Moyamoya Disease

Moyamoya disease is a rare, progressive cerebrovascular disorder characterized by the narrowing and eventual blockage of the internal carotid arteries and their major branches within the skull. The name "moyamoya" means "puff of smoke" in Japanese, describing the appearance of the tiny collateral blood vessels that develop to compensate for the blocked arteries. This condition primarily affects children and adults in their 30s-40s, with a higher prevalence in individuals of Asian descent, particularly Japanese and Korean populations. Without proper treatment, moyamoya disease can lead to stroke, seizures, and cognitive decline.

Medical Disclaimer: This information is for educational purposes only and should not replace professional medical advice. If you experience symptoms suggestive of moyamoya disease or stroke, seek immediate medical attention.

Overview

Moyamoya disease involves the progressive stenosis (narrowing) of the terminal portions of the bilateral internal carotid arteries (ICAs) and their proximal branches, including the middle cerebral arteries (MCAs) and anterior cerebral arteries (ACAs). As these major vessels narrow, the brain attempts to maintain adequate blood flow by developing an extensive network of small collateral vessels at the base of the brain. These collateral vessels, visible on angiography as a hazy, smoke-like appearance, give the disease its distinctive name.

The condition can present as either moyamoya disease (primary form) when no associated conditions are present, or moyamoya syndrome (secondary form) when it occurs in association with other conditions such as sickle cell disease, Down syndrome, neurofibromatosis, or prior radiation therapy. The disease follows a bimodal distribution, with peaks in the first decade of life and again in the fourth decade. Children typically present with ischemic symptoms, while adults more commonly experience hemorrhagic events.

The incidence of moyamoya disease varies significantly by geographic region and ethnicity. In Japan, the incidence is approximately 0.94 per 100,000 person-years, while in the United States, it's estimated at 0.086 per 100,000 person-years. The disease shows a female predominance with a ratio of approximately 2:1. Despite its rarity, moyamoya disease is a significant cause of stroke in children and young adults, particularly in East Asian populations. Early diagnosis and appropriate surgical intervention can significantly improve outcomes and prevent devastating neurological complications.

Symptoms

The symptoms of moyamoya disease vary depending on the age of onset, the degree of arterial narrowing, and the effectiveness of collateral circulation. The presentation differs significantly between children and adults, with children more likely to experience ischemic events and adults more prone to hemorrhagic complications.

Pediatric Presentation

  • Transient ischemic attacks (TIAs): Brief episodes of neurological dysfunction
    • Weakness or paralysis of one side of the body
    • Speech difficulties or aphasia
    • Visual disturbances
    • Often triggered by crying, hyperventilation, or playing wind instruments
  • Ischemic stroke: Permanent neurological deficits from brain tissue damage
  • Seizures: Focal or generalized, often the presenting symptom
  • Headaches: Frequent, may be migraine-like
  • Involuntary movements: Chorea or other movement disorders
  • Cognitive decline: Progressive intellectual deterioration if untreated

Adult Presentation

  • Intracranial hemorrhage: Sudden severe headache, often with neurological deficits
    • Intraventricular hemorrhage most common
    • Subarachnoid hemorrhage
    • Intracerebral hemorrhage
  • Ischemic symptoms: Similar to pediatric presentation but less common
  • Headaches: Often severe and recurrent
  • Cognitive symptoms: Memory problems, difficulty concentrating

Associated Symptoms

  • Depressive or psychotic symptoms - mood changes, behavioral alterations
  • Elbow weakness - part of hemiparesis pattern
  • Sensory disturbances - numbness, tingling
  • Visual field defects - hemianopia, diplopia
  • Dizziness and vertigo
  • Fatigue and exercise intolerance

Warning Signs Requiring Immediate Attention

  • Sudden severe headache ("thunderclap headache")
  • Sudden weakness or numbness on one side
  • Difficulty speaking or understanding speech
  • Loss of vision or double vision
  • Loss of consciousness
  • Seizures in a previously healthy individual

Causes

The exact cause of moyamoya disease remains unknown, but research suggests a combination of genetic factors and acquired conditions contribute to its development. The progressive arterial narrowing appears to result from smooth muscle cell proliferation in the arterial walls, but the trigger for this process is not fully understood.

