacunar infarcts, white matter lesions, large haemorrhages, and microbleeds. Because lacunar infarcts and white matter lesions are easily detected by neuroimaging, whereas small vessels are not, the term small vessel disease is frequently used to describe the parenchyma lesions rather than the underlying small vessel alterations. This classification, however, restricts the definition of small vessel disease to ischaemic lesions and might be misleading. Small vessel disease has an important role in cerebrovascular disease and is a leading cause of cognitive decline and functional loss in the elderly. Small vessel disease should be a main target for preventive and treatment strategies, but all types of presentation and complications should be taken into account.

Introduction

Small vessel disease is a term used with various meanings and in different contexts (ie, pathological, clinical, and neuroimaging aspects). These diseases are thought to be the most frequent pathological neurological processes1 and have a crucial role in at least three fields: stroke, dementia, and ageing. In this Review, the definition of small vessel disease is critically reassessed and an overview of recently described clinical consequences of cerebral forms of the disease is provided. Clarification of some of these concepts is needed because the term small vessel disease is likely to be used (or otherwise misused) more frequently in the near future as risk of developing these diseases increases with the ageing population and as increased use of MRI will identify more people with these diseases. Developing lines of research into the treatment of small vessel disease are outlined, and suggestions on the role of neuroimaging as a possible surrogate marker in therapeutic trials are provided. The aim of this Review is to provide clinicians and researchers with some basic concepts with a modern overview of small vessel disease to enable understanding of recent progress and future directions in the field.

Section snippets

Definitions

The term small vessel disease encompasses all the pathological processes that affect the small vessels of the brain, including small arteries and arterioles but also capillaries and small veins. However, the definition of a small vessel is not uniform: the results from a survey showed that there was less than 50% agreement among leading neuropathological centres on its definition.2 Most often, small vessel disease is used to refer only to the arterial vessels and little attention has been paid

Pathological features

Most of the topics dealt with in this Review are linked to the first two types of small vessel diseases and, therefore, only the pathological characteristics of these diseases are described.

Neuroimaging correlates of small vessel disease

As mentioned earlier, the consequences of small vessel disease on the brain parenchyma are heterogeneous, encompassing ischaemic and haemorrhagic manifestations (Figure 1, Figure 2). However, in neuroimaging, the term small vessel disease is often used misleadingly to describe the ischaemic consequences (ie, white matter lesions and lacunar lesions). Haemorrhagic lesions can be further distinguished as macrolesions and microlesions. Although major haemorrhages are easily recognised by

Small vessel disease and acute ischaemic stroke

Small vessel disease is the cause of about a quarter of all acute ischaemic strokes.104, 105 Overall, strokes caused by small vessel disease are less severe than other types of stroke in terms of the clinical picture during the acute phase and short-term prognosis.106, 107 However, the long-term outcome of these patients cannot be thought of as benign in terms of mortality and functional impairment.108 No specific treatment for strokes caused by small vessel disease in the acute phase has yet

Conclusions and future directions

Small vessel disease is an important cause of stroke, cognitive decline, and age-related disability. More attention and targeted efforts are needed to better understand the pathogenesis of vascular injury to the brain caused by small vessel disease and to thoroughly define the clinical consequences of these diseases. Given the frequent coexistence of different forms of small vessel disease (ie, white matter lesions, lacunar infarcts, and microbleeds), all relevant lesion types need to be taken

Search strategy and selection criteria

References for this Review were identified through searches of PubMed with the search terms “small vessel disease(s)”, “white matter lesions”, “white matter changes”, “lacunar infarcts”, “subcortical vascular dementia”, “vascular cognitive impairment”, “neuroimaging”, “pathology”, and “therapy” from 1966 to January, 2010. Articles were also identified through searches of the author's own files. Only papers published in English were reviewed.

References (151)

  • GC Román et al.

    Subcortical ischaemic vascular dementia

    Lancet Neurol

    (2002)
  • CS Thompson et al.

    Living beyond our physiological means: small vessel disease of the brain is an expression of a systemic failure in arteriolar function: a unifying hypothesis

    Stroke

    (2009)
  • L Pantoni et al.

    Postmortem examination of vascular lesions in cognitive impairment. A survey among neuropathological services

    Stroke

    (2006)
  • DM Moody et al.

    Periventricular venous collagenosis: association with leukoaraiosis

    Radiology

    (1995)
  • GF Rowbotham et al.

