Overview

Moyamoya disease is a rare disease, most common in female children of Asian ethnic backgrounds, characterised by narrowing blood vessels limiting blood supply into the brain. However, since moyamoya is so rare, its causes are not fully understood.¹ Scientists theorise many contributing factors leading to moyamoya development, with recent studies showing associations with autoimmune disorders.²

An autoimmune disorder is a condition where the body instructs the immune system to recognise its own healthy, non-threatening tissues as harmful foreign objects, causing damage to the body.³ This article aims to explore the potential link between moyamoya disease and autoimmune disorders, explore the role of the immune system in moyamoya disease progression, and the clinical implications of autoimmune disease on patients with moyamoya.

Understanding moyamoya disease

Pathophysiology 

The Japanese term “moyamoya” translates to “puff of smoke”, describing the warped appearance of the blood vessels seen in specialised blood vessel X-rays called angiographies. Blood vessels are usually wide, organised arrangements, however patients with moyamoya have very narrow and disorderly vessels. This impairs blood supply to the brain, increasing the risk of stroke.^1,4 

There are three main effects of moyamoya disease on the brain:⁴

1. Vascular changes - The inner lining of special blood vessels called internal carotid arteries, important for supplying oxygen via blood to the brain, are thickened. This thickening results in a narrower path for blood to travel through, restricting blood flow to the brain.
2. Collateral vessel formation - In response to reduced blood flow, the brain develops more disorderly vessels named collateral vessels. Although the formation of these vessels does increase blood flow, collateral vessels are very fragile and more prone to rupture, increasing the risk of strokes caused by bleeding into the brain (haemorrhagic strokes).
3. Haemodynamic stress - Narrowing of the internal carotid arteries increases the blood flow to the collateral vessels, increasing their workload (known as haemodynamic stress) causing them to become more fragile and prone to rupture. All of these factors make it more difficult for blood to travel through the brain, increasing the risk of strokes caused by a cut-off of blood flow (ischaemic strokes). 

Genetic factors

Moyamoya disease can either occur through a sporadic (unexpected non-inherited) mutation, or through inheritance from a family member.¹ The RNF213 gene, responsible for correct blood vessel formation (angiogenesis) and remodelling, is often defective in moyamoya disease, causing the improper delivery of blood to the brain. Although a mutant RNF213 gene increases moyamoya susceptibility, another second “hit” mutation is required for disease onset.²  

Symptoms 

The symptoms of moyamoya present similarly to those of a stroke, including:¹

• Slurred speech
• Blurred visionWeakness affecting one side of the bodyHeadaches
• Seizures

These symptoms may develop over time and become more manageable over time, or have a quick onset and remain present. These symptoms should be immediately assessed by a medical professional to prevent a stroke from occurring.

Epidemiology

Moyamoya disease is most prevalent in female Asian children below the age of twenty but occurs in almost every ethnic, gender, and age group.¹ In 2003, an estimated 3.16 in every 100,000 people in Japan were affected. Studies have estimated for every 1 male affected, 1.8 females are affected, and incidence is most common between the ages of 10 to 20, and 35 to 50 years.⁵

Overview of autoimmune disorders

Autoimmune disorders are the result of high-fired immune responses by the immune system. This means the body elicits a protective response to what it perceives as a dangerous foreign object to protect itself, when in actual fact it is responding to the body’s own tissue and causing more harm than good.³ An autoimmune disorder often results in the destruction of body tissue, abnormal organ growth in the form of cysts and inflamed tissues, and/or increased, decreased, or completely different function of organs. 

Examples of autoimmune disorders include; Addison’s disease, Coeliac disease, Graves’ disease, Hashimoto thyroiditis, Inflammatory bowel disease (Crohn's disease and Ulcerative colitis), Rheumatoid arthritis, Systemic lupus erythematosus, and Type I diabetes.⁶

Potential links between moyamoya disease and autoimmune disorders

RNF213 defects

Whilst RNF213 has been shown to be associated with moyamoya disease, RNF213 has also been shown to be essential in blood vessel lining endothelial cells for expressing appropriate genes for responding to inflammatory signals.⁷ Clinical reports have shown patients with depleted RNF213 to have increased signals promoting inflammation, highlighting associations with autoimmune disorders. This means that when an RNF213 defect is present, inflammation is more easily triggered by non-threatening objects, stimulating an autoimmune disorder which acts as the second “hit” for moyamoya disease development.² 

