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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.

Purpose: To evaluate a new method that registers phase-contrast magnetic resonance angiography images to time-of-flight magnetic resonance angiography images. Methods: Magnetic resonance angiography datasets of 10 healthy volunteers obtained by using two modalities (phase-contrast magnetic resonance angiography and time-of-flight magnetic resonance angiography) were preprocessed. Specifically, vessel regions were extracted using the region growing method with a threshold of 10% of the signal intensity maximum or 50% of the signal intensity maximum for phase-contrast magnetic resonance angiography images and time-of-flight magnetic resonance angiography images, respectively. Then, the normalized mutual information method was used to determine spatial positions, and registration between non-preprocessed phase-contrast magnetic resonance angiography and time-of-flight magnetic resonance angiography was performed using the spatial position information. Misalignment of 3 anatomical points was used to compare the accuracy of registration in this data group (the proposed method group) to that in the data group without registration (the non-registration group) and that in the data group subjected to normalized mutual information-based registration without preprocessing (the non-preprocessing group). Results: The mean misalignment of 3 anatomical points ± standard error was 1.69 ± 0.11 mm in the proposed method group, and 2.77± 0.13 mm and 90.28 ± 8.24 mm in the non-registration group and non-preprocessing group, respectively. The mean misalignment of 3 anatomical points was significantly smaller in the proposed method group than in the non-registration group (p = 0 001). Conclusions: The proposed preprocessing and registration method improved the accuracy of normalized mutual information-based registration between phase-contrast magnetic resonance angiography images and time-of-flight magnetic resonance angiography images.

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

Moyamoya disease is characterized by severe stenosis at the ends of the bilateral internal carotid arteries and the development of collateral circulation. The disease is very diverse in terms of age at onset, onset patterns, radiological findings, and genetic phenotypes. The pattern of onset is mainly divided into ischemic and hemorrhagic onsets. Recently, the opportunity to identify asymptomatic moyamoya disease, which sometimes manifests as nonspecific symptoms such as headache and dizziness, through screening with magnetic resonance imaging has been increasing. Various recent reports have investigated the associations between the clinical features of different onset patterns of moyamoya disease and the corresponding imaging characteristics. In this article, we have reviewed the natural history, clinical features, and imaging features of each onset pattern of moyamoya disease.

ObjectiveTo determine whether 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).MethodsThis 6-month interim analysis of the 1-year double-blind, randomized, surgical sham–controlled, phase 2 Stem Cell Therapy for Traumatic Brain Injury (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 multicenter trial (n = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, or 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (n = 61), and efficacy was assessed in the modified intent-to-treat population of randomized patients who underwent surgery (n = 61; SB623 = 46, control = 15).ResultsThe 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 (least square [LS] mean) 8.3 (standard error 1.4) vs 2.3 (standard error 2.5) for control at 6 months, the LS mean difference was 6.0 (95% confidence interval 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).ConclusionsSB623 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.ClinicalTrials.gov Identifier:NCT02416492.Classification of EvidenceThis study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.

Electrochromic devices (ECDs) fabricated using resin substrates are attracting considerable interest owing to their advantages of shape deformability and low weight. Acrylic substrates are used to fabricate aircraft windows because they are lighter and more impact-resistant than glass substrates. In this study, the wettability of an indium tin oxide (ITO) surface was enhanced using ultraviolet (UV) treatment prior to the spin-coating and deposition of Prussian blue (PB) and WO3 thin films, which were prepared using functional nanoparticle-dispersed inks on an ITO/acrylic substrate. The fabricated ECD was structured as acrylic/ITO/PB/K+-base gel electrolyte/WO3/ITO/acrylic, and was observed to exhibit excellent electrochromic performance. A high optical modulation and coloration efficiency of 76% and 118.37 cm2/C at a wavelength of 633 nm, respectively, and satisfactory cyclic durability over 1800 cycles were observed. The fabricated ECD possesses immense potential for application in various fields, especially in the field of smart windows for aircrafts.

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.

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.

BACKGROUND Ependymomas are currently classified into 9 subgroups by DNA methylation profiles. Although spinal cord ependymoma (SP-EPN) is distinct from other tumors, diversity within SP-EPN is still unclear. Here, we used transcriptomic and epigenomic profiles to investigate the diversity among Japanese SP-EPN cases. MATERIALS AND METHODS We analyzed 57 SP-EPN patients (32 males and 25 females, aged from 18 to 78 years, median: 52), including two cases of neurofibromatosis type 2, five cases of grade 3 (WHO grade). We obtained transcriptome (RNA-seq) and DNA methylation (Infinium Methylation EPIC array) data from fresh frozen specimens of SP-EPN resected at the University of Tokyo Hospital and our collaborative groups. RESULTS Three cases had a previous intracranial ependymoma operation. Hierarchical clustering of the DNA methylation data showed that these three cases of intracranial origin as a different cluster from spinal origin. The 45 grade 2 spinal ependymoma showed a relatively homogenous methylation pattern. However, the methylation status of HOX gene cluster regions is compatible with the segment of origin, which reflects the cells of origins are derived after the determination of segment identity. RNA sequencing of 57 cases revealed two subgroups within grade 2. Gene ontology analysis of differentially expressed genes suggested the difference in metabolic state such as rRNA translation and mitochondrial respiration between the two expression subgroups. CONCLUSION Epigenetic analysis indicated the accurate body segment origin of SP-EPN. We observed that metabolic states could divide grade 2 spinal cord ependymoma into 2 subgroups and will present the relationship to clinicopathological information.

