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.

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.

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, radiological 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 eight hemorrhages and two 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.

Clinical and radiological features of intracranial ancient schwannomas: a single-institution, retrospective analysis.

Ancient schwannoma (AS) is a subtype of schwannoma characterized by slow progression despite degenerative changes in pathology. Although it is considered a benign tumor, most previous reports have focused on extracranial AS; therefore, the clinical characteristics of intracranial AS is not clear. We included 174 patients who underwent surgery for sporadic intracranial schwannoma, and 13 patients (7.5%) were diagnosed with AS. Cysts were significantly more common in patients with AS than conventional schwannomas (92.3% vs. 44.7%, p < 0.001), as was bleeding (38.5% vs. 6.9%, p = 0.003) and calcification (15.4% vs. 1.3%, p = 0.029). The maximum tumor diameter was also larger in patients with AS (35 mm vs. 29 mm, p = 0.017). The median duration from symptom onset to surgery (7.0 vs. 12.5 months, p = 0.740) did not significantly differ between groups, nor did the probability of postoperative recurrence (p = 0.949). Intracranial AS was strongly associated with cyst formation and exhibited a benign clinical course with a lower rate of recurrence and need for salvage treatment. Extracranial AS is reportedly characterized by a slow progression through a long-term clinical course, whereas intracranial AS did not progress slowly in our study and exhibited different clinical features to those reported for extracranial AS.

Suzuki Stage VI Unilateral Moyamoya Disease Presenting With Massive Intraventricular Hemorrhage.

Moyamoya disease (MMD) is characterized by stenosis of the terminal portion of the internal carotid artery (ICA) and the development of collateral vessels. In late Suzuki stage MMD, ICA almost disappears, and the moyamoya vessels gradually regress. We report a case of late Suzuki stage unilateral MMD presenting with intraventricular hemorrhage. A 76-year-old woman who had previously been diagnosed with right ICA occlusive disease was referred to our hospital due to impaired consciousness. Radiological evaluation revealed massive intraventricular hemorrhage. After endoscopic hematoma removal, digital subtraction angiography (DSA) was performed to examine the vascular anatomy, which revealed numerous basal moyamoya vessels originating from the posterior cerebral artery. Three-dimensional rotational angiography identified a choroidal anastomosis originating from the posterior choroidal artery as the hemorrhage source. The patient had an RNF213 p.Arg4810Lys heterozygous variant in the germline. Based on the DSA findings, MMD was diagnosed, and the patient was transferred to a rehabilitation hospital with good postoperative consciousness. In conclusion, patients diagnosed with ICA occlusive disease may have late Suzuki stage MMD, potentially leading to major hemorrhage; therefore, antithrombotic medications should be administered with caution. In diagnosing ICA occlusive disease, the assessment of periventricular anastomosis should be considered, taking into account the possibility of MMD.

The importance of considering competing risks in recurrence analysis of intracranial meningioma.

BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. RESULTS: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). CONCLUSION: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

Causality Assessment Between Drugs and Fatal Cerebral Haemorrhage Using Electronic Medical Records: Comparative Evaluation of Disease-Specific and Conventional Methods.

INTRODUCTION: A new algorithm for causality assessment of drugs and fatal cerebral haemorrhage (ACAD-FCH) was published in 2021. However, its use in clinical practice has not been verified. OBJECTIVES: This study aimed to explore the practical value of the ACAD-FCH when applying information available in clinical practice. METHODS: The medical records of patients who died at the University of Tokyo Hospital in 2020 were reviewed, and cases with intracranial haemorrhage were selected. Two evaluators independently assessed these cases using three methods (the ACAD-FCH, Naranjo algorithm, and WHO-UMC scale). The number of 'Yes', 'No', and 'No information/Do not know' responses to each question by both evaluators were summed and compared. Inter-rater reliability was evaluated for each method using agreement rates and kappa coefficients with 95% confidence intervals (CI). RESULTS: Among 316 deaths, 24 cases with intracranial haemorrhage were evaluated. The proportion of ?No information/Do not know' responses for each question was 35.6% (95% CI 31.4-40.6%) for the ACAD-FCH and 66.9% (95% CI 62.5-71.1%) for the Naranjo algorithm. The respective agreement rates and kappa coefficients were 0.917 (0.798-1.00) and 0.867 (0.675-1.00) for the ACAD-FCH, 0.708 (0.512-0.904) and 0.139 (-0.236 to 0.513) for the Naranjo algorithm, and 0.50 (0.284-0.716) and 0.326 (0.110-0.541) for the WHO-UMC scale, respectively. CONCLUSION: Our findings suggest the utility of the ACAD-FCH when assessing death cases with intracranial haemorrhage. However, larger studies including intra-rater assessments are warranted for further validation of this algorithm.