Inflammation and immune response

Inflammatory responses accelerate Moyamoya disease by contributing to the narrowing of blood vessels in the brain. Inflammation in vascular walls causes cells to accumulate, increasing cell number in the blood vessel and promoting an immune response to these cells. This is a behaviour often seen in autoimmune disorders, where immune responses are elicited on the body’s own cells.² 

Vascular involvement in autoimmune diseases

Narrow vessels are a defining feature of Moyamoya disease, often assisted by inflammation. This trait is also shared by several autoimmune disorders including:²

• Granulomatosis with-polyangiitis, which causes severe inflammation of respiratory and urinary tract blood vessels restricting blood flow
• Rheumatoid arthritis, which causes inflammation in small- and medium-sized arteries in joints; and
• Systemic lupus erythematosus, which causes frequent inflammation of arteries leading into various organs, such as the kidneys, leading to damage

Specific autoimmune disorders associated with moyamoya disease

There are several autoimmune disorders associated with moyamoya, including:²

1. Antiphospholipid syndrome (APS) - causes abnormal blood clotting contributing to the narrowing of blood vessels seen in moyamoya disease
2. Graves’ disease - causes an immune attack of the thyroid gland, resulting in increased immune cells which are able to contribute to vascular changes seen in moyamoya
3. Hashimoto’s thyroiditis - also causes an immune attack on the thyroid gland and contributes to Moyamoya disease by increasing immune cells which are able to accelerate vascular changes.
4. Rheumatoid arthritis - leads to chronic inflammation of the joints, often causing blood vessel inflammation (vasculitis) which may contribute to developing moyamoya
5. Sjögren’s syndrome - is characterised by an immune-mediated attack of moisture-producing glands (such as tear and salivary glands), which can lead to systemic inflammation that is able to affect vessels and increase the risk of moyamoya disease. Systemic lupus erythematosus (SLE) - a systemic autoimmune condition which can cause vasculitis, key for moyamoya manifestation

Clinical implications

Diagnosis

In most cases, a GP will make a referral, based on patient symptoms, to a hospital where an angiogram will take place. An angiogram provides a visual map of the arteries in the brain, from which a diagnosis of moyamoya disease can be made without invasive techniques.¹

Treatment

The only viable long-term treatment for moyamoya is to reduce the reliance on narrowed arteries using surgery. There are several surgical options available, including:¹

• Direct arterial bypass, where neurosurgeons join a blood vessel from the scalp into the brain to avoid the use of narrowed arteries. Dural inversion, where a large artery within the skull named the meningeal vessel is modified to directly supply the brain to avert blood supply from narrowed vessels.
• EDAS (encephaloduroarteriosynangiosis), where the major artery of the head (named the superficial temporal artery) is positioned to allow the development of new vessels, usually as a last resort.
• EMS (encephalomyosynangiosis), where small parts of the muscle jaw are transplanted into the brain to offer an alternative blood supply.Omental transposition/transfer, where the blood-rich omentum, which lines the abdomen, is transplanted and laid over the brain surface to grow new vessels and eventually grow into the brain.Pial synangiosis, where healthy scalp blood vessels are re-routed into the brain to bypass narrowed vessels.

Between diagnosis and surgery, symptoms can be managed using pain relief medications, such as aspirin, and blood pressure-reducing calcium channel blockers, such as verapamil.

Prognosis

Moyamoya disease can cause life-threatening strokes, resulting in two-thirds of patients experiencing symptom progression over a five-year period with poor outcomes. Prognosis is greatly increased when patients seek early surgical treatment.⁸

Summary

The connection between Moyamoya disease and autoimmune disorders highlights the complex interplay between genetic and immune system factors in the development of this rare disease. Genetic mutations, particularly in the RNF213 gene, alongside autoimmune-induced inflammation, contribute significantly to the pathophysiology of Moyamoya disease. Recognising the association with autoimmune disorders such as Graves' disease, Hashimoto's thyroiditis, and systemic lupus erythematosus provides crucial insights into potential mechanisms driving the disease. This understanding can guide more accurate diagnoses and effective treatments, emphasising the importance of early surgical intervention to prevent life-threatening strokes.