Genetic and nongenetic factors for contralateral progression of unilateral moyamoya disease: the first report from the SUPRA Japan Study Group

Yohei Mineharu Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto;

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Yasushi Takagi Department of Neurosurgery, Tokushima University Graduate School of Medicine, Tokushima;

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Akio Koizumi Social Health Welfare Medicine Laboratory, Kyoto;

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Takaaki Morimoto Department of Neurosurgery, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki;

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Takeshi Funaki Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto;

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Tomohito Hishikawa Okayama University Graduate School of Medicine, Okayama;

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Yoshio Araki Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya;

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Hitoshi Hasegawa Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata;

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Jun C. Takahashi Department of Neurosurgery, National Cerebral and Cardiovascular Center, Suita;

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Satoshi Kuroda Department of Neurosurgery, Toyama University Graduate School of Medicine, Toyama; and

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Kiyohiro Houkin Department of Neurological Cell Therapy, Hokkaido University Graduate School of Medicine, Sapporo, Japan

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Susumu Miyamoto Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto;

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OBJECTIVE

Although many studies have analyzed risk factors for contralateral progression in unilateral moyamoya disease, they have not been fully elucidated. The aim of this study was to examine whether genetic factors as well as nongenetic factors are involved in the contralateral progression.

METHODS

The authors performed a multicenter cohort study in which 93 cases with unilateral moyamoya disease were retrospectively reviewed. The demographic features, RNF213 R4810K mutation, lifestyle factors such as smoking and drinking, past medical history, and angiographic findings were analyzed. A Cox proportional hazards model was used to find risk factors for contralateral progression.

RESULTS

Contralateral progression was observed in 24.7% of cases during a mean follow-up period of 72.2 months. Clinical characteristics were not significantly different between 67 patients with the R4810K mutation and those without it. Cox regression analysis showed that the R4810K mutation (hazard ratio [HR] 4.64, p = 0.044), childhood onset (HR 7.21, p < 0.001), male sex (HR 2.85, p = 0.023), and daily alcohol drinking (HR 4.25, p = 0.034) were independent risk factors for contralateral progression.

CONCLUSIONS

These results indicate that both genetic and nongenetic factors are associated with contralateral progression of unilateral moyamoya disease. The findings would serve to help us better understand the pathophysiology of moyamoya disease and to manage patients more appropriately.

ABBREVIATIONS

ACA = anterior cerebral artery; AUC = area under the curve; CI = confidence interval; ICA = internal carotid artery; MCA = middle cerebral artery; OR = odds ratio; PCA = posterior cerebral artery; ROC = receiver operating characteristic; SUPRA = Study of Unilateral Moyamoya Disease Progression and Associated-Gene in Japan; TIA = transient ischemic attack.

OBJECTIVE

Although many studies have analyzed risk factors for contralateral progression in unilateral moyamoya disease, they have not been fully elucidated. The aim of this study was to examine whether genetic factors as well as nongenetic factors are involved in the contralateral progression.

METHODS

The authors performed a multicenter cohort study in which 93 cases with unilateral moyamoya disease were retrospectively reviewed. The demographic features, RNF213 R4810K mutation, lifestyle factors such as smoking and drinking, past medical history, and angiographic findings were analyzed. A Cox proportional hazards model was used to find risk factors for contralateral progression.

RESULTS

Contralateral progression was observed in 24.7% of cases during a mean follow-up period of 72.2 months. Clinical characteristics were not significantly different between 67 patients with the R4810K mutation and those without it. Cox regression analysis showed that the R4810K mutation (hazard ratio [HR] 4.64, p = 0.044), childhood onset (HR 7.21, p < 0.001), male sex (HR 2.85, p = 0.023), and daily alcohol drinking (HR 4.25, p = 0.034) were independent risk factors for contralateral progression.

CONCLUSIONS

These results indicate that both genetic and nongenetic factors are associated with contralateral progression of unilateral moyamoya disease. The findings would serve to help us better understand the pathophysiology of moyamoya disease and to manage patients more appropriately.

In Brief

This multicenter study analyzed risk factors for contralateral progression of unilateral moyamoya disease. Male sex, childhood onset, the R4810K mutation in the RNF213 gene, and daily alcohol drinking were found to be independent risk factors, and the authors developed a scoring system to predict disease progression. These findings could help in better managing these patients.

Moyamoya disease is a unique cerebrovascular disease that causes both hemorrhagic and ischemic strokes.1 The distinguishing features of the disease are progressive occlusion at the terminal portion of the internal carotid artery (ICA) and the development of fine collaterals to compensate for the reduced blood flow, including basal moyamoya vessels, leptomeningeal anastomosis, and transdural anastomosis. Another form of collaterals is periventricular anastomosis, which has recently been recognized as a bleed-prone collateral.2 Inward remodeling is also a characteristic feature of moyamoya disease.3,4 Such angiographic and morphological changes of this chronically progressive disease have been gradually understood, but the mechanisms of the disease progression have not been fully elucidated.

Although moyamoya disease typically shows bilateral lesions, unilateral involvement also occurs. Because some patients with unilateral moyamoya disease develop bilateral lesions, and we can trace angiographic changes from a very early stage of the disease, research on contralateral progression in unilateral moyamoya disease provides valuable clues to understanding the mechanisms of disease progression. Thus, many studies have analyzed the risk factors for contralateral progression of unilateral moyamoya disease.5–20 However, younger age at diagnosis was the only factor that was consistently associated with contralateral progression in the previous literature.14,16,17 Herein, we conducted a collaborative study to collect enough patients with this rare condition. We extensively investigated possible risk factors of contralateral progression, which included the RNF213 (also called Mysterin) R4810K mutation (the most common genetic risk factor in the East Asian populations),21,22 lifestyle factors such as smoking and drinking, past medical history, angiographic characteristics, and demographic features. The study will serve to improve the management of patients by using risk stratification as well as to better understand the pathophysiology of moyamoya disease.

Methods

Study Population

This study was approved by the ethics committee of the IRB of Kyoto University, and all participants provided written informed consent. We reviewed clinical data and radiological examinations from their medical records, including 1.5- or 3.0-T MR images and conventional angiography if available. A total of 2 ml of whole blood was collected and the R4810K mutation in the RNF213 gene was genotyped using the TaqMan assay as previously described.23 One hundred thirty-five patients from 14 collaborating hospitals agreed to join the study and donated their blood samples. In addition to patients with unilateral moyamoya disease, patients with any lesions that resembled unilateral moyamoya disease were also included. Patients were diagnosed between January 1987 and June 2017. Two neurosurgeons reviewed the radiological examinations to confirm the diagnosis. If their diagnosis was different from the original diagnosis, or two reviewers gave different diagnoses, they discussed the differences to reach a final diagnosis following the official diagnostic criteria of the Research Committee on the Spontaneous Occlusion of the Circle of Willis from the Ministry of Health and Welfare, Japan. Any lesions that did not fulfill either of the two main criteria, i.e., 1) stenoocclusive findings at the terminal portion of the ICA and 2) development of moyamoya vessels, were diagnosed with non-moyamoya arteriopathy.

