Background

Moyamoya disease is a rare cerebrovascular disorder characterized by the progressive narrowing and blockage of the blood vessels supplying the brain, particularly the arteries at the base of the brain known as the circle of Willis.

The term “moyamoya” means “puff of smoke” in Japanese, which describes the appearance of the abnormal network of small blood vessels that form as collateral circulation in response to the blocked vessels.

Epidemiology

Moyamoya disease is considered a rare condition, but its exact prevalence and incidence rates are difficult to determine due to its rarity and variations in reporting across different populations. However, it is generally believed to be more prevalent in certain ethnic populations, particularly individuals of East Asian descent. The highest incidence rates of Moyamoya disease have been reported in Japan, where it is estimated to occur in approximately 1 in 100,000 individuals.

It is also relatively common in other East Asian countries, such as Korea and China, with reported incidence rates ranging from 0.54 to 2.8 per 100,000 individuals. Moyamoya disease is less commonly reported in other parts of the world, including North America, Europe, and other non-Asian populations. In these regions, the estimated incidence rates are considerably lower, ranging from 0.086 to 0.35 per 100,000 individuals. Moyamoya disease has a bimodal age distribution, with two peak age groups for diagnosis. The first peak occurs in children, usually between 5 and 10 years of age, while the second peak occurs in adults, typically between 30 and 50 years of age.

However, it can affect individuals of all age groups, including infants and the elderly. The female-to-male ratio in Moyamoya disease varies among different populations. In Asian countries, a slight female predominance has been observed, with a female-to-male ratio ranging from 1.2:1 to 2.6:1. In contrast, some studies in non-Asian populations have reported a more equal gender distribution. Although the exact etiology of Moyamoya disease is not fully understood, there is evidence to suggest a genetic predisposition in some cases.

Several genetic mutations have been identified in familial cases of Moyamoya disease, and it is believed to have an autosomal dominant inheritance pattern in these cases. However, the majority of cases are sporadic, without a clear family history of the condition. Overall, Moyamoya disease is a rare cerebrovascular disorder that predominantly affects individuals of East Asian descent, with a higher incidence observed in Japan, Korea, and China. While it can occur in other populations, its occurrence in non-Asian populations is relatively less common. Further research is needed to better understand the epidemiology of Moyamoya disease and its variations across different populations.

Anatomy

Pathophysiology

The pathophysiology of Moyamoya disease involves the progressive narrowing and occlusion of the arteries at the base of the brain, leading to the development of collateral blood vessels as a compensatory mechanism. The exact cause of the disease is still not fully understood, but several mechanisms have been proposed:

• Abnormalities in the walls of blood vessels: There is evidence to suggest that Moyamoya disease involves a combination of genetic and environmental factors that lead to abnormalities in the structure and function of the blood vessel walls. These abnormalities can include smooth muscle cell proliferation, fibrosis, and inflammation, leading to the narrowing and thickening of the arterial walls.
• Insufficient blood supply and ischemia: The progressive narrowing of the major arteries supplying the brain, particularly the internal carotid arteries and their branches, reduces the blood flow to the affected areas. This compromised blood supply can result in chronic ischemia (lack of oxygen and nutrients) to the brain tissues, which triggers a series of adaptive responses.
• Collateral vessel formation: In response to the reduced blood flow, the body attempts to compensate by forming new blood vessels in an attempt to bypass the blocked or narrowed arteries. These collateral vessels develop in a network known as the “moyamoya vessels” or “puff of smoke” appearance, which is characteristic of the disease. These collateral vessels are often small and fragile, and their development is an attempt to maintain adequate blood supply to the affected areas of the brain.
• Genetic factors: Genetic mutations and predispositions have been associated with Moyamoya disease, particularly in familial cases. Several genes have been identified, including RNF213, which is believed to play a role in the development of the disease. However, the exact mechanisms by which these genetic factors contribute to the pathophysiology of Moyamoya disease are still being investigated.

The progressive narrowing and occlusion of the arteries, along with the compensatory collateral vessel formation, can lead to a range of clinical manifestations and complications in Moyamoya disease. These can include transient ischemic attacks (TIAs), strokes, seizures, cognitive impairment, and other neurological deficits.

