Development and validation of a novel nomogram for predicting long-term rebleeding risk among patients with hemorrhagic moyamoya disease: a 10-year multicenter retrospective cohort study.

OBJECTIVE: The aim of this study was to develop and validate a predictive nomogram model for long-term rebleeding events in patients with hemorrhagic moyamoya disease (HMMD). METHODS: In total, 554 patients with HMMD from the Fifth Medical Center of the Chinese PLA General Hospital (5-PLAGH cohort) were included and randomly divided into training (390 patients) and internal validation (164 patients) sets. An independent cohort from the First Medical Center and Eighth Medical Center of Chinese PLA General Hospital (the 1-PLAGH and 8-PLAGH cohort) was used for external validation (133 patients). Univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression algorithm were used to identify significant factors associated with rebleeding, which were used to develop a nomogram for predicting 5- and 10-year rebleeding. RESULTS: Intraventricular hemorrhage was the most common type of cerebral hemorrhage (39.0% of patients in the 5-PLAGH cohort and 42.9% of the 1-PLAGH and 8-PLAGH cohort). During the mean ± SD follow-up period of 10.4 ± 2.9 years, 91 (16.4%) patients had rebleeding events in the 5-PLAGH cohort. The rebleeding rates were 12.3% (68 patients) at 5 years and 14.8% (82 patients) at 10 years. Rebleeding events were observed in 72 patients (14.3%) in the encephaloduroarteriosynangiosis (EDAS) surgery group, whereas 19 patients (37.3%) experienced rebleeding events in the conservative treatment group. This difference was statistically significant (p < 0.001). We selected 4 predictors (age at onset, number of episodes of bleeding, posterior circulation involvement, and EDAS surgery) for nomogram development. The concordance index (C-index) values of the nomograms of the training cohort, internal validation cohort, and the external validation cohort were 0.767 (95% CI 0.704-0.830), 0.814 (95% CI 0.694-0.934), and 0.718 (95% CI 0.661-0.775), respectively. The nomogram at 5 years exhibited a sensitivity of 48.1% and specificity of 87.5%. The positive and negative predictive values were 38.2% and 91.3%, respectively. The nomogram at 10 years exhibited a sensitivity of 47.1% and specificity of 89.1%. The positive and negative predictive values were 48.5% and 88.5%, respectively. CONCLUSIONS: EDAS may prevent rebleeding events and improve long-term clinical outcomes in patients with HMMD. The nomogram accurately predicted rebleeding events and assisted clinicians in identifying high-risk patients and devising individual treatments. Simultaneously, comprehensive and ongoing monitoring should be implemented for specific patients with HMMD throughout their entire lifespan.

Development and validation of a novel nomogram for predicting good neoangiogenesis after encephaloduroarteriosynangiosis in patients with moyamoya disease and type 2 diabetes mellitus: a case-control study.

OBJECTIVE: Diabetes is often linked to poorer outcomes in patients with moyamoya disease (MMD). However, experience has shown that certain individuals with diabetes have favorable outcomes after encephaloduroarteriosynangiosis (EDAS). The authors aimed to develop a nomogram to predict good neoangiogenesis in patients with MMD and type 2 diabetes mellitus (T2DM) to aid neurosurgeons in the identification of suitable candidates for EDAS. METHODS: Adults with MMD and T2DM who underwent EDAS between June 2004 and December 2018 were included in the analysis. In total, 126 patients (213 hemispheres) with MMD and T2DM from the Fifth Medical Centre of the Chinese PLA General Hospital were included and randomly divided into training (152 hemispheres) and internal validation (61 hemispheres) cohorts at a ratio of 7:3. Univariate logistic and least absolute shrinkage and selection operator regression analyses were used to identify the significant factors associated with good neoangiogenesis, which were used to develop a nomogram. The discrimination, calibration, and clinical utility were assessed. RESULTS: A total of 213 hemispheres in 126 patients were reviewed, including 152 (71.36%) hemispheres with good postoperative collateral formation and 61 (28.64%) with poor postoperative collateral formation. The authors selected 4 predictors (FGD5 rs11128722, VEGFA rs9472135, Suzuki stage, and internal carotid artery [ICA] moyamoya vessels) for nomogram development. The C-indices of the nomogram in the training and internal validation cohorts were 0.873 and 0.841, respectively. The nomogram exhibited a sensitivity of 84.5% and specificity of 81.0%. The positive and negative predictive values were 92.1% and 66.7%, respectively. The calibration curves indicated high predictive accuracy, and receiver operating characteristic curve analysis showed the superiority of the nomogram. The decision-making analysis validated the fitness and clinical application value of this nomogram. Then a web-based calculator to facilitate clinical application was generated. CONCLUSIONS: The nomogram developed in this study accurately predicted neoangiogenesis in patients with MMD and T2DM after EDAS and may assist neurosurgeons in identifying suitable candidates for indirect revascularization surgery.