We ascertained the medical history (hypertension, diabetes mellitus, autoimmune diseases, and other associated diseases), smoking habits (current or past smoker vs nonsmoker), drinking habits (everyday alcohol drinker vs occasional or nondrinker), sex, age, age at onset, age at diagnosis, first sign at onset (cerebral infarction, transient ischemic attack [TIA], intracranial hemorrhage, epilepsy, headache, asymptomatic, and others), laterality, ipsilateral progression, contralateral progression (> 50% of stenosis around the terminal portion of the ICA), posterior cerebral artery (PCA) involvement, antiplatelet use, and family history of moyamoya disease for all participants. Patients who were diagnosed under the age of 17 were treated as having childhood-onset moyamoya disease. Among 135 cases, 13 were excluded from the analysis: 5 were diagnosed with bilateral moyamoya disease and 8 lacked clinical information. We retrospectively reviewed 122 cases, in which 93 were confirmed to be unilateral moyamoya disease and 29 were diagnosed as unilateral non-moyamoya arteriopathy. Most non-moyamoya arteriopathy was middle cerebral artery (MCA) stenosis or occlusion without moyamoya collaterals, and twiglike MCA was not included. A contralateral abnormality was defined as any stenotic findings on MRI of the anterior cerebral artery (ACA) or MCA on the contralateral side of the unilateral arteriopathy.

Genotyping

Genomic DNA was obtained from peripheral blood samples using a DNA Blood Mini Kit (Qiagen). Genotyping of the RNF213 R4810K mutation was performed using TaqMan SNP Genotyping Assays (Applied Biosystems) as previously described.23

Statistical Analysis

Continuous variables were compared using the Mann-Whitney U-test. Categorical variables were compared with the chi-square or Fisher’s exact tests where appropriate. A log-rank test and Cox regression analysis were performed for the variables including the history of hypertension, history of diabetes mellitus, history of autoimmune diseases, smoking habits, drinking habits, sex, age at diagnosis (childhood vs adult onset), first sign at onset (ischemic vs others), antiplatelet use, family history of moyamoya disease, the R4810K mutation, contralateral abnormality, and PCA involvement. For multivariate Cox regression analysis, a stepwise method was used to select a good subset of variables with a p value < 0.10 as the entry criterion and a p value > 0.10 as the removal criterion. A p value < 0.05 was considered statistically significant. All data analyses were performed with JMP Pro (version 11.2.0, SAS Institute), the R project (version 3.3.0, www.r-project.org), and GraphPad Prism software (version 6.07, GraphPad Software).

Risk Score Analysis

To establish a scoring system to estimate the risk of contralateral progression, we divided our study cohort randomly into a test cohort (n = 62) and a replication cohort (n = 31). The scoring system model development was achieved from the test cohort. Variables incorporated into the system were selected by multivariate Cox regression analysis (stepwise method) and the proportional weight for each variable was determined by its β coefficient. The risk score was developed with the sum of the weighted score of each variable. The scoring system was validated in the replication cohort. The discriminating power of the risk score was measured by the area under a receiver operating characteristic (ROC) analysis and a log-rank test for trends.

Results

Difference Between Unilateral Moyamoya Disease and Non-Moyamoya Arteriopathy

We collected data not only in patients with unilateral moyamoya disease but also in patients with unilateral non-moyamoya arteriopathy. The clinical characteristics of these two phenotypes are shown in Supplemental Table 1. There was no significant difference in sex, age at diagnosis, past medical history, smoking or drinking habits, or the R4810K genotype. The number of patients with non-moyamoya arteriopathy who had the R4810K mutation was 16 of 29 (55.2%), which was not significantly different as compared with that of patients with moyamoya disease (67 of 93 [72.0%], p = 0.111). Asymptomatic cases of non-moyamoya arteriopathy were more frequently observed than those of moyamoya disease (24.1% vs 7.5%, p = 0.022). Contralateral progression was observed in 23 of 93 patients (24.7%) with unilateral moyamoya disease (13/34 [38.2%] in childhood onset, 10/59 [16.9%] in adult onset), whereas it was only observed in 1 (3.4%) of 29 patients with unilateral non-moyamoya arteriopathy.

Risk Factors for Contralateral Progression of Unilateral Moyamoya Disease

We then analyzed the risk factors of contralateral progression in unilateral moyamoya disease. Among the 23 patients who showed contralateral progression, 20 progressed to bilateral moyamoya disease and the other 3 had contralateral stenosis without moyamoya vessels. Clinical characteristics were compared between patients with and without contralateral progression and the results are summarized in Table 1. Among the demographic characteristics, childhood onset (odds ratio [OR] 2.99, 95% confidence interval [CI] 1.03–9.00; p = 0.027) and male sex (OR 5.85, 95% CI 2.07–16.6; p = 0.0014) were significantly associated with contralateral progression. Among genetic backgrounds, both the R4810K mutant (OR 5.48, 95% CI 1.18–25.4; p = 0.018) and family history (OR 3.94, 95% CI 1.21–19.4; p = 0.038) were associated with contralateral progression. Among lifestyle factors, daily drinking (OR 4.58, 95% CI 1.11–18.9; p = 0.039) was significantly associated with contralateral progression, whereas smoking habits showed no significant association.

TABLE 1.