Genetic Factors

  • RNF213 gene: The most significant genetic factor
    • Located on chromosome 17q25
    • R4810K variant found in 95% of familial cases in East Asia
    • Acts as a susceptibility gene rather than causative
    • Different variants in Caucasian populations
  • Familial clustering: 10-15% of cases have family history
  • Inheritance pattern: Likely polygenic with environmental factors
  • Other genetic associations: ACTA2, GUCY1A3 mutations in rare cases

Associated Conditions (Moyamoya Syndrome)

  • Genetic syndromes:
    • Down syndrome (Trisomy 21)
    • Neurofibromatosis type 1
    • Sickle cell disease
    • Turner syndrome
    • Alagille syndrome
  • Acquired conditions:
    • Prior cranial radiation therapy
    • Head trauma
    • Meningitis or encephalitis
    • Autoimmune diseases (SLE, Graves' disease)
    • Atherosclerosis (in adults)

Pathophysiological Mechanisms

  • Arterial wall changes:
    • Intimal thickening and fibrosis
    • Smooth muscle cell proliferation
    • Elastic lamina disruption
    • Absence of inflammatory or atherosclerotic changes
  • Angiogenic factors: Increased expression of growth factors
    • Basic fibroblast growth factor (bFGF)
    • Transforming growth factor-beta (TGF-β)
    • Vascular endothelial growth factor (VEGF)
  • Hemodynamic stress: Progressive narrowing creates turbulent flow

Environmental Factors

  • Geographic clustering suggests environmental influences
  • Possible infectious triggers (unproven)
  • Dietary factors under investigation
  • Stress and physical triggers for acute events

Risk Factors

Understanding the risk factors for moyamoya disease helps identify individuals who may benefit from screening and early intervention. While some risk factors are non-modifiable, awareness can lead to earlier diagnosis and better outcomes.

Demographic Risk Factors

  • Ethnicity: Highest risk in East Asian populations
    • Japanese: 10-fold higher incidence than Caucasians
    • Korean: Similar high incidence
    • Chinese: Moderate increased risk
    • Can occur in any ethnic group
  • Gender: Female-to-male ratio approximately 2:1
  • Age: Bimodal distribution
    • First peak: 5-10 years old
    • Second peak: 35-45 years old
  • Family history: 10-15% have affected family members

Medical Conditions Increasing Risk

  • Genetic disorders:
    • Down syndrome: 26-fold increased risk
    • Sickle cell disease: Significant risk, especially in children
    • Neurofibromatosis type 1
    • Turner syndrome
  • Autoimmune conditions:
    • Systemic lupus erythematosus
    • Antiphospholipid syndrome
    • Graves' disease/hyperthyroidism
    • Type 1 diabetes mellitus
  • Previous medical treatments:
    • Cranial radiation therapy (especially in childhood)
    • Chemotherapy for brain tumors

Risk Factors for Disease Progression

  • Age at onset: Earlier onset often means more severe progression
  • Bilateral disease: Worse prognosis than unilateral
  • Posterior circulation involvement: Associated with poorer outcomes
  • Inadequate collateral formation: Individual variation in response
  • Delayed diagnosis: Late treatment associated with irreversible damage

Triggers for Acute Events

  • Hyperventilation: Common trigger in children
    • Crying episodes
    • Playing wind instruments
    • Blowing up balloons
    • Exercise-induced hyperventilation
  • Dehydration: Reduces cerebral blood flow
  • Fever and infection: Increases metabolic demands
  • Anemia: Reduces oxygen-carrying capacity
  • Pregnancy: Hemodynamic changes increase risk

Diagnosis

Diagnosing moyamoya disease requires a combination of clinical evaluation, neuroimaging, and cerebral angiography. Early diagnosis is crucial for preventing irreversible neurological damage and implementing appropriate treatment strategies.

