Cerebral Small Vessel Disease (CSVD)

Cerebral small vessel disease (CSVD) is an umbrella term for a range of disease processes affecting the brain's small perforating arterioles, capillaries, venules and surrounding brain tissue. The condition affects the structure and function of the cerebral microvascular network and is characterized by both clinical manifestations and characteristic MRI findings¹. Common imaging findings include white matter hyperintensities (WMH), small subcortical infarcts, microinfarcts, lacunes, enlarged perivascular spaces (PVS), microbleeds, superficial siderosis, intracerebral hemorrhage (ICH) and cerebral atrophy.

Cerebral small vessel disease and brain microvascular changes

CSVD is therefore not a single disease, but a broad spectrum of microvascular changes that cause structural and functional disturbances in the brain. This may lead to neurological symptoms and reduced function depending on the location and extent of the lesions².

The most common clinical manifestations of CSVD include:

• Lacunar ischemic strokes: Small deep infarcts caused by occlusion of penetrating arteries.

• Intracerebral hemorrhage (ICH): Particularly in the basal ganglia, thalamus, brainstem and cerebellum.

• Cognitive impairment: Ranging from mild vascular cognitive impairment to vascular dementia.

Epidemiology

CSVD is the most common form of cerebrovascular disease and a leading cause of both ischemic stroke and vascular dementia. It accounts for a substantial proportion of:

• Ischemic strokes (exact percentage not provided in the source text)

• 45% of cases of vascular dementia

The prevalence of CSVD increases with age and has been identified in:

• 5% of people at 50 years of age

• Nearly 100% of people at 90 years of age³

CSVD shows no clear sex difference in prevalence, but for every symptomatic stroke, as many as ten asymptomatic 'silent' infarcts related to CSVD may occur. Even without acute symptoms, such silent infarcts are associated with a threefold higher risk of future symptomatic stroke, independent of other risk factors³.

CSVD often occurs together with other comorbidities, particularly hypertension, diabetes, cardiovascular disease and metabolic disorders. Clinical consequences such as gait impairment, increased fall risk and cognitive decline are therefore not necessarily a normal part of aging, but may reflect underlying small vessel disease. Distinguishing CSVD from other conditions requires careful assessment, including interpretation of neuroimaging¹.

Subtypes

Cerebral small vessel disease (CSVD) can be classified according to pathological, radiological and clinical criteria. A common distinction is made between amyloid-related and non-amyloid-related small vessel disease⁴. For a more detailed classification, CSVD has been divided into six main types according to the underlying disease mechanism and associated conditions:

• Type I: Arteriolosclerotic / Age-Related CSVDAssociated with hypertension and diabetes. This is the most common form and results from thickening and degeneration of small arterial walls with reduced perfusion of deep brain structures.

• Type II: Amyloid-Related CSVDAssociated with cerebral amyloid angiopathy and neurodegenerative diseases such as Alzheimer's disease and Down syndrome. Amyloid deposits weaken vessel walls and increase the risk of hemorrhage and cognitive impairment.

• Type III: Genetic CSVD (Not Amyloid-Related)Includes rare inherited forms such as:

  • CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)

  • CARASIL (autosomal recessive variant)

  • MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes)

  • Fabry disease

  • CSVD with COL4A1 mutation

  • Retinal vasculopathy with leukodystrophy due to TREX1 mutation

  • Hereditary multi-infarct dementia (Swedish type)

• Type IV: Immunological / Inflammatory CSVDAssociated with systemic vasculitides such as:

  • IgA vasculitis

  • Eosinophilic granulomatosis with polyangiitis

  • Granulomatosis with polyangiitis

  • Cryoglobulinemic vasculitis

  • Microscopic polyangiitis

  • Primary CNS vasculitis

  • Secondary vasculitis caused by infections (HIV, syphilis, tuberculosis)

  • Connective tissue diseases (SLE, scleroderma, rheumatoid vasculitis, dermatomyositis, Sjögren syndrome)

• Type V: Venous CollagenosisA less common subtype characterized by thickening of venous vessel walls, resulting in impaired drainage and subsequent brain injury.

• Type VI: Other CSVDIncludes rarer and unclassifiable variants.

Among these, type I and type II are the most common and represent age-related arteriolosclerosis and amyloid angiopathy, respectively⁴.

Clinical Manifestations

The clinical symptoms of CSVD depend on the location and extent of the lesions and include⁵:

• Ischemic lacunar strokes

• Intracerebral hemorrhages

• Cognitive impairment and vascular dementia

• Psychiatric symptoms, such as depression or apathy

• Gait disturbances, particularly a broad-based and slow gait

• Urinary incontinence, often occurring together with gait impairment and symptoms of dementia

Neuroimaging

CSVD is characterized by several typical MRI findings, including⁵:

• Small subcortical infarcts (often lacunar)

• White matter hyperintensities (WMH)

• Enlarged perivascular spaces (PVS)

• Microbleeds

• Cortical atrophy

• Lacunes

Associations have been reported between inflammatory biomarkers and the extent of periventricular white matter changes.

Risk Factors

The most common risk factors for CSVD can be divided into vascular, lifestyle-related, environmental and lifelong factors:

• Hypertension (the most important modifiable factor)

• Diabetes

• Smoking

• Obesity

• Depression

• Pregnancy-related conditions such as preeclampsia

• Dyslipidemia

Pathophysiological Process

The underlying mechanisms of CSVD are complex and not fully understood, but the following processes are recognized⁵:

• Endothelial dysfunction: Endothelial cells forming the interface between blood and the vessel wall become impaired during inflammation, disrupting the blood-brain barrier.

• Neuronal apoptosis

• Diffuse axonal injury

• Demyelination

• Loss of oligodendrocytes

In addition, sleep disturbances are associated with increased systemic inflammation and may contribute to cortical atrophy. Diabetes creates a state of persistent inflammation and further increases the risk of CSVD.

Sources:

1. Clancy U, Appleton JP, Arteaga C, Doubal FN, Bath PM, Wardlaw JM. Clinical management of cerebral small vessel disease: a call for a holistic approach. Chinese medical journal. 2021 Jan 20;134(02):127-42.:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817338/ (

2. Singh A, Bonnell G, De Prey J, Buchwald N, Eskander K, Kincaid KJ, Wilson CA. Small-vessel disease in the brain. American Heart Journal Plus: Cardiology Research and Practice. 2023 Mar 1;27:100277.

3. Anita Singh et al. Small-vessel disease in the brain . American Heart Journal Plus: Cardiology Research and Practice Volume 27, March 2023, 100277: https://www.sciencedirect.com/science/article/pii/S2666602223000290

4. Litak J, Mazurek M, Kulesza B, Szmygin P, Litak J, Kamieniak P, Grochowski C. Cerebral small vessel disease. International journal of molecular sciences. 2020 Dec 20;21(24):9729.

5. Hakim AM. Small vessel disease. Frontiers in neurology. 2019 Sep 24;10:1020.

6. American Brain Foundation. Cerebral Small Vessel Disease: Learn About One Person’s Story of Early Dementia, Misdiagnosis, and Living With CSVD. : https://www.americanbrainfoundation.org/julies-story/