Spinal extradural arteriovenous fistulas (AVFs) may be more difficult to prospectively identify than dural AVFs because they are less common than dural AVFs. The primary purpose was to further characterize the diagnostic imaging of spinal extradural AVFs with intradural retrograde venous drainage. The magnetic resonance (MR) imaging and angiographic results of 23 patients with suspected spinal dural AVFs were analyzed in order to distinguish dural and extradural AVFs. The diagnostic accuracy of MR angiography was retrospectively compared between dural and extradural AVFs. All 23 patients showed high intensity in the spinal cord on T2-weighted MR images. Eighteen out of 23 patients were diagnosed with dural AVFs, while the remaining 5 were diagnosed with extradural AVFs by angiography. Extradural AVFs were fed by a branch of the segmental artery to the vertebral body, characterized by a fistula located in the ventral extradural space, and drained retrogradely via an epidural venous pouch into intradural veins. The segmental artery was localized within 1 vertebral level using MRA in 12 out of 18 patients (67%) with dural AVFs and in 1 out of 5 patients (20%) with extradural AVFs (p=0.09). The reasons behind the lower accuracy was mainly the image misinterpretation. Congestion of the spinal cord in spinal extradural AVFs with intradural retrograde venous drainage was similar to that in dural AVFs, whereas its angioarchitecture differed from that of dural AVFs. A clearer understanding of the imaging features of extradural AVFs is important for improving the diagnostic accuracy and clarifying treatment targets.

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.

Successful resection of hemangioblastoma depends on preoperative assessment of the precise locations of feeding arteries and draining veins. Simultaneous 3D visualization of feeding arteries, draining veins, and surrounding structures is needed. The present study evaluated the usefulness of high-resolution 3D multifusion medical imaging (hr-3DMMI) for preoperative planning of hemangioblastoma. The hr-3DMMI combined MRI, MR angiography, thin-slice CT, and 3D rotated angiography. Surface rendering was mainly used for the creation of hr-3DMMI using multiple thresholds to create 3D models, and processing took approximately 3–5 hours. This hr-3DMMI technique was used in 5 patients for preoperative planning and the imaging findings were compared with the operative findings. Hr-3DMMI could simulate the whole 3D tumor as a unique sphere and show the precise penetration points of both feeding arteries and draining veins with the same spatial relationships as the original tumor. All feeding arteries and draining veins were found intraoperatively at the same position as estimated preoperatively, and were occluded as planned preoperatively. This hr-3DMMI technique could demonstrate the precise locations of feeding arteries and draining veins preoperatively and estimate the appropriate route for resection of the tumor. Hr-3DMMI is expected to be a very useful support tool for surgery of hemangioblastoma.

Background: The wall-to-lumen ratio (WLR) is an important parameter in vascular medicine because it indicates the character of vascular wall as well as the degree of stenosis. Despite the advances in medical imaging technologies, it is still difficult to measure the thin-walled normal intracranial arteries, and the reports on the WLR of normal intracranial artery are limited. It might be possible to calculate the WLR using the indocyanine green (ICG) angiography, which is used to observe intracranial vessels during microsurgery. Purpose: To evaluate the WLR of normal intracranial arteries using ICG angiography. Materials and Methods: From the three cases in which ICG angiography was recorded with a ruler during microsurgery, 20 measurement points were chosen for the analysis. The ICG was injected intravenously with a dose of 0.2 mg/kg, and the vessels were inspected at high magnification using an operating microscope equipped with near-infrared illumination system. The vessel outer diameter and the luminal diameter were measured using the images before and after the ICG arrival based on the pixel ratio method using a ruler as reference, respectively. The WLR was calculated as 0.5 × (vessel outer diameter − vessel luminal diameter). Results: The WLR (mean ± standard deviation) of normal intracranial arteries was 0.086 ± 0.022. The WLR tended to be high in small arteries. Conclusion: The WLR of normal intracranial arteries calculated using ICG angiography was consistent with the WLR reported in the previous reports based on human autopsy.

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.

Aiming to define the optimal treatment of large and giant aneurysms (LGAs) in the anterior circulation, we present our surgical protocol and patient outcome. A series of 42 patients with intracavernous LGAs (n = 16), paraclinoid (C2) LGAs (n = 17), and peripheral (middle cerebral artery—MCA or anterior cerebral artery—ACA) LGAs (n = 9) were treated after bypass under motor evoked potential (MEP) monitoring. Preoperatively, three categories of ischemic tolerance during internal carotid artery (ICA) occlusion were defined on conventional angiography: optimal, suboptimal, and insufficient collaterals. Accordingly, three types of bypass: low flow (LFB), middle flow (MFB) and high flow (HFB) were applied for the cases with optimal, suboptimal, and insufficient collaterals, respectively. Outcome was evaluated by the Glasgow Outcome Scale (GOS). All patients had excellent GOS score except one, who suffered a major ischemic stroke immediately after surgery for a paraclinoid lesion. Forty-one patients were followed up for 87.1 ± 40.1 months (range 13–144 months). Intracavernous LGAs were all treated by proximal occlusion with bypass surgery. Of paraclinoid LGA patients, 15 patients had direct clipping under suction decompression and other 2 patients with recurrent aneurysms had ICA (C2) proximal clipping with HFB. MEP monitoring guided for temporary clipping time and clip repositioning, observing significant MEP changes for up to 6 min duration. Of 9 peripheral LGAs patients 7 MCA LGAs had reconstructive clipping (n = 4) or trapping (n = 3) with bypass including LFB in 3 cases, MFB in 1 and HFB in 1. Two ACA LGAs had clipping (n = 1) or trapping (n = 1) with A3-A3 bypass. The applied protocol provided excellent results in intracavernous, paraclinoid, and peripheral thrombosed LGAs of the anterior circulation.

