What Is Moyamoya Disease?

Introduction

Moyamoya disease (MMD) is a rare disorder affecting the cerebrovascular blood vessels in the brain, which gets worse over time. This disease is characterized by the narrowing or complete closure of the carotid artery (the main artery which delivers blood to the brain).¹ To compensate for reduced blood flow to the brain, tiny vessels form to deliver the blood to the brain that the carotid artery was meant to deliver. These vessels are very fragile. In fact, moyamoya means “puff of smoke” in Japanese, which refers to the appearance of the many compensatory tiny vessels in the brain X-ray.² The progressive nature of the disease can result in ischaemic (lack of oxygen) or haemorrhagic (escape of blood from the vessels) strokes. This is associated with high rates of disability and death.¹ Moyamoya disease can occur spontaneously with no definite cause; however, it is also associated with other diseases and risk factors such as genetics, Down syndrome, and intracranial atherosclerosis.³ The prevalence of MMD peaks between 10 years old and between 30-45 years old.⁴ However, it is possible to develop the disease at any age. If left untreated, patients with moyamoya disease have an 18% stroke risk in the first year since diagnosis, followed by an annual stroke risk of 3.2% to 5% in the following years.¹

Pathophysiology

Moyamoya disease is characterised by the progressive narrowing to occlusion of the carotid artery which results in the formation of moyamoya collaterals. Moyamoya collaterals are small, fragile blood vessels that compensate for the lack of blood delivered to the brain by the carotid artery. Histopathology (the study of diseased tissue) shows that there is thickening to the inner wall of the blood vessel and reduced elasticity of the blood vessel.- This could increase the likelihood of blood clots forming within the blood vessels, which further reduces the amount of oxygen that can get to the brain. Therefore, this leads to recurrent transient ischemic attacks, particularly in children.3 The molecular mechanobiological pathway (the pathway that occurs as a result of mechanical stimuli) has been proposed as a mechanism that is responsible for the morphological changes associated with Moyamoya disease.⁵ 

The symptoms of moyamoya disease are varied and are dependent on the changes to the intracranial (inside the skull) blood flow dynamics and cerebral perfusion - the amount and location in the brain that oxygen is supplied to.⁵ There are four clinical forms of MMD where symptoms are all linked to the narrowing and occlusion of the carotid artery and the associated recurrent transient ischemic attacks:⁵

1. Ischaemic (more common in children)
2. Haemorrhagic (more common in adults)
3. Epileptic
4. Other

There are different stages of Moyamoya disease, and there are multiple proposals over how these stages are defined, such as the Suzuki and the posterior cerebral artery staging systems. 

The angiographic Suzuki grading system:^6,7

1. Narrowing at the intracranial bifurcation of the carotid fork
2. Moyamoya collaterals (tiny blood vessels) appear around the narrowed vessel 
3. Further addition of moyamoya collaterals and intracerebral major arteries begin to disappear
4. Further narrowing of vessels and moyamoya collaterals begin to disappear
5. Complete blockage of large vessels and further reduction of moyamoya collaterals
6. The disappearance of moyamoya collaterals and the cerebral (brain) circulation is maintained by either the external or vertebral artery. 

The angiographic posterior cerebral artery staging of Moyamoya disease:⁷

1. No narrowing of the posterior cerebral artery 
2. Some narrowing of the posterior cerebral artery with or without moyamoya collaterals
3. Severe narrowing or occlusion of the posterior cerebral artery with developed moyamoya collaterals
4. Occlusion of the posterior cerebral artery and reduced moyamoya collaterals

Causes

The exact cause of moyamoya disease is unknown. However, some studies have suggested that the pathogenesis of moyamoya disease could be down to angiogenesis, genetics, and immune reactions.¹

Primary moyamoya disease is associated with genetics. Therefore, it is possible to inherit Moyamoya disease. It is an autosomal recessive disease, so you must inherit the gene from both the father and mother for it to present in oneself. The prevalence of moyamoya disease is very high in Japan. For every 10,000 people, there are 10.5 patients with moyamoya in Japan. There has been research found to suggest that the occurrence of moyamoya is associated with chromosome 17.2  RNF213 is a major susceptibility gene for MMD - the MMD variant is seen much more commonly in people of Asian descent rather than white descent. Despite the evidence for a genetic basis, the proportion of people with the RNF213 susceptible variant and MMD is very low - 1%.⁸ Therefore, it is likely that there is a relationship between this gene and other genes, as well as effects from the environment. 

