[Genetic Analysis of Cerebrovascular Diseases].

With advances in genetic analysis technology, the genetic and molecular backgrounds of cerebrovascular diseases have become clearer. In moyamoya disease and intracranial artery stenosis, RNF213 p.Arg4810Lys has been identified as a disease susceptibility gene variant(germline variant), and various analyses have been conducted. PDGFRB mutations have been identified as characteristic somatic variants in cerebral aneurysms and are attracting attention. In addition, PIK3CA and MAP3K3 mutaions have been identified in cerebral cavernous malformations as somatic variants. Moreover, KRAS and BRAF mutations have been identified in arteriovenous malformations as somatic variants, respectively. Further studies are in progress. We reviewed the results of recent genetic analyses of cerebrovascular diseases, focusing particularly on genetic mutations.

Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations.

Orbital cavernous venous malformation (OCVM) is a sporadic vascular anomaly of uncertain etiology characterized by abnormally dilated vascular channels. Here, we identify a somatic missense mutation, c.121G > T (p.Gly41Cys) in GJA4, which encodes a transmembrane protein that is a component of gap junctions and hemichannels in the vascular system, in OCVM tissues from 25/26 (96.2%) individuals with OCVM. GJA4 expression was detected in OCVM tissue including endothelial cells and the stroma, through immunohistochemistry. Within OCVM tissue, the mutation allele frequency was higher in endothelial cell-enriched fractions obtained using magnetic-activated cell sorting. Whole-cell voltage clamp analysis in Xenopus oocytes revealed that GJA4 c.121G > T (p.Gly41Cys) is a gain-of-function mutation that leads to the formation of a hyperactive hemichannel. Overexpression of the mutant protein in human umbilical vein endothelial cells led to a loss of cellular integrity, which was rescued by carbenoxolone, a non-specific gap junction/hemichannel inhibitor. Our data suggest that GJA4 c.121G > T (p.Gly41Cys) is a potential driver gene mutation for OCVM. We propose that hyperactive hemichannel plays a role in the development of this vascular phenotype.

Genetics of brain arteriovenous malformations and cerebral cavernous malformations.

Cerebrovascular malformations comprise abnormal development of cerebral vasculature. They can result in hemorrhagic stroke due to rupture of lesions as well as seizures and neurological defects. The most common forms of cerebrovascular malformations are brain arteriovenous malformations (bAVMs) and cerebral cavernous malformations (CCMs). They occur in both sporadic and inherited forms. Rapidly evolving molecular genetic methodologies have helped to identify causative or associated genes involved in genesis of bAVMs and CCMs. In this review, we highlight the current knowledge regarding the genetic basis of these malformations.

Hypertensive disorders of pregnancy in moyamoya disease: A single institution experience.

OBJECTIVE: The characteristics of pregnancy and delivery in patients with moyamoya disease (MMD) remain unclear. We retrospectively investigated perinatal outcomes in patients with MMD to evaluate the risks associated to this condition. MATERIALS AND METHODS: Clinical data of women with MMD who delivered at the University of Tokyo Hospital between 2000 and 2021 were collected. Maternal characteristics including genetic data, obstetric complications, method of delivery and anesthesia, neonatal outcomes, neurological events during pregnancy, delivery, and postpartum course, were reviewed. RESULTS: Thirteen pregnancies with MMD were identified. The median maternal age was 30 years. The initial clinical symptoms were identified as transient ischemic attack, infarction, and headache. Eight patients had a history of bypass surgery. The median gestational age at delivery was 37 weeks. DNA samples were collected from five patients, responsible for six pregnancies. Of these six cases, five had the RNF213 c.14429G > A (p.Arg4810Lys) heterozygous variant. Of the 13 pregnancies, seven had hypertensive disorder of pregnancy (HDP). Additionally, three of five pregnancy cases with RNF213 p.Arg4810Lys heterozygous variant presented with HDP. Nine patients underwent cesarean section, and four delivered vaginally with epidural anesthesia. One case of ischemic stroke was confirmed during the postpartum period. Regarding newborns, neither Apgar scores lower than 7 nor neonatal intensive care unit admissions were reported. CONCLUSIONS: This study suggests that the frequency of HDP is higher in patients with MMD compared to those with normal pregnancies. Strict blood pressure control should be performed in patients with MMD during pregnancy and postpartum period.