In vivo growth factor (GF) treatment is a promising approach to enhance the regenerative capacity of neural stem cells (NSCs) for brain repair. However, how exogenous GFs affect endogenous NSCs is not well understood. This study investigated the impact of intraventricular administration of fibroblast growth factor 2 and epidermal growth factor on NSCs in the subventricular zone of intact adult mice. GFs were administered for various periods (3, 7, 10, and 14 days), and the proliferation and neuronal production of NSCs were assessed during and after GF treatment. We found that proliferation of NSCs and their progeny is markedly augmented during the first 7 days after the initiation of GF treatment. GF treatment for longer periods, however, did not lead to further increases in the NSC pool, but rather attenuated such proliferation and inhibited neurogenesis. As a result, the production of new olfactory bulb neurons was increased in animals treated with GFs for 7 days but decreased in animals treated for 14 days. These results show time-dependent changes in the response of NSCs to exogenous GFs and demonstrate that precise control of the duration of GF treatment is important for significant enhancement of neuronal production by NSCs in vivo for brain repair.

Reelin-Dab1 signaling is involved in brain development and neuronal functions. The abnormalities in the signaling through either reduction of Reelin and Dab1 gene expressions or the genomic mutations in the brain have been reported to be associated with psychiatric disorders. However, it has not been clear if the deficiency in Reelin-Dab1 signaling is responsible for symptoms of the disorders. Here, to examine the function of Reelin-Dab1 signaling in the forebrain, we generated dorsal forebrain-specific Dab1 conditional knockout mouse (Dab1 cKO) and performed a behavioral test battery on the Dab1 cKO mice. Although conventional Dab1 null mutant mice exhibit cerebellar atrophy and cerebellar ataxia, the Dab1 cKO mice had normal cerebellum and showed no motor dysfunction. Dab1 cKO mice exhibited behavioral abnormalities, including hyperactivity, decreased anxiety-like behavior, and impairment of working memory, which are reminiscent of symptoms observed in patients with psychiatric disorders such as schizophrenia and bipolar disorder. These results suggest that deficiency of Reelin-Dab1 signal in the dorsal forebrain is involved in the pathogenesis of some symptoms of human psychiatric disorders.

White matter injury is an important cause of functional disability of the brain. We comprehensively analyzed a modified endothelin-1 (ET-1) injection-induced white matter injury model in the rat which is very valuable for investigating the underlying mechanisms of subcortical ischemic stroke. ET-1 was stereotactically injected into the internal capsule of the rat. To avoid complications with leakage of ET-1 into the lateral ventricle, the safest trajectory angle to the target was established. Rats with white matter injury were extensively evaluated for structural changes and functional sequelae, using motor function tests, magnetic resonance (MR) imaging, histopathology evolution, volume estimation of the lesion, and neuroanatomical identification of affected neurons using the retrograde tracer hydroxystilbamidine. Optimization of the trajectory of the ET-1 injection needle provided excellent survival rate. MR imaging visualized the white matter injury 2 days after surgery. Motor function deficit appeared temporarily after the operation. Histological studies confirmed damage of axons and myelin sheaths followed by inflammatory reaction and gliosis similar to lacunar infarction, with lesion volume of less than 1% of the whole brain. Hydroxystilbamidine injected into the lesion revealed wide spatial distribution of the affected neuronal population. Compared with prior ET 1 injection models, this method induced standardized amount of white matter damage and temporary motor function deficit in a reproducible and safe manner. The present model is valuable for studying the pathophysiology of not only ischemia, but a broader set of white matter damage conditions in the lissencephalic brain.

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.

Objective To present treatment strategies for spinal extradural arteriovenous fistulas (AVFs) in relation to angioarchitecture. Methods A retrospective analysis comprising 14 patients treated at 2 hospitals was performed. Results The 14 AVFs included 4 cervical, 1 thoracic, and 9 lumbosacral lesions. Three key angiographic features were observed: the feeding artery, an enlarged extradural venous plexus, and intradural retrograde venous drainage. In 3 patients (3 cervical AVFs) with compressive myelopathy owing to an enlarged venous plexus, the treatment goal was mass reduction of the venous plexus. Combined endovascular and microsurgical treatments may be curative for a large venous lake with multiple feeders. No intradural procedure was required because of the absence of intradural venous drainage. In contrast, in the other 11 patients (1 cervical, 1 thoracic, and 9 lumbosacral AVFs) with congestive myelopathy owing to intradural retrograde venous drainage, the goal of treatment was occlusion of the intradural proximal vein. Microsurgery or endovascular treatment may be curative by itself for a small venous pouch with a single intradural draining vein. Extradural procedures were not required in most patients treated by microsurgery because the extradural venous plexus was small. In all 14 patients, neurologic deficits improved or stabilized, and no recurrence was noted in the follow-up period (29 months). Conclusions Spinal extradural AVFs consist of 2 subtypes—type A with intradural drainage and type B without intradural drainage—characterized by regional differences at each spinal level in angioarchitecture, causes of myelopathy, and treatment goals.

