2018年10月, 伊藤太郎学術賞　　　　　　　　　　　　　　　

2017年10月, 斎藤眞賞　　　　　　　　　　　　　　　
寳金 清博

2013年02月, 公益信託美原脳血管障害研究振興基金, 美原賞　　　　　　　　　　　　　　　
宝金 清博

2007年09月, 北海道医師会賞・北海道知事賞　　　　　　　　　　　　　　　
寳金 清博

1999年04月, 日本脳卒中の外科学会賞（鈴木賞）　　　　　　　　　　　　　　　

1993年12月, 第22回かなえ医学奨励賞　　　　　　　　　　　　　　　

Intracerebral transplantation of MRI-trackable autologous bone marrow stromal cells for patients with subacute ischemic stroke.
Masahito Kawabori, Satoshi Kuroda, Hideo Shichinohe, Kaoru Kahata, Souichi Shiratori, Satoshi Ikeda, Taisuke Harada, Kenji Hirata, Khin Khin Tha, Masato Aragaki, Shunsuke Terasaka, Yoichi M Ito, Naoki Nishimoto, Shunsuke Ohnishi, Ichiro Yabe, Kohsuke Kudo, Kiyohiro Houkin, Miki Fujimura
Med (New York, N.Y.), 2024年03月18日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Ischemic stroke is one of the leading causes of death and neurological disability worldwide, and stem cell therapy is highly expected to reverse the sequelae. This phase 1/2, first-in-human study evaluated the safety, feasibility, and monitoring of an intracerebral-transplanted magnetic resonance imaging (MRI)-trackable autologous bone marrow stromal cell (HUNS001-01) for patients with subacute ischemic stroke. METHODS: The study included adults with severe disability due to ischemic stroke. HUNS001-01 cultured with human platelet lysates and labeled with superparamagnetic iron oxide was stereotactically transplanted into the peri-infarct area 47-64 days after ischemic stroke onset (dose: 2 or 5 × 107 cells). Neurological and radiographic evaluations were performed throughout 1 year after cell transplantation. The trial was registered at UMIN Clinical Trial Registry (number UMIN000026130). FINDINGS: All seven patients who met the inclusion criteria successfully achieved cell expansion, underwent intracerebral transplantation, and completed 1 year of follow-up. No product-related adverse events were observed. The median National Institutes of Health Stroke Scale and modified Rankin scale scores before transplantation were 13 and 4, which showed improvements of 1-8 and 0-2, respectively. Cell tracking proved that the engrafted cells migrated toward the infarction border area 1-6 months after transplantation, and the quantitative susceptibility mapping revealed that cell signals at the migrated area constantly increased throughout the follow-up period up to 34% of that of the initial transplanted site. CONCLUSIONS: Intracerebral transplantation of HUNS001-01 was safe and well tolerated. Cell tracking shed light on the therapeutic mechanisms of intracerebral transplantation. FUNDING: This work was supported by the Japan Agency for Medical Research and Development (AMED; JP17bk0104045 and JP20bk0104011).

Posterior cerebral artery involvement in unilateral moyamoya disease is exclusively ipsilateral and influenced by RNF213 mutation gene dose: The SUPRA Japan study: PCA involvement in unilateral moyamoya.
Yohei Mineharu, Yasushi Takagi, Akio Koizumi, Takaaki Morimoto, Takeshi Funaki, Tomohito Hishikawa, Yoshio Araki, Hitoshi Hasegawa, Jun C Takahashi, Satoshi Kuroda, Kiyohiro Houkin, Susumu Miyamoto
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 33, 2, 107513, 107513, 2024年02月, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: The characteristics and clinical implications of posterior cerebral artery (PCA) involvement in unilateral moyamoya disease (U-MMD), such as laterality, frequency of the RNF213 p.R4810K mutation, and clinical outcomes, have not been well studied. POPULATION AND METHODS: We analyzed a cohort of 93 patients with U-MMD who participated in the SUPRA Japan study. Clinical characteristics and radiological examinations were collected from medical records. The presence of the p.R4810K mutation was determined using a TaqMan assay. The clinical outcome was assessed using the modified Rankin Scale (mRS). Univariate and multivariate logistic regression analyses were performed to assess the associations. RESULTS: Among the patients with U-MMD, PCA involvement was observed in 60.0 % (3/5) of patients with homozygous mutation, 11.3 % (7/62) of those with heterozygous mutation, and 3.8 % (1/26) of those with wild type, showing a significant linear trend (p < 0.001 for trend). PCA involvement was observed exclusively on the same side as the affected anterior circulation. Dyslipidemia and cerebral infarction at initial onset were independently associated with mRS ≥1. Hypertension was associated with mRS ≥1 and it was also linked to infarction at initial onset, suggesting a potential confounding effect. Although PCA involvement showed a trend for higher mRS, it was not statistically significant. CONCLUSIONS: Our findings indicate a gene dose effect of the p.R4810K mutation on PCA involvement, with the homozygous state showing the most significant effect. Both genetic and modifiable factors such as dyslipidemia may influence the progression of U-MMD.

Allogeneic Stem Cell Therapy for Acute Ischemic Stroke
Kiyohiro Houkin, Toshiya Osanai, Shinichiro Uchiyama, Kazuo Minematsu, Akihiko Taguchi, Katsuhiko Maruichi, Yoshimasa Niiya, Katsuyuki Asaoka, Yoshihiro Kuga, Katsumi Takizawa, Koichi Haraguchi, Shinichi Yoshimura, Kazumi Kimura, Koji Tokunaga, Atsuo Aoyama, Fusao Ikawa, Chikanori Inenaga, Tatsuya Abe, Atsushi Tominaga, Shinichi Takahashi, Kohsuke Kudo, Miki Fujimura, Taku Sugiyama, Masaki Ito, Masahito Kawabori, David C. Hess, Sean I. Savitz, Teruyuki Hirano, Kiyohiro Houkin, Toshiya Osanai, Katsuhiko Maruichi, Yoshimasa Niiya, Katsuyuki Asaoka, Katsumi Takizawa, Kouichi Haraguchi, Rokuya Tanikawa, Akira Tempaku, Yusuke Shimoda, Masanori Isobe, Kenji Kamiyama, Masafumi Ohtaki, Norihito Shimamura, Junta Moroi, Aiki Marushima, Shinichi Takahashi, Takao Urabe, Teruyuki Hirano, Kazumi Kimura, Kazuo Kitagawa, Hidetoshi Kasuya, Yoshikane Izawa, Yasuyuki Iguchi, Koichi Oki, Koichi Kato, Yoshihisa Yamano, Satoshi Kuroda, Atsushi Sato, Chikanori Inenaga, Keizo Yasui, Kazunori Toyoda, Shinichi Yoshimura, Nobuyuki Sakai, Yoshihiro Kuga, Atsuo Aoyama, Fusao Ikawa, Koji Tokunaga, Atsushi Tominaga, Yasushi Takagi, Masahiro Yasaka, Tatsuya Abe, Takayuki Matsuo, Toshiro Yonehara, Tadashi Terasaki, Hideki Matsuoka
JAMA Neurology, American Medical Association (AMA), 2024年01月16日
研究論文（学術雑誌）, Importance

Cell therapy is a promising treatment approach for stroke and other diseases. However, it is unknown whether MultiStem (HLCM051), a bone marrow–derived, allogeneic, multipotent adult progenitor cell product, has the potential to treat ischemic stroke.

Objective

To assess the efficacy and safety of MultiStem when administered within 18 to 36 hours of ischemic stroke onset.

Design, Setting, and Participants

The Treatment Evaluation of Acute Stroke Using Regenerative Cells (TREASURE) multicenter, double-blind, parallel-group, placebo-controlled phase 2/3 randomized clinical trial was conducted at 44 academic and clinical centers in Japan between November 15, 2017, and March 29, 2022. Inclusion criteria were age 20 years or older, presence of acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 8-20 at baseline), confirmed acute infarction involving the cerebral cortex and measuring more than 2 cm on the major axis (determined with diffusion-weighted magnetic resonance imaging), and a modified Rankin Scale (mRS) score of 0 or 1 before stroke onset. Data analysis was performed between May 9 and August 15, 2022.

Exposure

Patients were randomly assigned to either intravenous MultiStem in 1 single unit of 1.2 billion cells or intravenous placebo within 18 to 36 hours of ischemic stroke onset.

Main Outcomes and Measures

The primary end points were safety and excellent outcome at day 90, measured as a composite of a modified Rankin Scale (mRS) score of 1 or less, a NIHSS score of 1 or less, and a Barthel index score of 95 or greater. The secondary end points were excellent outcome at day 365, mRS score distribution at days 90 and 365, and mRS score of 0 to 1 and 0 to 2 at day 90. Statistical analysis of efficacy was performed using the Cochran-Mantel-Haenszel test.

Results

This study included 206 patients (104 received MultiStem and 102 received placebo). Their mean age was 76.5 (range, 35-95) years, and more than half of patients were men (112 [54.4%]). There were no between-group differences in primary and secondary end points. The proportion of excellent outcomes at day 90 did not differ significantly between the MultiStem and placebo groups (12 [11.5%] vs 10 [9.8%], P = .90; adjusted risk difference, 0.5% [95% CI, −7.3% to 8.3%]). The frequency of adverse events was similar between treatment groups.

Conclusions and Relevance

In this randomized clinical trial, intravenous administration of allogeneic cell therapy within 18 to 36 hours of ischemic stroke onset was safe but did not improve short-term outcomes. Further research is needed to determine whether MultiStem therapy for ischemic stroke has a beneficial effect in patients who meet specific criteria, as indicated by the exploratory analyses in this study.

Trial Registration

ClinicalTrials.gov Identifier: NCT02961504

A validation study for wide-range remote assessment of cognitive functions in the healthy older Japanese population: a pilot randomised crossover trial.
Yuki Takakura, Mika Otsuki, Ryo Takagi, Kiyohiro Houkin
BMC geriatrics, 23, 1, 575, 575, 2023年09月19日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The assessment of a wide range of cognitive functions using video teleconference (VTC) systems cannot be applied in practice yet. We aimed to determine the feasibility and reliability of previously unvalidated remote cognitive function tests in Japan using common information and communication technology (ICT) devices, software, and VTC systems compared with face-to-face (FTF) assessment. METHODS: The sample consisted of 26 participants from senior citizens clubs and an employment service centre in Sapporo Japan, including 11 females and 15 males (age averaged 78.6 ± 6.8 years). Tests included the RCPM, Story recall, 10/36 spatial recall, selective reminding test, SDMT, PASAT, FAB, TMT-A, TMT-B, visual cancellation task, digit span, tapping span. The experimental design was a counterbalanced crossover randomised controlled trial. Intraclass correlations (ICCs), paired-samples t-tests, Cohen's Kappa (κ) coefficients, and Wilcoxon signed-rank test were calculated to compare the scores between VTC and FTF assessments. RESULTS: All ICCs were significant and ranged from 0.47 (RCPM time) to 0.92 (RCPM score and PASAT), with a mean ICC of 0.75. Digit span using Cohen's Kappa (κ) coefficient was significant, but the tapping span was not. Paired samples t-test showed statistically significant differences in SDMT, RCPM time, and cancellation time. CONCLUSIONS: The results suggest that remote video conference-based neuropsychological tests even using familiar devices and software may be able to assess a wide range of cognitive functions in the Japanese older population. As for the processing speed tasks, we need to create our own standards for the remote condition. For the tapping span, we should consider increasing the number of trials.

Dual Antiplatelet Therapy With Cilostazol for Secondary Prevention in Lacunar Stroke: Subanalysis of the CSPS.com Trial.
Yasuhiro Nishiyama, Kazumi Kimura, Toshiaki Otsuka, Kazunori Toyoda, Shinichiro Uchiyama, Haruhiko Hoshino, Nobuyuki Sakai, Yasushi Okada, Hideki Origasa, Hiroaki Naritomi, Kiyohiro Houkin, Keiji Yamaguchi, Kazuo Minematsu, Masayasu Matsumoto, Teiji Tominaga, Hidekazu Tomimoto, Yasuo Terayama, Satoshi Yasuda, Takenori Yamaguchi
Stroke, 54, 3, 697, 705, 2023年03月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The effectiveness of long-term dual antiplatelet therapy (DAPT) to prevent recurrent strokes in patients with lacunar stroke remains unclarified. Therefore, this study aimed to compare and to elucidate the safety and effectiveness of DAPT and single antiplatelet therapy (SAPT) in preventing recurrence in chronic lacunar stroke. METHODS: CSPS.com (Cilostazol Stroke Prevention Study for Antiplatelet Combination) was a prospective, multicenter, randomized controlled trial. In this prespecified subanalysis, 925 patients (mean age, 69.5 years; 69.4% men) with lacunar stroke were selected from 1884 patients with high-risk noncardioembolic stroke, enrolled in the CSPS.com trial after 8 to 180 days following stroke. Patients were randomly assigned to receive either SAPT or DAPT using cilostazol and were followed for 0.5 to 3.5 years. The primary efficacy outcome was the first recurrence of ischemic stroke. The safety outcomes were severe or life-threatening bleeding. RESULTS: The DAPT group receiving cilostazol and either aspirin or clopidogrel and SAPT group receiving aspirin or clopidogrel alone comprised 464 (50.2%) and 461 (49.8%) patients, respectively. Ischemic stroke occurred in 12 of 464 patients (1.84 per 100 patient-years) in the DAPT group and 31 of 461 patients (4.42 per 100 patient-years) in the SAPT group, during follow-up. After adjusting for multiple potential confounding factors, ischemic stroke risk was significantly lower in the DAPT group than in the SAPT group (hazard ratio, 0.43 [95% CI, 0.22-0.84]). The rate of severe or life-threatening hemorrhage did not differ significantly between the groups (2 patients [0.31 per 100 patient-years] versus 6 patients [0.86 per 100 patient-years] in the DAPT and SAPT groups, respectively; hazard ratio, 0.36 [95% CI, 0.07-1.81]). CONCLUSIONS: In patients with lacunar stroke, DAPT using cilostazol had significant benefits in reducing recurrent ischemic stroke incidence compared with SAPT without increasing the risk of severe or life-threatening bleeding. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000012180.

Cost-effectiveness of seven-days-per-week rehabilitation schedule for acute stroke patients.
Yasuhiro Morii, Kagari Abiko, Toshiya Osanai, Jiro Takami, Takumi Tanikawa, Kensuke Fujiwara, Kiyohiro Houkin, Katsuhiko Ogasawara
Cost effectiveness and resource allocation : C/E, 21, 1, 12, 12, 2023年02月01日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Rehabilitation is an essential medical service for patients who have suffered acute stroke. Although the effectiveness of 7-days-per-week rehabilitation schedule has been studied in comparison with 5- or 6-days-per-week rehabilitation schedule, its cost-effectiveness has not been analyzed. In this research, to help formulate more cost-effective medical treatments for acute stroke patients, we analyzed the cost-effectiveness of 7-days-per-week rehabilitation for acute stroke from public health payer's perspective, and public healthcare and long-term care payer's perspective in Japan. METHODS: Cost-effectiveness of 7-days-per-week rehabilitation for acute stroke patients was analyzed based on the result from a previous study using a Japanese database examining the efficacy of 7-days-per-week rehabilitation. Cost utility analysis was conducted by comparing 7-days-per-week rehabilitation with 5- or 6-days-per-week rehabilitation, with its main outcome incremental cost-effectiveness ratio (ICER) calculated by dividing estimated incremental medical and long-term care costs by incremental quality-adjusted life years (QALY). The costs were estimated using the Japanese fee table and from published sources. The time horizon was 5 years, and Markov modeling was used for the analysis. RESULTS: The ICER was $6339/QALY from public health payer's perspective, lower than 5,000,000 Yen/QALY (approximately US$37,913), which was the willingness-to-pay used for the cost-effectiveness evaluation in Japan. The 7-day-per-week rehabilitation was dominant from public healthcare and long-term care payer's perspective. The result of sensitivity analysis confirmed the results. CONCLUSION: The results indicated that 7-days-per-week rehabilitation for acute stroke rehabilitation was likely to be cost-effective.

高齢者における脳トレアプリの効果的な使用条件の検討 PROBE法での無作為化比較試験
高倉 祐樹, 大槻 美佳, 高木 諒, 寳金 清博
老年精神医学雑誌, 33, 増刊II, 356, 356, (株)ワールドプランニング, 2022年11月
日本語

高齢者における脳トレアプリの効果的な使用条件の検討 PROBE法での無作為化比較試験　　　　　　　　　　　　　　　
高倉 祐樹, 大槻 美佳, 高木 諒, 寳金 清博
Dementia Japan, 36, 4, 802, 802, (一社)日本認知症学会, 2022年10月
日本語

Impact of RNF213 c.14576G>A Variant on the Development of Direct and Indirect Revascularization in Pediatric Moyamoya Disease
Masahito Kawabori, Masaki Ito, Ken Kazumata, Kikutaro Tokairin, Kanako C. Hatanaka, Susumu Ishikawa, Kiyohiro Houkin, Miki Fujimura
Cerebrovascular Diseases, 52, 2, 171, 176, S. Karger AG, 2022年09月05日
研究論文（学術雑誌）, Background: Superficial temporal artery (direct) and encephalomyosynangiosis (indirect) revascularization may develop after combined bypass surgery in pediatric patients with moyamoya disease (MMD). However, arterial development varies widely among patients, and the underlying mechanisms remain unknown. Objectives: We evaluated the relationship between the development of donor arteries after bypass surgery in pediatric patients with MMD and the MMD-susceptibility gene variant c.14576G>A of ring finger protein (RNF) 213. Methods: The data of pediatric patients with MMD (age <16 years at the time of surgery) treated with combined bypass surgery between September 2013 and April 2019 were consecutively analyzed. Quantitative measurements of the superficial temporal artery (STA), deep temporal artery (DTA), and middle meningeal artery (MMA) diameters with magnetic resonance angiography (MRA) source imaging were performed preoperatively and at 6–12 months postoperatively. The postoperative caliber change ratios (CCRs) were calculated. The relationship between CCRs and RNF213 c.14576G>A status was examined. Results: Forty-eight hemispheres from 28 pediatric patients with MMD were examined. Three hemispheres belonged to patients with the AA genotype; 33 to patients with the AG genotype (AA/AG group); and 12 to patients with the GG genotype (GG group; wild type). The CCRs for the DTA were significantly higher in patients with RNF213 variant (AA/AG group; 2.5 ± 0.1) than in the GG group (2.0 ± 0.2) (p = 0.03), whereas the CCRs for the STA were significantly higher in the GG (1.6 ± 0.1) than in the AA/AG group (1.3 ± 0.6) (p = 0.02). There was no significant difference in the CCRs for the MMA and basilar artery between the groups. Other factors, including sex, age, and MRA grading, were not associated with the development of specific bypass development. Conclusions: The extent of collateral development associated with direct or indirect bypass was found to differ between the genotypes of the RNF213 c.14576G>A associated with pediatric MMD. This genetic variant correlates with the development of the disease and affects revascularization after bypass surgery in pediatric patients with MMD.

脳深部刺激療法術後4年の経過に関する12例の検討　　　　　　　　　　　　　　　
白井 慎一, 江口 克紀, 山崎 和義, 松島 理明, 加納 崇裕, 笹森 徹, 平田 健司, 大槻 美佳, 北川 まゆみ, 寳金 清博, 佐々木 秀直, 藤村 幹, 矢部 一郎
パーキンソン病・運動障害疾患コングレスプログラム・抄録集, 16回, 80, 80, Movement Disorder Society of Japan (MDSJ), 2022年07月
日本語

脳深部刺激療法術後4年の経過に関する12例の検討　　　　　　　　　　　　　　　
白井 慎一, 江口 克紀, 山崎 和義, 松島 理明, 加納 崇裕, 笹森 徹, 平田 健司, 大槻 美佳, 北川 まゆみ, 寳金 清博, 佐々木 秀直, 藤村 幹, 矢部 一郎
パーキンソン病・運動障害疾患コングレスプログラム・抄録集, 16回, 80, 80, Movement Disorder Society of Japan (MDSJ), 2022年07月
日本語

Analysis of induced pluripotent stem cell clones derived from a patient with mosaic neurofibromatosis type 2.
Yukitomo Ishi, Takumi Era, Sayaka Yuzawa, Michinari Okamoto, Ryosuke Sawaya, Hiroaki Motegi, Shigeru Yamaguchi, Shunsuke Terasaka, Kiyohiro Houkin, Miki Fujimura
American journal of medical genetics. Part A, 2022年02月18日, ［国際誌］
英語, The diagnosis of mosaicism is challenging in patients with neurofibromatosis type 2 (NF2) subset due to low variant allele frequency. In this study, we generated induced pluripotent stem cells (iPSCs) were generated from a patient clinically diagnosed with NF2 based on multiple schwannomas, including bilateral vestibular schwannomas and meningiomas. Genetic analysis of the patient's mononuclear cells (MNCs) from peripheral blood failed to detect NF2 alteration but successfully found p.Q65X (c.193C>T) mutation in all separate tumors with three intracranial meningiomas and one intraorbital schwannoma, and confirming mosaicism diagnosis in NF2 alteration using deep sequencing. Five different clones with patient-derived iPSCs were established from MNCs in peripheral blood, which showed sufficient expression of pluripotent markers. Genetic analysis showed that one of five generated iPSC lines from MNCs had the same p.Q65X mutation as that found in NF2. There was no significant difference in the expression of genes related to NF2 between iPSC clones with the wild-type and mutant NF2. In this case, clonal expansion of mononuclear bone marrow-derived stem cells recapitulated mosaicism's genetic alteration in NF2. Patient-derived iPSCs from mosaic NF2 would contribute to further functional research of NF2 alteration.

Impact of RNF213 founder polymorphism (p.R4810K) on the postoperative development of indirect pial synangiosis after direct/indirect combined revascularization surgery for adult Moyamoya disease.
Masaki Ito, Masahito Kawabori, Taku Sugiyama, Kikutaro Tokairin, Ryota Tatezawa, Haruto Uchino, Ken Kazumata, Kiyohiro Houkin, Miki Fujimura
Neurosurgical review, 45, 3, 2305, 2313, 2022年02月07日, ［国際誌］
英語, 研究論文（学術雑誌）, Direct superficial temporal artery (STA) to middle cerebral artery (MCA) anastomosis combined with indirect pial synangiosis provides favorable surgical collaterals for Moyamoya disease (MMD), especially in adults; however, factors leading to the development of each direct and indirect collateral are not well documented.We aimed to investigate the association between RNF213 founder polymorphism (p.R4810K) and each direct and indirect collateral development. By qualitative and quantitative evaluations of direct and indirect surgical collaterals using time-of-flight MR angiography, postoperative development of each type of bypass was evaluated independently into two categories. Multivariate logistic regression analysis was performed to study the contributing factors for the development of each surgical collateral. Excellent development of postoperative direct and indirect bypass was observed in 65 hemispheres (70%) by qualitative evaluation, which was confirmed by quantitative evaluation. Multivariate logistic regression analysis of excellent indirect bypass development revealed a significant positive correlation with the p.R4810K (odds ratio, OR4.0; 95%-confidence interval, CI 1.2-16), advanced MR angiographic stage (OR9.5; 95%CI 1.7-73), and preoperative middle meningeal artery caliber (OR6.8; 95%CI 1.8-35), but a significant negative correlation was found with the excellent direct bypass development (OR0.17; 95%CI 0.03-0.75). No significant correlation was observed between excellent direct bypass development and the p.R4810K (OR0.95; 95%CI 0.37-2.4).In conclusion, excellent development of indirect collaterals after STA-MCA anastomosis combined with indirect pial synangiosis occurs more frequently in adult MMD with the RNF213 founder polymorphism, suggesting a role of the p.R4810K variant for marked in-growth of indirect collaterals and the utility of preoperative genetic analysis.

Cystic Intracranial Recurrence of Olfactory Neuroblastoma without Accumulation on Fluorine-18-fluorodeoxyglucose Positron Emission Tomography.
Yukitomo Ishi, Shigeru Yamaguchi, Kanako C Hatanaka, Emi Takakuwa, Hiroaki Motegi, Taishi Honda, Hiroyuki Kobayashi, Shunsuke Terasaka, Akihiro Homma, Miki Fujimura, Kiyohiro Houkin
Acta medica Okayama, 76, 1, 93, 98, 2022年02月, ［国内誌］
英語, A 66-year-old man underwent multimodal treatment for olfactory neuroblastoma (ONB). When he was 72 years old, a cystic intracranial lesion without accumulation on fluorine-18-fluorodeoxyglucose positron emission tomography was detected. Surgical resection was performed when the patient was 73 years old. The pathological examination revealed recurrence of ONB, and the patient underwent focal irradiation. At age 81, he presented with a second recurrence in the right occipital lobe with radiological and pathological findings similar to the prior recurrence. This case suggests that pathological confirmation should be considered in cases with atypical radiological findings following the treatment of ONB.

Intravenous transplantation of amnion-derived mesenchymal stem cells promotes functional recovery and alleviates intestinal dysfunction after spinal cord injury.
Soichiro Takamiya, Masahito Kawabori, Kazuyoshi Yamazaki, Sho Yamaguchi, Aki Tanimori, Koji Yamamoto, Shunsuke Ohnishi, Toshitaka Seki, Kotaro Konno, Khin Khin Tha, Daigo Hashimoto, Masahiko Watanabe, Kiyohiro Houkin, Miki Fujimura
PloS one, 17, 7, e0270606, 2022年, ［国際誌］
英語, 研究論文（学術雑誌）, Spinal cord injury (SCI) is often accompanied by gastrointestinal dysfunction due to the disconnection of the spinal autonomic nervous system. Gastrointestinal dysfunction reportedly upregulates intestinal permeability, leading to bacterial translocation of the gut microbiome to the systemic circulation, which further activates systemic inflammation, exacerbating neuronal damage. Mesenchymal stem cells (MSC) reportedly ameliorate SCI. Here, we aimed to investigate their effect on the associated gastrointestinal dysfunction. Human amnion-derived MSC (AMSCs) were intravenously transplanted one day after a rat model of midthoracic SCI. Biodistribution of transplanted cells, behavioral assessment, and histological evaluations of the spinal cord and intestine were conducted to elucidate the therapeutic effect of AMSCs. Bacterial translocation of the gut microbiome was examined by in situ hybridization and bacterial culture of the liver. Systemic inflammations were examined by blood cytokines, infiltrating immune cells in the spinal cord, and the size of the peripheral immune tissue. AMSCs released various neurotrophic factors and were mainly distributed in the liver and lung after transplantation. AMSC-transplanted animals showed smaller spinal damage and better neurological recovery with preserved neuronal tract. AMSCs transplantation ameliorated intestinal dysfunction both morphologically and functionally, which prevented translocation of the gut microbiome to the systemic circulation. Systemic inflammations were decreased in animals receiving AMSCs in the chronic phase. Intravenous AMSC administration during the acute phase of SCI rescues both spinal damage and intestinal dysfunction. Reducing bacterial translocation may contribute to decreasing systemic inflammation.

The prognostic improvement of add-on bevacizumab for progressive disease during concomitant temozolomide and radiation therapy in patients with glioblastoma and anaplastic astrocytoma
Shigeru Yamaguchi, Yukitomo Ishi, Hiroaki Motegi, Michinari Okamoto, Hiroyuki Kobayashi, Kenji Hirata, Yoshitaka Oda, Shinya Tanaka, Shunsuke Terasaka, Kiyohiro Houkin
Journal of Neurosurgical Sciences, 64, 6, 502, 508, Edizioni Minerva Medica, 2021年12月01日
英語, 研究論文（学術雑誌）, BACKGROUND: Although newly diagnosed high-grade glioma patients in Japan can receive bevacizumab (BEV) as first-line chemotherapy, randomized clinical trials have not shown a survival benefit for BEV for these patients. In this study, we investigated whether selective add-on BEV for patients with newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA) improves prognosis, in cases where tumors were continuously growing during radiotherapy concomitant with temozolomide (TMZ). METHODS: We conducted a retrospective survey of the overall survival (OS) of patients with GBM/AAs who were treated in our institution between 2006 and 2016. Patients whose tumors were continuously growing regardless of radiotherapy were categorized as the "progressive"group
remaining patients were categorized as the "non-progressive"group. Since 2013, patients in the "progressive"group received add-on BEV therapy with the Stupp regimen during or just after radiotherapy. RESULTS: Of 151 GBM/AApatients, 34 (22.5%) were categorized in the "progressive"group. Median OSs of the "progressive"and "non-progressive"groups were 13.2 months and 25.3 months, respectively (P<
0.001). Twelve patients in the "progressive"group received add-on BEV therapy, and their median OSwas 20.2 months
whereas for the remaining 22 patients in the "progressive"group who were treated before the BEV era, their median OS was 10.5 months. In the "progressive"group, add-on BEV significantly extended OS (P=0.018) and was the lone clinical factor of better prognosis. CONCLUSIONS: We found that, for patients with GBM/AAs whose tumors were continuously growing during radiotherapy, add-on BEV treata ment resulted in survival benefits.

脳血管障害の病態評価における脳画像の有用性 もやもや病の周術期画像マーカーとRNF213遺伝子多型の関連　　　　　　　　　　　　　　　
内野 晴登, 伊東 雅樹, 東海林 菊太郎, 舘澤 諒大, 川堀 真人, 数又 研, 宝金 清博, 藤村 幹
脳循環代謝, 33, 1, 70, 70, (一社)日本脳循環代謝学会, 2021年11月
日本語

RNF213創始者変異は成人もやもや病複合血行再建術後の間接バイパス路発達に寄与する　　　　　　　　　　　　　　　
伊東 雅基, 川堀 真人, 杉山 拓, 東海林 菊太郎, 舘澤 諒大, 内野 晴登, 数又 研, 寳金 清博, 藤村 幹
脳循環代謝, 33, 1, 94, 94, (一社)日本脳循環代謝学会, 2021年11月
日本語

RNF213創始者変異は成人もやもや病複合血行再建術後の間接バイパス路発達に寄与する　　　　　　　　　　　　　　　
伊東 雅基, 川堀 真人, 杉山 拓, 東海林 菊太郎, 舘澤 諒大, 内野 晴登, 数又 研, 寳金 清博, 藤村 幹
脳循環代謝, 33, 1, 94, 94, (一社)日本脳循環代謝学会, 2021年11月
日本語

Dual Antiplatelet Therapy Using Cilostazol in Patients With Stroke and Intracranial Arterial Stenosis.
Shinichiro Uchiyama, Kazunori Toyoda, Katsuhiro Omae, Ryotaro Saita, Kazumi Kimura, Haruhiko Hoshino, Nobuyuki Sakai, Yasushi Okada, Kortaro Tanaka, Hideki Origasa, Hiroaki Naritomi, Kiyohiro Houkin, Keiji Yamaguchi, Masanori Isobe, Kazuo Minematsu, Masayasu Matsumoto, Teiji Tominaga, Hidekazu Tomimoto, Yasuo Terayama, Satoshi Yasuda, Takenori Yamaguchi
Journal of the American Heart Association, 10, 20, e022575, 2021年10月19日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background Long-term benefit of dual antiplatelet therapy (DAPT) over single antiplatelet therapy (SAPT) for the prevention of recurrent stroke has not been established in patients with intracranial arterial stenosis. We compared the efficacy and safety of DAPT with cilostazol and clopidogrel or aspirin to those of SAPT with clopidogrel or aspirin in patients with intracranial arterial stenosis, who were recruited to the Cilostazol Stroke Prevention Study for Antiplatelet Combination trial, a randomized controlled trial in high-risk Japanese patients with ischemic stroke. Methods and Results We compared the vascular and hemorrhagic events between DAPT and SAPT in patients with ischemic stroke and symptomatic or asymptomatic intracranial arterial stenosis of at least 50% in a major intracranial artery. Patients were placed in two groups: 275 were assigned to receive DAPT and 272 patients SAPT. The risks of ischemic stroke (hazard ratio [HR], 0.47; 95% CI, 0.23-0.95); and composite of stroke, myocardial infarction, and vascular death (HR, 0.48; 95% CI, 0.26-0.91) were lower in DAPT than SAPT, whereas the risk of severe or life-threatening bleeding (HR, 0.72; 95% CI, 0.12-4.30) did not differ between the 2 treatment groups. Conclusions DAPT using cilostazol was superior to SAPT with clopidogrel or aspirin for the prevention of recurrent stroke and vascular events without increasing bleeding risk among patients with intracranial arterial stenosis after stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01995370.

妄想対象が「死別した近親者」ではない養生(nurturing)行動の発現機序　　　　　　　　　　　　　　　
高倉 祐樹, 大槻 美佳, 中川 賀嗣, 寳金 清博
Dementia Japan, 35, 4, 635, 635, (一社)日本認知症学会, 2021年10月
日本語

Efficacy of Carotid Artery Stenting Performed under General Anesthesia with Somatosensory Evoked Potential Monitoring.
Masayuki Gekka, Toshiya Osanai, Takeshi Aoki, Naoki Nakayama, Ken Kazumata, Kiyohiro Houkin, Miki Fujimura
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 30, 10, 106007, 106007, 2021年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: During carotid artery stenting (CAS), hemodynamics may be affected by the carotid sinus reflex in some cases. Although general anesthesia has been reported to stabilize intraoperative hemodynamics, the patient's neurological condition must be assessed indirectly. Therefore, we investigated the changes in intraoperative hemodynamics and perioperative complications of CAS under general anesthesia and evaluated the efficacy of somatosensory evoked potential (SEP) monitoring in detecting a reduction in perfusion during CAS. MATERIALS AND METHODS: From April 2011 to August 2016,57 consecutive patients who underwent CAS under general anesthesia were evaluated. The follow-up period ranged from 3 to 8 years. During CAS, anesthesiologists monitored and managed the hemodynamics. SEP monitoring was performed during the CAS procedure in all patients. RESULTS: Intraoperative hypotension (systolic blood pressure ≤ 100 mmHg) was evident in 16 patients (28.1%), and 13 patients (22.8%) experienced intraoperative bradycardia; however, all of these cases were promptly managed under general anesthesia. None of the patients showed systolic blood pressure < 50 mmHg from baseline. Regarding perioperative complications, none of the patients exhibited myocardial infarction or postoperative hyperperfusion symptoms, and there was no mortality. Among 21 patients (36.8%) with a decrease in the intraoperative SEP, 3 (5.3%) exhibited transient ischemic symptoms and 1 (1.8%) had postoperative infarction. CONCLUSIONS: CAS under general anesthesia is a safe and effective management option in terms of intraoperative hemodynamic stability. In addition, our findings indicate that SEP monitoring could be helpful in evaluating transient postoperative cerebral ischemia or cerebral infarction after CAS.

Correlation of active contact location with weight gain after subthalamic nucleus deep brain stimulation: a case series.
Katsuki Eguchi, Shinichi Shirai, Masaaki Matsushima, Takahiro Kano, Kazuyoshi Yamazaki, Shuji Hamauchi, Toru Sasamori, Toshitaka Seki, Kenji Hirata, Mayumi Kitagawa, Mika Otsuki, Tohru Shiga, Kiyohiro Houkin, Hidenao Sasaki, Ichiro Yabe
BMC neurology, 21, 1, 351, 351, BMC, 2021年09月13日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Weight gain (WG) is a frequently reported side effect of subthalamic deep brain stimulation; however, the underlying mechanisms remain unclear. The active contact locations influence the clinical outcomes of subthalamic deep brain stimulation, but it is unclear whether WG is directly associated with the active contact locations. We aimed to determine whether WG is associated with the subthalamic deep brain stimulation active contact locations. METHODS: We enrolled 14 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation between 2013 and 2019. Bodyweight and body mass index were measured before and one year following the surgery. The Lead-DBS Matlab toolbox was used to determine the active contact locations based on magnetic resonance imaging and computed tomography. We also created sweet spot maps for WG using voxel-wise statistics, based on volume of tissue activation and the WG of each patient. Fluorodeoxyglucose-positron emission tomography data were also acquired before and one year following surgery, and statistical parametric mapping was used to evaluate changes in brain metabolism. We examined which brain regions' metabolism fluctuation significantly correlated with increased body mass index scores and positron emission tomography data. RESULTS: One year after surgery, the body mass index increase was 2.03 kg/m2. The sweet spots for WG were bilateral, mainly located dorsally outside of the subthalamic nucleus (STN). Furthermore, WG was correlated with increased metabolism in the left limbic and associative regions, including the middle temporal gyrus, inferior frontal gyrus, and orbital gyrus. CONCLUSIONS: Although the mechanisms underlying WG following subthalamic deep brain stimulation are possibly multifactorial, our findings suggest that dorsal stimulation outside of STN may lead to WG. The metabolic changes in limbic and associative cortical regions after STN-DBS may also be one of the mechanisms underlying WG. Further studies are warranted to confirm whether dorsal stimulation outside of STN changes the activities of these cortical regions.

Genetic and nongenetic factors for contralateral progression of unilateral moyamoya disease: the first report from the SUPRA Japan Study Group.
Yohei Mineharu, Yasushi Takagi, Akio Koizumi, Takaaki Morimoto, Takeshi Funaki, Tomohito Hishikawa, Yoshio Araki, Hitoshi Hasegawa, Jun C Takahashi, Satoshi Kuroda, Kiyohiro Houkin, Susumu Miyamoto
Journal of neurosurgery, 136, 4, 1, 10, 2021年09月10日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Although many studies have analyzed risk factors for contralateral progression in unilateral moyamoya disease, they have not been fully elucidated. The aim of this study was to examine whether genetic factors as well as nongenetic factors are involved in the contralateral progression. METHODS: The authors performed a multicenter cohort study in which 93 cases with unilateral moyamoya disease were retrospectively reviewed. The demographic features, RNF213 R4810K mutation, lifestyle factors such as smoking and drinking, past medical history, and angiographic findings were analyzed. A Cox proportional hazards model was used to find risk factors for contralateral progression. RESULTS: Contralateral progression was observed in 24.7% of cases during a mean follow-up period of 72.2 months. Clinical characteristics were not significantly different between 63 patients with the R4810K mutation and those without it. Cox regression analysis showed that the R4810K mutation (hazard ratio [HR] 4.64, p = 0.044), childhood onset (HR 7.21, p < 0.001), male sex (HR 2.85, p = 0.023), and daily alcohol drinking (HR 4.25, p = 0.034) were independent risk factors for contralateral progression. CONCLUSIONS: These results indicate that both genetic and nongenetic factors are associated with contralateral progression of unilateral moyamoya disease. The findings would serve to help us better understand the pathophysiology of moyamoya disease and to manage patients more appropriately.

Dual Antiplatelet Therapy Using Cilostazol With Aspirin or Clopidogrel: Subanalysis of the CSPS.com Trial.
Haruhiko Hoshino, Kazunori Toyoda, Katsuhiro Omae, Noriyuki Ishida, Shinichiro Uchiyama, Kazumi Kimura, Nobuyuki Sakai, Yasushi Okada, Kortaro Tanaka, Hideki Origasa, Hiroaki Naritomi, Kiyohiro Houkin, Keiji Yamaguchi, Masanori Isobe, Kazuo Minematsu, Masayasu Matsumoto, Teiji Tominaga, Hidekazu Tomimoto, Yasuo Terayama, Satoshi Yasuda, Takenori Yamaguchi
Stroke, 52, 11, STROKEAHA121034378, 3439, 2021年08月18日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND PURPOSE: Although dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the recurrence of ischemic stroke while significantly increasing the bleeding events compared with monotherapy, the CSPS.com trial (Cilostazol Stroke Prevention Study combination) showed that DAPT using cilostazol was more effective without the bleeding risk. In the CSPS.com trial, aspirin or clopidogrel was used as the underlying antiplatelet drug. The effectiveness and safety of each combination were examined and clarified. METHODS: In the CSPS.com trial, a multicenter, open-label, randomized controlled study, patients with high-risk, noncardioembolic ischemic stroke 8 to 180 days after onset treated with aspirin or clopidogrel alone at the discretion of the physician in charge were recruited. Patients were randomly assigned to receive either monotherapy or DAPT using cilostazol and followed for 0.5 to 3.5 years. The primary efficacy outcome was first recurrence of ischemic stroke. The safety outcome was severe or life-threatening bleeding. The analysis was based on the underlying antiplatelet agents. RESULTS: A total of 763 patients taking aspirin and 1116 taking clopidogrel were included in the intention-to-treat analysis. Although the clopidogrel group had more risk factors than the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the 2 groups. In the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the DAPT group and the aspirin-monotherapy group. In the clopidogrel group, the primary end point occurred at a rate of 2.31 per 100 patient-years in the DAPT group and 5.19 per 100 patient-years in the clopidogrel-monotherapy group (hazard ratio, 0.447 [95% CI, 0.258-0.774]). Safety outcome did not differ significantly between groups (0.51 per 100 patient-years versus 0.71 per 100 patient-years, respectively; hazard ratio, 0.730 [95% CI, 0.206-2.588]). CONCLUSIONS: The combination of cilostazol and clopidogrel significantly reduced the recurrence of ischemic stroke without increasing the bleeding risk in noncardioembolic, high-risk patients. REGISTRATION: URL: http://www.clinicaltrials.gov; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012180.

Analyzing Cost-Effectiveness of Allocating Neurointerventionist for Drive and Retrieve System for Patients with Acute Ischemic Stroke.
Yasuhiro Morii, Toshiya Osanai, Kensuke Fujiwara, Takumi Tanikawa, Kiyohiro Houkin, Songzi Gu, Katsuhiko Ogasawara
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 30, 8, 105843, 105843, ELSEVIER, 2021年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: There are regional disparities in implementation rates of endovascular thrombectomy due to time and resource constraints such as endovascular thrombectomy specialists. In Hokkaido, Japan, Drive and Retrieve System (DRS), where endovascular thrombectomy specialists perform early endovascular thrombectomies by traveling from the facilities where they normally work to facilities closer to the patient. This study analyzed the cost-effectiveness of allocating a endovascular thrombectomy specialist for DRS to treat stroke patients. MATERIALS AND METHODS: he number of ischemic stroke patients expected to receive endovascular thrombectomy in Hokkaido in 2015 was estimated. It was assumed that an additional neutointerventionist was allocated for DRS. The analysis was performed from the government's perspective, which includes medical and nursing-care costs, and the personnel cost for endovascular thrombectomy specialist. The analysis was conducted comparing the current scenario, where patients received endovascular thrombectomy in facilities where endovascular thrombectomy specialists normally work, with the scenario with DRS within 60 min drive distance. Patient transport time was analyzed using geographic information system, and patient severity was estimated from the transport time. The primary outcome was incremental cost-effectiveness ratio (ICER) in each medical area which was calculated from the incremental costs and the incremental quality-adjusted life years (QALYs), estimated from patient severity using published literature. The entire process was repeated 100 times. RESULTS: DRS was most cost-effective in Kamikawachubu area, where the ICER was $14,173±16,802/QALY, significantly lower than the threshold that the Japanese guideline suggested. CONCLUSIONS: Since DRS was cost-effective in Kamikawachubu area, the area should be prioritized when a endovascular thrombectomy specialist for DRS is allocated as a policy.

Chronic deep brain stimulation reduces cortical β-γ phase amplitude-coupling in patients with Parkinson's disease.
Katsuki Eguchi, Shinichi Shirai, Masaaki Matsushima, Takahiro Kano, Tomohiro Ichikawa, Kazuyoshi Yamazaki, Shuji Hamauchi, Toru Sasamori, Toshitaka Seki, Mayumi Kitagawa, Hideaki Shiraishi, Kiyohiro Houkin, Hidenao Sasaki, Ichiro Yabe
Parkinsonism & related disorders, 89, 148, 150, ELSEVIER SCI LTD, 2021年08月, ［査読有り］, ［国際誌］
英語, We compared β-γ phase amplitude coupling (PAC) before and one year after chronic deep brain stimulation (DBS) in patients with Parkinson's disease using EEG and observed significant post-operative reduction of PAC values. Our findings suggest that the reduction in PAC due to DBS can be observed after chronic stimulation, which is not a transient phenomenon just after the start of DBS.

Clinical Outcome of Cytoreductive Surgery Prior to Bevacizumab for Patients with Recurrent Glioblastoma: A Single-center Retrospective Analysis.
Shigeru Yamaguchi, Hiroaki Motegi, Yukitomo Ishi, Michinari Okamoto, Ryosuke Sawaya, Hiroyuki Kobayashi, Shunsuke Terasaka, Kiyohiro Houkin
Neurologia medico-chirurgica, 61, 4, 245, 252, JAPAN NEUROSURGICAL SOC, 2021年04月15日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Bevacizumab (BEV) is a key anti-angiogenic agent used in the treatment for recurrent glioblastoma multiforme (GBM). The aim of this study was to investigate whether cytoreductive surgery prior to treatment with BEV contributes to prolongation of survival for patients with recurrent GBM. We retrospectively analyzed the treatment outcomes of 124 patients with recurrent GBM who were initially treated with the Stupp protocol between 2006 and 2019. Given that BEV has only been available in Japan since 2013, we grouped the patients into two groups according to the time of first recurrence: the pre-BEV group (N = 51) included patients who had recurrence before BEV approval, and the BEV group (N = 73) included patients with recurrence after BEV approval. The overall survival after first recurrence (OS-R) was analyzed according to the treatment strategy. Among 124 patients, 27 patients (19.4%) received cytoreductive surgery. There were nine cases in the pre-BEV group and 18 cases in the BEV group. Although the mean extent of resection for both groups was almost equal, OS-R was significantly different. The median OS-R was 8.1 m in the pre-BEV group and 16.3 m in the BEV group (P = 0.007). Multivariate analysis revealed that the unavailability of BEV postoperatively (P = 0.03) and decreasing performance status by surgery (P = 0.01) were significant poor prognostic factors for survival after surgery. With the advent of BEV, cytoreductive surgery might provide superior survival benefit at the time of GBM recurrence, especially in cases where surgery can be performed without deteriorating the patient's condition.

Intracerebral Transplantation of Autologous Bone Marrow Stem Cell (BMSC) for Subacute Ischemic Stroke, Phase 1 Clinical Trial (RAINBOW Trial)
Masahito Kawabori, Hideo Shichinohe, Satoshi Kuroda, Kiyohiro Houkin
STROKE, 52, LIPPINCOTT WILLIAMS & WILKINS, 2021年03月, ［査読有り］
英語

Novel risk factors and management of brain sag after brain tumor surgery
Hiroaki Motegi, Shigeru Yamaguchi, Michinari Okamoto, Yukitomo Ishi, Shogo Endo, Sadahiro Kaneko, Hiroyuki Kobayashi, Shunsuke Terasaka, Kiyohiro Houkin
INTERDISCIPLINARY NEUROSURGERY-ADVANCED TECHNIQUES AND CASE MANAGEMENT, 23, ELSEVIER, 2021年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective: Lumbar drains (LD) have been identified to cause brain sag (BS), which is a serious intracranial hypotension that causes coma; however, other contributing risk factors should also be considered. Therefore, this study aims to identify the BS risk factors and determine the proper treatment plan after brain tumor surgery for patients with BS.Methods: This retrospective study included patients who underwent brain tumor surgery between 2011 and 2015. BS was diagnosed based on the clinical signs of cerebrospinal fluid hypovolemia along with the radiological findings of the basal cistern effacement. Based on the data on the clinical features, the symptoms were used to determine the BS risk factors using logistic regression.Results: Overall, among the 412 patients included in this study, 12 (2.91%) were found to develop BS, 10 experienced altered consciousness, and 2 experienced orthostatic headaches. In all cases, radiological images at onset showed epidural/subdural fluid collection, along with basal cistern effacement. LD was inserted just before surgery in 11 cases, while a ventriculoperitoneal shunt was placed in one patient. The treatment strategies used are as follows: Ringer's solution infusion (n = 4), Trendelenburg position (n = 2), intrathecal injection of saline (n = 1), or no care due to misdiagnosis (n = 5). Moreover, the significant BS risk factors were determined to be the LD (odds ratio [OR] 30.70, CI 2.77-339.86), supratentorial skull base approach (SBA) (OR 35.71, CI 9.1922-138.7250), surgical time (1693.07, CI 69.5621-41207.448), and postoperative hyperosmotic diuretic use (OR 8.092, CI 2.485-26.345) after surgery.Conclusions: In the brain tumor surgery, aside from the LD, the application of supratentorial SBA, use of HD, and lengthy surgery are also found to be contributing risk factors for BS. Therefore, BS should be considered in the differential diagnosis of high-risk patients with postoperative altered consciousness.

Immersive 3-Dimensional Virtual Reality Modeling for Case-Specific Presurgical Discussions in Cerebrovascular Neurosurgery.
Taku Sugiyama, Tod Clapp, Jordan Nelson, Chad Eitel, Hiroaki Motegi, Naoki Nakayama, Tsukasa Sasaki, Kikutaro Tokairin, Masaki Ito, Ken Kazumata, Kiyohiro Houkin
Operative neurosurgery (Hagerstown, Md.), 20, 3, 289, 299, 2021年02月16日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Adequate surgical planning includes a precise understanding of patient-specific anatomy and is a necessity for neurosurgeons. Although the use of virtual reality (VR) technology is emerging in surgical planning and education, few studies have examined the effectiveness of immersive VR during surgical planning using a modern head-mounted display. OBJECTIVE: To investigate if and how immersive VR aids presurgical discussions of cerebrovascular surgery. METHODS: A multiuser immersive VR system, BananaVisionTM, was developed and used during presurgical discussions in a prospective patient cohort undergoing cerebrovascular surgery. A questionnaire/interview was administered to multiple surgeons after the surgeries to evaluate the effectiveness of the VR system compared to conventional imaging modalities. An objective assessment of the surgeon's knowledge of patient-specific anatomy was also conducted by rating surgeons' hand-drawn presurgical illustrations. RESULTS: The VR session effectively enhanced surgeons' understanding of patient-specific anatomy in the majority of cases (83.3%). An objective assessment of surgeons' presurgical illustrations was consistent with this result. The VR session also effectively improved the decision-making process regarding minor surgical techniques in 61.1% of cases and even aided surgeons in making critical surgical decisions about cases involving complex and challenging anatomy. The utility of the VR system was rated significantly higher by trainees than by experts. CONCLUSION: Although rated as more useful by trainees than by experts, immersive 3D VR modeling increased surgeons' understanding of patient-specific anatomy and improved surgical strategy in certain cases involving challenging anatomy.