Targeted deep sequencing of DNA from multiple tissue types improves the diagnostic rate and reveals a highly diverse phenotype of mosaic neurofibromatosis type 2.

BACKGROUND: Although 60% of patients with de novo neurofibromatosis type 2 (NF2) are presumed to have mosaic NF2, the actual diagnostic rate of this condition remains low at around 20% because of the existing difficulties in detecting NF2 variants with low variant allele frequency (VAF). Here, we examined the correlation between the genotype and phenotype of mosaic NF2 after improving the diagnostic rate of mosaic NF2. METHODS: We performed targeted deep sequencing of 36 genes including NF2 using DNA samples from multiple tissues (blood, buccal mucosa, hair follicle and tumour) of 53 patients with de novo NF2 and elucidated their genotype-phenotype correlation. RESULTS: Twenty-four patients (45.2%) had the NF2 germline variant, and 20 patients with NF2 (37.7%) had mosaic NF2. The mosaic NF2 phenotype was significantly different from that in patients with NF2 germline variant in terms of distribution of NF2-related disease, tumour growth rate and hearing outcome. The behaviour of schwannoma correlated to the extent of VAF with NF2 variant in normal tissues unlike meningioma. CONCLUSION: We have improved the diagnostic rate of mosaic NF2 compared with that of previous studies by targeted deep sequencing of DNA from multiple tissues. Many atypical patients with NF2 diagnosed with 'unilateral vestibular schwannoma' or 'multiple meningiomas' presumably have mosaic NF2. Finally, we suggest that the highly diverse phenotype of NF2 could result not only from the type and location of NF2 variant but also the extent of VAF in the NF2 variant within normal tissue DNA.

[Molecular Pathogenesis of Cerebral Cavernous Malformations].

Cerebral cavernous malformations(CCMs)are vascular anomalies characterized by clusters of dilated capillaries and veins. They frequently cause epileptic seizures, hemorrhagic strokes, and focal neurological deficits. At present, CCMs can be treated only by surgical resection. However, the identification of germline and somatic mutations and the associated signaling pathways have improved our understanding of the underlying mechanisms; this has further led to testing of targeted molecular therapies for the disease. This review summarizes the current knowledge on the molecular pathogenesis of CCMs.

[Genetic Factors of Intracranial Artery Stenosis and Potential for Personalized Medicine].

It has been verified that the missense variant c.14429G>A(p.Arg4810Lys, rs112735431)of RNF213(Ringer finger protein 213)is significantly associated with intracranial artery stenosis(ICAS). The clinical features of ICAS with RNF213 p.Arg4810Lys are also becoming clear. In addition, RNF213 p.Arg4810Lys has been found to be associated with coronary artery stenosis/renal artery stenosis and pulmonary hypertension, and has been attracting attention as a variant that causes systemic vascular disease. Functional analysis of RNF213 is also progressing, but the mechanism involved in disease onset has not yet been clarified, and further analysis is expected for the realization of personalized medicine for ICAS.

Association Between the Onset Pattern of Adult Moyamoya Disease and Risk Factors for Stroke.