Background Intracranial atherosclerosis (ICAS) involves diverse histologies and several remodeling patterns. Ring finger protein 213 (RNF213) c.14576G>A variant (rs112735431), recently reported to be associated with ICAS, may be linked with negative remodeling (outer diameter - reducing morphological alteration) of intracranial arteries. This study investigated the outer diameter of atherosclerotic middle cerebral artery (MCA). Methods Patients with unilateral atherosclerotic MCA stenosis/occlusion were enrolled in this single-hospital-based case-control study at The University of Tokyo Hospital. The patients were divided into two groups by the presence of RNF213 c.14576G>A (variant group and wild-type group) and the outer diameter of the MCA was measured with high-resolution magnetic resonance imaging. Results Twenty-eight patients with the wild type and 19 patients with the variant type were included. The outer diameter of the stenotic side MCA was smaller in the variant group than in the wild-type group (P = 8.3 × 10-6). The outer diameter of the normal side MCA was also smaller in the variant group than in the wild-type group (P = 5.2 × 10-3). The ratio of stenotic side to normal side was also smaller in the variant group than in the wild-type group (P = 1.5 × 10-5). Conclusions This study indicates that RNF213 c.14576G>A is associated with negative remodeling of ICAS.

Ring finger protein 213 (RNF213) has been reported to have association with various vascular diseases other than moyamoya disease (MMD). MMD-associated genetic variant RNF213 c.14576G>A had association with various degrees of intracranial major artery stenotic lesions including intracranial atherosclerosis (ICAS). RNF213 c.14576G>A could be the candidate genetic variant for this prevalence of ICAS in East Asian population. The presence of RNF213 c.14576G>A may associate with high blood pressure. Thus, RNF213 c.14576G>A could be a robust genetic risk indicator for ischemic stroke in East Asian population. RNF213 c.14576G>A may also have some association with quasi-MMD in East Asian population. Associations of RNF213 with fibromuscular dysplasia and intracranial aneurysm have also been reported in European population. These results indicate that RNF213 has a fundamental role in the pathophysiology of various vascular diseases.

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.

Summary:. 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.

Background and Purpose— Recently, we reported a common genetic variant, ring finger protein 213 ( RNF213 ) c.14576G>A variant, a susceptibility gene for moyamoya disease (MMD), among patients with intracranial major artery stenosis/occlusion (ICASO) in a selected Japanese population. The aim of this 2-center–based case–control study was to confirm our previous finding in a larger population. Methods— Study participants were recruited from The University of Tokyo Hospital and Kanto Neurosurgical Hospital. The occurrence rate of c.14576G>A variant was investigated in 323 patients, 22 with definite MMD, 8 with unilateral MMD, 84 with ICASO in the absence of MMD (non-MMD ICASO), 34 with extracranial carotid atherosclerosis, 44 with cerebral aneurysm, 21 with intracerebral hemorrhage, and 110 control subjects. Results— RNF213 c.14576G>A variant was found in 1.8% (2/110) of the normal control group and had significant associations with definite MMD ( P P =0.0001; odds ratio, 54.0; 95% confidence interval, 7.5–386.8), and non-MMD ICASO ( P Conclusions— A particular subset of patients with various phenotypes of ICASO has a common genetic variant, RNF213 c.14576G>A, indicating that RNF213 c.14576G>A variant is a high-risk allele for ICASO.

Background and Purpose— The frequency and pattern of symptomatic recurrence of spontaneous intracranial arterial dissection (IAD) are unknown. Methods— A follow-up study of 143 patients (85 men, 58 women; mean age, 50.7 [7–83] years) with spontaneous IADs at The University of Tokyo and affiliated hospitals from 1980 to 2000 was conducted. Tissue samples of IAD vessels obtained from 13 patients at various intervals from onset were also examined histologically. Results— With a mean follow-up of 8.2 years, symptomatic recurrence occurred in 47 patients (33%). Of 37 cases initially presenting with hemorrhage, 35 developed hemorrhagic recurrence with a mean interval of 4.8 days, and 2 developed nonhemorrhagic recurrences after 21 and 85 months, respectively. Of 10 patients initially presenting with nonhemorrhagic symptoms, 1 developed hemorrhagic recurrence 4 days later, and 9 developed nonhemorrhagic recurrences with a mean interval of 8.6 months. Histopathologically, the affected vessels in the acute stage of hemorrhage (days 0–6) demonstrated insufficient granulation formation within the pseudolumen, followed by marked intimal thickening around the pseudolumen and recanalizing vessel formation in the late stage (>day 30). In the late stage of brain ischemia, subintimal and subadventitial hemorrhage accompanied with intimal thickening was observed. Conclusions— These data indicate that IAD is a disease carrying a relatively high risk of symptomatic recurrence, apparently occurring in 3 phases and patterns: early hemorrhagic recurrence, late nonhemorrhagic recurrence, and chronic fusiform aneurysm transformation. Knowledge of this triphasic recurrence and corresponding histopathological characteristics help determine the treatment and follow-up strategy for IAD patients.