Clinical Evaluation

  • Medical history:
    • Pattern of neurological symptoms
    • Triggers for episodes (hyperventilation, crying)
    • Family history of stroke or moyamoya
    • Associated medical conditions
    • Previous radiation or chemotherapy
  • Neurological examination:
    • Motor strength and reflexes
    • Sensory testing
    • Cranial nerve assessment
    • Cognitive evaluation
    • Gait and coordination

Neuroimaging Studies

MRI and MRA (Magnetic Resonance Imaging/Angiography)

  • First-line imaging for suspected moyamoya
  • T2/FLAIR: Shows ischemic changes, prior infarcts
  • DWI (Diffusion-weighted imaging): Detects acute ischemia
  • MRA: Visualizes stenosis of ICAs and major branches
  • "Ivy sign": Linear high signal along cortical sulci
  • Flow voids from collateral vessels

CT and CTA (Computed Tomography/Angiography)

  • Useful in emergency settings
  • Shows calcifications in basal ganglia
  • CTA demonstrates vascular narrowing
  • Less sensitive than MRI for small infarcts

Digital Subtraction Angiography (DSA)

  • Gold standard for diagnosis
  • Shows characteristic "puff of smoke" appearance
  • Grades disease severity (Suzuki stages 1-6)
  • Evaluates collateral circulation
  • Required for surgical planning

Functional Studies

Perfusion Studies

  • SPECT (Single Photon Emission CT): Assesses cerebral blood flow
  • PET (Positron Emission Tomography): Measures metabolism and flow
  • Perfusion MRI: Non-invasive flow assessment
  • Xenon-CT: Quantitative blood flow measurement

Cerebrovascular Reserve Testing

  • Acetazolamide challenge with SPECT/PET
  • CO2 reactivity testing
  • Identifies areas at risk for stroke
  • Guides surgical decision-making

Laboratory Tests

  • Genetic testing: RNF213 mutation analysis
  • Screening for associated conditions:
    • Hemoglobin electrophoresis (sickle cell)
    • Thyroid function tests
    • Autoimmune markers (ANA, anti-dsDNA)
    • Inflammatory markers (ESR, CRP)

Diagnostic Criteria

Definitive diagnosis requires:

  • Bilateral stenosis/occlusion of terminal ICA
  • Abnormal vascular networks (moyamoya vessels) near stenotic lesions
  • Exclusion of other causes (atherosclerosis, vasculitis, etc.)

Treatment Options

Treatment of moyamoya disease focuses on improving cerebral blood flow and preventing stroke. While medical management can help control symptoms, surgical revascularization remains the definitive treatment for most patients. The choice of treatment depends on the patient's age, symptom severity, and overall health status.

Medical Management

Medical therapy alone cannot reverse arterial narrowing but helps manage symptoms and reduce stroke risk:

Antiplatelet Therapy

  • Aspirin: Most commonly used (3-5 mg/kg/day in children, 81-325 mg in adults)
  • Clopidogrel: Alternative for aspirin intolerance
  • Dual therapy: Reserved for high-risk cases
  • Reduces risk of ischemic events
  • Must balance bleeding risk in adults

Symptomatic Treatment

  • Calcium channel blockers: For headache management
    • Verapamil or nimodipine
    • May improve cerebral blood flow
  • Antiepileptic drugs: For seizure control
  • Pain management: For chronic headaches
  • Antidepressants: For mood symptoms

Surgical Revascularization

Surgery is the definitive treatment, aiming to augment cerebral blood flow:

Direct Revascularization

  • STA-MCA bypass: Superficial temporal artery to middle cerebral artery
    • Immediate flow augmentation
    • Technically challenging in children
    • Best for adults with adequate donor vessels
    • Success rate >90% in experienced centers
  • Double-barrel bypass: Using both branches of STA
  • High-flow bypass: Using radial artery or saphenous vein grafts

Indirect Revascularization

  • EDAS (Encephaloduroarteriosynangiosis):
    • STA laid on brain surface
    • Gradual collateral formation over 3-4 months
    • Preferred in young children
  • EMS (Encephalomyosynangiosis): Temporal muscle on brain
  • Multiple burr holes: Simple but less effective
  • Omental transplantation: For extensive disease

Combined Procedures

  • Direct bypass + EDAS/EMS
  • Maximizes revascularization potential
  • Increasingly preferred approach
  • Better long-term outcomes

Perioperative Management

  • Preoperative optimization:
    • Blood pressure control
    • Maintain adequate hydration
    • Continue antiplatelet therapy
    • Treat anemia if present
  • Intraoperative considerations:
    • Avoid hypotension and hypocapnia
    • Maintain normothermia
    • Minimize brain retraction
  • Postoperative care:
    • Blood pressure augmentation
    • Adequate hydration
    • Antiplatelet therapy
    • Monitor for hyperperfusion syndrome

