What is the pathophysiology of Moyamoya disease?

Pathophysiology of Moyamoya Disease

Moyamoya disease (MMD) is fundamentally characterized by progressive stenosis of the terminal portion of the internal carotid artery and the formation of an abnormal network of dilated, fragile perforator vessels at the base of the brain, with a strong genetic component primarily linked to mutations in the RNF213 gene. 1, 2

Vascular Pathology

• Progressive stenosis/occlusion centered on the terminal portion of the intracranial carotid artery
• Formation of abnormal collateral vessels ("moyamoya vessels") at the base of the brain
• Gradual conversion of cerebral blood supply from internal carotid system to external carotid system 1
• Progression through Suzuki stages (I-VI) reflecting increasing stenosis and collateral formation followed by regression of collaterals 1

Genetic Basis

• Strong genetic component with up to 12% of patients having positive family history 1, 2
• Autosomal dominant inheritance pattern with incomplete penetrance 2
• RNF213 is the primary susceptibility gene:
  • RNF213 R4810K variant predominant in East Asian populations (Japanese and Korean)
  • Non-R4810K variants increase risk in non-East Asian populations 1, 2
• Penetrance varies significantly:
  • Heterozygotes of RNF213 R4810K: approximately 0.67% (1 per 150)
  • Homozygotes: more than 78% 2

Molecular Mechanisms

• RNF213 functions as an E3 ubiquitin ligase
• Defective or hypomorphic RNF213 p.R4810K function may fail to properly degrade substrates NFAT1 and filamin A 1
• Disruption in cerebrovascular angiogenesis and remodeling processes 1
• Most RNF213 mutations are predominantly missense mutations 1

Disease Progression

• Bilateral involvement is common, but unilateral disease can progress to bilateral involvement 1
• Progression occurs in approximately 20% of both symptomatic and asymptomatic adult patients 1
• Progression can involve both anterior and posterior circulation 1
• Posterior circulation involvement is associated with worse clinical presentation and higher risk of hemorrhage 1

Moyamoya Disease vs. Moyamoya Syndrome

• Moyamoya disease: idiopathic form without associated conditions
• Moyamoya syndrome (MMS): when moyamoya vasculopathy is associated with other conditions, including:
  • Autoimmune diseases (SLE, antiphospholipid syndrome, etc.)
  • Down syndrome
  • Neurofibromatosis type 1
  • Sickle cell disease
  • Head irradiation
  • Meningitis
  • Brain tumors 1, 2

Pathophysiological Mechanisms of Clinical Manifestations

Ischemic Events

• Hemodynamic compromise due to progressive stenosis
• Watershed infarctions due to inadequate collateral circulation
• Thromboembolism from stenotic vessels

Hemorrhagic Events

• Rupture of fragile collateral vessels
• Extension and dilatation of choroidal collaterals increase bleeding risk 3
• Posterior cerebral artery involvement associated with higher rebleeding risk 3

Ethnic and Demographic Variations

• Higher prevalence in East Asian populations (Japan, Korea)
• Female predominance (female-to-male ratio up to 2.6:1) 1
• Bimodal age distribution with peaks around age 10 and 30-40 years 1, 4
• Different clinical presentations by age group:
  • Children: predominantly ischemic symptoms
  • Adults: higher incidence of hemorrhagic events 4

Pathophysiological Basis for Treatment

• Surgical revascularization aims to improve cerebral blood flow and prevent ischemic events
• Flow-augmentation bypass may reduce rebleeding risk in hemorrhagic MMD 5
• Medical management focuses on controlling vascular risk factors and judicious use of antithrombotics 6

Understanding the complex pathophysiology of Moyamoya disease is crucial for appropriate diagnosis, risk stratification, and treatment selection to reduce morbidity and mortality in affected patients.