Vulnerability to shear stress caused by altered peri-endothelial matrix is a key feature of Moyamoya disease.
Muneaki Matsuo, Satomi Nadanaka, Minami Soga, Taku Sugiyama, Shota Serigano, Kenjiro Shimano, Fumio Ichinose, Takuji Nakamura, Toshiyuki Maeda, Kiyohiro Houkin, Takumi Era, Hiroshi Kitagawa
Scientific reports, 11, 1, 1552, 1552, NATURE RESEARCH, 2021年01月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Moyamoya disease (MMD) is characterized by progressive bilateral stenotic changes in the terminal portion of the internal carotid arteries. Although RNF213 was identified as a susceptibility gene for MMD, the exact pathogenesis remains unknown. Immunohistochemical analysis of autopsy specimens from a patient with MMD revealed marked accumulation of hyaluronan and chondroitin sulfate (CS) in the thickened intima of occlusive lesions of MMD. Hyaluronan synthase 2 was strongly expressed in endothelial progenitor cells in the thickened intima. Furthermore, MMD lesions showed minimal staining for CS and hyaluronan in the endothelium, in contrast to control endothelium showing positive staining for both. Glycosaminoglycans of endothelial cells derived from MMD and control induced pluripotent stem cells demonstrated a decreased amount of CS, especially sulfated CS, in MMD. A computational fluid dynamics model showed highest wall shear stress values in the terminal portion of the internal carotid artery, which is the predisposing region in MMD. Because the peri-endothelial extracellular matrix plays an important role in protection, cell adhesion and migration, an altered peri-endothelial matrix in MMD may contribute to endothelial vulnerability to wall shear stress. Invading endothelial progenitor cells repairing endothelial injury would produce excessive hyaluronan and CS in the intima, and cause vascular stenosis.

慢性期頭部外傷患者に対する間葉系幹細胞(SB623)脳内投与の治験成績(STEMTRA研究)　　　　　　　　　　　　　　　
川堀 真人, 今井 英明, 安原 隆雄, 末永 潤, 中村 元, 唐沢 康暉, 宝金 清博
日本脳神経外傷学会プログラム・抄録集, 44回, 59, 59, (一社)日本脳神経外傷学会, 2021年01月
日本語

The Japan Neurosurgical Database: Statistics Update 2018 and 2019
Koji IIHARA, Nobuhito SAITO, Michiyasu SUZUKI, Isao DATE, Yukihiko FUJII, Kiyohiro HOUKIN, Tooru INOUE, Toru IWAMA, Takakazu KAWAMATA, Phyo KIM, Hiroyuki KINOUCHI, Haruhiko KISHIMA, Eiji KOHMURA, Kaoru KURISU, Keisuke MARUYAMA, Yuji MATSUMARU, Nobuhiro MIKUNI, Susumu MIYAMOTO, Akio MORITA, Hiroyuki NAKASE, Yoshitaka NARITA, Ryo NISHIKAWA, Kazuhiko NOZAKI, Kuniaki OGASAWARA, Kenji OHATA, Nobuyuki SAKAI, Hiroaki SAKAMOTO, Yoshiaki SHIOKAWA, Jun C. TAKAHASHI, Keisuke UEKI, Toshihiko WAKABAYASHI, Koji YOSHIMOTO, Hajime ARAI, Teiji TOMINAGA
Neurologia medico-chirurgica, Japan Neurosurgical Society, 2021年
研究論文（学術雑誌）

Corrigendum to "Evaluation of Novel Stereotactic Cannula for Stem Cell Transplantation against Central Nervous System Disease".
Masahito Kawabori, Aki Tanimori, Shinri Kitta, Hideo Shichinohe, Kiyohiro Houkin
Stem cells international, 2021, 9796010, 9796010, HINDAWI LTD, 2021年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, [This corrects the article DOI: 10.1155/2020/4085617.].

Mesenchymal Stem Cell Sheet Promotes Functional Recovery and Palliates Neuropathic Pain in a Subacute Spinal Cord Injury Model.
Kazuyoshi Yamazaki, Masahito Kawabori, Toshitaka Seki, Soichiro Takamiya, Kotaro Konno, Masahiko Watanabe, Kiyohiro Houkin, Miki Fujimura
Stem cells international, 2021, 9964877, 9964877, HINDAWI LTD, 2021年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Stem cell therapy has been shown to reverse the sequelae of spinal cord injury (SCI). Although the ideal treatment route remains unknown, providing a large number of stem cells to the injured site using less invasive techniques is critical to achieving maximal recovery. This study was conducted to determine whether administration of bone marrow stem cell (BMSC) sheet made on its own without a scaffold is superior to intramedullary cell transplantation in a rat subacute SCI model. Adult female Sprague-Dawley rats were subjected to SCI by 30 g clip compression at the level of Th6 and Th7 and were administered BMSC cell sheet (7 × 104 cells, subdural), cell suspension (7 × 104 cells, intramedullary), or control seven days after the injury. Motor and sensory assessments, as well as histological evaluation, were performed to determine the efficacy of the different cell transplantation procedures. While both the cell sheet and cell intramedullary injection groups showed significant motor recovery compared to the control group, the cell sheet group showed better results. Furthermore, the cell sheet group displayed a significant sensory recovery compared to the other groups. A histological evaluation revealed that the cell sheet group showed smaller injury lesion volume, less inflammation, and gliosis compared to other groups. Sensory-related fibers of μ-opioid receptors (MOR, interneuron) and hydroxytryptamine transporters (HTT, descending pain inhibitory pathway), located around the dorsal horn of the spinal cord at the caudal side of the SCI, were preserved only in the cell sheet group. Stem cells could also be found inside the peri-injured spinal cord in the cell sheet group. BMSC cell sheets were able to promote functional recovery and palliate neuropathic pain more effectively than intramedullary injections, thus serving as a good treatment option for SCI.

CAN HIGH LEVEL SERUM HCG-B BE CONSIDERED EQUIVALENT TO A DIAGNOSIS OF CHORIOCARCINOMA IN PRIMARY CENTRAL NERVOUS SYSTEM GERM-CELL TUMOR?
Hiroaki Motegi, Shigeru Yamaguchi, Yukitomo Ishi, Michinari Okamoto, Akihiro Iguchi, Yuko Cho, Minako Sugiyama, Atsushi Manabe, Kiyohiro Houkin
NEURO-ONCOLOGY, 22, 329, 330, OXFORD UNIV PRESS INC, 2020年12月, ［査読有り］
英語

DIAGNOSTIC CAPABILITY OF CSF-PLAP ON INTRACRANIAL GERM CELL TUMOR
Michinari Okamoto, Shigeru Yamaguchi, Yukitomo Ishi, Hiroaki Motegi, Yukayo Terashita, Shinsuke Hirabayashi, Minako Sugiyama, Yuko Cho, Akihiro Iguchi, Atushi Manabe, Kiyohiro Houkin
NEURO-ONCOLOGY, 22, 334, 334, OXFORD UNIV PRESS INC, 2020年12月, ［査読有り］
英語

INITIAL MANAGEMENT OF HYDROCEPHALUS IN THE PEDIATRIC AND YOUNG-ADULT PATIENTS WITH BRAIN TUMORS; THE EFFICACY OF LONG-TERM INDWELLING EXTERNAL VENTRICULAR DRAINAGE
Shigeru Yamaguchi, Hiroaki Motegi, Yukitomo Ishi, Michinari Okamoto, Akihiro Iguchi, Yuko Cho, Minako Sugiyama, Atushi Manabe, Kiyohiro Houkin
NEURO-ONCOLOGY, 22, 461, 461, OXFORD UNIV PRESS INC, 2020年12月, ［査読有り］
英語

脳梗塞に対する新規治療の開発-血栓回収療法時代のアンメットメディカルニーズと医薬品開発戦略- 主幹動脈閉塞脳梗塞患者に対する幹細胞脳内移植治験(RAINBOW研究)　　　　　　　　　　　　　　　
川堀 真人, 七戸 秀夫, 黒田 敏, 宝金 清博
脳循環代謝, 32, 1, 52, 52, (一社)日本脳循環代謝学会, 2020年11月
日本語

脳梗塞急性期患者への自家BMSC脳内投与による再生治療(Phase 1)とPhase 2に向けた取り組み　　　　　　　　　　　　　　　
川堀 真人, 七戸 秀夫, 黒田 敏, 宝金 清博
脳循環代謝, 32, 1, 60, 60, (一社)日本脳循環代謝学会, 2020年11月
日本語

脳神経細胞治療・遺伝子治療の実践 脳出血慢性期モデルに対する骨髄幹細胞+足場材製剤(CellSaic)の有効性　　　　　　　　　　　　　　　
高宮 宗一朗, 川堀 真人, 七戸 秀夫, 中村 健太郎, 北橋 宗, 岩澤 玲子, 古川 友子, 宝金 清博
脳循環代謝, 32, 1, 68, 68, (一社)日本脳循環代謝学会, 2020年11月
日本語

ラット亜急性期脊髄損傷モデルに対する骨髄間葉系幹細胞シート移植の治療効果検証　　　　　　　　　　　　　　　
山崎 和義, 川堀 真人, 関 俊隆, 高宮 宗一朗, 今野 幸太郎, 渡辺 雅彦, 宝金 清博
脳循環代謝, 32, 1, 82, 82, (一社)日本脳循環代謝学会, 2020年11月
日本語

Neuroprotective effects of combination therapy of regional cold perfusion and hemoglobin-based oxygen carrier administration on rat transient cerebral ischemia.
Yasuhiro Ito, Takeo Abumiya, Teruyuki Komatsu, Ryosuke Funaki, Masayuki Gekka, Kota Kurisu, Taku Sugiyama, Masahito Kawabori, Toshiya Osanai, Naoki Nakayama, Ken Kazumata, Kiyohiro Houkin
Brain research, 1746, 147012, 147012, ELSEVIER, 2020年11月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Regional cold perfusion and hemoglobin-based oxygen carrier administration both exert neuroprotective effects against cerebral ischemia reperfusion injury. We herein investigated whether the combination of these two therapies leads to stronger neuroprotective effects. Combination therapy was performed with the regional perfusion of cold HemoAct, a core-shell structured hemoglobin-albumin cluster, in a rat transient middle cerebral artery occlusion model. The effects of combination therapy, the intra-arterial administration of 10 °C HemoAct (10H) initiated at the onset of reperfusion, were compared with those of monotherapies, the intra-arterial administration of 10 °C saline (10S) and 37 °C HemoAct (37H), and an untreated control under the condition of 2-hour ischemia/24-hour reperfusion. The durability of therapeutic effects and the therapeutic time window of combination therapy were assessed based on comparisons with the 10H and control groups. Significantly better neurological findings and smaller infarct volumes were observed in the three treated (10S, 37H, and 10H) groups than in the control group. Among the 3 treated groups, only the 10H group showed significant improvements over the control group in the other items examined, including cerebral blood flow reduction, brain edema, and protein extravasation. The significant therapeutic effects of combination therapy on neurological disabilities and infarct volumes were confirmed at least until 7 days after reperfusion. Furthermore, combination therapy ameliorated neurological disabilities and hemorrhagic transformation in rats subjected to 4- and 5-hour ischemia/24-hour reperfusion. Since therapeutic effects may be expected until at least 5 h of complete ischemia and reperfusion, this combination therapy is a promising neuroprotective strategy against severe ischemic stroke.

Clinical Trials of Stem Cell Therapy for Cerebral Ischemic Stroke.
Masahito Kawabori, Hideo Shichinohe, Satoshi Kuroda, Kiyohiro Houkin
International journal of molecular sciences, 21, 19, 1, 21, MDPI, 2020年10月06日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Despite recent developments in innovative treatment strategies, stroke remains one of the leading causes of death and disability worldwide. Stem cell therapy is currently attracting much attention due to its potential for exerting significant therapeutic effects on stroke patients. Various types of cells, including bone marrow mononuclear cells, bone marrow/adipose-derived stem/stromal cells, umbilical cord blood cells, neural stem cells, and olfactory ensheathing cells have enhanced neurological outcomes in animal stroke models. These stem cells have also been tested via clinical trials involving stroke patients. In this article, the authors review potential molecular mechanisms underlying neural recovery associated with stem cell treatment, as well as recent advances in stem cell therapy, with particular reference to clinical trials and future prospects for such therapy in treating stroke.

FTY720 Protects Against Ischemia-Reperfusion Injury by Preventing the Redistribution of Tight Junction Proteins and Decreases Inflammation in the Subacute Phase in an Experimental Stroke Model.
Zifeng Wang, Kei Higashikawa, Hironobu Yasui, Yuji Kuge, Yusuke Ohno, Akio Kihara, Yenari A Midori, Kiyohiro Houkin, Masahito Kawabori
Translational stroke research, 11, 5, 1103, 1116, 2020年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Injury due to brain ischemia followed by reperfusion (I/R) may be an important therapeutic target in the era of thrombectomy. FTY720, a widely known sphingosine-1-phosphate receptor agonist, exerts various neuroprotective effects. The aim of this study was to examine the protective effect of FTY720 with respect to I/R injury, especially focusing on blood-brain barrier (BBB) protection and anti-inflammatory effects. Male rats were subjected to transient ischemia and administered vehicle or 0.5 or 1.5 mg/kg of FTY720 immediately before reperfusion. Positron emission tomography (PET) with [18F]DPA-714 was performed 2 and 9 days after the insult to serially monitor neuroinflammation. Bovine and rat brain microvascular endothelial cells (MVECs) were also subjected to oxygen-glucose deprivation (OGD) and reperfusion, and administered FTY720, phosphorylated-FTY720 (FTY720-P), or their inhibitor. FTY720 dose-dependently reduced cell death, the infarct size, cell death including apoptosis, and inflammation. It also ameliorated BBB disruption and neurological deficits compared to in the vehicle group. PET indicated that FTY720 significantly inhibited the worsening of inflammation in later stages. FTY720-P significantly prevented the intracellular redistribution of tight junction proteins but did not increase their mRNA expression. These results suggest that FTY720 can ameliorate I/R injury by protecting the BBB and regulating neuroinflammation.

Vascular Smooth Muscle Cell Derived from IPS Cell of Moyamoya Disease - Comparative Characterization with Endothelial Cell Transcriptome.
Kikutaro Tokairin, Shuji Hamauchi, Masaki Ito, Ken Kazumata, Taku Sugiyama, Naoki Nakayama, Masahito Kawabori, Toshiya Osanai, Kiyohiro Houkin
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 29, 12, 105305, 105305, 2020年09月23日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Moyamoya disease (MMD) is an occlusive cerebrovascular disease, causing stroke in children and young adults with unknown etiology. The fundamental pathology is fibrocellular intimal thickening of cerebral arteries, in which vascular smooth muscle cells (VSMCs) are observed as one of the major cell types. Although the characteristics of circulating smooth muscle progenitor cells have been previously reported, the VSMCs are poorly characterized in MMD. We aimed to characterize VSMCs in MMD using induced pluripotent stem cell (iPSC)-technology. METHODS: We differentiated VSMCs from neural crest stem cells (NCSCs) using peripheral blood mononuclear cell-derived iPSCs and compared biological and transcriptome features under naïve culture conditions between three independent healthy control (HC) subjects and three MMD patients. VSMC transcriptome profiles were also compared to those of endothelial cells (ECs) differentiated from the same iPSCs. RESULTS: Homogeneous spindle-shaped cells differentiated from iPSCs exhibited smooth muscle cell marker expressions, including α-smooth muscle actin (αSMA, 82.3 ± 6.7% and 81.0 ± 6.7%); calponin (91.3 ± 2.1% and 90.9 ± 1.3%); myosin heavy chain-11 (MYH11, 96.9 ± 0.7% and 97.1 ± 0.3%) without significance of differences between the two groups. Real-time PCR showed few PECAM1 and CD34 gene expressions in both groups, indicating features of differentiated VSMCs. There were no significant differences in cellular proliferation (p = 0.45), migration (p = 0.60), and contractile abilities (p = 0.96) between the two groups. Transcriptome analysis demonstrated similar gene expression profiles of VSMCs in HC subjects and MMD patients with six differentially expressed genes (DEGs); while ECs showed a distinct transcriptome profile in MMD patients with 120 DEGs. The Wnt-signaling pathway was a significant pathway in VSMCs. CONCLUSIONS: This is the first study that established VSMCs from NCSCs using MMD patient-derived iPSCs and demonstrated similar biological function and transcriptome profile of iPSC-derived VMSCs in MMD patients and HC subjects under naïve single culture condition. Comparative transcriptome features between iPSC-derived VSMCs and ECs, displaying distinct transcriptome in the ECs, suggested that pathological traits can be driven by naïve ECs predominantly and VSMCs may require specific environmental factors in MMD, which provides novel insight into the pathophysiology of MMD. Our iPSC derived VSMC model can contribute to further investigations of diagnostic and therapeutic target of MMD in addition to the current iPSC derived EC model.

Specific clinical features and one-stage revascularization surgery for moyamoya disease with severe cerebral ischemia in the territory of posterior cerebral artery.
Hisayasu Saito, Daina Kashiwazaki, Haruto Uchino, Shusuke Yamamoto, Kiyohiro Houkin, Satoshi Kuroda
Acta neurochirurgica, 163, 2, 583, 592, 2020年09月14日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: There are no reports describing the surgical procedure for moyamoya disease (MMD) patients with severe cerebral ischemia in the territory of the posterior cerebral artery (PCA) at initial presentation. In this study, therefore, we describe their clinical and radiological features and clinical results of one-stage revascularization surgery for both anterior and posterior circulation. METHODS: This study included 6 MMD patients who had severe cerebral ischemia in the PCA territory and underwent one-stage revascularization surgery for both anterior and posterior circulation. Of these, one patient underwent it on both sides. Their clinical and radiological data were precisely analyzed. Compared with usual procedure, craniotomy was extended towards the temporo-parietal area more widely. The parietal branch of superficial temporal artery (STA) was anastomosed to the angular or posterior temporal artery, while the frontal branch was anastomosed to the frontal branch of MCA. Ultimate indirect bypass was added. Their clinical and radiological outcomes were evaluated. RESULTS: Their neurological symptoms included visual and speech disturbance as well as numbness of the extremities. Cerebral infarct was distributed in the posterior temporal, parietal, and/or occipital lobe. Cerebral hemodynamics and metabolism were also impaired in the same regions. These findings were completely different from those in MMD patients without PCA lesion. Postoperative course was uneventful, and none of them recurred stroke during a mean follow-up period of 10.5 years. Surgical collaterals widely provided blood flow to the entire hemispheres, including the occipital lobe. Cerebral hemodynamics and metabolism markedly improved after surgery. CONCLUSION: One-stage revascularization surgery for both anterior and posterior circulation is feasible and effective to prevent future stroke in MMD patients with severe cerebral ischemia in the PCA territory at initial presentation.

Diagnostic Capability of Cerebrospinal Fluid-Placental Alkaline Phosphatase Value in Intracranial Germ Cell Tumor.
Michinari Okamoto, Shigeru Yamaguchi, Yukitomo Ishi, Hiroaki Motegi, Takashi Mori, Takayuki Hashimoto, Yukayo Terashita, Shinsuke Hirabayashi, Minako Sugiyama, Akihiro Iguchi, Yuko Cho, Atsushi Manabe, Kiyohiro Houkin
Oncology, 99, 1, 1, 9, KARGER, 2020年09月09日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Most types of intracranial germ cell tumors (IGCTs) are sensitive to chemoradiation. However, biopsy specimens are usually small and thus cannot be used for obtaining an accurate pathological diagnosis. Recently, the cerebrospinal fluid (CSF) placental alkaline phosphatase (PLAP) value has been considered a new biomarker of IGCTs. The present study aimed to evaluate the discriminatory characteristics of the CSF-PLAP value upon diagnosis and at the time of recurrence in patients with IGCTs. METHODS: Between 2015 and 2019, this study included 37 patients with tumors located in the intraventricular and/or periventricular region. The CSF-PLAP level was assessed before the patients received any treatment. The PLAP level was evaluated during and after first-line chemoradiotherapy in 7 patients with IGCTs. The CSF-PLAP values were compared according to histological diagnosis, and the correlation between these values and radiographical features was assessed. The CSF-PLAP values of 6 patients with IGCTs with suspected recurrence were evaluated based on neuroimaging findings. RESULTS: The CSF-PLAP values were significantly higher in patients with IGCTs than in those with other types of brain tumor (n = 19 vs. 18; median: 359.0 vs. <8.0 pg/mL). The specificity and sensitivity were 88 and 95%, respectively, with a cutoff value of 8.0 pg/mL. In patients with IGCT, the CSF-PLAP value was higher in patients with germinoma than in those with nongerminomatous germ cell tumors (n = 12 vs. 7; median: 415.0 vs. 359.0 pg/mL). Regarding the time course, the CSF-PLAP value decreased to below the detection limit after the reception of first-line chemoradiotherapy in all 7 patients. A significant correlation was observed between the initial CSF-PLAP value and the tumor reduction volume after receiving first-line chemoradiotherapy (p < 0.0003, R2 = 0.6165, logY = 1.202logX - 1.727). Among the patients with suspected IGCT recurrence (n = 6), the CSF-PLAP value was high in patients with recurrence (n = 3; median: 259.0 pg/mL), and that in patients (n = 3) without recurrence was below the lower detection limit. CONCLUSIONS: The CSF-PLAP level is a useful biomarker during the initial diagnosis of IGCTs and at the time of recurrence. It may be associated with the volume of germinomatous components of tumors.

Responses of immune organs following cerebral ischemic stroke.
Chengbo Tan, Zifeng Wang, Miao Zheng, Songji Zhao, Hideo Shichinohe, Kiyohiro Houkin
Journal of Nippon Medical School = Nippon Ika Daigaku zasshi, 88, 3, 228, 237, MEDICAL ASSOC NIPPON MEDICAL SCH, 2020年08月31日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Stroke is a leading cause of death and disability worldwide. Recently, brain secondary damage has been hypothesized to be a key aggravating element in an ischemic cascade. However, the interaction between cerebral infarction and immune organs has yet to be fully understood. In this study, we investigated the changes in the rat brain, spleen, thymus, mesenteric lymph node, and liver at 3, 7, and 13 days after transient middle cerebral artery occlusion (tMCAO) by immunohistochemistry. MATERIAL AND METHODS: Rat models of stroke were made by tMCAO. Functional assessment was performed 3 h, and 1, 3, 5, 7, 9, 11, and 13 days after MCAO. Rat organs were harvested for 2,3,5-triphenyltetrazolium chloride staining and Immunohistochemistry. RESULTS: The CD8α+ T cells was found to decrease in the spleen, thymus, mesenteric lymph node, and liver, whereas it increased in the brain. Those of Iba1+ and CD68+ macrophages were decreased in the spleen, thymus, and mesenteric lymph node, whereas they were elevated in the brain and liver. Ki67+ cells showed the same characteristics as macrophages, and increased numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive apoptotic cells were found in the spleen, mesenteric lymph node, liver, and brain. CONCLUSIONS: The present results demonstrated that stroke is a systemic disease, which not only affects the brain, but also induces responses of immune organs. On the basis of these results, a systemic treatment might be a good strategy for clinical stroke care.

FTY720 Attenuates Neuropathic Pain after Spinal Cord Injury by Decreasing Systemic and Local Inflammation in a Rat Spinal Cord Compression Model.
Kazuyoshi Yamazaki, Masahito Kawabori, Toshitaka Seki, Soichiro Takamiya, Takahiro Tateno, Kotaro Konno, Masahiko Watanabe, Kiyohiro Houkin
Journal of neurotrauma, 37, 15, 1720, 1728, MARY ANN LIEBERT, INC, 2020年08月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Neuropathic pain severely impairs rehabilitation and quality of life after spinal cord injury (SCI). The sphingosine-1-phosphate receptor agonist, FTY720, plays an important protective role in neuronal injury. This study aims to examine the effects of FTY720 in a rat acute SCI model, focusing on neuropathic pain. Female rats with SCI induced by 1-min clip compression were administered vehicle or 1.5 mg/kg of FTY720 24 h after the injury. Using the mechanical nociceptive threshold test, we monitored neuropathic pain and performed histological analysis of the pain pathway, including the μ opioid receptor (MOR), hydroxytryptamine transporter (HTT), and calcitonin gene-related peptide (CGRP). Motor score, SCI lesion volume, residual motor axons, inflammatory response, glial scar, and microvascular endothelial dysfunction were also compared between the two groups. FTY720 treatment resulted in significant attenuation of post-traumatic neuropathic pain. It also decreased systemic and local inflammation, thereby reducing the damaged areas and astrogliosis and resulting in motor functional recovery. Whereas there was no difference in the CGRP expression between the two groups, FTY720 significantly preserved the MOR in both the caudal and rostral areas of the spinal dorsal horn. Whereas HTT was preserved in the FTY720 group, it was significantly increased in the rostral side and decreased in the caudal side of the injury in the vehicle group. These results suggest that FTY720 ameliorates post-traumatic allodynia through regulation of neuroinflammation, maintenance of the blood-brain barrier, and inhibition of glial scar formation, thereby preserving the connectivity of the descending inhibitory pathway and reducing neuropathic pain.

Microsurgical Findings of Pial Arterial Feeders in Intracranial Dural Arteriovenous Fistulae: A Case Series.
Michinari Okamoto, Taku Sugiyama, Naoki Nakayama, Satoshi Ushikoshi, Ken Kazumata, Toshiya Osanai, Kikutaro Tokairin, Yusuke Shimoda, Kiyohiro Houkin
Operative neurosurgery (Hagerstown, Md.), 19, 6, 691, 700, OXFORD UNIV PRESS INC, 2020年07月27日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Pial arterial feeders in an intracranial dural arteriovenous fistula (dAVF) are risk factors for both ischemic and hemorrhagic complications during endovascular embolization. Microsurgery in dAVF with pial arterial feeders has rarely been reported. OBJECTIVE: To assess our original experience with microsurgery for dAVF with pial arterial feeders by investigating surgical findings and outcomes. METHODS: In 40 patients with intracranial dAVF who underwent microsurgery, we found 8 patients who had pial arterial feeders. A retrospective review was conducted. RESULTS: The locations of the dAVFs were as follows: tentorium, 2 patients; Galenic system, 1; straight sinus, 1; torcula, 1; transverse sinus, 1; ethmoid, 1; and convexity, 1. Preoperative angiography revealed that the pial arterial feeders originated from the middle cerebral artery in 2 patients, the anterior cerebral artery in 1, the posterior cerebral artery in 2, and the posterior medial choroidal artery in 1. Of note, in 2 patients (6.7%), feeders from the superior cerebellar artery were determined to be angiographically occult during preoperative examination and were detected through careful intraoperative observation and arachnoid dissection. In 5 cases, the additional obliteration of the pial arterial feeders and/or more distal cortical venous drainers after the simple disconnection of proximal cortical drainers was necessary to cure the dAVF. Finally, all shunts were cured with only 1 minor complication. CONCLUSION: Although microsurgical results were acceptable, the surgeon should be aware of the presence of pial arterial feeders even after the simple disconnection of cortical venous drainage. Angiographically occult feeders may also exist.

Clinical Trials of Stem Cell Treatment for Spinal Cord Injury.
Kazuyoshi Yamazaki, Masahito Kawabori, Toshitaka Seki, Kiyohiro Houkin
International journal of molecular sciences, 21, 11, MDPI, 2020年06月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, There are more than one million patients worldwide suffering paralysis caused by spinal cord injury (SCI). SCI causes severe socioeconomic problems not only to the patients and their caregivers but also to society; therefore, the development of innovative treatments is crucial. Many pharmacological therapies have been attempted in an effort to reduce SCI-related damage; however, no single therapy that could dramatically improve the serious long-term sequelae of SCI has emerged. Stem cell transplantation therapy, which can ameliorate damage or regenerate neurological networks, has been proposed as a promising candidate for SCI treatment, and many basic and clinical experiments using stem cells for SCI treatment have been launched, with promising results. However, the cell transplantation methods, including cell type, dose, transplantation route, and transplantation timing, vary widely between trials, and there is no consensus regarding the most effective treatment strategy. This study reviews the current knowledge on this issue, with a special focus on the clinical trials that have used stem cells for treating SCI, and highlights the problems that remain to be solved before the widespread clinical use of stem cells can be adopted.

The Japan Neurosurgical Database: Overview and Results of the First-year Survey.
Koji Iihara, Teiji Tominaga, Nobuhito Saito, Michiyasu Suzuki, Isao Date, Yukihiko Fujii, Kazuhiro Hongo, Kiyohiro Houkin, Amami Kato, Yoko Kato, Takakazu Kawamata, Phyo Kim, Hiroyuki Kinouchi, Eiji Kohmura, Kaoru Kurisu, Keisuke Maruyama, Nobuhiro Mikuni, Susumu Miyamoto, Akio Morita, Hiroyuki Nakase, Yoshitaka Narita, Ryo Nishikawa, Kazuhiko Nozaki, Kuniaki Ogasawara, Kenji Ohata, Nobuyuki Sakai, Hiroaki Sakamoto, Yoshiaki Shiokawa, Yukihiko Sonoda, Jun C Takahashi, Keisuke Ueki, Toshihiko Wakabayashi, Takamitsu Yamamoto, Kazunari Yoshida, Takamasa Kayama, Hajime Arai
Neurologia medico-chirurgica, 60, 4, 165, 190, 2020年04月15日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The Japan Neurosurgical Database (JND) is a prospective observational study registry established in 2017 by the Japan Neurosurgical Society (JNS) to visualize real-world clinical practice, promote science, and improve the quality of care and neurosurgery board certification in Japan. We summarize JND's aims and methods, and describes the 2018 survey results. The JND registered in-hospital patients' clinical data mainly from JNS training institutions in 2018. Caseload, patient demographics, and in-hospital outcomes of the overall cohort and a neurosurgical subgroup were examined according to major classifications of main diagnosis. Neurosurgical caseload per neurosurgeon in training in core hospitals in 2018 was calculated as an indicator of neurosurgical training. Of 523,283 cases (male 55.3%) registered from 1360 participating institutions, the neurosurgical subgroup comprised of 33.9%. Among the major classifications, cerebrovascular diseases comprised the largest proportion overall and in the neurosurgical subgroup (53.1%, 41.0%, respectively), followed by neurotrauma (19.1%, 25.5%), and brain tumor (10.4%, 12.8%). Functional neurosurgery (6.4%, 3.7%), spinal and peripheral nerve disorders (5.1%, 10.1%), hydrocephalus/developmental anomalies (2.9%, 5.3%), and encephalitis/infection/inflammatory and miscellaneous diseases (2.9%, 1.6%) comprised smaller proportions. Most patients were aged 70-79 years in the overall cohort and neurosurgical subgroup (27.8%, 29.4%). Neurotrauma and cerebrovascular diseases in the neurosurgical subgroup comprised a higher and lower proportion, respectively, than in the overall cohort in elderly patients (e.g. 80 years, 46.9% vs. 33.5%, 26.8% vs. 54.4%). The 2018 median neurosurgical caseload per neurosurgeon in training was 80.7 (25-75th percentile 51.5-117.5). These initial results from 2018 reveal unique aspects of neurosurgical practice in Japan.

Combined structural and diffusion tensor imaging detection of ischemic injury in moyamoya disease: relation to disease advancement and cerebral hypoperfusion.
Ken Kazumata, Kikutaro Tokairin, Masaki Ito, Haruto Uchino, Taku Sugiyama, Masahito Kawabori, Toshiya Osanai, Khin Khin Tha, Kiyohiro Houkin
Journal of neurosurgery, 134, 4, 1, 10, 2020年04月03日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: The microstructural integrity of gray and white matter is decreased in adult moyamoya disease, suggesting covert ischemic injury as a mechanism of cognitive dysfunction. Establishing a microstructural brain imaging marker is critical for monitoring cognitive outcomes following surgical interventions. The authors of the present study determined the pathophysiological basis of altered microstructural brain injury in relation to advanced arterial occlusion, cerebral hypoperfusion, and cognitive function. METHODS: The authors examined 58 patients without apparent brain lesions and 30 healthy controls by using structural MRI, as well as diffusion tensor imaging (DTI). Arterial occlusion in each hemisphere was classified as early or advanced stage based on MRA and posterior cerebral artery (PCA) involvement. Regional cerebral blood flow (rCBF) was measured with N-isopropyl-p-[123I]-iodoamphetamine SPECT. Furthermore, cognitive performance was examined using the Wechsler Adult Intelligence Scale, Third Edition and the Trail Making Test (TMT). Both voxel- and region of interest-based analyses were performed for groupwise comparisons, as well as correlation analysis, using parameters such as cognitive test scores; gray matter volume; fractional anisotropy (FA) of association fiber tracts, including the inferior frontooccipital fasciculus (IFOF) and superior longitudinal fasciculus (SLF); PCA involvement; and rCBF. RESULTS: Compared to the early stages, advanced stages of arterial occlusion in the left hemisphere were associated with a lower Performance IQ (p = 0.031), decreased anterior cingulate volumes (p = 0.0001, uncorrected), and lower FA in the IFOF, cingulum, and forceps major (all p < 0.01, all uncorrected). There was no significant difference in rCBF between the early and the advanced stage. In patients with an advanced stage, PCA involvement was correlated with a significantly lower Full Scale IQ (p = 0.036), cingulate volume (p < 0.01, uncorrected), and FA of the left SLF (p = 0.0002, uncorrected) compared to those with an intact PCA. The rCBF was positively correlated with FA of the SLF, IFOF, and forceps major (r > 0.34, p < 0.05). Global gray matter volumes were moderately correlated with TMT part A (r = 0.40, p = 0.003). FA values in the left SLF were moderately associated with processing speed (r = 0.40, p = 0.002). CONCLUSIONS: Although hemodynamic compensation may mask cerebral ischemia in advanced stages of adult moyamoya disease, the disease progression is detrimental to gray and white matter microstructure as well as cognition. In particular, additional PCA involvement in advanced disease stages may impair key neural substrates such as the cingulum and SLF. Thus, combined structural MRI and DTI are potentially useful for tracking the neural integrity of key neural substrates associated with cognitive function and detecting subtle anatomical changes associated with persistent ischemia, as well as disease progression.

Le Fort I型骨切り術に合併したmaxillary動静脈瘻に対し血管内塞栓術を行った1例
後藤秀輔, 長内俊也, 牛越聡, 栗栖宏多, 下田祐介, 寳金清博
Neurological Surgery, 48, 4, 335, 340, 2020年04月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, BACKGROUND: Le Fort I osteotomy, one of the most common techniques applied to correct jaw deformities, is generally considered operatively safe. However, a few articles reported that this procedure can lead to formation of arteriovenous fistulae(AVF)involving the maxillary artery infrequently. CASE REPORT: A man in his 40s with a jaw deformity underwent Le Fort I osteotomy. Two days later, he noticed pulsating tinnitus in his right ear. Angiography revealed AVF between the proximal part of the maxillary artery(first segment)and the pterygoid plexus. On further evaluation, AVF were embolized with n-butyl-2-cyanoacrylate(NBCA). Obliteration of AVF was confirmed on the final angiography. The tinnitus resolved shortly after the embolization. CONCLUSION: Embolization with NBCA is a promising treatment for maxillary AVF after Le Fort I osteotomy.

Predictive factors for acute thrombogenesis occurring immediately after bypass procedure for moyamoya disease.
Takeshi Mikami, Hime Suzuki, Ryo Ukai, Katsuya Komatsu, Yukinori Akiyama, Masahiko Wanibuchi, Kiyohiro Houkin, Nobuhiro Mikuni
Neurosurgical review, 43, 2, 609, 617, 2020年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Extracranial-to-intracranial (EC-IC) bypass surgery is an effective treatment for patients with moyamoya disease and other conditions. Some patients with moyamoya disease have a risk of acute thrombogenesis at the anastomotic site just after bypass surgery. The purpose of this study was to study risk factors of acute thrombogenesis and determine effective countermeasures. This study included 48 patients (66 EC-IC bypass procedures) with moyamoya disease and 52 controls (54 procedures) without moyamoya disease. The development of acute thrombogenesis was compared between the moyamoya disease and control groups. In the moyamoya disease group, clinical and radiological characteristics were assessed with respect to acute thrombogenesis. In the patients with acute thrombogenesis, causes of technical problems were retrospectively examined. The incidence of acute thrombogenesis was significantly higher in the moyamoya disease group than those in the control group. In the moyamoya disease group, acute thrombogenesis was observed in seven patients. In the moyamoya disease group, the magnetic resonance angiography (MRA) scores were significantly higher in patients with acute thrombogenesis than those in the patients without acute thrombogenesis. In the multivariate analysis, the predictive factor of acute thrombogenesis in moyamoya disease was a high MRA score (odds ratio, 2.336; p = 0.009). During EC-IC bypass surgery for moyamoya disease, acute thrombogenesis should be considered to obtain a high patency rate, particularly in patients with high MRA scores. Acute thrombogenesis will not influence morbidity if proper countermeasures are followed; therefore, the prediction and recognition of white thrombus are important for a successful bypass surgery.

A register-based SAH study in Japan: high incidence rate and recent decline trend based on lifestyle.
Fusao Ikawa, Akio Morita, Takeo Nakayama, Yoshihito Goto, Nobuyuki Sakai, Koji Iihara, Yoshiaki Shiokawa, Isao Date, Kazuhiko Nozaki, Hiroyuki Kinouchi, Kiyohiro Houkin, Nobuhito Saito, Teiji Tominaga, Michiyasu Suzuki, Susumu Miyamoto, Kaoru Kurisu, Hajime Arai
Journal of neurosurgery, 134, 3, 1, 9, 2020年03月27日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Japan has been reported to have the highest (and increasing) incidence of subarachnoid hemorrhage (SAH) in the world. However, there has never been a report on the nationwide incidence rate and recent trends for SAH in Japan. In this register-based study, the authors aimed to clarify the estimated nationwide SAH incidence rate and the recent trend in SAH incidence in Japan and the reasons for any changes in this trend. METHODS: The authors compiled data from the Japanese Ministry of Health, Labour and Welfare and from the records of the Japan Neurosurgical Society. They reviewed the age-standardized nationwide SAH mortality rate, the estimated age-standardized SAH incidence rate according to the age-standardized SAH mortality rate, and the estimated crude SAH incidence rate, including the 95% confidence intervals, from 2003 to 2015. The trends in the number of treatments for unruptured and ruptured cerebral aneurysms, as well as the prevalence of hypertension, current smoking status, and use of cholesterol-lowering drugs, were assessed. The estimated treatment rate for unruptured cerebral aneurysms (UCAs) was also calculated along with the 95% confidence interval. RESULTS: The estimated age-standardized nationwide SAH incidence rate significantly declined from 31.34 cases (95% CI 31.32-31.34) to 27.63 (95% CI 27.59-27.63; decrease by 11.8%) per 100,000 person-years. This decline was based on the 2010 population as the reference from 2003 through 2015 and a case-fatality rate of SAH that was assumed to decrease by 1% annually from 44% in 2003 to 32% in 2015. According to sensitivity analysis, the change rate of the estimated age-standardized SAH incidence rate ranged from -56.69% to 23.27%, with a mean of -30.91% (SD 20.52%), and there were decline trends in 92% of all trends. The estimated nationwide crude SAH incidence rate also showed a significant decline from 23.79 (95% CI 23.78-23.79) to 20.25 (95% CI 20.24-20.25; decrease by 14.9%) per 100,000 person-years. The trend in treatment numbers for UCAs increased significantly (p < 0.0001) from 2003 through 2015; however, the estimated treatment rate for UCAs was only 0.19 (95% CI 0.19-0.20) to 0.51 (95% CI 0.50-0.51) among all UCA patients. The prevalence of hypertension (males, p = 0.0003; females, p < 0.0001) and current smoking status (males, p < 0.0001; females, p = 0.0002) declined significantly from 2003 through 2015, while the use of cholesterol-lowering drugs increased significantly (males, p < 0.0001; females, p = 0.0005) during the same period. CONCLUSIONS: The estimated nationwide SAH incidence rate in Japan was higher than rates in other countries, although it has declined recently. An improving lifestyle may have contributed to the declining rate of SAH incidence in Japan.

Late (5-20 years) outcomes after STA-MCA anastomosis and encephalo-duro-myo-arterio-pericranial synangiosis in patients with moyamoya disease.
Satoshi Kuroda, Naoki Nakayama, Shusuke Yamamoto, Daina Kashiwazaki, Haruto Uchino, Hisayasu Saito, Emiko Hori, Naoki Akioka, Naoya Kuwayama, Kiyohiro Houkin
Journal of neurosurgery, 134, 3, 1, 8, AMER ASSOC NEUROLOGICAL SURGEONS, 2020年03月13日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Surgical revascularization is known to reduce the incidence of further ischemic and hemorrhagic events in patients with moyamoya disease, but the majority of previous studies report only short-term (< 5 years) outcomes. Therefore, in this study the authors aimed to evaluate late (5-20 years) outcomes of moyamoya patients after superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis and indirect bypass (encephalo-duro-myo-arterio-pericranial synangiosis [EDMAPS]). METHODS: Cumulative incidences of late morbidity/mortality and disease progression were evaluated among 93 patients who underwent STA-MCA anastomosis and EDMAPS. All of the patients were prospectively followed up for longer than 5 years postsurgery (10.5 ± 4.4 years). There were 35 pediatric and 58 adult patients. Initial presentation included transient ischemic attack/ischemic stroke in 80 patients and hemorrhagic stroke in 10 patients, and 3 patients were asymptomatic. Surgery was performed in a total of 141 hemispheres. Follow-up MRI/MRA was performed within a 6- or 12-month interval during the follow-up periods. RESULTS: During the follow-up periods, 92/93 patients were free from any stroke or death, but 1 patient had a recurrence of hemorrhagic stroke (0.10% per patient-year). Disease progression occurred in the territory of the contralateral carotid or posterior cerebral artery (PCA) in 19 hemispheres of 15 patients (1.5% per patient-year). The interval between initial surgery and disease progression varied widely, from 0.5 to 15 years. Repeat bypass surgery for the anterior and posterior circulation resolved ischemic attacks in all 10 patients. CONCLUSIONS: The study results indicate that STA-MCA anastomosis and EDMAPS would be the best choice to prevent further ischemic and hemorrhagic stroke for longer than 10 years on the basis of the demonstrated widespread improvement in cerebral hemodynamics in both the MCA and ACA territories in the study patients. However, after 10 years postsurgery regular follow-up is essential to detect disease progression in the territory of the contralateral carotid artery and PCA and prevent late cerebrovascular events.

Impact of cortical hemodynamic failure on both subsequent hemorrhagic stroke and effect of bypass surgery in hemorrhagic moyamoya disease: a supplementary analysis of the Japan Adult Moyamoya Trial.
Jun C Takahashi, Takeshi Funaki, Kiyohiro Houkin, Satoshi Kuroda, Miki Fujimura, Yasutake Tomata, Susumu Miyamoto
Journal of neurosurgery, 134, 3, 1, 6, AMER ASSOC NEUROLOGICAL SURGEONS, 2020年03月13日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Here, the authors aimed to determine whether the presence of cerebral hemodynamic failure predicts subsequent bleeding attacks and how it correlates with the effect of direct bypass surgery in hemorrhagic moyamoya disease. METHODS: Data from the Japanese Adult Moyamoya (JAM) Trial were used in this study: 158 hemispheres in 79 patients. A newly formed expert panel evaluated the SPECT results submitted at trial enrollment and classified the cortical hemodynamic state of the middle cerebral artery territory of each hemisphere into one of the following three groups: SPECT stage (SS) 0 as normal, SS1 as decreased cerebrovascular reserve (CVR), and SS2 as decreased CVR with decreased baseline blood flow. In the nonsurgical cohort of the JAM Trial, the subsequent hemorrhage rate during the 5-year follow-up was compared between the SS0 (hemodynamic failure negative) and SS1+2 (hemodynamic failure positive) groups. The effect of direct or combined direct/indirect bypass surgery on hemorrhage prevention was examined in each subgroup. RESULTS: The hemodynamic grade was SS0 in 59 (37.3%) hemispheres, SS1 in 87 (55.1%), and SS2 in 12 (7.6%). In the nonsurgical cohort, subsequent hemorrhage rates in the SS0 and SS1+2 groups were 12 cases per 1000 person-years and 67 cases per 1000 person-years, respectively. Kaplan-Meier analysis revealed that hemorrhagic events were significantly more common in the SS1+2 group (p = 0.019, log-rank test). Cox regression analysis showed that hemodynamic failure was an independent risk factor for subsequent hemorrhage (HR 5.37, 95% CI 1.07-27.02). In the SS1+2 subgroup, bypass surgery significantly suppressed hemorrhagic events during 5 years (p = 0.001, HR 0.16, 95% CI 0.04-0.57), with no significant effect in the SS0 group (p = 0.655, HR 1.56, 95% CI 0.22-11.10). Examination of effect modification revealed that the effect of surgery tended to differ nonsignificantly between these two subgroups (p = 0.056). CONCLUSIONS: Hemodynamic failure is an independent risk factor for subsequent hemorrhage in hemorrhagic moyamoya disease. Direct bypass surgery showed a significant preventive effect in the hemodynamically impaired hemispheres. Thus, hemodynamic failure, as well as previously proposed factors such as choroidal anastomosis, should be considered for the surgical indication in hemorrhagic moyamoya disease.Clinical trial registration no.: C000000166 (umin.ac.jp).

Constant current stimulation may improve apraxia of eyelid opening induced by deep brain stimulation
Eguchi K, Yabe I, Shirai S, Iwata I, Matsushima M, Yamazaki K, Hamauchi S, Sasamori T, Seki T, Houkin K, Sasaki H
Interdisciplinary Neurosurgery, 19, 100565, 100565, 2020年03月, ［査読有り］
英語, 研究論文（学術雑誌）

Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells.
Smile Echizenya, Yukiko Ishii, Satoshi Kitazawa, Tadashi Tanaka, Shun Matsuda, Eriko Watanabe, Masao Umekawa, Shunsuke Terasaka, Kiyohiro Houkin, Tomohisa Hatta, Tohru Natsume, Yoshimasa Maeda, Shin-Ichi Watanabe, Shinji Hagiwara, Toru Kondo
Neuro-oncology, 22, 2, 229, 239, 2020年02月20日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Glioblastoma-initiating cells (GICs) comprise a tumorigenic subpopulation of cells that are resistant to radio- and chemotherapies and are responsible for cancer recurrence. The aim of this study was to identify novel compounds that specifically eradicate GICs using a high throughput drug screening approach. METHODS: We performed a cell proliferation/death-based drug screening using 10 560 independent compounds. We identified dihydroorotate dehydrogenase (DHODH) as a target protein of hit compound 10580 using ligand-fishing and mass spectrometry analysis. The medical efficacy of 10580 was investigated by in vitro cell proliferation/death and differentiation and in vivo tumorigenic assays. RESULTS: Among the effective compounds, we identified 10580, which induced cell cycle arrest, decreased the expression of stem cell factors in GICs, and prevented tumorigenesis upon oral administration without any visible side effects. Mechanistic studies revealed that 10580 decreased pyrimidine nucleotide levels and enhanced sex determining region Y-box 2 nuclear export by antagonizing the enzyme activity of DHODH, an essential enzyme for the de novo pyrimidine synthesis. CONCLUSION: In this study, we identified 10580 as a promising new drug against GICs. Given that normal tissue cells, in particular brain cells, tend to use the alternative salvage pathway for pyrimidine synthesis, our findings suggest that 10580 can be used for glioblastoma therapy without side effects.Key Points1.  Chemical screening identified 10580 as a novel GIC-eliminating drug that targets DHODH, an essential enzyme for the de novo pyrimidine synthesis pathway. 2. Compound 10580 induced cell cycle arrest, apoptosis, and differentiation in GICs.

Crossed cerebellar diaschisis as an indicator of severe cerebral hyperperfusion after direct bypass for moyamoya disease.
Haruto Uchino, Ken Kazumata, Masaki Ito, Naoki Nakayama, Satoshi Kuroda, Kiyohiro Houkin
Neurosurgical review, 44, 1, 599, 605, SPRINGER, 2020年02月19日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Cerebral hyperperfusion (HP) complicates the postoperative course of patients with moyamoya disease (MMD) after direct revascularization surgery. Crossed cerebellar diaschisis (CCD) has been considered to be rarely associated with HP after revascularization surgery. This study aimed to describe the clinical features and factors associated with CCD secondary to cerebral HP after revascularization surgery for MMD. We analyzed 150 consecutive hemispheres including 101 in adults and 49 in pediatric patients who underwent combined direct and indirect bypass for MMD. Using single-photon emission computed tomography (SPECT), serial cerebral blood flow (CBF) was measured immediately after the surgery and on postoperative days 2 and 7. Pre- and postoperative voxel-based analysis of SPECT findings was performed to compare the changes in regional CBF. Multivariate logistic regression analysis was performed to test the effect of multiple variables on CCD. Asymptomatic and symptomatic HP was observed in 41.3% (62/150) and 16.7% (25/150) of the operated hemispheres, respectively. CCD was observed in 18.4% (16/87) of these hemispheres with radiological HP. Multivariate analysis revealed that the occurrence of CCD was significantly associated with symptomatic HP (p = 0.0015). Voxel-based analysis showed that the CBF increase in the operated frontal cortex, and the CBF reduction in the contralateral cerebellar hemisphere on day 7 were significantly larger in symptomatic HP than in asymptomatic HP (median 11.3% vs 7.5%; - 6.0% vs - 1.7%, respectively). CCD secondary to postoperative HP is more common than anticipated in MMD. CCD could potentially be used as an indicator of severe postoperative HP in patients with MMD.

Association of the FGFR1 mutation with spontaneous hemorrhage in low-grade gliomas in pediatric and young adult patients.
Yukitomo Ishi, Shigeru Yamaguchi, Kanako C Hatanaka, Michinari Okamoto, Hiroaki Motegi, Hiroyuki Kobayashi, Shunsuke Terasaka, Kiyohiro Houkin
Journal of neurosurgery, 134, 3, 1, 9, 2020年02月14日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: The authors aimed to investigate genetic alterations in low-grade gliomas (LGGs) in pediatric and young adult patients presenting with spontaneous hemorrhage. METHODS: Patients younger than 30 years of age with a pathological diagnosis of World Health Organization (WHO) grade I or II glioma and who had undergone treatment at the authors' institution were retrospectively examined. BRAF V600E, FGFR1 N546/K656, IDH1 R132, IDH2 R172, and KIAA1549-BRAF (K-B) fusion genetic alterations were identified, and the presence of spontaneous tumoral hemorrhage was recorded. RESULTS: Among 66 patients (39 with WHO grade I and 27 with grade II tumors), genetic analysis revealed K-B fusion in 18 (27.3%), BRAF V600E mutation in 14 (21.2%), IDH1/2 mutation in 8 (12.1%), and FGFR1 mutation in 4 (6.1%). Spontaneous hemorrhage was observed in 5 patients (7.6%); 4 of them had an FGFR1 mutation and 1 had K-B fusion. Univariate analysis revealed a statistically significant association of an FGFR1 mutation and a diencephalic location with spontaneous hemorrhage. Among 19 diencephalic cases including the optic pathway, hypothalamus, and thalamus, an FGFR1 mutation was significantly associated with spontaneous hemorrhage (p < 0.001). Four FGFR1 mutation cases illustrated the following results: 1) a 2-year-old female with pilomyxoid astrocytoma (PMA) harboring the FGFR1 K656E mutation presented with intraventricular hemorrhage (IVH); 2) a 6-year-old male with PMA harboring FGFR1 K656E and D652G mutations presented with intratumoral hemorrhage (ITH); 3) a 4-year-old female with diffuse astrocytoma harboring FGFR1 K656M and D652G mutations presented with IVH; and 4) a young adult patient with pilocytic astrocytoma with the FGFR1 N546K mutation presented with delayed ITH and IVH after 7 years of observation. CONCLUSIONS: Although the mechanism remains unclear, the FGFR1 mutation is associated with spontaneous hemorrhage in pediatric and young adult LGG.