Comparison of clinical characteristics between patients with unilateral moyamoya disease who had contralateral progression and those who did not

VariableContralateral Progressionp ValueOR (95% CI)
NoYes
No. of patients70 23
Mean age at diagnosis (SD), yrs31.8 (17.6)20.5 (17.0)0.00670.96 (0.93–0.99)
Childhood onset, n (%)21 (30.0)13 (56.5)0.0272.99 (1.03–9.00)
Male, n (%)11 (15.7)12 (52.2)0.00145.85 (2.07–16.6)
Right side, n (%)44 (62.9)10 (43.5)0.148
Ipsilateral progression, n (%)11 (15.7)8 (34.8)0.072
Antiplatelet use, n (%)31 (44.3)10 (43.5)1
Family history, n (%)7 (10.0)7 (30.4)0.0383.94 (1.21–19.4)
Hypertension, n (%)11 (15.7)3 (13.0)1
Diabetes, n (%)1 (1.4)1 (4.3)0.436
Autoimmune diseases, n (%)5 (7.1)1 (4.3)1
Smoking habits, n (%)9 (12.9)3 (13.0)1
Drinking every day, n (%)4 (5.7)5 (21.7)0.0394.58 (1.11–18.9)
Asymptomatic, n (%)7 (10.0)0 (0)0.187
Ischemic stroke, n (%)13 (18.6)2 (8.7)0.343
Ischemic symptoms,* n (%)44 (62.9)20 (87)0.0383.94 (1.07–14.6)
R4810K mutation, n (%)46 (65.7)21 (91.3)0.0185.48 (1.18–25.4)
RNF213 genotypes, n (%)
 AA4 (5.7)1 (4.3)0.034NA
 GA42 (60)20 (87)
 GG24 (34.3)2 (8.7)
Contralateral abnormality, n (%)11 (15.7)11 (47.8)0.00364.92 (1.74–13.9)
PCA involvement, n (%)8 (11.4)4 (17.4)0.459

NA = not applicable.

Ischemic symptoms include TIAs.

As for clinical manifestation, ischemic symptoms at onset (TIAs and ischemic stroke) showed a significant association with contralateral progression (OR 3.94, 95% CI 1.07–14.6; p = 0.038). No past medical history or medication such as hypertension, diabetes, or antiplatelet use was associated with contralateral progression.

Among radiological findings, contralateral abnormalities on the ACA or MCA were associated with contralateral progression (OR 4.92, 95% CI 1.74–13.9; p = 0.0036). However, ipsilateral disease progression, laterality (right or left), or PCA involvement did not predict contralateral progression (data not shown). We also performed an adults-only analysis, and the results did not fundamentally change.

Log-Rank Test and Cox Proportional Hazards Model

We next analyzed the association of contralateral progression via an estimated progression-free survival from initial diagnosis to the last available MRI follow-up. The mean follow-up period was 72.2 months (range 0–355 months) and mean time to progression was 48.6 months (19.6 months for childhood-onset patients and 86.2 months for adult-onset patients). The R4810K mutation showed a trend for a significant association with contralateral progression, with a log rank p value of 0.052 (Fig. 1A). The risk of contralateral progression did not differ between homozygote (AA) and heterozygote (GA) genotypes for the R4810K mutation (p = 0.92, log-rank test; Fig. 1B). The association was prominently seen in patients with childhood onset (p = 0.017, log-rank test) as compared with patients with adult onset (p = 0.19, log-rank test; Fig. 1C and D).

FIG. 1.
FIG. 1.

Risk of contralateral progression in patients with unilateral moyamoya disease according to their RNF213 genotypes. A: The risk of contralateral progression was compared using a log-rank test according to the genotypes of the RNF213 R4810K mutation (AA = homozygote; GA = heterozygote; GG = wild type). B: The difference between homozygote and heterozygote was also analyzed. C and D: Patients with unilateral moyamoya disease were further divided into two groups according to their age at diagnosis, i.e., childhood onset (C) and adult onset (D).

When we compared childhood- and adult-onset patients (Fig. 2A), the timing of contralateral progression was much earlier in childhood-onset patients than in adult-onset patients, but the proportion of contralateral progression was similar (both were approximately 50%). In childhood-onset patients, most cases develop contralateral lesions within 30 months under the age of 12. Men showed an earlier and higher risk of contralateral progression than did women (Fig. 2B, p = 0.0015). Among patients with adult-onset unilateral moyamoya disease, daily alcohol drinking was significantly associated with contralateral progression (Fig. 2C, p = 0.0019). In contrast to the positive association of contralateral abnormal angiographic findings with contralateral progression using the Fisher’s exact test, a positive association was not observed in the log-rank test (Fig. 2D). Other significant variables included ischemic symptoms at onset (p = 0.031), although it was not significant when adjusted for age at diagnosis (childhood and adult onset).

FIG. 2.
FIG. 2.

Predictors of contralateral progression of unilateral moyamoya disease. The risks of contralateral progression identified by multivariate regression analysis were further analyzed using a log-rank test. Progression-free survival was significantly different between childhood and adult onset (A), between men and women (B), and between daily drinkers and others (C, adult-only analysis). There was no significant difference for contralateral angiographic abnormality on the ACA or MCA (D).

Multivariate Cox regression analysis was performed using the stepwise method. As shown in Table 2, four variables were selected as the final multivariate model, which included childhood onset (hazard ratio [HR] 7.21, 95% CI 2.45–21.2; p < 0.001), male sex (HR 2.85, 95% CI 1.16–7.05; p = 0.023), the R4810K mutation (HR 4.64, 95% CI 1.04–20.7; p = 0.044) and daily alcohol drinking (HR 4.25, 95% CI 1.11–16.2; p = 0.034). These variables were significant independent risk factors for contralateral progression.

TABLE 2.

Multivariate Cox proportional hazard model of contralateral progression-free survival of patients with unilateral moyamoya disease

VariableHR (95% CI)p Value
Childhood-onset7.21 (2.45–21.22)<0.001
Male2.85 (1.16–7.05)0.023
R4810K mutation4.64 (1.04–20.75)0.044
Daily drinking4.25 (1.11–16.22)0.034

The final multivariate model included age at diagnosis (childhood or adult onset), sex, the R4810K mutation, and daily alcohol drinking.

Risk Stratification by a Combination of Three Predictors

Based on the Cox proportional hazards model, age at diagnosis, sex, the R4810K mutation, and daily drinking are the most likely to contribute to risk stratification. To test whether the R4810K mutation is confounded by other variables, we compared the clinical characteristics between patients with the R4810K mutation and those without the mutation (Supplemental Table 2). There was no significant difference in characteristics between the two groups including age at diagnosis and sex. As shown in Fig. 3, age at diagnosis was not significantly different among the R4810K genotypes (wild type, heterozygote, and homozygote).

FIG. 3.
FIG. 3.

Distribution of age at diagnosis of unilateral moyamoya disease according to the RNF213 R4810K genotypes. The age distribution showed two peaks, i.e., childhood onset under the age of 20 years and adult onset during the patient’s 30s and 40s. There was no significant difference of age at diagnosis among the genotypes of the RNF213 R4810K mutation (wild type, heterozygote, and homozygote).

