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.

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.

Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation.

Ependymomas encompass multiple clinically relevant tumor types based on localization and molecular profiles. Tumors of the methylation class "spinal ependymoma" (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical relevance have been described in a large, epigenetically defined series. Transcriptomic (n = 72), epigenetic (n = 225), genetic (n = 134), and clinical data (n = 112) were integrated for a detailed molecular overview on SP-EPN. Additionally, we mapped SP-EPN transcriptomes to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. The integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord revealed that SP-EPN display the highest similarities to mature adult ependymal cells. Unsupervised hierarchical clustering of transcriptomic data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype A tumors primarily carried previously known germline or sporadic NF2 mutations together with 22q loss (bi-allelic NF2 loss), resulting in decreased NF2 expression. Furthermore, they more often presented as multilocular disease and demonstrated a significantly reduced progression-free survival as compared to SP-EP subtype B. In contrast, subtype B predominantly contained samples without NF2 mutation detected in sequencing together with 22q loss (monoallelic NF2 loss). These tumors showed regular NF2 expression but more extensive global copy number alterations. Based on integrated molecular profiling of a large multi-center cohort, we identified two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.

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.

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.

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.

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.

Genome-Wide Association Study of Intracranial Artery Stenosis Followed by Phenome-Wide Association Study.

The genetic background of intracranial artery stenosis (ICAS), a major cause of ischemic stroke, remains elusive. We performed the world's first genome-wide association study (GWAS) of ICAS using DNA samples from Japanese subjects, to identify the genetic factors associated with ICAS and their correlation with clinical features. We also conducted a phenome-wide association study (PheWAS) of the top variant identified via GWAS to determine its association with systemic disease. The GWAS involved 408 patients with ICAS and 349 healthy controls and utilized an Asian Screening Array of venous blood samples. The PheWAS was performed using genotypic and phenotypic data of the Biobank Japan Project, which contained information on 46 diseases and 60 quantitative trait data from > 150,000 Japanese individuals. The GWAS revealed that the East Asian-specific functional variant of RNF213, rs112735431 (c.14429G > A, p.Arg4810Lys), was associated with ICAS (odds ratio, 12.3; 95% CI 5.5 to 27.5; P = 7.8 × 10-10). Stratified analysis within ICAS cases demonstrated that clinical features of those with and without the risk allele were different. PheWAS indicated that high blood pressure and angina were significantly associated with RNF213 rs112735431. The first GWAS of ICAS, which stratifies subpopulations within the ICAS cases with distinct clinical features, revealed that RNF213 rs112735431 was the most significant variant associated with ICAS. Thus, RNF213 rs112735431 shows potential as an important clinical biomarker that characterizes pleiotropic risk in various vascular diseases, such as blood pressure and angina, thereby facilitating personalized medicine for systemic vascular diseases in East Asian populations.

RNF213 p.Arg4810Lys Heterozygosity in Moyamoya Disease Indicates Early Onset and Bilateral Cerebrovascular Events.

The relationship between RNF213 c.14429G > A (p.Arg4810Lys) heterozygous variants and clinical manifestation in patients with Moyamoya disease (MMD) remains unclear. We performed a retrospective cohort analysis to clarify the genotype-phenotype correlation of this RNF213 hotspot variant in MMD patients, especially between wild-type (GG) and heterozygous (GA) genotypes. Clinical and genetic data were obtained from patients diagnosed with MMD in our institutions between October 2011 and November 2020. Clinical data included age, sex, neurological status at diagnosis, medical history, smoking history, alcohol intake, and family history. Of the 225 enrolled patients, 160 (71.1%) were symptomatic, 3 (1.3%) had the homozygous variant, and 149 (66.2%) had the heterozygous variant (GA). Analysis of all enrolled patients showed that the GA group was prone to present bilateral symptoms (p = 0.008) and progressive status (Suzuki grade ≥ 4; p = 0.017). Analysis limited to symptomatic patients revealed that the GA group had bilateral symptoms (p = 0.017), younger age at onset (p = 0.043), and, in particular, a higher proportion of onset before 25 years of age (p = 0.021). Multivariate logistic regression analysis of overall patients revealed that earlier age at diagnosis (p < 0.001, OR 0.936, 95% CI 0.914-0.959) and GA group (p = 0.017, OR 3.326, 95%CI 1.237-8.941) were significantly associated with bilateral symptoms. MMD patients diagnosed at a young age with the RNF213 heterozygous variant should be followed up with consideration of possible contralateral stroke if one hemisphere is already symptomatic or of early cerebrovascular events if bilateral hemispheres are asymptomatic.

Cell Therapy for Chronic TBI: Interim Analysis of the Randomized Controlled STEMTRA Trial.