Induction of large cerebral aneurysms by intraperitoneal administration of β-aminopropionitrile fumarate in male rats.
Yusuke Shimoda, Naoki Nakayama, Takuya Moriwaki, Takeo Abumiya, Masahito Kawabori, Kota Kurisu, Masayuki Gekka, Masaaki Hokari, Yasuhiro Ito, Kiyohiro Houkin
Journal of neurosurgical sciences, 2020年02月04日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: It is necessary and useful to obtain an experimental model which steadily and rapidly induces aneurysms for investigation of the pathogenesis of cerebral aneurysm. We attempted to examine whether intraperitoneal administration of β-aminopropionitrile fumarate (BAPN-F) with additional treatments of induced hypertension and hemodynamic stress could steadily and rapidly induce aneurysms in male rats. METHODS: Seven-week-old male Sprague-Dawley rats pretreated with ligation of left common carotid and bilateral posterior renal arteries were administrated BAPN-F intraperitoneally. Induction rate and size of aneurysms was investigated with varying dose and duration of BAPN-F administration (low dose; 400 mg/kg/week for 4 or 8 weeks and high dose; 2800 mg/kg/week for 8 or 12 weeks). RESULTS: Induction rate in the high-dose groups was significantly higher (p<0.01) than that in the low-dose groups. Making comparisons between 8 and 12 weeks of the high-dose groups, while there was no difference in induction rate (8 weeks; 85.2% vs 12 weeks; 76.9%), aneurysmal size was larger in 12 weeks (8 weeks; 127.5 μm, vs 12 weeks; 181.7 μm in terms of median) but lethal intrathoracic hemorrhage was increased in 12 weeks (8 weeks; 7.4% vs 12 weeks; 30.8%). Induction rate of large aneurysm was 22.2% and 30.8% in 8 and 12 weeks of the high-dose groups, respectively. CONCLUSIONS: High-dose BAPN-F administration can cause high-frequency aneurysmal induction. Although there was the difference in size and mortality rate based on administration duration, intraperitoneal administration of 2800 mg/kg/week BAPN-F for 8 weeks would be suitable for aneurysmal induction.

Reversible Cerebral Angiopathy after Viral Infection in a Pediatric Patient with Genetic Variant of RNF213.
Ikuma Echizenya, Kikutaro Tokairin, Masahito Kawabori, Ken Kazumata, Kiyohiro Houkin
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 29, 2, 104549, 104549, 2020年02月, ［査読有り］, ［国際誌］
英語, Ring finger protein (RNF) 213 is known as a susceptibility gene for moyamoya disease (MMD), which is characterized by bilateral carotid folk stenosis. Cerebral angiopathy after viral infection has been known to present angiographical appearance resembling MMD, however its pathogenesis and genetic background are not well known. We report a case of reversible cerebral angiopathy after viral infection in a pediatric patient with genetic variant of RNF213 mutation. The patient had developed a severe headache after hand, foot, and mouth disease. Magnetic resonance imaging and magnetic resonance angiography (MRA) performed 2-3 weeks after disease onset revealed bilateral carotid folk stenosis and an old cerebral infarction in the left putamen. The patient's headache spontaneously resolved and the follow-up MRA showed a complete spontaneous resolution of the arterial stenosis after 9 months. We were able to determine genetic predisposition to angiopathy by identifying the RNF213 c.14576G>A (rs112735431, p.R4859K) mutation. Based on the present case, we hypothesize that an RNF213 variant might play an important role for the onset of postviral cerebral angiopathy.

Complication rate, cure rate, and long-term outcomes of microsurgery for intracranial dural arteriovenous fistulae: a multicenter series and systematic review.
Taku Sugiyama, Naoki Nakayama, Satoshi Ushikoshi, Ken Kazumata, Michinari Okamoto, Masaki Ito, Toshiya Osanai, Yusuke Shimoda, Kazuki Uchida, Daisuke Shimbo, Yasuhiro Ito, Katsuyuki Asaoka, Toshitaka Nakamura, Satoshi Kuroda, Kiyohiro Houkin
Neurosurgical review, 44, 1, 435, 450, Springer Science and Business Media {LLC}, 2020年01月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Although microsurgery is an established treatment modality for intracranial dural arteriovenous fistula (dAVF), data regarding the perioperative complication rate, cure rate, and long-term outcomes remain scarce. The aims of this study were to describe our original experience with microsurgery, including the surgical complications and pitfalls, and conduct a systematic review of the relevant literature. A multicenter cohort of patients with dAVF treated by microsurgery was retrospectively assessed. In addition, the PubMed database was searched for published studies involving microsurgery for dAVF, and the complication rate, cure rate, and long-term outcomes were estimated. The total number of patients in our multicenter series and published articles was 553 (593 surgeries). The overall rates of transient complications, permanent complications, death, and incomplete treatment were 11.4, 4.0, 1.2, and 6.5%, respectively. A favorable outcome was achieved for 90.1% patients, even though almost half of the patients presented with intracranial hemorrhage. Of note, the incidence of recurrence was only one per 8241 patient-months of postoperative follow-up. Surgeries for anterior cranial fossa dAVF were associated with a lower complication rate, whereas those for tentorial dAVF were associated with higher complication and incomplete treatment rates. The complication and incomplete treatment rates were lower with simple disconnection of cortical venous drainage than with radical occlusion/resection of dural shunts. Our findings suggest that the cure rate, complication rates, and outcomes of microsurgery for dAVF are acceptable; thus, it could be a feasible second-line treatment option for dAVF. However, surgeons should be aware of the specific adverse events of microsurgery.

ラット脊髄損傷モデルにおける骨髄間葉系幹細胞シートによる治療効果の検証
山崎和義, 川堀真人, 川堀真人, 関俊隆, 高宮宗一朗, 寳金清博, 寳金清博
日本脳神経外傷学会プログラム・抄録集, 43rd, 2020年

膠芽腫の治療成績:MEPを中心とした術中モニタリングによる術後performance status温存の重要性
山口秀, 茂木洋晃, 伊師雪友, 岡本迪成, 澤谷亮佑, 寳金清博
日本脳腫瘍の外科学会プログラム・抄録集, 25th, 2020年

Long-Term Clinical Outcome and Prognosis After Thrombectomy in Patients With Concomitant Malignancy.
Sogo Oki, Masahito Kawabori, Sumire Echizenya, Yusuke Shimoda, Daisuke Shimbo, Toshiya Osanai, Kazuki Uchida, Kiyohiro Houkin
Frontiers in neurology, 11, 572589, 572589, FRONTIERS MEDIA SA, 2020年, ［国際誌］
英語, 研究論文（学術雑誌）, Endovascular thrombectomy (EVT) is the preferred treatment strategy for patients with acute ischemic stroke (AIS). However, clinical outcome and prognosis in patients who undergo EVT in response to AIS with concomitant malignancy have not been fully elucidated. Data of patients with malignancy who underwent EVT at participating institutions between January 2015 and April 2019 were retrospectively analyzed. Patient characteristics, treatment methods, posttreatment strategy, and long-term prognosis were evaluated in 12 patients with prediagnoses of malignancy. Good revascularization (TICI 2b or higher) was achieved in 10 of 12 patients. Among the eight patients who survived more than 2 weeks from onset, four patients showed good clinical outcome [modified Rankin Scale (mRS) <2] at 60 days posttreatment and were able to continue treatment for malignancy. However, seven of eight patients died within a year of EVT (median survival, 83 days) due to progression of malignancy. One-year survival was achieved in only one patient whose etiology of stroke was determined as infectious endocarditis and not Trousseau syndrome. Even after successful revascularization and good short-term clinical outcome, the long-term prognosis after thrombectomy in patients with malignancy was poor. Thrombectomy for concomitant malignancy requires judicious decision, and further studies are necessary to fully elucidate its efficacy.

Evaluation of Novel Stereotactic Cannula for Stem Cell Transplantation against Central Nervous System Disease.
Masahito Kawabori, Aki Tanimori, Shinri Kitta, Hideo Shichinohe, Kiyohiro Houkin
Stem cells international, 2020, 4085617, 4085617, 2020年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Cell therapy for central nervous system (CNS) disorders is beginning to prove its safety and efficiency. Intraparenchymal transplantation can be an option for cell delivery; however, one concern regarding this method is that the transplantation cannula may cause additional brain injuries. These include vessel damage, which results in brain hemorrhage, and clogging of the cannula by brain debris and/or cell clusters, which requires replacement of the cannula or forced injection causing jet flow of the cell suspension. We compared cannulas for cell delivery used in clinical trials, the Pittsburg and Mizuho cannulas, to a newly designed one, MK01, to assess their usability. MK01 has a spherical-shaped tip with a fan-like open orifice on the side of the cannula, which prevents vessel damage, clogging of brain debris, and jet flow phenomenon. We compared the extent of rat cervical and abdominal arterial damage with the cannula, the amount of debris in the cannula, the force needed to cause jet flow, and cell viability. While the viability of cells passed through the cannulas was almost the same among cannulas (approximately 95%), the Pittsburg cannula caused cervical arterial injury and subsequent hemorrhage, as it required a significantly smaller force to penetrate the arterial wall. Moreover, the Pittsburg cannula, but not the Mizuho and MK01 cannulas, showed high frequency of brain debris in the needle tip (approximately 80%) after brain puncture. While jet flow of the injection liquid was observed even when using smaller forces in the Pittsburg and Mizuho cannulas, MK01 constantly showed low jet flow occurrence. Thus, MK01 seems to be safer than the previously reported cannulas, although further investigation is necessary to validate its safety for clinical use.

FTY720 (Fingolimod) Ameliorates Brain Injury through Multiple Mechanisms and is a Strong Candidate for Stroke Treatment.
Zifeng Wang, Masahito Kawabori, Kiyohiro Houkin
Current medicinal chemistry, 27, 18, 2979, 2993, 2020年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, FTY720 (Fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist that exerts strong anti-inflammatory effects and was approved as the first oral drug for the treatment of multiple sclerosis by the US Food and Drug Administration (FDA) in 2010. FTY720 is mainly associated with unique functional "antagonist" and "agonist" mechanisms. The functional antagonistic mechanism is mediated by the transient down-regulation and degradation of S1P receptors on lymphocytes, which prevents lymphocytes from entering the blood stream from the lymph node. This subsequently results in the development of lymphopenia and reduces lymphocytic inflammation. Functional agonistic mechanisms are executed through S1P receptors expressed on the surface of various cells including neurons, astrocytes, microglia, and blood vessel endothelial cells. These functions might play important roles in regulating anti-apoptotic systems, modulating brain immune and phagocytic activities, preserving the Blood-Brain-Barrier (BBB), and the proliferation of neural precursor cells. Recently, FTY720 have shown receptor-independent effects, including intracellular target bindings and epigenetic modulations. Many researchers have recognized the positive effects of FTY720 and launched basic and clinical experiments to test the use of this agent against stroke. Although the mechanism of FTY720 has not been fully elucidated, its efficacy against cerebral stroke is becoming clear, not only in animal models, but also in ischemic stroke patients through clinical trials. In this article, we review the data obtained from laboratory findings and preliminary clinical trials using FTY720 for stroke treatment.

Simplified Dural Reconstruction Procedure Using Biocompatible Polyglycolic Acid Felt with Autologous Abdominal Fat Grafts after a Transpetrosal Approach.
Shigeru Yamaguchi, Shunsuke Terasaka, Michinari Okamoto, Yukitomo Ishi, Hiroaki Motegi, Hiroyuki Kobayashi, Kiyohiro Houkin
World neurosurgery, 132, e710-e715, E715, ELSEVIER SCIENCE INC, 2019年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Dural reconstruction after transpetrosal approaches is complicated because complete primary closure of presigmoid dura mater is difficult to achieve. To address this problem, we use biocompatible polyglycolic acid (PGA) felt (Durawave) to reconstruct dural defects. To evaluate the use of PGA felt in dural reconstruction, we compared these results with those after conventional duraplasty using autologous fascia grafts. METHODS: We retrospectively surveyed all cases involving a transpetrosal approach reported since 2013. In the conventional procedure, autologous fascia was fixed over the dural defect using stay sutures; any remaining dead space was obliterated by placing abdominal fat grafts. Since April 2017, we have used PGA felt instead of fascia. RESULTS: Of the 37 cases identified, 27 were reconstructed according to the conventional procedure, and the remaining 10 cases were reconstructed using PGA felt. Among the 27 conventional cases, 8 involved cerebrospinal fluid (CSF)-related complications, including 3 cases of rhinorrhea and 5 cases of subcutaneous fluid collection, and 2 cases (7%) required repair surgery. Of the 10 cases involving PGA felt, 1 case (10%) involved subcutaneous fluid collection and required repair surgery, and whereas the remaining 9 cases had no evidence of CSF leakage. In addition, the median dural reconstruction time using PGA felt was 9 minutes, significantly shorter than that when autologous fascia was used (median, 44 minutes). CONCLUSIONS: Using PGA felt for presigmoid dura simplifies dural reconstruction because it obviates the need to suture in a deep field. PGA felt has the potential to prevent CSF-related complications after transpetrosal approaches.

Inflammation promotes progression of thrombi in intracranial thrombotic aneurysms.
Hime Suzuki, Takeshi Mikami, Tomoaki Tamada, Ryo Ukai, Yukinori Akiyama, Akinori Yamamura, Kiyohiro Houkin, Nobuhiro Mikuni
Neurosurgical review, 43, 6, 1565, 1573, SPRINGER, 2019年11月04日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Advances in the understanding of the pathogenesis of arteriosclerosis, abdominal aorta aneurysms and dissections, and carotid artery plaques have focused on chronic inflammation. In this study, we report that inflammatory changes of thrombi contribute to the enlargement and growth of giant intracranial thrombotic aneurysms. Surgical and postmortem samples were collected from 12 cases of large or giant intracranial thrombotic aneurysms diagnosed via pathological investigations. Degeneration of the aneurysmal wall and the infiltration of inflammatory cells in the thrombi were assessed. The number of blood cells and immunohistochemical stain-positive cells was enumerated, and the inflammation and neovascularization in the thrombi were assessed. In all cases, the appearance of inflammatory cells (CD68+ cells, CD206+ cells, lymphocytes, and neutrophils) was apparent in the thrombi. The number of CD34+ cells was moderately correlated with the number of CD68+ cells, and CD34+ cells significantly and strongly correlated with the number of CD206+ cells. Based on the number of neutrophils per CD68+ cells, we classified the cases into 2 groups: a macrophage inflammation-dominant group and a neutrophilic inflammation-dominant group. The neutrophilic inflammation-dominant group had significantly more cases with previous treatments and neurological symptoms due to mass effect than the macrophage inflammation-dominant group. Chronic inflammation due to macrophages in thrombi is a fundamental mechanism in the enlargement of an intracranial thrombotic aneurysm, and neutrophilic inflammation can accelerate this process. Microvascularization in thrombi is linked to inflammation and might promote thickening of the intima and repeated intimal microbleeds.

Development of Hemorrhage-prone Anastomoses in Asymptomatic Moyamoya Disease-A Comparative Study with Japan Adult Moyamoya Trial.
Shusuke Yamamoto, Takeshi Funaki, Miki Fujimura, Jun C Takahashi, Haruto Uchino, Kiyohiro Houkin, Teiji Tominaga, Susumu Miyamoto, Satoshi Kuroda
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 28, 11, 104328, 104328, ELSEVIER, 2019年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Present study was aimed to precisely evaluate the angio-architectures in patients with asymptomatic moyamoya disease (MMD) by comparing with those with hemorrhagic stroke. METHODS: This study used the data set of cerebral angiography in Asymptomatic Moyamoya Registry (AMORE) Study and Japan Adult Moyamoya (JAM) Trial at enrollment. The development of 3 subtypes of collateral vessels, including lenticulostriate, thalamic, and choroidal anastomosis, was evaluated on cerebral angiography. Suzuki's angiographical stage and posterior cerebral artery (PCA) involvement were also assessed. These findings were compared between asymptomatic (AMORE) and hemorrhagic (JAM) groups. RESULTS: This study included 55 hemispheres of 35 patients in asymptomatic group and 75 hemispheres of 75 patients in hemorrhagic group. In asymptomatic group, thalamic anastomosis was less developed than in hemorrhagic group (P = .011), but there were no significant differences in the development of lenticulostriate and choroidal anastomosis between the 2 groups (P = .077 and P = .26, respectively). Suzuki's stage was more progressed and the prevalence of PCA involvement was significantly higher in hemorrhagic group than in asymptomatic group (P = .0033 and P = .016, respectively). CONCLUSIONS: This study reveals no significant differences in the development of choroidal anastomoses between asymptomatic and hemorrhagic-onset MMD. On the other hand, disease stage and PCA involvement were less advanced in asymptomatic MMD than in hemorrhagic-onset MMD. These findings strongly suggest a certain subgroup of asymptomatic patients with MMD is at potential risk for hemorrhagic stroke.

Association of cognitive function with cerebral blood flow in children with moyamoya disease.
Ken Kazumata, Kikutaro Tokairin, Taku Sugiyama, Masaki Ito, Haruto Uchino, Toshiya Osanai, Masahito Kawabori, Naoki Nakayama, Kiyohiro Houkin
Journal of neurosurgery. Pediatrics, 1, 7, 2019年10月11日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: The cognitive effects of main cerebral artery occlusive lesions are unclear in children with moyamoya disease (MMD). The authors aimed to investigate cognitive function in the presurgical phase of pediatric patients with MMD with no apparent brain lesions. METHODS: In this prospective, observational, single-center study, 21 children (mean age 10 ± 3.0 years, range 5-14 years) diagnosed with MMD at Hokkaido University Hospital between 2012 and 2018 were enrolled. A cross-sectional evaluation of intellectual ability was performed using the Wechsler Intelligence Scale for Children-Fourth Edition at the initial diagnosis. rCBF was measured using [123I] N-isopropyl p-iodoamphetamine/SPECT. The associations among clinical factors, disease severity, regional cerebral blood flow (rCBF), and intelligence test scores were also examined. RESULTS: The mean full-scale intelligence quotient (FIQ) was 101.8 ± 12.5 (range 76-125) in children with no apparent brain lesions. A significant difference in the intelligence scale index score was observed, most frequently (42.9%) between working memory index (WMI) and verbal comprehension index (VCI; VCI - WMI > 11 points). Regional CBF was significantly reduced both in the left and right medial frontal cortices (left: 61.3 ± 5.3 ml/100 g/min, right 65.3 ± 5.3 ml/100 g/min; p < 0.001) compared to the cerebellum (77.8 ± 6.8 ml/100 g/min). There was a significant association of rCBF in the left dorsolateral prefrontal cortex (DLPFC) with FIQ (r = 0.46, p = 0.034), perceptual reasoning index (PRI; r = 0.44, p = 0.045), and processing speed index (PSI; r = 0.44, p = 0.045). There was an association between rCBF of the left medial frontal cortex and PSI (r = 0.49, p = 0.026). Age of onset, family history, ischemic symptoms, and angiographic severity were not associated with poor cognitive performance. CONCLUSIONS: Although average intellectual ability was not reduced in children with MMD, the association of reduced rCBF in the left DLPFC and medial frontal cortex with FIQ, PRI, and PSI suggests mild cognitive dysfunction due to cerebral hypoperfusion.

A Rare Case of Idiopathic Temporal Muscle Abscess in a Nine-month-old Infant.
Sogo Oki, Masahito Kawabori, Hiroaki Motegi, Shigeru Yamaguchi, Hiroyuki Kobayashi, Shunsuke Terasaka, Kiyohiro Houkin
Internal medicine (Tokyo, Japan), 58, 18, 2699, 2702, 2019年09月15日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Temporal muscle abscess in children usually occurs from acute otitis media, and rapid progression and concomitant infectious disease often make it easy to diagnose. We report a rare case of a nine-month-old infant who showed right temporal mass with no evidence of infection. Computed tomography showed an osteolytic round mass, and magnetic resonance imaging revealed heterogenous enhancement with a high apparent diffusion coefficient. Malignant tumor was first suspected, but an open biopsy revealed the swelling to be temporal muscle abscess. It should be noted that temporal abscess may mimic the features of a malignant tumor, and multiple examinations should be performed for an accurate diagnosis.

A Pilot Study on Measuring Tissue Motion During Carotid Surgery Using Video-Based Analyses for the Objective Assessment of Surgical Performance.
Taku Sugiyama, Toshitaka Nakamura, Yasuhiro Ito, Kikutaro Tokairin, Ken Kazumata, Naoki Nakayama, Kiyohiro Houkin
World journal of surgery, 43, 9, 2309, 2319, 2019年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The 'gentle' handling of tissue (i.e., 'respect for tissue') is a fundamental aspect of surgical performance and learning. To date, there have been no methodological assessments that quantitatively measure 'gentleness.' Therefore, the aims of this study were (1) to propose a novel metric for gentle surgical maneuvers, (2) to validate the feasibility of this methodology, and (3) to explore safer surgical techniques through this methodology. METHODS: Using surgical video-based motion software, the motion of the carotid artery around plaque was analyzed and quantified during a carotid endarterectomy. Kinematic parameters (minimum and maximum acceleration, and maximum and mean velocity) were compared among the surgical tasks and techniques, as well as between novice and expert surgeons. RESULTS: The surgical tasks of dissecting the common carotid artery, passing the proximal vessel loops, and ligating vessels showed the highest absolute values of kinematic parameters. Dissections perpendicular to the line of the internal carotid artery tended to show higher kinematic parameters than those in the parallel direction, with blunt dissections typically higher than sharp dissections. The kinematic parameters of novice surgeons were significantly higher than those of experts, and receiver operating curve analysis showed a strong discriminative power. CONCLUSION: This study shows that tissue motion parameters could be a novel and feasible surrogate marker for the objective assessment on the 'gentleness' of surgical performance. Future studies should be performed to further elucidate the relationship on the direct correlation between tissue kinematic data and clinical outcomes or surgical adverse events.

Cost Effectiveness of Drive and Retrieve System in Hokkaido for Acute Ischemic Stroke Patient Treatment Using Geographic Information System.
Yasuhiro Morii, Toshiya Osanai, Tomoki Ishikawa, Kensuke Fujiwara, Takumi Tanikawa, Kiyohiro Houkin, Eiichi Kobayashi, Katsuhiko Ogasawara
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 28, 8, 2292, 2301, 2019年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND PURPOSE: Although endovascular thrombectomy combined with recombinant tissue-type plasminogen activator is effective for treatment of acute ischemic stroke, regional disparities in implementation rates of those treatments have been reported. Drive and retrieve system, where a qualified neurointerventionist travels to another primary stroke center for endovascular thrombectomy, has been practiced in parts of Hokkaido, Japan. This study aims to simulate the cost effectiveness of the drive and retrieve system, which can be a method to enhance equality and cost effectiveness of treatments for acute ischemic stroke. MATERIALS AND METHODS: The number of patients who had acute ischemic stroke in 2015 is estimated. Those patients are generated according to the population distribution, and thereafter patient transport time is analyzed in the 3 scenarios (1) 60-minute drive scenario, (2) 90-minute drive scenario, in which the drive and retrieve system operates within 60-minute or 90-minute driving distance (3) without the system, using geographic information system. Incremental cost-effectiveness rate, quality-adjusted life years, and medical and nursing care costs are estimated from the analyzed transport time. FINDINGS: The incremental cost-effectiveness rate by implementing the system was dominant. Cost reductions of $213,190 in 60-minute drive scenario, and $247,274 in the 90-minute scenario were expected, respectively. Such benefits are the most significant in Soya, Emmon, Rumoi, and Kamikawahokubu medical areas. CONCLUSIONS: The drive and retrieve system could enhance regional equality and cost effectiveness of ischemic stroke treatments in Hokkaido, which can be achieved using existing resources. Further studies are required to clarify its cost effectiveness from hospital perspective.

Characteristics of Moyamoya Disease Based on National Registry Data in Japan.
Yoko Sato, Ken Kazumata, Eiji Nakatani, Kiyohiro Houkin, Yasuhiro Kanatani
Stroke, 50, 8, 1973, 1980, LIPPINCOTT WILLIAMS & WILKINS, 2019年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose- A public registration system for intractable diseases was started in Japan in 1972 to investigate the etiology and pathogenesis of intractable diseases while reducing out-of-pocket medical expenses on patients. The goal of this study was to investigate the epidemiology and clinical characteristics of Moyamoya disease using data from applications submitted to this system between 2004 and 2008. Methods- In addition to demographic factors such as onset age and family history, we evaluated clinical presentation type, imaging findings, clinical symptoms, and functioning in activities of daily living (ADL). Results- Of 3859 cases for which applications were submitted, 2545 were confirmed to meet the diagnostic criteria after data cleansing. Onset age showed a bimodal distribution, and Moyamoya disease had a higher incidence in women than in men. The presence of occlusion and infarction in the proximal region of the anterior cerebral artery was more frequent in pediatric cases than adult cases. Our findings also indicated that 23% of patients required assistance with ADL. Cerebral infarction (odds ratio [OR], 12.5; 95% CI, 3.55-44.66), seizure (OR, 7.44; 95% CI, 1.29-42.96), and sensory disorders (OR, 5.23; 95% CI, 1.15-23.75) were identified as significant predictors of impaired ADL in pediatric cases 3 years after the initial application. Moderate ADL function (OR, 11.59; 95% CI, 5.29-25.39) and intellectual disabilities (OR, 4.38; 95% CI, 1.58-12.17) at the time of the application were identified as significant prognostic factors in adults. Conclusions- The results of this study indicated that characteristics of Moyamoya disease such as onset type, symptoms, and imaging abnormalities differ with onset age. Prognostic analyses suggested that pediatric cases with good ADL but with infarct type onset, seizure, or sensory disorders might have a subsequent decline in ADL.

Investigation of the Neuropathic Pain Caused by Syringomyelia Associated with Chiari I Malformation.
Toshitaka Seki, Shuji Hamauchi, Masayoshi Yamazaki, Kazutoshi Hida, Shunsuke Yano, Kiyohiro Houkin
Asian spine journal, 13, 4, 648, 653, 2019年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Study Design: Retrospective cohort study. Purpose: To investigate the correlation between the syrinx morphology and neuropathic pain caused by syringomyelia associated with Chiari I malformation. Overview of Literature: Neuropathic pain caused by syringomyelia is refractory and markedly impairs the patient. Methods: We examined 24 patients with neuropathic pain caused by syringomyelia associated with Chiari I malformation. We statistically analyzed the illness duration and age at surgery between patients with and without neuropathic pain. Additionally, we classified the morphology of the syringes into deviated (D), enlarged (E), central (C), and bulkhead (B) types using T2-weighted axial imaging. Moreover, we investigated the correlation between syrinx morphology and neuropathic pain. A Mann-Whitney U-test was performed to compare between the presence or absence of neuropathic pain and the presence or absence of type D syringes. Results: The median age at surgery was 27.5 years, and the median illness duration was 24 months. Among the 24 patients, 11 had preoperative neuropathic pain, one of which was free of neuropathic pain during the final follow-up period. Among patients with neuropathic pain, the syringes' preoperative morphology was type D in nine patients and types E and C in one patient each. No patient exhibited type B morphology. Among patients without neuropathic pain, the preoperative morphology of the syringes was type D in three patients, type E in seven patients, and types C and B in two patients each. For types D and E, a correlation between neuropathic pain and syrinx morphology was observed. Moreover, type D was associated with significant neuropathic pain in both preoperative and postoperative states. Conclusions: This study showed a correlation between the morphological features of the syringes and the occurrence of neuropathic pain in patients with syringomyelia associated with Chiari I malformation.

Efficacy of 'drive and retrieve' as a cooperative method for prompt endovascular treatment for acute ischemic stroke.
Toshiya Osanai, Yasuhiro Ito, Satoshi Ushikoshi, Takeshi Aoki, Masahito Kawabori, Kensuke Fujiwara, Katsuhiko Ogasawara, Kikutaro Tokairin, Katsuhiko Maruichi, Naoki Nakayama, Ken Kazumata, Kota Ono, Kiyohiro Houkin
Journal of neurointerventional surgery, 11, 8, 757, 761, 2019年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Outcomes of endovascular treatment for acute ischemic stroke depend on the time interval from onset to reperfusion. Although the centralized 'mothership' method is considered preferable, the required transportation time increases the risk that a patient with a stroke may not receive intravenous or endovascular therapy. In contrast, 'drive and retrieve' describes a system wherein doctors from comprehensive stroke centers travel to primary stroke centers and provide endovascular treatment for acute ischemic stroke. OBJECTIVE: To describe the drive and retrieve system and verify the effects of this new collaboration on outcomes in patients with acute ischemic stroke among facilities. METHODS: This non-randomized, single-arm study retrospectively analyzed patients who met the inclusion criteria for endovascular treatment provided through a drive and retrieve system. Among the 122 patients treated by this system, we analyzed the time of onset to recanalization as the primary outcome. We also analyzed the efficacy of the drive and retrieve system using geographic information system analysis. RESULTS: The median time from onset to recanalization was 229 min (IQR 170-307 min, 95% CI 201 to 252 min). The upper limit of the 95% CI for the time from onset to recanalization was shorter than the median times reported in two previous trials. Geographic information system analysis revealed an upward trend in the population coverage rate in each secondary medical area after the drive and retrieve method was introduced. CONCLUSION: The drive and retrieve method may be an effective form of cooperation between facilities located within 1 hour of a comprehensive stroke center.

Contrecoup Injury-Induced Middle Meningeal Arteriovenous Fistula Detected by Time-of-Flight Magnetic Resonance Angiography and Magnetic Resonance Arterial Spin Labeling: Case Report and Review of the Literature.
Kikutaro Tokairin, Toshiya Osanai, Ken Kazumata, Ryosuke Sawaya, Kiyohiro Houkin
World neurosurgery, 127, 79, 84, 2019年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Middle meningeal arteriovenous fistula (MM-AVF) is rare; however, it will sometimes be followed by intracranial hemorrhage or progressive symptoms caused by abnormal shunt flow. Radiological examination and endovascular treatment of this condition have recently advanced; thus, we have described the pathogenesis, clinical features, and appropriate diagnostic and therapeutic management of MM-AVF. We also reviewed the reported data of the past 35 years, including 30 cases of MM-AVF. CASE DESCRIPTION: We report the case of 24-year-old man who had presented with right tinnitus who had experienced previous head trauma on the opposite side to the tinnitus ear. Time-of-flight magnetic resonance angiography and magnetic resonance arterial spin labeling findings were suggestive of MM-AVF, and catheter angiography confirmed MM-AVF with shunt flow draining into the cavernous sinus. Endovascular transarterial embolization was performed, and the MM-AVF was embolized successfully using detachable coils and n-butyl-2-cyanoacrylate. The tinnitus disappeared completely immediately after the treatment. CONCLUSIONS: MM-AVF is caused, not only by coup injury, but also by contrecoup injury. Time-of-flight magnetic resonance angiography and magnetic resonance arterial spin labeling are useful for detecting MM-AVF. Endovascular transarterial embolization is an effective and safe treatment.

Correlation between magnetic resonance imaging characteristics and BRAF alteration status in individuals with optic pathway/hypothalamic pilocytic astrocytomas.
Yukitomo Ishi, Shigeru Yamaguchi, Michiharu Yoshida, Hiroaki Motegi, Hiroyuki Kobayashi, Shunsuke Terasaka, Kiyohiro Houkin
Journal of neuroradiology = Journal de neuroradiologie, 48, 4, 266, 270, MASSON EDITEUR, 2019年06月20日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND PURPOSE: Most individuals with optic pathway/hypothalamic pilocytic astrocytoma (OPHPA) harbor either the BRAF V600E mutation or KIAA1549-BRAF fusion (K-B). This study aimed to investigate the imaging characteristics of OPHPA in relation to BRAF alteration status. MATERIALS AND METHODS: Seven cases of OPHPA harboring either the BRAF V600E mutation or K-B fusion were included in the study. Preoperative magnetic resonance imaging (MRI) was assessed for degree of T2 hyperintensity on T2-weighted images (T2WI) and the ratio of nonenhancing T2 or fluid-attenuated inversion recovery (FLAIR) hyperintense area to the contrast enhanced area (CE) on gadolinium-enhanced-T1 weighted images (T2/FLAIR-CE mismatch). The T2 signal intensity was normalized to cerebrospinal fluid (T2/CSF) for both the V600E and K-B group and compared. T2/FLAIR-CE mismatch was assessed by calculating the proportion of the tumor volume of nonenhancing high T2 signal intensity to the whole lesion (nonenhancing and enhancing components). RESULTS: Four and three cases of OPHPA harboring the BRAF V600E mutation and K-B, respectively, were analyzed. The T2/CSF value was higher in the K-B group than in the V600E group. Moreover, the V600E group had a larger T2/FLAIR-CE mismatch than the K-B group. CONCLUSIONS: The BRAF alteration status in individuals with OPHPA was associated with preoperative MRI by focusing on T2 signal intensity and T2/FLAIR-CE mismatch. The BRAF V600E mutation was associated with a lower T2/CSF value and larger T2/FLAIR-CE mismatch, whereas K-B fusion was associated with a higher T2/CSF value and smaller T2/FLAIR-CE mismatch.

Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischaemic stroke in Japan: a multicentre, open-label, randomised controlled trial.
Kazunori Toyoda, Shinichiro Uchiyama, Takenori Yamaguchi, J Donald Easton, Kazumi Kimura, Haruhiko Hoshino, Nobuyuki Sakai, Yasushi Okada, Kortaro Tanaka, Hideki Origasa, Hiroaki Naritomi, Kiyohiro Houkin, Keiji Yamaguchi, Masanori Isobe, Kazuo Minematsu
The Lancet. Neurology, 18, 6, 539, 548, 2019年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although dual antiplatelet therapy with aspirin and clopidogrel reduces early recurrence of ischaemic stroke, with long-term use this type of therapy is no longer effective and the risk of bleeding increases. Given that cilostazol prevents stroke recurrence without increasing the incidence of serious bleeding compared with aspirin, we aimed to establish whether dual antiplatelet therapy involving cilostazol is safe and appropriate for long-term use. METHODS: In a multicentre, open-label, randomised controlled trial across 292 hospitals in Japan, patients with high-risk non-cardioembolic ischaemic stroke identified on MRI were randomly assigned to two groups in a 1:1 ratio to receive monotherapy with either oral aspirin (81 or 100 mg, once per day) or clopidogrel (50 or 75 mg, once per day) alone, or a combination of cilostazol (100 mg, twice per day) with aspirin or clopidogrel. Randomisation was done centrally (using block randomisation with a block size of six per each participating hospital) through a web-based registration system and was done by EPS Corporation. The patients were required to have at least 50% stenosis of a major intracranial or extracranial artery or two or more of the vascular risk factors. Trial medication was continued for half a year or longer, for a maximum of 3·5 years. The primary efficacy outcome was the rate of first recurrence of symptomatic ischaemic stroke. Safety outcomes were severe or life-threatening bleeding; any adverse events; serious adverse events; and any bleeding events. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in the as-treated population. This trial was registered with ClinicalTrials.gov (number NCT01995370) and UMIN Clinical Trials Registry (number 000012180). FINDINGS: Participants were recruited from Dec 13, 2013, to March 31, 2017. 932 patients assigned to the dual therapy group and 947 patients assigned to the monotherapy group were included in the intention-to-treat analysis. The trial was stopped after the enrolment of 1884 patients of an anticipated 4000 patients because of the delay in recruitment. Ischaemic stroke recurred in 29 (3%) of 932 patients (annualised rate 2·2%) on dual therapy including cilostazol and 64 (7%) of 947 patients (annualised rate 4·5%) on monotherapy during a median 1·4 years follow-up (hazard ratio [HR] 0·49, 95% CI 0·31-0·76, p=0·0010). Severe or life-threatening bleeding occurred in eight patients (annualised rate 0·6%) on dual therapy and 13 patients (annualised rate 0·9%) on monotherapy (HR 0·66, 95% CI 0·27-1·60, p=0·35). Occurrence of any type of adverse event was similar between the groups (255 [28%] of 910 patients in the dual therapy group vs 219 [24%] of 921 patients in the monotherapy group); as was occurrence of serious adverse events (87 [10%] vs 142 [15%]) and bleeding events (38 [4%] vs 33 [4%]). Gastrointestinal bleeding, which affected nine (<1%) of 910 patients in the monotherapy group and nine (<1%) of 921 patients in the dual therapy group, was the most common type of bleeding. INTERPRETATION: The combination of cilostazol with aspirin or clopidogrel had a reduced incidence of ischaemic stroke recurrence and a similar risk of severe or life-threatening bleeding compared with treatment with aspirin or clopidogrel alone in patients at high risk for recurrent ischaemic stroke. FUNDING: Otsuka Pharmaceutical.

Identification of PEPT2 as an important candidate molecule in 5-ALA-mediated fluorescence-guided surgery in WHO grade II/III gliomas.
Chongxian Hou, Shigeru Yamaguchi, Yukitomo Ishi, Shunsuke Terasaka, Hiroyuki Kobayashi, Hiroaki Motegi, Kanako C Hatanaka, Kiyohiro Houkin
Journal of neuro-oncology, 143, 2, 197, 206, 2019年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery (FGS) appears to be a promising treatment for glioma. However, 5-ALA-mediated fluorescence cannot always be detected in grade II/III gliomas. We hypothesized that gene expression patterns in the Protoporphyrin IX (PpIX) synthesis pathway may be associated with intraoperative fluorescence status of grade II/III gliomas, and then attempted to identify the key molecule of 5-ALA-mediated fluorescence. METHODS: Using 50 surgically obtained specimens, which were diagnosed as grade II and III gliomas, we analyzed gene expression within the PpIX synthesis pathway to identify candidate molecules according to intraoperative 5-ALA-mediated fluorescence status. The most likely candidate gene was selected and confirmed by protein expression analysis. To evaluate the biological function of the molecule in PpIX synthesis, functional analysis was performed using specific, small interference (si)RNA in the SW-1783 human grade III glioma cell line. RESULTS: Among the genes involved in the porphyrin synthesis pathway, the mRNA expression of Peptide transporter 2 (PEPT2) in FGS fluorescence-positive gliomas was significantly higher than that in fluorescence-negative gliomas. Protein expression of PEPT2 was also significantly higher in the fluorescence-positive gliomas, which was confirmed by western blot analysis and immunofluorescence analysis. The siRNA-mediated downregulation of the mRNA and protein expression of PEPT2 led to decreased PpIX fluorescence intensity, as confirmed by fluorescence spectrum analysis. CONCLUSIONS: The results suggest PEPT2 is an important candidate molecule in 5-ALA-mediated FGS in grade II/III gliomas. As the overexpression of PEPT2 was associated with higher PpIX fluorescence intensity, PEPT2 may improve fluorescence-guided resection in grade II/III gliomas.

Strategy and effect of repeat bypass surgery for anterior/posterior circulation in refractory moyamoya disease.
Haruto Uchino, Daina Kashiwazaki, Naoki Akioka, Masaki Koh, Naoya Kuwayama, Kiyohiro Houkin, Satoshi Kuroda
Journal of neurosurgery, 132, 6, 1, 11, 2019年05月31日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: In this study the authors aimed to describe clinical features, surgical techniques, and long-term outcomes of repeat bypass surgery required for a certain subset of patients with moyamoya disease. METHODS: The authors retrospectively reviewed a total of 22 repeat bypass surgeries for 20 patients (age range 1-69 years) performed during the last 20 years at their institutions. The patients were classified into 2 groups. Group A included 10 patients who underwent repeat bypass surgery for anterior circulation due to insufficient revascularization on the ipsilateral side. Group B included 10 patients who underwent repeat bypass surgery for posterior circulation due to the involvement of the posterior cerebral artery (PCA) after successful initial surgery for anterior circulation. RESULTS: Preoperative symptoms included headache in 3 patients, transient ischemic attack in 10, cerebral infarction in 3, and intracranial hemorrhage in 4 patients. Intervals between the initial bypass surgery and repeat bypass surgery were 0.3-30 years (median 3 years). In group A, superficial temporal artery to middle cerebral artery (MCA) anastomosis and indirect bypass were performed on 7 hemispheres. Only indirect bypass was performed on 3 hemispheres because of the lack of suitable donor or recipient arteries. In group B, occipital artery (OA) to PCA anastomosis and indirect bypass were conducted on 4 hemispheres, and OA-MCA anastomosis and indirect bypass on 1 hemisphere. Only indirect bypass was conducted on 7 hemispheres because of the lack of suitable recipient arteries. All 22 repeat bypass surgeries were successfully conducted. During follow-up periods (median 4 years), none of the patients suffered repeat stroke except 1 patient who died of recurrent intracerebral hemorrhage 3 years after repeat bypass surgery for anterior circulation. CONCLUSIONS: Repeat bypass surgery was feasible and effective to reduce further incidence of headache attack, transient ischemic attack, and ischemic/hemorrhagic stroke in moyamoya disease patients. Through precise radiological analysis, surgical procedures should be planned to yield maximal therapeutic effects.

Intrinsic development of choroidal and thalamic collaterals in hemorrhagic-onset moyamoya disease: case-control study of the Japan Adult Moyamoya Trial.
Miki Fujimura, Takeshi Funaki, Kiyohiro Houkin, Jun C Takahashi, Satoshi Kuroda, Yasutake Tomata, Teiji Tominaga, Susumu Miyamoto
Journal of neurosurgery, 130, 5, 1453, 1459, 2019年05月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: This study was performed to identify the angiographic features of hemorrhagic-onset moyamoya disease (MMD) in comparison with those of patients with ischemic-onset MMD. METHODS: This case-control study compared the data set of the Japan Adult Moyamoya (JAM) Trial with the angiographic data of adult patients with ischemic-onset MMD. The authors analyzed angiograms obtained at onset, classifying the collaterals into 3 subtypes: lenticulostriate anastomosis, thalamic anastomosis, and choroidal anastomosis. They then compared the extent of these collaterals, as indicated by the collateral development grade from 0 to 2 in each subtype, between the JAM Trial group and the ischemic-onset group. They also compared the involvement of the posterior cerebral artery (PCA) and Suzuki's angiographic staging between each group. RESULTS: Among 89 ischemic-onset patients, 103 symptomatic hemispheres in 80 patients were analyzed and compared with 75 hemorrhagic hemispheres from the JAM Trial. The hemorrhagic-onset patients showed a significantly higher proportion of thalamic anastomosis (p = 0.043) and choroidal anastomosis (< 0.001), as indicated by grade 2 in each subtype, compared with ischemic-onset patients. Suzuki's angiographic staging was significantly higher in the hemorrhagic group (< 0.038). There was no difference in the extent of lenticulostriate anastomosis and PCA involvement between the groups. CONCLUSIONS: In adult MMD, the characteristic pattern of the abnormal vascular networks at the base of the brain is different between each onset type. In light of the more prominent development of thalamic and choroidal anastomosis in the JAM Trial group in the present study, development of these collaterals, especially the choroidal collateral extending beyond the lateral ventricle, may play a critical role in hemorrhagic presentation in MMD.Clinical trial registration no. C000000166 (http://www.umin.ac.jp/ctr/index.htm).

Mollaret Meningitis with a High Level of Cytokines in the Cerebrospinal Fluid Successfully Treated by Indomethacin.
Masahito Kawabori, Kota Kurisu, Yoshimasa Niiya, Yuzuru Ohta, Shoji Mabuchi, Kiyohiro Houkin
Internal medicine (Tokyo, Japan), 58, 8, 1163, 1166, 2019年04月15日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A rare case of Mollaret meningitis characterized by four recurrent episodes of aseptic meningitis during a three-year period is reported. The patient showed a high fever and severe headache accompanied by a high level of cerebrospinal fluid (CSF) cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). The symptoms and high CSF cytokines were resolved immediately after introducing indomethacin treatment. Reactivation of the latent virus is considered to be the cause of this rare disease, and indomethacin is believed to inhibit the periodic abnormal generation of eicosanoid in the brain, resulting in a reduction in the fever and subsequent inflammation.

Estimation of the number of feeding arteries of spinal arteriovenous malformations by using three-dimensional digital subtraction angiography.
Soichiro Takamiya, Toshiya Osanai, Toshitaka Seki, Noriyuki Fujima, Kazutoshi Hida, Takeshi Asano, Kazuyoshi Yamazaki, Shuji Hamauchi, Toru Sasamori, Kota Ono, Shunsuke Terasaka, Kiyohiro Houkin
European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society, 28, 4, 842, 848, 2019年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Spinal angiography is the gold standard for evaluation or diagnosis of spinal arteriovenous malformations (AVMs). However, some feeding arteries might be overlooked when multiple feeders exist. This study aimed to retrospectively review cases of spinal intra-dural AVMs, which were identified by three-dimensional digital subtraction angiography (3D-DSA), and attempted to estimate the number of feeding arteries. METHODS: We retrospectively reviewed patients with spinal intra-dural AVMs who underwent 3D-DSA at Hokkaido University Hospital from January 2005 to December 2016. We selected 9 patients in whom we could obtain data of multi-planar reconstruction of 3D-DSA. We measured the computed tomography (CT) values of feeding arteries and draining veins. The CT values represented the averages of maximum CT values of 5 continuous axial slices. The ratio of the CT value of feeders to that of drainers (F/D ratio) was calculated. The correlation between the F/D ratio and the number of feeders was examined with Pearson's correlation coefficient. RESULTS: The average number of feeders was 2.3 (1-4), and the number of feeders was significantly positively correlated with the F/D ratio (r = 0.855, P = .003). CONCLUSIONS: We conclude that the number of feeding arteries of spinal intra-dural AVMs can be estimated by using the F/D ratio obtained from 3D-DSA. These slides can be retrieved under Electronic Supplementary Material.

Effect of choroidal collateral vessels on de novo hemorrhage in moyamoya disease: analysis of nonhemorrhagic hemispheres in the Japan Adult Moyamoya Trial.
Takeshi Funaki, Jun C Takahashi, Kiyohiro Houkin, Satoshi Kuroda, Miki Fujimura, Yasutake Tomata, Susumu Miyamoto
Journal of neurosurgery, 132, 2, 408, 414, 2019年02月08日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Following hemorrhagic stroke in moyamoya disease, de novo intracranial hemorrhage can occur in the previously unaffected nonhemorrhagic hemisphere. In the present analysis the authors intended to determine whether the presence in the nonhemorrhagic hemisphere of choroidal collateral vessels, which have been the focus of attention as a source of bleeding, affects the risk of de novo hemorrhage. METHODS: The subject of focus of the present cohort study was the nonhemorrhagic hemispheres of adult patients with hemorrhagic moyamoya disease enrolled in the Japan Adult Moyamoya Trial and allocated to the nonsurgical arm. The variable of interest was the presence of choroidal collaterals (also termed choroidal anastomoses), identified with baseline angiography and represented by a connection (anastomosis) between the anterior or posterior choroidal arteries and the medullary arteries. The outcome measure was de novo hemorrhage during the 5-year follow-up period, assessed in all nonhemorrhagic hemispheres. The incidence of de novo hemorrhage in the collateral-positive and -negative groups was compared. RESULTS: Choroidal collaterals were present in 15 of 36 (41.7%) nonhemorrhagic hemispheres analyzed. The overall annual risk of de novo hemorrhage was 2.0%. Three de novo hemorrhages occurred in the collateral-positive group, whereas no hemorrhage occurred in the collateral-negative group. The annual risk of de novo hemorrhage was significantly higher in the collateral-positive group than in the collateral-negative group (5.8% per year vs 0% per year; p = 0.017). All hemorrhage sites corresponded to the distribution of choroidal collaterals. CONCLUSIONS: The present preliminary results suggest that the presence of choroidal collaterals affects the risk of de novo hemorrhage in the nonhemorrhagic hemisphere, subject to verification in larger studies. Further studies are needed to determine the optimal treatment strategy for nonhemorrhagic hemispheres and asymptomatic patients.

Rivaroxaban administration after acute ischemic stroke: The RELAXED study
Masahiro Yasaka, Kazuo Minematsu, Kazunori Toyoda, Etsuro Mori, Teruyuki Hirano, Toshimitsu Hamasaki, Hiroshi Yamagami, Takehiko Nagao, Shinichi Yoshimura, Shinichiro Uchiyama, Takenori Yamaguchi, Yasushi Okada, Satoshi Okuda, Kazumi Kimura, Norio Tanahashi, Yasuo Terayama, Yoichiro Hashimoto, Yasuhiro Hasegawa, Kiyohiro Houkin, Masayasu Matsumoto, Kazuo Kitagawa, Masahiro Yasaka, Ken Nagata, Shigeru Nogawa, Yoshiaki Kumon, Takeshi Kimura, Yutaka Furukawa, Tomohiro Sakamoto, Makoto Sakai, Kohsuke Kudo, Toshinori Hirai, Shotai Kobayashi
PLOS ONE, 14, 2, PUBLIC LIBRARY SCIENCE, 2019年02月, ［査読有り］
英語, 研究論文（学術雑誌）, The efficacy of early anticoagulation in acute stroke with nonvalvular atrial fibrillation (NVAF) remains unclear. We performed a study to evaluate the risk of recurrent ischemic stroke (IS) and major bleeding in acute IS patients with NVAF who started rivaroxaban. This observational study evaluated patients with NVAF and acute IS/transient ischemic attack (TIA) in the middle cerebral arterial territory who started rivaroxaban within 30 days after the index IS/TIA. The primary endpoints were recurrent IS and major bleeding within 90 days after the index IS/TIA. The relationship between the endpoints and the time to start rivaroxaban was evaluated by correlation analysis using cerebral infarct volume, determined by diffusion-weighted magnetic resonance images within 48 hours of onset of the index IS/TIA. Of 1309 patients analyzed, recurrent IS occurred in 30 (2.3%) and major bleeding in 11 (0.8%) patients. Among patients with known infarct size (N = 1207), those with small (<4.0 cm(3)), medium (>= 4.0 and <22.5 cm(3)), and large (>= 22.5 cm(3)) infarcts started rivaroxaban a median of 2.9, 2.9, and 5.8 days, respectively, after the index IS/TIA. Recurrent IS was significantly less frequent when starting rivaroxaban <= 14 days versus >= 15 days after IS (2.0% versus 6.8%, P=0.0034). Incidences of recurrent IS and major bleeding in whom rivaroxaban was started <3 days (N = 584) after IS were also low: 1.5% and 0.7%, respectively. Initiation of rivaroxaban administration in acute IS or TIA was associated with a low recurrence of IS (2.3%), and a low incidence of major bleeding events (0.8%) for 90 days after the index stroke. For the prevention of recurrent attacks in acute IS patients with NVAF, it is feasible to start the administration of rivaroxaban within 14 days of onset. Rivaroxaban started within 3 days of onset may be a feasible treatment option for patients with a small or medium-sized infarction.