Then we tested whether the combination of three risk factors including age at diagnosis, sex, and the R4810K mutation can stratify the risk of contralateral progression more properly and improve the risk prediction. Daily drinking was not included because it is restricted to adult patients. As shown in Fig. 4A, the three factors contributed greatly to the risk stratification of contralateral progression. Among patients with the R4810K mutation, men with childhood-onset disease (100%), men with adult-onset disease (55.6%), women with childhood-onset disease (37.5%), and women with adult-onset disease (13.5%) had higher risks of contralateral progression, in that order. Among patients without the R4810K mutation, only men with childhood-onset disease showed contralateral progression (33.3%). The combination of daily alcohol drinking and the R4810K mutation also effectively stratified the risk of contralateral progression. Patients with the R4810K mutation who drank alcohol every day had a high risk of contralateral progression (71.4%, Fig. 4B). Kaplan-Meier estimates also showed that the R4810K mutation, age at diagnosis, and sex efficiently stratified the risk of contralateral progression (Fig. 4C and D).

FIG. 4.
FIG. 4.

Risk stratification. A: The combination of three risk factors, i.e., R4810K mutation, age at diagnosis, and sex, improved the accuracy of risk stratification. The R4810K mutation showed the highest impact on the risk of contralateral progression. Among individuals with the R4810K mutation, men with childhood onset (100%), men with adult onset (55.6%), women with childhood onset (37.5%), and women with adult onset (13.5%) had a higher risk of contralateral progression in that order. Among the individuals without the R4810K mutation, only men with childhood onset showed contralateral progression. B: The combination of daily alcohol drinking and the R4810K mutation for risk prediction. For patients with the R4810K mutation, those who drank alcohol every day had a higher risk (71.4%) of contralateral progression as compared with those who did not. C and D: Progression-free survival was stratified according to age at diagnosis and sex for patients with the R4810K mutation (C) and those without the mutation (D).

Risk Score for Contralateral Progression

We next aimed to establish the scoring system to estimate the risk of contralateral progression. In the multivariate Cox regression analysis in the test cohort, childhood onset, males, the R4810K mutation, and daily alcohol drinking were again selected as the final model, and the β coefficient for each variable was 1.38, 1.59, 1.44, and 2.08 (relative ratio of 1.00, 1.15, 1.04, and 1.51, respectively). Based on the β coefficients of these variables, a weighted risk score for each variable was set at 1 point for childhood onset, 1 point for male, 1 point for the R4810K mutation, and 1 point for daily alcohol drinking. A weight of 1.5 points for daily alcohol drinking did not change the risk classification. The total risk score of contralateral progression was calculated by the sum of the weighted score of each variable. Because childhood-onset male patients with the R4810K mutation showed contralateral progression before the age of 18 in all cases, none had drinking habits and the maximum risk score was 3.

As shown in Fig. 5A, 90-month progression-free survival for the risk scores of 0, 1, 2, and 3 were 100%, 96.5%, 60.9%, and 20.0%, respectively. Median progression-free survival for the risk scores of 0, 1, 2, and 3 were “not reached,” 202 months, 106 months, and 23 months, respectively. The log-rank test for trends was statistically significant (p < 0.001), showing that our scoring system can efficiently predict the risk of contralateral progression. The scoring system was applied to the replication cohort, and the log-rank test for trends was statistically significant (p = 0.015; Fig. 5B). ROC analysis showed that our model has good discrimination capacity with an area under the curve (AUC) of 0.846 (p < 0.001) for the test cohort and 0.857 (p < 0.001) for the replication cohort (Fig. 5C and D).

FIG. 5.
FIG. 5.

Scoring system for prediction of contralateral progression. The scoring system model development was achieved from the test cohort (n = 62), and the model was validated in the replication cohort (n = 31). The risk score was calculated by the sum of the weighted points for each variable (1 point for the R4810K mutation, 1 point for childhood onset, 1 point for male, and 1 point for daily alcohol drinking). A: In the test cohort, the number of patients with the score of 0, 1, 2, and 3 were 5, 29, 23, and 5, respectively. Contralateral progression-free survival at 90 months for the risk scores of 0, 1, 2, and 3 were 100%, 96.5%, 60.9% and 20.0%, respectively, and the log-rank test for trends was statistically significant (p < 0.001). B: The p value for trends in the log-rank test was also significant in the replication cohort, showing that our scoring system can efficiently predict the risk of contralateral progression. C and D: ROC analysis showed good discrimination capacity of the scoring system both in the test cohort (AUC = 0.846) and in the replication cohort (AUC = 0.857). LR = likelihood ratio.

Discussion

Our data showed that male sex, younger age at diagnosis, the RNF213 R4810K mutation, and daily drinking were independent risk factors for contralateral progression in unilateral moyamoya disease, indicating that both genetic and nongenetic factors affect the progression of the disease. We also showed that angiographical features, i.e., contralateral abnormalities around the terminal portion of the ICA, can help to predict contralateral progression. As compared with previous studies as listed in Table 3,6–8,10,12,14,15,17–19,25 we identified male sex, the R4810K mutation, and daily drinking as new risk factors. Importantly, the combination of age at diagnosis, sex, and the R4810K mutation could effectively stratify patients with unilateral moyamoya disease according to the risk of contralateral progression. Among individuals who had the R4810K mutation, men with childhood onset had the highest risk of disease progression (100%), followed by men with adult onset (55.6%), women with childhood onset (37.5%), and women with adult onset (13.6%). Among individuals who did not have the R4810K mutation, only men with childhood onset (33.3%) had contralateral progression. These findings suggest that the R4810K mutation has the strongest risk prediction, followed by sex, and age at diagnosis. Based on these findings, we developed a scoring system to predict contralateral progression. We incorporated four independent risk factors (the R4810K mutation, male sex, childhood onset, and daily drinking) in the risk assessment model, which gave a rate of 90-month progression-free survival of 100% for score 0, 96.5% for score 1, 60.9% for score 2, and 20.0% for score 3. The discrimination power of the risk score was validated in the internal replication cohort. A significant difference in progression-free survival according to the risk score suggests that the R4810K genotyping is important for risk prediction and control of alcohol drinking may have an impact on risk reduction.

TABLE 3.