Association between polymorphism in the MTHFR gene and encephaloduroarteriosynangiosis-induced collateral circulation formation.

OBJECTIVE: This study aimed to investigate whether high homocysteine (Hcy) levels associated with the MTHFR gene influence the formation of the collateral vascular network in patients with moyamoya disease (MMD) after encephaloduroarteriosynangiosis (EDAS) by influencing the number of endothelial progenitor cells (EPCs) in peripheral blood. METHODS: A total of 118 Chinese patients with bilateral primary MMD were prospectively included. Blood samples were collected from the anterior cubital vein before surgery, and MTHFR rs9651118 was genotyped using high-throughput mass spectrometry to determine the genotype of the test specimen. Serum Hcy and EPC levels were measured, the latter with flow cytometry. Digital subtraction angiography was performed 6 months after EDAS, and the formation of collateral circulation was evaluated using the Matsushima grade system. The correlations between MTHFR rs9651118 genotype, Hcy and EPC levels, and Matsushima grade were compared. RESULTS: Among the 118 patients, 53 had the TT genotype (wild type) of MTHFR rs9651118, 33 TC genotype (heterozygous mutation), and 32 CC genotype (homozygous mutation). The mean ± SD Hcy level was 13.4 ± 9.5 µmol/L in TT patients, 9.8 ± 3.2 µmol/L in TC patients, and 8.9 ± 2.9 µmol/L in CC patients (p < 0.001). The level of EPCs in the venous blood of TT patients was 0.039% ± 0.016%, that of TC patients 0.088% ± 0.061%, and that of CC patients 0.103% ± 0.062% (p < 0.001). When the rs9651118 gene locus was mutated, Matsushima grade was better (p < 0.001) but there was no difference between heterozygous and homozygous mutations. CONCLUSIONS: The results suggest that the MTHFR rs9651118 polymorphism is a good biomarker for collateral vascular network formation after EDAS in MMD patients.

Isolated anterior cerebral artery occlusion: an atypical form of moyamoya disease.

BACKGROUND: The relationship between anterior cerebral artery (ACA) occlusion and moyamoya disease (MMD) has rarely been studied. In this study, we focused on a special type of MMD: isolated ACA-occlusive MMD. We investigated clinical attributes, genotypes and progression risk factors in patients with ACA-occlusive MMD, providing initial insights into the relationship between ACA occlusion and MMD. METHODS: We retrospectively analysed digital subtraction angiography (DSA) from 2486 patients and diagnosed 139 patients with ACA-occlusive MMD. RNF213 p.R4810K (rs112735431) mutation analysis was performed. Patients were categorised into progression and non-progression groups based on whether they progressed to typical MMD. Differences in clinical characteristics, neuropsychological assessment, radiological findings and genotypes were evaluated. Logistic regression analyses identified risk factors for ACA-occlusive MMD progression. RESULTS: The median age of patients with ACA-occlusive MMD was 36 years, and the primary symptom was transient ischaemic attack (TIA). 72.3% of ACA-occlusive MMD patients had cognitive decline. Of 116 patients who underwent RNF213 gene mutation analysis, 90 patients (77.6%) carried the RNF213 p.R4810K GG allele and 26 (22.4%) carried the GA allele. Of 102 patients with follow-up DSA data, 40 patients (39.2%) progressed. Kaplan-Meier curve estimates indicated a higher incidence of ischaemic stroke in the progression group during follow-up (p=0.035). Younger age (p=0.041), RNF213 p.R4810K GA genotype (p=0.037) and poor collateral compensation from the middle cerebral artery (MCA) to ACA (p<0.001) were risk factors of ACA-occlusive MMD progression to typical MMD. CONCLUSIONS: Cognitive decline and TIA might be the main manifestations of ACA-occlusive MMD. Isolated ACA occlusion may be an early signal of MMD. The initial lesion site of MMD is not strictly confined to the terminal portion of the internal carotid artery. Younger patients, patients with RNF213 p.R4810K GA genotype or those with inadequate MCA-to-ACA compensation are more likely to develop typical MMD.

High Level of Serum Complement C3 Expression is Associated with Postoperative Vasculopathy Progression in Moyamoya Disease.