High rebleeding risk associated with choroidal collateral vessels in hemorrhagic moyamoya disease: analysis of a nonsurgical cohort in the Japan Adult Moyamoya Trial.
Takeshi Funaki, Jun C Takahashi, Kiyohiro Houkin, Satoshi Kuroda, Shigekazu Takeuchi, Miki Fujimura, Yasutake Tomata, Susumu Miyamoto
Journal of neurosurgery, 130, 2, 337, 673, 2019年02月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVEChoroidal collateral vessels typical of moyamoya disease have received attention as a potential bleeding source. The authors' previous angiographic cross-sectional analysis suggested a possible association between choroidal collaterals and posterior hemorrhage, indicating a high risk for rebleeding. The present longitudinal analysis is intended to determine whether choroidal collaterals are a predictor of rebleeding in hemorrhagic moyamoya disease.METHODSThe Japan Adult Moyamoya Trial group designed an ancillary cohort study using 5-year follow-up data on 37 patients included in the nonsurgical arm of the original randomized controlled trial and compared the rebleeding rate of those with and those without choroidal collaterals, represented by the connection between the anterior or posterior choroidal arteries and the medullary arteries. An expert panel determined whether a choroidal collateral was present in each patient through the measurement of baseline angiography studies. The rebleeding rate comparison was adjusted for age, diagnosis of hypertension, and involvement of the posterior cerebral artery.RESULTSChoroidal collaterals were present in 21 patients (56.8%). The rebleeding rate was 13.1% per year in the collateral-positive group as compared with 1.3% in the negative group (p = 0.008, log-rank test). The adjusted hazard ratio for rebleeding in the collateral-positive group relative to the negative group remained statistically significant (HR 11.10, 95% CI 1.37-89.91). Radiographic assessment of the collateral-positive group revealed good correspondence between the distribution of collaterals and rebleeding sites.CONCLUSIONSResults of this study suggest that choroidal collaterals are a bleeding source with a high risk for hemorrhagic recurrence and a predictor of rebleeding in hemorrhagic moyamoya disease.

Long-Term Evaluation of Combination Treatment of Single Agent HD-MTX Chemotherapy up to Three Cycles and Moderate Dose Whole Brain Irradiation for Primary CNS Lymphoma.
Hiroyuki Kobayashi, Shigeru Yamaguchi, Hiroaki Motegi, Sadahiro Kaneko, Shogo Endou, Rikiya Onimaru, Shunsuke Terasaka, Kiyohiro Houkin
Journal of chemotherapy (Florence, Italy), 31, 1, 35, 41, 2019年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, High-dose methotrexate (HD-MTX)-based chemotherapy in combination with whole brain radiotherapy (WBRT) has been a common therapy for primary central nervous system lymphoma (PCNSL). The aim of this study was to evaluate the survival benefit of a minimized cycle of HD-MTX monotherapy prior to WBRT. A maximum of three cycles of HD-MTX was combined with a WBRT dose of 30 Gy and an additional localized boost was administered where remnant was observed. A total of 54 patients with newly diagnosed PCNSL were enrolled in this study. The objective response rate for HD-MTX was 80% and the median overall survival was 58.4 months. Responders to HD-MTX demonstrated better survival than patients with resistance. The concentration of MTX in serum and cerebrospinal fluid was not related the chemotherapeutic response. This study demonstrated the efficacy of HD-MTX prior to WBRT and indicated that three cycles of HD-MTX monotherapy may be sufficient in combination with radiotherapy.

SONODYNAMIC THERAPY FOR MALIGNANT GLIOMA USING 220-KHZ TRANSCRANIAL MAGNETIC RESONANCE IMAGING-GUIDED FOCUSED ULTRASOUND AND 5-AMINOLEVULINIC ACID
Michiharu Yoshida, Hiroyuki Kobayashi, Shunsuke Terasaka, Shogo Endo, Shigeru Yamaguchi, Hiroaki Motegi, Rachmilevitch Itay, Shiji Suzuki, Omer Brokman, Yeruham Shapira, Kenji Moriyama, Yumiko Kawase, Toshiaki Akahane, Yasutaka Kato, Hajime Kamada, Kiyohiro Houkin
ULTRASOUND IN MEDICINE AND BIOLOGY, 45, 2, 526, 538, ELSEVIER SCIENCE INC, 2019年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Sonodynamic therapy (SDT) is used to treat various malignancies and can be applied to brain tumors using a transcranial magnetic resonance imaging-guided focused ultrasound (TcMRgFUS) device. This study investigated the efficacy of 220-kHz TcMRgFUS combined with 5-aminolevulinic acid (5-ALA) on malignant glioma in vitro and in vivo. F98 cells were irradiated with focused ultrasound (FUS) (4000 J, 20 W, 240 s, 100% duty cycle, target medium temperature <40 degrees C) after treatment with 200 mu g/mL 5-ALA, and cell viability and apoptosis were evaluated with the water-soluble tetrazolium-1 assay, triple fluorescent staining and Western blot analysis 20 h later. The anti-tumor effects of 5-ALA combined with FUS (500 J, 18 W, 30 s, 100% duty cycle, 10 repeats, target tissue temperature <= 42 degrees C) were assessed on the basis of changes in tumor volume determined by MRI and histopathological analysis before and after treatment. The FUS/5-ALA combination reduced cell viability by inducing apoptosis and suppressed tumor proliferation and invasion as well as angiogenesis in vivo, while causing minimal damage to normal brain tissue. SDT with 220-kHz TcMRgFUS and 5-ALA can be safely used for the treatment of malignant glioma. (E-mail: hiro-ko@med.hokudai.ac.jp) (C) 2018 World Federation for Ultrasound in Medicine & Biology. All rights reserved.

ラット亜急性期脊髄損傷モデルにおける骨髄間葉系幹細胞シートによる治療効果の検証
山崎和義, 川堀真人, 関俊隆, 七戸秀夫, 高宮宗一郎, 濱内祝嗣, 寳金清博, 寳金清博
日本分子脳神経外科学会プログラム・抄録集, 20th, 2019年

脳梗塞亜急性期に対する自家骨髄間質細胞の脳内投与 第一相治験:RAINBOW研究
川掘真人, 七戸秀夫, 黒田敏, 寳金清博
脳循環代謝(Web), 31, 1, 2019年

ラット脊髄損傷モデルにおけるFTY720の治療効果の検証
山崎和義, 川堀真人, 関俊隆, 濱内祝嗣, 寳金清博
日本脊髄外科学会プログラム・抄録集, 34th, 2019年

成人脊髄係留症候群:当院12症例の検討
高宮宗一朗, 関俊隆, 濱内祝嗣, 山崎和義, 飛彈一利, 小柳泉, 寳金清博
日本脊髄外科学会プログラム・抄録集, 34th, 2019年

もやもや病(ウイリス動脈輪閉塞症)の診断,治療に関する研究
寳金清博
もやもや病(ウイリス動脈輪閉塞症)の診断、治療に関する研究 平成30年度 総括研究報告書(Web), 2019年

もやもや病(ウイリス動脈輪閉塞症)の診断,治療に関する研究 日本もやもやレジストリ構築の進捗状況
数又研, 寳金清博
もやもや病(ウイリス動脈輪閉塞症)の診断、治療に関する研究 平成30年度 総括研究報告書(Web), 2019年

術前にCTガイド下経皮的嚢胞穿刺を行ったperineural cystの一例
濱内祝嗣, 関俊隆, 森田亮, 木村輔, 阿保大介, 寳金清博
日本脊髄外科学会プログラム・抄録集, 34th, 2019年

下錐体静脈洞サンプリングにおけるアクセスルートMR venography
東海林菊太郎, 長内俊也, 藤間憲幸, 牛越聡, 茂木洋晃, 伊師雪友, 寳金清博
脳血管内治療(Web), 4, Supplement, 2019年

北海道での理想的な血栓回収療法提供体制の確立に向けた取り組み
長内俊也, 東海林菊太郎, 今井哲秋, 寳金清博, 小笠原克彦
脳血管内治療(Web), 4, Supplement, 2019年

脊髄神経膠腫の分子診断と予後
伊師雪友, 関俊隆, 高宮宗一郎, 山崎和義, 濱内祝嗣, 山口秀, 寳金清博, 飛騨一利, 石田雄介, 小田義崇, 田中仲哉, 茂木洋晃, 岡本迪成
日本脳腫瘍学会プログラム・抄録集, 37th, 2019年

Postoperative Intracerebral Hemorrhage After Combined Revascularization Surgery in Moyamoya Disease: Profiles and Clinical Associations.
Kikutaro Tokairin, Ken Kazumata, Haruto Uchino, Masaki Ito, Kota Ono, Ryota Tatezawa, Takafumi Shindo, Masahito Kawabori, Naoki Nakayama, Kiyohiro Houkin
World neurosurgery, 120, e593-e600, e600, 2018年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: In combined revascularization surgery for patients with moyamoya disease, intracerebral hemorrhage (ICH) during the postoperative acute phase is a rarely observed but severe complication. Its clinical features remain unclear because of its low incidence rate. The aim of this study was to clarify the clinical characteristics of immediate postoperative ICH. METHODS: The frequency, onset timing, and hematoma location of patients who demonstrated immediate postoperative ICH were investigated in 201 consecutive surgeries performed in 134 patients. Associations between immediate postoperative ICH and demographics, clinical presentation type, perioperative blood pressure (BP), and neuroimaging data were analyzed. RESULTS: Postoperative ICH was observed in 6 cases (2.99%; mean age, 46.0 ± 7.6 years). The onset timing of ICH was within 24 hours after surgery in most patients (83.3%). Hematomas were located at the subcortical lesion beneath the anastomosed cortex (n = 5) and caudate head (n = 1). Three cases (50.0%) required hematoma evacuation. A higher age at surgery was associated with postoperative ICH (P = 0.046). In adult cases (132 surgeries, 65.7%), hemorrhagic presentation at onset (P = 0.0027) and an increase in BP from pre- to postoperative stage (systolic BP increase: P = 0.0058, diastolic BP increase: P = 0.0274) were significantly associated with postoperative ICH. CONCLUSIONS: The results suggest that older patients, with hemorrhagic presentation and greater postoperative BP increase, should be carefully managed to avoid postoperative ICH. Immediate hematoma evacuation may be effective in preventing devastating outcomes after postoperative ICH.

The validity of the Acute Stroke Assessment using rapid Pseudo-continuous arterial spin labeling (ASAP-ASL) method for acute thrombectomy.
Daisuke Oura, Masahito Kawabori, Yoshimasa Niiya, Motoyuki Iwasaki, Shinpei Satoh, Takumi Yokohama, Shoji Mabuchi, Kiyohiro Houkin
Journal of neurosurgical sciences, 2018年11月21日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Recent clinical trials demonstrated the efficacy of thrombectomy for ischemic stroke against acute large vessel occlusion (LVO). To overcome the problem with excessive examination time for diagnosis of cerebral perfusion and/or the use of contrast agent to determine penumbra, we adopted a new magnetic resonance imaging technique named Acute Stroke Assessment using rapid Pseudo-continuous arterial spin labeling (ASAP-ASL) method. METHODS: The study included healthy volunteers and clinical patients. The signal to noise ratio (SNR) and acquisition time were compared with various numbers of signal average (NSA) of rapid pseudo-continuous arterial spin labeling (pCASL) using the 10-mm thick slice width and narrow scan range focusing the level of basal ganglia by healthy volunteers. After applying clinically acceptable protocol for ASAP-ASL, we then checked image qualities and an accuracy of the method by comparing with the angiographical imaging obtained from the clinical patients regarding the degree of consistency. RESULTS: NSA were compared between two and fourteen, and 10 NSA was decided to be introduced for clinical use (1 minutes and 17 second) for obtaining clinically acceptable image, which was shorter than the time required for ordinary whole brain pCASL (approximately 5 minutes). In the clinical study, the occlusion site estimated by ASAP-ASL showed high correlation with that of digital subtraction angiography (κ = 0.63-0.79). CONCLUSIONS: ASAP-ASL method requires approximately one minutes to obtain clinically relevant brain perfusion imaging which can successfully identify ischemic region in LVO patients.

Intraoperative real-time identification of abnormal vessels within the bright field by superselective arterial injection of saline and its slow-motion recording using a high frame rate digital camera during surgical treatment of spinal arteriovenous shunts: technical note.
Shuji Hamauchi, Toshiya Osanai, Toshitaka Seki, Masahito Kawabori, Michinari Okamoto, Kazutoshi Hida, Kiyohiro Houkin
Journal of neurosurgery. Spine, 29, 5, 576, 581, 2018年11月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The authors describe a novel method of observing blood flow in abnormal vessels with slow-motion video during surgical treatment of spinal arteriovenous shunts. The method is based on the use of superselective angiography with saline for visualizing abnormal vessels in bright field and commercially available high frame rate digital camera for recording slow-motion video.

Electrocardiogram-Triggered Angiography Non-Contrast-Enhanced (TRANCE) Imaging to Assess Access Route Before Diagnostic Cerebral Angiography.
Toshiya Osanai, Ken Kazumata, Satoshi Kobayashi, Noriyuki Fujima, Kota Kurisu, Yuusuke Shimoda, Kiyohiro Houkin
World neurosurgery, 119, 237, 241, 2018年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Electrocardiogram (ECG)-triggered angiography non-contrast-enhanced (TRANCE) imaging is useful for investigating peripheral vessel diseases; however, its efficacy for access route assessment in cerebral angiography has yet to be reported. Therefore we aimed to evaluate the efficacy of TRANCE imaging in the assessment of the access route before diagnostic subtraction angiography for cerebral vascular disorders. METHODS: TRANCE imaging was performed in all patients undergoing catheter angiography for disease diagnosis at our institute between April 2014 and March 2015. This study included 31 patients (14 men, 17 women) and investigated potential changes in the planned puncture site before and during the procedure (including the reason for the change) as our main outcome. RESULTS: TRANCE was successfully conducted in all of the patients recruited. TRANCE images led to an alteration in the approach vessel for 5 cases. The mean procedure time for angiography was <60 minutes. The median total number of catheters and guidewires used during catheter angiography was 1 (range: 1-3) and 1 (range: 1-2), respectively. There were no catheter angiography-related complications. CONCLUSIONS: TRANCE imaging before diagnostic angiography is useful because it allows detailed assessment of the access route. This practice may reduce procedure time, thus resulting in fewer complications.

Direct common carotid artery puncture for acute thrombectomy against ischemic stroke.
Masahito Kawabori, Toshiya Osanai, Shuho Goto, Motoyuki Iwasaki, Yoshimasa Niiya, Shoji Mabuchi, Kiyohiro Houkin
Journal of neurosurgical sciences, 62, 5, 612, 614, 2018年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Identification of plaque location using intraoperative indocyanine green during carotid endarterectomy for patient with near occlusion.
Masahito Kawabori, Yoshimasa Niiya, Motoyuki Iwasaki, Shoji Mabuchi, Kiyohiro Houkin
Journal of neurosurgical sciences, 65, 4, 397, 401, EDIZIONI MINERVA MEDICA, 2018年09月25日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Microscope-integrated near-infrared indocyanine green (ICG) videoangiography (VA) is an effective method of intraoperative blood flow assessment and identification of plaque location during carotid endarterectomy (CEA). However, the validity of ICG-VA during CEA for patient with near occlusion has not been elucidated. PATIENTS AND METHODS: Thirty-four CEA procedures were performed between June 2009 and December 2017 for patient with near occlusion, which are more than 95% stenosis. The lesions were classified into three groups according to the diameter of distal ICA compared with ipsilateral external carotid artery (ECA), as normal diameter (>100%), moderate diameter reduction (50-100%), severe diameter reduction (<50%). 5 mg of ICG was injected intravenously before arteriotomy, and ICG-VA was taken to identify the distal end of the plaque. Depiction of the distal end and its accuracy were retrospectively reviewed. RESULTS: There were 18 cases with normal diameter group, 14 cases with moderate diameter reduction group, and 2 cases with severe diameter reduction group. All but one case in the severe diameter reduction group showed apparent distal end signal which were confirmed by arteriotomy afterward. CONCLUSIONS: The present study clearly denotes that ICG-VA can visualize the carotid plaque distal end during the CEA, even with the patient with near occlusion. However, it should be noted that there may be a difficulty in visualization of the distal plaque end for patient with severely collapsed distal ICA.

Trends of Antiplatelet Therapy for the Management of Moyamoya Disease in Japan: Results of a Nationwide Survey.
Oki K, Katsumata M, Izawa Y, Takahashi S, Suzuki N, Houkin K, Research Committee on, Spontaneous Occlusion of Circle of Willis, Moyamoya disease
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 27, 12, 3605, 3612, 2018年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The efficacy and safety of antiplatelet drugs in the treatment of moyamoya disease remain unclear. This study reports results of a nationwide survey conducted in 2016 on the trends of antiplatelet therapy for moyamoya disease in Japan. METHODS: Data were obtained through questionnaires related to treatment policies regarding antiplatelet drugs from each specialized stroke management department of 765 hospitals in Japan. Data were also compared between experienced facilities (defined as facilities managing more than 10 cases per year) and those less experienced (not more than 10 cases per year) to determine experts' opinion. RESULTS: Of the 389 departments in 375 hospitals that responded, 330 departments provided medical care for moyamoya disease. Regarding ischemic stroke, numerous departments considered the use of antiplatelet drugs "in principle" (218 departments). After surgery for ischemic moyamoya disease, the use of antiplatelet drugs for a certain period of time was the most popular opinion (74 departments). Regarding asymptomatic moyamoya disease, majority departments reported no use of APDs "in principle" (256 departments). The experienced facilities reported "no use of antiplatelet drugs" more frequently than those less experienced for treating asymptomatic moyamoya disease. In moyamoya disease, aspirin was the most commonly used antiplatelet drugs followed by cilostazol and clopidogrel. CONCLUSIONS: This survey revealed details of treatment policies, and the selection of antiplatelet drugs widely varied across facilities. Further prospective studies are necessary to improve the current unclear situation regarding the use of antiplatelet drugs for the management of moyamoya disease.

Novel Hemoglobin-Based Oxygen Carrier Bound With Albumin Shows Neuroprotection With Possible Antioxidant Effects.
Masayuki Gekka, Takeo Abumiya, Teruyuki Komatsu, Ryosuke Funaki, Kota Kurisu, Daisuke Shimbo, Masato Kawabori, Toshiya Osanai, Naoki Nakayama, Ken Kazumata, Kiyohiro Houkin
Stroke, 49, 8, 1960, 1968, 2018年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose- A hemoglobin-albumin cluster, 1 core of hemoglobin covalently bound with 3 shell albumins, designated as HemoAct was developed as a hemoglobin-based oxygen carrier. We aim to investigate neuroprotection by HemoAct in transient cerebral ischemia and elucidate its underlying mechanisms. Methods- Male rats were subjected to 2-hour transient middle cerebral artery occlusion and were then administered HemoAct transarterially at the onset of reperfusion. Neurological and pathological findings were examined after 24 hours of reperfusion to identify neuroprotection by HemoAct. Intermittent measurements of cortical blood flow and oxygen content were performed, and a histopathologic analysis was conducted on rats during the early phase of reperfusion to assess the therapeutic mechanism of HemoAct. In addition, the antioxidant effects of HemoAct were examined in hypoxia/reoxygenation-treated rat brain microvascular endothelial cells. Results- Neurological deterioration, infarct and edema development, and the activation of MMP-9 (matrix metalloprotease-9) and lipid peroxidation after 24 hours of reperfusion were significantly ameliorated by the HemoAct treatment. Reductions in blood flow and tissue partial oxygen pressure in the cortical penumbra after 6 hours of reperfusion were significantly ameliorated by the HemoAct treatment. The histopathologic analysis of the cortical penumbra revealed that HemoAct in HemoAct-treated rats showed superior microvascular perfusion with the mitigation of microvascular narrowing changes than autologous erythrocytes in nontreated rats. Although HemoAct extravasated into the ischemic core with serum protein, it did not induce an increase in serum extravasation or reactive oxygen species production in the ischemic core. In vitro experiments with rat brain microvascular endothelial cells revealed that HemoAct significantly suppressed cellular reactive oxygen species production in hypoxia/reoxygenation-treated cells, similar to albumin. Conclusions- HemoAct exerted robust neuroprotection in transient cerebral ischemia. Superior microvascular perfusion with an oxygen delivery capability and possible antioxidant effects appear to be the underlying neuroprotective mechanisms.

Myelocystocele mimicking myelomeningocele: A case report and review of the literature.
Takamiya S, Seki T, Ikeda T, Shinada SI, Hamauchi S, Terasaka S, Houkin K
World neurosurgery, 119, 172, 175, 2018年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Myelocystoceles, which are classified as closed neural tube defects, are usually covered by skin and rarely complicated by hydrocephalus. We encountered an unusual case of a terminal myelocystocele with hydrocephalus with clinical characteristics of a myelomeningocele. CASE DESCRIPTION: Severe hydrocephalus and a lumbosacral lesion were detected in the fetus of a gravid 34-year-old woman. Cesarean section was performed at 37 weeks. The neonate presented with a lumbosacral mass with a partial skin defect. As myelomeningocele was suspected, the neonate underwent surgery on the day of birth. The intraoperative findings pointed to a myelocystocele rather than a myelomeningocele. After insertion of a ventriculoperitoneal shunt, the neonate was discharged without any neurologic deficits. CONCLUSIONS: Presence of skin abnormalities, hydrocephalus, and lumbosacral mass strongly suggests a diagnosis of myelomeningocele. However, such cases should be differentiated from myelocystocele, especially when associated with severe hydrocephalus.

Circulating miRNome profiling in Moyamoya disease-discordant monozygotic twins and endothelial microRNA expression analysis using iPS cell line.
Uchino H, Ito M, Kazumata K, Hama Y, Hamauchi S, Terasaka S, Sasaki H, Houkin K
BMC medical genomics, 11, 1, 72, 72, 2018年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Moyamoya disease (MMD) is characterized by progressive stenosis of intracranial arteries in the circle of Willis with unknown etiology even after the identification of a Moyamoya susceptible gene, RNF213. Recently, differences in epigenetic regulations have been investigated by a case-control study in MMD. Here, we employed a disease discordant monozygotic twin-based study design to unmask potential confounders. METHODS: Circulating genome-wide microRNA (miRNome) profiling was performed in MMD-discordant monozygotic twins, non-twin-MMD patients, and non-MMD healthy volunteers by microarray followed by qPCRvalidation, using blood samples. Differential plasma-microRNAs were further quantified in endothelial cells differentiated from iPS cell lines (iPSECs) derived from another independent non-twin cohort. Lastly, their target gene expression in the iPSECs was analyzed. RESULTS: Microarray detected 309 plasma-microRNAs in MMD-discordant monozygotic twins that were also detected in the non-twin cohort. Principal component analysis of the plasma-microRNA expression level demonstrated distinct 2 groups separated by MMD and healthy control in the twin- and non-twin cohorts. Of these, differential upregulations of hsa-miR-6722-3p/- 328-3p were validated in the plasma of MMD (absolute log2 expression fold change (logFC) > 0.26 for the twin cohort; absolute logFC > 0.26, p < 0.05, and q < 0.15 for the non-twin cohort). In MMD derived iPSECs, hsa-miR-6722-3p/- 328-3p showed a trend of up-regulation with a 3.0- or higher expression fold change. Bioinformatics analysis revealed that 41 target genes of miR-6722-3p/- 328-3p were significantly down-regulated in MMD derived iPSECs and were involved in STAT3, IGF-1-, and PTEN-signaling, suggesting a potential microRNA-gene expression interaction between circulating plasma and endothelial cells. CONCLUSIONS: Our MMD-discordant monozygotic twin-based study confirmed a novel circulating microRNA signature in MMD as a potential diagnostic biomarker minimally confounded by genetic heterogeneity. The novel circulating microRNA signature can contribute for the future functional microRNA analysis to find new diagnostic and therapeutic target of MMD.

THE DEVELOPMENT AND EVALUATION OF A NEW SIMPLE MODIFIED ANEURYSM CLIP FOR SMALL ANIMAL SCI MODELS
Kazuyoshi Yamazaki, Toshitaka Seki, Masahito Kawabori, Syuji Hamauchi, Izumi Koyanagi, Kiyohiro Houkin
JOURNAL OF NEUROTRAUMA, 35, 16, A168, A168, MARY ANN LIEBERT, INC, 2018年08月, ［査読有り］
英語

The prognostic improvement of add-on bevacizumab for progressive disease during concomitant temozolomide and radiation therapy in the patients with glioblastoma and anaplastic astrocytoma.
Shigeru Yamaguchi, Yukitomo Ishi, Hiroaki Motegi, Michinari Okamoto, Hiroyuki Kobayashi, Kenji Hirata, Yoshitaka Oda, Shinya Tanaka, Shunsuke Terasaka, Kiyohiro Houkin
Journal of neurosurgical sciences, 64, 6, 502, 508, EDIZIONI MINERVA MEDICA, 2018年07月09日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although newly diagnosed high-grade glioma patients in Japan can receive bevacizumab (BEV) as first-line chemotherapy, randomized clinical trials have not shown a survival benefit for BEV for these patients. In this study, we investigated whether selective add-on BEV for patients with newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA) improves prognosis, in cases where tumors were continuously growing during radiotherapy concomitant with temozolomide (TMZ). METHODS: We conducted a retrospective survey of the overall survival (OS) of patients with GBM/AAs who were treated in our institution between 2006 and 2016. Patients whose tumors were continuously growing regardless of radiotherapy were categorized as the "progressive" group; remaining patients were categorized as the "non-progressive" group. Since 2013, patients in the "progressive" group received add-on BEV therapy with the Stupp regimen during or just after radiotherapy. RESULTS: Of 151 GBM/AA patients, 34 (22.5%) were categorized in the "progressive" group. Median OSs of the "progressive" and "non-progressive" groups were 13.2 months and 25.3 months, respectively (P < 0.001). Twelve patients in the "progressive" group received add-on BEV therapy, and their median OS was 20.2 months; whereas for the remaining 22 patients in the "progressive" group who were treated before the BEV era, their median OS was 10.5 months. In the "progressive" group, add-on BEV significantly extended OS (P = 0.018) and was the lone clinical factor of better prognosis. CONCLUSIONS: We found that, for patients with GBM/AAs whose tumors were continuously growing during radiotherapy, add-on BEV treatment resulted in survival benefits.

Interdisciplinary Prevention and Management of Wound-Related Complications in Extracranial-to-Intracranial Bypass Surgery
Rintaro Yokoyama, Takeshi Mikami, Ryo Ukai, Katsuya Komatsu, Yusuke Kimura, Hime Suzuki, Toshimi Honma, Toru Hirano, Tamotsu Saito, Ken Yamashita, Takatoshi Yotsuyanagi, Kiyohiro Houkin, Nobuhiro Mikuni
WORLD NEUROSURGERY, 115, 247, 253, ELSEVIER SCIENCE INC, 2018年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Extracranial-to-intracranial (EC-IC) bypass surgery may be necessary in patients with moyamoya disease and other ischemic conditions. However, there is a potential risk of wound-related complications in some cases. In this study, we report our approach to the prevention of wound-related complications in EC-IC bypass. Technical considerations and pitfalls of surgery are also discussed. This study included 89 patients with ischemic-onset moyamoya disease and atherosclerotic disease who underwent 108 superficial temporal artery (STA) etoemiddle cerebral artery bypass procedures. Our study emphasized 3 major features. First, 3-dimensional simulation imaging was used to confirm STA anatomy. Second, the STA was meticulously dissected on the epigaleal layer to protect the galeal layer. Third, scalp skin ischemia was taken into consideration at each step until skin closure. There was no neurologic morbidity or mortality in this series. There were 2 cases of major wound-related complications requiring plastic surgical intervention, and 4 cases of minor complications that were treated conservatively. In major complication cases, the scalp defect was treated with pedicle flap reconstruction. In EC-IC bypass surgery, interdisciplinary management involving neurosurgery, plastic surgery, and radiology should reduce wound-related complications and achieve safe surgery.

Development of moyamoya disease after non-herpetic acute limbic encephalitis: A case report
Yasuhiro Takahashi, Takeshi Mikami, Hime Suzuki, Katsuya Komatsu, Daisuke Yamamoto, Shun Shimohama, Kiyohiro Houkin, Shintaro Sugita, Tadashi Hasegawa, Nobuhiro Mikuni
Journal of Clinical Neuroscience, 53, 250, 253, Churchill Livingstone, 2018年07月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We report a case of moyamoya disease (MMD), which developed after non-herpetic acute limbic encephalitis (NHALE) associated with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody. The patient's mother had a history of MMD. No vascular lesions were identified at the time of the NHALE. Nine years later, the patient visited our hospital due to memory disturbances and repeated transient ischemic attacks affecting the right limb. Diffusion-weighted magnetic resonance imaging revealed scattered areas of signal hyperintensity, and the patient was ultimately diagnosed with MMD based on angiography. Revascularization surgery was performed on the left side, where cerebral blood flow was impaired on 123I-N-isopropyl-p-iodoamphetamine single photon emission computed tomography. Postoperatively, the patient was discharged with a normal neurological examination. NHALE associated with LGI1 antibodies is an autoimmune disease. Although autoimmune disease is the most frequent finding other than atherosclerosis in quasi-MMD, this is the first report of NHALE associated with anti-LGI1 antibodies mimicking quasi-MMD. Inflammation and angiogenesis may contribute to the development of MMD, in addition to genetic background.

Surgical outcomes of pediatric patients with asymptomatic tethered cord syndrome
Toshitaka Seki, Kazutoshi Hida, Shunsuke Yano, Kiyohiro Houkin
Asian Spine Journal, 12, 23, 551, 555, Korean Society of Spine Surgery, 2018年06月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Study Design: A retrospective cohort study. Purpose: To examine the validity of prophylactic surgery for children with tethered cord syndrome (TCS). Overview of Literature: Prophylactic surgery for pediatric patients with TCS remains controversial. Methods: We retrospectively analyzed the surgical outcomes of 14 children (nine boys and five girls) with asymptomatic TCS who were surgically treated at Hokkaido University Hospital between 1989 and 2015. Results: The median age at the time of initial surgery for asymptomatic TCS was 28.6 months (range, 0-66 months). The median final follow-up period was 142 months (range, 7-232 months). Of the 14 children with asymptomatic TCS, 12 had lumbosacral lipoma and two had meningocele. According to the classification of spinal lipoma, two children had dorsal type, four had caudal type, two had transitional type, and four had filar type. There were no children with lipomyelomeningocele. All children were free of neurological symptoms until 94 months after the initial surgery. Subsequently, one child exhibited delayed neurological deficits and underwent a second surgery because of motor and sensory disturbances
slight sensory disturbance was noted at the final follow-up examination. Another child later showed bowel and bladder dysfunction. However, a second surgery was not performed for this child because his motor and sensory functions were normal
hence, we chose to avoid nerve injury in the case of dissecting adhesion. Conclusions: All 14 children with asymptomatic TCS were free of neurological symptoms until 94 months after the initial surgery. However, two children exhibited delayed neurological deficits at 94 months and 177 months. We believe that prophylactic surgery for asymptomatic TCS is effective for a certain period. However, because the natural history of TCS is poorly understood, strict follow-up after surgery is necessary.

Treatment evaluation of acute stroke for using in regenerative cell elements (TREASURE) trial: Rationale and design.
Toshiya Osanai, Kiyohiro Houkin, Shinichiro Uchiyama, Kazuo Minematsu, Akihiko Taguchi, Shunsuke Terasaka
International journal of stroke : official journal of the International Stroke Society, 13, 4, 444, 448, 2018年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Rationale MultiStem® (HLM051) is one of the promising allogenic cell products for acute ischemic stroke with strong evidence. A previous phase 2 randomized, double-blind, placebo-controlled, multicenter dose-escalation trial showed the safety of MultiStem® for acute ischemic stroke, with a time window beyond that of rt-PA and endovascular thrombectomy. We aim to obtain stronger evidence and to show the efficacy of the MultiStem® for treatment of ischemic stroke. Sample size Estimated sample size is 220 (110 patients per group), which has 90% power at 5% significance level. Methods and design TREASURE is a randomized, double-blind, placebo-controlled, multicenter phase 2/3 trial. The trial will be done at 31 medical centers in Japan. Patients with acute ischemic stroke including motor or speech deficit defined by a National Institution of Health Stroke Scale (NIHSS) score of 8-20 at baseline will be randomized 1:1 to receive a single intravenous infusion of MultiStem® or placebo within 18-36 h of stroke onset. Study outcomes Primary outcome in this study is the proportion of patients with an excellent outcome at day 90 defined by the functional assessment. Trial registration ClinicalTrials.gov (NCT02961504). Conclusion The TREASURE trial will provide a novel treatment option and expand the therapeutic window for patients with stroke if the results are positive.

[18F]DPA-714 PET imaging shows immunomodulatory effect of intravenous administration of bone marrow stromal cells after transient focal ischemia.
Chengbo Tan, Songji Zhao, Kei Higashikawa, Zifeng Wang, Masahito Kawabori, Takeo Abumiya, Naoki Nakayama, Ken Kazumata, Naoyuki Ukon, Hironobu Yasui, Nagara Tamaki, Yuji Kuge, Hideo Shichinohe, Kiyohiro Houkin
EJNMMI research, 8, 1, 35, 35, 2018年05月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The potential application of bone marrow stromal cell (BMSC) therapy in stroke has been anticipated due to its immunomodulatory effects. Recently, positron emission tomography (PET) with [18F]DPA-714, a translocator protein (TSPO) ligand, has become available for use as a neural inflammatory indicator. We aimed to evaluate the effects of BMSC administration after transient middle cerebral artery occlusion (MCAO) using [18F]DPA-714 PET. The BMSCs or vehicle were administered intravenously to rat MCAO models at 3 h after the insult. Neurological deficits, body weight, infarct volume, and histology were analyzed. [18F]DPA-714 PET was performed 3 and 10 days after MCAO. RESULTS: Rats had severe neurological deficits and body weight loss after MCAO. Cell administration ameliorated these effects as well as the infarct volume. Although weight loss occurred in the spleen and thymus, cell administration suppressed it. In both vehicle and BMSC groups, [18F]DPA-714 PET showed a high standardized uptake value (SUV) around the ischemic area 3 days after MCAO. Although SUV was increased further 10 days after MCAO in both groups, the increase was inhibited in the BMSC group, significantly. Histological analysis showed that an inflammatory reaction occurred in the lymphoid organs and brain after MCAO, which was suppressed in the BMSC group. CONCLUSIONS: The present results suggest that BMSC therapy could be effective in ischemic stroke due to modulation of systemic inflammatory responses. The [18F]DPA-714 PET/CT system can accurately demonstrate brain inflammation and evaluate the BMSC therapeutic effect in an imaging context. It has great potential for clinical application.

Characteristics of Symptomatic Intracerebral Hemorrhage in Patient Receiving Direct Oral Anticoagulants: Comparison with Warfarin.
Masahito Kawabori, Yoshimasa Niiya, Motoyuki Iwasaki, Shoji Mabuchi, Hiroyuki Ozaki, Koji Matsubara, Kiyohiro Houkin
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 27, 5, 1338, 1342, 2018年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Direct oral coagulants (DOAC) have been shown to decrease the frequency of intracerebral hemorrhage (ICH) compared with warfarin. However, the precise characteristics, such as the size and locations of the hemorrhage, and outcome and onset time of ICH in patient taking DOAC are not fully elucidated. METHODS: We retrospectively analyzed the characteristics of symptomatic patients with ICH taking either DOAC or warfarin between January 2012 and December 2015. RESULTS: Out of 400 consecutive patients with ICH, 15 patients were DOAC-ICH and 24 patients were warfarin-ICH. DOAC-ICH was observed in 6 patients with 10 mg of rivaroxaban, 5 patients with 15 mg of rivaroxaban, and 1 patient with 10 mg of apixaban, 5 mg of apixaban, 30 mg of edoxaban, and 60 mg of edoxaban. Prothrombin time was well controlled in most of the warfarin-ICH patients (83.3%). The locations of ICH were similar in both groups; however, median ICH volume was significantly smaller in DOAC-ICH patients than in warfarin-ICH patients (P < .01) and ICH around basal ganglia seemed to show great difference between the groups. DOAC-ICH patients showed better neurological outcome at the time of discharge than warfarin patients (P < .01), and the ratio of good prognosis was significantly higher in the DOAC-ICH patients than in the warfarin-ICH patients (P < .01). The onset of warfarin-ICH was frequently observed in the morning and evening, whereas DOAC-ICH did not show any specific onset time. CONCLUSIONS: Patients with DOAC-ICH showed smaller ICH volume and better clinical outcomes than patients with warfarin-ICH, and DOAC-ICH did not show any specific onset peak.

Accelerating Cell Therapy for Stroke in Japan: Regulatory Framework and Guidelines on Development of Cell-Based Products.
Kiyohiro Houkin, Hideo Shichinohe, Koji Abe, Teruyo Arato, Mari Dezawa, Osamu Honmou, Nobutaka Horie, Yasuo Katayama, Kohsuke Kudo, Satoshi Kuroda, Tomohiro Matsuyama, Ichiro Miyai, Izumi Nagata, Kuniyasu Niizuma, Ken Sakushima, Masanori Sasaki, Norihiro Sato, Kenji Sawanobori, Satoshi Suda, Akihiko Taguchi, Teiji Tominaga, Haruko Yamamoto, Toru Yamashita, Toshiki Yoshimine
Stroke, 49, 4, e145-e152, e152, 2018年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Angiographic features of hemorrhagic moyamoya disease with high recurrence risk: a supplementary analysis of the Japan Adult Moyamoya Trial.
Takeshi Funaki, Jun C Takahashi, Kiyohiro Houkin, Satoshi Kuroda, Shigekazu Takeuchi, Miki Fujimura, Yasutake Tomata, Susumu Miyamoto
Journal of neurosurgery, 128, 3, 777, 784, 2018年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE In this paper, the authors set out to identify the angiographic features of moyamoya disease with posterior hemorrhage, which is a strong predictor of rebleeding. METHODS This cross-sectional study used the data set of the Japan Adult Moyamoya Trial (clinical trial registration no.: C000000166 [ www.umin.ac.jp/ctr/index.htm ]). The panel designed the ancillary measurement of angiography at onset, classifying the collateral vessels into 3 subtypes: lenticulostriate anastomosis, thalamic anastomosis, and choroidal anastomosis. The association between each collateral and the hemorrhage site (anterior vs posterior) was assessed in the hemorrhagic hemisphere by using multivariate adjustment for potential confounders, including age, sex, and involvement of the posterior cerebral artery (PCA). The association was confirmed through topographical analysis of bleeding points. RESULTS Among the 80 participants, 75 hemorrhagic hemispheres of 75 patients were analyzed. Lenticulostriate anastomosis was detected in 21 (28.0%) hemorrhagic hemispheres, thalamic anastomosis in 22 (29.3%), and choroidal anastomosis in 35 (46.7%). Choroidal anastomosis was a factor associated with posterior hemorrhage (OR 2.77 [95% CI 1.08-7.10], p = 0.034) and remained statistically significant after the multivariate adjustment (OR 2.66 [95% CI 1.00-7.07], p = 0.049). PCA involvement was also associated with posterior hemorrhage in both univariate and multivariate analyses. Topographical analysis revealed good correspondence between bleeding points associated with positive choroidal anastomosis and the anatomical distribution of the choroidal arteries, including the thalamus and the wall of the atrium. CONCLUSIONS Choroidal anastomosis and PCA involvement are characteristic of posterior hemorrhage in moyamoya disease. Choroidal anastomosis might be considered a potential source of posterior hemorrhage at high risk of rebleeding.

Adult-Onset Orbital Sinus Pericranii with T2 Hyperintensity Lesion: A Case Report
Toshiya Osanai, Kiyohiro Houkin
Case Reports in Neurology, 10, 1, 112, 117, S. Karger AG, 2018年02月14日, ［査読有り］
英語, 研究論文（学術雑誌）, Sinus pericranii is a rare vascular anomaly, and most cases occur in children and develop at the midline. In previous reports of sinus pericranii, T2 hyperintensity lesion has not been regarded as a common sequela. We report an extremely rare case of orbital sinus pericranii with associated T2 hyperintensity lesion. A 50-year-old man was admitted to our hospital with a history of right upper eyelid swelling that had been present for several years. Computed tomography, magnetic resonance imaging, and digital subtraction angiography demonstrated a connection between the lesion and normal cerebral venous system. Thus, we diagnosed the lesion as a sinus pericranii despite its atypical features. We elected to observe the patient, and the lesion had remained the same size without any adverse events, such as hemorrhage, occurring throughout the 5-year follow-up. An atypical sinus pericranii should be considered in patients with a soft compressible swelling on the head, even if the lesion is located off the midline.

Factors influencing cerebral aneurysm obliteration and reliability of indocyanine green video-angiography
Masayuki Gekka, Naoki Nakayama, Haruto Uchino, Kiyohiro Houkin
Acta Neurochirurgica, 160, 2, 269, 276, Springer-Verlag Wien, 2018年02月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Indocyanine green video-angiography (ICG-V) is commonly used for intraoperative confirmation of aneurysm obliteration following clipping. However, direct puncture of the aneurysm wall occasionally results in blood leakage in patients for whom ICG-V has indicated complete closure. Therefore, the present study aimed to determine the reliability of ICG-V for confirming complete aneurysm closure, and to elucidate the factors underlying aneurysm obliteration and the occurrence of false-negative ICG-V findings. Methods: Between June 2012 and June 2016, 89 patients (107 aneurysms total) undergoing aneurysm clipping were examined using ICG-V to confirm aneurysm closure. In ICG-V-negative cases, further confirmation of complete aneurysm closure was obtained via direct puncture of the aneurysm wall, except in cases where this procedure was deemed unsafe. To elucidate the possible causes of ICG-V inaccuracies, positive, negative, and false-negative ICG-V findings were compared in terms of aneurysm location (maximum height and length), neck width (parallel and orthogonal directions to the branching vessels), wall thickness around the neck, bifurcation angle, and direction of the clipping closure line. Statistical analyses were performed using the Welsh’s t test and Chi-square test. Results: Intraoperative ICG-V detected seven cases of incomplete aneurysm closure (6.5%), defined as positive ICG-V findings. Following direct aneurysm wall puncture, nine patients (8.4%) exhibited false-negative ICG-V findings. A Chi-square test revealed that false-negative ICG-V findings were significantly influenced by the presence of heterogeneous arteriosclerosis, and wall thickening at the clipping site, which were subjectively defined by the surgeon and confirmed by an independent observer, depending on the wall color and hardness, respectively. Conclusions: Although ICG-V is useful for intraoperative confirmation of aneurysm obliteration, our findings further highlight the risk of false-negative ICG-V findings. Acknowledgement of risk factors is crucial for efficient detection of false-negative ICG-V findings.

Human Recombinant Peptide Sponge Enables Novel, Less Invasive Cell Therapy for Ischemic Stroke.
Michiyuki Miyamoto, Kentaro Nakamura, Hideo Shichinohe, Tomohiro Yamauchi, Masaki Ito, Hisayasu Saito, Masahito Kawabori, Toshiya Osanai, Tasuku Sasaki, Kiyohiro Houkin, Satoshi Kuroda
Stem cells international, 2018, 4829534, 4829534, 2018年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Bone marrow stromal cell (BMSC) transplantation has the therapeutic potential for ischemic stroke. However, it is unclear which delivery routes would yield both safety and maximal therapeutic benefits. We assessed whether a novel recombinant peptide (RCP) sponge, that resembles human collagen, could act as a less invasive and beneficial scaffold in cell therapy for ischemic stroke. BMSCs from green fluorescent protein-transgenic rats were cultured and Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAo). A BMSC-RCP sponge construct was transplanted onto the ipsilateral intact neocortex 7 days after MCAo. A BMSC suspension or vehicle was transplanted into the ipsilateral striatum. Rat motor function was serially evaluated and histological analysis was performed 5 weeks after transplantation. The results showed that BMSCs could proliferate well in the RCP sponge and the BMSC-RCP sponge significantly promoted functional recovery, compared with the vehicle group. Histological analysis revealed that the RCP sponge provoked few inflammatory reactions in the host brain. Moreover, some BMSCs migrated to the peri-infarct area and differentiated into neurons in the BMSC-RCP sponge group. These findings suggest that the RCP sponge may be a promising candidate for animal protein-free scaffolds in cell therapy for ischemic stroke in humans.

国際臨床医学会 大きな第二歩へ
寳金清博, 寳金清博, 寳金清博, 寳金清博, 寳金清博
国際臨床医学会雑誌(Web), 2, 1, 2018年

頭蓋内硬膜動静脈瘻に対する4D-MRAの検討
東海林菊太郎, 長内俊也, 藤間憲幸, 牛越聡, 寳金清博
脳血管内治療(Web), 3, Supplement, 2018年

Accessibility to Tertiary Stroke Centers in Hokkaido, Japan: Use of Novel Metrics to Assess Acute Stroke Care Quality.
Kensuke Fujiwara, Toshiya Osanai, Eiichi Kobayashi, Takumi Tanikawa, Ken Kazumata, Kikutaro Tokairin, Kiyohiro Houkin, Katsuhiko Ogasawara
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 27, 1, 177, 184, 2018年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Both the accessibility and availability of stroke specialists are major determinants of patient outcomes following acute ischemic stroke (AIS). The purpose of this study was to implement novel metrics to assess the accessibility of tertiary stroke centers as well as to evaluate regional disparities in stroke specialists. METHODS: Using network analysis in a geographic information system, we calculated areas within 30- and 60-minute travel times to facilities providing intravenous recombinant tissue-type plasminogen activator and mechanical thrombectomy. We further evaluated the accessibility for the proportion of the population aged 65 years or older that resided outside of these areas. Uniformity in the geographical distribution of stroke specialists was then evaluated using optimal statistical analysis. RESULTS: Accessibility varied widely from region to region, with low accessibility being concentrated in rural areas with low population density. Accessibility to facilities providing mechanical thrombectomy was especially low, and 17.8% of elderly individuals lived ≥60 minutes from treatment facilities. In addition, the distribution of stroke specialists was uneven compared with the distribution of hospital beds and full-time medical doctors. CONCLUSION: The results of this study revealed regional disparities in the spatial accessibility to treatment facilities, as well as in the distribution of stroke specialists in Hokkaido. These findings provide useful information that could be employed to appropriately allocate resources toward the formation of a medical supply system for patients with AIS.

Intraoperative Visualization of a Spinal Arachnoid Cyst Using Pyoktanin Blue
Soichiro Takamiya, Toshitaka Seki, Kazuyoshi Yamazaki, Toru Sasamori, Kiyohiro Houkin
World Neurosurgery, 109, 18, 23, Elsevier Inc., 2018年01月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background Spinal arachnoid cysts (SACs) are filled with cerebrospinal fluid, and they include the arachnoid membrane, making it difficult to distinguish the walls of the cyst from the arachnoid membrane and excise the cyst as a lump. Here we report a technique for the intraoperative visualization of SACs, involving the use of pyoktanin blue. Methods Four patients with spinal intradural arachnoid cysts underwent total excision of the cysts between October 2016 and April 2017. In 1 case, magnetic resonance imaging revealed the cyst clearly, but in the other cases, the cysts were unclear. All cysts were injected with 1% pyoktanin blue (Wako Pure Chemical Industries, Osaka, Japan) diluted 500 times with physiological saline before excision. When it was difficult to distinguish the cyst from the normal arachnoid membrane, 1% pyoktanin blue diluted 1000 times with physiological saline was injected into both the cyst and the subarachnoid space, and the spread of the stain was observed. Results The cysts were better visualized after pyoktanin blue injection than before injection. When it was difficult to distinguish the cyst from the normal arachnoid space, pyoktanin blue injection was useful for judging the cyst space. There were no perioperative complications, and the patients’ symptoms improved partially or completely after treatment. Conclusions Our technique of pyoktanin blue injection into SACs could make their excision easy and safe.

Berlin Grading System Can Stratify the Onset and Predict Perioperative Complications in Adult Moyamoya Disease
Daina Kashiwazaki, Naoki Akioka, Naoya Kuwayama, Kiyohiro Houkin, Marcus Czabanka, Peter Vajkoczy, Satoshi Kuroda
NEUROSURGERY, 81, 6, 986, 991, OXFORD UNIV PRESS INC, 2017年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The grading system for moyamoya disease is not established.
OBJECTIVE: To assess the usefulness of a recently proposed grading system for stratifying the clinical severity and predicting postoperative morbidity in adult moyamoya disease.
METHODS: We investigated 176 hemispheres from 89 adult patients who were diagnosed with moyamoya disease in Japan. Their data were analyzed using the Berlin grading system with minor modifications. After summarizing the numerical values for digital subtraction angiography (1-3 points), magnetic resonance imaging (0-1 points), and single-photon emission computed tomography (0-2 points), 3 grades of moyamoya disease were defined: mild (grade I) = 1 to 2 points, moderate (grade II) = 3 to 4 points, and severe (grade III) = 5 to 6 points. In total, 82 of 161 hemispheres underwent superficial temporal artery to middle cerebral artery anastomosis and indirect synangiosis. Postoperative neurological morbidity was included within 30 d after surgery.
RESULTS: Preoperative examinations categorized 87 hemispheres as grade I, 39 as grade II, and 50 as grade III. There was a significant correlation between the Berlin grading system and clinical severity (P<.001). Perioperative complications occurred in 12 of 82 (14.6%) hemispheres, including transient ischemic attack in 3 hemispheres, ischemic stroke in 4 hemispheres, symptomatic hyperperfusion in 4 hemispheres, and intracerebral hemorrhage in 1 hemisphere. The Berlin grading system was related to their occurrence (P<.001).
CONCLUSION: The Berlin grading system facilitates the stratification of clinical severity and predicting postoperative neurological morbidity in adult moyamoya disease, thereby suggesting its general usage in clinical practice.

Superior Microvascular Perfusion of Infused Liposome-Encapsulated Hemoglobin Prior to Reductions in Infarctions after Transient Focal Cerebral Ischemia
Daisuke Shimbo, Takeo Abumiya, Kota Kurisu, Toshiya Osanai, Hideo Shichinohe, Naoki Nakayama, Ken Kazumata, Hideki Nakamura, Hiroshi Shimuzu, Kiyohiro Houkin
JOURNAL OF STROKE & CEREBROVASCULAR DISEASES, 26, 12, 2994, 3003, ELSEVIER SCIENCE BV, 2017年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: The development of cerebral infarction after transient ischemia is attributed to postischemic delayed hypoperfusion in the microvascular region. In the present study, we assessed the microvascular perfusion capacity of infused liposome-encapsulated hemoglobin (LEH) in a therapeutic approach for transient middle cerebral artery occlusion (tMCAO). Methods: Two-hour middle cerebral artery occlusion rats were immediately subjected to intra-arterial infusion of LEH (LEH group) or saline (vehicle group) or no treatment (control group), and then to recanalization. Neurological findings, infarct and edema progression, microvascular endothelial dysfunction, and inflammatory reactions were compared between the 3 groups after 24 hours of reperfusion. Microvascular perfusion in the early phase of reperfusion was evaluated by hemoglobin immunohistochemistry and transmission electron microscopy. Results: The LEH group achieved significantly better results in all items evaluated than the other groups. Hemoglobin immunohistochemistry revealed that the number of hemoglobin-positive microvessels was significantly greater in the LEH group than in the other groups (P < .01), with microvascular perfusion being more likely in narrow microvessels (<= 5 mu m in diameter). An electron microscopic examination revealed that microvessels in the control group were compressed and narrowed by swollen astrocyte end-feet, whereas those in the LEH group had a less deformed appearance and contained LEH particles and erythrocytes. Conclusion: The results of the present study demonstrated that the infusion of LEH reduced infarctions after tMCAO with more hemoglobin-positive and less deformed microvessels at the early phase of reperfusion, suggesting that the superiority of the microvascular perfusion of LEH mediates its neuroprotective effects.