Summary of previous reports regarding the predictors of contralateral progression in unilateral moyamoya disease

Authors & YearNo. of PtsProgression RateF-M RatioMean Age at Diagnosis (yrs)*FU PeriodTime to ProgressionRisk of Contralateral Progression
ChildAdult
Matsushima et al., 1994562/6 (33.3%)NA17.24.7 yrs2.16 yrs
Kawano et al., 199463212/18 (66.7%)5/14 (35.7%)2.66.6/36.6 2.8 yrs2.6 yrs
Houkin et al., 19967101/4 (25%)0/6 (0%)19.0/40.3 3.5 yrs0.5 yrs
Hirotsune et al., 19978176/12 (50%)0/5 (0%)1.413.520 mos20 mos
Ikezaki et al., 1997918012/180 (6.7%) 1.652 peaks6.6 yrs78 mos 
Kuroda et al., 20051011NA4/11 (36.4%)NANANA60 mos
Seol et al., 20061172/7 (28.6%)NA2.55.164.7 mos25.5 mos
Kelly et al., 200612182/5 (40%)5/13 (38.5%)2.629.819.3 mos12.7 mosContralateral abnormality
Nagata et al., 200613205/20 (25%)NANA6.2126.8 mos42.8 mos
Smith & Scott, 200814338/29 (27.6%)2/4 (50%)1.28.1/26.8 5.3 yrs2.2 yrs<7 yrs, cardiac anomaly, Asian ancestry, family history
Hayashi et al., 20101590/1 (0%)0/8 (0%)23955.7 mosNA
Park et al., 2011163420/34 (58.8%)NA0.888.735.3 mos17.4 mos<8 yrs, family history, contralateral abnormality
Yeon et al., 201117458/45 (17.8%)NA0.889.953.4 mos27.0 mos<9 yrs
Lee et al., 20141841NA6/41 (14.6%)3.141.150.1 mos34 mosContralateral abnormality
Zhang et al., 2016191096/27 (22.2%)12/82 (14.6%)1.130.843.8 mosNAContralateral abnormality
Church et al., 20202021718/217 (8.3%)2.433.85.8 yrs5.8 yrsContralateral abnormality, hyperlipidemia
Present study9313/34 (38.2%)10/59 (16.9%)3.08.8/40.772.2 mos48.6 mosChildhood-onset (<12 yrs), R4810K mutation, male, daily alcohol drinking

F-M ratio = female-to-male ratio; FU = follow-up; NA = data not available; Pts = patients.

Mean age at diagnosis was shown separately for childhood/adult onset, if applicable.

In 2011, Yeon et al. reported that contralateral progression was mostly observed in patients under the age of 9 years old and they developed contralateral lesions within 3 years after the initial diagnosis.17 Other reports also showed that contralateral progression was mostly observed in patients under the age of 7 or 8 years.14,16 Consistent with their data, our results also showed that all cases with contralateral progression were under the age of 12 and they developed contralateral lesions mostly within 30 months. While 50% of child patients develop contralateral lesion in 3 years, 50% of adult patients develop contralateral lesions in 10 years. Therefore, closer follow-up using MRI would be necessary for child patients as compared with adult patients.

Patients with the R4810K mutation had a significantly higher risk of contralateral progression than those without the mutation. This is consistent with the finding that the prevalence of the R4810K mutation was higher in patients with bilateral moyamoya disease (80%–90%) than those with unilateral moyamoya disease (50%–70%).22,25 A higher risk of contralateral progression in Asian populations14 is probably due to a higher prevalence of the R4810K mutation in East Asian populations.21 As was shown in previous studies,25–27 the R4810K mutation was associated with PCA involvement. These results indicate that the mutation is likely to be related to a broader distribution of arterial narrowing. Only 5% of patients without the R4810K mutation had bilateral progression, thus genetic testing will be useful to predict contralateral progression of unilateral moyamoya disease. As for the difference between homozygote (AA) and heterozygote (GA) genotypes for the R4810K mutation, our data did not show a significant difference in the risk of contralateral progression, although the number of patients with a homozygote genotype (n = 5) might not be sufficient to draw conclusions.

Interestingly, not only genetic factors but also lifestyle factors, i.e., daily alcohol drinking, were significantly associated with contralateral progression. Among 8 patients who drank alcohol every day, 5 were women and 2 did not have the R4810K mutation, suggesting that the association of alcohol and contralateral progression was unlikely to be confounded by sex or the R4810K genotype. Because alcohol inhibits folate metabolism, it may accelerate disease progression via a decrease of folate or increase of homocysteine, a well-known risk factor for quasi-moyamoya disease28 and moyamoya disease.29 Another possible mechanism may be that alcohol affects methylation of the CAV1 gene,30 which has been reported to be associated with moyamoya disease.31,32 Although our data only considered the frequency of drinking, an average amount of daily alcohol consumption is much higher for daily drinkers than others (e-Stat; https://www.e-stat.go.jp/). Together with the recent finding that dyslipidemia was associated with contralateral progression,20 lifestyle counseling may have some effect in preventing the progression of moyamoya disease.

Although the prevalence of moyamoya disease is higher in women, our data showed that disease progression was less frequent and slower in women than in men. A similar phenomenon was observed in familial moyamoya disease. Mineharu et al. reported that the prevalence of moyamoya disease was much higher in women than men (2.1 to 1), but that women were more likely to be asymptomatic or adult-onset patients (20/31 vs 3/11, p = 0.033).33 Although the precise mechanism for how initiation and progression differ remains unknown, one possible explanation may be that the R4810K mutation determines the speed and distribution of arterial narrowing, while another factor, such as infection, determines the initiation of the disease.

Few studies have compared the risk of contralateral progression between patients with unilateral moyamoya disease and unilateral non-moyamoya arteriopathy. The present study showed that non-moyamoya arteriopathy rarely develops contralateral lesions regardless of the presence or absence of the R4810K mutation. Contralateral progression was observed in 23 cases (24.7%) of unilateral moyamoya disease, whereas it was only observed in 1 case (3.4%) of unilateral non-moyamoya arteriopathy. This means that the presence of moyamoya vessels or the involvement of the terminal portion of the ICA, both hallmarks (diagnostic criteria) of moyamoya disease, may be an important predictor for contralateral progression. As for angiographic findings, our study also showed that contralateral abnormality was an independent predictor of contralateral progression. This result is consistent with previous studies showing that narrowing of the contralateral ACA or MCA was a predictor for contralateral progression.12,18,19 Zhang and colleagues also showed that contralateral progression-free survival was significantly lower in patients with contralateral abnormality than those without it.19 Although we could not show significant differences in the log-rank test, this may be due to the lack of statistical power or due to the unadjusted timing of diagnostic radiological examinations.