OBJECTIVE: To determine if chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623). METHODS: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multi-center trial (N = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (N = 61), and efficacy in the modified intent-to-treat population of randomized patients who underwent surgery (N = 61; SB623 = 46, control = 15). RESULTS: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (LS mean [SE]) +8.3 (1.4) vs +2.3 (2.5) for control at 6 months, the LS mean difference was 6.0 (95% CI: 0.3-11.8); p = 0.040. Secondary efficacy endpoints improved from baseline, but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25). CONCLUSIONS: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.

Treatment of ischemic neuronal death by introducing brain-derived neurotrophic factor mRNA using polyplex nanomicelle.

Ischemic neuronal death causes serious lifelong neurological deficits; however, there is no proven effective treatment that can prevent neuronal death after the ischemia. We investigated the feasibility of mRNA therapeutics for preventing the neuronal death in a rat model of transient global ischemia (TGI). By intraventricular administration of mRNA encoding brain-derived neurotrophic factor (BDNF) using a polymer-based carrier, polyplex nanomicelle, the mRNA significantly increased the survival rate of hippocampal neurons after TGI, with a rapid rise of BDNF in the hippocampus. Interestingly, mRNA administration on Day 2 after TGI provided significantly better survival rate than the administration immediately after TGI. Eventually, dosing twice on Day 2 and 5 exerted long-term therapeutic effects, which were confirmed by a Y-maze behavioral test demonstrating improved spatial memory compared with untreated rats on Day 20. Immunohistochemical analysis showed that astrocytes were chief targets of the BDNF mRNA-loaded nanomicelles, suggesting that the augmented BDNF secretion from astrocytes creates a supportive microenvironment for the neurons to tolerate changes caused by ischemic stresses, and terminate the process of progressive neuronal death after the ischemic attack. Overall, the unique mechanism of action of mRNA therapeutics provide a promising approach for preventing ischemic neuronal death.

Multiple Spinal Syphilitic Gummas Diagnosed by Postoperative Histopathology and Antibiotic Responsiveness: A Case Report.

Neurosyphilis is an infection of the central nervous system by Treponema pallidum. Gummatous neurosyphilis, especially spinal syphilitic gumma, is an exceedingly rare manifestation and may be misdiagnosed as other tumors due to its rarity. A 42-year-old man with a medical history of treatment for syphilis presented with rapidly progressive leg paralysis, leg sensory disturbance, and bladder and rectal disturbance. Spinal MRI demonstrated an intradural extramedullary lesion strongly compressing the spinal cord at the T6/7 level, which was accompanied with dural tail sign and perilesional meningeal thickening at the T6-T8 levels. Small intradural extramedullary lesions were also detected at the T1 and T8 levels. Serological and cerebrospinal fluid examinations for syphilis were both positive. In the treatment of spinal syphilitic gumma, the decompression of the spinal cord by lesionectomy followed by postoperative antibiotic treatment is considered to be an optimal procedure in patients with rapid progression of neurological deterioration. In the present case, the symptomatic main lesion that was compressing the thoracic cord was excised by surgery and analyzed by histopathological examination, and another small asymptomatic lesion was resolved by postoperative antibiotic treatment. Spinal syphilitic gumma was diagnosed using both histopathological findings of the surgically resected lesion and another residual lesion that was resolved by postoperative antibiotic treatment.

Giant Fusiform and Dolichoectatic Aneurysms of the Basilar Trunk and Vertebrobasilar Junction-Clinicopathological and Surgical Outcome.

BACKGROUND: Giant fusiform and dolichoectatic aneurysms of the basilar trunk and vertebrobasilar junction (BTVBJ-GFDA) are extremely difficult to treat. OBJECTIVE: To evaluate factors influencing survival and outcome of BTVBJ-GFDA by performing a retrospective multicenter cohort study. METHODS: A total of 32 patients with BTVBJ-GFDA were included in this study. Clinicopathological characteristics, treatment measures, and outcomes were collected from medical records and imaging studies. Autopsy and histological findings of the aneurysm and adjacent brain tissue were also obtained in 9 cases. RESULTS: A total of 11 patients did not undergo surgery, of whom 10 died; 3 from progressive brainstem compression, 4 from subarachnoid hemorrhage, 2 from brainstem infarction, and 1 from associated atherosclerotic disease. The remaining 21 patients underwent a surgical treatment, consisting of immediately proximal parent artery occlusion, remotely proximal parent artery occlusion, clip reconstruction, and distal bypass and achieved significantly longer overall survival compared with those who received conservative therapy (adjusted hazard ratio 1.508, 95% CI 1.058-2.148, P = .02). Histological examination of the aneurysms demonstrated staged clots, open lumen, and intrathrombotic channels with endothelial lining. The patients younger than 45 yr of age showed statistically longer survival than those equal and older than 45 yr (P = .03). CONCLUSION: Surgical intervention achieved greater survival than conservative management in BTVBJ-GFDA. Narrow ideal treatment window of the blood flow within the aneurysm to maintain sufficient but not excess supply should be targeted based on the hemodynamics of both the posterior communicating arteries and perforating vessel collaterals.

Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis.

