Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disorder characterized by progressive stenosis and occlusion of the bilateral terminal internal carotid arteries, proximal anterior cerebral arteries, and proximal middle cerebral arteries. The name derives from the abnormal collateral vessels seen on cerebral angiography, which resemble a puff of smoke (moyamoya).
Even when similar angiographic findings are present, cases with underlying conditions such as Down syndrome, sickle cell disease, systemic lupus erythematosus (SLE), neurofibromatosis type 1 (NF1), or thalassemia are distinguished as moyamoya syndrome (MMS)3).
The incidence is highest in Japan and South Korea. In Japan, the incidence is 0.54 per 100,000 people, about 10 times that in North America and Europe. In the United States, an incidence of 0.57 per 100,000 has been reported. The male-to-female ratio is 1:1.8, with peak prevalence in males in their teens and females in their 20s. Familial cases account for 12.1% in Japan and about 4% in North America.
There is a strong association with trisomy 21 (Down syndrome), and the prevalence of MMD is reported to be up to 26 times higher than in the general population.
Moyamoya disease refers to bilateral progressive stenosis of the internal carotid artery system without an underlying condition. Similar angiographic findings associated with specific underlying diseases such as Down syndrome, sickle cell disease, or SLE are called moyamoya syndrome and are distinguished3). Treatment strategies and prognosis may differ depending on the presence of an underlying condition.
Ocular symptoms are not always present, but the following symptoms have been reported.
Amaurosis Fugax
Pathophysiology: Caused by circulatory occlusion in the internal carotid artery system. Thromboembolism and hypoperfusion are the underlying mechanisms.
Characteristics: Paroxysmal, recurrent painless vision loss. An important sign of intracranial vascular disease.
Central Retinal Artery Occlusion
Cherry-red spot: A characteristic red lesion appears at the fovea.
Fluorescein fundus angiography (FFA): Can confirm delayed filling of the retinal artery.
Peculiarity in MMD: Retinal vascular abnormalities are rare because collateral circulation develops via the external carotid artery. Occlusion often occurs distal to the ophthalmic artery bifurcation.
Ocular ischemic syndrome
Pathogenesis: Chronic retinal and choroidal ischemia leads to excessive VEGF production. Neovascularization forms in the iris and angle.
Neovascular glaucoma (NVG): Angle-closure glaucoma develops.
Hypotony tendency: Relative hypotony may occur due to decreased aqueous humor production from ciliary body hypoperfusion. It may be accompanied by anterior uveitis.
Morning glory syndrome
Definition: A congenital optic nerve anomaly characterized by an enlarged funnel-shaped optic disc excavation, peripapillary pigmentary changes, and central glial tissue.
Association with MMD: It is accompanied by abnormal retinal vascular course, and abnormal embryonic vascular development may underlie the association with MMD. Intracranial vascular abnormalities must be ruled out by MRA.
Other findings include bilateral corneal opacities and complete blindness reported in MMS patients with Schimke immuno-osseous dysplasia (SIOD) 4). OCT angiography has shown an increase in the superficial vascular complex (SVC) in eyes with MMD secondary shunts, which disappears after STA-MCA bypass surgery.
In MMD, even if the internal carotid artery is occluded, collateral circulation via the external carotid artery develops, so blood flow to the ophthalmic artery is relatively well preserved. Also, occlusion often occurs distal to the ophthalmic artery bifurcation. Therefore, retinal vascular abnormalities are considered rare compared to CRAO from other causes.
The etiology of MMD is largely unknown and is considered a multifactorial disease.
VEGF, bFGF, and TGF-β1 have been detected, promoting smooth muscle proliferation in the intima and causing stenosis. Inflammatory cytokines such as IFN-β, IFN-γ, TNF-α, IL-6, and IL-1 may activate transcription of RNF2132).
It is known to be associated with the following diseases:
| Disease | Notes |
|---|---|
| Trisomy 21 (Down syndrome) | MMD prevalence up to 26 times higher than general population |
| Sickle cell disease | MMS complication rate 20–30% |
| SLE | Immunological background |
| NF1 (Neurofibromatosis type 1) | — |
| Schimke immuno-osseous dysplasia (SIOD) | SMARCAL1 gene mutation. Bilateral corneal opacity and blindness have been reported4) |
| Multiple sclerosis (MS) | Cases of co-occurrence with MMS have been reported2) |
It is suggested that vascular developmental abnormalities associated with trisomy 21 and immunological background may be involved, but the detailed mechanism is not yet clear. The prevalence has been reported to be up to 26 times higher than in the general population, so when neurological symptoms appear in patients with Down syndrome, it is important to actively suspect MMS.