There are several limitations in this study. First, because of the nature of a retrospective study, asymptomatic patients and those with severe clinical outcomes tend to be lost to follow-up, which may affect the results of the analysis. In addition, the follow-up period for some cases was short. Thus, a prospective study will be warranted to confirm our results. Second, regarding drinking habits, only frequency was recorded, and the amount of alcohol was not considered. Further clinical and preclinical studies are needed to clarify the effect of alcohol in the development and progression of moyamoya disease. Third, contralateral abnormality was defined as any narrowing of the A1 and M1 segments, which may misclassify A1 hypoplasia as a contralateral abnormality. Even so, our data show that angiographic judgment has some clinical significance for predicting contralateral progression of unilateral moyamoya disease. Fourth, we did not collect information on past medical history of dyslipidemia. It will worth testing whether the association of the history of dyslipidemia with contralateral progression will be replicated and whether the inclusion of this variable improves the discrimination capacity of our risk scoring system. Lastly, we did not collect information on surgical treatment or type of surgery. Although none of the four predictors (R4810K mutation, age, sex, and contralateral abnormality) are likely to be confounded by history of surgical treatment, the effects of surgical treatment on contralateral progression must be further investigated.

Conclusions

We showed that age at diagnosis, sex, and the R4810K mutation could reliably stratify the risk of contralateral progression in unilateral moyamoya disease. In addition to these unmodifiable risk factors, we also identified daily alcohol drinking as a modifiable risk factor for contralateral progression. Taken together, our results have important implications for the pathophysiology of moyamoya disease as well as the appropriate management of patients.

Acknowledgments

We thank the following members of the SUPRA Japan Study Group for their efforts in patient recruitment: Okayama University (Dr. Isao Date), Nagoya University (Dr. Toshihiko Wakabayashi, Dr. Shinsuke Muraoka, and Dr. Kenji Uda), Niigata University (Dr. Yukihiko Fujii and Dr. Bunpei Kikuchi), National Cerebral and Cardiovascular Research Center (Dr. Hiroharu Kataoka and Dr. Eika Hamano), Toyama University (Dr. Daina Kashiwazaki), Hiroshima University (Dr. Kaoru Kurisu, Dr. Takahito Okazaki, and Dr. Taizo Ishii), Gifu University (Dr. Toru Iwama and Ms. Miyuki Tomoi), Nara Medical University (Dr. Hiroyuki Nakase, Dr. Yasuo Hironaka, and Dr. Shuichi Yamada), Kyushu University (Dr. Koji Iihara and Dr. Ataru Nishimura), Fukuoka Sannou Hospital (Dr. Toshio Matsushima, Dr. Toshiyuki Enomoto, and Dr. Hideaki Tanaka), Hokkaido University (Dr. Ken Kazumata, Dr. Haruto Uchino, and Dr. Kikutaro Toukairin), Tokushima University (Dr. Shinji Nagahiro, Dr. Junichiro Satomi, Dr. Yasuhisa Kanematsu, and Dr. Etsuko Ohtomo), Sapporo Medical University (Dr. Nobuhiro Mikuni and Dr. Tsuyoshi Mikami), Iwate Medical University (Dr. Kuniaki Ogasawara and Dr. Kohei Chida), University of Tokyo (Dr. Nobuto Saito and Dr. Satoru Miyawaki) and Kurume University (Dr. Motohiro Morioka). Statistical analyses were checked by Dr. Satoshi Morita. The ethical issues were double-checked by Dr. Shinji Kosugi. This study was supported by Grants in Aid for Scientific Research (B) to S.M. (nos. 16H05437 and 19H03770), a Grant in Aid for Scientific Research (A) to A.K. (no. 25253047), and a Grant in Aid for Young Scientists (B) to Y.M. (no. 15K19963).

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Miyamoto, Mineharu. Acquisition of data: Mineharu, Funaki, Hishikawa, Araki, Hasegawa. Analysis and interpretation of data: Mineharu, Takagi, Koizumi, Morimoto, Funaki. Drafting the article: Mineharu. Critically revising the article: Miyamoto, Takagi, Morimoto, Funaki, Hishikawa, Araki, Hasegawa. Reviewed submitted version of manuscript: Koizumi, Takahashi, Kuroda, Houkin. Approved the final version of the manuscript on behalf of all authors: Miyamoto. Statistical analysis: Mineharu, Funaki. Study supervision: Miyamoto, Takagi.

Supplemental Information

Online-Only Content

Supplemental material is available with the online version of the article.

Current Affiliations

Dr. Takahashi: Department of Neurosurgery, Kindai University, Osaka-Sayama, Japan.

References

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  • 2

    Funaki T, Takahashi JC, Yoshida K, et al. Periventricular anastomosis in moyamoya disease: detecting fragile collateral vessels with MR angiography. J Neurosurg. 2016;124(6):17661772.

    • Crossref
    • PubMed
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    • Export Citation
  • 3

    Ryoo S, Cha J, Kim SJ, et al. High-resolution magnetic resonance wall imaging findings of moyamoya disease. Stroke. 2014;45(8):24572460.

  • 4

    Kuroda S, Kashiwazaki D, Akioka N, et al. Specific shrinkage of carotid forks in moyamoya disease: a novel key finding for diagnosis. Neurol Med Chir (Tokyo). 2015;55(10):796804.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Matsushima T, Inoue T, Natori Y, et al. Children with unilateral occlusion or stenosis of the ICA associated with surrounding moyamoya vessels—"unilateral" moyamoya disease. Acta Neurochir (Wien). 1994;131(3-4):196202.

    • Crossref
    • PubMed
    • Search Google Scholar
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    Kawano T, Fukui M, Hashimoto N, Yonekawa Y. Follow-up study of patients with “unilateral” moyamoya disease. Neurol Med Chir (Tokyo). 1994;34(11):744747.

  • 7

    Houkin K, Abe H, Yoshimoto T, Takahashi A. Is “unilateral” moyamoya disease different from moyamoya disease?. J Neurosurg. 1996;85(5):772776.

  • 8

    Hirotsune N, Meguro T, Kawada S, et al. Long-term follow-up study of patients with unilateral moyamoya disease. Clin Neurol Neurosurg. 1997;99(suppl 2):S178S181.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Ikezaki K, Inamura T, Kawano T, Fukui M. Clinical features of probable moyamoya disease in Japan. Clin Neurol Neurosurg. 1997;99(Suppl 2):S173S177.

  • 10

    Kuroda S, Ishikawa T, Houkin K, et al. Incidence and clinical features of disease progression in adult moyamoya disease. Stroke. 2005;36(10):21482153.

  • 11

    Seol HJ, Wang KC, Kim SK, et al. Unilateral (probable) moyamoya disease: long-term follow-up of seven cases. Childs Nerv Syst. 2006;22(2):145150.

  • 12

    Kelly ME, Bell-Stephens TE, Marks MP, et al. Progression of unilateral moyamoya disease: a clinical series. Cerebrovasc Dis. 2006;22(2-3):109115.