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.

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.

Long-term outcomes of stereotactic radiosurgery for intracranial schwannoma in neurofibromatosis type 2: a genetic analysis perspective.

PURPOSE: Neurofibromatosis type 2 (NF2) is intractable because of multiple tumors involving the nervous system and is clinically diverse and genotype-dependent. Stereotactic radiosurgery (SRS) for NF2-associated schwannomas remains controversial. We aimed to investigate the association between radiosurgical outcomes and mutation types in NF2-associated schwannomas. METHODS: This single-institute retrospective study included consecutive NF2 patients with intracranial schwannomas treated with SRS. The patients' types of germline mutations ("Truncating," "Large deletion," "Splice site," "Missense," and "Mosaic") and Halliday's genetic severity scores were examined, and the associations with progression-free rate (PFR) and overall survival (OS) were analyzed. RESULTS: The study enrolled 14 patients with NF2 with 22 associated intracranial schwannomas (median follow-up, 102 months).　The PFRs in the entire cohort were 95% at 5 years and 90% at 10-20 years. The PFRs tended to be worse in patients with truncating mutation exons 2-13 than in those with other mutation types (91% at 5 years and 82% at 10-20 years vs. 100% at 10-20 years, P = 0.140). The OSs were 89% for patients aged 40 years and 74% for those aged 60 years in the entire cohort and significantly lower in genetic severity group 3 than in the other groups (100% vs. 50% for those aged 35 years; P = 0.016). CONCLUSION: SRS achieved excellent PFR for NF2-associated intracranial schwannomas in the mild (group 2A) and moderate (group 2B) groups. SRS necessitates careful consideration for the severe group (group 3), especially in cases with NF2 truncating mutation exons 2-13.

Case report and literature review: exploration of molecular therapeutic targets in recurrent malignant meningioma through comprehensive genetic analysis with Todai OncoPanel.

Background: Despite accumulating research on the molecular characteristics of meningiomas, no definitive molecularly targeted therapy for these tumors has been established to date. Molecular mechanisms underlying meningioma progression also remain unclear. Comprehensive genetic testing approaches can reveal actionable gene aberrations in meningiomas. However, there is still limited information on whether profiling the molecular status of subsequent recurrent meningiomas could influence the choice of molecular-targeted therapies. Case presentation: We report a case of meningioma with malignant progression and multiple recurrences. We performed matched tumor pair analysis using the Todai OncoPanel to investigate the possibility of additional standard treatments. The loss of several chromosomal regions, including NF2 and CDKN2A, which is associated with aggressive meningiomas, was considered a significant driver event for malignant progression. Using additional matched tumor pair analysis, mutations in TRAF7, ARID1A, and ERBB3 were identified as subclonal driver events at the time of recurrence. No genetic aberrations were found for which evidence-based targeted therapy was applicable. We also reviewed previous reports of molecular therapies in meningioma to discuss issues with the current molecular testing approach. Conclusion: Gene panel testing platforms such as the Todai OncoPanel represent a powerful approach to elucidate actionable genetic alterations in various types of tumors, although their use is still limited to the diagnosis and prediction of prognosis in meningiomas. To enable targeted molecular therapy informed by gene-panel testing, further studies including matched tumor pair analyses are required to understand the molecular characteristics of meningiomas and develop treatments based on genetic abnormalities.

Meningiomas in patients with neurofibromatosis type 2 predominantly comprise 'immunogenic subtype' tumours characterised by macrophage infiltration.

