Moyamoya Disease and Syndrome

Introduction

Moyamoya disease (MMD) is a chronic, occlusive cerebrovascular disease with an unknown etiology. It is characterized by steno-occlusive changes at the terminal portion of the internal carotid artery (ICA), and an abnormal vascular network at the base of the brain . When there are causative diseases or associated conditions, the terms “moyamoya syndrome” and “angiographic moyamoya” are often used .

Epidemiology

MMD is relatively common in the East Asian countries . The reported incidence and prevalence rate in Japan were 0.35 and 3.16/100,000, respectively, in 1995, which increased to 0.54 and 6.03/100,000, in 2003. An epidemiological study from Korea based on National Health Insurance (NHI) data reported that MMD prevalence increased from 6.3/100,000 in 2004 to 9.1/100,000 in 2008. From 2007 to 2011, the annual incidence increased from 1.7 to 2.3 per 100,000 persons. In a study based on the Taiwan NHI program, the annual incidence of MMD was 0.15/100,000, while a study conducted in the area of Nanjing, China showed a prevalence of 3.92/100, 000 during 2000–2007. National data on mainland China are not available. Both in Japan and Korea, the male-to-female ratio was about 1:2, and 10–15% of the patients had MMD family history. There were two age peaks, at ages 10–20 and 35–50 years ( Fig 109.1 ).

Figure 109.1, Incidence of moyamoya disease by sex and age in Korea, 2007–2011.

Studies from outside of Asia are rare. In the states of Washington and California in the United States, the incidence of MMD was 0.086/100,000. The incidence was the highest among Asians, followed by African Americans, Whites, and Hispanics. However, a recent study based on the Nationwide Inpatient Sample (NIS) reported that MMD appears to be distributed among the races/ethnic groups based on their proportions of the total US population. Similar to East Asian patients, there was a bimodal age distribution, and female-to-male ratio was 2.2, but familial occurrence seems to be less common (about 2%).

There is an increasing incidence and prevalence of MMD over time worldwide. This finding may indicate an actual increase in patients with MMD. A more plausible explanation would be an increment in the number of newly diagnosed patients following the recent advent of noninvasive diagnostic tools, such as magnetic resonance angiography (MRA) and computed tomography angiography (CTA). Another reason is an increasing number of survivors due to improved management.

Pathology and Pathogenesis

Pathology

The main pathological changes of the stenotic segment of MMD are fibrocellular thickening of the intima, irregular undulation of the internal elastic lamina, medial thinness (attenuation of media), and decrease in the outer diameter. Histopathological findings in the distal ICA have shown proliferation of smooth muscle cells or endothelium, and stenosis or occlusion associated with fibrocellular thickening of the intima . The moyamoya vessels are the dilated perforating arteries associated with various histopathological changes including fibrin deposits in the wall, fragmented elastic lamina, attenuated media, and microaneurysms formation. Aside from the moyamoya vessels, another important finding of MMD is cortical microvascularization, which is characterized by increased microvascular density and vascular diameter.

Genetics Underlying MMD

A 2011 genome-wide association study identified the ring finger protein 213 ( RNF213 ) gene in the 17q25.3 region as a susceptibility gene for MMD among East Asian population . A single nucleotide polymorphism (SNP) of c.14576G>A variant in RNF213 was detected in 95% of familial MMD and 79% of sporadic cases among Japanese patients. Homozygous c.14576G>A variant of RNF213 appears to predict early-onset and a severe form of MMD. In addition, novel variants in RNF213 in non-c.14576G>A were recently found in Caucasian and Chinese MMD patients.

The exact function of RNF213 and the role of SNP of RNF213 in the pathogenesis of MMD are still undetermined. In vivo experiments reported in 2013 using genetically engineered mice ( RNF213 -deficient mice and RNF213 -knock-in mice expressing a missense mutation in mouse RNF213 , p.R4828K) failed to produce histological and angiographic findings of MMD under normal condition. On the contrary, post-ischemic angiogenesis was significantly enhanced in mice lacking RNF213 after chronic hind-limb ischemia. These results, together with the low penetrance rate of RNF213 polymorphisms, suggest the importance of environmental factors in addition to a genetic predisposition . Autoimmunity, infection or chronic inflammatory conditions, and cranial irradiation have been suggested to be candidates for secondary insults in MMD patients.

Moyamoya Syndrome With Associated Conditions

MMD-like vasculopathy associated with other disease conditions is called the “moyamoya syndrome.” The disease conditions include: (1) genetic , hereditary disorders : neurofibromatosis type 1, Down syndrome, Noonan syndrome, and trisomy 12p syndrome; (2) hematological disorders : sickle cell disease, essential thrombocythemia, hereditary spherocytosis, protein C deficiency, and protein S deficiency; (3) connective tissue diseases : systemic lupus erythematosus, antiphospholipid syndrome, livedo reticularis; (4) infectious or chronic inflammatory conditions : pneumococcal meningitis tuberculous meningitis, HIV infection, leptospirosis, cat scratch disease, pulmonary sarcoidosis, Behçet’s disease; (5) metabolic diseases : diabetes mellitus, thyrotoxicosis, and hyperhomocysteinemia; (6) vascular injury : radiation therapy; and (7) others : renovascular hypertension and oral contraceptive use, especially in cigarette smokers.

It remains unclear how these disorders are related to the moyamoya vasculopathy, but they may play the role of triggering factors or secondary insults in susceptible patients.

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