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Predictors of neoangiogenesis after indirect revascularisation in moyamoya disease: a 10-year follow-up study
  1. Qian-Nan Wang1,
  2. Ri-Miao Yang2,
  3. Zheng-Xing Zou2,
  4. Xiao-Peng Wang2,
  5. Qian Zhang2,
  6. De-Sheng Li2,
  7. Xiang-Yang Bao2,
  8. Lian Duan2
  1. 1 Department of Neurosurgery, Chinese PLA General Hospital (Former Department of Neurosurgery, the Eighth Medical Center of Chinese PLA General Hospital), Beijing, China
  2. 2 Department of Neurosurgery, Chinese PLA General Hospital (Former Department of Neurosurgery, the Fifth Medical Center of Chinese PLA General Hospital), Beijing, China
  1. Correspondence to Dr Lian Duan, Neurosurgery, Chinese PLA General Hospital, Beijing 100071, China; duanlian307{at}

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Moyamoya disease (MMD) is a rare, chronic and progressive cerebrovascular disorder that is characterised by stenosis and occlusion of the distal carotid, proximal middle and anterior cerebral arteries and is accompanied by the development of small collateral vessel networks.1 Encephaloduroarteriosynangiosis (EDAS) has been a widely established treatment strategy for patients with MMD, however, the factors that affect the formation of collateral circulation after EDAS are unclear. We selected patients who had undergone cerebral angiography at least 5 years after the operation and investigated the relevant factors including RNF213 variation that could affect postoperative collateral formation.

Materials and methods

We identified all patients with MMD treated by EDAS at the Department of Neurosurgery in the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China, from January 2002 through January 2015. Patients who received long-term postoperative digital subtraction angiography (duration ≥5 years after surgical revascularisation up to the latest follow-up angiography) were selected. All patients with MMD enroled in the study underwent EDAS.

The basic clinical data were collected. The angiographic collateral grade was evaluated according to the system described in our recent study.2 Genotyping of p.R4810K was performed following the protocol described in our previous study.3

The last follow-up angiographies were conducted at least 5 years after EDAS. The development of collateral circulation of the middle cerebral artery (MCA) through bypass was graded according to the system described by Matsushima et al.4 Follow-up events included recurrent cerebral haemorrhage, cerebral infarction, and death.


A total of 83 patients with MMD who underwent EDAS in our hospital were enroled in this study between January 2002 and January 2015. The clinical characteristics of the study subjects are summarised in table 1.

Table 1

Baseline characteristics of patients

The mutation rate in cases carrying RNF213 p.R4810K in our study was 24.1% (20/83). All the variant p.R4810K genotypes carried heterozygous mutations (guanine–adenine, GA), no homozygous mutations (adenin–adenine, AA) were detected (table 1).

In 150 hemispheres (16 patients with unilateral hemisphere), the last follow-up angiographies were conducted at a median of 10.4 years after surgical revascularisation.

The heterozygous mutations occurred significantly more frequently in the poor collateral stage group (p=0.003), and their neurological status was mostly poor (p=0.006). Compared with the guanine–guanine (GG) group, the most common clinical manifestation in the GA group was cerebral infarction (42.1% vs 20.5%, p=0.022).

A total of 150 hemispheres received EDAS treatment. The long-term postoperative angiographic findings showed that good Matsushima grade was correlated with a lower preoperative collateral stage (p=0.001). The univariate analysis showed that younger age at onset was associated with good Matsushima grade (p=0.044), and postoperative collateral formation was better in GA than in GG given by better Matsushima grades on lateral views (p=0.005). The multivariate analysis revealed that only age, preoperative collateral stage, and p.R4810K variant were significantly correlated with good collateral circulation post-EDAS (p=0.039, p=0.017 and p=0.023, respectively).

Patients were followed for an average duration of 10.4±2.1 (5.1–18.3) years, and overall experienced significant clinical improvements. However, 9 (10.8%) of 83 patients suffered cerebral stroke after EDAS. Among them, five patients had cerebral infarction and four patients had cerebral haemorrhage.

In the GA group, cerebral stroke was observed in two hemispheres (5.3%) and none of these hemispheres developed rebleeding. In the GG group, cerebral stroke was observed in seven hemispheres (6.3%), including four hemispheres which developed rebleeding. While the annual incidence rate was higher for the GG group than the GA group, according to the Kaplan-Meier analysis, this difference was not statistically significant (p=0.914 for log-rank test).


EDAS is an essential component of the surgical treatment of MMD. However, there are still many unknowns about this procedure. Limited studies with small samples and short-term follow-up angiographies focused the factors of neoangiogenesis after indirect revascularisation. To the best of our knowledge, this is the first report to explore relevant factors including RNF123 that affect long-term (10.4±2.1 years) postoperative collateral formation.

In this study, we found that good Matsushima grade occurred significantly more frequently in those with younger age at onset, posterior circulation involvement, poor neurological status, poor spontaneous collateral circulation and heterozygous mutations of RNF213 p.R4810K (GA). Obviously, in addition to the age of onset and heterozygous mutations of RNF213 p.R4810K, all other influencing factors could indicate the severity of cerebral ischaemia with MMD, especially our newly proposed collateral circulation evaluation system.

The spontaneous collateral circulation, especially the leptomeningeal system, plays the most important role in collateral supply of the ischaemic cortex in the anterior cerebral artery and MCA territory in patients with MMD. The presence of collateral flow via the posterior communicating artery (PComA) in the Circle of Willis is also associated with a low prevalence of border zone infarcts. Therefore, lower collateral circulation score often indicates more severe cerebral ischaemia. Our research also found that the heterozygous mutations were significantly correlated with poor spontaneous collateral circulation, which may be the cause of the severe symptoms and worse neurological status. We speculate that patients with heterozygous mutations in RNF213 have more severe cerebral ischaemia, and the hypoxic brain environment mobilises the proliferation and activation of vascular endothelial cells, thereby obtaining better collateral circulation after surgery.

Over the long-term follow-up in our study, the frequency of recurrent stroke was low, regardless of the genotype, and the Kaplan-Meier curve suggested that there was no significant difference in recurrent stroke between the genotypes of the p.R4810K founder variant. Although the heterozygous mutations occurred significantly more frequently in the poor collateral stage group and their neurological status was mostly poor, indicating more severe ischaemia and poor prognosis due to surgical intervention, the patients obtained better formation of collateral circulation, and thus effectively prevented the occurrence of stroke. These findings suggest that not only homozygous but heterozygous c.14429G>A (p.R4810K) may be useful as a specific biomarker for severe MMD with an unfavourable prognosis that requires early intervention for revascularisation surgery.

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  • Q-NW, R-MY and X-YB contributed equally.

  • Correction notice This article has been corrected since it appeared Online First. Author affiliations have been corrected.

  • Contributors Q-NW did the paper writing. R-MY helped in paper writing and data collection. Z-XZ was involved in experimental operation. X-PW helped in statistical analysis. QZ helped in data collection. D-SL helped in surgical procedures. X-YB was involved in surgical procedures and statistical analysis. LD helped in experimental design and surgical procedures.

  • Funding This study was supported by grant from the National Natural Science Foundation of China (Grant No. 81571136).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.