Although recent molecular analyses revealed that sporadic meningiomas have various genetic, epigenetic, and transcriptomic profiles, meningioma in patients with neurofibromatosis type 2 (NF2) have not been fully elucidated. This study investigated meningiomas' clinical, histological, and molecular characteristics in NF2 patients. A long-term retrospective follow-up (13.5 ± 5.5 years) study involving total 159 meningiomas in 37 patients with NF2 was performed. Their characteristics were assessed using immunohistochemistry (IHC), bulk-RNA sequencing, and copy number analysis. All variables of meningiomas in patients with NF2 were compared with those in 189 sporadic NF2-altered meningiomas in 189 patients. Most meningiomas in NF2 patients were stable, and the mean annual growth rate was 1.0 ± 1.8 cm3/year. Twenty-eight meningiomas (17.6%) in 25 patients (43.1%) were resected during the follow-up period. WHO grade I meningiomas in patients with NF2 were more frequent than in sporadic NF2-altered meningiomas (92.9% vs. 80.9%). Transcriptomic analysis for patients with NF2/sporadic NF2-altered WHO grade I meningiomas (n = 14 vs. 15, respectively) showed that tumours in NF2 patients still had a higher immune response and immune cell infiltration than sporadic NF2-altered meningiomas. Furthermore, RNA-seq/IHC-derived immunophenotyping corroborated this enhanced immune response by identifying myeloid cell infiltration, particularly in macrophages. Clinical, histological, and transcriptomic analyses of meningiomas in patients with NF2 demonstrated that meningiomas in NF2 patients showed less aggressive behaviour than sporadic NF2-altered meningiomas and elicited a marked immune response by identifying myeloid cell infiltration, particularly of macrophages.

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.

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.

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.

White epidermoid cyst transformation after stereotactic radiosurgery: illustrative case.

BACKGROUND: White epidermoid cysts (WECs) are a rare type of epidermoid cyst with atypical radiological features. The epidemiological aspects and mechanisms of their onset remain unknown. Herein, the authors report a unique case of WEC transformation from a typical epidermoid cyst after stereotactic radiosurgery (SRS), confirmed by radiological and pathological findings. OBSERVATIONS: The case involved a 78-year-old man with a history of 2 surgeries for a left cerebellopontine angle typical epidermoid cyst 23 years earlier and SRS using the CyberKnife for recurrent trigeminal neuralgia (TN) 14 years earlier. The tumor with high intensity on T1-weighted imaging, low intensity on T2-weighted imaging, without restriction on diffusion-weighted imaging had gradually enlarged after SRS. Therefore, a salvage surgery was performed via a left suboccipital craniotomy, and the intraoperative findings showed a cyst with a brown, viscous liquid component, consistent with those of WECs. Histopathologically, keratin calcification and hemorrhage were identified, leading to a diagnosis of WEC. The postoperative course was uneventful, and the TN resolved. No tumor recurrence was recorded at 2 years postoperatively. LESSONS: To the best of the authors' knowledge, this is the first world case of WEC transformation from a typical epidermoid cyst after SRS, confirmed by radiological and pathological findings. Radiation effects could have been involved in this transformation.

Long-Term Outcomes of Stereotactic Radiosurgery for Postoperative World Health Organization Grade I Skull Base Meningioma: Utility of Ki-67 Labeling Index as a Prognostic Indicator.

BACKGROUND: Gross total resection, without causing neurological deficits, is challenging in skull base meningioma (SBM). Therefore, stereotactic radiosurgery (SRS) is an important approach for SBMs; however, it is difficult to predict the long-term prognosis. OBJECTIVE: To identify the predictive factors for tumor progression after SRS for World Health Organization (WHO) grade I SBMs, focusing on the Ki-67 labeling index (LI). METHODS: In this single-center retrospective study, factors affecting progression-free survival rates (PFSs) and neurological outcomes in patients undergoing SRS for postoperative SBMs were evaluated. Based on the Ki-67 LI, patients were classified into 3 groups: low (<4%), intermediate (4%-6%), and high LI (>6%). RESULTS: In the 112 patients enrolled, the cumulative 5- and 10-year PFSs were 93% and 83%, respectively. The PFSs were significantly higher in the low LI group (95% at 10 years) compared with the other groups (intermediate LI, 60% at 10 years, P = .007; high LI, 20% at 10 years, P = .001). Multivariable Cox proportional hazard analysis demonstrated that the Ki-67 LI was significantly associated with the PFSs (low vs intermediate LI; hazard ratio, 6.00; 95% CI, 1.41-25.54; P = .015; low vs high LI; hazard ratio, 31.90; 95% CI, 5.59-181.77; P = .001). CONCLUSION: Ki-67 LI may be a useful predictor of long-term prognosis in SRS for postoperative WHO grade I SBM. SRS provides excellent long- and mid-term PFSs in SBMs with Ki-67 LIs <4% or 4% to 6%, with a low risk of radiation-induced adverse events.

