Adult Moyamoya Disease and Moyamoya Syndrome: What Is New? Open Access

Moyamoya disease (MMD) is an uncommon, progressive vascular disorder of unknown etiology, in which arteries of the circle of Willis become stenosed or obstructed bilaterally, reducing blood flow to the brain [1, 2]. Tiny blood vessels develop at the base of the brain to supply blood to the brain. The word “moyamoya” means “puff of smoke” in Japanese, a term describing the appearance of net-like tiny blood vessels [3]. MMD is observed worldwide but is more common in East Asia [4]. MMD may cause headache, seizure, transient ischemic attack (TIA), stroke, aneurysm, or bleeding in the brain. Ischemic stroke is dominant in children and hemorrhagic stroke is dominant in adults [2, 4]. It can also cause cognitive and developmental delays or disability. Cerebral angiography is mandatory for the definitive diagnosis of MMD [5, 6]. Ring finger protein (RNF213) was identified as a susceptibility gene for East Asian populations [7, 8].

Moyamoya syndrome (MMS) or quasi-MMD is a term used to describe moyamoya-like vasculopathy associated with various systemic diseases or conditions [5, 6, 9, 10]. MMS is observed in any race or ethnicity over the world. Congenital diseases are common in children and acquired diseases are common in adults as underlying diseases in MMS. The relatively common associated diseases in adult MMS are atherosclerosis, autoimmune diseases, head trauma, brain tumor, radiation, and meningitis. Unilateral involvement is more common in MMS than in MMD. The clinical manifestations of MMS are complicated because the symptoms due to both moyamoya vasculopathy and underlying diseases are mixed.

In 2011, a genome-wide association study identified RNF213 as the first MMD gene in Japanese patients with familiar MMD [7]. Thereafter, RNF213 was identified as a susceptibility gene for not only Japanese but also Korean and Chinese populations [8]. In East Asia, the founder variant RNF213 p.R4810K is much more frequently found in patients with MMD (Japanese, 90.1%; Korean, 78.9%; Chinese, 23.1%) than the general population (Japanese, 2.5%; Korean, 2.7%; Chinese, 0.9%), whereas it is not found in Caucasians, in whom D4013N may have a founder effect in Caucasian populations [11]. A polymorphism in c.14576G>A in RNF213 (originally reported variant identical to RNF213 p.R4810K) was identified in 95% of familial patients with MMD and 79% of sporadic cases. Patients with this polymorphism had significantly earlier disease onset and a more severe form of MMD, such as the presentation of cerebral infarction and posterior cerebral artery stenosis [12].

RNF213 has been reported to be a susceptibility gene not only for MMD but also for atherosclerotic intracranial arterial stenosis and ischemic stroke attributable to large artery atherosclerosis. According to a single-hospital-based case-control study in Japan, 9 of 41 patients (21.9%) with non-MMD intracranial arterial stenosis or occlusion (ICASO) and 41 of 48 (85.4%) with MMD had the c.14576G>A variant [13]. This study indicates that a particular subset of Japanese patients with ICASO has a genetic variant associated with MMD. In a larger two-center-based case-control study, RNF213 c.14576G>A variant was found in 1.8% (2/110) of the normal control group and was significantly associated with definite MMD (odds ratio [OR] 144.0, 95% confidence interval [CI], 26.7–775.9, p < 0.0001), unilateral MMD (OR: 54.0, 95% CI: 7.5–386.8, p = 0.0001), and non-MMD ICASO (OR: 16.8, 95% CI: 3.81–74.5, p < 0.0001) [14]. This result replicated previous findings that a particular subset of patients with various ICASO phenotypes has a common genetic variant, RNF213 c.14576G>A, which is a high-risk allele for ICASO. In a 2-stage case-control study, data analyzed from three independent Japanese population studies with a total of 46,958 individuals of East Asian ancestry (17,752 cases and 29,206 controls), the RNF213 p.R4810K variant was found in 5.2% of patients with non-cardioembolic stroke and 2.1% of controls (OR: 2.60, 95% CI: 1.39–4.85, p = 0.0019) [15]. When stratified by the ischemic stroke subtype, only large artery atherosclerosis was significantly associated with the variant. In the variant carriers, the mean age at stroke onset was younger, and women and intracranial anterior circulation stenosis were more common.

The gold standard for angiographic diagnosis of MMD is the Suzuki grading system (Table 1) [3]. The Houkin magnetic resonance angiography (MRA) score is commonly used, is highly correlated with the Suzuki score, and has high sensitivity and specificity (Table 2) [16]. Table 3 shows diagnostic criteria for MMD established by the Research Committee on MMD (RCMD) of the Ministry of Health, Labor and Welfare, Japan [17]. The criteria include radiological findings on cerebral angiography and magnetic resonance imaging (MRI)/MRA, and differential diagnosis. MMD is diagnosed when radiological findings are present and MMS is excluded. The RCMD Guidelines presented important new accords regarding the locations and magnitude of involvement necessary for the definition of MMD, which is the steno-occlusive involvement of the arteries centered on the terminal portion of the intracranial carotid artery in the absence of other causes that can produce arterial stenosis/occlusion [5]. This eliminated the limitations of the previous definition, which required bilateral involvement of the intracranial carotid artery. Currently, proximal middle cerebral artery or anterior cerebral artery involvement suffices, and unilateral disease is acceptable for diagnosis, given the increasing evidence of progression to bilateral involvement in unilateral MMD.