Novel insights into symptomatology of moyamoya disease in pediatric patients: survey of symptoms suggestive of orthostatic intolerance
Haruto Uchino, Ken Kazumata, Masaki Ito, Naoki Nakayama, Kiyohiro Houkin
JOURNAL OF NEUROSURGERY-PEDIATRICS, 20, 5, 485, 488, AMER ASSOC NEUROLOGICAL SURGEONS, 2017年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE A specific population of young patients with moyamoya disease (MMD) persistently experience physical symptoms not attributable to focal ischemia. These symptoms, highly suggestive of orthostatic intolerance (also termed "orthostatic dysregulation"), were investigated and reported as potential determinants of quality of life in young MMD patients.
METHODS Forty-six patients (6-30 years of age) were selected from a group of 122 patients who were diagnosed with MMD before 18 years of age. The authors administered a structured questionnaire consisting of 11 items based on screening checklists published in the Japanese clinical guidelines for juvenile orthostatic dysregulation in young patients. The results were tabulated, and correlations with clinical data were explored.
RESULTS Thirty-seven (80%) patients (mean age 15.9 years) responded to the questionnaire. Frequent headache, vertigo/dizziness on standing, fatigue, difficulty with getting out of bed, and motion sickness were the top 5 symptoms, resulting in 57% of patients being unable to attend school. Forty-three percent of the patients demonstrated multiple symptoms suggestive of orthostatic intolerance, even as long as 5 years after revascularization surgery. The number of symptoms was inversely associated with the number of years after surgery (p = 0.028). The number of symptoms was not associated with a history of surgery, clinical presentations, vascular involvement, cerebral perfusion, brain lesions, or history of transient ischemic attacks.
CONCLUSIONS The present study provided novel insight into the symptomatology of young patients with MMD. Failure to notice nonfocal physical symptoms can significantly impair quality of life in young patients with MMD even years after successful revascularization surgery. These symptoms may serve as independent clinical markers used to assess disease outcome, although the underlying mechanisms of this disease are, as of yet, unclear.

Diencephalic pediatric low-grade glioma harboring the BRAF V600E mutation presenting with various morphologies in sequential biopsy specimens
Yukitomo Ishi, Kanako C. Hatanaka, Shigeru Yamaguchi, Hiromi Fujita, Hiroaki Motegi, Hiroyuki Kobayashi, Shunsuke Terasaka, Kiyohiro Houkin
BRAIN TUMOR PATHOLOGY, 34, 4, 165, 171, SPRINGER JAPAN KK, 2017年10月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 5-year-old boy underwent biopsy of an intra-axial calcified tumor in the hypothalamus, which was incidentally found. Based on the presence of ganglion-like cells combined with glial cell element, the pathological diagnosis was ganglioglioma. Because the tumor grew gradually in size over the next 2 years, he underwent chemotherapy with temozolomide. However, at 8 years of age, the boy developed hydrocephalus and the cystic lesion had re-grown. Endoscopic cyst fenestration and tumor biopsy was performed, and pathological diagnosis was tentatively oligodendroglioma based on the presence of tumor cells with a perinuclear halo. At 10 years of age, hydrocephalus recurred and the cystic lesion had re-grown. A second round of endoscopic cyst fenestration and tumor biopsy led to a pathological diagnosis of pilocytic astrocytoma due to a biphasic appearance with areas of dense tumor cells and microcystic areas, tumor cells with eosinophilic processes, and the presence of an eosinophilic granular body. Genetic analysis of the first biopsy successfully identified the BRAF V600E mutation. Because pathological diagnosis of diencephalic low-grade glioma harboring BRAF V600E would be sometimes difficult due to pathological variations, pathological diagnosis should be performed under the consideration of molecular diagnosis of BRAF V600E for optimal diagnosis and treatment.

Double Crush of L5 Spinal Nerve Root due to L4/5 Lateral Recess Stenosis and Bony Spur Formation of Lumbosacral Transitional Vertebra Pseudoarticulation: A Case Report and Review.
Iwasaki M, Akiyama M, Koyanagi I, Niiya Y, Ihara T, Houkin K
NMC case report journal, 4, 4, 121, 125, 2017年10月, ［査読有り］, ［国内誌］
英語, We present a case of double-crushed L5 nerve root symptoms caused by inside and outside of the spinal canal with spur formation of the lumbosacral transitional vertebra (LSTV). A 78-year-old man presented with 7-year history of moderate paresis of his toe and left leg pain when walking. Magnetic resonance imaging (MRI) revealed spinal stenosis at the L3/4 and 4/5 spinal levels and he underwent wide fenestration of both levels. Leg pain disappeared and 6-min walk distance (6MWD) improved after surgery, however, the numbness in his toes increased and 6MWD decreased 9 months after surgery. Repeated MR and 3D multiplanar reconstructed computed tomography (CT) images showed extraforaminal impingement of the L5 root by bony spur of the left LSTV. He underwent second decompression surgery of the L5/S via the left sided Wiltse approach, resulting in the improvement of his symptoms. The impingement of L5 spinal nerve root between the transverse process of the fifth lumbar vertebra and the sacral ala is a rare entity of the pathology called "far-out syndrome (FOS)". Especially, the bony spur formation secondary to the anomalous articulation of the LSTV (LSPA) has not been reported. These articulations could be due to severe disc degeneration, following closer distance and contact between the transverse process and the sacral ala. To our knowledge, this is the first report describing a case with this pathology and may be considered in cases of failed back surgery syndromes (FBSS) of the L5 root symptoms.

Research on advanced intervention using novel bone marrOW stem cell (RAINBOW): a study protocol for a phase I, open-label, uncontrolled, dose-response trial of autologous bone marrow stromal cell transplantation in patients with acute ischemic stroke
Hideo Shichinohe, Masahito Kawabori, Hiroaki Iijima, Tuyoshi Teramoto, Takeo Abumiya, Naoki Nakayama, Ken Kazumata, Shunsuke Terasaka, Teruyo Arato, Kiyohiro Houkin
BMC NEUROLOGY, 17, 1, 179, 179, BIOMED CENTRAL LTD, 2017年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Stroke is a leading cause of death and disability, and despite intensive research, few treatment options exist. However, a recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. Although some pioneer studies on the use of cell therapy for treating stroke have been reported, certain problems remain unsolved. Recent studies have demonstrated that bone marrow stromal cells (BMSCs) have therapeutic potential against stroke. We investigated the use of autologous BMSC transplantation as a next-generation cell therapy for treating stroke. In this article, we introduce the protocol of a new clinical trial, the Research on Advanced Intervention using Novel Bone marrOW stem cell (RAINBOW).
Methods/design: RAINBOW is a phase 1, open-label, uncontrolled, dose-response study, with the primary aim to determine the safety of the autologous BMSC product HUNS001-01 when administered to patients with acute ischemic stroke. Estimated enrollment is 6-10 patients suffering from moderate to severe neurological deficits. Approximately 50 mL of the bone marrow is extracted from the iliac bone of each patient 15 days or later from the onset. BMSCs are cultured with allogeneic human platelet lysate (PL) as a substitute for fetal calf serum and are labeled with superparamagnetic iron oxide for cell tracking using magnetic resonance imaging (MRI). HUNS00101 is stereotactically administered around the area of infarction in the subacute phase. Each patient will be administered a dose of 20 or 50 million cells. Neurological scoring, MRI for cell tracking, F-18-fuorodeoxyglucose positron emission tomography, and I-123-Iomazenil singlephoton emission computed tomography will be performed for 1 year after the administration.
Discussion: This is a first-in-human trial for HUNS001-01 to the patients with acute ischemic stroke. We expect that intraparenchymal injection can be a more favorable method for cell delivery to the lesion and improvement of the motor function than intravenous infusion. Moreover, it is expected that the bio-imaging techniques can clarify the therapeutic mechanisms.

Ten-Year Retrospective Study on the Management of Spinal Arteriovenous Lesions: Efficacy of a Combination of Intraoperative Digital Subtraction Angiography and Intraarterial Dye Injection
Toshiya Osanai, Kazutoshi Hida, Takeshi Asano, Toshitaka Seki, Toru Sasamori, Kiyohiro Houkin
WORLD NEUROSURGERY, 104, 841, 847, ELSEVIER SCIENCE INC, 2017年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The goal of treatment for spinal arteriovenous lesions is to completely obliterate the shunt. In our institution, intraoperative digital subtraction angiography and intraarterial injection of contrast agent have been used to accurately identify the site of arteriovenous shunts. We describe the intraoperative digital subtraction angiography and intraarterial dye injection procedures and how they may improve surgical outcomes.
METHODS: We retrospectively investigated 22 patients with intradural arteriovenous lesions (n = 19) or spinal dural arteriovenous fistulas (n = 3). A microcatheter was used during the procedures to avoid catheter migration.
RESULTS: There were 29 procedures performed. To support the surgical procedures, indigo carmine was used 17 times and indocyanine green was used 12 times. There were no complications associated with these procedures. The indocyanine green procedure required a lower concentration of dye in the artery than in the vein to clarify the shunt point and visualized complex lesions more clearly. These methods allowed surgeons to orientate the complex vessel structure.
CONCLUSIONS: Intraoperative digital subtraction angiography and intraarterial dye injection are useful tools for management of spinal arteriovenous lesions.

Prevalence of and risk factors for enlarged perivascular spaces in adult patients with moyamoya disease
Tomoyoshi Kuribara, Takeshi Mikami, Katsuya Komatsu, Hime Suzuki, Hirofumi Ohnishi, Kiyohiro Houkin, Nobuhiro Mikuni
BMC NEUROLOGY, 17, 1, 149, 149, BIOMED CENTRAL LTD, 2017年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Enlarged perivascular spaces (EPVS) are often observed with magnetic resonance imaging in patients with small vessel disease. However, the risk factors, radiological features, and clinical relevance of EPVS in patients with moyamoya disease are poorly understood. The purpose of this study was to evaluate EPVS, the risk factors of many EPVS, and the pathophysiology of EPVS in adult patients with moyamoya disease.
Methods: One hundred cerebral hemispheres of 50 adult patients with moyamoya disease were examined. The control group consisted of 50 age/sex-matched patients without ischemic disease. The numbers of EPVS at the level of the centrum semiovale per hemisphere were compared between the moyamoya disease and control groups. In each hemisphere, the total numbers of EPVS were categorized into five grades (0-4), and the clinical and radiological characteristics of the predictive factors in patients in the high EPVS grade group (EPVS grade = 4) were assessed.
Results: The EPVS counts and grades were significantly higher in the moyamoya disease group. Analyses of the background characteristics of the patients with moyamoya disease revealed that significantly higher prevalence of high EPVS grades were associated with the female sex, hypertension, high magnetic resonance angiography scores, high numbers of flow voids in the basal ganglia, high brain atrophy scores, ivy signs, and white matter lesions. A logistic multivariate analysis of the patients with high EPVS grades revealed significant associations with the female sex, hypertension, and flow voids in the basal ganglia.
Conclusions: Increased EPVS were confirmed in adult patients with moyamoya disease, and the associated clinical and radiological factors were identified. The presence of hypertension, the female sex, and flow voids in the basal ganglia were important for predicting high EPVS grades in patients with moyamoya disease. Reductions in arterial pulsations with steno-occlusive changes can inhibit the flow of interstitial fluid, which can increase the number of EPVS in patients with moyamoya disease. Other clinical factors, such as the female sex and hypertension, may promote secondary brain damage in patients with moyamoya disease. Further evaluations of EPVS in patients with moyamoya disease are needed to better understand their pathophysiological importance.

Regional transarterial hypothermic infusion in combination with endovascular thrombectomy in acute ischaemic stroke with cerebral main arterial occlusion: protocol to investigate safety of the clinical trial
Kikutaro Tokairin, Toshiya Osanai, Takeo Abumiya, Ken Kazumata, Kota Ono, Kiyohiro Houkin
BMJ OPEN, 7, 8, e016502, BMJ PUBLISHING GROUP, 2017年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Introduction Acute cerebral ischaemia with main cerebral artery occlusion requires treatment with intravenous tissue plasminogen activator administration and/or endovascular thrombectomy. However, some patients fail to recover even after recanalisation because of ischaemia/reperfusion (I/R) injury. We hypothesised that regional transarterial hypothermic infusion would be effective for patients with I/R injury. The aim of this study is to validate the safety of this procedure.
Methods and analysis This is a clinical exploratory study to evaluate safety of regional transarterial hypothermic infusion in combination with endovascular thrombectomy. Patients with acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 5-29 who require endovascular thrombectomy are eligible for the study. When no improvement in NIHSS score after the recanalisation is achieved by thrombectomy, cold saline (15 degrees C) will be administered through a microcatheter located in the ipsilateral internal carotid artery. The primary endpoints of this study are mortality and morbidity. The secondary endpoint is deleterious effects on clinical data such as symptoms, radiographic findings and physiological data. The primary and secondary endpoints will be accumulated as case series because this study will be conducted on a small sample of seven patients.
Ethics and dissemination All protocols and the informed consent form comply with the Ethics Guideline for Clinical Research (Japanese Ministry of Health, Labour and Welfare). Ethics review committees at the Hokkaido University Hospital approved the study protocols. The results of the study will be disseminated at several research conferences and also contributed to peer-reviewed journals. The study will be implemented and reported in line with the SPIRIT statement.

Effect of Headache on the Pathologic Findings of Unruptured Cerebral Saccular Aneurysms
Masaaki Hokari, Naoki Nakayama, Yusuke Shimoda, Kiyohiro Houkin
WORLD NEUROSURGERY, 103, 431, 441, ELSEVIER SCIENCE INC, 2017年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Some patients with aneurysm exhibit warning headaches without minor bleeding, and this could be caused by stretching of the aneurysm wall. Recently, our pathologic study observed subintimal fibrin deposition in a majority of the ruptured aneurysms. However, these findings also were observed in some unruptured aneurysms. In this report, 2 unruptured aneurysms exhibited subintimal fibrin, and interestingly, one of the patients experienced severe headache within 1 month before neuroimaging.
OBJECTIVE: We performed pathologic analysis of unruptured aneurysms and collected their various clinical variables, including severe headache, to clarify the clinical characteristics of "dangerous" unruptured aneurysms. METHODS: This study included unruptured saccular aneurysm samples (n = 17) that were resected after clipping. We compared the differences in clinical variables, including warning headache, between aneurysms with and without fibrin deposition.
RESULTS: Fibrin deposition was present in the subintimal layer in 4 patients and in the periouter membrane in 4 patients. Three of the 4 former patients experienced warning headaches, and one presented aneurysm growth. Of the latter 4 patients, one exhibited aneurysm growth, whereas the others presented with relatively large aneurysms. In the remaining 9 aneurysms without fibrin deposition, monocyte infiltration was observed in one, all aneurysms were small, and no patients experienced warning headaches or aneurysm growth.
CONCLUSIONS: Subintimal fibrin deposition is observed frequently in patients with aneurysm with warning headaches. These pathologic findings are clinically inspiring and may suggest that these aneurysms exhibit rapid stretching by newly formed aneurysms, which can result in rupture at an early stage.

Pathophysiological consideration of medullary streaks on FLAIR imaging in pediatric moyamoya disease
Hime Suzuki, Takeshi Mikami, Tomoyoshi Kuribara, Kazuhisa Yoshifuji, Katsuya Komatsu, Yukinori Akiyama, Hirofumi Ohnishi, Kiyohiro Houkin, Nobuhiro Mikuni
JOURNAL OF NEUROSURGERY-PEDIATRICS, 19, 5, 560, 566, AMER ASSOC NEUROLOGICAL SURGEONS, 2017年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE Medullary streaks detected on fluid-attenuated inversion recovery (FLAIR) imaging have been considered to be reflected ischemic regions in pediatric moyamoya disease. The purpose of this study was to evaluate these medullary streaks both clinically and radiologically and to discuss associated pathophysiological concerns.
METHODS The authors retrospectively reviewed data from 14 consecutive pediatric patients with moyamoya disease treated between April 2009 and June 2016. Clinical and radiological features and postoperative imaging changes were analyzed. In 4 patients, hyperintense medullary streaks on FLAIR imaging (HMSF) at the level of the centrum semiovale were detected.
RESULTS The HMSF were coincident with hyperintense medullary streaks on a T2-weighted image, though they were not completely coincident with the vasculature on either a T2*-weighted image or contrast-enhanced CT. Analysis revealed significantly higher values in terms of MR angiography scores, number of flow voids of the basal ganglia, and the presence of the medullary artery in the group with HMSF than in those without. In contrast, the presence of white matter damage was significantly less frequent in the HMSF group. All HMSF disappeared after surgery, and the mean apparent diffusion coefficient at the same level was significantly reduced postoperatively.
CONCLUSIONS Although HMSF should be associated with collateral circulation in moyamoya disease, other factors may be involved, including stagnated cerebrospinal fluid or vasogenic edema that is relevant to the impaired state of the white matter. Findings in this study provide insight into the pathophysiological basis of the perivascular space in moyamoya disease.

Efficacy and safety of non-suture dural closure using a novel dural substitute consisting of polyglycolic acid felt and fibrin glue to prevent cerebrospinal fluid leakage-A non-controlled, open-label, multicenterclinical trial-
Shunsuke Terasaka, Toshiaki Taoka, Satoshi Kuroda, Nobutaka Mikuni, Toru Nishi, Hiroyuki Nakase, Yukihiko Fujii, Yasuhiko Hayashi, Jun-ichi Murata, Ken-ichiro Kikuta, Toshihiko Kuroiwa, Sachie Shimokawa, Kiyohiro Houkin
JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE, 28, 5, 69, 69, SPRINGER, 2017年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The objective of this study is to evaluate the efficacy and safety of non-suture dural closure using a novel dural substitute (GM111) consisting of polyglycolic acid felt with a fibrin-glue-coated area commensurate in size with the dural defect. This was a non-controlled, open-label, multicenter clinical trial. The efficacy evaluation endpoints were (1) GM111's intra-operative capability to close dural defects and (2) prevention of cerebrospinal fluid (CSF) leakage and subcutaneous CSF retention throughout the postoperative period (evaluated by diagnostic imaging). Patients meeting the following three preoperative and two intra-operative selection criteria were enrolled: (1) between 12 and <75 years of age; (2) the dura is surmised to be defective and in need of reconstruction; (3) informed written consent was obtained from the patient; (4) the surgical wound is class 1; and (5) the size of duraplasty is >= 0.2 cm(2) to <100 cm(2). Sixty patients were enrolled. The craniotomy site was supratentorial in 77.2%, infratentorial in 12.3% and sellar in 10.5%. The GM111 prosthesis size ranged from 0.24 to 42 cm(2). To evaluate the efficacy, intra-operative closure was confirmed by Valsalva's maneuver, water infusion, etc., in all patients. CSF leakage and subcutaneous CSF retention throughout the postoperative period were found in four patients. Adverse events for which a causal relationship with GM111 could not be ruled out occurred in 8.8% of the patients. There were no instances of postoperative infection due to GM111. GM111 showed good closure capability and safety when used for non-suture dural closure.

Direct Anastomosis Using Occipital Artery for Additional Revascularization in Moyamoya Disease After Combined Superficial Temporal Artery-Middle Cerebral Artery and Indirect Bypass
Ken Kazumata, Hiroyasu Kamiyama, Hisayasu Saito, Katsuhiko Maruichi, Masaki Ito, Haruto Uchino, Naoki Nakayama, Satoshi Kuroda, Kiyohiro Houkin
OPERATIVE NEUROSURGERY, 13, 2, 213, 222, OXFORD UNIV PRESS INC, 2017年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The posterior cerebral artery (PCA) is involved in approximately 30% of moyamoya disease (MMD) cases. However, there have been insufficient reports describing revascularization techniques in the posterior portion of the brain, particularly of direct anastomosis. OBJECTIVE: To perform a technical assessment in patients with MMD who underwent either occipital artery (OA)-PCA bypass or OA-middle cerebral artery (MCA) bypass.
METHODS: Atotal of 428 revascularization procedures in 368 patients were retrospectively assessed by reviewing clinical charts and radiological data.
RESULTS: Ten patients (3.5%) were treated with direct bypass after the anterior revascularization with a median interval of 30 months (range, 5 months-16 years). Seven patients were <18 years of age (average age, 17.5 +/- 15.6 years). Preoperative symptoms included transient motor deficits involving the lower extremities (n = 5), visual disturbances (n = 6), and cerebral infarctions (n = 6). A favorable outcome (modified Rankin Scale score <3) was achieved in 9 of these 10 patients. Direct anastomosis was performed in 3 hemispheres with an OA-MCA bypass and in 8 hemispheres with an OA-PCA bypass. Patency of the direct bypass was confirmed on angiogram in 7 of 7 patients who underwent conventional angiogram performed within 1 year after the surgery. None of the 10 patients demonstrated cerebral infarctions after the posterior revascularization.
CONCLUSION: In MMD, symptomatic PCA regression after anterior revascularization was found predominantly in children and young adults. Direct anastomosis in the posterior portion of the brain can be successfully achieved and is effective in preventing ischemic events.

Surgical Outcome of Cerebral Aneurysm Clipping Treated with Immunosuppressants: Report of 11 Cases and Review of the Literature
Masaaki Hokari, Naoki Nakayama, Ken Kazumata, Toshiya Osanai, Hideo Shichinohe, Takeo Abumiya, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 57, 3, 122, 127, JAPAN NEUROSURGICAL SOC, 2017年03月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, There are no reports on the outcomes of clippings in patients who receive immunosuppressants, for example, due to connective tissue diseases or following organ transplantation. We thoroughly reviewed these cases focusing on the perioperative management phase. The study included 11 patients with intracranial aneurysms who were taking immunosuppressants; between 2007 and 2014. We performed 12 clipping surgeries. Their clinical records were reviewed for age and gender, aneurysms' location and size, perioperative management of the immunosuppressive drugs, and surgical complications. The study included nine females and two males, aged between 52 and 71 years (mean 60.1 +/- 8.5 years). The clinical presentation in five cases was subarachnoid hemorrhage (SAH); the aneurysm was incidentally diagnosed in six patients (7 aneurysms). The reasons for taking immunosuppressants were autoimmune disorder in nine patients and liver transplantation in two patients. Daily intake of oral immunosuppressants for the patients with liver transplantation was discontinued for 2-4 days, and no infectious complications were evidenced. The weekly course of immunosuppressive drugs for the patients with autoimmune disorder was continued in eight of nine patients. Caution must be exercised when considering the suitability of clipping for patients taking immunosuppressants, but surgery outcomes are generally favorable; when operative treatment is required, we believe it to be comparatively safe, if the perioperative management is conducted in close collaboration with the relevant departments.

Application of cell sheet technology to bone marrow stromal cell transplantation for rat brain infarct
Masaki Ito, Hideo Shichinohe, Kiyohiro Houkin, Satoshi Kuroda
JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, 11, 2, 375, 381, WILEY, 2017年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Bone marrow stromal cells (BMSC) transplantation enhances functional recovery after cerebral infarct, but the optimal delivery route is undetermined. This study was aimed to assess whether a novel cell-sheet technology non-invasively serves therapeutic benefits to ischemic stroke. First, the monolayered cell sheet was engineered by culturing rat BMSCs on a temperature-responsive dish. The cell sheet was analysed histologically and then transplanted onto the ipsilateral neocortex of rats subjected to permanent middle cerebral artery occlusion at 7 days after the insult. Their behaviours and histology were compared with those in the animals treated with direct injection of BMSCs or vehicle over 4 weeks post-transplantation. The cell sheet was 27.9+/-8.0 mu m thick and was composed of 9.8+/-2.4x10(5) cells. Cell sheet transplantation significantly improved motor function when compared with the vehicle-injected animals. Histological analysis revealed that the BMSCs were densely distributed to the neocortex adjacent to the cerebral infarct and expressed neuronal phenotype in the cell sheet-transplanted animals. These findings were almost equal to those for the animals treated with direct BMSC injection. The attachment of the BMSC sheet to the brain surface did not induce reactive astrocytes in the adjacent neocortex, although direct injection of BMSCs profoundly induced reactive astrocytes around the injection site. These findings suggest that the BMSCs in cell sheets preserve their biological capacity of migration and neural differentiation. Cell-sheet technology may enhance functional recovery after ischaemic stroke, using a less invasive method. Copyright (C) 2014 John Wiley & Sons, Ltd.

Development of Database and Genomic Medicine for von Hippel-Lindau Disease in Japan
Shunsaku Takayanagi, Akitake Mukasa, Hirofumi Nakatomi, Hiroshi Kanno, Jun-ichi Kuratsu, Ryo Nishikawa, Kazuhiko Mishima, Atushi Natsume, Toshihiko Wakabayashi, Kiyohiro Houkin, Shunsuke Terasaka, Masahiro Yao, Nobuo Shinohara, Taro Shuin, Nobuhito Saito
NEUROLOGIA MEDICO-CHIRURGICA, 57, 2, 59, 65, JAPAN NEUROSURGICAL SOC, 2017年02月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, von Hippel-Lindau (VHL) disease is a hereditary tumor disease in which tumors develop in multiple organs, not only as hemangioblastomas (HBs) in the central nervous system, but also as kidney tumors, pheochromocytomas, and so on. Much about the epidemiology of VHL disease remained unknown until fairly recently in Japan, leading to calls for the establishment of a VHL disease epidemiological database in Japanese. To elucidate its epidemiology in Japan, the Japanese Ministry of Health, Labour and Welfare created the VHL Disease Study Group, which was put in charge of carrying out a nationwide epidemiological survey. The survey found close to 400 Japanese VHL disease patients throughout the country. Based on those results, the VHL Disease Study Group created the VHL Disease Treatment Guideline and also a severity classification. It is thought that the prognosis of VHL disease patients can be improved by performing genetic diagnosis and careful follow-up. Accordingly, the University of Tokyo Hospital put in place an in-hospital system for implementing genomic medicine for VHL disease based on genetic diagnosis. For that system, it was especially important to establish (I) accurate genetic diagnostic techniques, (II) genetic counseling capabilities for the patients and their families, and (III) a system of cooperation among multiple departments, including urology departments, and so on. Further elucidation of the epidemiology and the development of genomic medicine are needed to improve the treatment results of VHL disease in Japan.

Proposal for a Prospective Registry for Moyamoya Disease in Japan
Ken Kazumata, Masaki Ito, Haruto Uchino, Hiroshi Nishihara, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 57, 2, 66, 72, JAPAN NEUROSURGICAL SOC, 2017年02月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The number of clinical research papers published worldwide on moyamoya disease (MMD) has increased recently. However, the majority of the literature comprises retrospective single-center studies collecting data on small numbers of patients. Several multi-center studies are ongoing in Japan; however, the current data are insufficient for comprehensively outlining the various characteristics of MMD. To enhance our knowledge on epidemiologic, vascular, and genetic aspects of MMD, a prospective multicenter registry will be established in Japan that will help to streamline clinical research as well as improve clinical treatments and long-term outcomes. Patients with MMD or secondary moyamoya syndrome referred to the participating centers will be invited to the registry. Demographic and physiological parameters, along with neuroimaging data will be collected chronologically. Clinical events, including neurological, medical, and surgical interventions will be recorded. Whole blood samples will be collected. Extra-and intracranial vascular tissue, and/or cerebrospinal fluid will also be collected from patients who undergo surgical revascularization. These biospecimens will be stored at the repositories and utilized for genome-wide association studies for identifying genetic variants, as well as tissue-specific proteomic, and/or molecular analyses. Ethics approval will be obtained at all facilities collecting biospecimens. The registry will provide descriptive statistics on functional outcomes, surgical techniques used, medications, and neurological events stratified according to patients' clinical characteristics. We expect this study to provide novel insights in the management of MMD patients and design better therapies.

Synergistic Interactions Between Direct and Indirect Bypasses in Combined Procedures: The Significance of Indirect Bypasses in Moyamoya Disease.
Uchino H, Kim JH, Fujima N, Kazumata K, Ito M, Nakayama N, Kuroda S, Houkin K
Neurosurgery, 80, 2, 201, 209, 2017年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Whether additional indirect bypasses effectively contribute to revascularization in combined procedures remains unclear in patients with moyamoya disease. Objective: To evaluate the longitudinal changes associated with combined procedures while following up pediatric and adult patients long term and to assess whether any other clinical factors or hemodynamic parameters affected these changes to determine an optimal surgical strategy. Methods: We studied 58 hemispheres in 43 adults and 39 hemispheres in 26 children who underwent combined revascularization for moyamoya disease. To evaluate bypass development, we assessed the sizes of the superficial temporal artery and middle meningeal artery using magnetic resonance angiography. Multivariate analysis determined the effects of multiple variables on bypass development. Results: Indirect bypass (middle meningeal artery) development occurred in 95% and 78% of the pediatric and adult hemispheres, respectively. Of these, dual development of direct and indirect bypasses occurred in 54% of the pediatric hemispheres and in 47% of the adult hemispheres. Reciprocal superficial temporal artery regression occurred in 28% of the hemispheres during the transition from the postoperative acute phase to the chronic phase during indirect bypass development. Good indirect bypass development was associated with adult hemispheres at Suzuki stage 4 or greater (odds ratio, 7.4; 95% confidence interval, 1.4-39.4; P = .02). Disease onset type and preoperative hemodynamic parameters were not considered predictors for the development of surgical revascularization. Conclusion: Simultaneous direct and indirect bypass development was most frequently observed, regardless of patient age and hemodynamic status. Applying indirect bypass as an adjunct to direct bypass could maximize revascularization in adults and children.

Synergistic Interactions Between Direct and Indirect Bypasses in Combined Procedures: The Significance of Indirect Bypasses in Moyamoya Disease
Haruto Uchino, Jae-Hoon Kim, Noriyuki Fujima, Ken Kazumata, Masaki Ito, Naoki Nakayama, Satoshi Kuroda, Kiyohiro Houkin
NEUROSURGERY, 80, 2, 201, 208, OXFORD UNIV PRESS INC, 2017年02月, ［査読有り］
英語, 研究論文（学術雑誌）, BACKGROUND: Whether additional indirect bypasses effectively contribute to revascular-ization in combined procedures remains unclear in patients with moyamoya disease.
OBJECTIVE: To evaluate the longitudinal changes associated with combined procedures while following up pediatric and adult patients long term and to assess whether any other clinical factors or hemodynamic parameters affected these changes to determine an optimal surgical strategy.
METHODS: We studied 58 hemispheres in 43 adults and 39 hemispheres in 26 children who underwent combined revascularization for moyamoya disease. To evaluate bypass development, we assessed the sizes of the superficial temporal artery and middle meningeal artery using magnetic resonance angiography. Multivariate analysis determined the effects of multiple variables on bypass development.
RESULTS: Indirect bypass ( middle meningeal artery) development occurred in 95% and 78% of the pediatric and adult hemispheres, respectively. Of these, dual development of direct and indirect bypasses occurred in 54% of the pediatric hemispheres and in 47% of the adult hemispheres. Reciprocal superficial temporal artery regression occurred in 28% of the hemispheres during the transition from the postoperative acute phase to the chronic phase during indirect bypass development. Good indirect bypass development was associated with adult hemispheres at Suzuki stage 4 or greater ( odds ratio, 7.4; 95% confidence interval, 1.4-39.4; P = .02). Disease onset type and preoperative hemodynamic parameters were not considered predictors for the development of surgical revascularization.
CONCLUSION: Simultaneous direct and indirect bypass development was most frequently observed, regardless of patient age and hemodynamic status. Applying indirect bypass as an adjunct to direct bypass could maximize revascularization in adults and children.

病院到着前の情報からtPA静注療法もしくは血栓回収療法を必要とする症例の予測因子に関する検討
東海林菊太郎, 東海林菊太郎, 長内俊也, 川堀真人, 川堀真人, 新谷好正, 寳金清博
脳血管内治療(Web), 2, Supplement, 2017年

Functional bio-imaging
Hisayasu Saito, Michiyuki Miyamoto, Hideo Shichinohe, Kiyohiro Houkin, Satoshi Kuroda
Cell Therapy against Cerebral Stroke: Comprehensive Reviews for Translational Researches and Clinical Trials, 111, 119, Springer Japan, 2017年01月01日, ［査読有り］
英語, 論文集(書籍)内論文, Cell transplantation therapy has been expected to promote functional recovery in various kinds of central nervous system (CNS) disorders, including cerebral stroke. However, there are several concerns to be resolved before clinical application of cell therapy for CNS disorders. The issues include the development of imaging techniques to monitor the response of the host CNS. It would be essential to establish functional bio-imaging technique serially and noninvasively validating the effects of cell therapy on the host CNS in order to achieve clinical application of cell therapy for cerebral stroke. Nuclear imaging technique is one of the most useful methods to assess the functional change in various kinds of CNS disorders, including cerebral stroke. Very recently, using a small-animal SPECT/CT apparatus, we could serially visualize the effects of BMSC transplantation on the distribution of 123I-IMZ in the infarct brain of the living rodents longitudinally and noninvasively. Furthermore, we serially assessed local glucose metabolism in the rats subjected to permanent MCA occlusion and found that BMSC transplantation significantly enhances the recovery in the peri-infarct area, using smallanimal 18F-FDG PET/CT system. The BMSCs may enhance the recovery of local glucose metabolism by improving neuronal integrity in the peri-infarct area, when directly transplanted into the infarct brain. Although there are few studies that indicate the utility of imaging techniques to monitor the response of the host CNS after cell therapy and further investigation is needed, 123I-IMZ SPECT and 18FFDG PET may be promising modalities to assess the therapeutic benefits of cell therapy for ischemic stroke without subjective bias in clinical situation.

Cell culture
Masaki Ito, Kiyohiro Houkin
Cell Therapy against Cerebral Stroke: Comprehensive Reviews for Translational Researches and Clinical Trials, 49, 72, Springer Japan, 2017年01月01日, ［査読有り］
英語, 論文集(書籍)内論文, Cell production under Good Manufacturing Practice (GMP) protocol is mandatory for the proper application of therapeutic cells in clinical settings. If cells are produced under GMP conditions, chemically defined conditions and a controlled environment would be ensured. However, such practices do not specify the use of animal-derived or xenogeneic recombinant supplements, which might raise some concern for clinical-grade cell preparations. At the very least, information of these materials should be provided to the patients treated with cell therapy to ensure proper understanding and informed assent. Therefore, in this chapter, the conventional cell culture methods employed for cell preparation (isolation, expansion, and/or derivation) are discussed, with a particular focus on each of the cell types employed in clinical trials of cell therapy against cerebral stroke.

In vivo cell tracking techniques for applications in central nervous system disorders
Taku Sugiyama, Satoshi Kuroda, Kiyohiro Houkin
Cell Therapy against Cerebral Stroke: Comprehensive Reviews for Translational Researches and Clinical Trials, 101, 110, Springer Japan, 2017年01月01日, ［査読有り］
英語, 論文集(書籍)内論文, Cell therapy is expected to promote functional recovery in various kinds of central nervous system disorders. Many studies show beneficial effects of cell therapy, and several clinical studies have already been initiated worldwide. Although these results are encouraging, several problems remain, including elucidating the therapeutic mechanisms, treatment timing, optimal cell dose, type of cells, and cell delivery route. For further optimization of this therapy, it is essential to develop in vivo cell tracking techniques. Longitudinal and serial analyses of the fate of transplanted cells are quite important for solving these problems. There are several cell labeling techniques and imaging modalities, including magnetic resonance imaging, nuclear imaging, and optical imaging. However, any single imaging modality has its own distinct advantages and drawbacks. Proper understanding of each technique’s characteristics is crucial for successful in vivo imaging. In this chapter, we present a literature survey of cell tracking techniques used in clinical settings and laboratories and introduce recent advances in this field.

Cell therapy for ischemic stroke with bone marrow stromal cells
Satoshi Kuroda, Hideo Shichinohe, Kiyohiro Houkin
Cell Therapy against Cerebral Stroke: Comprehensive Reviews for Translational Researches and Clinical Trials, 15, 25, Springer Japan, 2017年01月01日, ［査読有り］
英語, 論文集(書籍)内論文, In this article, the authors review recent advancements and perspective on cell therapy for ischemic stroke with bone marrow-derived cells, including bone marrow stromal cells (BMSCs) and multilineage-differentiating stress-enduring (Muse) cells. They can be easily isolated from the patients themselves and transplanted into them without any ethical and immunological problem. Animal experiments have shown that direct transplantation of these adult stem cells significantly enhances the recovery of motor function in various types of neurological disorders, including ischemic stroke. They aggressively migrate toward the damaged tissue and proliferate in the host brain. The BMSCs may contain heterogeneous subpopulations and contribute to functional recovery through multiple mechanisms, including neuroprotection, inflammatory modulation, cell fusion, and neural differentiation. On the other hands, Muse cells may promote functional recovery after ischemic stroke by reorganizing the infarct brain.

Health-related quality of life in patients with spinal dural arteriovenous fistulae
Toru Sasamori, Kazutoshi Hida, Toshiya Osanai, Shunsuke Yano, Toshitaka Seki, Kiyohiro Houkin
NEUROSURGICAL REVIEW, 40, 1, 83, 86, SPRINGER, 2017年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Neurological improvement in patients with spinal dural arteriovenous fistulae (SDAVF) is often partial even after adequate treatment. While treatment outcomes have been evaluated primarily on the basis of the postoperative changes in neurological deficits, outcome measures should also reflect the patient-reported outcome (PRO). We conducted a health-related quality of life (HRQOL) survey in 52 SDAVF patients; 33 (63.5%) completed the short-form 36 Health Survey (SF-36) questionnaire. They were 25 males and 8 females ranging in age from 47 to 85 years (mean age 70.0 years). The mean follow-up period was 95.6 months. We analyzed the completed questionnaires and examined the clinical factors associated with their HRQOL. After treatment, gait- and micturition disturbances persisted in 31 (93.9%) and 31 (93.9%) of our patients; 26 (78.8%) reported chronic leg pain. The SF-36 scores of treated SDAVF patients were significantly lower than the national average of 50 for all 8 sub-items in the questionnaire. The scores for physical functioning (PF) and role-physical (RP) were particularly low. With the exception of bodily pain (BP), there was a significant negative correlation between the Aminoff-Logue scale (ALS) scores for gait- and micturition and the sub-item scores. The score for BP showed a significant positive correlation with the scores for the 7 other SF-36 sub-items. The HRQOL of treated SDAVF patients was lower than the national average with respect to both physical and mental aspects. Persistent post-treatment pain and gait- and micturition disturbances were responsible for their lower HRQOL.

[Utility of Intraoperative Catheter Myelography during Intrathecal Baclofen Pump Implantation:Report of 2 Cases].
Takamiya S, Sasamori T, Hamauchi S, Seki T, Kano T, Yabe I, Sasaki H, Houkin K
No shinkei geka. Neurological surgery, 45, 1, 53, 58, 2017年01月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, We report two patients in whom the intrathecal baclofen(ITB)catheter was located in the subdural space, although we had confirmed good outflow of spinal fluid from the spinal catheter. Patient 1 was a woman in her 30s with spastic quadriplegia due to subarachnoid hemorrhage. An ITB pump was implanted, and a good outflow of spinal fluid from the spinal catheter was observed during the surgery. Postoperatively, her spasticity did not improve. Catheter myelography revealed that the spinal catheter was located in the subdural space. Using intraoperative catheter myelography, we corrected the position of the catheter. Patient 2 was a man in his 20s diagnosed with adrenoleukodystrophy. An ITB therapy was performed to improve his spastic gait. Intraoperative catheter myelography showed that the spinal catheter was located in the subdural space, although there was good outflow of spinal fluid from the catheter. Our experience suggests that the outflow of spinal fluid alone should not be used to determine the location of the spinal catheter. Intraoperative catheter myelography is useful for the correct placement of the spinal catheter in the subarachnoid space.

Meandering flow void around the splenium in moyamoya disease
Takeshi Mikami, Tomoyoshi Kuribara, Katsuya Komatsu, Yusuke Kimura, Masahiko Wanibuchi, Kiyohiro Houkin, Nobuhiro Mikuni
NEUROLOGICAL RESEARCH, 39, 8, 702, 708, TAYLOR & FRANCIS LTD, 2017年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Objectives: Meandering flow void around the splenium, which can be recognized on conventional T2-weighted images, implicates collateral flow in the splenial artery in patients with moyamoya disease. In this report, curves of flow voids around the splenium (SFVs) were evaluated in patients with moyamoya disease, and their diagnostic value and pathophysiology were verified.
Methods: A total of 65 consecutive patients with moyamoya disease were included in this analysis. The number of SFV curves was counted on each side. The numbers of SFV curves in patients with moyamoya disease was compared with those in the control group. The clinical features of patients with large numbers of flow voids were analyzed.
Results: The mean number of SFVs was significantly higher in the moyamoya disease group than in the control group or the atherosclerotic disease group. The cut-off SFV count for a diagnosis of moyamoya disease should be set to 2.25 in consideration of receiver operating characteristic curve analysis. A multivariate logistic analysis of SFV data in moyamoya disease revealed significant differences between the high SFV count group (2.25) and the low SFV count group (<2.25) in age, flow voids in the basal ganglia, and magnetic resonance angiography score of the internal carotid artery and anterior cerebral artery.
Conclusion: Based on this study, number of SFV curves on conventional T2-weighted imaging could be a useful measurement for confirming a diagnosis of moyamoya disease. Increased number of SFV curves was associated with age and progress of disease.

A prospective, multicentre, single-arm clinical trial of bevacizumab for patients with surgically untreatable, symptomatic brain radiation necrosis^†.
Furuse M, Nonoguchi N, Kuroiwa T, Miyamoto S, Arakawa Y, Shinoda J, Miwa K, Iuchi T, Tsuboi K, Houkin K, Terasaka S, Tabei Y, Nakamura H, Nagane M, Sugiyama K, Terasaki M, Abe T, Narita Y, Saito N, Mukasa A, Ogasawara K, Beppu T, Kumabe T, Nariai T, Tsuyuguchi N, Nakatani E, Kurisu S, Nakagawa Y, Miyatake SI
Neuro-oncology practice, 3, 4, 272, 280, 2016年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Brain radiation necrosis (BRN) can be a complication of radiotherapy for primary and secondary brain tumors, as well as head and neck tumors. Since vascular endothelial growth factor (VEGF) is also a vascular permeability factor in the brain, bevacizumab, a humanized antibody that inhibits VEGF, would be expected to reduce perilesional edema that often accompanies BRN. METHODS: Patients with surgically untreatable, symptomatic BRN refractory to conventional medical treatments (eg, corticosteroid, anticoagulants, or hyperbaric oxygen therapy) were enrolled. We judged that a major cause of perilesional edema with a lesion-to-normal brain ratio ≤1.8 on 11C-methionine or ≤2.5 on 18F-boronophenylalanine PET was BRN, not tumor recurrence, and 6 cycles of biweekly bevacizumab (5 mg/kg) were administered. The primary endpoint was a ≥30% reduction from the patients' registration for perilesional edema continuing for ≥1 month. RESULTS: Of the 41 patients enrolled, 38 were fully eligible for the response assessment. The primary endpoint was achieved in 30 of the 38 (78.9%) patients at 3.0 months (median) after enrollment. Sixteen patients (42.1%) experienced improvement of their Karnofsy Performance Score. Corticosteroid use could be reduced in 29 patients (76.3%). Adverse events at grade ≥3 occurred in 10 patients (24.4%). CONCLUSIONS: Bevacizumab treatment offers certain clinical benefits for patients with surgically untreatable, symptomatic BRN. The determination of BRN using amino-acid PET, not biopsy, is adequate and less invasive for determining eligibility to receive bevacizumab.

Change in F-18-Fluoromisonidazole PET Is an Early Predictor of the Prognosis in the Patients with Recurrent High-Grade Glioma Receiving Bevacizumab Treatment
Shigeru Yamaguchi, Kenji Hirata, Takuya Toyonaga, Kentaro Kobayashi, Yukitomo Ishi, Hiroaki Motegi, Hiroyuki Kobayashi, Tohru Shiga, Nagara Tamaki, Shunsuke Terasaka, Kiyohiro Houkin
PLOS ONE, 11, 12, e0167917, PUBLIC LIBRARY SCIENCE, 2016年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BackgroundBevacizumab (BEV), a humanized monoclonal antibody, become a currently important chemotherapeutic option for the patients with recurrent glioma. The aim of this retrospective study is to investigate whether 18 F-Fluoromisonidazole (FMISO) PET have the potential to detect BEV-resistant gliomas in the early-stage.MethodsWe reviewed the FMISO PET and MRI appearances before and 3 to 4 courses after BEV treatment on 18 recurrent glioma patients. FMISO accumulation was assessed by visual inspection and semi-quantitative values which were tumor-to-normal (T/N) ratio and hypoxic volume. MRI responses were evaluated based on RANO (Response Assessment in Neuro-Oncology) criteria. The prognostic analysis was performed in relation to the response assessment by FMISO PET and MRI using overall survival (OS) after BEV application.ResultsAfter BEV application, MRI revealed partial response in 14 of 18 patients (78%), of which 9 patients also demonstrated decreased FMISO accumulation. These 9 patients (50%) were classified as "MRI-FMISO double responder". As for the other 5 patients (28%), FMISO accumulation volumes increased or remained stable after BEV treatment although partial responses were achieved on MRI. Therefore, these cases were classified as "MRI-only responder". The remaining 4 patients (22%) did not show treatment response on FMISO PET or MRI ("non-responder"). MRI-FMISO double responders showed significantly longer OS than that in other groups (median 12.4 vs 5.7 months; P < 0.001), whereas there were no overall survival difference between MRI-only responders and non-responders (median OS, 5.7 and 4.8 months; P = 0.58). Among the pre-treatment clinical factors, high FMISO T/N ratio was a significant prognostic factor of overall survival in these patients under the assessment of Cox proportional hazard model.ConclusionsRecurrent gliomas with decreasing FMISO accumulation after short-term BEV application could derive a survival benefit from BEV treatment. Change in FMISO PET appearance can identify BEV-resistant gliomas in early-stage regardless of MRI findings in a comprehensible way.

Increased Blood Viscosity in Ischemic Stroke Patients with Small Artery Occlusion Measured by an Electromagnetic Spinning Sphere Viscometer
Koji Furukawa, Takeo Abumiya, Keiji Sakai, Miki Hirano, Toshiya Osanai, Hideo Shichinohe, Naoki Nakayama, Ken Kazumata, Kazutoshi Hida, Kiyohiro Houkin
JOURNAL OF STROKE & CEREBROVASCULAR DISEASES, 25, 11, 2762, 2769, ELSEVIER SCIENCE BV, 2016年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose: High blood viscosity causes blood stagnation and subsequent pathological thrombotic events, resulting in the development of ischemic stroke. We hypothesize that the contribution of blood viscosity may differ among ischemic stroke subtypes based on specific pathological conditions. We tried to verify this hypothesis by measuring blood viscosity in acute ischemic stroke patients using a newly developed electromagnetic spinning sphere (EMS) viscometer. Methods: Measurements in acute ischemic stroke patients were performed 4 times during admission and data were compared with those obtained from 100 healthy outpatient volunteers. Results: We enrolled 92 patients (cardioembolism: 25, large artery atherosclerosis: 42, and small artery occlusion [SAO]: 25) in this study. Comparisons of blood viscosity between the ischemic stroke subgroups and control group revealed that blood viscosity at the date of admission was significantly higher in the SAO group (5.37 +/- 1.11 mPa.s) than in the control group (4.66 +/- .72 mPa.s) (P <.01). Among all subtype groups showing a reduction in blood viscosity after 2 weeks, the SAO group showed the highest and most significant reduction, indicating that SAO patients had the most concentrated blood at the onset. Conclusions: Blood viscosity was significantly increased in the SAO group at the date of admission, which indicated the contribution of dehydration to the onset of ischemic stroke. The importance of dehydration needs to be emphasized more in the pathogenesis of SAO. The clinical application of the EMS viscometer is promising for understanding and differentiating the pathogenesis of ischemic stroke.

Transarterial regional hypothermia provides robust neuroprotection in a rat model of permanent middle cerebral artery occlusion with transient collateral hypoperfusion
Kota Kurisu, Takeo Abumiya, Masaki Ito, Masayuki Gekka, Toshiya Osanai, Hideo Shichinohe, Naoki Nakayama, Ken Kazumata, Kiyohiro Houkin
BRAIN RESEARCH, 1651, 95, 103, ELSEVIER SCIENCE BV, 2016年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The robust neuroprotective effects of transarterial regional hypothermia have been demonstrated in the typical transient middle cerebral artery occlusion (tMCAO) model, but have not yet been tested in other ischemic stroke models, even though clinical ischemic conditions are diverse. In order to clarify these effects in a different ischemic stroke model, we employed a rat model of permanent MCAO (pMCAO) with transient collateral hypoperfusion (tCHP), which was achieved by direct MCA ligation through craniotomy and 1-h bilateral common carotid artery occlusion at the beginning of pMCAO. The infusion of 20 ml/kg of 4 degrees C cold saline (CS) or 37 degrees C warm saline (WS) into the ipsilateral internal carotid artery (ICA) was performed for 15 min in intra- or post-tCHP. Neurological scores, infarct/edema volumes, and neuronal apoptosis and reactive gliosis were compared between the CS and WS groups and a non-infusion control group after 48 h of reperfusion. Although brain temperatures were only reduced by 2-3 degrees C for 15 min, the CS group had significantly better neurological scores, smaller infarct/edema volumes, and less penumbral neuronal apoptosis and reactive gliosis than the control and WS groups. The post-tCHP CS group exhibited prominent neuroprotective effects, even though infarct volumes and neuronal apoptosis were reduced less than those in the intra-tCHP CS group. In conclusion, we demonstrated the neuroprotective effects of transarterial regional hypothermia in an ischemic model of pMCAO with tCHP. Even though MCAO is persistent, cold infusion via the ICA is neuroprotective for the penumbra, suggesting the wider therapeutic application of this therapy. (C) 2016 Elsevier B.V. All rights reserved.

A significant correlation between delayed cure after microvascular decompression and positive response to preoperative anticonvulsant therapy in patients with hemifacial spasm
Shunsuke Terasaka, Katsuyuki Asaoka, Shigeru Yamaguchi, Hiroyuki Kobayashi, Hiroaki Motegi, Kiyohiro Houkin
NEUROSURGICAL REVIEW, 39, 4, 607, 612, SPRINGER, 2016年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Although microvascular decompression (MVD) is a reliable treatment for hemifacial spasm (HFS), the postoperative course is varied. We retrospectively analyzed the resolution pattern of the spasm and specified predictors for delayed cure after MVD. This study included 114 consecutive patients with typical HFS. All of them were followed up for at least 1 year after operation. Patients were divided into three groups depending on the postoperative course: immediate cure, delayed cure, and failure. To identify the predictive factors for delayed cure after MVD, logistic regression analyses were applied using candidate clinical factors, such as duration of symptom, the tendency of the spasm, preoperative medical treatment, and offending vessels. Among the 114 patients, 107 patients were cured. For those cured, 65 patients were classified as immediate cure and 42 patients were classified as delayed cure. Cumulative spasm-free rates after 1 week, 1 month, and 3 months after MVD were 70, 88, and 97 %, respectively. No predictive factors between the cured and failure groups were observed. According to multivariate analysis, preoperative anticonvulsant therapy was found to be the sole significant predictive factor for delayed cure after MVD (p = 0.025). A significant correlation between delayed cure and preoperative anticonvulsant therapy was found in our study, which suggests that hyperexcitation of the facial nucleus plays an important role in pathogenesis of delayed cure. Therefore, if a patient demonstrating a positive response to preoperative anticonvulsant therapy showed a persistent spasm after MVD, reoperation should be delayed for at least 3 months after the initial operation.