Etiology

The exact etiology of Moyamoya disease remains unclear. However, there is evidence to suggest that it is a multifactorial condition influenced by both genetic and environmental factors.

Genetic Factors:

• Familial Cases: Moyamoya disease can occur in families and is known as familial Moyamoya disease (FMMD). In FMMD, the condition is inherited in an autosomal dominant pattern with variable penetrance. Several genetic mutations have been associated with FMMD, with the most common being a mutation in the RNF213 gene. However, not all cases of Moyamoya disease have a clear genetic component, and the majority of cases are sporadic.
• Genetic Predisposition: Even in non-familial cases, there is evidence to suggest a genetic predisposition to Moyamoya disease. Genome-wide association studies have identified genetic variations associated with an increased susceptibility to the condition. These genetic factors may contribute to the abnormal vascular development and predispose individuals to the development of Moyamoya disease.

Environmental Factors:

• Ethnicity and Geography: Moyamoya disease is more prevalent in certain ethnic populations, particularly individuals of East Asian descent. The condition has a higher incidence in Japan, Korea, and China compared to other regions of the world. This suggests that there may be geographic or environmental factors that contribute to its development.
• Radiation Exposure: Exposure to ionizing radiation, particularly during childhood, has been identified as a potential risk factor for the development of Moyamoya disease. It has been observed that individuals who received radiation therapy for conditions such as brain tumors or hematological malignancies are at an increased risk of developing Moyamoya disease later in life.
• Other Risk Factors: Various other factors have been suggested as potential contributors to the development of Moyamoya disease, although their exact role and significance are still under investigation. These factors include certain viral infections, autoimmune disorders, and other genetic or acquired vascular conditions.

Genetics

Prognostic Factors

The prognosis of Moyamoya disease can vary depending on several factors, including the age at diagnosis, the severity of symptoms, the extent of vascular involvement, the presence of complications, and the response to treatment. Here are some key aspects to consider regarding the prognosis of Moyamoya disease:

• Disease Progression: Moyamoya disease is a progressive condition, and if left untreated, it can lead to an increased risk of recurrent ischemic strokes, intracranial hemorrhage, and neurological deficits. The rate of disease progression can vary among individuals, and some may experience a more rapid decline in neurological function compared to others.
• Age at Diagnosis: The age at which Moyamoya disease is diagnosed can impact the prognosis. Children who are diagnosed earlier in life may have a longer duration of the disease and a higher risk of developing complications over time. However, early diagnosis and prompt treatment can help improve outcomes and reduce the risk of stroke.
• Treatment Response: Revascularization surgery, either direct or indirect bypass procedures, aims to improve blood flow to the brain and reduce the risk of stroke. The success of these surgical interventions can vary, and the extent of revascularization achieved can influence the prognosis. In some cases, additional surgeries or interventions may be required if the disease progresses despite initial treatment.
• Complications: Moyamoya disease can be associated with various complications, such as recurrent strokes, seizures, cognitive impairments, and visual deficits. The presence and severity of these complications can impact the overall prognosis and quality of life for individuals with Moyamoya disease.
• Multidisciplinary Management: Close monitoring and ongoing multidisciplinary management are crucial in optimizing outcomes. Regular follow-up with healthcare professionals, including neurologists, neurosurgeons, and rehabilitation specialists, allows for the timely adjustment of treatment plans, management of complications, and support for the individual’s specific needs.

Clinical History

Clinical history

The clinical history of Moyamoya disease can vary depending on the age of onset, the severity of the disease, and the specific manifestations in each individual. Here are some common features seen in the clinical history of Moyamoya disease:

Neurological Symptoms:

• Transient Ischemic Attacks (TIAs): Recurrent episodes of temporary neurological deficits that occur due to insufficient blood flow to the brain. TIAs can cause symptoms such as weakness, numbness, difficulty speaking, visual disturbances, and paralysis.
• Strokes: Moyamoya disease increases the risk of ischemic and hemorrhagic strokes. Ischemic strokes occur when blood flow to a specific area of the brain is blocked, while hemorrhagic strokes result from bleeding into the brain.
• Seizures: Moyamoya disease can be associated with seizures, which may be focal or generalized. Seizures can manifest as convulsions, altered consciousness, or abnormal movements.