Intracranial artery stenosis (ICAS) is the most common cause of ischemic stroke worldwide. RNF213 single nucleotide variant c.14429G > A (p.Arg4810Lys, rs112735431) was recently reported to be associated with ICAS in East Asians. However, the disease susceptibility of other RNF213 variants has not been clarified. This study comprehensively investigated ICAS-associated RNF213 variants in a pool of 168 Japanese ICAS patients and 1,194 control subjects. We found 138 nonsynonymous germline variants by target resequencing of all coding exons in RNF213. Association study between ICAS patients and control subjects revealed that only p.Arg4810Lys had significant association with ICAS (P = 1.5 × 10-28, odds ratio = 29.3, 95% confidence interval 15.31-56.2 [dominant model]). Fourteen of 138 variants were rare variants detected in ICAS patients not harboring p.Arg4810Lys variant. Two of these rare variants (p.Cys118Arg and p.Leu2356Phe) consistent with variants previously reported in moyamoya disease patients characterized by stenosis of intracranial artery and association with RNF213, and three rare variants (p.Ser193Gly, p.Val1817Leu, and p.Asp3329Tyr) were found neither in control subjects and Single Nucleotide Polymorphism Database. The present findings may improve our understanding of the genetic background of intracranial artery stenosis.

Treating Pulsatile Exophthalmos in Child with Minimally Invasive Approach and Custom-made Titanium Mesh Plate.

Orbital roof fracture is a relatively rare trauma. In most cases, surgical intervention is not needed since the fracture is slight. However, invasive surgical procedures are inevitable once pulsatile exophthalmos occurs if vision impairment is to be avoided. We report our rare experience of orbital roof fracture in a child with pulsatile exophthalmos. Good reconstruction of the anterior cranial base was achieved using a custom-made titanium mesh and a minimally invasive approach. A 3-year-old girl who had been diagnosed with subdural hematoma, brain contusion, and fracture of the right orbital roof caused by facial bruising underwent emergent external decompression by coronal skin incision and a transcranial approach on the same day as the trauma. Cranioplasty using autologous frozen bone in the same approach was performed 103 days posttrauma, but this was followed by pulsatile exophthalmos. After recovering from critical stage, the girl was brought to our department for reconstruction of the anterior base. Risk of vision impairment was also one reason for reconstruction, but the neurosurgeon hesitated to approach the region using a coronal approach considering the possibility of infection in the frozen autologous bone. Through cross-team discussion, reconstruction using a subeyebrow incision was performed with a custom-made titanium mesh plate. Pulsatile exophthalmos completely disappeared. Pulsatile exophthalmos is a very rare but serious complication that carries a risk of vision impairment. By applying a custom-made titanium mesh plate, precise reconstruction was enabled with minimal invasiveness and low risk.

Surgical management for a huge presacral teratoma and a meningocele in an adult with Currarino triad: a case report.

BACKGROUND: The Currarino triad is a rare hereditary syndrome comprising anorectal malformation, sacral bony defect, and presacral mass. Most of the patients are diagnosed during infancy. CASE PRESENTATION: A 44-year-old man was diagnosed with Currarino triad, with a huge presacral teratoma and meningocele. One-stage surgery via posterior approach was successful. CONCLUSIONS: Treatment of the presacral mass in the Currarino triad, diagnosed in adulthood, is challenging. Multidisciplinary management and detailed planning before surgery are important for a satisfactory outcome.

Microsurgery Simulator of Cerebral Aneurysm Clipping with Interactive Cerebral Deformation Featuring a Virtual Arachnoid.

BACKGROUND: A virtual reality simulator for aneurysmal clipping surgery is an attractive research target for neurosurgeons. Brain deformation is one of the most important functionalities necessary for an accurate clipping simulator and is vastly affected by the status of the supporting tissue, such as the arachnoid membrane. However, no virtual reality simulator implementing the supporting tissue of the brain has yet been developed. OBJECTIVE: To develop a virtual reality clipping simulator possessing interactive brain deforming capability closely dependent on arachnoid dissection and apply it to clinical cases. METHODS: Three-dimensional computer graphics models of cerebral tissue and surrounding structures were extracted from medical images. We developed a new method for modifiable cerebral tissue complex deformation by incorporating a nonmedical image-derived virtual arachnoid/trabecula in a process called multitissue integrated interactive deformation (MTIID). MTIID made it possible for cerebral tissue complexes to selectively deform at the site of dissection. Simulations for 8 cases of actual clipping surgery were performed before surgery and evaluated for their usefulness in surgical approach planning. RESULTS: Preoperatively, each operative field was precisely reproduced and visualized with the virtual brain retraction defined by users. The clear visualization of the optimal approach to treating the aneurysm via an appropriate arachnoid incision was possible with MTIID. CONCLUSION: A virtual clipping simulator mainly focusing on supporting tissues and less on physical properties seemed to be useful in the surgical simulation of cerebral aneurysm clipping. To our knowledge, this article is the first to report brain deformation based on supporting tissues.

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.