Reliability of the Size Evaluation Method for Meningiomas: Maximum Diameter, ABC/2 Formula, and Planimetry Method
Yukitomo Ishi, Shunsuke Terasaka, Shigeru Yamaguchi, Michiharu Yoshida, Shogo Endo, Hiroyuki Kobayashi, Kiyohiro Houkin
WORLD NEUROSURGERY, 94, 80, 88, ELSEVIER SCIENCE INC, 2016年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: To evaluate the accuracy of tumor size by maximum diameter, ABC/2 formula, and planimetry method using thick-slice and thin-slice magnetic resonance imaging (MRI).
METHODS: Maximum diameter and tumor volume calculated using ABC/2 formula (V1) and planimetry method with thick-slice MRI (V2) and thin-slice MRI (V3) were examined in 83 meningiomas. Form factor (FF) analysis was performed to assess irregularity of the tumor. V3 values were considered as real tumor volumes. The accuracy of V1 and V2 was evaluated using ratio and difference from V3. Meningiomas were categorized by tumor locations: skull base (anterior, middle, and posterior) and noneskull base (calvaria and other sites).
RESULTS: Correlation between maximum diameter and V3 was statistically significant (r =0.91), but the error was significant in tumors with longer maximum diameters. Correlation between V1 and V3 was significant (r =0.97). However, V1 tended to be larger in middle skull base meningiomas or in tumors with low FF values (R-2 =0.21). V2 represented relatively accurate volumes in both groups except in the case of small meningiomas. When tumors were demonstrated within 3 fractions on thick-slice MRI, the ratio of V2 to V3 showed significant variability.
CONCLUSIONS: Using the ABC/2 formula, the volume of meningiomas in the middle skull base or meningiomas with low FF value might be calculated larger than the real tumor volume. The planimetry method with thick-slice MRI demonstrated relatively accurate volumes if the tumor was fractionated in > 4 slices.

Utility of noncontrast-enhanced time-resolved four-dimensional MR angiography with a vessel-selective technique for intracranial arteriovenous malformations
Noriyuki Fujima, Toshiya Osanai, Yukie Shimizu, Atsushi Yoshida, Taisuke Harada, Naoki Nakayama, Kohsuke Kudo, Kiyohiro Houkin, Hiroki Shirato
JOURNAL OF MAGNETIC RESONANCE IMAGING, 44, 4, 834, 845, WILEY-BLACKWELL, 2016年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PurposeTo evaluate the utility of a vessel-selective four-dimensional (4D) magnetic resonance angiography (MRA) technique for the evaluation of intracranial arteriovenous malformations (AVMs).
Materials and MethodsTwelve AVM patients were evaluated retrospectively. Time-of-flight (TOF) MRA, nonvessel-selective 4D-MRA (NS-4D-MRA), and vessel-selective 4D-MRA (VS-4D-MRA) were performed using a 3T MR unit in all patients, and used to identify feeding arteries and draining veins and measure nidus size. The diagnostic accuracy of the three techniques was compared using digital subtraction angiography (DSA). If a multifeeder was observed, the percentage of blood flow of each feeding artery to the entire nidus was evaluated and compared to the DSA findings using the error value, defined as the degree of overestimation of the blood flow. All imaging findings were assessed by two neuroradiologists.
ResultsIn both raters, the detectability of feeding arteries by VS-4D-MRA (12 and 11 patients) was significantly higher than those of TOF-MRA (7 and 6 patients) and NS-4D-MRA (8 and 7 patients) (P < 0.016). The detectability of drainer veins by TOF-MRA (10 and 10 patients) was significantly higher than that of VS-4D-MRA (7 and 6 patients). In the percentage of the blood flow of each feed artery to the entire nidus, the DSA findings (error value; 27.15.7) indicated overestimations of the blood flow compared to the VS-4D-MRA (error value; 7.1 +/- 3.9) (P < 0.001).
ConclusionVS-4D-MRA was shown to be a useful technique for the evaluation of intracranial AVMs, especially for detecting feed arteries and estimating details of the nidus structure. J. MAGN. RESON. IMAGING 2016;44:834-845.

Cellular Functions and Gene and Protein Expression Profiles in Endothelial Cells Derived from Moyamoya Disease-Specific iPS Cells
Shuji Hamauchi, Hideo Shichinohe, Haruto Uchino, Shigeru Yamaguchi, Naoki Nakayama, Ken Kazumata, Toshiya Osanai, Takeo Abumiya, Kiyohiro Houkin, Takumi Era
PLOS ONE, 11, 9, e0163561, PUBLIC LIBRARY SCIENCE, 2016年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Background
and purpose Moyamoya disease (MMD) is a slow, progressive steno-occlusive disease, arising in the terminal portions of the cerebral internal carotid artery. However, the functions and characteristics of the endothelial cells (ECs) in MMD are unknown. We analyzed these features using induced pluripotent stem cell (iPSC)-derived ECs.
Methods
iPSC lines were established from the peripheral blood of three patients with MMD carrying the variant RNF213 R4810K, and three healthy persons used as controls. After the endothelial differentiation of iPSCs, CD31(+)CD144(+) cells were purified as ECs using a cell sorter. We analyzed their proliferation, angiogenesis, and responses to some angiogenic factors, namely VEGF, bFGF, TGF-beta, and BMP4. The ECs were also analyzed using DNA microarray and proteomics to perform comprehensive gene and protein expression analysis.
Results
Angiogenesis was significantly impaired in MMD regardless of the presence of any angiogenic factor. On the contrary, endothelial proliferation was not significant between controland MMD-derived cells. Regarding DNA microarray, pathway analysis illustrated that extracellular matrix (ECM) receptor-related genes, including integrin beta 3, were significantly down-regulated in MMD. Proteomic analysis revealed that cytoskeleton-related proteins were downregulated and splicing regulation-related proteins were upregulated in MMD.
Conclusions
Downregulation of ECM receptor-related genes may be associated with impaired angiogenic activity in ECs derived from iPSCs from patients with MMD. Upregulation of splicing regulation-related proteins implied differences in splicing patterns between control and MMD ECs.

Measurement of human blood viscosity by an electromagnetic spinning sphere viscometer.
Koji Furukawa, Takeo Abumiya, Keiji Sakai, Miki Hirano, Toshiya Osanai, Hideo Shichinohe, Naoki Nakayama, Ken Kazumata, Toshimitsu Aida, Kiyohiro Houkin
Journal of medical engineering & technology, 40, 6, 285, 92, 2016年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We herein applied an electromagnetic spinning sphere (EMS) viscometer to the measurement of human blood viscosity for the first time. We collected blood samples from 100 healthy outpatient volunteers in order to analyse viscosity dependence on blood cell parameters and on the shear rate with a simple approximation formula [ηi (γ)\, = Ai γ(- pi) + η0]. Viscosity dependence on blood cell parameters was relatively high at a high shear rate, but became lower as the shear rate decreased. The approximation formula with appropriate parameters of Ai and pi nearly faithfully reproduced actual blood rheological behaviour with a standard deviation of 1.5%. The distributions of Ai and pi values were broad, suggesting that the pattern of viscosity dependence on the shear rate varied with individual differences. The results obtained using the EMS viscometer suggest that blood viscosity values are individual-specific and actual individual measurements are important for understanding rheological conditions.

Treatment of Recurrent Intracranial Aneurysms After Clipping: A Report of 23 Cases and a Review of the Literature
Masaaki Hokari, Ken Kazumara, Naoki Nakayama, Satoshi Ushikoshi, Taku Sugiyama, Katsunori Asaoka, Kazuki Uchida, Daisuke Shimbo, Koji Itamoto, Yuka Yokoyama, Masanori Isobe, Tetsuaki Imai, Toshiya Osanai, Kiyohiro Houkin
WORLD NEUROSURGERY, 92, 434, 444, ELSEVIER SCIENCE INC, 2016年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: There are no established treatment strategies for aneurysms that recur after clipping. In this study, we present cases of patients who experienced recurrent aneurysms after clipping and subsequently underwent surgical intervention.
METHODS: Between 2004 and 2015, we surgically treated 23 aneurysms that recurred at a previously clipped site. Patient characteristics and clinical history were retrospectively reviewed.
RESULTS: Patients included 19 women and 4 men 45-81 years old. Aneurysms recurred 3-31 years (mean, 15.4 years) after the initial operation. For 18 cases, the first clinical presentation was a subarachnoid hemorrhage; aneurysms were incidentally diagnosed in 5 patients. Aneurysm locations were as follows: 9 on the internal carotid artery; 4 on the middle cerebral artery; 7 on the anterior communicating artery; 2 on the distal anterior cerebral artery; and 1 on the basilar artery. The reasons for retreatment included subarachnoid hemorrhage (n = 9) and aneurysm regrowth detected on follow-up examinations (n = 14). Endovascular treatment was performed in 10 cases, and direct surgery was performed in 13 cases (clipping in 8, clipping or trapping with bypass in 5). Various complex vascular reconstructions, including high-flow bypass and intracranial-intracranial in situ bypass, were performed for recurrent aneurysms.
CONCLUSIONS: In our experience, coil embolization is a safe and effective procedure for treating recurrent aneurysms. When cases are unsuitable for coil embolization, surgical treatment often requires neurosurgeons not only to overcome the general technical difficulty of reoperative clipping but also to perform challenging vascular reconstruction.

Transarterial Regional Brain Hypothermia Inhibits Acute Aquaporin-4 Surge and Sequential Microvascular Events in Ischemia/Reperfusion Injury
Kota Kurisu, Takeo Abumiya, Hideki Nakamura, Daisuke Shimbo, Hideo Shichinohe, Naoki Nakayama, Ken Kazumata, Hiroshi Shimizu, Kiyohiro Houkin
NEUROSURGERY, 79, 1, 125, 134, LIPPINCOTT WILLIAMS & WILKINS, 2016年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although transarterial regional hypothermia is an attractive alternative to general hypothermia, its efficacy and underlying mechanisms remain unclear.
OBJECTIVE: To confirm transarterial regional hypothermia therapeutic effects on ischemia/reperfusion (I/R) injury and to elucidate the mechanisms responsible.
METHODS: The therapeutic effects of transarterial regional hypothermia were initially investigated in 2-hour middle cerebral artery occlusion rats regionally infused with 10 degrees C saline (cold saline group) or 37 degrees C saline (warm saline group) and untreated rats (control group) just before the onset of 24 hours of reperfusion. The time course of infarct and edema progression, inflammatory reactions, microvascular morphological changes, and aquaporin-4 (AQP4) expression was analyzed after 0, 2, 6, and 24 hours of reperfusion.
RESULTS: Cold saline infusion only lowered brain temperatures for 30 minutes but mediated strong neuroprotective effects with infarct volume reductions of less than one- third. The time-course analysis revealed the following sequence of ischemia/reperfusion injury-related events in the control group: upregulated expression of AQP4 (2 hours); microvascular narrowing resulting from swollen astrocytic end-feet (2-6 hours); infarct and edema progression, blood-brain barrier disruption, and upregulated expression of intracellular adhesion molecule-1 (6-24 hours); and the activation of other inflammatory reactions (24 hours). These sequential events were inhibited in the cold saline group.
CONCLUSION: Transarterial regional hypothermia initially inhibited the acute AQP4 surge and then attenuated microvascular narrowing, blood-brain barrier disruption, and activation of other inflammatory reactions, leading to strong neuroprotective effects. More direct and intensive cooling of the endothelium and its surroundings may contribute to these effects.

Edaravone Reduces Hyperperfusion-Related Neurological Deficits in Adult Moyamoya Disease Historical Control Study
Haruto Uchino, Naoki Nakayama, Ken Kazumata, Satoshi Kuroda, Kiyohiro Houkin
STROKE, 47, 7, 1930, 1932, LIPPINCOTT WILLIAMS & WILKINS, 2016年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose-Postoperative hyperperfusion-related transient neurological deficits (TNDs) are frequently observed in adult patients with moyamoya disease who undergo direct bypass procedures. The present study evaluated the effect of the free radical scavenger edaravone on postoperative hyperperfusion in adult moyamoya disease.
Methods-This study included 92 hemispheres in 72 adult patients who underwent direct bypass for moyamoya disease. Serial measurements of cerebral blood flow were conducted immediately after surgery and on postoperative days 2 and 7. In 40 hemispheres for 36 patients, edaravone (60 mg/d) was administered from the day of surgery to postsurgical day 7. The incidence of postoperative hyperperfusion and associated TNDs were compared with a control group that included 52 hemispheres in 36 patients.
Results-Radiological hyperperfusion was observed in 28 of 40 (70.0%) and 39 of 52 (75.0%) hemispheres in the edaravone and control groups, respectively (P=0.30). Hyperperfusion-related TND incidences were significantly lower in the edaravone group compared with the control group (12.5% versus 32.7%; P=0.024). Multivariate analysis demonstrated that edaravone administration (P=0.009) and left-sided surgery (P=0.037) were significantly correlated with hyperperfusion-related TNDs (odds ratios, 0.3 and 4.2, respectively).
Conclusions-Perioperative administration of edaravone reduced the incidence of hyperperfusion-related TNDs after direct bypass procedures in adult patients with moyamoya disease.

[Efficiency of Embosphere in the Pre-Operative Embolization of Meningioma:Clinical Experience].
Yusuke Shimoda, Toshiya Osanai, Syunsuke Terasaka, Hiroyuki Kobayashi, Shigeru Yamaguchi, Shogo Endo, Kanako Hatanaka, Kiyohiro Houkin
No shinkei geka. Neurological surgery, 44, 7, 555, 60, 2016年07月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Embosphere^® was approved in Japan for embolizing intracranial arteries for the reduction of intraoperative bleeding in January 2014. Until August 2015, we performed embolization for four meningiomas using Embosphere^®. We performed an initial evaluation of all the cases, including evaluation of the clinical courses, change in the maximum tumor diameters and volumes, alteration in the appearance on magnetic resonance imaging(MRI), amount of intraoperative bleeding, complications, and histopathological findings. After embolization, the maximum tumor diameters and volumes slightly decreased on MRI, whereas the signal change on diffusion-weighted imaging(DWI)or fluid-attenuated inversion recovery(FLAIR)varied in each case. One case demonstrated a partial signal change on DWI one day after the initial procedure, and another case demonstrated a decrease in perifocal edema on FLAIR. Among our patients, least bleeding was recorded at 6 days after the embolization. Histopathological analysis revealed coagulative necrotic lesions in two cases. The von Kossa stain was used to distinguish Embosphere^® from the psammoma body. One case involved a thromboembolic complication of the retinocentral artery caused by an Embosphere^® of 100-300 μm. Our early-stage experience suggests that an Embosphere^® of 300-500 μm should be used for safe embolization before resection to avoid thromboembolic complications because an Embosphere^® of 100-300 μm can pass through the dangerous anastomosis. Our present strategy was to resect the tumor approximately seven days after the embolization using Embosphere^®. However, further studies and discussion on the size of Embosphere^®, and the interval between pre-operative embolization and surgical removal are needed.

Primary pineal rhabdomyosarcoma successfully treated by high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation: case report
Yukitomo Ishi, Shigeru Yamaguchi, Akihiro Iguchi, Yuko Cho, Junjiro Ohshima, Kanako C. Hatanaka, Emi Takakuwa, Hiroyuki Kobayashi, Shunsuke Terasaka, Kiyohiro Houkin
JOURNAL OF NEUROSURGERY-PEDIATRICS, 18, 1, 41, 45, AMER ASSOC NEUROLOGICAL SURGEONS, 2016年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Primary intracranial rhabdomyosarcoma is quite rare, and its prognosis is poor compared with that for rhabdomyosarcoma in other organs. The authors present a case of pineal rhabdomyosarcoma successfully managed with multimodal therapy including surgery, chemotherapy, radiation, and high-dose chemotherapy (HDC) followed by autologous peripheral blood stem cell transplantation (HDC/APBSCT). An 8-year-old girl presenting with headache and nausea was referred to the authors' institution. Computed tomography and MRI revealed a pineal tumor associated with obstructive hydrocephalus. Subsequently, an emergent endoscopic tumor biopsy and third ventriculostomy were performed. The patient's symptoms immediately improved. The most likely pathological diagnosis was embryonal rhabdomyosarcoma. Chemotherapy with etoposide, cyclophosphamide, cisplatin, pirarubicin, ifosfamide, actinomycin D, and vincristine was followed by a second-look operation and whole-brain and craniospinal radiation. Because the intraoperative findings and pathological examination of the second operation suggested a definitive diagnosis of rhabdomyosarcoma and the presence of viable residual tumor cells, HDC with etoposide and melphalan was followed by APBSCT. The patient was discharged from the hospital without residual tumor or any neurological deficit. No recurrence was observed at 30 months. This is the first case of primary pineal rhabdomyosarcoma treated with HDC/APBSCT. Although the efficacy of HDC/APBSCT for rhabdomyosarcoma has not been established, the prognosis of primary intracranial rhabdomyosarcoma treated with conventional treatment is quite poor. High-dose chemotherapy followed by APBSCT may contribute to a better prognosis for primary intracranial rhabdomyosarcoma.

Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system
Sayaka Yuzawa, Hiroshi Nishihara, Shigeru Yamaguchi, Hiromi Mohri, Lei Wang, Taichi Kimura, Masumi Tsuda, Mishie Tanino, Hiroyuki Kobayashi, Shunsuke Terasaka, Kiyohiro Houkin, Norihiro Sato, Shinya Tanaka
MODERN PATHOLOGY, 29, 7, 708, 716, NATURE PUBLISHING GROUP, 2016年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Recent genetic analyses using next-generation sequencers have revealed numerous genetic alterations in various tumors including meningioma, which is the most common primary brain tumor. However, their use as routine laboratory examinations in clinical applications for tumor genotyping is not cost effective. To establish a clinical sequencing system for meningioma and investigate the clinical significance of genotype, we retrospectively performed targeted amplicon sequencing on 103 meningiomas and evaluated the association with clinicopathological features. We designed amplicon-sequencing panels targeting eight genes including NF2 (neurofibromin 2), TRAF7, KLF4, AKT1, and SMO. Libraries prepared with genomic DNA extracted from PAXgenefixed paraffin-embedded tissues of 103 meningioma specimens were sequenced using the Illumina MiSeq. NF2 loss in some cases was also confirmed by interphase-fluorescent in situ hybridization. We identified NF2 loss and/or at least one mutation in NF2, TRAF7, KLF4, AKT1, and SMO in 81 out of 103 cases (79%) by targeted amplicon sequencing. On the basis of genetic status, we categorized meningiomas into three genotype groups: NF2 type, TRAKLS type harboring mutation in TRAF7, AKT1, KLF4, and/or SMO, and 'not otherwise classified' type. Genotype significantly correlated with tumor volume, tumor location, and magnetic resonance imaging findings such as adjacent bone change and heterogeneous gadolinium enhancement, as well as histopathological subtypes. In addition, multivariate analysis revealed that genotype was independently associated with risk of recurrence. In conclusion, we established a rapid clinical sequencing system that enables final confirmation of meningioma genotype within 7 days turnaround time. Our method will bring multiple benefits to neuropathologists and neurosurgeons for accurate diagnosis and appropriate postoperative management.

小児脊髄係留症候群の治療成績
関 俊隆, 飛騨 一利, 矢野 俊介, 笹森 徹, 濱内 祝嗣, 寶金 清博
小児の脳神経, 41, 1, 126, 126, (一社)日本小児神経外科学会, 2016年05月
日本語

Development of a nonintermediate-incision ventriculoperitoneal shunt procedure using a nasogastric feeding tube for infant patients with hydrocephalus: technical note
Shuji Hamauchi, Toshitaka Seki, Toru Sasamori, Kiyohiro Houkin
JOURNAL OF NEUROSURGERY-PEDIATRICS, 17, 5, 540, 543, AMER ASSOC NEUROLOGICAL SURGEONS, 2016年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Intermediate incisions are considered necessary to pass a catheter tube from the head to the abdomen in ventriculo-peritoneal (VP) shunting via a frontal bur hole. However, an intermediate incision can sometimes become dehiscent, resulting in CSF leakage or infection of the shunt system in the early period after shunt implantation, particularly in infant. patients. In this article, the authors describe a novel method of VP shunt insertion that does not require an intermediate incision. This nonintermediate-incision VP shunt procedure was performed in 3 infant patients with hydrocephalus and was not associated with any complications. This method can eliminate the intermediate incision, which is a disadvantage of VP shunt insertion via a frontal bur hole.

Familial moyamoya disease in two Turkish siblings with same polymorphism in RNF213 gene but different clinical features
Ayse Kacar Bayram, Ebru Yilmaz, Huseyin Per, Masaki Ito, Haruto Uchino, Selim Doganay, Kiyohiro Houkin, Ekrem Unal
CHILDS NERVOUS SYSTEM, 32, 3, 569, 573, SPRINGER, 2016年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Moyamoya disease is an uncommon, progressive, and occlusive cerebrovascular disorder, predominantly affecting the terminal segment of the internal carotid arteries and its main branches. This occlusion results at the formation of a compensatory collateral arterial network (moyamoya vessels) developing at the base of the brain. The c.14576G > A variant in ring finger protein 213 (RNF213) was recently reported as a susceptibility gene for moyamoya disease.
We describe two Turkish pediatric siblings with moyamoya disease born to consanguineous, unaffected Turkish parents.
The first patient (proband) is a 2-year-old boy who presented with afebrile focal seizures, moderate psychomotor retardation, paresis in the left upper and lower extremity, multiple infarctions of the brain, stenosis of the bilateral internal carotid artery and the middle cerebral artery, and stenosis of the right posterior cerebral artery. The second patient is a 10-year-old girl who is an elder sister of proband. She showed normal psychomotor development, millimetric signal enhancement without diffusion limitation of the brain, and stenosis of the bilateral internal carotid artery.
We herein report pediatric sibling patients of moyamoya disease who have homozygous wild-type c.14576G > A variant in RNF213, showing different clinical course and disease severity. This is the first report of pediatric siblings with moyamoya disease from Turkey validating the genetic background of most frequent variant in East Asian patients with moyamoya disease.

De novo arteriovenous malformation in a patient with hereditary hemorrhagic telangiectasia.
Yusuke Shimoda, Toshiya Osanai, Naoki Nakayama, Satoshi Ushikoshi, Masaaki Hokari, Hideo Shichinohe, Takeo Abumiya, Ken Kazumata, Kiyohiro Houkin
Journal of neurosurgery. Pediatrics, 17, 3, 330, 5, 2016年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant systemic disorder characterized by the enlargement of capillaries, recurrent nosebleeds, and multiple arteriovenous malformations (AVMs). Although cerebral AVMs are traditionally considered to be congenital lesions, some reports have described de novo AVMs, which suggests that the authors believed them to be dynamic conditions. In this article, the authors describe the case of a 5-year-old boy with HHT in whom a de novo cerebral AVM was detected after a negative MRI result at 5 months. To the authors' knowledge, this is the first report of a de novo AVM in a patient with HHT. In patients with a family history of HHT, de novo AVMs are possible, even when no lesions are detected at the first screening. Therefore, regular screenings need to be performed, and the family should be informed that AVMs could still develop despite normal MRI results.

Long-term outcomes after surgical and endovascular treatment of spinal dural arteriovenous fistulae
Toru Sasamori, Kazutoshi Hida, Shunsuke Yano, Takeshi Asano, Toshitaka Seki, Kiyohiro Houkin
EUROPEAN SPINE JOURNAL, 25, 3, 748, 754, SPRINGER, 2016年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, To examine the validity of our treatment strategy for spinal dural arteriovenous fistulae (SDAVF), based on the treatment results and the long-term outcome.
This study included 50 SDAVF patients (38 men, 12 women, mean age 63.2 years) with progressive myelopathy. The treatment strategy involved embolization as the initial management tool and surgery if embolization was considered unsuitable. Their medical records were evaluated to identify the treatment results and functional outcomes. The mean follow-up period was 81.2 months (range 27-184 months).
Complete obliteration was achieved in 22 (71.0 %) of 31 embolized patients and in 18 of 19 (94.7 %) operated patients. The initial success rate was significantly lower in embolized than operated patients. At the last follow-up, 33 of the 50 patients (66 %) manifested improved gait and 16 (32 %) improved micturition. The activity of daily living (ADL) was improved in 33 (66 %). When we compared the rates of functional improvement at the last follow-up, there was no significant difference between patients treated initially by embolization or surgery.
The long-term outcomes in SDAVF patients treated by multidisciplinary management with first-line embolization were comparable to those in earlier surgical series. However, our results were unable to demonstrate the superiority of endovascular embolization to surgical treatment for SDAVF. For the purpose of justifying endovascular embolization as a first-line treatment for SDAVF, it will be necessary to show further improvement in both the initial treatment success and the complication rates.

A Novel Large Cerebral Aneurysm Model in Rats with Intraperitoneal Administration of Beta-Amino Propio Nitril-Fumarate.
Shimoda Yusuke, Moriwaki Takuya, Nakayama Naoki, Abumiya Takeo, Kazumata Ken, Shichinohe Hideo, Houkin Kiyohiro
STROKE, 47, 2016年02月, ［査読有り］

New Clinical Application of Measurement of Blood Viscosity With an Electromagnetically Spinning Sphere Viscometer in Acute Ischemic Stroke Patients
Abumiya Takeo, Furukawa Koji, Sakai Keiji, Hirano Miki, Osanai Toshiya, Shichinohe Hideo, Nakayama Naoki, Kazumata Ken, Aida Toshimitsu, Houkin Kiyohiro
STROKE, 47, 2016年02月, ［査読有り］

The Next Generation of Autologous Bone Marrow Stromal Cell Transplantation Against Stroke
Shichinohe Hideo, Tan Chengbo, Saito Hisayasu, Miyamoto Michiyuki, Hamauchi Shuji, Abumiya Takeo, Nakayama Naoki, Kazumata Ken, Houkin Kiyohiro, Kuroda Satoshi
STROKE, 47, 2016年02月, ［査読有り］

Trans-arterial Regional Hypothermia Provides Robust Neuroprotection in Rat Permanent Middle Cerebral Artery Occlusion Model
Kurisu Kota, Abumiya Takeo, Ito Masaki, Shichinohe Hideo, Nakayama Naoki, Kazumata Ken, Osanai Toshiya, Houkin Kiyohiro
STROKE, 47, 2016年02月, ［査読有り］

Effects of Surgery and Antiplatelet Therapy in Ten-Year Follow-Up from the Registry Study of Research Committee on Moyamoya Disease in Japan
Satoshi Yamada, Koichi Oki, Yoshiaki Itoh, Satoshi Kuroda, Kiyohiro Houkin, Teiji Tominaga, Susumu Miyamoto, Nobuo Hashimoto, Norihiro Suzuki
JOURNAL OF STROKE & CEREBROVASCULAR DISEASES, 25, 2, 340, 349, ELSEVIER SCIENCE BV, 2016年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Despite the common practice of surgery and antiplatelet therapy for the prevention of recurrent stroke in patients with moyamoya disease, the benefit of these treatments is controversial. We analyzed the stroke recurrence rate in the Registry Study of Research Committee on Moyamoya Disease in Japan funded by the Health, Labor and Welfare Ministry of Japan. Methods: An annual follow-up study of the registered cases was continued for 10 years. The rate of recurrent stroke, including cerebral infarction and hemorrhage but not transient ischemic attack and seizure, was evaluated with Kaplan-Meier analysis. Results: The proportion of childhood-onset cases decreased in recently registered cases (within 10 years, n = 541) compared to remote cases (> 10 years, n = 735). Among types at disease onset in adult-onset cases, intracerebral hemorrhage decreased recently. In recent cases, the rate of subsequent cerebral hemorrhage was much higher in the hemorrhagic group (10.9 +/- 3.3%/5 years) than in the ischemic group (2.0 +/- .9%/5 years). The recurrence rate of cerebral infarction was lower in the surgery group (1.8 +/- .9%/5 years) than in the nonsurgery group (3.8 +/- 2.2%/5 years). In the adult-onset ischemic group, the proportion of surgically treated patients increased and their recurrence rate was lower than that of nonsurgery patients. In the ischemic group, the rate of cerebral infarction was not significantly different between the antiplatelet subgroup and the non-antiplatelet subgroup, whereas the rate of cerebral hemorrhage was higher in the non-antiplatelet subgroup than in the antiplatelet subgroup. Conclusions: Our results suggest revascularization surgery may suppress recurrent ischemic attacks in patients with moyamoya disease. (C) 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Successful Acute Endovascular Therapy of Cerebral Embolism for a Patient with Ventricle-assist Device: Case Report
Kobayashi Satoshi, Osanai Toshiya, Miyamoto Michiyuki, Shimoda Yusuke, Ushikochi Satoshi, Ooka Tomonori, Matsui Yoshiro, Hatanaka Kanako, Houkin Kiyohiro
Journal of Neuroendovascular Therapy, 特定非営利活動法人 日本脳神経血管内治療学会, 2016年
英語, Objective: Ventricular assist devices (VAD) are used as a bridge to heart transplantation. Cerebral embolism can develop in patients with VADs despite a strict anticoagulation therapy. We report two cases of successful acute endovascular therapy with Penumbra system for cerebral embolism.Case Presentations: Case 1: A 20-year-old woman with a VAD presented with right facial palsy and right monoparesis. 3D-computed tomography angiography (3D-CTA) demonstrated left middle cerebral artery (MCA) occlusion. We successfully performed endovascular recanalization of the left MCA with Thrombolysis in Cerebral Infarction (TICI) Grade3 perfusion, and the patient's symptoms significantly improved. The patient's condition improved to nearly the pre-treatment state. However, due to repeated strokes, the patient developed disturbances of consciousness, aphasia, and complete paralysis of the left lower limb. Furthermore, the infection worsened, and the patient eventually developed a circulatory disorder of the VAD and died. Case 2: A 34-year-old man with VAD presented with sudden disturbances of consciousness and right hemiparesis. Computed tomography (CT) scan revealed no early abnormalities. We performed endovascular recanalization of the left internal carotid artery (IC) top with TICI 3 perfusion. After endovascular treatment, CT scan did not reveal a cerebral infarction. The patient eventually achieved an National Institutes of Health Stroke Scale (NIHSS) score of 0 point and received a heart transplant. In case 2, we pathologically analyzed the retrieved thrombus and confirmed the thrombus to be mainly composed of fibrin. There were no complications of hemorrhage in either case.Conclusion: A suction-type thrombectomy device is believed to be the first choice for patients with VAD.

脳梗塞に対する自家骨髄間質細胞移植
七戸秀夫, 寳金清博
脳循環代謝(Web), 28, 1, 2016年

脳梗塞の細胞治療と『革新的医薬品・医療機器・再生医療製品実用化促進事業』
寳金清博
レギュラトリーサイエンス学会誌, 6, Supplement, 2016年

Feasibility and Efficiency of Human Bone Marrow Stromal Cell Culture with Allogeneic Platelet Lysate-Supplementation for Cell Therapy against Stroke
Chengbo Tan, Hideo Shichinohe, Zifeng Wang, Shuji Hamauchi, Takeo Abumiya, Naoki Nakayama, Ken Kazumata, Tsuneo Ito, Kohsuke Kudo, Shigeru Takamoto, Kiyohiro Houkin
Stem Cells International, 2016, Hindawi Limited, 2016年, ［査読有り］
英語, 研究論文（学術雑誌）, Currently, there is increasing interest in human bone marrow stromal cells (hBMSCs) as regeneration therapy against cerebral stroke. The aim of the present study was to evaluate the feasibility and validity of hBMSC cultures with allogeneic platelet lysates (PLs). Platelet concentrates (PC) were harvested from healthy volunteers and made into single donor-derived PL (sPL). The PL mixtures (mPL) were made from three different sPL. Some growth factors and platelet cell surface antigens were detected by enzyme-linked immunosorbent assay (ELISA). The hBMSCs cultured with 10% PL were analyzed for their proliferative potential, surface markers, and karyotypes. The cells were incubated with superparamagnetic iron oxide (SPIO) agents and injected into a pig brain. MRI and histological analysis were performed. Consequently, nine lots of sPL and three mPL were prepared. ELISA analysis showed that PL contained adequate growth factors and a particle of platelet surface antigens. Cell proliferation capacity of PLs was equivalent to or higher than that of fetal calf serum (FCS). No contradiction in cell surface markers and no chromosomal aberrations were found. The MRI detected the distribution of SPIO-labeled hBMSCs in the pig brain. In summary, the hBMSCs cultured with allogeneic PL are suitable for cell therapy against stroke.

Postoperative Acute Submandibular Sialadenitis after Neurosurgery: Two Case Reports and a Review of the Literature.
Uchino H, Motegi H, Kobayashi H, Kamoshima Y, Kazumata K, Terasaka S, Houkin K
NMC case report journal, 3, 1, 1, 4, 2016年01月, ［査読有り］, ［国内誌］
英語, This article details two case reports and reviews the extant literature concerning acute postoperative submandibular sialadenitis occurring in the side contralateral to the operated site after neurosurgery. Although its precise pathogenesis remains to be elucidated, it is likely related to intraoperative compression of the submandibular gland and surrounding tissues, caused by head positioning and the endotracheal tube. Submandibular swelling rapidly deteriorates after surgery, and emergent airway protection is required in most cases in order to avoid fatal airway obstruction. To avoid serious sequelae, we should be aware of acute submandibular sialadenitis that occurs contralateral to the surgical side, which, although rare, is more probable after posterior fossa surgery. When it occurs, early airway protection is crucial, and the following conservative treatment could provide a good prognosis.

In Reply: A Survey of Chronic Pain Due to Spinal Dural Arteriovenous Fistulae
Toru Sasamori, Kazutoshi Hida, Toshiya Osanai, Shunsuke Yano, Toshitaka Seki, Kiyohiro Houkin
NEUROSURGERY, 78, 1, E162, E162, LIPPINCOTT WILLIAMS & WILKINS, 2016年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Application of endoscopic ultrasonography to intraventricular lesions
Hiroaki Motegi, Hiroyuki Kobayashi, Shunsuke Terasaka, Shigeru Yamaguchi, Yukitomo Ishi, Yasuhiro Ito, Kiyohiro Houkin
ACTA NEUROCHIRURGICA, 158, 1, 87, 92, SPRINGER WIEN, 2016年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Anatomical landmarks such as choroid plexus and foramen of Monro are very important to undergo intraventricular surgery safely and effectually. These landmarks would be unclear in cases with a huge cyst or repeat surgery. We report the usability and precautions to apply a bronchoscope with an ultrasonic convex probe to intraventricular surgery.
Two patients diagnosed with obstructive hydrocephalus, one with a large cyst and the other with recurrent craniopharyngioma in the third ventricle, were applied to the EBUS system.
In both patients, the EBUS system was applied safely, and lesions beyond the wall of ventricles or the cyst were visible. Color Doppler ultrasonography detected choroid plexus and internal cerebral veins. Furthermore, we performed real-time ultrasound-guided cyst puncture safely on the case with a large cyst. The most important precaution is that the curved portion of the EBUS system is too long to be bent within cerebral ventricles.
The new EBUS system with an ultrasonic convex probe is a novel and effectual device to perform intraventricular surgery.

Ultrasound-guided Femoral Artery Access for Minimally Invasive Neuro-intervention and Risk Factors for Access Site Hematoma
Kota Kurisu, Toshiya Osanai, Ken Kazumata, Naoki Nakayama, Takeo Abumiya, Hideo Shichinohe, Yusuke Shimoda, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 56, 12, 745, 752, JAPAN NEUROSURGICAL SOC, 2016年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Although ultrasound (US) guidance for venous access is becoming the "standard of care" for preventing access site complications, its feasibility for arterial access has not been fully investigated, especially in the neuro-interventional population. We conducted the first prospective cohort study on US-guided femoral artery access during neuro-interventional procedure. This study included 64 consecutive patients who underwent US-guided femoral artery access through 66 arterial access sites for diagnostic and/or neurointerventional purposes. The number of attempts required for both the sheath insertion and the success of anterior wall puncture were recorded. In addition, the occurrence of major complications and hematoma formation on the arterial access site examined by US were statistically analyzed. The median number of attempts was 1 (1-2) and first-pass success rate was 63.6%. Anterior wall puncture was achieved in 98.5%. In one case (1.5%), a pseudoaneurysm was observed. In all cases, US clearly depicted a common femoral artery (CFA) and its bifurcation. Post-procedural hematoma was detected in 13 cases (19.7%), most of which were "tiny" or "moderate" in size. Low body mass index and antiplatelet therapy were the independent risk factors for access site hematoma. The US-guided CFA access was feasible even in neuro-interventional procedure. The method was particularly helpful in the patients with un-palpable pulsation of femoral arteries. To prevent arterial access site hematoma, special care should be taken in patients with low body mass index and who are on antiplatelet therapy.

Cell Therapy for Stroke: Review of Previous Clinical Trials and Introduction of Our New Trials
Hideo Shichinohe, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 56, 10, 592, 596, JAPAN NEUROSURGICAL SOC, 2016年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Stroke is still a leading cause of death and disability, and despite intensive research, few treatment options exist. A recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. Although some pioneer studies on the use of cell therapy for the treatment of stroke have been reported, certain problems still remain unsolved. We investigated the use of autologous bone marrow stromal cell (BMSC) transplantation for the treatment of stroke, to develop it as the next-generation cell therapy. In this study, we introduce the preparation of a new clinical trial, the Research on Advanced Intervention using Novel Bone marrow stem cell (RAINBOW) study. The trial will start in 2016, and we hope that it will not only be helpful for treating patients but also for clarifying the therapeutic mechanisms. Moreover, we review stem cell therapeutics as an emerging paradigm in stroke (STEPS) and the guidelines for the development of cell therapy for stroke in the United States as well as introduce the development of new guidelines in Japan. These guidelines are expected to encourage the development of cell therapy for stroke management.

Clinical factors for prognosis and treatment guidance of spinal cord astrocytoma
Toshitaka Seki, Kazutoshi Hida, Shunsuke Yano, Takeshi Aoyama, Izumi Koyanagi, Toru Sasamori, Shuji Hamauch, Kiyohiro Houkin
Asian Spine Journal, 10, 4, 748, 754, Korean Society of Spine Surgery, 2016年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Study Design: Retrospective study. Purpose: To obtain information useful in establishing treatment guidelines by evaluating baseline clinical features and treatment outcomes of patients with spinal cord astrocytoma (SCA). Overview of Literature: The optimal management of SCA remains controversial, and there are no standard guidelines. Methods: The study included 20 patients with low-grade and 13 with high-grade SCA surgically treated between 1989 and 2014. Patients were classified according to the extent of surgical resection. Survival was assessed using Kaplan-Meier plots and compared between groups by log-rank tests. Neurological status was defined by the modified McCormick scale and compared between groups by Mann-Whitney U tests. Results: Surgical resection was performed for 19 of 20 low-grade (95%) and 10 of 13 high-grade (76.9%) SCA patients. Only nine patients (27.3%) underwent gross total resection, all of whom had low-grade SCA. Of all patients, 51.5% showed deteriorated neurological status compared to preoperative baseline. Median overall survival was significantly longer for low-grade SCA than that for high-grade SCA (91 months, 78% at 5 years vs. 15 months, 31% at 5 years
p =0.007). Low-grade SCA patients benefited from more aggressive resection, whereas high-grade SCA patients did not. Multivariate analysis revealed histology status (hazard ratio [HR], 0.30
95% confidence interval [CI], 0.09-0.98
p <
0.05) and postoperative neurological status (HR, 0.12
CI, 0.02-0.95
p <
0.05) as independent predictors of longer overall survival. Adjuvant radiotherapy had no significant impact on survival rate. However, a trend for increased survival was observed with radiation cordotomy (RCT) in high-grade SCA patients. Conclusions: Aggressive resection for low-grade and RCT for high-grade SCA may prolong survival. Preservation of neurological status is an important treatment goal. Given the low incidence of SCA, establishing strong collaborative, interdisciplinary, and multiinstitutional study groups is necessary to define optimal treatments.

Lateral position of the external carotid artery: A rare variation to be recognized during carotid endarterectomy
Masaki Ito, Yoshimasa Niiya, Masashi Kojima, Hiroyuki Itosaka, Motoyuki Iwasaki, Ken Kazumata, Shoji Mabuchi, Kiyohiro Houkin
Acta Neurochirurgica, Supplementum, 123, 115, 122, Springer-Verlag Wien, 2016年, ［査読有り］, ［国際誌］
英語, 論文集(書籍)内論文, Background: External carotid artery (ECA) positioned laterally to the internal carotid artery (ICA) at the level of the common carotid artery (CCA) bifurcation is occasionally encountered during carotid endarterectomy (CEA). This study aimed to determine the frequency of this phenomenon and provide technical tips for performing CEA. Methods: The study included 199 consecutive patients (209 carotid arteries) who underwent CEA at Otaru Municipal Medical Center in 2007–2014. The position of the ECA with respect to the ICA at the CCA bifurcation was preoperatively rated as either lateral or normal, using three-dimensional computerized tomographic angiography (3-D CTA) anteroposterior projections. Postoperative diffusion-weighted images (DWIs), and postoperative 3-D CTA images were reviewed. Results: Among the 209 carotid arteries with atherosclerosis, 11 instances (5.3%) of lateral position of the ECA were detected in 11 patients. Ten of these arteries (91%) were right-sided (odds ratio 11.1
95% confidence interval 1.38–88.9). Wider longitudinal exposure of the arteries was used during CEA, and the CCA and ECA were rotated clockwise or counter clockwise. The ICA lying behind the ECA along the surgical access route was then pulled out laterally and moved to the shallow surgical field. Cross-clamping, arteriotomy, plaque removal, and wall suturing were performed as usual. No cerebral infarcts were detected on postoperative DWIs, and 3-D CTA revealed no CCA and ICA kinking. Conclusions: Lateral position of the ECA is not extremely rare in patients undergoing CEA for atherosclerosis and may be a congenital variation, although this is still controversial. CEA can be performed safely if the arteries from the CCA to the ICA are rotated, and the ICA is moved to the shallow surgical field under wider longitudinal exposure. Although no postoperative cerebral infarcts were detected, the risk of artery-toartery embolism resulting from artery repositioning prior to plaque removal should be taken into consideration.

Endoscopic transsphenoidal surgery using pedicle vascularized nasoseptal flap for cholesterol granuloma in petrous apex: A technical note
Yukitomo Ishi, Hiroyuki Kobayashi, Hiroaki Motegi, Shogo Endo, Shigeru Yamaguchi, Shunsuke Terasaka, Kiyohiro Houkin
NEUROLOGIA I NEUROCHIRURGIA POLSKA, 50, 6, 504, 510, ELSEVIER URBAN & PARTNER SP Z O O, 2016年, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Compared with surgical resection, endoscopic transsphenoidal surgery (TSS) for cholesterol granuloma (CG) in the petrous apex (PA) is associated with local recurrence due to obstruction of the drainage route. We present a detailed procedure of an endoscopic TSS using pedicle vascularized nasoseptal flap (PVNF).
Methods: A 40-year-old woman with a history of repeated surgery for left tympanitis was referred to our institution. Neurological examination revealed severe hearing loss in the left ear. Radiologic examination presented a round mass in the left PA and significant fluid collection in the mastoid air cells of the left temporal bone. CG was strongly suspected, and endoscopic TSS using PVNF was performed. Prior to endoscopic drainage, a PVNF was harvested from the mucosa of the ipsilateral nasal septum, with an attempt to preserve the sphenopalatine artery in the flap. Following this, puncture and adequate irrigation of the lesion was performed by endoscopic TSS, with neuro-navigation system assistance; the apex of PVNF was then placed into the lesion to prevent the obstruction of the drainage route. An absorbable polyglycolic acid sheet and fibrin glue were applied on the flap to prevent spontaneous deviation from the lesion.
Results: The patient was discharged without any further neurological complications. Eight month postoperative computed tomography images showed no recurrence; the drainage route was patent and the fluid collection in the left mastoid air cells was resolved. Moreover, hearing loss was improved.
Conclusions: Endoscopic TSS using PVNF may be one of available surgical options for PACG. (C) 2016 Polish Neurological Society. Published by Elsevier Sp. z o.o. All rights reserved.

Surgical outcome of children and adolescents with tethered cord syndrome
Toshitaka Seki, Kazutoshi Hida, Shunsuke Yano, Toru Sasamori, Shuji Hamauch, Izumi Koyanagi, Kiyohiro Houkin
Asian Spine Journal, 10, 5, 940, 944, Korean Society of Spine Surgery, 2016年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Study Design: Retrospective cohort study. Purpose: To compare long-term results of surgery with the outcomes of symptomatic and asymptomatic tethered cord syndrome (TCS) in children and adolescents and to assess the surgery duration for those with TCS. Overview of Literature: Pediatric patients with TCS continue to pose significant diagnostic and management challenges. Methods: We retrospectively analyzed the outcomes of 31 patients (16 males, 15 females) with TCS, including 21 with lumbosacral lipoma. All were surgically treated between 1989 and 2015. They were divided into symptomatic and asymptomatic TCS groups. The results of the treatment were summarized and analyzed using a non-parametric Mann-Whitney U test. Results: Nineteen patients had symptomatic TCS and 12 had asymptomatic TCS. Patients had a median age of 34 months (range, 0-201 months). The median follow-up period was 116 months (range, 7-223 months). Of the 19 symptomatic TCS patients, preoperative deficits improved after surgery in two (10.5%) and remained stable in 17 (89.5%) patients. One of the 12 asymptomatic TCS (8.3%) patients showed an exacerbated illness after surgery, and one in 11 patients remained stable (11.7%). There were significant differences in monthly age at surgery, preoperative bowel and bladder dysfunction, neurological function, presence/absence of clean intermittent catheterization introduction, and presence/absence of motor disorder at final follow-up (all p <
0.05). In the univariate analysis, the presence/absence of preoperative bowel and bladder dysfunction, and symptoms were strongly associated with the risk of children and adolescents with TCS (p <
0.05). Conclusions: Early accurate diagnosis and adequate surgical release might lead to successful outcomes in children and adolescents with TCS. Surgical untethering is a safe and effective method for treatment of children with TCS.

Feasibility and Efficiency of Human Bone Marrow Stromal Cell Culture with Allogeneic Platelet Lysate-Supplementation for Cell Therapy against Stroke
Chengbo Tan, Hideo Shichinohe, Zifeng Wang, Shuji Hamauchi, Takeo Abumiya, Naoki Nakayama, Ken Kazumata, Tsuneo Ito, Kohsuke Kudo, Shigeru Takamoto, Kiyohiro Houkin
STEM CELLS INTERNATIONAL, 2016, 6104780, 6104780, HINDAWI LTD, 2016年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Currently, there is increasing interest in human bone marrow stromal cells (hBMSCs) as regeneration therapy against cerebral stroke. The aim of the present study was to evaluate the feasibility and validity of hBMSC cultures with allogeneic platelet lysates (PLs). Platelet concentrates (PC) were harvested from healthy volunteers and made into single donor-derived PL (sPL). The PL mixtures (mPL) were made from three different sPL. Some growth factors and platelet cell surface antigens were detected by enzyme-linked immunosorbent assay (ELISA). The hBMSCs cultured with 10% PL were analyzed for their proliferative potential, surface markers, and karyotypes. The cells were incubated with superparamagnetic iron oxide (SPIO) agents and injected into a pig brain. MRI and histological analysis were performed. Consequently, nine lots of sPL and three mPL were prepared. ELISA analysis showed that PL contained adequate growth factors and a particle of platelet surface antigens. Cell proliferation capacity of PLs was equivalent to or higher than that of fetal calf serum (FCS). No contradiction in cell surface markers and no chromosomal aberrations were found. The MRI detected the distribution of SPIO-labeled hBMSCs in the pig brain. In summary, the hBMSCs cultured with allogeneic PL are suitable for cell therapy against stroke.

Significance of the Hemorrhagic Site for Recurrent Bleeding Prespecified Analysis in the Japan Adult Moyamoya Trial
Jun C. Takahashi, Takeshi Funaki, Kiyohiro Houkin, Tooru Inoue, Kuniaki Ogasawara, Jyoji Nakagawara, Satoshi Kuroda, Keisuke Yamada, Susumu Miyamoto
STROKE, 47, 1, 37, 43, LIPPINCOTT WILLIAMS & WILKINS, 2016年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose The primary results of the Japan Adult Moyamoya Trial revealed the statistically marginal superiority of bypass surgery over medical treatment alone in preventing rebleeding in moyamoya disease. The purpose of this analysis is to test the prespecified subgroup hypothesis that the natural course and surgical effects vary depending on the hemorrhagic site at onset.
Methods The hemorrhagic site, classified as either anterior or posterior, was the only stratifying variable for randomization. Statistical analyses were focused on the assessment of effect modification according to the hemorrhagic site and were based on tests of interaction.
Results Of 42 surgically treated patients, 24 were classified as anterior hemorrhage and 18 as posterior hemorrhage; of 38 medically treated patients, 21 were classified as anterior and 17 as posterior. The hazard ratio of the primary end points (all adverse events) for the surgical group relative to the nonsurgical group was 0.07 (95% confidence interval, 0.01-0.55) for the posterior group, as compared with 1.62 (95% confidence interval, 0.39-6.79) for the anterior group (P=0.013 for interaction). Analysis within the nonsurgical group revealed that the incidence of the primary end point was significantly higher in the posterior group than in the anterior group (17.1% per year versus 3.0% per year; hazard ratio, 5.83; 95% confidence interval, 1.60-21.27).
Conclusions Careful interpretation of the results suggests that patients with posterior hemorrhage are at higher risk of rebleeding and accrue greater benefit from surgery, subject to verification in further studies.

全身血管病に起因する頚部内頚動脈解離性動脈瘤に対してstent-assisted coil embolizationが有効であった1例
高宮宗一朗, 長内俊也, 牛越聡, 栗栖宏多, 下田祐介, 伊藤康裕, 伊師雪友, 穂刈正昭, 中山若樹, 数又研, 鐙谷武雄, 七戸秀夫, 寳金清博
Neurological Surgery, 44, 1, 39, 45, 2016年01月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Systemic vascular diseases such as fibromuscular dysplasia, Ehlers-Danlos syndrome, Marfan syndrome, and Behçet's disease are known to cause spontaneous dissecting aneurysms of the cervical internal carotid artery. These diseases are generally associated with vascular fragility; therefore, invasive treatments are avoided in many cases of dissecting aneurysms, and a conservative approach is used for the primary disease. Surgical or intravascular treatment may be chosen when aneurysms are progressive or are associated with a high risk of hemorrhage; however, there is no consensus on which treatment is better. We report a case of a dissecting aneurysm of the cervical internal carotid artery in a patient with suspected Behçet's disease, which was treated using stent-assisted coil embolization. A man in his 40's, with suspected Behçet's disease, presented with an enlarged dissecting aneurysm of the right cervical internal carotid artery. The lesion was present for approximately 10 years. We performed stent-assisted coil embolization for the lesion. Post-surgery, no aneurysms were detected with carotid artery echography. Our case report suggests that stent-assisted coil embolization is a promising treatment for dissecting aneurysms of the cervical internal carotid artery. In addition, the procedure demonstrates the utility of carotid artery echograms for examining recanalization after stent-assisted coil embolization.