    Circulation of the cerebral hemispheres

    Br J Surg

    (1965)
  • R van den Bergh

    Centrifugal elements in the vascular pattern of the deep intracerebral blood supply

    Angiologica

    (1969)
  • J De Reuck

    The human periventricular arterial blood supply and the anatomy of cerebral infarctions

    Eur Neurol

    (1971)
  • L Pantoni et al.

    Pathogenesis of leukoaraiosis: a review

    Stroke

    (1997)
  • K Hara et al.

    Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease

    N Engl J Med

    (2009)
  • E Ballabio et al.

    Monogenic vessel diseases related to ischemic stroke: a clinical approach

    J Cereb Blood Flow Metab

    (2007)
  • SS Razvi et al.

    Single gene disorders causing ischaemic stroke

    J Neurol

    (2006)
  • JC Jennette et al.

    Small-vessel vasculitis

    N Engl J Med

    (1997)
  • A Furuta et al.

    Medullary arteries in aging and dementia

    Stroke

    (1991)
  • GA Lammie et al.

    Nonhypertensive cerebral small-vessel disease. An autopsy study

    Stroke

    (1997)
  • J Ogata et al.

    Neuropathology of ischemic brain injury

  • K-L Ho et al.

    Neuropathology of small blood vessels in selected diseases of the cerebral white matter

  • L Pantoni et al.

    Cerebral small vessel disease: pathological and pathophysiological aspects in relation to vascular cognitive impairment

  • HV Vinters

    Cerebral amyloid angiopathy. A critical review

    Stroke

    (1987)
  • JP Vonsattel et al.

    Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study

    Ann Neurol

    (1991)
  • KA Jellinger et al.

    Incidence of cerebrovascular lesions in Alzheimer's disease: a postmortem study

    Acta Neuropathol

    (2003)
  • M Haglund et al.

    Severe cerebral amyloid angiopathy characterizes an underestimated variant of vascular dementia

    Dement Geriatr Cogn Disord

    (2004)
  • F Coria et al.

    Cerebral amyloid angiopathies

    Neuropathol Appl Neurobiol

    (1996)
  • EE Smith et al.

    Cerebral amyloid angiopathy and lobar intracerebral hemorrhage

    Arch Neurol

    (2006)
  • HC Koennecke

    Cerebral microbleeds on MRI: prevalence, associations, and potential clinical implications

    Neurology

    (2006)
  • A Viswanathan et al.

    Cerebral microhemorrhage

    Stroke

    (2006)
  • F Gray et al.

    Leukoencephalopathy in diffuse hemorrhagic cerebral amyloid angiopathy

    Ann Neurol

    (1985)
  • K Imaoka et al.

    Leukoencephalopathy with cerebral amyloid angiopathy: a semiquantitative and morphometric study

    J Neurol

    (1999)
  • WT Kimberly et al.

    Silent ischemic infarcts are associated with hemorrhage burden in cerebral amyloid angiopathy

    Neurology

    (2009)
  • AH Hainsworth et al.

    Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review

    J Cereb Blood Flow Metab

    (2008)
  • SM Greenberg et al.

    Microbleeds versus macrobleeds: evidence for distinct entities

    Stroke

    (2009)
  • L Pantoni

    Pathophysiology of age-related cerebral white matter changes

    Cerebrovasc Dis

    (2002)
  • L Pantoni et al.

    Cerebral white matter is highly vulnerable to ischemia

    Stroke

    (1996)
  • CK Petito et al.

    Selective glial vulnerability following transient global ischemia in rat brain

    J Neuropathol Exp Neurol

    (1998)
  • A Brun et al.

    A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study

    Ann Neurol

    (1986)
  • JH Garcia et al.

    Incomplete infarct and delayed neuronal death after transient middle cerebral artery occlusion in rats

    Stroke

    (1997)
  • CM Fisher

    Lacunes: small, deep cerebral infarcts

    Neurology

    (1964)
  • CM Fisher

    Lacunar strokes and infarcts: a review

    Neurology

    (1982)
  • C Millikan et al.

    The fallacy of the lacune hypothesis

    Stroke

    (1990)
  • J Boiten et al.

    Lacunar infarcts. Pathogenesis and validity of the clinical syndromes

    Stroke

    (1991)
  • JM Wardlaw et al.

    Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia?

    Stroke

    (2003)
  • Cited by (2453)

    • Causal role of immune cell traits in stroke: A Mendelian randomization study

      2024, Journal of Stroke and Cerebrovascular Diseases
    View all citing articles on Scopus
    View full text