BACKGROUND AND PURPOSE: Few previous studies have comprehensively explored the relationship between the onset pattern of adult moyamoya disease and risk factors for stroke. We performed a retrospective analysis focusing on risk factors for stroke and related findings on magnetic resonance imaging/angiography with respect to the pattern of disease onset. We also examined whether risk factors for stroke were associated with an increased risk for symptomization in asymptomatic patients. METHODS: A total of 178 adult patients with moyamoya disease (asymptomatic, n=84; ischemic, n=71; hemorrhagic, n=23) at the University of Tokyo Hospital from 2000 to 2018 were included in this study. Data pertaining to patient background and magnetic resonance imaging findings were analyzed retrospectively. In the asymptomatic group, the effects of stroke-associated risk factors on symptom onset were analyzed. RESULTS: Comparisons among the 3 groups revealed no significant difference in the frequency of risk factors for stroke. The proportion of patients with magnetic resonance imaging/angiography findings indicating anterior choroidal artery anastomosis or microbleeds was significantly higher in the hemorrhagic group than in the asymptomatic or ischemic group. Among asymptomatic patients, the hazard ratios for symptomization with hypertension and dyslipidemia were 6.69 ([95% CI, 1.23-36.4] P=0.028) and 8.14 ([95% CI, 1.46-45.2] P=0.017), respectively. CONCLUSIONS: The development of anterior choroidal artery anastomosis and microbleeds on magnetic resonance imaging/angiography was significantly associated with hemorrhagic onset. Hypertension and dyslipidemia may increase the risk of cerebrovascular events in asymptomatic patients, and thus, early intervention to these factors may be important.

Genetic Analysis of Ring Finger Protein 213 (RNF213) c.14576G>A in Intracranial Atherosclerosis of the Anterior and Posterior Circulations.

BACKGROUND: Intracranial atherosclerosis of the anterior circulation (anterior ICAS) and intracranial atherosclerosis of the posterior circulation (posterior ICAS) are thought to involve different pathogeneses and risk factors. Recently, we identified a genetic variant that has a significant association with ICAS. The variant was ring finger protein 213 (RNF213) c.14576G>A (rs112735431), which was originally identified as a susceptibility genetic variant for moyamoya disease (MMD). The present study investigated the association of RNF213 c.14576G>A with anterior and posterior ICAS. MATERIALS AND METHODS: A total of 221 study participants (43 with anterior ICAS, 61 with posterior ICAS, 12 with extracranial carotid atherosclerosis [ECAS], 5 with MMD, and 100 control subjects) were recruited from April 2015 to October 2015. A genetic analysis of RNF213 c.14576G>A and an association study with these cerebrovascular diseases were performed. RESULTS: RNF213 c.14576G>A was present in 10 of 43 patients in the anterior ICAS group and 4 of 5 patients in the MMD group, but was not present in the patients in the posterior ICAS and ECAS groups. c.14576G>A was found in 2 of 100 patients in the control group. RNF213 c.14576G>A showed a significant association with anterior ICAS (allele count: P = 3.9 × 10-5, odds ratio [OR] = 13.0, 95% confidence interval [CI] = 2.8-60.8; prevalence of carriers of c.14576G>A: P = 2.6 × 10-5, OR = 14.8, 95% CI = 3.1-71.3). However, RNF213 c.14576G>A showed no association with posterior ICAS. RNF213 c.14576G>A also had a significant association with MMD and had no association with ECAS. CONCLUSIONS: The genetic variant RNF213 c.14576G>A is significantly associated with anterior ICAS but not with posterior ICAS. The present findings may indicate factors involved in the pathogenesis of ICAS-related stroke.

Dermatomal sensory manifestations in lateral medullary infarction.

A 61-year-old man who experienced a sudden onset of unstable gait followed by nuchal pain was admitted to our department. The neurologic examination revealed right-sided limb ataxia, right partial ptosis, and decreased sensation to 50% of the normal side to pinprick and temperature stimuli on the left side below the level of the T-6 dermatome. A lateral medullary infarction caused by spontaneous vertebral artery dissection was diagnosed by magnetic resonance imaging and computed tomography angiography. In conclusion, lateral medullary infarction is an important entity to consider in the differential diagnosis of dermatomal sensory manifestations.

A bibliometric analysis of the 100 most-cited clinical articles in the research of intracranial artery stenosis and intracranial atherosclerosis.