Background and Purpose— The c.14576G>A variant in ring finger protein 213 (RNF213) was recently identified as a susceptibility gene variant for moyamoya disease (MMD). The occurrence of c.14576G>A variant was evaluated in patients with intracranial major artery stenosis/occlusion (ICASO) without signs of MMD (non-MMD ICASO), as well as in patients with MMD and other cerebrovascular diseases as controls. Methods— This single-hospital–based case-control study was completed in 7 months (from October 2011–April 2012) at Department of Neurosurgery, The University of Tokyo Hospital. The occurrence of c.14576G>A variant was analyzed in 41 patients with non-MMD ICASO, in 48 with MMD, in 21 with cervical disease, in 61 with cerebral aneurysm, and in 25 normal subjects. Results— Nine of 41 patients (21.9%) with non-MMD ICASO and 41 of 48 (85.4%) with MMD had the c.14576G>A variant. One of 61 patients (1.6%) with cerebral aneurysm and no patients with cervical disease or normal subjects had the variant. Comparison of each phenotype group with the normal subjects showed that presence of c.14576G>A variant had significant associations with MMD (odds ratio [OR], 292.8; 95% confidence interval [CI], 15.4–5153.0; P Conclusions— The present study indicates that a particular subset of Japanese patients with non-MMD ICASO has a genetic variant associated with MMD. Therefore, we propose the existence of a new entity of ICASO caused by the c.14576G>A variant in RNF213.

Background Hemangioblastomas are hypervascular lesions and hence their surgical management is challenging. In particular, if complete resection is to be attained, all feeding and draining vessels must be occluded. Although most intramedullary spinal cord tumors are treated utilizing a posterior approach, we describe an anterior surgical strategy for resection of an intramedullary cervical hemangioblastoma. Case description A 36-year-old female with a spinal hemangioblastoma located in the anterior cervical spinal cord presented with a long-standing history of motor weakness of the right upper extremity. Magnetic resonance imaging revealed a large multilevel extensive syrinx and a focal intramedullary enhanced tumor at the C6 level. Angiography showed that the main feeder to the tumor was the left radicular artery (C8), which originated from the thyrocervical trunk, penetrated the dura mater, and branched both rostrally and caudally into the anterior spinal artery (ASA). Three-dimensional computer graphic images showed the tumor was located in the anterior part of the spinal cord, adjacent to and supplied by the ASA. The planned anterior surgical approach involved a total corpectomy of C6 and partial corpectomies of C5 and C7. The tumor was entirely removed despite multiple adhesions, and was successfully freed from the ASA. Patency of the ASA was confirmed utilizing intraoperative indocyanine green videoangiography. Intraoperatively, no monitoring changes were encountered. The pathological diagnosis was of a hemangioblastoma. No postoperative deficit occurred. Conclusions An anterior approach for the resection of an anteriorly located intramedullary spinal hemangioblastomas was successfully accomplished in this case.

Prenatal exposure of methylazoxymethanol acetate, a DNA methylating agent, to pregnant rats on embryonic day 15 is known to produce hippocampal malformation and laminar disorganization of the cerebral cortex. However, there are few studies to demonstrate developmental processes of abnormal structures in the hippocampus. In the present study, we examined complete serial sections of rat brains on postnatal day 0 to 2, which pretreated with methylazoxymethanol acetate on embryonic day 15. At birth, massive cellular clusters were found under the white matter of the cerebral cortex and then, a part of these clusters entered into the hippocampal CA1 sector on postnatal day 2. These ectopic cellular clusters in the CA1 were immunoreactive to anti-calbindin antibody, suggesting that the origin of these cellular clusters is equivalent to that of the cortical layer II/III neurons. Next, we injected FluoroGold into the lateral septal nucleus to examine hippocampo-septal projection. FluoroGold-labeled neurons were scattered in the ectopic cellular cluster, implying that CA1 pyramidal neurons project normally to the lateral septal nucleus. In conclusion, a majority of neurons found in the ectopic cellular cluster caused by prenatal methylazoxymethanol treatment is derived from cortical neurons, and some intrinsic pyramidal neurons in the CA1 of hippocampus are scattered throughout the ectopic cellular cluster.

Reactive oxygen species (ROS) are involved in several cell death processes, including cerebral ischemic injury. We found that glutamate-induced ROS accumulation and the associated cell death in mouse hippocampal cell lines were delayed by pharmacological inhibition of autophagy or lysosomal activity. Glutamate, however, did not stimulate autophagy, which was assessed by a protein marker, LC3, and neither changes in organization of mitochondria nor lysosomal membrane permeabilization were observed. Fluorescent analyses by a redox probe PF-H(2)TMRos revealed that autophagosomes and/or lysosomes are the major sites for basal ROS generation in addition to mitochondria. Treatments with inhibitors for autophagy and lysosomes decreased their basal ROS production and caused a burst of mitochondrial ROS to be delayed. On the other hand, attenuation of mitochondrial activity by serum depletion or by high cell density culture resulted in the loss of both constitutive ROS production and an ROS burst in mitochondria. Thus, constitutive ROS production within mitochondria and lysosomes enables cells to be susceptible to glutamate-induced oxidative cytotoxicity. Likewise, inhibitors for autophagy and lysosomes reduced neural cell death in an ischemia model in rats. We suggest that cell injury during periods of ischemia is regulated by ROS-generating activity in autophagosomes and/or lysosomes as well as in mitochondria.

