What is Moyamoya disease, a condition affecting blood vessels in the brain, particularly in individuals of East Asian descent or those with underlying medical conditions such as sickle cell disease, Down syndrome, or neurofibromatosis type 1?

What is Moyamoya Disease?

Moyamoya is a progressive cerebrovascular disease characterized by stenosis or occlusion of the terminal portions of the internal carotid arteries with development of abnormal collateral vessels at the base of the brain that appear as a "puff of smoke" on angiography. 1

Definition and Terminology

Moyamoya—meaning "puff of smoke" in Japanese—describes the characteristic angiographic appearance of a network of small, dilated collateral vessels that develop in response to progressive arterial narrowing. 1 The condition exists in two forms:

• Moyamoya disease (MMD): Bilateral involvement occurring as an isolated condition without identifiable underlying cause 1
• Moyamoya syndrome (MMS): Unilateral or bilateral involvement associated with systemic disorders such as sickle cell disease, Down syndrome, neurofibromatosis type 1, lupus erythematosus, or rheumatoid arthritis 1

Pathophysiology

The disease involves progressive stenosis of the terminal internal carotid arteries and proximal portions of the anterior and middle cerebral arteries. 2 As these major vessels narrow, fragile collateral vessels develop from the circle of Willis—primarily from intracranial portions of the internal carotid arteries, anterior choroidal arteries, and posterior cerebral arteries—forming complex channels that penetrate the base of the brain at the thalamoperforate and lenticulostriate regions. 2

Both genetic factors (particularly the RNF213 gene on chromosome 17q25-ter in East Asian populations) and nongenetic factors such as autoimmunity, radiation, and infection contribute to disease development. 1, 3

Epidemiology

Moyamoya disease is most prevalent in East Asian populations, particularly Japan and Korea, with a much lower incidence in Western populations. 3 In the United States, the disease affects approximately 1 in 1 million children and accounts for 6% of all childhood strokes. 1

The disease demonstrates:

• Bimodal age distribution with peaks at 5 years and around 40 years of age 1, 4
• Female predominance with a higher female-to-male ratio 2
• Familial clustering in approximately 15% of cases 4

Clinical Presentations

Ischemic Manifestations

The ischemic type predominates in children and includes: 1

• Transient ischemic attacks and strokes (usually in carotid branches and watershed territories)
• Both hypoperfusive and thromboembolic mechanisms
• Triggers related to hemodynamic demand: fever, dehydration, physical activity, hyperventilation, hypercoagulable conditions

Hemorrhagic Manifestations

Adult patients more commonly present with hemorrhagic events: 1

• Intracerebral or intraventricular hemorrhage (occasionally subarachnoid)
• Due to rupture of deep neovascularization collaterals and pseudoaneurysms
• Occasionally associated with aneurysms

Other Neurological Symptoms

Patients may also present with: 1

• Headaches: migraine (most common), tension-type, hemiplegic migraine, or cluster headaches
• Neurocognitive impairment from chronic cerebral hypoperfusion
• Secondary movement disorders
• Seizures and intellectual decline (more common in children) 3

Diagnostic Criteria

Gold Standard Imaging

Digital subtraction angiography remains the gold standard for diagnosis. 1 Required findings include: 1

• Stenosis or occlusion in arteries centered on the terminal portion of the intracranial internal carotid artery
• Moyamoya vessels (abnormal vascular networks) in the vicinity of occlusive or stenotic lesions in the arterial phase
• Both unilateral and bilateral involvement satisfy diagnostic criteria

Alternative Imaging Modalities

MRI and MRA (using ≥1.5 Tesla scanner) can establish diagnosis when showing: 1

• Stenosis/occlusion of the terminal portion of intracranial internal carotid artery
• Decreased outer diameter of the terminal internal carotid artery and horizontal middle cerebral artery bilaterally on heavy T2-weighted MRI
• At least 2 visible flow voids (unilateral or bilateral) at the basal ganglia or periventricular white matter representing abnormal vascular networks

Suzuki Classification System

The disease progresses through six angiographic stages, from Stage I (narrowing of the carotid fork) to Stage VI (disappearance of moyamoya vessels with cerebral blood flow derived only from external carotid and vertebrobasilar systems). 1, 2 However, this classification has limited practical application in individual cases without serial evaluations. 1

Natural History and Prognosis

Without treatment, moyamoya disease carries a high risk of recurrent cerebrovascular events. 1 In symptomatic patients in the United States with conservative management:

• 5-year risk of recurrent ischemic events: 65% in unilateral disease, 82% in bilateral involvement 1
• Recurrent hemorrhage occurs in 30-60% of Japanese patients over long-term follow-up 1
• Disease progression from unilateral to bilateral occurs in approximately 20% of both symptomatic and asymptomatic patients 1

In asymptomatic patients, the annual risk of cerebrovascular events is approximately 5%, with disease progression in 20% over mean follow-up of 6 years. 1

Patients with posterior circulation involvement have more severe clinical manifestations and higher rates of recurrent hemorrhage. 1

Key Clinical Pitfalls

• Moyamoya disease is an exclusion diagnosis—any possible causes of moyamoya syndrome must be excluded before confirming MMD 1
• The disease is progressive in nearly all individuals, with more than two-thirds experiencing symptomatic progression within 5 years 1
• Intracerebral hemorrhage in moyamoya is more often accompanied by intraventricular hemorrhage compared to hypertensive intracerebral hemorrhage 3