Background: Intracranial arterial stenosis (ICAS), caused by intracranial atherosclerosis, is one of the major causes of ischemic stroke. This study identified the top 100 most-cited publications on ICAS through a bibliometric analysis. Methods: Two independent authors conducted a search in the Web of Science database for clinical articles on ICAS published between 1993 and 2022. The top 100 most-cited articles were then extracted. For each article, the analysis covered the title, author, country of origin/affiliation, journal, total number of citations, number of citations per year, and type of study. Results: The top 100 most-cited papers in the ICAS were authored by 565 authors from 12 countries and published in 29 journals. In terms of the 5-year trend, the largest number of papers were published between 2003 and 2007 (n = 31). The median number of citations for the 100 papers was 161 (range 109-1,115). The journal with the highest proportion of the 100 most published articles was Stroke, accounting for 41% of articles and 37% of the citations. According to country of origin, the United States of America accounted for the largest number of articles, followed by China, Japan, and South Korea, with these four countries together accounting for 81% of the total number of articles and 88% of the citations. Trends in the past five years included the use of terms such as acute ischemic stroke and mechanical thrombectomy. Conclusion: The findings of this study provide novel insight into this field and will facilitate future research endeavors.

Clinical Characteristics of Immediate Contralateral Ischemia Subsequent to Revascularization for Moyamoya Disease.

BACKGROUND: Moyamoya disease is a bilateral steno-occlusive disease involving the cerebral vasculature. While some patients are affected by procedure-related ipsilateral ischemia, ischemic complications contralateral to the revascularization are rarely observed. METHODS: We retrospectively investigated 135 hemispheres (103 patients) that underwent revascularization in our institution between April 2006 and September 2022. Revascularization surgery comprised single superficial temporal artery-middle cerebral artery anastomosis and encephalo-myo-synangiosis. Certain patients aged under 10 years underwent indirect revascularization. Bilateral revascularization was performed with an interval of >3 months. Medical records and neuroimages were reviewed, and patients with contralateral ischemic complications were identified. Some cases underwent genetic analysis. RESULTS: The mean age was 34.5 (range: 5-71) years, and 95 cases (70.4%) were in women. Of the 102 cases examined for the RNF213 c.14429 G > A (p.Arg4810Lys) variant, 33 (32.4%) and 69 (67.6%) showed the GG and GA genotype, respectively. Three cases (2.2%, all female, age range 44-71 years) were complicated with contralateral infarction. The infarcted area distributions of the 2 cases with RNF213 c.14429 G > A variant were patchy and peripheral. The other case showed on magnetic resonance imaging (MRI) angiography total occlusion of the internal carotid artery where patency had been confirmed preoperatively. CONCLUSIONS: Contralateral ischemia after revascularization occurred in 2.2% of cases. We classified them into peripheral and central types: peripheral type, an infarction owing to hemodynamic insufficiency or intracranial blood flow redistribution; central type, total occlusion of the contralateral internal carotid artery. Intensive preoperative management can minimize the risk of peripheral types, and neurosurgeons should beware of severe central types.

POLR2A Mutation is a Poor Prognostic Marker of Cerebellopontine Angle Meningioma.

