Pathology of Moyamoya Disease in Children

Pathophysiology

  • Primary event stenosis of distal internal carotid artery: The etiology of stenosis of distal internal carotid artery or its branches are unknown. Enlargement of basal perforators with occasional microaneurysm formation and bleeding, leptomeningeal and other anastomotic vessel formation, and cerebral infarction are regarded as secondary events to the stenosis or occlusion of the distal internal carotid artery and its primary branches.
  • Clinical manifestations due to ischemia: Transient ischemic symptoms are results of decreased cerebral perfusion. Patients with Moyamoya Disease are sensitive to hyperventilation that causes physiologic cerebral arterial narrowing in normal condition. Seizure may accompany ischemia, infarction or bleeding. Headache may reflect compensatory vasodilatation of cerebral arterial trees with chronic or compensated cerebral ischemia.

Molecular/genetic Pathology

  • RNF213 and other causes: In North America, only a small minority of pediatric moyamoya cases (<5%) appear to have clear mutational associations, unless the child has Asian heritage (30-40 % of Asians have RNF213 mutations) (6,14,16,38).  The presence of a RNF213 mutation with moyamoya has marked significance for familial screening, as data suggests that familial penetrance is ~23% and, if an individual carries the mutation, there is a near 50% likelihood of manifesting arteriopathy (38,42).  Other mutations are more rare, but may be detected by specific clinical or radiographic phenotypes (ACTA2 carriers with distinctive stellate arteries branching from a dilated proximal internal carotid, GUCY mutations with achalasia, etc.) (6,15,16,38,42,44,46,62).
 

Mutations associated with moyamoya (15,16,44)
ACTA2 R179
BRCC3/MTCPI
GUCYIA3
RNF213
SAMHD1

Primary Histopathology

  • Narrowing artery: The vessels of stenosis show narrowing of external and luminal diameters of arteries with thickening of intima.  This is due to fibrocellular thickening with smooth muscle cell proliferation of intima, irregular undulation of the internal elastic lamina and attenuation of the media.  Inflammatory cell infiltration and lipid deposits are absent or rare (10,41).