3-dimensional constructive interference in steady-state (3D-CISS) imaging on MRI [18] is useful for the differential diagnosis of MMD from atherosclerosis [19]. This is because 3D-CISS clearly demonstrates a markedly reduced outer diameter in patients with unilateral MMD, which is specific for MMD and never seen in atherosclerosis. Figure 1 shows a diagram of a hypothesis for MMD development [19]. Initially, intimal thickening causes luminal stenosis of the carotid folk. The carotid folk simultaneously starts to decrease in the outer diameter. These alterations may progress gradually as the disease progresses. Both medial thinning and waving of the elastic lamina may be closely related to shrinkage of the carotid folk.

Ladner et al. [20] proposed a scoring system for the degree of moyamoya vasculopathy, Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD), which applies a combination of conventional angiography and noninvasive structural and hemodynamic 3 Tesla MRI parameters. The hemispheres were divided into three severity grades based on the total PIRAMD score, as follows: grade 1, 0–5 points; grade 2, 6–9 points; and grade 3, 10 points. Patients with PIRAMD 3, if not already symptomatic, might have a high risk of becoming symptomatic, and surgery should be more strongly considered. In contrast, patients with PIRAMD 1 might not become symptomatic, and conservative management with serial monitoring may be recommended.

While MMD is relatively rare in non-East Asian countries and patients with proximal intracranial arterial stenosis of unknown etiology, regardless of unilateral or bilateral involvements, especially in young adults, screening for MMD is recommended [21]. As noted in the considerations of clinical practice by the Scientific Statement from the American Heart Association/American Stroke Association (AHA/ASA), relatives of affected patients have an increased risk of having MMD compared with the general population [6]. Therefore, a family medical history of MMD is quite important in the interview of suspected patients.

The primary cause of moyamoya stenosis is a concentric fibro-cellular hyperplasia of the intima [22]. This hyperplasia is characterized by the proliferation of smooth muscle cells and extracellular matrix within the intima that leads to progressive intimal thickening. Additionally, the internal elastic lamina is altered to wavy, duplicated, and disrupted. In contrast to the significant intimal thickening, the tunica media progressively becomes thinner. This thinning occurs despite intimal expansion, the outer vessel diameter progressively decreases in association with luminal stenosis over time.

RNF213 plays a role in cerebrovascular angiogenesis and remodeling [6]. RNF213 functions as an E3 ubiquitin ligase. Therefore, defective or hypomorphic RNF213 p.R4810K function may fail to degrade the 2 substrates, NFAT1 and filamin A [11, 23]. Most RNF213 mutations are predominantly missense mutations located at the C-terminals [6]. This suggests that the mutations have a dominant-negative or gain-of-function effect. Most of the RNF213 mutations do not fall into the category of null mutations, resulting in a loss-of-function (nonsense or frame-shift mutations) [11]. Recent molecular studies have indicated that RNF213 may play a role as an antimicrobial protein with important functions in the immune system [24, 25].

RNF213 deficiency could lead to vascular fragility including medial thinness, which may make vessels more vulnerable to hemodynamic stress and secondary insults, which facilitates the development of MMD. Furthermore, it is conceivable that secondary insults in addition to RNF213 abnormality, such as an autoimmune response, infection/inflammation, and radiation may be necessary for the development of MMD. Experimental results that neither RNF213 knock-out nor knock-in mice spontaneously develop MMD support this hypothesis [26, 27]. The incidence rate of MMD was shown to be as low as 0.53 per 100,000 population in Japan [4], while 1% of the Japanese population carries the polymorphism of c.14576G>A in the RNF213 gene [8], also suggesting the importance of additional insults to induce MMD. This observation could be illustrated as a “two-hit theory,” as is also true in a variety of disorders (Fig. 2) [28].

In 2021, Japanese Guidelines for the Management of MMD, it was documented that oral administration of antiplatelet agents may be considered a medical treatment for ischemic MMD [5]. It was noted in the AHA/ASA Scientific Statement that in patients with MMD, use of antiplatelet therapy, typically monotherapy, for the prevention of ischemic stroke or TIA may be reasonable [6]. No specific recommendation for cilostazol use in ischemic MMD was made from the AHA/ASA statement or Japanese Guidelines [6, 17, 29, 30]. In a recent meta-analysis of nine studies involving 16,186 patients with MMD, antiplatelet therapy reduced the risk of hemorrhagic stroke but neither reduced the risk of ischemic stroke nor increased the proportion of independent patients [31].