BACKGROUND AND OBJECTIVES: Recent molecular analyses have shown that the driver genetic mutations of meningiomas were associated with the anatomic location. Among these, POLR2A mutation is common among lesions in the skull base, mainly in the cerebellopontine angle (CPA). The objective of this study was to investigate the efficacy of POLR2A mutation as a prognostic marker for CPA meningiomas. METHODS: We retrospectively analyzed the clinical data of 70 patients who had World Health Organization grade I CPA meningiomas. Somatic DNA was analyzed by Sanger sequencing and microsatellite array to examine for NF2 , AKT1 , KLF4 , SMO , and POLR2A mutations and 22q loss. Genetic and clinical parameters were analyzed to identify the factors related with tumor recurrence. RESULTS: We detected clearly the clinical features of the CPA cases with POLR2A mutation. Compared with cases without POLR2A mutation, cases with POLR2A mutation had more meningothelial type ( P = 6.9 × 10 -4 ), and higher rate of recurrence ( P = .04). We found that the poor prognostic factors associated with the recurrence of CPA meningiomas were POLR2A mutation ( P = .03, hazard ratio [HR] 9.38, 95% CI 1.26-70.0) and subtotal resection (STR) ( P = 5.1 × 10 -4 , HR 63.1, 95% CI 6.09-655.0). In addition, in the group that underwent STR, POLR2A mutation was a poor prognostic factor associated with tumor recurrence ( P = .03, HR 11.1, 95% CI 1.19-103.7). CONCLUSION: POLR2A mutation and STR were the poor prognostic markers associated with the recurrence of CPA meningioma. For CPA meningioma cases that underwent STR, only POLR2A mutation was a poor prognostic factor. Detecting POLR2A mutation may be a cost-effective, easy, and useful marker for prognostication.

Stroke Events and Risk Factors in Older Patients with Moyamoya Disease.

BACKGROUND: We aimed to comprehensively analyze the epidemiology, natural history, stroke events and their risk factors, and the RNF213 p.Arg4810Lys variant in older patients with moyamoya disease (MMD). METHODS: We enrolled patients with MMD followed-up at our hospital between 2000 and 2023. Those who developed MMD at age ≥60 years or were diagnosed at a younger age and followed-up after age 60 years were included. Baseline characteristics, onset type, radiologic features, and RNF213 p.Arg4810Lys variant status were investigated. RESULTS: Among 56 patients with 100 affected hemispheres, 62 were asymptomatic, 26 experienced ischemic onset, and 12 had hemorrhagic onset. A higher incidence of anterior choroidal artery (AchA) dilatation and lower proportion of favorable modified Rankin scale scores were detected in hemorrhagic onset, whereas greater prevalence of bypass surgery in ischemic onset. Of 76 asymptomatic hemispheres at the age of 60 years, subsequent stroke events occurred in 10 hemispheres, comprising 8 hemorrhages and 2 ischemias. Risk factors for de novo hemorrhage in asymptomatic hemispheres included AchA dilatation and choroidal anastomosis. Comparison of the RNF213 p.Arg4810Lys variant status showed no significant differences in baseline characteristics, onset types, or imaging findings, except for a higher percentage of patients in the GA group with a family history of MMD. CONCLUSIONS: Hemorrhagic events were the most prevalent and prognostically deteriorating factors in older patients with MMD aged ≥60 years. AchA dilatation and choroidal anastomosis were predictors of de novo hemorrhage in asymptomatic nonsurgical hemispheres in older patients with MMD.

Suppression of essential oil biosynthesis in sweet basil cotyledons under hypergravity conditions.

The mechanism through which gravity influences the biosynthesis of essential oils in herbs is an important issue for plant and space biology. Sweet basil (Ocimum basilicum L.) seedlings were cultivated under centrifugal hypergravity conditions at 100 g in the light, and the growth of cotyledons, development of glandular hairs, and biosynthesis of essential oils were analyzed. The area and fresh weight of the cotyledons increased by similar amounts irrespective of the gravitational conditions. On the abaxial surface of the cotyledons, glandular hairs, where essential oils are synthesized and stored, developed from those with single-cell heads to those with four-cell heads; however, hypergravity did not affect this development. The main components, methyl eugenol and 1,8-cineole, in the essential oils of cotyledons were lower in cotyledons grown under hypergravity conditions. The gene expression of enzymes in the phenylpropanoid pathway involved in the synthesis of methyl eugenol, such as phenylalanine ammonia lyase (PAL) and eugenol O-methyltransferase (EOMT), was downregulated by hypergravity. Hypergravity also decreased the gene expression of enzymes in the 2C-methyl-d-erythritol 4-phosphate (MEP) pathway involved in the synthesis of 1,8-cineole, such as 1-deoxy-d-xylulose-5-phosphate synthase (DXS) and 1,8-cineole synthase (CINS). These results indicate that hypergravity without affecting the development of glandular hairs, decreases the expression of genes related to the biosynthesis of methyl eugenol and 1,8-cineole, which may cause a decrease in the amounts of both essential oils in sweet basil cotyledons.