Background: The immune system plays an important role in the onset and development of moyamoya disease (MMD), but the specific mechanisms remain unclear. This study aimed to explore the relationship between the expression of complements and immunoglobulin in serum and progression of MMD. Methods: A total of 84 patients with MMD and 70 healthy individuals were enrolled. Serum immunoglobulin and complement C3 and C4 expression were compared between healthy individuals and MMD patients. Follow-up was performed at least 6 months post-operation. Univariate and multivariate analysis after adjusting different covariates were performed to explore predictive factors associated with vasculopathy progression. A nomogram basing on the results of multivariate analysis was established to predict vasculopathy progression. Results: Compared to healthy individuals, MMD patients had significantly lower expression of serum complements C3 (P = 0.003*). Among MMD patients, C3 was significantly lower in those with late-stage disease (P = 0.001*). Of 84 patients, 27/84 (32.1%) patients presented with vasculopathy progression within a median follow-up time of 13.0 months. Age (P=0.006*), diastolic blood pressure (P=0.004*) and serum complement C3 expression (P=0.015*) were associated with vasculopathy progression after adjusting different covariables. Conclusion: Complement C3 is downregulated in moyamoya disease and decreases even further in late-Suzuki stage disease. Age, diastolic blood pressure and serum complement C3 expression are associated with vasculopathy progression, suggesting that the complement might be involved in the development of moyamoya disease.

Clinical and genetic factors associated with contralateral progression in unilateral moyamoya disease: Longitudinal and Cross-Sectional Study.

Objective: This study aimed to explore the long-term outcome of unilateral moyamoya disease and predict the clinical and genetic factors associated with contralateral progression in unilateral moyamoya disease. Methods: We retrospectively recruited unilateral moyamoya disease patients with available genetic data who underwent encephaloduroarteriosynangiosis (EDAS) surgery at our institution from January 2009 to November 2017. Long-term follow-up data, including clinical outcomes, angiographic features, and genetic information, were analyzed. Results: A total of 83 unilateral moyamoya disease patients with available genetic data were enrolled in our study. The mean duration of clinical follow-up was 7.9 ± 2.0 years. Among all patients, 19 patients demonstrated contralateral progression to bilateral disease. Heterozygous Ring Finger Protein 213 p.R4810K mutations occurred significantly more frequently in unilateral moyamoya disease patients with contralateral progression. Furthermore, patients with contralateral progression typically demonstrated an earlier age of onset than those with non-progressing unilateral moyamoya disease. In the contralateral progression group, posterior circulation involvement was observed in 11 (11/19, 57.9%) patients compared to 12 (12/64, 18.8%) in the non-contralateral progression group (P = 0.001). The time to peak of cerebral perfusion and neurological status showed significant postoperative improvement. Conclusion: Long-term follow-up revealed that the EDAS procedure might provide benefits for unilateral moyamoya disease patients. Ring Finger Protein 213 p.R4810K mutations, younger age, and posterior circulation involvement might predict the contralateral progression of unilateral moyamoya disease.

Long-term outcomes after conservative and EDAS treatment for 111 elderly patients with moyamoya disease: longitudinal and cross-sectional study.

OBJECTIVE: This study aimed to explore the clinical features of moyamoya disease (MMD) and the efficacy of encephaloduroarteriosynangiosis (EDAS) in elderly patients with MMD and to identify the risk factors for long-term stroke events. METHODS: Clinical data were retrospectively collected on elderly patients with MMD (age ≥ 60 years) who had been treated at the authors' center from May 2007 to December 2017. Clinical features, angiographic findings, and long-term outcomes (> 5-year follow-up) were analyzed. Cox regression analysis was performed to determine the risk factors for postoperative stroke events. Long-term stroke events were analyzed using Kaplan-Meier curves. RESULTS: The mean age at symptom onset was 62.9 ± 3.0 years among 111 elderly patients with MMD. Vascular comorbidities were present in 80 (72.1%) patients. The ratio of female to male patients was 1:1.2. Familial MMD was found in 7 (6.3%) patients. Cerebral ischemia was the most common clinical manifestation observed in 82 (73.9%) patients. Most patients (59.5%) presented with Suzuki stages 5 and 6 MMD, and 29 (26.1%) patients presented with stenosis or occlusion of the posterior circulation. Unilateral MMD was present in 17 (15.3%) patients. Among the 58 (52.3%) patients who underwent EDAS, 28 (48.3%) and 30 (51.7%) underwent bilateral and unilateral surgeries, respectively. Overall, 53 (47.7%) patients were treated conservatively using internal medicine. After a median follow-up duration of 8.2 years, stroke incidence in the EDAS and conservative treatment groups was respectively 17.2% (7 and 3 cases of cerebral infarction and hemorrhage, respectively) and 49.1% (22 and 4 cases of cerebral infarction and hemorrhage, respectively). The stroke incidence rate was higher in the conservative group than in the EDAS group, with a statistically significant difference (p = 0.001) according to results of the Kaplan-Meier analysis. The identified predictor of postoperative stroke events was initial hemorrhage in the EDAS group and advanced age, aneurysm, and initial ischemia in the conservative treatment group. CONCLUSIONS: The postoperative long-term stroke rate among elderly patients with MMD was lower in the EDAS group than in the conservative treatment group. Long-term stroke events were associated with advanced age, aneurysm, and initial ischemia after conservative treatment and only initial hemorrhage after EDAS.