Secondary moyamoya disease is when MMD is associated with other diseases and disorders, such as:⁹

• Sickle cell disease
• Down syndrome
• Neurofibromatosis type I 
• Atherosclerosis

Symptoms

Individuals with Moyamoya disease can have a range of symptoms, but some of the most common ones include:^3,10

• Strokes
• Transient ischemic attacks (the most important clinical manifestation for adults and children)
• Intracranial haemorrhages (more common in adults)
• Seizures
• Migraines
• Convulsions

Risk factors

Asian heritage

Moyamoya disease has been observed in individuals from many different ethnic backgrounds. However, the highest prevalence of moyamoya patients is of East Asian descent. MMD is the most common pediatric cerebrovascular disease in East Asia.¹ MMD prevalence in Japan is 0.34-0.94 per 100,000 but only 0.086 per 100,000 in the United States.³ The descent with the highest prevalence of moyamoya disease were Japanese, Korean, and Chinese.¹ It could be suggested that there may be a higher prevalence of MMD susceptibility genes in the East Asian population compared to the European and United States populations.

Family history of MMD

If a family member has MMD, you are 12% more likely to develop MMD, as discovered in a 2003 survey.² Similarly, if you have a prior medical condition, it may also influence your likelihood of developing MMD.

Sex 

People assigned females at birth have a higher susceptibility to MMD than males assigned at birth. A study from 2002 to 2006 showed that the ratio of the occurrence of moyamoya disease in females to males was 2.18:1, respectively.² 

Complications

People with MMD, especially children, are likely to have:¹¹

• A developmental delay
• Stroke
• Hemorrhage
• Seizures

Diagnosis

Diagnosis is generally carried out using catheter angiography which includes MRA and CT scanning - both of which are non-invasive.¹² In most cases, the diagnosis can be confirmed using MRI and MRA.

The Japanese guidelines for MMD diagnosis state that the Digital Subtraction Angiography (DSA) must meet one or more of these points:³

• Blocking of  the terminal region of the intracranial internal carotid artery or the proximal regions of the anterior or middle cerebral artery 
• Abnormal vascular networks at the point of blockage or narrowing in the artery
• These findings are bilateral

If all of the following points are not met using MRI and MRA, it is mandatory to carry out conventional cerebral angiography:³

• Blockage at the terminal region of the intracranial internal carotid artery and at the proximal regions of the anterior and middle cerebral artery 
• Abnormal vascular network at the basal ganglia (structures in your brain that allow the brain to form connections)
• Both points are bilaterally found

Treatment

Treatments for moyamoya disease can be medical or surgical. It is important to note that current single-drug therapy is insufficient to prevent MMD progression. It is also important to appreciate that more research into the etiology of the disease will help to design better treatments to improve therapeutic outcomes for MMD patients.8 Without treatment, it will be a fatal outcome for patients due to haemorrhaging in the brain. 

Symptomatic treatments are usually pharmaceutical, including:¹³

• medications to relieve headaches, 
• antiepileptic drugs
• antiplatelet agents (to reduce the risk of blood clotting).

Recently, pain control has been taken more seriously for people with MDD, including the increased use of regional anesthesia.¹⁰

Surgical treatments aim to improve blood flow to areas of the brain where blood flow is reduced.1 It has been proven to be the most effective method of improving the clinical manifestations of moyamoya disease. The surgeries aim to improve cerebral blood flow, ensuring sufficient blood from to the brain. Surgery is considered the best option for patients with MMD ischemic stroke and patients with haemorrhage.12 However, a lack of understanding around the etiology of MMD means that still no consensus has been reached about when surgery should be performed for the best outcome.¹

STA-MCA anastomosis is a standard surgical procedure for symptomatic MMD patients.³⁵¹ It helps by preventing rebleeding and stroke occurrence. However, surgical complications of this treatment can lead to neurological decline.¹²

Summary

Moyamoya disease can affect individuals of all ethnicities and ages. However, it is the most prevalent in people of East Asian descent and in ages 5-10 and 30-45 years old. It is a cerebrovascular disease where the carotid artery narrows and occludes, causing ischaemia in the brain. The lack of oxygen in the brain causes transient ischaemic attacks and these are responsible for the symptoms associated with MMD. It is appreciated that the current treatment options are not as effective and advanced as they should be, so further research into moyamoya disease will help guide future treatment plans.