Reappraisal of Microsurgical Revascularization for Anterior Circulation Ischemia in Patients with Progressive Stroke.
Taku Sugiyama, Ken Kazumata, Katsuyuki Asaoka, Toshiya Osanai, Daisuke Shimbo, Kazuki Uchida, Yuka Yokoyama, Naoki Nakayama, Kouji Itamoto, Kiyohiro Houkin
World neurosurgery, 84, 6, 1579, 88, 2015年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Intravenous thrombolysis using tissue plasminogen activator and endovascular treatment for acute ischemic stroke is becoming an established standard therapy. However, there is no consensus in the treatment of patients who are suffering from progressive neurologic symptoms in the later stages. The purpose of this study was to evaluate the safety and efficacy of microsurgical revascularization in such patients with progressive stroke. METHODS: We retrospectively reviewed the clinical and radiological records of 14 consecutive patients with progressive stroke who underwent emergency open surgery for anterior circulation occlusion within 7 days after onset. Surgical candidates were carefully selected on the basis of symptom severity, diffusion-weighted imaging, and perfusion study. Superficial temporal artery to middle cerebral artery bypass was applied for atherosclerotic occlusion, and microsurgical embolectomy was applied for embolic occlusion. RESULTS: Superficial temporal artery to middle cerebral artery bypass was performed in 12 patients, microsurgical embolectomy in 1, and the combination of these modalities in 1. As a result, complete revascularization was achieved in all patients. The National Institutes of Health Stroke Scale scores significantly improved after surgery (at third postoperative day, P < 0.05; at 14th postoperative day, P < 0.01). A favorable outcome (modified Rankin Scale 0-2) was achieved in 12 of the 14 (85.7%) patients. Minor intracerebral hemorrhage occurred in 1 patient and hyperperfusion syndrome occurred in 1 patients; however, the patients subsequently recovered without additional treatment. CONCLUSIONS: Microsurgical revascularization is a feasible treatment option for patients with progressive stroke due to anterior circulation major vessel occlusion.

脊髄硬膜動静脈瘻に対する血管内治療の現状と塞栓術成功因子の検討
栗栖 宏多, 長内 俊也, 飛彈 一利, 浅野 剛, 牛越 聡, 関 俊隆, 笹森 徹, 寶金 清博
JNET: Journal of Neuroendovascular Therapy, 9, 6, S316, S316, (NPO)日本脳神経血管内治療学会, 2015年11月
日本語

Risk of rupture of unruptured cerebral aneurysms in elderly patients
Tomohito Hishikawa, Isao Date, Koji Tokunaga, Shinjiro Tominari, Kazuhiko Nozaki, Yoshiaki Shiokawa, Kiyohiro Houkin, Yuichi Murayama, Toshihiro Ishibashi, Hiroyuki Takao, Toshikazu Kimura, Takeo Nakayama, Akio Morita
NEUROLOGY, 85, 21, 1879, 1885, LIPPINCOTT WILLIAMS & WILKINS, 2015年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Objectives:The aim of this study was to identify risk factors for rupture of unruptured cerebral aneurysms (UCAs) in elderly Japanese patients aged 70 years or older.Methods:The participants included all patients 70 years of age or older in 3 prospective studies in Japan (the Unruptured Cerebral Aneurysm Study of Japan [UCAS Japan], UCAS II, and the prospective study at the Jikei University School of Medicine). A total of 1,896 patients aged 70 years or older with 2,227 UCAs were investigated. The median and mean follow-up periods were 990 and 802.7 days, respectively.Results:The mean aneurysm size was 6.2 3.9 mm. Sixty-eight patients (3.6%) experienced subarachnoid hemorrhage during the follow-up period. Multivariable analysis per patient revealed that in patients aged 80 years or older (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.16-3.49, p = 0.012), aneurysms 7 mm or larger (HR, 3.08; 95% CI, 1.35-7.03, p = 0.007 for 7-9 mm; HR, 7.82; 95% CI, 3.60-16.98, p < 0.001 for 10-24 mm; and HR, 43.31; 95% CI, 12.55-149.42, p < 0.001 for 25 mm) and internal carotid-posterior communicating artery aneurysms (HR, 2.45; 95% CI, 1.23-4.88, p = 0.011) were independent predictors for UCA rupture in elderly patients.Conclusions:In our pooled analysis of prospective cohorts in Japan, patient age and aneurysm size and location were significant risk factors for UCA rupture in elderly patients.

キャンサーボードが機能した1症例　　　　　　　　　　　　　　　
遠藤 将吾, 寺坂 俊介, 小林 浩之, 山口 秀, 茂木 洋晃, 金子 貞洋, 井口 晶裕, 長 祐子, 大島 淳二郎, 寺坂 友佳代, 杉山 未奈子, 橋本 孝之, 鬼丸 力也, 清水 伸一, 有賀 正, 白戸 博樹, 寳金 清博
日本小児血液・がん学会雑誌, 52, 3, 343, 343, (NPO)日本小児血液・がん学会, 2015年10月
日本語

A novel application of four-dimensional magnetic resonance angiography using an arterial spin labeling technique for noninvasive diagnosis of Moyamoya disease
Haruto Uchino, Masaki Ito, Noriyuki Fujima, Ken Kazumata, Kazuyoshi Yamazaki, Naoki Nakayama, Satoshi Kuroda, Kiyohiro Houkin
CLINICAL NEUROLOGY AND NEUROSURGERY, 137, 105, 111, ELSEVIER SCIENCE BV, 2015年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Noncontrast-enhanced time-resolved four-dimensional magnetic resonance angiography using an arterial spin labeling technique (ASL-4D MRA) is emerging as a next generation angiography for the management of neurovascular diseases. This study evaluated the feasibility of ASL-4D MRA for the diagnosis of Moyamoya disease (MMD) and MMD staging by using digital subtraction angiography (DSA) and time-of-flight MRA (TOF MRA) as current standards.
Methods: Eleven consecutive non-operated patients who underwent DSA for the diagnosis of MMD were recruited. Two independent observers evaluated the three tests. The data were analyzed for inter-observer and inter-modality agreements on MMD stage. Nine of 22 hemispheres underwent surgical revascularization and ASL-4D MRA was repeated postoperatively.
Results: Time-resolved inflow of blood through the cerebral vessels, including moyamoya vessels, was visualized in all the 22 non-operated hemispheres. MMD stages assessed by DSA and ASL-4D MRA were completely matched in 18 hemispheres, with a significant positive correlation between these modalities (r=0.93, P<0.001). Inter-observer agreement with ASL-4D MRA (K=0.91 +/- 0.04, P<0.001) and inter-modality agreement between ASL-4D MRA and DSA (K = 0.93 +/- 0.04, P<0.001) were both excellent. MMD stages assessed by ASL-4D MRA have also a significant positive correlation with those assessed by TOF MRA (r=0.68, P=0.004). Repeated ASL-4D MRA clearly demonstrated the bypassed arteries and changes in the dynamic flow patterns of cerebral arteries in all the nine hemispheres after surgical revascularization. Of these, postoperative focal hyperperfusion was detected by single photon emission tomography in 7 hemispheres. In five of the seven hemispheres (71%) with postoperative hyperperfusion, ASL-4D MRA demonstrated focal hyperintense signals in the bypassed arteries, although TOF MRA did not.
Conclusions: Noninvasive ASL-4D MRA is feasible for the diagnosis of MMD staging. This next generation angiography may be useful for monitoring disease evolution and treatment response in cerebral arteries after revascularization surgery in MMD. (C) 2015 Elsevier B.V. All rights reserved.

Ceacam1L Modulates STAT3 Signaling to Control the Proliferation of Glioblastoma-Initiating Cells
Sadahiro Kaneko, Yuka Nakatani, Tatsuya Takezaki, Takuichiro Hide, Daisuke Yamashita, Naoki Ohtsu, Takanori Ohnishi, Shunsuke Terasaka, Kiyohiro Houkin, Toru Kondo
CANCER RESEARCH, 75, 19, 4224, 4234, AMER ASSOC CANCER RESEARCH, 2015年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Glioblastoma-initiating cells (GIC) are a tumorigenic cell subpopulation resistant to radiotherapy and chemotherapy, and are a likely source of recurrence. However, the basis through which GICs are maintained has yet to be elucidated in detail. We herein demonstrated that the carcinoembryonic antigen-related cell adhesion molecule Ceacam1L acts as a crucial factor in GIC maintenance and tumorigenesis by activating c-Src/STAT3 signaling. Furthermore, we showed that monomers of the cytoplasmic domain of Ceacam1L bound to c-Src and STAT3 and induced their phosphorylation, whereas oligomerization of this domain ablated this function. Our results suggest that Ceacam1L-dependent adhesion between GIC and surrounding cells play an essential role in GIC maintenance and proliferation, as mediated by signals transmitted by monomeric forms of the Ceacam1L cytoplasmic domain. (C) 2015 AACR.

Cerebral aneurysms associated with segmental dilative arteriopathy of the circle of Willis
Yoshifumi Horita, Takeshi Mikami, Kiyohiro Houkin, Nobuhiro Mikuni
Surgical Neurology International, 6, Suppl 9, S291, S294, Medknow Publications, 2015年09月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Dilative arteriopathy is a form of dolichoectasia. It is sometimes observed in the posterior circulation, and it may be associated with various type of stroke. Herein, we report two unusual cases of saccular aneurysms associated with a segmental dilative arteriopathy located in the anterior circulation. Case Descriptions: The first case is a 39-year-old woman with irregular tortuosity and coiling of the left internal cerebral artery along with saccular aneurysms in this artery. The second case is a 45-year-old woman presenting with a ruptured saccular aneurysm in the coiling of the anterior cerebral artery. In both cases, the aneurysm was clipped successfully, and the patients recovered uneventfully with no neurological deficits. Conclusion: Dilative arteriopathy of the circle of Willis is an unusual anomaly and is characterized by tortuous and elongated arteries, which are sometimes observed in patients with a congenital anomaly. This report describes two cases of saccular aneurysm associated with dilative arteriopathy of the circle of Willis with no medical history, which to the best of our knowledge has not previously been described.

Porphyrin Derivatives-Mediated Sonodynamic Therapy for Malignant Gliomas In Vitro.
Endo S, Kudo N, Yamaguchi S, Sumiyoshi K, Motegi H, Kobayashi H, Terasaka S, Houkin K
Ultrasound in medicine & biology, 41, 9, 2458, 2465, ELSEVIER SCIENCE INC, 2015年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Because it is highly infiltrative, malignant glioma is a cancer with a poor prognosis despite multidisciplinary treatment strategies, such as aggressive surgery and chemoradiotherapy, necessitating new therapeutic approaches to control migration of tumor cells. In our study, we investigated the efficacy of sonodynamic therapy of glioma cells in vitro using porphyrin derivatives, including 5-aminolevulinic acid, protoporphyrin IX and talaporfin sodium, as sonosensitizers. These substances have been known to accumulate in glioma cells and are expected to have cytotoxic effects on sonication. Our study found that the cytotoxicity of sonication of glioma cells is enhanced by each sonosensitizer and that the efficacy of sonodynamic therapy may depend on the degree of intracellular accumulation of sonosensitizer. Also, the study suggests that induction of apoptosis is a major mechanism underlying cell death. Though further investigations are necessary, our preliminary result indicates a potential for sonodynamic therapy with sonosensitizers in glioma treatment. (C) 2015 World Federation for Ultrasound in Medicine & Biology.

Inside Intramural Thrombus Formation with Inflammatory Reactions is Relevant to the Rupture of Cerebral Aneurysms
Shimoda Yusuke, Nakayama Naoki, Hokari Masaaki, Abumiya Takeo, Shichinohe Hideo, Kazumata Ken, Houkin Kiyohiro
JOURNAL OF NEUROSURGERY, 123, 2, A526, 2015年08月, ［査読有り］

Surgical Outcomes for Cervical Carotid Artery Stenosis: Treatment Strategy for Bilateral Cervical Carotid Artery Stenosis.
Masaaki Hokari, Naoki Nakayama, Ken Kazumata, Toshiya Osanai, Toshitaka Nakamura, Hiroshi Yasuda, Satoshi Ushikoshi, Hideo Shichinohe, Takeo Abumiya, Satoshi Kuroda, Kiyohiro Houkin
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 24, 8, 1768, 74, 2015年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Carotid endarterectomy (CEA) and carotid stenting (CAS) are beneficial procedures for patients with high-grade cervical carotid stenosis. However, it is sometimes difficult to manage patients with bilateral carotid stenosis. To decide the treatment strategy, one of the most important questions is whether contralateral stenosis increases the risk of patients undergoing CEA. METHODS: This retrospective study included 201 patients with carotid stenosis who underwent a total of 219 consecutive procedures (CEA 189/CAS 30). We retrospectively analyzed outcomes in patients with carotid stenosis who were treated with either CEA or CAS and evaluated whether or not contralateral lesions increases the risk of patients undergoing CEA or CAS. Furthermore, we retrospectively verified our treatment strategy for bilateral carotid stenosis. RESULTS: The incidences of perioperative complications were 5.3% in the CEA patients and 6.7% in the CAS patients, respectively. There was no significant difference between these 2 groups. The existences of contralateral occlusion and/or contralateral stenosis were not associated with perioperative complications in both the groups. There were 32 patients with bilateral severe carotid stenosis (>50%). Of those, 13 patients underwent bilateral revascularizations; CEA followed by CEA in 8, CEA followed by CAS in 3, CAS followed by CEA + coronary artery bpass grafting in 1, and CAS followed by CAS in 1. CONCLUSIONS: Our date showed that the existence of contralateral carotid lesion was not associated with perioperative complications, and most of our cases with bilateral carotid stenosis initially underwent CEA.

Risk factors for adverse events after implantation of BCNU wafers in high-grade gliomas
Michiharu Yoshida, Shigeru Yamaguchi, Yukitomo Ishi, Shogo Endo, Hiroaki Motegi, Hiroyuki Kobayashi, Katsuyuki Asaoka, Yuuta Kamoshima, Shunsuke Terasaka, Kiyohiro Houkin
Neurological Surgery, 43, 7, 603, 610, Igaku-Shoin Ltd, 2015年07月01日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Background: In Japan, patients with malignant glioma have been treated with BCNU wafers (Gliadel®) since January 2013. Several adverse events (AEs) associated with implantation of BCNU wafers, including cerebral edema or cyst formation, are recognized. Here, we report a retrospective review of the experience with implantation of BCNU wafers in our institutions and our findings regarding the risk factors for the AEs. Methods: We reviewed the records of patients with malignant glioma who were implanted with BCNU wafers between April 2013 and September 2014. Their AEs were examined clinically and radiologically and evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) grading. For investigating the association between risk factors and incidence of AEs, histological diagnosis, extent of resection, and period of BCNU wafers implantation surgery were selected as possible risk factors. Results: Twenty-one patients were included in this investigation. There were no associations among incidence of AEs and histological diagnosis or extent of tumor resection. However, regarding the period of BCNU wafers implantation, additional resection for newly diagnosed tumors and resection for recurrent tumors tended to increase the rate and severity of AEs, especially cerebral edema, compared to primary resection Conclusion: In cases of BCNU wafers implantation, the incidence and degree of AEs might increase if additional resection for newly diagnosed tumors or resection for recurrent tumors is performed. Our investigation revealed that AEs associated with implantation of BCNU wafers tend to occur in the repeated glioma surgery.

A Survey of Chronic Pain Due to Spinal Dural Arteriovenous Fistulae.
Toru Sasamori, Kazutoshi Hida, Toshiya Osanai, Shunsuke Yano, Toshitaka Seki, Kiyohiro Houkin
Neurosurgery, 77, 1, 113, 8, 2015年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Chronic pain due to spinal dural arteriovenous fistulae (SDAVF) during follow-up is a serious issue because it can affect patients' quality of life. The severity of posttreatment chronic leg pain in patients with SDAVF is unclear. OBJECTIVE: To investigate the prevalence, severity, and characteristics of chronic leg pain in patients with SDAVF and to examine the clinical factors associated with chronic pain. METHODS: We conducted a survey of their chronic posttreatment leg pain in 49 SDAVF patients. It consisted of a numeric rating scale and a neuropathic pain symptom inventory (NPSI). Of the 49 patients, 32 (65.3%) completed the questionnaire. There were 24 males and 8 females whose mean age was 69.1 years. The mean follow-up period was 86.3 months. RESULTS: Chronic leg pain was reported by 26 (81.3%) of 32 patients; 14 experienced pain before treatment and 12 had new-onset posttreatment pain. The pain was reported as moderate to severe by 21 (80.8%) of 26 patients; the mean numeric rating scale and NPSI scores were 6.0 ± 2.3 and 17.4 ± 10.3, respectively. The NPSI subscores were significantly higher for spontaneous pain and paresthesia/dysesthesia than for paroxysmal pain. We found no significant clinical factors related to chronic posttreatment pain; on magnetic resonance imaging scans we identified spinal cord atrophy in 8 patients with chronic pain. CONCLUSION: Most of our SDAVF patients reported moderate to severe chronic leg pain characterized by spontaneous pain and paresthesia/dysesthesia. Spinal cord atrophy on magnetic resonance imaging scans was a characteristic in patients with chronic pain.

Pathological findings of saccular cerebral aneurysms-impact of subintimal fibrin deposition on aneurysm rupture
Masaaki Hokari, Naoki Nakayama, Hiroshi Nishihara, Kiyohiro Houkin
NEUROSURGICAL REVIEW, 38, 3, 531, 540, SPRINGER, 2015年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Although several studies have suggested that aneurysmal wall inflammation and laminar thrombus are associated with the rupture of saccular aneurysms, the mechanisms leading to the rupture remain obscure. We performed full exposure of aneurysms before clip application and attempted to keep the fibrin cap on the rupture point. Using these specimens in a nearly original state before surgery, we conducted a pathological analysis and studied the differences between ruptured and unruptured aneurysms to clarify the mechanism of aneurysmal wall degeneration. This study included ruptured (n=28) and unruptured (n=12) saccular aneurysms resected after clipping. All of the ruptured aneurysms were obtained within 24 h of onset. Immunostainings for markers of inflammatory cells (CD68) and classical histological staining techniques were performed. Clinical variables and pathological findings from ruptured and unruptured aneurysms were compared. Patients with ruptured or unruptured aneurysms did not differ by age, gender, size, location, and risk factors, such as hypertension, smoking, and hyperlipidemia. The absence or fragmentation of the internal elastica lamina, the myointimal hyperplasia, and the thinning of the aneurysmal wall were generally observed in both aneurysms. The existence of subintimal fibrin deposition, organized laminar thrombus, intramural hemorrhage, neovascularization, and monocyte infiltration are more frequently observed in ruptured aneurysms. Multivariate logistic regression analysis showed that ruptured aneurysm was associated with presence of subintimal fibrin deposition and monocyte infiltration. These findings suggest that subintimal fibrin deposition and chronic inflammation have a strong impact on degeneration of the aneurysmal wall leading to their rupture, and this finding may be caused by endothelial dysfunction.

Prediction model for 3-year rupture risk of unruptured cerebral aneurysms in Japanese patients
Shinjiro Tominari, Akio Morita, Toshihiro Ishibashi, Tomosato Yamazaki, Hiroyuki Takao, Yuichi Murayama, Makoto Sonobe, Masahiro Yonekura, Nobuhito Saito, Yoshiaki Shiokawa, Isao Date, Teiji Tominaga, Kazuhiko Nozaki, Kiyohiro Houkin, Susumu Miyamoto, Takaaki Kirino, Kazuo Hashi, Takeo Nakayama
ANNALS OF NEUROLOGY, 77, 6, 1050, 1059, WILEY, 2015年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, ObjectiveTo build a prediction model that estimates the 3-year rupture risk of unruptured saccular cerebral aneurysms.
MethodsSurvival analysis was done using each aneurysm as the unit for analysis. Derivation data were from the Unruptured Cerebral Aneurysm Study (UCAS) in Japan. It consists of patients with unruptured cerebral aneurysms enrolled between 2000 and 2004 at neurosurgical departments at tertiary care hospitals in Japan. The model was presented as a scoring system, and aneurysms were classified into 4 risk grades by predicted 3-year rupture risk: I,<1%; II, 1 to 3%; III, 3 to 9%, and IV, >9%. The discrimination property and calibration plot of the model were evaluated with external validation data. They were a combination of 3 Japanese cohort studies: UCAS II, the Small Unruptured Intracranial Aneurysm Verification study, and the study at Jikei University School of Medicine.
ResultsThe derivation data include 6,606 unruptured cerebral aneurysms in 5,651 patients. During the 11,482 aneurysm-year follow-up period, 107 ruptures were observed. The predictors chosen for the scoring system were patient age, sex, and hypertension, along with aneurysm size, location, and the presence of a daughter sac. The 3-year risk of rupture ranged from <1% to >15% depending on the individual characteristics of patients and aneurysms. External validation indicated good discrimination and calibration properties.
InterpretationA simple scoring system that only needs easily available patient and aneurysmal information was constructed. This can be used in clinical decision making regarding management of unruptured cerebral aneurysms. Ann Neurol 2015;77:1050-1059

Short-, middle- and long-term safety of superparamagnetic iron oxide-labeled allogeneic bone marrow stromal cell transplantation in rat model of lacunar infarction
Chengbo Tan, Hideo Shichinohe, Takeo Abumiya, Naoki Nakayama, Ken Kazumata, Masaaki Hokari, Shuji Hamauchi, Kiyohiro Houkin
NEUROPATHOLOGY, 35, 3, 197, 208, WILEY-BLACKWELL, 2015年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Recently, both basic and clinical studies demonstrated that bone marrow stromal cell (BMSC) transplantation therapy can promote functional recovery of patients with CNS disorders. A non-invasive method for cell tracking using MRI and superparamagnetic iron oxide (SPIO)-based labeling agents has been applied to elucidate the behavior of transplanted cells. However, the long-term safety of SPIO-labeled BMSCs still remains unclear. The aim of this study was to investigate the short-, middle- and long-term safety of the SPIO-labeled allogeneic BMSC transplantation. For this purpose, BMSCs were isolated from transgenic rats expressing green fluorescent protein (GFP) and were labeled with SPIO. The Na/K ATPase pump inhibitor ouabain or vehicle was stereotactically injected into the right striatum of wild-type rats to induce a lacunar lesion (n=22). Seven days after the insult, either BMSCs or SPIO solution were stereotactically injected into the left striatum. A 7.0-Tesla MRI was performed to serially monitor the behavior of BMSCs in the host brain. The animals were sacrificed after 7 days (n=7), 6 weeks (n=6) or 10 months (n=9) after the transplantation. MRI demonstrated that BMSCs migrated to the damage area through the corpus callosum. Histological analysis showed that activated microglia were present around the bolus of donor cells 7 days after the allogeneic cell transplantation, although an immunosuppressive drug was administered. The SPIO-labeled BMSCs resided and started to proliferate around the route of the cell transplantation. Within 6 weeks, large numbers of SPIO-labeled BMSCs reached the lacunar infarction area from the transplantation region through the corpus callosum. Some SPIO nanoparticles were phagocytized by microglia. After 10 months, the number of SPIO-positive cells was lower compared with the 7-day and 6-week groups. There was no tumorigenesis or severe injury observed in any of the animals. These findings suggest that BMSCs are safe after cell transplantation for the treatment of stroke.

脊髄動静脈瘻手術における術中MEPモニタリングの有用性
山本 雅史, 関 俊隆, 笹森 徹, 飛騨 一利, 奥原 浩之, 村上 望, 田中 小枝子, 川口 朋香, 中根 進児, 渋谷 斉, 重松 明男, 清水 力, 寶金 清博
脊髄外科, 29, 1, 42, 46, (一社)日本脊髄外科学会, 2015年04月
日本語, 当科で脊髄動静脈瘻(spinal AVF)手術を行った46例を対象に、術中MEPモニタリングの有用性について検討した。その結果、ほぼ全例の被検筋において術中MEPが高振幅で導出可能であった。脊髄硬膜動静脈瘻(dAVF)14例では、全例が上下肢ともに術中MEPの振幅低下を認めず、さらに術後麻痺も認めなかった。dAVFにおける偽陽性率、偽陰性率はともに0%であった。一方、脊髄辺縁部動静脈瘻(perimedullary AVF)では32例中6例が振幅の低下を認め、うち3例では術後麻痺を認めた。perimedullary AVFにおける偽陽性率は9.7%、偽陰性率は0%であった。以上、spinal AVFにおける術中モニタリングは術後麻痺の危険性を予測することが可能であり、有用性が示唆された。

Neuroprotective effects of cilostazol are mediated by multiple mechanisms in a mouse model of permanent focal ischemia
Hideo Shichinohe, Chengbo Tan, Takeo Abumiya, Naoki Nakayama, Ken Kazumata, Masaaki Hokari, Kiyohiro Houkin, Satoshi Kuroda
BRAIN RESEARCH, 1602, 53, 61, ELSEVIER SCIENCE BV, 2015年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The phosphodiesterase (PDE) 3 inhibitor cilostazol, used as an anti-platelet drug, reportedly can also ameliorate ischemic brain injury. Here, we investigated the effects of cilostazol in a permanent focal ischemia mice model. Male Balb/c mice were subjected to permanent middle cerebral artery occlusion. Mice were then treated with either cilostazol (10 or 20 mg/kg) or vehicle administered at 30 min and 24 h post-ischemia, and infarct volumes were assessed at 48 h post-ischemia. Mice treated with 20 mg/kg of cilostazol or vehicle were sacrificed at 6 h or 24 h post-ischemia and immunohistochemistry was used for brain sections. Treatment with 20 mg/kg of cilostazol significantly reduced infarct volumes to 70.1% of those with vehicle treatment. Immunohistochemistry results for 8-hydroxydeoxyguanosine (OHdG) expression showed that some neurons underwent oxidative stress around the ischemic boundary zone at 6 h post-ischemia. Cilostazol treatment significantly reduced the percentage of 8-0HdGpositive neurons (65.8+33.5% with vehicle and 21.3+9.9% with cilostazol). Moreover, NADPH oxidase (NOX) 2-positive neurons were significantly reduced with cilostazol treatment. In contrast, immunohistochemistry results for phosphorylated cyclic-AMP response element binding protein (pCREB) showed that there were significantly more pCREB-positive neurons around the ischemic boundary zone of cilostazol-treated mice than in those of vehicle-treated mice at 24 h post-ischemia. These results suggested that cilostazol might have multiple mechanisms of action to ameliorate ischemic tissue damage, by attenuating oxidative stress mediated by suppressing NOX2 expression by ischemic neurons and an anti-apoptotic effect mediated through the pCREB pathway. (C) 2015 Elsevier B.V. All rights reserved.

Therapeutic Effects of Human Multilineage-Differentiating Stress Enduring (MUSE) Cell Transplantation into Infarct Brain of Mice
Tomohiro Yamauchi, Yasumasa Kuroda, Takahiro Morita, Hideo Shichinohe, Kiyohiro Houkin, Mari Dezawa, Satoshi Kuroda
PLOS ONE, 10, 3, e0116009, PUBLIC LIBRARY SCIENCE, 2015年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, ObjectiveBone marrow stromal cells (BMSCs) are heterogeneous and their therapeutic effect is pleiotropic. Multilineage-differentiating stress enduring (Muse) cells are recently identified to comprise several percentages of BMSCs, being able to differentiate into triploblastic lineages including neuronal cells and act as tissue repair cells. This study was aimed to clarify how Muse and non-Muse cells in BMSCs contribute to functional recovery after ischemic stroke.MethodsHuman BMSCs were separated into stage specific embryonic antigen-3-positive Muse cells and -negative non-Muse cells. Immunodeficient mice were subjected to permanent middle cerebral artery occlusion and received transplantation of vehicle, Muse, non-Muse or BMSCs (2.5x10(4) cells) into the ipsilateral striatum 7 days later.ResultsMotor function recovery in BMSC and non-Muse groups became apparent at 21 days after transplantation, but reached the plateau thereafter. In Muse group, functional recovery was not observed for up to 28 days post-transplantation, but became apparent at 35 days post-transplantation. On immunohistochemistry, only Muse cells were integrated into peri-infarct cortex and differentiate into Tuj-1- and NeuN-expressing cells, while negligible number of BMSCs and non-Muse cells remained in the peri-infarct area at 42 days post-transplantation.ConclusionsThese findings strongly suggest that Muse cells and non-Muse cells may contribute differently to tissue regeneration and functional recovery. Muse cells may be more responsible for replacement of the lost neurons through their integration into the peri-infarct cortex and spontaneous differentiation into neuronal marker-positive cells. Non-Muse cells do not remain in the host brain and may exhibit trophic effects rather than cell replacement.

Cognitive dysfunction survey of the japanese patients with moyamoya disease (Cosmo-japan study): Study protocol
Yasushi Takagi, Susumu Miyamoto, COSMO-Japan Study Group, Kiyohiro Houkin, Joji Nakagawara, Kuniaki Ogasawara, Teiji Tominaga, Yoshikazu Okada, Tadashi Nariai, Satoshi Kuroda, Yukihiko Fujii, Toshihiko Wakabayashi, Kazuo Yamada, Susumu Miyamoto, Hiroyuki Nakase, Koji Iihara, Toshio Matsushima, Izumi Nagata, Toshiya Murai, Tomohisa Okada, Yasushi Takagi
Neurologia Medico-Chirurgica, 55, 3, 199, 203, Japan Neurosurgical Society, 2015年02月20日, ［査読有り］
英語, 研究論文（学術雑誌）, Moyamoya disease is a cerebrovascular occlusive disease characterized by progressive stenosis or by occlusion at the terminal portion of the bilateral internal carotid arteries. The unusual vascular network (moyamoya vessels) at the base of the brain with this disease as collateral channels is developed in this disease. Social independence because of cognitive impairment has recently been recognized as an important unsolved social issue with adult moyamoya disease. The patients with cognitive impairment have difficulty in proving their status because the standard neuroradiological and neuropsychological methods to define cognitive impairment with moyamoya disease are not determined. These patients with cognitive impairment should be supported by social welfare as psychologically handicapped persons. Thus Cognitive Dysfunction Survey of the Japanese Patients with Moyamoya Disease (COSMO-JAPAN study) is planned. In this study, we want to establish a standard finding of the cognitive impairment in patients with moyamoya disease.

骨転移をきたした小脳膠芽腫の1例　　　　　　　　　　　　　　　
湊川 英樹, 森 崇, 鬼丸 力也, 小野寺 俊輔, 白土 博樹, 東海林 菊太郎, 吉田 道春, 小林 浩之, 寳金 清博, 菅野 宏美, 田中 伸哉
Japanese Journal of Radiology, 33, Suppl., 4, 4, (公社)日本医学放射線学会, 2015年02月
日本語

Prediction of Postoperative Hyperperfusion by Intraoperative Assessment of Indocyanine Green Videoangiography in Moyamoya Disease
Uchino Haruto, Ito Masaki, Kazumata Ken, Nakayama Naoki, Kuroda Satoshi, Houkin Kiyohiro
STROKE, 46, 2015年02月, ［査読有り］

Cilostazol Can Attenuate Oxidative Stress by Suppressing Nox2 on Neurons in Mice Permanent Focal Ischemia
Shichinohe Hideo, Kuroda Satoshi, Tan Chengbo, Abumiya Takeo, Nakayama Naoki, Kazumata Ken, Hokari Masaaki, Houkin Kiyohiro
STROKE, 46, 2015年02月, ［査読有り］

Inside Intramural Thrombus Formation with Inflammatory Reactions Is Relevant to the Rupture of Cerebral Aneurysms
Shimoda Yusuke, Nakayama Naoki, Hokari Masaaki, Abumiya Takeo, Shichinohe Hideo, Kazumata Ken, Houkin Kiyohiro
STROKE, 46, 2015年02月, ［査読有り］

Post-ischemic Trans-arterial Regional Hypothermia Therapy Attenuates Microvascular Narrowing due to Astrocyte End-feet Swelling and Inhibits Subsequent Inflammatory Reactions in Ischemia Reperfusion Injury
Kurisu Kota, Abumiya Takeo, Nakamura Hideki, Shimbo Daisuke, Kazumata Ken, Nakayama Naoki, Shichinohe Hideo, Hokari Masaaki, Osanai Toshiya, Shimizu Hiroshi, Houkin Kiyohiro
STROKE, 46, 2015年02月, ［査読有り］

Utility of 4D-MRA to Measure Blood Flow Velocity in Cerebral Major Arteries
Abumiya Takeo, Fujima Noriyuki, Kudo Kohsuke, Ishi Yukitomo, Gekka Masayuki, Shichinohe Hideo, Kazumata Ken, Nakayama Naoki, Houkin Kiyohiro
STROKE, 46, 2015年02月, ［査読有り］

Combined use of 18 F-FDG PET and corticosteroid for diagnosis of deep-seated primary central nervous system lymphoma without histopathological confirmation
Shigeru Yamaguchi, Kenji Hirata, Sadahiro Kaneko, Hiroyuki Kobayashi, Tohru Shiga, Kentaro Kobayashi, Rikiya Onimaru, Hiroki Shirato, Nagara Tamaki, Shunsuke Terasaka, Kiyohiro Houkin
ACTA NEUROCHIRURGICA, 157, 2, 187, 194, SPRINGER WIEN, 2015年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Although histological diagnosis is indispensable in treating primary central nervous system lymphoma (PCNSL), we sometimes face an intractable situation in which tissue can be obtained only from a deep-seated brain lesion. In place of a histological diagnosis, the diagnostic adequacy of the combined use of 18 F-FDG PET and corticosteroid administration for PCNSL located in a deep-seated brain structure is reported.Patients with a deep-seated tumor were treated as having PCNSL without histological confirmation, based on the following criteria: (1) there was no evidence of systemic malignancy; (2) the tumor showed an extremely high FDG uptake relative to normal gray matter on pretreatment 18 F-FDG PET; (3) the tumor decreased in size 1 week after diagnostic therapy by corticosteroid administration on contrast-enhanced T1-weighted magnetic resonance imaging (MRI). FDG uptake of the lesion was evaluated by the maximum of standardized uptake values (SUVmax) and tumor-to-normal ratio of the SUV (T/N ratio). The extent of the tumor reduction was calculated by volumetric analysis for the treatment response to corticosteroid administration.Ten patients (4 males and 6 females) matched these criteria. On pretreatment 18 F-FDG PET, mean SUVmax in the tumor was 24.8 (8.75-60.75), and mean T/N ratio was 3.24 (2.17-5.12). The extent of tumor volume reduction was shown to be 21 to 68 % 1 week after diagnostic therapy by corticosteroids. Mean total dose and duration of corticosteroids were 719 mg as prednisolone and 6.5 days, respectively. Nine patients achieved complete response and one patient achieved partial response on MRI after standard treatment for PCNSL with high-dose methotrexate and/or whole-brain irradiation.Although the value of biopsy is universal, combining 18 F-FDG PET and corticosteroid administration is an important alternative method that may lead to the diagnosis of deep-seated PCNSLs in cases with intractable histopathological confirmations.

Chronic Ischemia Alters Brain Microstructural Integrity and Cognitive Performance in Adult Moyamoya Disease
Ken Kazumata, Khin Khin Tha, Hisashi Narita, Ichiro Kusumi, Hideo Shichinohe, Masaki Ito, Naoki Nakayama, Kiyohiro Houkin
STROKE, 46, 2, 354, 360, LIPPINCOTT WILLIAMS & WILKINS, 2015年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose-The mechanisms underlying frontal lobe dysfunction in moyamoya disease (MMD) are unknown. We aimed to determine whether chronic ischemia induces subtle microstructural brain changes in adult MMD and evaluated the association of changes with neuropsychological performance.
Methods-MRI, including 3-dimensional T1-weighted imaging and diffusion tensor imaging, was performed in 23 adult patients with MMD and 23 age-matched controls and gray matter density and major diffusion tensor imaging indices were compared between them; any alterations in the patients were tested for associations with age, ischemic symptoms, hemodynamic compromise, and neuropsychological performance.
Results-Decrease in gray matter density, associated with hemodynamic compromise (P<0.05), was observed in the posterior cingulate cortex of patients with MMD. Widespread reduction in fractional anisotropy and increases in radial diffusivity and mean diffusivity in some areas were also observed in bilateral cerebral white matter. The fractional anisotropy (r=0.54; P<0.0001) and radial diffusivity (r=-0.41; P<0.01) of white matter significantly associated with gray matter density of the cingulate cortex. The mean fractional anisotropy of the white matter tracts of the lateral prefrontal, cingulate, and inferior parietal regions were significantly associated with processing speed, executive function/attention, and working memory.
Conclusions-In adult MMD, there were more white matter abnormalities than gray matter changes. Disruption of white matter may play a pivotal role in the development of cognitive dysfunction.

Comparison of postoperative volume status and hemodynamics between surgical clipping and endovascular coiling in patients after subarachnoid hemorrhage
Tatsushi Mutoh, Ken Kazumata, Yuka Yokoyama, Tatsuya Ishikawa, Yasuyuki Taki, Shunsuke Terasaka, Kiyohiro Houkin
Journal of Neurosurgical Anesthesiology, 27, 1, 7, 15, Lippincott Williams and Wilkins, 2015年01月12日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Recent clinical data suggest that postoperative hemodynamic profile and fluid management may differ in aneurysmal subarachnoid hemorrhage patients depending on the treatment option: surgical clipping or endovascular coiling. Our aim was to determine the differences in hemodynamic parameters between the 2 modalities using an advanced transpulmonary thermodilution technique.
Methods: We studied 73 consecutive aneurysmal subarachnoid hemorrhage patients treated with either clipping or coiling. Transpulmonary thermodilution was established for monitoring cardiac index, global end-diastolic volume index (GEDI), and extravascular lung water index (ELWI). Blood biochemical markers were sampled in parallel.
Results: Hypovolemia (GEDI: 656±72 vs. 713±40 mL/m2
P=0.0001) and elevated plasma brain natriuretic peptide (114.0±56.7 vs. 68.6±47.4 pg/mL
P=0.0004) were evident on initial measurements in the clipping group. The number of fluid challenges until normalization of GEDI and ROC-based prediction of the responders (GEDI ≥10%) during vasospasm risk period (day 4 to 14 of ictus) were less with coiling than with clipping (P<
0.05). Therapy-related pulmonary edema was detected only in the clipping group (8%, n=3). Although length of intensive care unit stay was shorter in the coiling group (P=0.016), incidences of delayed ischemia (13% vs. 11%
P=0.50) and poor functional outcome on modified Rankin Scale score 4 to 6 at 1 month (37% vs. 46%
P=0.30) were not statistically different.
Conclusions: Surgical clipping is associated with higher cardiac output and hypovolemia in the early postoperative stage and poorer preload responsiveness to volume therapy during the vasospasm risk period compared with endovascular coiling.

Bone Marrow Stromal Cells Rescue Ischemic Brain by Trophic Effects and Phenotypic Change Toward Neural Cells
Hideo Shichinohe, Takeshi Ishihara, Koji Takahashi, Yoshikazu Tanaka, Michiyuki Miyamoto, Tomohiro Yamauchi, Hisayasu Saito, Hiroshi Takemoto, Kiyohiro Houkin, Satoshi Kuroda
NEUROREHABILITATION AND NEURAL REPAIR, 29, 1, 80, 89, SAGE PUBLICATIONS INC, 2015年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background. Transplantation of bone marrow stromal cells (BMSCs) may contribute to functional recovery after stroke. This study was designed to clarify their mechanisms, trophic effects of neurotrophic factors, and neural differentiation. Methods. Mouse neurons exposed to glutamate were cocultured with mouse BMSCs. Either neutralizing antibodies against brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF) or Trk inhibitor K252a was added to explore the mechanism of their protective effects. Fluorescence in situ hybridization (FISH) was used to assess BDNF or NGF mRNA expression in BMSCs. The mice were subjected to permanent focal ischemia, and 7 days later, either BMSCs or the vehicle was stereotactically transplanted into the ipsilateral striatum. The mouse brains were processed for FISH and immunostaining 2 or 4 weeks after transplantation. Results. BMSCs significantly ameliorated glutamate-induced neuronal death. Treatment with anti-BDNF antibody significantly reduced their protective effects. FISH analysis showed that the majority of BMSCs expressed BDNF and NGF mRNA in vitro. BMSC transplantation significantly improved the survival of neurons in peri-infarct areas. FISH analysis revealed that approximately half of BMSCs expressed BDNF and NGF mRNA 2 weeks after transplantation; however, the percentage of BDNF and NGF mRNA-positive cells decreased thereafter. Instead, the percentage of microtubule-associated protein 2-positive BMSCs gradually increased during 4 weeks after transplantation. Conclusions. These findings strongly suggest that BDNF may be a key factor underlying the trophic effects of BMSCs. BMSCs might exhibit the trophic effect in the early stage of cell therapy and the phenotypic change toward neural cells thereafter.

キャンサーボードが機能した1症例
遠藤将吾, 寺坂俊介, 小林浩之, 山口秀, 茂木洋晃, 金子貞洋, 井口晶裕, 長祐子, 大島淳二郎, 寺坂友佳代, 杉山未奈子, 橋本孝之, 鬼丸力也, 清水伸一, 有賀正, 白戸博樹, 寳金清博
日本小児血液・がん学会雑誌(Web), 52, 3, 2015年

Surgical outcomes of high-grade spinal cord gliomas
Toshitaka Seki, Kazutoshi Hida, Syunsuke Yano, Takeshi Aoyama, Izumi Koyanagi, Kiyohiro Houkin
Asian Spine Journal, 9, 6, 935, 941, Korean Society of Spine Surgery, 2015年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Study Design: A retrospective study. Purpose: The purpose of this study was to obtain useful information for establishing the guidelines for treating high-grade spinal cord gliomas. Overview of Literature: The optimal management of high-grade spinal cord gliomas remains controversial. We report the outcomes of the surgical management of 14 high-grade spinal glioma. Methods: We analyzed the outcomes of 14 patients with high-grade spinal cord gliomas who were surgically treated between 1989 and 2012. Survival was charted with the Kaplan-Meier plots and comparisons were made with the log-rank test. Results: None of the patients with high-grade spinal cord gliomas underwent total resection. Subtotal resection was performed in two patients, partial resection was performed in nine patients, and open biopsy was performed in three patients. All patients underwent postoperative radiotherapy and six patients further underwent radiation cordotomy. The median survival time for patients with high-grade spinal cord gliomas was 15 months, with a 5-year survival rate of 22.2%. The median survival time for patients with World Health Organization grade III tumors was 25.5 months, whereas the median survival time for patients with glioblastoma multiforme was 12.5 months. Both univariate and multivariate Cox proportional hazards models demonstrated a significant effect only in the group that did not include cervical cord lesion as a factor associated with survival (p =0.04 and 0.03). Conclusions: The surgical outcome of patients diagnosed with high-grade spinal cord gliomas remains poor. Notably, only the model which excluded cervical cord lesions as a factor significantly predicted survival.

Unilateral Moyamoya Phenomenon with a String-of-beads Appearance in an Elderly Patient with the c.14576G > A Heterozygous Variant of RNF213
Junya Aoki, Kensaku Shibazaki, Masaki Ito, Naoki Saji, Junichi Uemura, Kiyohiro Houkin, Kazumi Kimura
INTERNAL MEDICINE, 54, 8, 971, 974, JAPAN SOC INTERNAL MEDICINE, 2015年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, We herein report a case of ischemic stroke in a 69-year-old man with unilateral moyamoya vessels originating from the proximal portion of the left middle cerebral artery. In addition, digital-subtraction angiography demonstrated a string-of-beads-like appearance in the cavernous portion of the left internal carotid artery. A genetic analysis revealed a heterozygous c.14576G>A variant in ring finger protein 213. The patient's younger brother had a history of hemorrhagic stroke and had been diagnosed with moyamoya disease. We finally considered that the unilateral moyamoya vessel and string-of-beads appearance observed in the current case were not simply caused by atherosclerosis, but rather represented symptoms within the moyamoya spectrum.

Cerebral aneurysms associated with segmental dilative arteriopathy of the circle of Willis.
Horita Y, Mikami T, Houkin K, Mikuni N
Surgical neurology international, 6, Suppl 9, S291, 4, 2015年, ［査読有り］

Predictive Factors for Epilepsy in Moyamoya Disease
Takeshi Mikami, Satoko Ochi, Kiyohiro Houkin, Yukinori Akiyama, Masahiko Wanibuchi, Nobuhiro Mikuni
JOURNAL OF STROKE & CEREBROVASCULAR DISEASES, 24, 1, 17, 23, ELSEVIER SCIENCE BV, 2015年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Epilepsy cannot always be recognized in patients with moyamoya disease. In this report, the clinical features of patients with epilepsy were evaluated for assessing the predictive factors of epilepsy in moyamoya disease. Methods: A total of 64 consecutive patients with moyamoya disease were included in this study. During their follow-up periods, 7 patients were diagnosed with epilepsy. Then, the patients with epilepsy were compared with the patients without epilepsy regarding their clinical features. Results: Analysis of patient background characteristics revealed a significantly higher incidence of epilepsy in patients with high modified Rankin Scale (mRS) scores, high cerebrovascular attack scores, onset age of 3 years or less, early seizures, cortical involvement, stroke subtype, and diffuse brain atrophy. A logistic analysis of epilepsy data revealed significant differences between the 2 groups in mRS score, cerebrovascular attack score, onset age 3 years or less, early seizure, cortical involvement, stroke subtype, and diffuse brain atrophy. Of these, significant differences were noted in 3 items (mRS score, early seizure, and diffuse brain atrophy) on multivariate analysis. These 3 items were selected as the basis of our new moyamoya disease epilepsy risk scale (MDERS), which we then evaluated. The cutoff value estimated by the receiver operating characteristic curve was set at 1 (sensitivity,.857; specificity,.825) or 2 (sensitivity,.571; specificity, 1.000). Conclusions: Epilepsy in moyamoya disease is associated with clinical factors and is not an independent category. For prediction of epilepsy in moyamoya disease, MDERS is a simple and convenient assessment scale.

Platelet Lysate and Granulocyte-Colony Stimulating Factor Serve Safe and Accelerated Expansion of Human Bone Marrow Stromal Cells for Stroke Therapy
Tomohiro Yamauchi, Hisayasu Saito, Masaki Ito, Hideo Shichinohe, Kiyohiro Houkin, Satoshi Kuroda
TRANSLATIONAL STROKE RESEARCH, 5, 6, 701, 710, SPRINGER, 2014年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Autologous human bone marrow stromal cells (hBMSCs) should be expanded in the animal serum-free condition within clinically relevant periods in order to secure safe and effective cell therapy for ischemic stroke. This study was aimed to assess whether the hBMSCs enhance their proliferation capacity and provide beneficial effect in the infarct brain when cultured with platelet lysate (PL) and granulocyte-colony stimulating factor (G-CSF). The hBMSCs were cultured in the fetal calf serum (FCS)-, PL-, or PL/G-CSF-containing medium. Cell growth kinetics was analyzed. The hBMSCs-PL, hBMSC-PL/G-CSF, or vehicle was stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion 7 days after the insult. Motor function was assessed for 8 weeks, and the fate of transplanted hBMSCs was examined using immunohistochemistry. As the results, the hBMSCs-PL/G-CSF showed more enhanced proliferation than the hBMSCs-FCS and hBMSCs-PL. Transplantation of hBMSCs expanded with the PL- or PL/G-CSF-containing medium equally promoted functional recovery compared with the vehicle group. Histological analysis revealed that there were no significant differences in their migration, survival, and neural differentiation in the infarct brain between the hBMSCs-PL and hBMSCs-PL/G-CSF. These findings strongly suggest that the combination of PL and G-CSF may accelerate hBMSC expansion and serve safe cell therapy for patients with ischemic stroke at clinically relevant timing.

Successful acute endovascular therapy of cerebral embolism for a patient with ventricular assist device: A case report
Satoshi Kobayashi, Michiyuki Miyamoto, Shinichiro Shinada, Yukitomo Ishi, Yusuke Shimoda, Kazuyoshi Yamazaki, Satoshi Ushikoshi, Tomonori Ooka, Yoshiro Matsui, Kiyohiro Houkin
Neurological Surgery, 42, 11, 1057, 1062, Igaku-Shoin Ltd, 2014年11月01日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, The number of patients with a ventricular assist device (VAD) will increase with the spread of heart transplantation in Japan. On the other hand, it is likely that VADs could cause cerebral embolism. However, there are few reports about endovascular therapy for intracranial embolic infarction from VAD The authors report successful acute endovascular therapy for cerebral embolism A 19-year-old woman with a VAD who received anti-coagulant treatment by warfarin sodium presented disturbance of consciousness and right hemiparesis CT scan showed early CT sign in the left middle cerebral artery (MCA) area. 3D-CTA demonstrated occlusion of the left MCA and basilar artery (BA). We first performed endovascular recanalization in the left MCA. because IV tPA was ineligible. The left MCA was recanalized with TICI 2b perfusion and her symptoms were significantly improved. The treatment of the VAD patient reveals important issues First, the femoral puncture requires ultrasound due to pulseless femoral artery. Second, the access route is an intact artery because of the anatomy of the VAD. Third, even if the patient has a hemorrhagic complication by intervention, the patient must be kept on anti-coagulant treatment because the VAD requires it Careful consideration should be given to recanalization of occlusive vessels.

Surgical Management of Combined Intramedullary Arteriovenous Malformation and Perimedullary Arteriovenous Fistula within the Hybrid Operating Room after Five Years of Performing Focus Fractionated Radiotherapy: Case Report
Masayuki Gekka, Toshitaka Seki, Kazutoshi Hida, Toshiya Osanai, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 54, 11, 936, 940, JAPAN NEUROSURGICAL SOC, 2014年11月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Perimedullary arteriovenous fistula (AVF) shunts occur on the spinal cord surface and can be treated surgically or by endovascular embolization. In contrast, the nidus of an intramedullary arteriovenous malformation (AVM) is located in the spinal cord and is difficult to treat surgically or by endovascular techniques. The benefits of radiotherapy for treating intramedullary AVM have been published, but are anecdotal and consist largely of case reports. We present a case of combined cervical intramedullary AVM and perimedullary AVF which received surgical treatment within a hybrid operating room (OR) after 5 years of focus fractionated radiotherapy. A 37-year-old male presented with stepwise worsening myelopathy. Magnetic resonance imaging and spinal angiography revealed intramedullary AVM and perimedullary AVF at the C3 to C5 levels. In order to reduce nidus size and blood flow, we first performed focal fractionated radiotherapy. Five years later, the lesion volume was reduced. Following this, direct surgery was performed by an anterior approach using corpectomy in the hybrid OR. The spinal cord was monitored by motor-evoked potential throughout the surgery. Complete obliteration of the fistulous connection was confirmed by intraoperative indocyanine green video-angiography and intraoperative angiography, preserving the anterior spinal artery. We conclude that surgical treatment following focal fractionated radiotherapy may become one strategy for patients who are initially deemed ineligible for endovascular embolization and surgical treatment. Furthermore, the hybrid OR enables safe and precise treatment for spinal vascular disorders in the fields of endovascular treatment and neurosurgery.

