Cerebral small vessel disease

Cerebral small vessel disease, also known as subcortical small vessel disease, chronic small vessel disease, or cerebral microangiopathy), is an umbrella term for lesions in the subcortical brain attributed to pathologic changes in the small vessels. It is the most common cause of vascular dementia/cognitive impairment and is a major cause of ischaemic and haemorrhagic strokes.

Terminology

There is wide variability in the literature regarding terminology for small vessel disease. 

With respect to anatomy, small vessels include arterioles, capillaries, and small veins/venules. The arterial bed has been a primary focus of the literature, with arterial small vessel disease being a proposed term for this entity, but venous collagenosis is also responsible for some of the changes ¹⁵. The small vessels involved are too small to visualise by imaging, so imaging focuses on their sequelae.

With respect to morphologic changes visible on imaging, small vessel disease includes small subcortical (lacunar) infarcts (of deep gray nuclei and deep white matter), haemorrhages, perivascular spaces, and diffuse white matter changes ^14,16. The latter has received much attention in particular and is the focus of this article. Analogous signal changes in the subcortical gray matter and brainstem are typically excluded from discussion unless explicitly stated, leading to terms that focus on small vessel disease of white matter ¹⁶.

The term leukoaraiosis is a radiological descriptor applied to white matter hypodensities on CT and high signal changes on T2-weighted MRI of presumed vascular origin ^14,16. These lesions are also called white matter lesions, white matter hyperintensities (for MRI), or white matter changes ¹⁶. Similar terms focussed on the white matter include white matter disease, white matter damage, and leukoencephalopathy (the latter usually used in the context of CADASIL) ¹⁶. Less commonly, the lesions are called unidentified bright objects on MRI, but this term has also confusingly been used to refer to the focal areas of signal intensity in brains of children with neurofibromatosis type 1, which is an unrelated process.

Many etiopathogenic types of small vessel disease are described (see below). The most common is arteriolosclerosis, or age and vascular risk factor related small vessel disease, which based on a progressive clinical syndrome of cognitive impairment and compatible imaging features is diagnosed as Binswanger disease ¹⁴, although this term has fallen in popularity. Many variant terms for this entity presume an age-related aetiology, such as age-related white matter hyperintensities/changes/disease/damage ¹⁶, although noting that not all age-related white matter changes are attributed to small vessel disease ¹⁴.

The nature of infarcts and white matter changes are primarily ischaemic, so other terms used include small vessel chronic ischaemia, microvascular ischaemia, ischaemic microangiopathy, and variants of the above terms such as ischaemic white matter disease. However, haemorrhagic manifestations of small vessel disease (cerebral(cerebral microbleeds, intracerebral haemorrhage, and cortical superficial cortical siderosis) are also important to consider for differential diagnosis and therapeutic reasons ^15,16.

Epidemiology

Chronic small vessel disease is more common with increasing age. The prevalence of white matter lesions in the general population is reported to be between 39 to 96% ¹¹.

Clinical presentation

Chronic small vessel disease is often an incidental asymptomatic finding on imaging. However, it has been shown to cause vascular dementia and it is more common in patients with dementia (vascular dementia, Alzheimer disease, Lewy body dementia) compared to the general population (100% v. 92% respectively in one study) ^11,12.

Pathology

Aetiology

There are several etiopathogenic types of cerebral small vessel diseases ¹⁵:

1. arteriolosclerosis (age-related and vascular risk factor-related small vessel disease): see Binswanger disease

2. cerebral amyloid angiopathy (sporadic or hereditary)

3. inherited/genetic small vessel diseases other than cerebral amyloid angiopathy, such as

   • CADASIL

   • CARASIL

   • MELAS

   • Fabry disease

   • retinal vasculopathy with cerebral leukoencephalopathy

   • COL4A1 brain small-vessel disease

4. inflammatory and immunologically mediated small vessel diseases (CNS vasculitis)

5. venous collagenosis

6. other small vessel diseases, such as

   • post-radiation angiopathy

   • non-amyloid microvessel degeneration in Alzheimer disease

Microscopic appearance

Histology from these lesions shows atrophy of axons and decreased myelin, although MRI overestimates the degree of demyelination with many regions of FLAIR abnormality being due to increased fluid rather than demyelination ¹⁷.  

The pathophysiology of white matter lesions is different depending on the area of involvement, i.e. periventricular or deep (subcortical) white matter. This difference is emphasised in the Fazekas scale in which the two are separated. Pathogenesis and especially its clinical significance are still incompletely understood ^3,5,17.

Periventricular white matter lesions 

Periventricular white matter changes (3-13 mm from the ventricular surface) are thought to be haemodynamically determined rather than only related to small vessel disease ⁸. This region is a vascular border zone vascularised by non-collateralising ventriculofugal vessels arising from subependymal arteries. As such, it is prone to local and systemic decrease in cerebral blood flow. It is a predictor of watershed infarcts especially when located along the posterior horns and it is correlated with carotid artery stenosis ⁸.

It is worth noting that juxtaventricular white matter changes (<3 mm from the ventricular surface), such as ependymitis granularis, are not related to small vessel disease, but rather represent cerebrospinal fluid leak due to disruption of the ependyma ¹⁰.

Deep and subcortical white matter lesions

Deep white matter changes (>13 mm from the ventricular surface, >4 mm from the corticomedullary junction) are thought to be caused by lipohyalinosis (small vessel disease), i.e. incomplete arteriosclerosis ^8,9. They are a predictor of lacunar infarcts.

Radiographic features

Chronic small vessel disease consists of bilateral patchy or diffuse white matter changes often observed on imaging studies ^6,7. The Fazekas scale has been proposed to quantify white matter lesions related to leukoaraiosis. This is especially useful in the setting of dementia. 

CT

• non-enhancing white matter hypodensities

MRI

• T1: hypointense or isointense, less conspicuous than on T2/FLAIR

• T2/FLAIR: hyperintense

• DWI: no diffusion restriction

• T1 C+ (Gd): non-enhancing

History and etymology

The term leukoaraiosis means white matter rarefaction and comes from the Greek (leuko = white and araios = rarefaction). It was first proposed by Vladimir Hachinski(fl. 2021) a Ukrainian-born Canadian neurologist. He also coined the term multi-infarct dementia and developed the Hachinski ischaemic scale ^6,13.

Differential diagnosis

The differential causes of small vessel disease are enumerated above in the Aetiology section.