Cognitive and Developmental Issues:

• Intellectual Impairment: Some individuals with Moyamoya disease may experience cognitive impairment, including difficulties with memory, attention, problem-solving, and academic performance.
• Developmental Delay: Children with Moyamoya disease may exhibit delays in reaching developmental milestones, such as walking, talking, or fine motor skills.

Headaches:

Headaches, often migrainous in nature, can occur in individuals with Moyamoya disease. The headaches may be recurrent, severe, and associated with other symptoms such as nausea or sensitivity to light and sound.

Hemorrhage:

In some cases, the fragile blood vessels in Moyamoya disease can rupture, leading to intracranial hemorrhage. Hemorrhages can cause sudden severe headaches, loss of consciousness, focal neurological deficits, or even coma.

Other Symptoms:

• Movement Disorders: Moyamoya disease can occasionally be associated with movement disorders such as dystonia, chorea, or tremors.
• Visual Impairment: Reduced visual acuity, visual field defects, or other visual disturbances can occur in individuals with Moyamoya disease due to the involvement of the cerebral vasculature supplying the visual pathways.

Physical Examination

Physical examination

The physical examination findings in Moyamoya disease can vary depending on the stage of the disease and the presence of associated complications. Here are some key aspects that may be observed during the physical examination:

Neurological Examination:

• Motor Function: The examiner assesses muscle strength, tone, coordination, and reflexes. Weakness or abnormalities in muscle tone may be present, particularly if the patient has experienced previous strokes or transient ischemic attacks.
• Sensory Function: Sensory examination evaluates the patient’s ability to perceive touch, pain, and temperature sensations.
• Coordination and Balance: Tests such as finger-to-nose and heel-to-shin maneuvers can be performed to assess coordination and balance.
• Cranial Nerves: A thorough evaluation of cranial nerves is conducted, focusing on abnormalities in visual acuity, visual fields, extraocular movements, facial sensation, facial movements, hearing, and swallowing.

Blood Pressure and Heart Examination:

• Blood Pressure: Hypertension can be associated with Moyamoya disease and is commonly assessed during the physical examination.
• Cardiac Auscultation: A basic cardiac examination may be performed to identify any abnormalities such as murmurs or irregular heart rhythms.

Head and Neck Examination:

• Visual Assessment: Visual acuity, visual fields, and fundoscopic examination may be performed to evaluate for any signs of optic nerve involvement or retinal abnormalities.
• Neck Examination: The carotid arteries may be examined for bruits (abnormal sounds caused by turbulent blood flow) or other signs of vascular pathology.

Other Systemic Examination:

• Skin: The skin may be assessed for signs of underlying systemic conditions associated with Moyamoya syndrome, such as neurofibromatosis or Down syndrome.
• Growth and Development: In pediatric patients, growth parameters and developmental milestones may be evaluated to assess for any delays or abnormalities.

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Differential diagnosis

When considering the differential diagnosis of Moyamoya disease, it is important to evaluate other conditions that can present with similar clinical features or radiological findings. The following are some of the conditions that may be considered in the differential diagnosis:

• Atherosclerosis: Atherosclerosis is a common condition characterized by the buildup of plaque within the arteries, leading to narrowing and blockage of the blood vessels. It can affect the cerebral arteries and cause symptoms similar to Moyamoya disease. However, atherosclerosis typically affects older individuals and is associated with risk factors such as hypertension, hyperlipidemia, and smoking.
• Other Vasculopathies: Various vasculopathies can lead to stenosis or occlusion of cerebral arteries and result in similar clinical presentations to Moyamoya disease. Examples include fibromuscular dysplasia, vasculitis (e.g., granulomatosis with polyangiitis), and arterial dissections. A thorough evaluation of the patient’s clinical history, laboratory findings, and imaging studies can help differentiate these conditions from Moyamoya disease.
• Moyamoya Syndrome: Moyamoya syndrome refers to the development of moyamoya-like vessels secondary to other underlying conditions. These conditions can include sickle cell disease, neurofibromatosis type 1, Down syndrome, cranial irradiation, and other genetic or acquired disorders. Distinguishing between primary Moyamoya disease and Moyamoya syndrome is important as the underlying cause may require specific management or treatment.
• Cerebral Vasculitis: Inflammatory conditions affecting the cerebral blood vessels, such as primary angiitis of the central nervous system (PACNS) or secondary vasculitides, can present with similar imaging findings and neurological symptoms to Moyamoya disease. Clinical features, laboratory investigations, and brain biopsy (if indicated) can help differentiate vasculitis from Moyamoya disease.
• Other Cerebrovascular Malformations: Arteriovenous malformations (AVMs), cavernous malformations, or other cerebral vascular anomalies may exhibit radiological features that resemble Moyamoya disease. A thorough evaluation of the vascular anatomy, presence of abnormal vessels, and associated clinical features can help differentiate these conditions from Moyamoya disease.
• Migraine with Aura: Migraine with aura can manifest with transient neurological symptoms, such as visual disturbances, sensory changes, or language difficulties. These symptoms can sometimes mimic transient ischemic attacks (TIAs) seen in Moyamoya disease. Detailed clinical history and a careful evaluation of the characteristics and duration of symptoms can aid in distinguishing between migraine with aura and Moyamoya disease.

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

The treatment of Moyamoya disease aims to improve blood flow to the brain, prevent stroke, and manage associated symptoms. The specific treatment approach depends on several factors, including the age of the patient, the severity of symptoms, the extent of vascular involvement, and the presence of any underlying conditions. Here are the main treatment options for Moyamoya disease:

Medical Management:

• Antiplatelet Agents: Medications such as aspirin or clopidogrel may be prescribed to reduce the risk of blood clot formation and prevent ischemic events.
• Blood Pressure Control: Maintaining optimal blood pressure control is important to reduce the risk of stroke and minimize further damage to the blood vessels.
• Seizure Management: If seizures occur, antiepileptic drugs may be prescribed to control and prevent seizure activity.

Revascularization Surgery:

• Direct Bypass Surgery: This surgical procedure involves creating a direct connection between a donor blood vessel (usually the superficial temporal artery) and a brain artery, bypassing the narrowed or occluded vessels. The goal is to improve blood flow to the affected areas of the brain.
• Indirect Bypass Surgery: In this procedure, the surgeon creates a network of new blood vessels near the brain, allowing blood flow to be redirected and bypass the narrowed or blocked vessels. This can be done using techniques such as encephaloduroarteriosynangiosis (EDAS) or encephalomyosynangiosis (EMS).
• Combined Bypass Surgery: In some cases, both direct and indirect bypass procedures may be performed to maximize revascularization.

Symptomatic Management:

• Medications: Depending on the specific symptoms experienced, medications such as anticonvulsants for seizures, analgesics for headaches, or cognitive enhancers for cognitive impairments may be prescribed.
• Physical Therapy: Physical therapy and rehabilitation can help manage motor deficits, improve muscle strength, coordination, and optimize overall functional abilities.
• Speech Therapy: Speech therapy may be beneficial for individuals with speech and language difficulties resulting from Moyamoya disease.
• Vision and Occupational Therapy: In cases where visual impairments or occupational limitations are present, specialized therapy may be recommended to address these specific challenges.

Regular follow-up with a multidisciplinary team of specialists, including neurologists, neurosurgeons, and rehabilitation experts, is important to monitor disease progression, adjust treatment plans, and manage potential complications. Early diagnosis and intervention are crucial to optimize outcomes and reduce the risk of stroke and other serious complications associated with Moyamoya disease. Treatment decisions should be individualized based on each patient’s specific needs and guided by expert medical advice.

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Future Trends

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References

https://www.ncbi.nlm.nih.gov/books/NBK535455/