Background and Purpose— Lacunar infarction accounts for 25% of ischemic strokes, but the pathological characteristics have not been investigated systematically. A new experimental model of lacunar infarction in the miniature pig was developed to investigate the pathophysiological changes in the corticospinal tract from the acute to chronic phases. Methods— Thirty-five miniature pigs underwent transcranial surgery for permanent anterior choroidal artery occlusion. Animals recovered for 24 hours (n=7), 2 (n=5), 3 (n=2), 4 (n=2), 6 (n=1), 7 (n=7), 8 (n=2), and 9 days (n=1), 2 weeks (n=2), 4 weeks (n=3), and more than 4 weeks (n=3). Neurology, electrophysiology, histology, and MRI were performed. Seven additional miniature pigs underwent transient anterior choroidal artery occlusion to study muscle motor-evoked potentials and evaluate corticospinal tract function during transient anterior choroidal artery occlusion. Results— The protocol had a 91.4% success rate in induction of internal capsule infarction 286±153 mm 3 (mean±SD). Motor-evoked potentials revealed the presence of penumbral tissue in the internal capsule after 6 to 15 minutes anterior choroidal artery occlusion. Total neurological deficit scores of 15.0 (95% CI, 13.5 to 16.4) and 3.4 (0.3 to 6.4) were recorded for permanent anterior choroidal artery occlusion and sham groups, respectively ( P P Conclusions— This new model of lacunar infarction induces a reproducible infarct in subcortical white matter with a measurable functional deficit and evidence of penumbral tissue acutely.

Increased calcium sensitization mediated by Rho/Rho-kinase may be important in the pathogenesis of cerebral vasospasm. The effects of a highly selective Rho-kinase inhibitor, Y-27632, were investigated on spasmogen-induced contractions of canine basilar artery.Typical spasmogenic substances present after subarachnoid hemorrhage (SAH), including prostaglandin F2a (PGF2a), 12-deoxyphorbol 13-isobutyrate (DPB), sphingosylpho-sphorylcholine (SPC) and high K+, were used in the study. Isometric tension was recorded in canine basilar artery rings in vitro. Intracellular calcium concentration ([Ca2+]i) and contraction force were measured simultaneously in fura-2-loaded canine basilar artery strips. The myosin light chain (MLC) phosphorylation levels were measured by glycerol gel electrophoresis followed by Western blotting.Isometric tension recording revealed that the Rho-kinase inhibitor, Y-27632, dose-dependently inhibited vasocontraction induced by PGF2a and SPC, but not that induced by DPB. Simultaneous recordings of [Ca2+]i and tension revealed that the vasorelaxing effect of Y-27632 was not associated with changes in [Ca2+]i, suggesting that Y-27632 may inhibit calcium sensitization. Vasocontraction induced by DPB was not inhibited by Y-27632, but was inhibited by staurosporine. Phosphorylation of MLC was increased by PGF2a and SPC, and significantly inhibited by Y-27632, whereas such phosphorylation was increased by DPB, but not significantly inhibited by Y-27632.Several spasmogenic mediators released after SAH may cause vasospasm through Rho-kinase-mediated increase in calcium sensitization. Rho-kinase inhibitors, including Y-27632, may be effective for the prevention of cerebral vasospasm after SAH.

We previously showed that transplantation of brain microvascular endothelial cells (MVECs) greatly stimulated remyelination in the white matter infarct of the internal capsule (IC) induced by endothelin-1 injection and improved the behavioral outcome. In the present study, we examined the effect of MVEC transplantation on the infarct volume using intermittent magnetic resonance image and on the behavior of oligodendrocyte lineage cells histochemically. Our results in vivo show that MVEC transplantation reduced the infarct volume in IC and apoptotic death of oligodendrocyte precursor cells (OPCs). These results indicate that MVECs have a survival effect on OPCs, and this effect might contribute to the recovery of the white matter infarct. The conditioned-medium from cultured MVECs reduced apoptosis of cultured OPCs, while the conditioned medium from cultured fibroblasts did not show such effect. These results suggest a possibility that transplanted MVECs increased the number of OPCs through the release of humoral factors that prevent their apoptotic death. Identification of such humoral factors may lead to the new therapeutic strategy against ischemic demyelinating diseases.

Background: De novo aneurysm formation after intracranial anastomotic surgery is a relatively rare complication with fewer than 20 reported cases, and the mechanism is still unclear. Case Description: A 63-year-old male treated for symptomatic internal carotid artery occlusion developed de novo aneurysms twice after anastomoses first of the superficial temporal artery-middle cerebral artery and second of the external carotid artery-radial artery-middle cerebral artery over a 10-year period. The first de novo aneurysm was successfully resected with pathological diagnosis of true aneurysm. The second de novo aneurysm thrombosed naturally after gradual growth. Genetic testing of the patient revealed the c.14576G>A (p.R4859K) variant in ring finger protein 213, which is a susceptibility gene for moyamoya disease. Conclusions: This genetic variant was probably involved in the repeated de novo aneurysm formation, and this case represents a rare phenotype of the genetic variant.