RNF213 p.Arg4810Lys Wild Type is Associated with De Novo Hemorrhage in Asymptomatic Hemispheres with Moyamoya Disease.

Clinical implications of RNF213 genetic variants, other than p.Arg4810Lys, in moyamoya disease (MMD), remain unclear. This study aimed to investigate the association of RNF213 variants with clinical phenotypes in MMD. This retrospective cohort study collected data regarding the clinical characteristics of 139 patients with MMD and evaluated the angioarchitectures of 253 hemispheres using digital subtraction angiography at diagnosis. All RNF213 exons were sequenced, and the associations of clinical characteristics and angiographical findings with p.Arg4810Lys, p.Ala4399Thr, and other rare variants (RVs) were examined. Among 139 patients, 100 (71.9%) had p.Arg4810Lys heterozygote (GA) and 39 (28.1%) had the wild type (GG). Fourteen RVs were identified and detetcted in 15/139 (10.8%) patients, and p.Ala4399Thr was detected in 17/139 (12.2%) patients. Hemispheres with GG and p.Ala4399Thr presented with significantly less ischemic events and more hemorrhagic events at diagnosis (p = 0.001 and p = 0.028, respectively). In asymptomatic hemispheres, those with GG were more susceptible to de novo hemorrhage than those with GA (adjusted hazard ratio [aHR] 5.36) with an increased risk when accompanied by p.Ala4399Thr or RVs (aHR 15.22 and 16.60, respectively). Within the choroidal anastomosis-positive hemispheres, GG exhibited a higher incidence of de novo hemorrhage than GA (p = 0.004). The GG of p. Arg4810Lys was a risk factor for de novo hemorrhage in asymptomatic MMD hemispheres. This risk increased with certain other variants and is observed in choroidal anastomosis-positive hemispheres. A comprehensive evaluation of RNF213 variants and angioarchitectures is essential for predicting the phenotype of asymptomatic hemispheres in MMD.

Clinical and Genetic Characteristics of Patients with Moyamoya Disease who Experienced Both Ischemic and Hemorrhagic Events.

OBJECTIVE: Cerebrovascular events in moyamoya disease are mainly classified into ischemic or hemorrhagic onset. It is rare for one patient to develop both ischemia and hemorrhage in moyamoya disease; detailed clinical course and genetic characteristics of such patients have not been elucidated. We aimed to clarify the clinical features of patients with both ischemic and hemorrhagic cerebrovascular events. METHODS: We analyzed the background factors, radiological features, and genotype of ring finger protein 213 c.14429 G > A (p.Arg4810Lys) of patients with moyamoya disease who visited our hospital between 1996 and 2020, and experienced both ischemic and hemorrhagic cerebrovascular events. Additionally, we analyzed factors that caused subsequent hemorrhage in adult-onset ischemic moyamoya disease. RESULTS: Of 262 patients, 12 presented with both ischemia and hemorrhage, of which, 4 exhibited pediatric onset and 8 had adult onset. In pediatric-onset subjects, ischemia was the initial event in all cases. Hemorrhagic events occurred at a median of 24.7 years postoperatively in patients who had undergone bypass surgery. In adult-onset subjects, ischemia preceded hemorrhage in 7 patients. In males, the interval to subsequent hemorrhage was significantly shorter for adult-onset ischemic moyamoya disease, and the hazard ratio for hemorrhagic events was 5.45. The ring finger protein 213 p.Arg4810Lys heterozygous variant was present in 9 patients. CONCLUSIONS: A majority of patients with moyamoya disease with both ischemia and hemorrhage experience an ischemic event first. Patients who developed ischemia in childhood may develop subsequent hemorrhage in approximately 20-25 years after bypass surgery. Male sex is a risk factor for a subsequent hemorrhagic event in adult-onset ischemic moyamoya disease.