The following three items are required for the clinical diagnosis of MMD.
Unilateral cases are considered “suspected cases,” but often progress to the contralateral side within a few years. In the revised Japanese guidelines, unilateral cases can also be diagnosed as MMD.
| Test | Features |
|---|---|
| DSA (Digital Subtraction Angiography) | Gold standard. Also used for surgical planning. |
| MRA | Non-invasive. Reported sensitivity 69.2%, specificity 93.3%3) |
| CTA | High sensitivity and specificity. Useful for emergency evaluation3) |
| Transcranial Doppler (TCD) | Low diagnostic sensitivity but high specificity; used for preoperative assessment3) |
| Vessel Wall MRI (VW-MRI) | Evaluates vessel wall thickening and contrast enhancement. Useful for differentiating from vasculitis2) |
In the differential diagnosis of OIS, it is important to distinguish it from diabetic retinopathy and central retinal vein occlusion (CRVO).
There is no curative treatment, and there is no way to reverse intracranial stenosis.
This is the only effective treatment for ischemic MMD. Without surgery, the one-year stroke risk reaches 32%, whereas surgery reduces it to less than 5% at both one and five years 3). A surgical delay of more than two months after diagnosis increases the risk of preoperative infarction, especially in children under 6 years of age 3).
Direct Bypass Surgery
STA-MCA anastomosis: Direct anastomosis of the superficial temporal artery (STA) to the middle cerebral artery (MCA).
Advantage in adults: In adults, it is reported to be superior to indirect bypass 3). It has a rapid effect, with increased blood flow expected immediately after surgery.
Indirect Bypass Surgery
EDAS (Encephalo-duro-arterio-synangiosis): The STA is placed in contact with the brain surface to promote angiogenesis 3).
EMAS (Encephalo-myo-arterio-synangiosis): The temporalis muscle is placed on the cortical surface 3).
Pial synangiosis: The STA is sutured to the pia mater 3).
Multiple burr hole trephination (MBHT): Can be performed bilaterally in one stage 5). Commonly used in pediatric cases.
Treatment of ocular ischemic syndrome is based on treating the underlying disease (carotid artery stenosis), and collaboration with neurologists and neurosurgeons is essential. If neovascular glaucoma occurs, intraocular pressure management is necessary.
Treatment of the underlying disease is prioritized. In SIOD, management of hypertension and dyslipidemia along with antiplatelet drugs is central 4).
There are direct bypass (STA-MCA anastomosis) and indirect bypass (EDAS, EMAS, pial synangiosis, multiple burr holes, etc.). Direct bypass is considered to have rapid effect and is preferred in adults, while indirect bypass is often used in children 3). Both significantly reduce the risk of stroke compared to no surgery.
Intimal thickening due to migration and proliferation of smooth muscle cells in the distal internal carotid artery narrows the arterial lumen 3). Immunological mechanisms include deposition of IgG, IgM, and C3 in the vessel wall, along with infiltration of macrophages and T lymphocytes 2).
The double hit hypothesis proposes that vasculopathy develops when genetic predisposition (e.g., RNF213 mutation) combines with environmental factors such as infection, immune response, and flow-induced endothelial injury (shear stress) 2).
In response to progressive ischemia, moyamoya vessels develop at the base of the brain, but these are fragile and carry a risk of bleeding. In adults, the hemorrhagic type is more common than in children.
Canavero et al. (2025) reported two cases of combined MMA and MS, suggesting involvement of RNF213 in oligodendrocyte differentiation and myelin loss, and proposed a common pathomechanism of synergistic activation of RNF213 transcription by inflammatory cytokines 2).
Comparing retinal photographs of MMD patients and control groups, development of a deep learning algorithm using retinal photographs as biomarkers for MMD is underway. Application to non-invasive early screening via retinal photography is expected.
In eyes with MMD secondary shunts, an increase in the superficial vascular complex (SVC) has been detected, and it has been reported to disappear after STA-MCA bypass surgery. Its usefulness as a postoperative cerebral blood flow evaluation index is being investigated.
Santoto et al. (2022) reported novel missense mutations (p.Phe4120Leu, p.Ser4118Cys, p.Glu4867Lys) in three European families 5). These are associated with syndromic MMA involving liver dysfunction, extracranial vascular lesions, and skin symptoms, and phenotypic diversity in Europeans is becoming evident.
Based on reports of high expression and pathogenic mutations of RNF213 in familial MS patients, a common mechanism of inflammatory pathways and neurovascular unit dysfunction has been proposed as a hypothesis 2). This finding may provide new insights into the diagnosis and treatment of comorbid cases of MMA and MS.
