Introduction 

Moyamoya disease is a long-term, progressive disorder affecting the brain's arteries. Individuals with this condition experience narrowing of these blood vessels, leading to blockages that can ultimately result in stroke and seizures. The brain tries to make up for the reduced blood flow by developing new blood vessels, known as collaterals. Although these vessels can temporarily improve blood supply, they eventually become ineffective.

Moyamoya disease is typically diagnosed in children aged 10 to 14 or adults in their forties. It is more common among people assigned female at birth (AFAB)and individuals of Asian descent, with studies indicating a genetic component.^1,2,3 The term "Moyamoya" derives from the Japanese language and means “a hazy puff of smoke or cloud”, which refers to the appearance of the collateral vessels in affected people in the angiogram (see Figure 1), a type of brain scan.^3,4

Figure 1. The Moyamoya collateral vessels (highlighted in red), also known as the Moyamoya fog.⁴ 

The condition was first identified in Japan, where it remains most prevalent, affecting about 11 in 100,000 individuals, with 7-10% of cases being familial. In Japan, Moyamoya disease typically occurs in people AFAB under 20 years old. It is also relatively common in other Asian populations. In South Korea, the prevalence rate is 16.1 for every 100,000 individuals and in China, it is 3.92 for every 100,000 individuals. The disease has also been found in the United States, where it affects approximately 0.09 in every 100,000 individuals – although it is a significantly lower prevalence rate than that in Asian countries, the trend has been steadily increasing in the past few years, possibly due to new means of diagnosis. Although Moyamoya disease has also been found in Australia, North and South America, and Africa, it is ten times less common in Europe.⁵

The genetics of Moyamoya disease are not yet fully understood. Research indicates that the condition can be hereditary, with changes in the RNF213 gene associated with it, with other unidentified genes may also be involved. Additionally, it is likely that other factors, such as infection or inflammation, in combination with genetic predisposition, contribute to the development of the condition. Several acquired factors have been proposed to contribute to disease progression, including vasculitis, infections, cranial trauma, and post-irradiation states, among others.^1,2,3

Moyamoya disease differs from Moyamoya syndrome, also known as quasi-Moyamoya disease. Although patients with Moyamoya syndrome exhibit similar blood vessel patterns on scans, the narrowing of vessels is due to different causes other than the genetic mutation responsible for Moyamoya disease. Differential diagnosis is important to determine the right approach for treatment.¹

Symptoms of Moyamoya disease

Symptoms of Moyamoya disease are rather unspecific and can vary according to the age of development and the stage of the disease. Common symptoms are described below:^1,2

• Transient ischemic attacks (TIAs)
• Haemorrhagic strokes, due to bleeding in the brain (more frequent in adult patients)
• Ischemic strokes can also happen, although less frequent, due to blockages in the arteries
• Motor decline (weakness or paralysis in one side of the body), due to the ischemic events
• Cognitive impairment, due to lack of blood perfusion in the brain
• Seizures
• Cognitive and memory issues caused by repeated strokes and brain bleeding
• Blurry vision
• Headaches

Diagnosis of Moyamoya disease

Diagnosis of Moyamoya disease is not a straightforward process and involves a multifaceted approach. The first step is to collect the patient’s medical history to identify potential risk factors and a physical examination to assess signs and symptoms. Blood tests are usually performed and they typically include full blood count (all the blood components), inflammatory markers namely ESR (Erythrocyte Sedimentation Rate) and CRP (C-reactive Protein), some specific antibodies like ANA and antiphospholipid antibodies, and sometimes genetic testing. Lumbar puncture may also be performed to exclude inflammatory or central nervous system conditions. In some cases, a biopsy may be appropriate to distinguish between Moyamoya and vasculitis or brain tumour, for instance. However, the diagnosis of Moyamoya disease is largely based on imaging studies. Usually, the diagnostic process starts with non-invasive tests such as MRI or CT scan. A brain angiography is usually performed to confirm the diagnosis, determine the precise extent of blood vessel narrowing, visualize existing blood flow patterns to different brain regions, and guide treatment decisions.^1,6

• Cerebral Angiography: the preferred method of diagnosis; it is like a “map” of the brain that allows detection of arterial stenosis or occlusions and the typical "puff of smoke" collateral vessels
• Magnetic Resonance Imaging (MRI): can be used to identify cerebral infarctions, long-term ischemic alterations, and collateral vessels
• Magnetic Resonance Angiography (MRA): It is a less invasive method and can show vascular changes similar to those observed in cerebral angiography
• Computed Tomography (CT) and CT Angiography (CTA): help detect bleeding and major vessel defects
• Single-photon emission Computed Tomography (SPECT) or Positron Emission Tomography (PET): assesses cerebral perfusion and metabolic activity
• Electroencephalography (EEG): a test that produces a trace that allows assessment of the electric activity in the brain. It may be necessary when patients have seizures. There is an EEG result that is common in approximately 50% of people with Moyamoya disease. It is called the “rebuild-up” phenomenon and translates into the presence of high amplitude slow waves 20 to 60 seconds after a hyperventilation episode. This happens because of reduced blood flow

Differential diagnosis

The differential diagnosis of Moyamoya disease encompasses a range of conditions that may have similar clinical and radiological features. These are typically classified into other vascular conditions, genetic syndromes, inflammatory and autoimmune diseases, and other systemic conditions.^1,6,7

Treatment for Moyamoya disease

Treatment for Moyamoya disease is highly dependent on differential diagnosis, hence it is so important to establish the diagnosis appropriately. Some treatment options include:

• Medical Management: antiplatelet tablets which stop blood from clotting to reduce the risk of ischemic events. It is also important to control risk factors such as hypertension and hyperlipidaemia
• Surgical Interventions: revascularization procedures, namely direct (e.g., superficial temporal artery to middle cerebral artery bypass) or indirect (e.g. encephaloduroarteriosynangiosis) methods to improve cerebral perfusion
• Close follow-up: with imaging studies to assess disease progression and treatment efficacy

Differential diagnosis enables appropriate management and improves patient outcomes by tailoring treatment options to the underlying condition. As our understanding of Moyamoya disease and its mimics evolves, ongoing research and advances in diagnostic modalities will continue to refine the diagnostic process and enhance patient care.¹

Summary

• Moyamoya disease is more prevalent in Asian populations, people AFAB, children, and adults in their 40s
• Although the causes are not fully known, there seems to be a genetic component that is highly correlated to the onset of the disease
• Imaging studies assist in distinguishing Moyamoya disease from other conditions with similar symptoms
• Differential diagnosis is vital to guide treatment
• The most accurate method for diagnosis is brain angiography