Dopamine plays a key role in the regulation of sleep–wake states, as revealed by the observation that dopamine-releasing agents such as methylphenidate have wake-promoting effects. However, the precise mechanisms for the wake-promoting effect produced by the enhancement of dopamine transmission are not fully understood. Although dopamine D1, D2, and D3 receptors are known to have differential effects on sleep architecture, the role of D4 receptors (D4Rs), and particularly the influence of D4R activation on the sleep–wake state, has not been studied so far. In this study, we investigated for the first time the effects of two structurally different D4R agonists, Ro 10-5824 and A-412997, on the sleep–wake states in rats. We found that both D4R agonists generally increased waking duration, and conversely, reduced non-rapid eye movement (NREM) sleep duration in rats. The onset of NREM sleep was also generally delayed. However, only the A-412997 agonist (but not the Ro 10-5824) influenced rapid eye movement sleep onset and duration. Furthermore, these effects were accompanied with an enhancement of EEG spectral power in the theta and the gamma bands. Our results suggest the involvement of dopamine D4R in the regulation of sleep–wake states. The activation of the D4R could enhance the arousal states as revealed by the behavioral and electrophysiological patterns in this study. Dopamine D4R may contribute to the arousal effects of dopamine-releasing agents such as methylphenidate.

Background and Purpose— To evaluate whether delayed treatment with the antiplatelet agent cilostazol reduces the volume of infarction in the gray and white matter in a rodent model of permanent focal cerebral ischemia and to explore the mechanism of the neuroprotective effect in vivo. Methods— Cilostazol (30 or 50 mg/kg) or vehicle was administered by gavage 30 minutes and 4 hours after the induction of cerebral ischemia by permanent occlusion of the left middle cerebral artery (MCA). Animals were euthanized 24 hours after MCA occlusion, and the volume of gray matter damage was evaluated by quantitative histopathology. Axonal damage was determined with amyloid precursor protein immunohistochemistry. Dynamic susceptibility contrast MRI was used to assess regional cerebral blood volume (CBV) and cerebral blood flow (CBF). Results— Treatment with the higher dose of cilostazol (50 mg/kg) significantly reduced the volume of gray matter damage and axonal damage in the cerebral hemisphere by 45.0% ( P P P Conclusions— Treatment with cilostazol significantly reduced the gray and white matter damage associated with permanent focal ischemia. Cilostazol improved CBV and CBF in the peri-infarct area. The major action of cilostazol is to increase perfusion in the ischemic penumbra.

Background: Cerebral vasospasm is one of the important pathological phenomena which influence morbidity and mortality following subarachnoid haemorrhage. Reactive oxygen species (ROSs) generated by the autoxidation of oxyhemoglobin to methemoglobin may be one of the essential factors in the pathogenesis of cerebral vasospasm. The direct vasocontractile effects of hydrogen peroxide (H2O2), superoxide anion (O2 −), and hydroxyl radical (*OH) on the canine basilar artery and the inhibitory effects of MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one), a new *OH scavenger, were investigated. Method: Isometric tension was recorded in basilar artery rings from dogs in vitro. H2O2, pyrogallol (O2 − donor), and vitamin C (VitC)/Fe2+ (*OH-generating system) were used to generate the ROSs. Findings: H2O2 (10 μmol/L), pyrogallol (10 μmol/L), and VitC/Fe2+ (100 μmol/L each) induced fast onset and transient, slow onset and transient, and sustained contraction, respectively, in the canine basilar artery. Contractions induced by H2O2 were almost completely inhibited by pre-incubation with catalase (800 U/mL) and those by pyrogallol with superoxide dismutase (150 U/mL), but neither with MCI-186 (10 μmol/L). The contraction induced by VitC/Fe2+ was clearly inhibited by pre-incubation with MCI-186, but not with catalase or superoxide dismutase. Interpretation: ROSs have direct vasocontractile effects on the canine basilar artery in vitro, but different ROSs have different contractile characteristics. Such contractions might be related to the pathophysiology of cerebral vasospasm. MCI-186 had a clear and selective inhibitory effect against *OH-induced contraction in vitro. Comparison of different radical scavengers may be important in pharmacological assessment, especially targeted on cerebral vasospasm.

Cell cycle proteins play key roles in cell survival or death under pathological conditions. Expression of growth arrest and DNA damage-inducible protein, GADD34 and proliferating cell nuclear antigen (PCNA) have been investigated in the core and peri-infarct zone at 2 and 24 h after middle cerebral artery occlusion (MCAO). At these times after MCAO, numerous GADD34-positive cells were present, particularly in the peri-infarct zone (e.g. 24 +/- 4 and 52 +/- 6 immunopositive cells/0.25 mm2 at 2 and 24 h, respectively, in cortex). PCNA-immunopositive cells were barely detectable in the peri-infarct zone at 2 h; however, numerous PCNA-immunopositive cells were present in this zone by 24 h (0.7 +/- 0.3 and 10.6 +/- 1.5 immunopositive cells/0.25 mm2, respectively) as well as in the adjacent cortex and in the contralateral cingulate cortex. Most GADD34-immunopositive cells coexpressed the neuronal marker Neu-N with a smaller number coexpressing the microglial marker, Mrf-1. Evidence of morphologically 'abnormal' and 'normal' GADD34 immunopositive neurons was found within the peri-infarct zone. The majority of PCNA immunopositive cells were Mrf-1 positive with a smaller number Neu-N positive. Double-labelling revealed colocalization of GADD34 and PCNA in some cells within the peri-infarct zone and in the ependymal cells lining the ventricles. The presence of GADD34 and PCNA in a key anatomical location pertinent to the evolving ischaemic lesion indicates that GADD34, either alone or in combination with PCNA, has the potential to influence cell survival in ischaemically compromised tissue.

