Small Vessel Cerebrovascular Disease

With increasing age, people are at a greater risk of developing conditions such as strokes and dementia. These conditions have always been considered to be multifactorial (can be caused for many reasons), but they might just be attributed to a widespread age-related brain disease that still needs to be extensively researched and understood.

With improvement in life expectancy, there is an increasing prevalence of Cerebral Small Vessel Disease or CSVD. CSVD is a broad term used to describe abnormal changes seen in small blood vessels (tubes) that supply the deeper structures of the brain leading to “small vessel ischemic lesions (changes)” seen on brain scans (MRI). These changes can be found in 5% of people over 50 to almost 100% of people older than 90 years. CSVD is known to cause 25% of strokes and 45% of cases of dementia in this age group.¹

Now, let's dive into more detail about what all this means.

What is cerebral small vessel disease

Cerebral Small Vessel Disease or CSVD is a broad umbrella term used to describe several diseases that affect the small blood vessels; small arteries, arterioles, capillaries, and venules of the brain. CSVD presents as a variety of abnormal changes seen on radiological imaging (CT/MRI scans) in the brain's subcortex (white matter and deep grey areas). These changes or lesions are seen very commonly in the aging population and are mostly silent. They do not cause any symptoms but can, later on, cause problems like Cognitive decline (impaired thinking, attentiveness), Dementia, Gait disturbance (problem with walking) and Strokes. CSVD is the leading cause of functional loss and disability in the elderly, but unfortunately, research on the exact cause of the disease is limited, and there are no specific preventive and targeted treatment methods available.

Understanding CSVD

Small vessels of the brain

Like every other organ in the body, the brain gets nutrition and oxygen through the blood. The blood rich in oxygen and nutrients travel to the brain from the heart through blood vessels(tubes) called arteries and return to the heart through veins. The arteries and veins are connected by small blood vessels called capillaries. Capillaries help deliver oxygen and nutrients to the cells.

An extensive network of blood vessels supplies the brain. Large arteries entering the brain undergo multiple divisions to become smaller arteries that penetrate the brain's deeper structures. These small arteries are termed arterioles. These arterioles connect with capillaries that, in turn, connect with venules. The venules are small vessels that join together to form larger veins.

All these small blood vessels supplying the brain's deep structures are typically 50-400 micrometres in diameter and are affected in Cerebral Small Vessel Disease.² When these vessels are affected, it can decrease blood supply to different areas of the brain, causing the death of the brain tissue. This is called ischemia and is seen as changes or lesions on radiological scans and CT/MRI of the brain.

Sometimes these diseased vessels can also cause leakage and bleeding inside the brain. 

White matter and grey matter

The central nervous system comprises a collection of nerve cells called neurons. These neurons have cell bodies and long fibers.

Grey matter is the collection of neuronal cell bodies present on the surface of the brain. This is also known as the cortex. The grey matter is pinkish-grey in color and is mainly responsible for generating neuronal electrical impulses or signals.

White matter comprises a collection of neuronal fibers and is mainly responsible for transmitting nerve impulses. It is white and is present under the brain's grey matter forming the sub-cortex.

There are also islands of grey matter embedded in the white matter, forming the deep grey areas of the brain. They are mainly responsible for the coordination of movement.

In CSVD, changes are seen in the brain's subcortical white matter and deep grey areas.

CSVD on neuroimaging

Small blood vessels are difficult to see directly on brain scans. Hence abnormal changes called lesions that are caused by these diseased blood vessels are defined as markers that can be used to diagnose small vessel cerebrovascular disease.

Doctors use these biomarkers there to diagnose CSVD. You can see them written on brain MRI reports:

• Small subcortical infarcts – these are small strokes
• White matter hyperintensities (WMH) – typical radiological finding of CSVD
• Lacunes and lacunar infarcts – another type of small stroke 
• Cerebral microbleeds (CMB) – bleeding inside the brain from small vessels
• Enlarged perivascular space (PVS) – radiological findings
• Cerebral atrophy – loss of brain cells³

Causes and risk factors of CSVD

CSVD is an umbrella term for many different diseases and pathological processes that cause damage to small blood vessels; hence the exact cause is still unknown.

Certain causes that have been defined in research are:

1. Genetic – several genetic conditions are known to cause rare types of CSVD, for example, Fabry disease
2. Hereditary – the most common hereditary condition known to cause CSVD is Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This is also a rare disorder
3. Sporadic – means without having any cause
4. Cerebral amyloid angiopathy is a disease in which the abnormal deposition of amyloid proteins in the brain blood vessels leads to the blockage of small blood vessels
5. Radiation exposure – radiation exposure to the brain has been known to cause damage to small blood vessels
6. Immune-mediated vasculitides – certain immunological diseases like SLE and different vasculitis can cause damage to small blood vessels in the brain
7. Certain infections like Meningovascular neurosyphilis, hepatitis B and C, and HIV have been linked to causing damage to the small blood vessels in the brain
8. Atheroma of a large artery – deposition of fatty material in the walls of large arteries can decrease the blood traveling to the small blood vessels through them
9. Embolism from the heart or carotid artery – emboli are blood clots that can travel and get lodged anywhere in their course and cause blockage of blood supply^1,3,4

As CSVD primarily causes stroke in the elderly and can itself also be caused after a stroke, certain traditional risk factors of stroke are also assumed to be linked to CSVD. There is a lot of controversy regarding these risk factors, as controlling or treating them does not always prevent CSVD. Hencefurther studies are required to understand the disease process.  

