Adult Moyamoya Disease: A Burden of Intracranial Stenosis in East Asians?

Abstract

Background: Both Moyamoya disease (MMD) and intracranial atherosclerotic stenosis (ICAS) are more prevalent in Asians than in Westerners. We hypothesized that a substantial proportion of patients with adult-onset MMD were misclassified as having ICAS, which may in part explain the high prevalence of intracranial atherosclerotic stroke in Asians.

Method: We analyzed 352 consecutive patients with ischemic events within the MCA distribution and relevant intracranial arterial stenosis, but no demonstrable carotid or cardiac embolism sources. Conventional angiography was performed in 249 (70.7%) patients, and the remains underwent MRA. The occurrence of the c.14429G>A (p.Arg4810Lys) variant in ring finger protein 213 (RNF213) was analyzed. This gene was recently identified as a susceptibility gene for MMD in East Asians.

Results: The p.Arg4810Lys variant was observed in half of patients with intracranial stenosis (176 of 352, 50.0%), in no healthy control subjects (n = 51), and in 3.2% of stroke control subjects (4 of 124 patients with other etiologies). The presence of basal collaterals, bilateral involvement on angiography, and absence of diabetes were independently associated with the presence of the RNF213 variant. Among 131 patients who met all three diagnostic criteria and were diagnosed with MMD, three-fourths (75.6%) had this variant. However, a significant proportion of patients who met two criteria (57.7%), one criterion (28.6%), or no criteria (20.0%) also had this variant. Some of them developed typical angiographic findings of MMD on follow-up angiography.

Conclusions: Careful consideration of MMD is needed when diagnosing ICAS because differential therapeutic strategies are required for these diseases and due to the limitations of the current diagnostic criteria for MMD.

Fig 1. Number of cases with RNF213 variant+ among intracranial patients with healthy and stroke controls.

Fig 2. Angiographic progression of MMD in an adult patient with intracranial stenosis.

A 42-year-old female presented with transient numbness and clumsiness of her left hand. She had mild stenosis on bilateral and proximal middle cerebral arteries. There was no stenosis of the distal internal carotid artery and basal collaterals, called Moyamoya vessels, on conventional angiography (upper lane). Angiographic findings taken one year later show the progression of stenosis and Moyamoya vessels bilaterally (lower lane). Genetic study revealed RNF213 mutation associated with MMD (p.Arg4810Lys).

Fig 3. Neuroimaging and genetic findings of a patient with non-Moyamoya-type intracranial arterial occlusive disease.

(a) Conventional angiography of a 53-year-old male shows stenosis of the proximal MCA, but intact distal ICA and absence of Moyamoya vessels. (b) Family tree. This patient has a family history of MMD and RNF213 p.Arg4810Lys mutations. Small black points indicate members who were directly examined. (c) High-resolution MRI reveals a smaller outer diameter (2.32 mm) and the absence of focal plaque in the stenotic segment (arrow). ICH, intracranial hemorrhage.