Surgical outcomes following encephaloduroarteriosynangiosis in moyamoya disease associated with hyperhomocysteinemia.

INTRODUCTION: This study investigated the effect of indirect revascularization surgery in adult patients with moyamoya disease (MMD) complicated with hyperhomocysteinemia (HHcy), and the effect of HHcy on the progression of adult MMD. METHODS: A retrospective case-control study was conducted in patients with MMD, with or without HHcy (n = 123). Postoperative collateral angiogenesis was evaluated using the Matsushima grading system and disease progression using the Suzuki staging system. Cerebral blood flow was evaluated before and after surgery using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) and neurological function prognosis using the improved Rankin score (mRS). Univariate and multivariate logistic regression analyses were performed to determine risk factors for the clinical outcomes. RESULTS: There was no significant difference in the Suzuki stage composition ratios between the HHcy group and the non-HHcy group before and after surgery. Non-HHcy patients were more likely to grow new collateral circulating vessels after encephaloduroarteriosynangiosis (EDAS). Moreover, postoperative DSC-MRI indicated that the time to peak significantly improved. CONCLUSIONS: HHcy level may be a specific predictor of adverse clinical outcomes after EDAS in patients with MMD and a risk factor for poor collateral circulation and poor prognosis. Patients with MMD complicated with HHcy need to strictly control homocysteine levels before EDAS surgery.

In this retrospective study, we found that patients with MMD complicated by HHcy had poor collateral angiogenesis after EDAS, faster disease progression, and worse clinical outcomes.

Natural course and risk factors of moyamoya disease with unruptured intracranial aneurysm.

Background and objective: The natural course and risk factors of moyamoya disease (MMD) associated with unruptured intracranial aneurysms involving stenosed parental arteries are scarcely studied. This study aimed to elucidate the natural course of MMD and its associated risk factors in patients with MMD with unruptured aneurysms. Methods: Between September 2006 and October 2021, patients with MMD with intracranial aneurysms at our center were examined. The natural course, clinical features, radiological features, and follow-up outcomes after revascularization were analyzed. Results: This study included 42 patients with MMD with intracranial aneurysms (42 aneurysms). The age distribution of MMD cases ranged from 6 to 69 years, with four children (9.5%) and 38 adults (90.5%). A total of 17 male and 25 female subjects were included (male-to-female ratio: 1:1.47). The first symptom was cerebral ischemia in 28 cases, and cerebral hemorrhage occurred in 14 cases. There were 35 trunk aneurysms and seven peripheral aneurysms. There were 34 small aneurysms (<5 mm) and eight medium aneurysms (5-15 mm). During the average clinical follow-up period of 37.90 ± 32.53 months, there was no rupture or bleeding from aneurysms. Twenty-seven of these patients underwent a cerebral angiography review, in which it was found that one aneurysm had enlarged, 16 had remained unchanged, and 10 had shrunk or disappeared. A correlation exists between the reduction or disappearance of aneurysms and the progression of the Suzuki stages of MMD (P = 0.015). Nineteen patients underwent EDAS on the aneurysm side, and nine aneurysms disappeared, while eight patients did not undergo EDAS on the aneurysm side and one aneurysm disappeared. Conclusion: The risk of rupture and hemorrhage of unruptured intracranial aneurysms is low when the parent artery already has stenotic lesions, thus, direct intervention may not be necessary for such aneurysms. The progression of the Suzuki stage of moyamoya disease may play a role in the shrinkage or disappearance of the aneurysms, thereby decreasing the risk of rupture and hemorrhage. Encephaloduroarteriosynangiosis (EDAS) surgery may also help promote atrophy or even the disappearance of the aneurysm, thus reducing the risk of further rupture and bleeding.