  • 13

    Nagata S, Matsushima T, Morioka T, et al. Unilaterally symptomatic moyamoya disease in children: long-term follow-up of 20 patients. Neurosurgery. 2006;59(4):830837.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Smith ER, Scott RM. Progression of disease in unilateral moyamoya syndrome. Neurosurg Focus. 2008;24(2):E17.

  • 15

    Hayashi K, Suyama K, Nagata I. Clinical features of unilateral moyamoya disease. Neurol Med Chir (Tokyo). 2010;50(5):378385.

  • 16

    Park EK, Lee YH, Shim KW, et al. Natural history and progression factors of unilateral moyamoya disease in pediatric patients. Childs Nerv Syst. 2011;27(8):12811287.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Yeon JY, Shin HJ, Kong DS, et al. The prediction of contralateral progression in children and adolescents with unilateral moyamoya disease. Stroke. 2011;42(10):29732976.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Lee SC, Jeon JS, Kim JE, et al. Contralateral progression and its risk factor in surgically treated unilateral adult moyamoya disease with a review of pertinent literature. Acta Neurochir (Wien). 2014;156(1):103111.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Zhang Q, Wang R, Liu Y, et al. Clinical features and long-term outcomes of unilateral moyamoya disease. World Neurosurg. 2016;96:474482.

  • 20

    Church EW, Bell-Stephens TE, Bigder MG, et al. Clinical course of unilateral moyamoya disease. Neurosurgery. 2020;87(6):12621268.

  • 21

    Liu W, Morito D, Takashima S, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One. 2011;6(7):e22542.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Mineharu Y, Takagi Y, Miyamoto S. Significance of RNF213 in clinical management in Japan. In: Koizumi A, Nagata K, Houkin K, et al, eds. Moyamoya Disease Explored Through RNF213: Genetics, Molecular Pathology, and Clinical Sciences. Springer;2017:137150.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Morimoto T, Mineharu Y, Ono K, et al. Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease. PLoS One. 2017;12(4):e0175649.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Hallemeier CL, Rich KM, Grubb RL Jr, et al. Clinical features and outcome in North American adults with moyamoya phenomenon. Stroke. 2006;37(6):14901496.

  • 25

    Moteki Y, Onda H, Kasuya H, et al. Systematic validation of RNF213 coding variants in Japanese patients with moyamoya disease. J Am Heart Assoc. 2015;4(5):e001862.

  • 26

    Miyatake S, Miyake N, Touho H, et al. Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology. 2012;78(11):803810.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Cheng W, Xue S, Wu F, et al. The clinical and vascular characteristics of RNF213 c.14576G>A variant-related intracranial major artery disease in China. Behav Neurol. 2019;2019:7908392.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Wei YC, Liu CH, Chang TY, et al. Coexisting diseases of moyamoya vasculopathy. J Stroke Cerebrovasc Dis. 2014;23(6):13441350.

  • 29

    Ge P, Zhang Q, Ye X, et al. Modifiable risk factors associated with moyamoya disease: a case-control study. Stroke. 2020;51(8):24722479.

  • 30

    Yuan HF, Zhao K, Zang Y, et al. Effect of folate deficiency on promoter methylation and gene expression of Esr1, Cav1, and Elavl1, and its influence on spermatogenesis. Oncotarget. 2017;8(15):2413024141.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Chung JW, Kim DH, Oh MJ, et al. Cav-1 (Caveolin-1) and arterial remodeling in adult moyamoya disease. Stroke. 2018;49(11):25972604.

  • 32

    Bang OY, Chung JW, Kim SJ, et al. Caveolin-1, Ring finger protein 213, and endothelial function in Moyamoya disease. Int J Stroke. 2016;11(9):9991008.

  • 33

    Mineharu Y, Takenaka K, Yamakawa H, et al. Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting. J Neurol Neurosurg Psychiatry. 2006;77(9):10251029.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Collapse
  • Expand

Illustration from Zipfel (937–938). Copyright Gregory J. Zipfel. Published with permission.

  • FIG. 1.

    Risk of contralateral progression in patients with unilateral moyamoya disease according to their RNF213 genotypes. A: The risk of contralateral progression was compared using a log-rank test according to the genotypes of the RNF213 R4810K mutation (AA = homozygote; GA = heterozygote; GG = wild type). B: The difference between homozygote and heterozygote was also analyzed. C and D: Patients with unilateral moyamoya disease were further divided into two groups according to their age at diagnosis, i.e., childhood onset (C) and adult onset (D).

  • FIG. 2.

    Predictors of contralateral progression of unilateral moyamoya disease. The risks of contralateral progression identified by multivariate regression analysis were further analyzed using a log-rank test. Progression-free survival was significantly different between childhood and adult onset (A), between men and women (B), and between daily drinkers and others (C, adult-only analysis). There was no significant difference for contralateral angiographic abnormality on the ACA or MCA (D).

  • FIG. 3.

    Distribution of age at diagnosis of unilateral moyamoya disease according to the RNF213 R4810K genotypes. The age distribution showed two peaks, i.e., childhood onset under the age of 20 years and adult onset during the patient’s 30s and 40s. There was no significant difference of age at diagnosis among the genotypes of the RNF213 R4810K mutation (wild type, heterozygote, and homozygote).

  • FIG. 4.

    Risk stratification. A: The combination of three risk factors, i.e., R4810K mutation, age at diagnosis, and sex, improved the accuracy of risk stratification. The R4810K mutation showed the highest impact on the risk of contralateral progression. Among individuals with the R4810K mutation, men with childhood onset (100%), men with adult onset (55.6%), women with childhood onset (37.5%), and women with adult onset (13.5%) had a higher risk of contralateral progression in that order. Among the individuals without the R4810K mutation, only men with childhood onset showed contralateral progression. B: The combination of daily alcohol drinking and the R4810K mutation for risk prediction. For patients with the R4810K mutation, those who drank alcohol every day had a higher risk (71.4%) of contralateral progression as compared with those who did not. C and D: Progression-free survival was stratified according to age at diagnosis and sex for patients with the R4810K mutation (C) and those without the mutation (D).

  • FIG. 5.

    Scoring system for prediction of contralateral progression. The scoring system model development was achieved from the test cohort (n = 62), and the model was validated in the replication cohort (n = 31). The risk score was calculated by the sum of the weighted points for each variable (1 point for the R4810K mutation, 1 point for childhood onset, 1 point for male, and 1 point for daily alcohol drinking). A: In the test cohort, the number of patients with the score of 0, 1, 2, and 3 were 5, 29, 23, and 5, respectively. Contralateral progression-free survival at 90 months for the risk scores of 0, 1, 2, and 3 were 100%, 96.5%, 60.9% and 20.0%, respectively, and the log-rank test for trends was statistically significant (p < 0.001). B: The p value for trends in the log-rank test was also significant in the replication cohort, showing that our scoring system can efficiently predict the risk of contralateral progression. C and D: ROC analysis showed good discrimination capacity of the scoring system both in the test cohort (AUC = 0.846) and in the replication cohort (AUC = 0.857). LR = likelihood ratio.