Association of Genetic Variants with Postoperative Donor Artery Development in Moyamoya Disease: RNF213 and Other Moyamoya Angiopathy-Related Gene Analysis.

Robust postoperative bypass development is a characteristic of moyamoya disease (MMD); however, genetic factors mediating this phenomenon remain incompletely understood. Therefore, we aimed to elucidate the relationship between postoperative donor artery development and genetic variants. We retrospectively enrolled 63 patients (79 hemispheres) who underwent combined revascularization surgery. Postoperative development of the superficial temporal artery (STA), middle meningeal artery, and deep temporal artery (DTA) was assessed using the caliber-change ratio determined from magnetic resonance angiography measurements. We analyzed RNF213 and 36 other moyamoya angiopathy-related genes by whole-exome sequencing and extracted rare or damaging variants. Thirty-five participants carried RNF213 p.Arg4810Lys (all heterozygotes), whereas 5 had RNF213 rare variants (RVs). p.Arg4810Lys was significantly associated with postoperative DTA development, while age at surgery, hypertension, and hyperlipidemia were inversely associated. Multiple regression analysis revealed that age and p.Arg4810Lys held statistical significance (P = 0.044, coefficient - 0.015, 95% confidence interval (CI) - 0.029 to 0.000 and P = 0.001, coefficient 0.670, 95% CI 0.269 to 1.072, respectively). Those with RNF213 RV without p.Arg4810Lys exhibited a significant trend toward poor DTA development (P = 0.001). Hypertension demonstrated a significant positive association with STA development, which remained significant even after multiple regression analysis (P = 0.001, coefficient 0.303, 95% CI 0.123 to 0.482). Following Bonferroni correction for multiple comparisons, targeted analyses of RNF213 and 36 moyamoya angiopathy-related genes showed a significant association of only RNF213 p.Arg4810Lys with favorable DTA development (P = 0.001). A comprehensive analysis of RNF213, considering both p.Arg4810Lys and RVs, may provide a clearer prediction of postoperative DTA development.

Association of rare variants in RNF213 with severe progression of intracranial artery stenosis in quasi-moyamoya disease.

OBJECTIVE: The genetic basis underlying the pathophysiology of quasi-moyamoya disease (qMMD) is unclear. Herein, the authors aimed to comprehensively analyze genetic variants in qMMD and investigate their association with clinical phenotypes, focusing on RNF213 and other moyamoya angiopathy (MMA)-related genes. METHODS: The authors evaluated 14 consecutive cases of qMMD, whose underlying conditions included autoimmune disease, head irradiation, meningitis/pachymeningitis, and Turner syndrome, and 9 cases of hyperthyroidism-associated MMD (hMMD). The frequencies of RNF213 p.Arg4810Lys in qMMD and hMMD were each compared to those in healthy controls and in patients with MMD. Whole-exome sequencing was performed, and rare variants (RVs) or damaging variants were analyzed in RNF213 and 36 MMA-related genes. RESULTS: The frequencies of p.Arg4810Lys were significantly higher in patients with qMMD (28.6%) and hMMD (33.3%) than in controls (1.1%; p < 0.001) and lower in the two former groups than in the MMD group (67.6%; p = 0.003 and 0.065, respectively). In qMMD, no significant clinical differences were observed based on the presence of p.Arg4810Lys. A novel RNF213 RV was identified in four cases with qMMD. These same cases also presented with significant worsening of intracranial main artery stenosis, which suggests a possible association between RNF213 RVs and the severe progression of qMMD. Among the 36 MMA-related genes, no variants correlated with specific phenotypes. CONCLUSIONS: While the clinical implications of p.Arg4810Lys in cases with qMMD were not identified, the study findings suggest a potential association between RNF213 RVs and the significant progression of intracranial artery stenosis. Genetic analysis should not focus solely on p.Arg4810Lys but instead consider a comprehensive analysis of RNF213 for more accurate clinical prognostication of qMMD.