In the 2021 Japanese Guidelines for the Management of MMD, intravenous thrombolysis with recombinant tissue plasminogen activator should be considered under careful evaluation of the risk of hemorrhagic complication in the hyperacute phase of cerebral ischemia in MMD [17]. Endovascular interventional stent placement fails to prevent future ischemic events and does not halt the progression of MMD [32]. Patients with MMD are more prone to aneurysm formation than patients in the general population who are commonly treated with endovascular therapy [33].

If symptoms become worse or if tests show evidence of low blood flow, revascularization surgery is recommended (Fig. 3) [21, 34]. Direct or indirect revascularization procedures or a combination of both may be used. Indirect procedures include encephaloduroarteriosynangiosis and encephalomyosynangiosis. In direct revascularization surgery, the scalp artery is sutured directly to the brain artery to immediately increase the blood flow to the brain.

In the Japan Adult Moyamoya trial, which was a randomized controlled trial for bilateral extracranial-intracranial direct bypass versus conservative therapy in 80 patients with MMD at the age of 18–65 years, the incidence of intracranial hemorrhage, recurrent bleeding, completed stroke, or crescendo TIA was significantly lower in direct bypass than in conservative care [35]. The prespecified subgroup analysis suggests that patients with posterior hemorrhage are at higher risk of rebleeding and accrue greater benefit from surgery [36].

The natural history of MMD remains elusive, but is important to make a prognosis and to determine the optimal timing for interventions [37]. According to a meta-analysis on predictors of MMD progression, younger age, family history, and contralateral vessel abnormalities were found to be risk factors [38]. Follow-up by radiological modalities on moyamoya vasculopathy and cerebrovascular reserve may provide reliable information on the timing of therapeutic options to determine the patients’ prognosis.

Previous studies suggested that patients with MMD had more modifiable risk factors for stroke, especially metabolic risk factors. It has been reported that increased body mass index and homocysteine were associated with a higher risk of MMD, and increased albumin and high-density lipoprotein cholesterol were associated with a lower risk of MMD [39]. Secondary insults in addition to genetic risk factors might include metabolic risk factors. Therefore, modification of these metabolic factors may also be helpful for the development of MMD.

When a patient meets the diagnostic criteria for MMD but has other comorbidities associated with vasculopathy, the condition is designated as MMS, also known in Eastern countries as “quasi-moyamoya” [5, 6, 9, 10]. Many diseases are associated with moyamoya-like vasculopathy (Table 3) [6], that is, location-specific stenosis/occlusion of vessels around the distal internal carotid arteries [10]. MMD and MMS share a cerebral vasculopathy phenotype, at least to some degree. If they have a similar phenotype, they may have a common pathogenesis of vascular occlusion and collateral vessel development.

From the viewpoint of the outer diameter of involved carotid forks, MMS is likely to include two different groups: arterial shrinkage and non-shrinkage [40]. The former is consistent with definitive MMD, but the latter may be essentially analogous to atherosclerosis. The relationship between genetic variants and arterial shrinkage may provide a key clue to clarify the etiology and diagnosis of MMD/MMS because it has been reported that nonatherosclerotic MMS did not have RNF213 c.14576G>A variant, while 66 (84.6%) of 78 patients with MMD had the variant [41].

According to a Japanese national survey by Hayashi et al. [42] diseases other than atherosclerosis constitute 17.2% of all inflammatory diseases associated with MMS. Among common autoimmune disorders related to MMS, meningitis, hyperthyroidism, and other autoimmune disorders constitute 2.2%, 7.5%, and 17.2%, respectively. It may be difficult to distinguish the mechanisms associated with a distinct autoimmune disorder from those associated with MMS because of the complexity of the differentiation between causality and correlation [42].

The Japanese RCMD Guidelines excluded hyperthyroidism from autoimmune diseases as the list of comorbidities for MMS in the 2021 version of the diagnostic criteria [17]. Hyperthyroidism and elevated anti-thyroid autoantibodies were significantly more frequent in East Asian patients with adult MMD than in healthy subjects [43]. Figure 4 shows reduced outer diameters (due to negative remodeling) of the terminal internal carotid arteries in a patient with Graves’ disease, which is an identical finding to that in patients with definitive MMD. However, it was noted in the Scientific Statement from the AHA/ASA that the latest Japanese Guidelines exclude atherosclerosis, hyperthyroidism, and head trauma, but there is no universal agreement [6]. The AHA/ASA Statement also notified that the Japanese Guidelines do not include sickle cell disease, which has a low incidence among East Asian populations, although the association between sickle cell disease and MMS has long been recognized in Western countries with larger populations of African descent [6].

The authors have no conflicts of interest to declare.

The authors did not receive any funding for preparing, writing, submitting, or revising this manuscript.

Shinichiro Uchiyama wrote the original draft and revisions. Miki Fujimura contributed to revising the manuscript by giving helpful advice and providing important information.