Special Considerations

Hemorrhagic Moyamoya

  • Controversial surgical indications
  • May benefit from indirect revascularization
  • Avoid anticoagulation
  • Blood pressure control crucial

Pregnancy Management

  • High-risk pregnancy requiring specialized care
  • Continue aspirin if benefits outweigh risks
  • Caesarean section often preferred
  • Avoid hypotension during delivery

Long-term Management

  • Regular neurological follow-up
  • Periodic imaging (MRA every 1-2 years)
  • Continued antiplatelet therapy
  • Risk factor modification
  • Cognitive rehabilitation if needed
  • Genetic counseling for family planning

Prevention

While moyamoya disease itself cannot be prevented due to its genetic and idiopathic nature, strategies focus on preventing stroke and managing risk factors for disease progression. Early detection in high-risk individuals and prevention of acute events are key components.

Primary Prevention

Screening High-Risk Populations

  • Family members of affected individuals:
    • MRA screening considered for first-degree relatives
    • Genetic counseling and testing
    • Annual neurological evaluation
  • High-risk medical conditions:
    • Down syndrome: Regular screening from age 3-5
    • Sickle cell disease: Annual neuroimaging
    • Neurofibromatosis: Baseline and periodic MRA
    • History of cranial radiation: Long-term surveillance

Secondary Prevention (Preventing Stroke)

Lifestyle Modifications

  • Avoid triggers:
    • Prevent hyperventilation episodes
    • Modify activities (avoid wind instruments)
    • Stress management techniques
    • Adequate rest and sleep
  • Maintain optimal health:
    • Stay well-hydrated
    • Avoid extreme temperatures
    • Prompt treatment of infections
    • Maintain normal hemoglobin levels

Medical Interventions

  • Antiplatelet therapy: Long-term aspirin for most patients
  • Blood pressure management: Avoid hypotension
  • Anemia correction: Maintain adequate oxygen delivery
  • Infection prevention: Vaccinations, prompt treatment

Preventing Complications

Post-Surgical Care

  • Adherence to antiplatelet therapy
  • Regular follow-up imaging
  • Monitor for graft patency
  • Prevent hyperperfusion syndrome

Cognitive Preservation

  • Early intervention for learning difficulties
  • Cognitive rehabilitation programs
  • Educational accommodations
  • Regular neuropsychological assessment

Patient and Family Education

  • Recognition of warning signs:
    • FAST acronym for stroke symptoms
    • When to seek emergency care
    • Importance of medication compliance
  • Activity guidelines:
    • Safe exercise recommendations
    • Travel precautions
    • School/work accommodations
  • Emergency preparedness:
    • Medical alert identification
    • Emergency action plan
    • Communication with schools/employers

When to See a Doctor

Call 911 immediately for any stroke symptoms (FAST):

  • Face drooping on one side
  • Arm weakness or numbness
  • Speech difficulty or slurring
  • Time to call emergency services
  • Sudden severe headache ("worst headache of life")
  • Loss of consciousness or seizures
  • Sudden vision loss or double vision

Seek urgent medical evaluation for:

  • Brief episodes of weakness or numbness (TIAs)
  • New or worsening headaches in a child
  • Episodes triggered by crying or hyperventilation
  • Progressive cognitive decline or school difficulties
  • Involuntary movements or tremors
  • Depression or behavioral changes

Schedule consultation for:

  • Family history of moyamoya disease
  • Child with Down syndrome or sickle cell disease
  • Previous cranial radiation therapy
  • Recurrent unexplained neurological symptoms
  • Need for genetic counseling

Regular follow-up needed for:

  • Established moyamoya disease patients
  • Post-surgical revascularization
  • Medication monitoring
  • Neuropsychological assessment
  • Family screening discussions

Related Conditions

References

  1. Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis. Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo). 2012;52(5):245-266.
  2. Fujimura M, Tominaga T. Diagnosis of moyamoya disease: international consensus and remaining issues. World Neurosurg. 2019;127:e814-e819.
  3. Kim JS. Moyamoya Disease: Epidemiology, Clinical Features, and Diagnosis. J Stroke. 2016;18(1):2-11.
  4. Kuroda S, Houkin K. Moyamoya disease: current concepts and future perspectives. Lancet Neurol. 2008;7(11):1056-1066.
  5. Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med. 2009;360(12):1226-1237.