Cerebrovascular Events During Treatment for Systemic Malignant Tumors in Patients with Moyamoya Disease.

OBJECTIVE: With the increasing incidence of malignancies, the importance of cancer-associated stroke is emphasized. Although moyamoya disease is a leading cause of stroke, no reports have documented cancer-associated stroke in patients with this condition. We aimed to investigate cerebrovascular events during malignancy treatments in patients with moyamoya disease. METHODS: A total of 405 patients with moyamoya disease who visited our hospital between January 2000 and March 2022 were retrospectively examined. We evaluated the management of moyamoya disease, presence of the ring finger protein 213 p.Arg4810Lys variant, treatments for malignant tumors, presence of cerebrovascular events during treatment, and follow-up periods and outcomes. RESULTS: Among the 405 patients, 17 patients with moyamoya disease (4.2%) were diagnosed with malignancies. Among patients aged 60 years and over, 7 out of 67 (10.4%) had malignancies. Of the 17 patients, 11 (64.7%) were symptomatic, and 7 (41.2%) had revascularization surgery. 9 patients were treated with oral antiplatelet drugs. There was no significant difference between the groups with and without malignancy regarding the presence of the ring finger protein 213 p.Arg4810Lys variant (80.0% vs. 62.7%, P = 0.33). All patients underwent surgical treatment, and 7 (41.2%) received chemotherapy. One death due to tumor progression was reported. No cerebrovascular event was observed during malignancy treatments and follow-up periods, which had a mean duration of 6 years. CONCLUSIONS: In our cohort, malignancy treatments in patients with moyamoya disease were safely conducted without cerebrovascular events. However, it is advisable to avoid hypotension, dehydration, hyperventilation, and long-term discontinuation of antiplatelet drugs during the treatment of malignant tumors.

Bypass Surgery for Adult-Onset Hemorrhagic Moyamoya Disease: Analysis Classified by Site of Initial Bleeding.

OBJECTIVE: Prevention of rebleeding events is crucial for patients with hemorrhagic moyamoya disease (MMD), as these increase the risk of mortality. Bypass surgery is effective in preventing subsequent hemorrhage, particularly in patients with posterior hemorrhage, but its efficacy in those with anterior hemorrhage remains unclear. We analyzed the effects of surgical intervention, stroke risk factors, and radiological features on rebleeding events. METHODS: Patients with hemorrhagic-onset MMD who were followed at our institution between 2000 and 2022 were included (41 adult patients, 45 hemispheres). Baseline characteristics and radiological features (anterior or posterior hemorrhagic site, Suzuki grade, posterior cerebral artery involvement, and periventricular anastomosis) were thoroughly reviewed. RESULTS: Of the 45 hemispheres, hemorrhage developed in 9 (20%) hemispheres, with a median duration until rebleeding of 38 (range: 1-44) months. Rebleeding rates were significantly lower in the surgical group than in the nonsurgical group (odds ratio: 0.09; 95% confidence interval [CI]: 0.01-0.79; P = 0.011), and Kaplan-Meier analysis revealed a significantly longer interval between bleeding events in the surgical group (1.3%/y vs. 5.3%/y; P = 0.002), especially in the anterior hemorrhage group (1.3%/y vs. 5.1%/y; P = 0.019). The hazard ratio of surgical intervention for rebleeding with initial anterior hemorrhage was 0.11 (95% CI: 0.01-0.98; P = 0.048). In the nonsurgical group, the presence of hypertension shortened the time to subsequent hemorrhage (P = 0.004). CONCLUSIONS: Surgical intervention may decrease the risk of rebleeding in hemorrhagic onset MMD patients, even in those presenting with anterior hemorrhage. Hypertension was a significant risk factor for rebleeding in nonsurgical patients.