The optimal surgical procedure (direct, indirect, or combined anastomosis) for management of moyamoya disease is still debated. We evaluated the outcome of our broad area revascularization protocol, the Tokyo Daigaku (The University of Tokyo) (TODAI) protocol, analyzing the relative importance of direct, indirect, and combination revascularization strategies to identify the optimal surgical protocol.The TODAI protocol was used to treat 65 patients with moyamoya disease (91 hemispheres, including 48 in 29 childhood cases collected during 1996-2012). The TODAI protocol combined direct superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis with indirect revascularization using encephalo-myo-synangiosis (EMS) for patients ≥10 years old or indirect revascularization using encephalo-duro-arterio-synangiosis (EDAS) with EMS for patients ≤9 years old. Clinical outcome was evaluated retrospectively. Digital subtraction angiography was performed for postoperative evaluation of revascularization in 47 patients (62 hemispheres; 27 adults and 35 children). Based on the relative contribution of additional flow from each revascularization path, 4 revascularization patterns were established.The mean follow-up period was 90 months in children and 72 months in adults. Perioperative complications were seen in 4 of 48 operations in children and 1 of 43 operations in adults. Except for 1 child with recurrent transient ischemic attacks and 1 adult with intracerebral hemorrhage, the patients showed excellent clinical outcomes. Postoperative digital subtraction angiography evaluation showed that in STA-MCA anastomosis + EMS cases (34 hemispheres; 25 adults and 9 children), STA-MCA anastomosis provided greater revascularization than EMS (STA-MCA anastomosisEMS) in 7 hemispheres, the opposite was true (STA-MCA anastomosisEMS) in 14 hemispheres, an equivalent contribution to revascularization (STA-MCA anastomosis ≈ EMS) was present in 12 hemispheres, and no functioning anastomosis was present in 1 hemisphere. In cases of EDAS + EMS (28 hemispheres; 2 adults and 26 children), all hemispheres showed revascularization: EDAS was dominant to EMS (EDASEMS) in 1 hemisphere, the opposite (EMSEDAS) was true in 14 hemispheres, and EDAS was equivalent to EMS (EDAS ≈ EMS) in 13 hemispheres. EMS plus direct or indirect anastomosis is an effective surgical procedure in adults and children.The TODAI protocol provided efficient revascularization and yielded excellent results in preventing strokes in patients with moyamoya disease with very few complications. EMS had a main role in revascularization in each of the combined techniques.

Background Quasi-moyamoya disease (MMD) and MMD (definite MMD) have similar cerebral angiographic features, but whether these related diseases have similar etiology or genetic background remains unclear. Recently, we have reported that the recently identified MMD susceptibility gene variant RNF213 c.14576G>A (rs112735431) was associated with atherosclerotic intracranial major artery stenosis/occlusion. The present study investigated the occurrence of RNF 213 c.14576G>A in patients with nonatherosclerotic quasi-MMD. Methods This study was a 2-hospital–based case–control study conducted at the Department of Neurosurgery, The University of Tokyo Hospital and Kanto Neurosurgical Hospital. A total of 87 Japanese patients who agreed to participate in this study were enrolled among both new and revisiting outpatients from October 2011 to December 2013 as follows: 78 patients with definite MMD and 9 patients with nonatherosclerotic quasi-MMD. Results The 9 patients with nonatherosclerotic quasi-MMD included 3 patients with previous irradiation, 2 with hyperthyroidism, 1 with Turner syndrome, 1 with meningitis, 1 with Behcet disease, and 1 with idiopathic pachymeningitis. The 78 patients with definite MMD included 66 patients (84.6%) with the c.14576G>A variant (64 heterozygotes and 2 homozygous). In contrast, no patients with nonatherosclerotic quasi-MMD had the variant. Conclusions Nonatherosclerotic quasi-MMD did not have RNF213 c.14576G>A variant. Moyamoya disease and related diseases might be classified by genetic analysis of the RNF213 c.14576G>A genotype. Further larger studies are required to confirm the present findings.

Here, we present a case of a 55-year-old woman with a 10-year history of hemifacial spasm accompanied by 1-month ipsilateral paroxysmal otalgia. Magnetic resonance imaging revealed the presence of vessels around the facial nerve root. Surgical exploration via suboccipital retromastoid craniotomy showed converging compression of the facial nerve root and intermediate nerve from both sides by an anterior inferior cerebellar artery loop. The patient's hemifacial spasm and ipsilateral otalgia were completely relieved after microvascular decompression of the facial nerve root and intermediate nerve. Intraoperative findings and the postoperative result of this case confirmed that vascular compression of the intermediate nerve was the exclusive cause of paroxysmal otalgia. The presence of ipsilateral hemifacial spasm, combined with preoperative neuroimaging studies, contributed to the diagnosis of intermediate nerve neuralgia. Microvascular decompression should be considered for the management of patients with intermediate nerve neuralgia.