  • 1

    Hishikawa T, Sugiu K, Date I. Moyamoya disease: a review of clinical research. Acta Med Okayama. 2016;70(4):229236.

  • 2

    Funaki T, Takahashi JC, Yoshida K, et al. Periventricular anastomosis in moyamoya disease: detecting fragile collateral vessels with MR angiography. J Neurosurg. 2016;124(6):17661772.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Ryoo S, Cha J, Kim SJ, et al. High-resolution magnetic resonance wall imaging findings of moyamoya disease. Stroke. 2014;45(8):24572460.

  • 4

    Kuroda S, Kashiwazaki D, Akioka N, et al. Specific shrinkage of carotid forks in moyamoya disease: a novel key finding for diagnosis. Neurol Med Chir (Tokyo). 2015;55(10):796804.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Matsushima T, Inoue T, Natori Y, et al. Children with unilateral occlusion or stenosis of the ICA associated with surrounding moyamoya vessels—"unilateral" moyamoya disease. Acta Neurochir (Wien). 1994;131(3-4):196202.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Kawano T, Fukui M, Hashimoto N, Yonekawa Y. Follow-up study of patients with “unilateral” moyamoya disease. Neurol Med Chir (Tokyo). 1994;34(11):744747.

  • 7

    Houkin K, Abe H, Yoshimoto T, Takahashi A. Is “unilateral” moyamoya disease different from moyamoya disease?. J Neurosurg. 1996;85(5):772776.

  • 8

    Hirotsune N, Meguro T, Kawada S, et al. Long-term follow-up study of patients with unilateral moyamoya disease. Clin Neurol Neurosurg. 1997;99(suppl 2):S178S181.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Ikezaki K, Inamura T, Kawano T, Fukui M. Clinical features of probable moyamoya disease in Japan. Clin Neurol Neurosurg. 1997;99(Suppl 2):S173S177.

  • 10

    Kuroda S, Ishikawa T, Houkin K, et al. Incidence and clinical features of disease progression in adult moyamoya disease. Stroke. 2005;36(10):21482153.

  • 11

    Seol HJ, Wang KC, Kim SK, et al. Unilateral (probable) moyamoya disease: long-term follow-up of seven cases. Childs Nerv Syst. 2006;22(2):145150.

  • 12

    Kelly ME, Bell-Stephens TE, Marks MP, et al. Progression of unilateral moyamoya disease: a clinical series. Cerebrovasc Dis. 2006;22(2-3):109115.

  • 13

    Nagata S, Matsushima T, Morioka T, et al. Unilaterally symptomatic moyamoya disease in children: long-term follow-up of 20 patients. Neurosurgery. 2006;59(4):830837.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Smith ER, Scott RM. Progression of disease in unilateral moyamoya syndrome. Neurosurg Focus. 2008;24(2):E17.

  • 15

    Hayashi K, Suyama K, Nagata I. Clinical features of unilateral moyamoya disease. Neurol Med Chir (Tokyo). 2010;50(5):378385.

  • 16

    Park EK, Lee YH, Shim KW, et al. Natural history and progression factors of unilateral moyamoya disease in pediatric patients. Childs Nerv Syst. 2011;27(8):12811287.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Yeon JY, Shin HJ, Kong DS, et al. The prediction of contralateral progression in children and adolescents with unilateral moyamoya disease. Stroke. 2011;42(10):29732976.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Lee SC, Jeon JS, Kim JE, et al. Contralateral progression and its risk factor in surgically treated unilateral adult moyamoya disease with a review of pertinent literature. Acta Neurochir (Wien). 2014;156(1):103111.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Zhang Q, Wang R, Liu Y, et al. Clinical features and long-term outcomes of unilateral moyamoya disease. World Neurosurg. 2016;96:474482.

  • 20

    Church EW, Bell-Stephens TE, Bigder MG, et al. Clinical course of unilateral moyamoya disease. Neurosurgery. 2020;87(6):12621268.

  • 21

    Liu W, Morito D, Takashima S, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One. 2011;6(7):e22542.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Mineharu Y, Takagi Y, Miyamoto S. Significance of RNF213 in clinical management in Japan. In: Koizumi A, Nagata K, Houkin K, et al, eds. Moyamoya Disease Explored Through RNF213: Genetics, Molecular Pathology, and Clinical Sciences. Springer;2017:137150.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Morimoto T, Mineharu Y, Ono K, et al. Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease. PLoS One. 2017;12(4):e0175649.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Hallemeier CL, Rich KM, Grubb RL Jr, et al. Clinical features and outcome in North American adults with moyamoya phenomenon. Stroke. 2006;37(6):14901496.

  • 25

    Moteki Y, Onda H, Kasuya H, et al. Systematic validation of RNF213 coding variants in Japanese patients with moyamoya disease. J Am Heart Assoc. 2015;4(5):e001862.

  • 26

    Miyatake S, Miyake N, Touho H, et al. Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology. 2012;78(11):803810.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Cheng W, Xue S, Wu F, et al. The clinical and vascular characteristics of RNF213 c.14576G>A variant-related intracranial major artery disease in China. Behav Neurol. 2019;2019:7908392.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Wei YC, Liu CH, Chang TY, et al. Coexisting diseases of moyamoya vasculopathy. J Stroke Cerebrovasc Dis. 2014;23(6):13441350.

  • 29

    Ge P, Zhang Q, Ye X, et al. Modifiable risk factors associated with moyamoya disease: a case-control study. Stroke. 2020;51(8):24722479.

  • 30

    Yuan HF, Zhao K, Zang Y, et al. Effect of folate deficiency on promoter methylation and gene expression of Esr1, Cav1, and Elavl1, and its influence on spermatogenesis. Oncotarget. 2017;8(15):2413024141.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Chung JW, Kim DH, Oh MJ, et al. Cav-1 (Caveolin-1) and arterial remodeling in adult moyamoya disease. Stroke. 2018;49(11):25972604.

  • 32

    Bang OY, Chung JW, Kim SJ, et al. Caveolin-1, Ring finger protein 213, and endothelial function in Moyamoya disease. Int J Stroke. 2016;11(9):9991008.

  • 33

    Mineharu Y, Takenaka K, Yamakawa H, et al. Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting. J Neurol Neurosurg Psychiatry. 2006;77(9):10251029.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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