These risk factors are:

1. Increasing age
2. Hypertension – blood pressure greater than 140/90mmHg
3. Diabetes
4. Hypercholesterolemia – high level of cholesterol in the blood
5. Current or former Smoking
6. Lack of exercise
7. Poor diet – high salt intake
8. Heart attacks
9. Obstructive sleep apnea
10. Chronic kidney disease¹
11. Low vitamin B12 and folate levels⁵

Consequences and complications of CSVD

Cerebral small vessel disease has a diverse clinical presentation which depends on how the disease in the small vessels occurs and the area of the brain affected. Different lesions (changes) on MRI cause different symptoms and their severity can also be graded into mild, moderate, and severe CSVD lesions. CSVD is a progressive disease in which the lesions can increase in number and size with duration.

Acute cerebral small vessel disease

When the disease occurs suddenly or over a short time, it causes stroke symptoms. These strokes occur because of blockage of small blood vessels supplying the deeper areas of the brain and are known as Lacunar stroke syndrome or Lacunar Infarcts.

According to the area of the brain affected, they can be of the following types:

1. Pure motor stroke (PMS) – paralysis of one side of the body
2. Pure sensory stroke (PSS) – loss of sensation (numbness) of one side of the body
3. Sensory motor stroke (SMS) – loss of sensation (numbness) and paralysis of one side of the body
4. Ataxic hemiparesis (AH) – incoordination and tremors of one side of the body with mild weakness
5. Dysarthria clumsy hand syndrome (DCHS) – difficulty speaking, clumsiness(weakness) of the hand (unable to write)²

Chronic cerebral small vessel disease

When the disease of the small blood vessels and the lesions (changes) on MRI occur over a long period of duration, the symptoms are usually not noticeable in the elderly. They are calledsilent CSVD and are picked up by accident on brain scans.

These changes can progress further and cause many problems, such as

1. Cognitive Impairment – CSVD causes cognitive decline in patients, which can present with: 
   • Executive dysfunction – disruption of the person’s ability to manage their thoughts, emotions, and actions
   • Delayed recall and memory problems
   • Slower speed of information processing and understanding
   • Attention decline
   • Decreased verbal fluency
2. Behavioral problems and symptoms – Apathy (lack of interest/ enthusiasm), mood disorders
3. Neuropsychiatric symptoms – Depression, Anxiety, Agitation, Irritability
4. Dementia – CSVD can double the risk of developing dementias.³ Vascular dementia is a type of dementia occurring secondary to CSVD. It is also associated with increased severity of other types of dementias, like Alzheimer
5. Sleep disorders and disturbances
6. Balance problems and Vertigo(sensation of spinning)
7. Hearing disorders and Tinnitus – ringing sensation in ears
8. Mild tremors of the limbs
9. Problems with posture and walking – lead to increased falls and injuries
10. Urinary problems – increased frequency and urgency and an inability to control one’s bladder
11. Strokes – CSVD triples the risk of developing strokes in the future³

These symptoms of CSVD progress gradually, causing a global decline in function, disability, and loss of independence. There is an increased risk of death mainly due to falls and accompanying injuries.^2,4

Treatment and prevention

Despite extensive research on CSVD, there are still uncertainties regarding the disease process. This has led to a delay in developing the effective targeted treatment strategies for CSVD.

As CSVD and stroke share a common disease process, experts focus on treating the traditional risk factors for stroke.

1. Treating and controlling hypertension – hypertension is the most important risk factor for stroke, but controlling hypertension in CSVD is still controversial as studies show mixed results. Some studies show that decreasing blood pressure slows the progression of mild CSVD in people below the age of 80. However, when the blood pressure is lowered in people who have extensive CSVD or are above the age of 80 or have long-standing high blood pressure, it worsens the disease. 

Experts recommend maintaining a blood pressure of < 130 mm hg, but this should be done cautiously in people above 80 with extensive disease.

2. Treating high cholesterol levels, treating high cholesterol levels with drugs such as statins is also controversial in treating CSVD. Even though statins decrease the chances of strokes, they can increase the chances of bleeding in certain cases of CSVD
3. Reducing and quitting smoking
4. Salt-free diet
5. Increased physical activity
6. Vitamin B supplements – recent studies show vitamin B supplementation can decrease the progression of CSVD
7. Vitamin E tocotrienols – These were recently found to decrease the progression of CSVD
8. Thrombolytic therapy – Blood clot-dissolving drug, intravenous (IV) tissue plasminogen activator (tPA) is used to treat stroke syndromes

Current research

Cerebral Small Vessel Disease still needs to be extensively researched as the prevalence of the disease is increasing with better life expectancy. With the advancement of neuroimaging, there is a chance of diagnosing these changes earlier, so their progression can be delayed. Recent studies are working on finding blood markers to diagnose CSVD that can help understand the disease process. 

Summary

Cerebral Small Vessel Disease or CSVD is a prevalent neurological disease in the elderly. It is a collective term used to describe the disease of the small blood vessels of the brain's deep areas, leading to changes (lesions) on the brain MRI scans. It can be silent and found by accident on brain scans, or it can cause lacunar strokes. Many clinical presentations of these changes can be global signs and symptoms previously attributed to old age, like cognitive decline, attention and memory problems, dementia, walking balance problems, and confusion. No specific cause is identified. Themost important risk factor is high blood pressure. CSVD can increase the chances of developing future stroke, or it can also be caused by stroke. Despite extensive research, targeted treatment and preventive guidelines are not available. Still, current researchers are working on identifying early warning signs to diagnose these changes and prevent the development of dementia and strokes.