Pathological Considerations for Unruptured Dissecting Aneurysm in the Posterior Inferior Cerebellar Artery: Case Report.
Miyamoto M, Nakayama N, Hokari M, Kuroda S, Takikawa S, Houkin K
NMC case report journal, 1, 1, 9, 11, 2014年10月, ［査読有り］, ［国内誌］
英語, Because of the wide spread of magnetic resonance image (MRI), it may be increasing to find a dissecting aneurysm (DA) of the posterior inferior cerebellar artery (PICA) that causes headache without associated hemorrhage or infarction. Generally, surgical treatment might be considered in cases of DA with hemorrhage. However, the treatment of an unruptured DA with headache or infarction has not been well established. This is the first report regarding the pathology of an intact DA of the PICA that presents with headache only, and the pathological findings showed interesting figures. A 44-year-old man with an unruptured DA of the left PICA presented with sudden left occipital headache. MRI revealed no hemorrhage or infarction. Magnetic resonance angiography (MRA) showed growth of the DA 12 days after the onset of headache. Therefore, surgery was performed to prevent aneurysmal rupture. This DA aneurysm was trapped and removed after an occipital artery (OA)-PICA anastomosis was performed. The surgery was performed without complication. Pathological findings showed folding of the internal elastic lamina, and the true lumen was torn by the false lumen. The dissection reached the adventitia and the wall had numerous macrophages. Pathological findings might help understanding the etiology of DAs and inflammation might play an important role in DAs.

Intraoperative assessment of cortical perfusion by indocyanine green videoangiography in surgical revascularization for moyamoya disease
Haruto Uchino, Ken Kazumata, Masaki Ito, Naoki Nakayama, Satoshi Kuroda, Kiyohiro Houkin
ACTA NEUROCHIRURGICA, 156, 9, 1753, 1760, SPRINGER WIEN, 2014年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Postoperative hyperperfusion is a potential complication of the direct bypass procedure for moyamoya disease (MMD). However, no reliable modality is available yet for the prediction of postoperative hyperperfusion during surgery for MMD. This study aimed to investigate whether semiquantitative analysis of indocyanine green (ICG) videoangiography could contribute to the prediction of postoperative hyperperfusion in MMD.
This study included 12 hemispheres from 10 patients who underwent surgical revascularization for MMD. Intraoperative ICG videoangiography was performed before and after a direct bypass procedure. The ICG intensity-time curves were semiquantitatively analyzed to evaluate cortical perfusion by calculating the blood flow index (BFI). Using single-photon emission computed tomography (SPECT), postoperative cerebral blood flow measurements were performed thrice: immediately, and 2 and 7 days after surgery.
BFI significantly increased from 21.3 +/- 10.5 to 38.4 +/- 20.0 after bypass procedures in all the hemispheres (p < 0.01). The ratio of BFI before and after the bypass procedure was 2.4 +/- 2.0, ranging from 0.5 to 8.0. Postoperative hyperperfusion was observed in nine of the 12 operated hemispheres within 7 days after surgery. Of these, three hemispheres developed hyperperfusion immediately after surgery. In the adult cases, the increase in the ratio of BFI after bypass was significantly greater in those who developed hyperperfusion immediately after surgery than in those who did not (6.5 +/- 0.5 vs. 1.8 +/- 2.1, p < 0.01). In contrast, no significant increase in BFI was observed in the pediatric MMD patients who experienced immediate hyperperfusion. No correlation between the changes in BFI and the occurrence of delayed hyperperfusion was observed.
Our results suggest that semiquantitative analysis of BFI by intraoperative ICG videoangiography is useful in evaluating changes in cortical perfusion after bypass procedures for MMD and can predict the occurrence of early-onset hyperperfusion in MMD patients after direct bypass.

Effects of Surgical Revascularization on Cerebral Oxygen Metabolism in Patients With Moyamoya Disease An O-15-Gas Positron Emission Tomographic Study
Satoshi Kuroda, Daina Kashiwazaki, Kenji Hirata, Tohru Shiga, Kiyohiro Houkin, Nagara Tamaki
STROKE, 45, 9, 2717, 2721, LIPPINCOTT WILLIAMS & WILKINS, 2014年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose-This prospective study was aimed to evaluate the effects of surgical revascularization on cerebral oxygen metabolism in moyamoya disease.
Methods-This study included totally 69 hemispheres of 42 patients who underwent superficial temporal artery to middle cerebral artery anastomosis and indirect bypass for moyamoya disease between 2000 and 2011. There were 12 children and 30 adults. MRI and O-15-gas positron emission tomography were performed before and 3 to 4 months after surgery. Hemodynamic and metabolic parameters were precisely quantified and statistically analyzed.
Results-Preoperative positron emission tomographic scans revealed that cerebral blood flow was decreased, cerebral blood volume was increased, and cerebral metabolic rate for oxygen was decreased in both pediatric and adult patients. Cerebral metabolic rate for oxygen reduction was observed in approximate to 80% of pediatric (16/21; 76%) and adult hemispheres (38/48; 79%). Surgical revascularization resolved hemodynamic compromise in all operated hemispheres. Cerebral metabolic rate for oxygen significantly improved in pediatric patients without parenchymal lesions (n=8), but not those with parenchymal lesions (n=8). Multivariate analysis revealed that cerebral metabolic rate for oxygen significantly improved in younger adult patients without parenchymal lesions (P=0.0264; odds ratio, 0.88; 95% confidence interval, 0.79-0.99).
Conclusions-Cerebral oxygen metabolism is significantly depressed in approximate to 80% of the involved hemispheres of moyamoya disease and improves in pediatric and younger adult patients without parenchymal lesions after bypass surgery. Cerebral oxygen metabolism may be reversibly depressed in response to cerebral ischemia in them although the underlying mechanisms are still unclear.

The frequency of postoperative stroke in moyamoya disease following combined revascularization: a single-university series and systematic review
Ken Kazumata, Masaki Ito, Kikutaro Tokairin, Yasuhiro Ito, Kiyohiro Houkin, Naoki Nakayama, Satoshi Kuroda, Tatsuya Ishikawa, Hiroyasu Kamiyama
JOURNAL OF NEUROSURGERY, 121, 2, 432, 440, AMER ASSOC NEUROLOGICAL SURGEONS, 2014年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Object. Although combined direct and indirect anastomosis in patients with moyamoya disease immediately increases cerebral blood flow, the surgical procedure is more complex. Data pertinent to the postoperative complications associated with combined bypass are relatively scarce compared with those associated with indirect bypass. This study investigated the incidence and characteristics of postoperative stroke in combined bypass and compared them with those determined from a literature review to obtain data from a large population.
Methods. A total of 358 revascularization procedures in 236 patients were retrospectively assessed by reviewing clinical charts and radiological data. PubMed was searched for published studies on surgical treatment to determine the incidence of postoperative complications in a larger population.
Results. Seventeen instances of postoperative stroke were observed in 16 patients (4.7% per surgery, 95% CI 2.8%-7.5%). Postoperative stroke was more frequent (7.9% per surgery) in adults than in pediatric patients (1.7% per surgery, OR 4.07, 95% CI 1.12-14.7; p < 0.05). Acute progression of stenoocclusive changes were identified in the major cerebral arteries (anterior cerebral artery, n = 3; middle cerebral artery, n = 1; posterior cerebral artery, n = 2). The postoperative stroke rate was comparable with that (5.4%) determined from a literature search that included studies reporting more than 2000 direct/combined procedures. No differences in the stroke rates between the direct/combined and indirect procedures were found. In the literature review, direct/combined bypass was more often associated with excellent revascularization (angiographic pacification greater than two-thirds) than indirect bypass (p < 0.05).
Conclusions. This experience of 358 consecutive procedures is one of the largest series for which the postoperative stoke rate for direct/combined bypass performed with a unified strategy has been reported. A systematic review confirmed that the postoperative stroke rate for the direct/combined procedure was comparable to that for the indirect procedure.

Type 1 collagen as a potential niche component for CD133-positive glioblastoma cells
Hiroaki Motegi, Yuuta Kamoshima, Shunsuke Terasaka, Hiroyuki Kobayashi, Kiyohiro Houkin
NEUROPATHOLOGY, 34, 4, 378, 385, WILEY-BLACKWELL, 2014年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Cancer stem cells are thought to be closely related to tumor progression and recurrence, making them attractive therapeutic targets. Stem cells of various tissues exist within niches maintaining their stemness. Glioblastoma stem cells (GSCs) are located at tumor capillaries and the perivascular niche, which are considered to have an important role in maintaining GSCs. There were some extracellular matrices (ECM) on the perivascular connective tissue, including type 1 collagen. We here evaluated whether type 1 collagen has a potential niche for GSCs. Imunohistochemical staining of type 1 collagen and CD133, one of the GSCs markers, on glioblastoma (GBM) tissues showed CD133-positive cells were located in immediate proximity to type 1 collagen around tumor vessels. We cultured human GBM cell lines, U87MG and GBM cells obtained from fresh surgical tissues, T472 and T555, with serum-containing medium (SCM) or serum-free medium with some growth factors (SFM) and in non-coated (Non-coat) or type 1 collagen-coated plates (Col). The RNA expression levels of CD133 and Nestin as stem cell markers in each condition were examined. The Col condition not only with SFM but SCM made GBM cells more enhanced in RNA expression of CD133, compared to Non-coat/SCM. Semi-quantitative measurement of CD133-positive cells by immunocytochemistry showed a statistically significant increase of CD133-positive cells in Col/SFM. In addition, T472 cell line cultured in the Col/SFM had capabilities of sphere formation and tumorigenesis. Type 1 collagen was found in the perivascular area and showed a possibility to maintain GSCs. These findings suggest that type 1 collagen could be one important niche component for CD133-positive GSCs and maintain GSCs in adherent culture.

The diagnostic role of F-18-FDG PET for primary central nervous system lymphoma
Shigeru Yamaguchi, Kenji Hirata, Hiroyuki Kobayashi, Tohru Shiga, Osamu Manabe, Kentaro Kobayashi, Hiroaki Motegi, Shunsuke Terasaka, Kiyohiro Houkin
ANNALS OF NUCLEAR MEDICINE, 28, 7, 603, 609, SPRINGER, 2014年08月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, F-18-FDG PET has become one of the most important methods for studying malignant lymphoma, but its diagnostic role for primary central nervous system lymphoma (PCNSL) has not been established. The aim of this study was to determine the appropriate cut-off values of FDG uptake and to investigate how corticosteroid administration influences PCNSL.We retrospectively reviewed 82 patients with contrast-enhanced brain tumors who underwent an FDG PET scan at onset, including 19 PCNSLs. FDG uptake of the lesion was assessed by the maximum standardized uptake value (SUVmax) and the ratio of tumor to normal contralateral cortex activity (T/N ratio). Receiver operating characteristic (ROC) curves were generated from the SUVmax and T/N ratios. To investigate the influence of corticosteroid application before a FDG PET scan, we evaluated the association between the FDG uptake of the lesion and the cumulative dose of corticosteroid administration on 13 PCNSL patients who had received steroid treatment before an FDG PET examination.The mean FDG SUVmax and T/N ratio of PCNSLs were 22.6 and 2.79, respectively, and these values were significantly higher than those of the other malignant brain tumors. ROC analysis indicated that the evaluation of FDG uptake using the T/N ratio was more reliable than the SUVmax with respect to the differential diagnosis. When PCNSL patients went without steroid application before FDG PET, the accuracy of the T/N ratio with a cut-off point of 2.0 was 91.1 %, the sensitivity was 94.7 %, and the specificity was 87.3 %. Although there are no significant differences in the FDG T/N ratio for PCNSL patients with or without steroid treatment, a negative correlation was found between the T/N ratio and cumulative dose of corticosteroid before PET study (r = -0.71, p = 0.032).We concluded that the T/N ratio was superior to SUVmax for FDG uptake assessment as for distinguishing PCNSLs from other malignant brain tumors; the appropriate T/N ratio cut-off point was 2.0. In addition, FDG uptake could be influenced by cumulative doses of corticosteroid before a PET scan, and thus this fact should be taken into consideration when evaluating FDG PET for PCNSL diagnosis.

Impact of cervical internal carotid clamping and radial artery graft bypass on cortical arterial perfusion pressure during craniotomy
Ken Kazumata, Hiroyasu Kamiyama, Tatsuya Ishikawa, Toshitaka Nakamura, Shunsuke Terasaka, Kiyohiro Houkin
NEUROSURGICAL REVIEW, 37, 3, 493, 500, SPRINGER, 2014年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Strategic cervical internal carotid occlusion is employed either temporarily or permanently in various neurosurgical procedures. The aim of the present study was to assess changes in cortical arterial pressure during cervical internal carotid cross-clamping before and after the placement of radial artery (RA) graft bypass in the treatment of complex carotid artery aneurysms. Perfusion pressure of the middle cerebral artery (MCA) was assessed in 22 patients with complex carotid aneurysm treated with RA graft bypass. Regional cerebral blood flow was assessed postoperatively using single-photon computed tomography. Mean cortical blood pressure (mcBP) was found to be 48.2 +/- 24.2 and 97.0 +/- 24.0 % of baseline after clamping the cervical internal carotid artery and opening the RA graft bypass, respectively. Cerebral perfusion pressure estimated by the mcBP failed to sustain a critical limit of greater than 70 mmHg under craniotomy in 16 out of 20 (80 %) patients. There was an inverse correlation in mcBP between the baseline and after the placement of the RA graft bypass (r = 0.66, P < 0.005). Postoperative regional cerebral blood flow in the MCA territory on the ipsilateral side of the aneurysm was 97 +/- 7 % of that of the contralateral side after internal carotid artery (ICA) ligation combined with RA graft bypass. Substantial pressure reductions in cerebral cortical arteries were observed during the cervical internal carotid cross-clamping. Perfusion pressure in peripheral cortical arteries after the placement of the RA graft bypass was comparable to the state before ICA clamping.

Thalamic arteriovenous malformation fed by the artery of Percheron originating from the contralateral posterior cerebral artery in a child
Hiroaki Motegi, Shunsuke Terasaka, Hideaki Shiraishi, Kiyohiro Houkin
CHILDS NERVOUS SYSTEM, 30, 7, 1313, 1315, SPRINGER, 2014年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Artery of Percheron (AOP) is a rare variant of thalamoperforating artery with a single common trunk feeding both thalami and with or without contribution to the rostral midbrain. We report the first case of thalamic arteriovenous malformation (AVM) fed by AOP with hemorrhagic onset.
A 12-month-old girl suddenly weakened and developed coma. Left thalamic hemorrhage was detected with the third and both lateral ventricles' hematoma. Thalamic AVM was discovered to be fed by an AOP originating from the contralateral posterior cerebral artery.
Endovascular embolization of AVM was impossible due to a risk of bilateral thalamic infarction and anatomical inaccessibility. Thalamic AVM was removed by high superior parietal approach without new neurological symptoms.
The first case of thalamic AVM fed by AOP originating from the contralateral posterior cerebral artery is reported. Surgical removal of AVM would be at the heart of treatment in order to avoid bilateral thalamic infarction.

Spatial Relationship between Cerebral Microbleeds, Moyamoya Vessels, and Hematoma in Moyamoya Disease
Ken Kazumata, Daisuke Shinbo, Masaki Ito, Hideo Shichinohe, Satoshi Kuroda, Naoki Nakayama, Kiyohiro Houkin
JOURNAL OF STROKE & CEREBROVASCULAR DISEASES, 23, 6, 1421, 1428, ELSEVIER SCIENCE BV, 2014年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Adult moyamoya disease (MMD) is known to have high incidence of cerebral microbleeds (cMBs); however, the clinical significance still remains unclear. We investigated the frequency of cMBs in a large number of patients and analyzed the patterns of MB distribution in association with the location of the hematoma and moyamoya vessels. Methods: We studied 259 consecutive patients with MMD using prospectively collected database. One hundred ninety-one patients were eligible for the present study, and image analysis was performed retrospectively. The presence of cMBs and remains of hemorrhage were determined using gradient-echo T2*-weighted sequence (1.5 T). The development of moyamoya vessels was assessed on source images of time-of-flight magnetic resonance angiography. The analysis consists of descriptive assessment of the spatial relationship between cMB, remains of hemorrhage, and moyamoya vessels. Statistical analysis was performed to calculate relative risk ratio in the presence of cMBs in relation to the remains of hemorrhage (macrohematoma), age of onset, and the presence of concomitant moyamoya vessels. Results: Thirty MBs were observed in 20 adult MMD patients (16.9%). MBs were located predominantly in the periventricular white matter (63.3%) followed by the basal ganglia/thalami (20%). Comparing the patients with cMBs from those without, hematoma was more frequently observed in patients with cMBs (odds ratio [OR] 4.29; 95% confidence interval [CI] 1.58-11.62; P = .0062). Patients with adult onset was more likely to demonstrate cMBs (14.4%) compared with the patients with pediatric onset (4.1%) (OR 3.93; 95% CI 1.11-13.91). Moyamoya vessels appeared in the lateral part of the trigon, and the periventricular white matter was significantly associated with the presence of cMBs (lateral part of the trigon; OR 3.29 [1.59-6.82], P - .0019, periventricle of the body of lateral ventricle; OR 2.40 [1.20-4.79], P = .0214, respectively). cMBs accompanied concomitant arteries in 23 (76.7%) lesions. The subependymal-leptomeningeal artery anastomosis was the most common pattern (n = 20, 66.7%). Conclusions: Spatial relationship was demonstrated between the moyamoya vessels and perivascular hemosiderin deposition particularly around the subependymal-leptomeningeal anastomosis, suggesting the mechanism for the development of cMBs in MMD. Present study further supports previous findings that cMBs potentially serve as a marker for the bleeding- prone microangiopathy in MMD. The significance of the present study lies in selecting optimal surgical candidate for preventing future hemorrhage by the presence of the cMBs, whereas current surgical indication relying on the degree of ischemia frequently fails to detect patients with future hemorrhage. (C) 2014 by National Stroke Association

Irregular Neointimal Lining with Prominent Proliferative Activity After Carotid Patch Angioplasty: An Autopsy Case Report
Masaki Ito, Yoshimasa Niiya, Haruto Uchino, Naoki Nakayama, Shoji Mabuchi, Kiyohiro Houkin
WORLD NEUROSURGERY, 82, 1-2, ELSEVIER SCIENCE INC, 2014年07月, ［査読有り］
英語, 研究論文（学術雑誌）, OBJECTIVE: Although the healing response after carotid balloon injury and carotid patch angioplasty injury has been well-documented in animal models, there is limited information about this process after carotid endarterectomy (CEA) in human patients.
CASE DESCRIPTION: We describe the autopsy results of a 79-year-old man who died 18 days after CEA with patch angioplasty. The treated carotid artery had an adequate luminal diameter. Elastica-Masson staining revealed that the treated portion was covered with neointima but the patch graft was exposed to the arterial lumen at 18 days after CEA. Immunohistochemistry staining for alpha-smooth muscle actin (alpha-SMA), von-Willebrand factor, and vascular endothelial growth factor receptor-2 revealed that the neointima was mainly composed of alpha-SMA-positive cells. In addition, the alpha-SMA-rich neointima had many more Ki-67-positive cells than did the internal carotid artery intima in the area beyond the CEA-treated portion.
CONCLUSIONS: This case report is the first to describe an entire carotid artery specimen in the acute stage after CEA with patch angioplasty. These findings suggest that an alpha-SMA-rich neointima with prominent proliferative activity covers the inner surface of the treated carotid artery, but patch grafts are left uncovered. The intrinsic arterial wall may have an important role in intimal regeneration after CEA, although the nature of the neointima and the mechanism by which it regulates proliferative activity remain unclarified.

Prognostic Factors for Survival in Patients with High-Grade Meningioma and Recurrence-Risk Stratification for Application of Radiotherapy
Shigeru Yamaguchi, Shunsuke Terasaka, Hiroyuki Kobayashi, Katsuyuki Asaoka, Hiroaki Motegi, Hiroshi Nishihara, Hiromi Kanno, Rikiya Onimaru, Yoichi M. Ito, Hiroki Shirato, Kiyohiro Houkin
PLOS ONE, 9, 5, e97108, PUBLIC LIBRARY SCIENCE, 2014年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Radiotherapy for high-grade meningioma (HGM) is one of the essential treatment options for disease control. However, appropriate irradiation timing remains under debate. The object of this study is to discern which prognostic factors impact recurrence in HGM patients and to propose a risk-stratification system for the application of postoperative radiotherapy.Methods: We retrospectively reviewed 55 adult patients who were diagnosed with Grade II and III intracranial meningioma. Cox regression models were applied to the analysis for impact on early recurrence in HGM patients without postoperative radiotherapy.Results: Grade III malignancy (P = 0.0073) and transformed histology (P = 0.047) proved to be significantly poor prognostic factors of early recurrence by multivariate analysis. The other candidates for recurrence factors were Simpson Grade 3-5 resection, preoperative Karnofsky Performance status, <= 70%, and MIB-1 labeling index >= 15%. According to these prognostic factors, postoperative HGM patients could be stratified into three recurrence-risk groups. The prognoses were significantly different between each group, as the 3-year actual recurrence-free rates were 90% in low-risk group, 31% in intermediate-risk group, and 15% in high-risk group.Conclusion: We propose recurrence-risk stratification for postoperative HGM patients using clinically available factors. Our results suggest that the prognosis for patients with high-risk HGMs is dismal, whereas HGM patients belonging to the low-risk group could have favorable prognoses. This stratification provides us with the criteria necessary to determine whether to apply adjuvant radiotherapy to postoperative HGM patients, and to also help identify potentially curable HGMs without adjuvant radiotherapy.

Utility of Early Post-treatment Single-Photon Emission Computed Tomography Imaging to Predict Outcome in Stroke Patients Treated with Intravenous Tissue Plasminogen Activator
Takeo Abumiya, Masahito Katoh, Takuya Moriwaki, Masami Yoshino, Takeshi Aoki, Hiroyuki Imamura, Toshimitsu Aida, Hideo Scichinohe, Naoki Nakayama, Ken Kazumata, Kiyohiro Houkin
JOURNAL OF STROKE & CEREBROVASCULAR DISEASES, 23, 5, 896, 901, ELSEVIER SCIENCE BV, 2014年05月, ［査読有り］
英語, 研究論文（学術雑誌）, It is important to predict the outcome of tissue plasminogen activator (tPA)-treated patients early after the treatment for considering the post-tPA treatment option. We assessed cerebral blood flow (CBF) of tPA-treated patients with single-photon emission computed tomography (SPECT) 1 hour after tPA infusion to predict the patient outcome. Technetium-99m-hexamethylpropyleneamine oxime SPECT was performed in 35 consecutive tPA-treated patients. Asymmetry index, a contralateral-to-ipsilateral ratio of CBF, was calculated to analyze CBF quantitatively. Hypoperfusion or hyperperfusion was defined as a decrease of 25% or more or a increase of 25% or more in asymmetry index, respectively. Of all 35 patients, 23 had only hypoperfusion, 8 had both hypoperfusion and hyperperfusion, 2 had only hyperperfusion, and 2 had no perfusion abnormality. When evaluating the association between hypoperfusion and outcome, hypoperfusion volumes were significantly correlated with the modified Rankin Scale at 3 months (r = .634, P < .001). Hyperperfusion was observed in 10 patients (28.6%) and they showed a marked National Institutes of Health Stroke Scale score improvement in the first 24-hour period, which were significantly greater than those of 25 patients without hyperperfusion (P = .033). Eight patients (22.9%) with intracerebral hemorrhage (ICH) were all asymptomatic. Most ICHs were located in hypoperfusion areas, and no ICH was related to hyperperfusion. The results of the present study demonstrated that hypoperfusion volume was associated with poor outcome, whereas the presence of hyperperfusion seemed to be predictive of symptom improvement but not of development of ICH. Taken together, early post-treatment SPECT imaging seems to be a useful biomarker of outcome in tPA-treated patients.

Clinicopathologic Study of Pineal Parenchymal Tumors of Intermediate Differentiation
Tamio Ito, Hiromi Kanno, Ken-ichi Sato, Mitsuteru Oikawa, Yoshimaru Ozaki, Hirohiko Nakamura, Shunsuke Terasaka, Hiroyuki Kobayashi, Kiyohiro Houkin, Kanako Hatanaka, Jyun-ichi Murata, Shinya Tanaka
WORLD NEUROSURGERY, 81, 5-6, 783, 789, ELSEVIER SCIENCE INC, 2014年05月, ［査読有り］
英語, 研究論文（学術雑誌）, OBJECTIVE: Pineal parenchymal tumors of intermediate differentiation (PPTID) are extremely rare tumor entities, and only limited data are available regarding their pathologic features and biologic behaviors. Because grading criteria of pineal parenchymal tumors (PPTs) have yet to be established, the treatment strategy and prognosis of PPTIDs remain controversial. We describe the clinicopathologic study of six patients with PPTID and compare responses for the treatment and prognosis with cases of pineocytoma (PC) and pine-oblastoma (PB). From this analysis, we attempt to clarify the treatment strategy for PPTIDs.
METHODS: This study included 15 patients with PPTs, consisting of 6 PCs, 6 PPTIDs, and 3 PBs. We focused on the 6 patients with PPTIDs. All PPTID cases were treated surgically, and radiotherapy and chemotherapy were administered as adjuvant therapies in some cases. We have earlier reported the histopathologic study (Neuropathology 32: 647-653, 2012). Briefly, we examined mitotic figures and necrosis by hematoxylin-eosin staining and immunohistochemical markers such as neuronal markers (synaptophysin, neurofilament (NF), and neuronal nuclear antigen), and an MIB-1 labeling index was determined.
RESULTS: In the PPTID cases, the extent of resection was variable and the recurrence rates among patients varied according to stage and treatment. All PC patients underwent total resection with no recurrence. All PB patients underwent resection and adjuvant therapy with radiotherapy and chemotherapy. There were no recurrences in patients with PC or PB. The results of histopathologic findings have been already reported as mentioned above. Briefly, the results indicated no mitotic figure or necrosis in any of the six cases of PPTID, but those features were observed in PB cases. All cases even including PC and PB were immunopositive for neuronal markers. The MIB-1 labeling index of PPTID was 3.5%, whereas it was 0% in PC and 10.5% in PB. CONCLUSIONS: Good radiosensitivity of PPTIDs was observed in our series. Because there are cases with discrepancies between images and pathologic findings, it is very difficult to determine the proper treatment strategy for PPTIDs. Proliferative potential was correlated with World Health Organization grade, although the immunoreactivity of neuronal markers did not correlate with the histologic grade.

Regression of dural arteriovenous fistulae after venous flow reconstructive surgery in a case with hemangiopericytoma at the confluence of sinuses.
Kota Kurisu, Hiroaki Motegi, Toshiya Osanai, Hiroyuki Kobayashi, Shunsuke Terasaka, Kiyohiro Houkin
Case reports in neurology, 6, 2, 207, 12, 2, 2014年05月, ［査読有り］, ［国際誌］
英語, BACKGROUND: The mechanism by which acquired dural arteriovenous fistula (dAVF) develops is still unclear. Few cases have been reported with both dAVF and intracranial tumors, and in these few cases the authors have proposed that induced venous hypertension may lead to the pathogenesis of dAVF. We experienced a case of intrasinusoidal hemangiopericytoma (HPC) with dAVF development. In addition to its rare pathology and tumor location, this case showed regression of dAVF immediately after tumor removal. CASE REPORT: The patient was a 23-year-old man who developed progressively worse headaches and papilledema. The HPC was located entirely inside the confluence of the sinuses (CoS) and resulted in venous sinus occlusion. Cerebral angiography demonstrated a dAVF located in the straight sinus, upstream of the occluded CoS, which was fed by the dural branch of the posterior cerebral artery. After the endovascular embolization of the tumor feeders, subsequent surgery included venous reconstruction in addition to tumor excision. Although the dAVF was not treated with an endovascular procedure or surgery, postoperative angiography revealed complete disappearance of the dAVF. CONCLUSION: We conclude that venous reconstructive surgery greatly contributed to the immediate regression of the dAVF. When planning the treatment strategy for such cases, it should be remembered that acquired dAVF may regress due to the normalization of venous hypertension.

Successful removal of a metastatic gastrointestinal stromal tumor in the craniovertebral junction using an occipital artery to posterior inferior cerebellar artery bypass
Yukitomo Ishi, Naoki Nakayama, Hiroyuki Kobayashi, Shigeru Yamaguchi, Shunsuke Terasaka, Kiyohiro Houkin
Case Reports in Neurology, 6, 2, 139, 143, S. Karger AG, 2014年04月16日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms arising from the gastrointestinal tract. The authors present a case of the successful removal of a metastatic GIST in the craniovertebral junction, using an occipital artery to posterior inferior cerebellar artery (OA-PICA) bypass. The patient is a 54-year-old male who underwent his first surgery for a small-bowel tumor at the age of 45 and was diagnosed with GIST. Nine years after his primary diagnosis, the patient suffered from severe neck pain. MRI demonstrated a large demarcated mass adjacent to the right atlas. The right vertebral artery (VA), completely engulfed by the tumor, showed a narrowing and ended in the PICA. Poor collateral blood supply in the right PICA territory was presumed. To prevent ischemic complications, an OA-PICA bypass was performed prior to the tumor resection. After the OA-PICA bypass, the tumor associated with the right VA was successfully removed, and the patient was discharged without any neurological deficits.

A case of cervical juxtafacet cyst with extensive rim enhancement on Gd-DTPA MRI
Toru Sasamori, Kazutoshi Hida, Kimio Anzai, Shunsuke Yano, Yasutaka Kato, Shinya Tanaka, Hisatoshi Saito, Kiyohiro Houkin
CLINICAL IMAGING, 38, 2, 199, 201, ELSEVIER SCIENCE INC, 2014年03月, ［査読有り］
英語, 研究論文（学術雑誌）, The authors reported a case of cervical juxtafacet cyst with extensive rim enhancement on gadolinium-diethylenetriamine pentaacid magnetic resonance imaging. Operative finding revealed the epidural space around the mass filled with abundant venous plexus. Histological examination demonstrated that cyst wall was composed of the well-vascularized fibrous connective tissue with some inflammatory changes. We speculate that extensive rim enhancement of juxtafacet cyst may be attributed not only to the chronic inflammatory changes of cyst wall, but to engorged venous plexus within the widened epidural space. (c) 2014 Elsevier Inc. All rights reserved.

Post-ischemic intra-arterial infusion of liposome-encapsulated hemoglobin can reduce ischemia
Daisuke Shimbo, Takeo Abumiya, Hideo Shichinohe, Naoki Nakayama, Ken Kazumata, Kiyohiro Houkin
BRAIN RESEARCH, 1554, 59, 66, ELSEVIER SCIENCE BV, 2014年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Despite successful revascularization, reperfusion after prolonged ischemia causes ischemia reperfusion (I/R) injury. Recruitment and activation of neutrophils is thought to be a key event causing I/R injury. We examined whether post-ischemic intra-arterial infusion of liposome-encapsulated hemoglobin (LEH), an artificial oxygen carrier without neutrophils, could reduce I/R injury in a rat transient middle cerebral artery occlusion (MCAO) model. Male Sprague-Dawley rats were subjected to 2-h MCAO and then were divided into three groups: (1) LEH group (n=7) infused with LEH (Hb concentration of 6 g/dl, 10 ml/kg/h) through the recanalized internal carotid artery for 2 h, (2) vehicle group (n=8) infused with saline (10 ml/kg/h) in the same manner as the LEH group, and (3) control group (n=9) subjected to recanalization only. After 24-h reperfusion, all rats were tested for neurological score and then sacrificed to examine infarct and edema volumes, myeloperoxidase (MPO) expression, matrix metalloproteinase-9 (MMP-9) expression and activity, and reactive oxygen species (ROS) production. Compared with the control group and the vehicle group, the LEH group showed a significantly better neurological score and significantly smaller infarct and edema volumes. MPO expression, MMP-9 expression and activity, and ROS production in the LEH group were also significantly lower than those in the control and vehicle groups. The results in the present study suggest that post-ischemic intra-arterial infusion of LEH can reduce I/R injury through reducing the effect of MMP-9, most likely produced by neutrophils. This therapeutic strategy may be a promising candidate to prevent I/R injury after thrombolysis and/or thromboectomy. (C) 2014 Elsevier B.V. All rights reserved.

Changing Treatment Strategy From Clipping to Radial Artery Graft Bypass and Parent Artery Sacrifice in Patients With Ruptured Blister-Like Internal Carotid Artery Aneurysms
Ken Kazumata, Naoki Nakayama, Toshitaka Nakamura, Hiroyasu Kamiyama, Shunsuke Terasaka, Kiyohiro Houkin
NEUROSURGERY, 10, 1, 66, 72, LIPPINCOTT WILLIAMS & WILKINS, 2014年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Blood blister-like aneurysms (BBAs) are aneurysms with ill-defined fragile necks arising from an internal carotid artery (ICA) and associated with high mortality.
OBJECTIVE: To describe strategies and outcomes in patients in whom radial artery (RA) graft bypass with ICA sacrifice was considered as the primary treatment during the acute phase of subarachnoid hemorrhage.
METHODS: The authors analyzed the clinical records of 20 patients who were treated between 2004 and 2011 at their hospital and affiliate institutions.
RESULTS: A majority of the patients were treated during the acute phase (< 24 hours, n = 15). A favorable outcome was achieved in 18 (90%) patients. The treatment strategies used were as follows: (1) ICA trapping/external carotid artery (ECA)-RA-middle cerebral artery (MCA) bypass (n = 13), (2) ICA trapping/superficial temporal artery-MCA bypass (n = 2), (3) aneurysm clipping with RA-MCA temporary bypass (n = 3), (3) aneurysm clipping with proximal ICA ligation and ECA-RA-MCA bypass (n = 1), and (4) direct clipping (n = 1). Postoperative infarction was observed in 6 patients and was ascribed to vasospasm (n = 1), retrograde thrombosis associated with trapping (n = 2), and reasons unrelated to the surgical procedures (n = 3).
CONCLUSION: Trapping with RA graft bypass demonstrated favorable results in patients with internal carotid BBAs. Although trapping/RA graft bypass is a definitive treatment for BBAs located proximal to the origin of the posterior communicating artery, some distal BBAs preclude ICA trapping to spare the perforating arteries.

Hemorrhagic onset of hemangioblastoma located in the dorsal medulla oblongata presenting with tako-tsubo cardiomyopathy and neurogenic pulmonary edema: A case report
Masayuki Gekka, Shigeru Yamaguchi, Ken Kazumata, Hiroyuki Kobayashi, Hiroaki Motegi, Shunsuke Terasaka, Kiyohiro Houkin
Case Reports in Neurology, 6, 1, 68, 73, S. Karger AG, 2014年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Here, we present a case of dorsal medulla oblongata hemangioblastoma with fourth ventricular hemorrhage. A 23-year-old female developed sudden consciousness disturbance, and CT revealed hemorrhage in all cerebral ventricles and a hyperdense mass in the cisterna magna. Although the reddish tumor located in the dorsal medulla oblongata was successfully removed, she suffered from severe tako-tsubo cardiomyopathy (TTC) and neurogenic pulmonary edema (NPE) because of baroreflex failure and damage to the solitary tract nuclei. After intensive care for 12 weeks following surgery, she was discharged without any neurological or radiological deficits. Pathogenesis of TTC/NPE is discussed in this paper. © 2014 S. Karger AG, Basel.

脊髄空洞症を合併した硬膜内くも膜嚢胞の1例
伊師雪友, 青山剛, 栗栖宏多, 飛騨一利, 寳金清博
Neurological Surgery, 42, 5, 467, 472, Igaku-Shoin Ltd, 2014年, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, An intradural arachnoid cyst is a relatively rare condition, occurring within the spinal subarachnoid space. We present the even-more rare case of an intradural arachnoid cyst associated with syringomyelia at the same spinal level. The patient was a 66-year-old man who presented with bilateral leg numbness and gait disturbance. Magnetic resonance imaging (MRI) revealed an intradural arachnoid cyst located dorsal to, and compressing, the thoracic spinal cord at the level of the 7th thoracic vertebra (Th 7). In addition, syringomyelia existed at the level of Th 8, slightly caudal to the intradural arachnoid cyst. We dissected the cyst but did not perform any surgical procedures for the syringomyelia. Post-operative MRI showed that the cyst had disappeared and the syringomyelia had spontaneously shrunk. The patient was discharged with improvement in his numbness and gait disturbance. There are a few case reports of intradural arachnoid cysts associated with syringomyelia, but recent evidence suggests that its occurrence is more common than previously thought. A combination of these two diseases is thought to be caused by blockage of cerebrospinal fluid (CSF) flow, which is also thought to cause adhesive arachnoiditis. For this reason, resection of the arachnoid cyst could improve the CSF flow and contribute to the shrinkage of syringomyelia. Furthermore, early treatment may correlate with improvement in radiological findings and neurological symptoms.

Clinical significance of STA-MCA double anastomosis for hemodynamic compromise in post-JET/COSS era
Satoshi Kuroda, Masahito Kawabori, Kenji Hirata, Tohru Shiga, Daina Kashiwazaki, Kiyohiro Houkin, Nagara Tamaki
ACTA NEUROCHIRURGICA, 156, 1, 77, 83, SPRINGER WIEN, 2014年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Even after the recent randomized clinical trials JET and COSS, it is still unclear that impaired cerebrovascular reactivity (CVR) to acetazolamide and oxygen extraction fraction (OEF) can identify the candidates for superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis. This prospective study was aimed to evaluate the benefits of STA-MCA "double" anastomosis on long-term outcome in patients with reduced cerebral blood flow (CBF) and CVR (Type 3 ischemia) and elevated OEF attributable to occlusive carotid diseases.
This study included 49 patients with reduced CBF and CVR on SPECT in the ipsilateral MCA area. Using O-15-gas PET, OEF was also measured in all patients. STA-MCA double anastomosis was recommended to the patients with Type 3 and elevated OEF. Those with Type 3 but normal OEF were medically treated.
Of 36 patients with Type 3 and elevated OEF, 25 consented to surgery. No perioperative morbidity or mortality were noted. The other 11 patients with Type 3 and elevated OEF were medically treated. Annual incidence of ipsilateral stroke was 0.7 % and 6.5 % in surgically and medically treated patients with Type 3 and elevated OEF, respectively (P = 0.0188). None of patients with Type 3 but normal OEF developed ipsilateral stroke during follow-up periods. STA-MCA "double" anastomosis significantly decreased OEF.
STA-MCA "double" anastomosis may still have the potential to reduce the risk of recurrent ipsilateral stroke in hemodynamically compromised patients. Further studies would be essential to advance diagnosis, surgical procedures, and perioperative managements to bring out maximal effects of bypass surgery.

Increased expression of vascular endothelial growth factor and its receptor in enlarging brain arteriovenous malformations - a case report
Daina Kashiwazaki, Rina Kobayashi, Kiyohiro Houkin, Satoshi Kuroda
BRITISH JOURNAL OF NEUROSURGERY, 28, 1, 119, 121, INFORMA HEALTHCARE, 2014年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Case. A 24-year-old man with Spetzler-Martin (S-M) Grade III arteriovenous malformation (AVM). He was conservatively treated, but AVM significantly increased in size over 5 years, judged as Grade IV. Subsequently, he developed intracerebral hemorrhage. AVM was totally removed. Immunohistochemistry showed that the endothelial cells in the dura and nidus were positive for VEGF and VEGF-R.

SPIOでラベリングした骨髄間質細胞,脳梗塞再生医療のソースとしての長期安全性
譚成博, 七戸秀夫, 寳金清博
再生医療, 13, 2014年

Platelet lysateで培養した骨髄間質細胞移植による脳梗塞再生医療
七戸秀夫, 寳金清博
血液事業, 36, 4, 2014年

脊髄硬膜動静脈瘻患者における痛みの質的評価
笹森徹, 関俊隆, 矢野俊介, 飛騨一利, 齋藤久壽, 寳金清博
日本脊髄外科学会プログラム・抄録集, 29th, 2014年

特発性脊髄空洞症の臨床像
伊師雪友, 関俊隆, 飛騨一利, 笹森徹, 寳金清博
日本脊髄外科学会プログラム・抄録集, 29th, 2014年

ピオクタニンを用いたperineural cystの1手術例
東海林菊太郎, 東海林菊太郎, 飛騨一利, 関俊隆, 矢野俊介, 寳金清博
日本脊髄外科学会プログラム・抄録集, 29th, 2014年

脊髄硬膜動静脈瘻患者における痛み,生活の質の調査
笹森徹, 関俊隆, 矢野俊介, 飛騨一利, 齋藤久壽, 寳金清博
日本脊髄外科学会プログラム・抄録集, 29th, 2014年

バイオイメージングを駆使した脳梗塞に対する再生医療
七戸秀夫, 寳金清博, 黒田敏
日本磁気共鳴医学会雑誌, 34, 2, 2014年

自家骨髄間質細胞移植による脳梗塞再生医療をめざして
七戸秀夫, 寳金清博
神経治療学, 31, 3, 2014年

自家骨髄細胞移植による脳梗塞再生医療をめざして:日本発の前臨床/臨床試験ガイドラインの必要性
七戸秀夫, 寳金清博
再生医療, 13, 2014年

脳梗塞に対する細胞治療,その神経保護効果について
七戸秀夫, 寳金清博, 黒田敏
日本脳循環代謝学会総会プログラム・抄録号, 26th, 2014年

SPIOでラベリングした他家骨髄間質細胞の脳内投与による安全性
譚成博, 七戸秀夫, 鐙谷武雄, 中山若樹, 数又研, 穂刈正昭, 浜内祝嗣, 寳金清博
日本脳循環代謝学会総会プログラム・抄録号, 26th, 2014年

新規医薬品・医療機器等の創出,難治性疾患の治療法の開発および最適な治療法の確立に関する研究 研究事業 1.新規培養法による自己骨髄間質細胞による脳梗塞の再生医療
寳金清博
新規医薬品・医療機器等の創出、難治性疾患の治療法の開発および最適な治療法の確立に関する研究 平成25年度 総括・分担研究報告書, 2014年

治療戦略を目指した研究 再生・移植基礎研究 脳虚血後の神経再生
七戸秀夫, 寳金清博
日本臨床, 72, 2014年

髄腔外転移を来した天幕上頭蓋内退形成性上衣腫の1症例
遠藤将吾, 寺坂俊介, 茂木洋晃, 寳金清博
小児の脳神経, 38, 6, 2014年

マウス局所脳虚血モデルに対する,シロスタゾールのROS産生抑制作用を介した脳保護効果
七戸秀夫, 鐙谷武雄, 中山若樹, 数又研, 穂刈正昭, 譚成博, 寳金清博, 黒田敏
日本脳循環代謝学会総会プログラム・抄録号, 26th, 2014年

Ivy sign, misery perfusion, and asymptomatic moyamoya disease: FLAIR imaging and 15O-gas positron emission tomography
Sandra Vuignier, Masaki Ito, Kota Kurisu, Ken Kazumata, Naoki Nakayama, Hideo Shichinohe, Tohru Shiga, Jozsef Zoltan Kiss, Nagara Tamaki, Kiyohiro Houkin
Acta Neurochirurgica, 155, 11, 2097, 2104, 11, 2013年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: The prevalence of ivy sign on fluid-attenuated inversion recovery (FLAIR) imaging in patients with asymptomatic moyamoya disease is unclear. The aim of this study was to clarify the incidence of ivy sign in these patients, as well as the correlation between MRI and 15O gas PET findings. Methods: A retrospective analysis including 16 consecutive patients with asymptomatic moyamoya disease enrolled between 2001 and 2010 in a single center. FLAIR imaging at the initial visit was categorized as ivy sign present, negative, or equivocal. Hemodynamic and metabolic parameters were quantified in 11 of 16 patients by 15O-gas positron emission tomography, and the relationship between ivy sign and 15O-gas PET parameters was analyzed. Cerebrovascular events within the follow-up period (54 ± 28 months) were also examined. Results: Five of 16 asymptomatic moyamoya patients (31.3 %) had positive ivy sign (6/30 hemispheres, 20 %). In 15O-gas PET examinations, 18 % of 22 hemispheres had elevated oxygen extraction fraction values that were significantly associated with positive ivy sign. Of these 16 asymptomatic moyamoya patients, six patients (37.5 %) underwent combined surgical revascularization. In this series, no patients experienced ischemic stroke, but one had intraventricular bleeding 1 year after surgery. Conclusions: Ivy sign on FLAIR imaging is still not rare in patients with moyamoya disease, even when asymptomatic. Although optimal management is still under debate, ivy sign may be an indicator of misery perfusion, and patients with asymptomatic moyamoya disease and ivy sign on FLAIR imaging will benefit from more careful follow-up. © 2013 Springer-Verlag Wien.

Usefulness of FMISO-PET for Glioma Analysis
Hiroyuki Kobayashi, Kenji Hirata, Shigeru Yamaguchi, Shunsuke Terasaka, Tohru Shiga, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 53, 11, 773, 778, JAPAN NEUROSURGICAL SOC, 2013年11月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Glioma is one of the most common brain tumors in adults. Its diagnosis and management have been determined by histological classifications. It is difficult to establish new paradigms because the pathology has matured and a great deal of knowledge has accumulated. On the other hand, we understand that there are limitations to this gold-standard because of the heterogeneity of glioma. Thus, it is necessary to find new criteria independent of conventional morphological diagnosis. Molecular imaging such as positron emission tomography (PET) is one of the most promising approaches to this challenge. PET provides live information of metabolism through the behavior of single molecules. The advantage of PET is that its noninvasive analysis does not require tissue sample, therefore examination can be performed repeatedly. This is very useful for capturing changes in the biological nature of tumor without biopsy. In the present clinical practice for glioma, F-18-fluorodeoxyglucose (FDG) PET is the most common tracer for predicting prognosis and differentiating other malignant brain tumors. Amino acid tracers such as C-11-methionine (MET) are the most useful for detecting distribution of glioma, including low-grade. Tracers to image hypoxia are under investigation for potential clinical use, and recently, F-18-fluoromisonidazole (FMISO) has been suggested as an effective tracer to distinguish glioblastoma multiforme from others.

Effective Surgical Revascularization Improves Cerebral Hemodynamics and Resolves Headache in Pediatric Moyamoya Disease
Masahito Kawabori, Satoshi Kuroda, Naoki Nakayama, Kenji Hirata, Toru Shiga, Kiyohiro Houkin, Nagara Tamaki
WORLD NEUROSURGERY, 80, 5, 612, 619, ELSEVIER SCIENCE INC, 2013年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Headache is one of the major clinical presentations in pediatric Moyamoya disease. However, the clinical features and underlying mechanisms are not fully understood. This study aimed to clarify the clinical feature of headache in pediatric Moyamoya disease and the effect of surgical revascularization.
METHODS: This study included 29 pediatric patients who underwent superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis and indirect bypass for Moyamoya disease. Their medical records were precisely evaluated to identify the clinical features of their headache. The findings on magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography also were analyzed.
RESULTS: Preoperative headache was documented in 11 (38%) of 29 patients. The majority of them complained of severe headache in the frontal or temporal region in the morning. Headache was significantly related to more advanced disease stage and to the decreases in cerebral blood flow and its reactivity to acetazolamide. Surgical revascularization completely resolved headache in all 11 patients.
CONCLUSIONS: These findings strongly suggest that disturbed cerebral hemodynamics may play key roles in developing severe headache in pediatric Moyamoya disease. STA-MCA anastomosis and encephalo-duro-myo-arterio-pericranial synangiosis may be effective procedures to rapidly resolve headache by widely supplying collateral blood flow to the operated hemispheres.

I-123-Iomazenil Single Photon Emission Computed Tomography Visualizes Recovery of Neuronal Integrity by Bone Marrow Stromal Cell Therapy in Rat Infarct Brain
Hisayasu Saito, Keiichi Magota, Songji Zhao, Naoki Kubo, Yuji Kuge, Hideo Shichinohe, Kiyohiro Houkin, Nagara Tamaki, Satoshi Kuroda
STROKE, 44, 10, 2869, 2874, LIPPINCOTT WILLIAMS & WILKINS, 2013年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose This study was aimed to assess whether I-123-iomazenil (IMZ) single photon emission computed tomography can serially monitor the effects of bone marrow stromal cell (BMSC) transplantation on neuronal integrity in infarct brain of rats.
Methods The BMSCs were harvested from green fluorescent protein-transgenic rats and were cultured. The rats were subjected to permanent middle cerebral artery occlusion. Their motor function was serially quantified throughout the experiments. The BMSCs or vehicle was stereotactically transplanted into the ipsilateral striatum at 7 days after the insult. Using small-animal single photon emission computed tomography/computed tomography apparatus, the I-123-IMZ uptake was serially measured at 6 and 35 days after the insult. Finally, fluorescence immunohistochemistry was performed to evaluate the distribution of engrafted cells and their phenotypes.
Results The distribution of I-123-IMZ was markedly decreased in the ipsilateral neocortex at 6 days postischemia. The vehicle-transplanted animals did not show a significant change at 35 days postischemia. However, BMSC transplantation significantly improved the distribution of I-123-IMZ in the peri-infarct neocortex as well as motor function. The engrafted BMSCs were densely distributed around cerebral infarct, and some of them expressed neuronal nuclear antigen and -aminobutyric acid type-A receptor.
Conclusions The present findings strongly suggest that the BMSCs may enhance functional recovery by improving the neuronal integrity in the peri-infarct area, when directly transplanted into the infarct brain at clinically relevant timing. I-123-IMZ single photon emission computed tomography may be a promising modality to scientifically prove the beneficial effects of BMSC transplantation on the host brain in clinical situation.

Long-term prognosis in patients with clipped unruptured cerebral aneurysmsaEuro center dot increased cerebrovascular events in patients with surgically treated unruptured aneurysms
Masaaki Hokari, Satoshi Kuroda, Naoki Nakayama, Kiyohiro Houkin, Tatsuya Ishikawa, Hiroyasu Kamiyama
NEUROSURGICAL REVIEW, 36, 4, 567, 571, SPRINGER, 2013年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We retrospectively investigated surgical immediate and long-term overall results after clipping of the unruptured aneurysms. Between 1991 and 2008, 166 patients underwent neck clipping of unruptured saccular aneurysms at our institute. Patients were subsequently followed to clarify the occurrence of subarachnoid hemorrhage (SAH), and stroke other than SAH, aneurysm recurrence, cerebrovascular death, all-cause death, and risk factors. Surgical complication was noted in 14 patients (8.4 %) and surgical morbidity in two patients (1.2 %). Of 164 patients except for these two patients who suffered surgical morbidity, we could obtain more than 3 years follow-up information for 144 patients (87.8 %). There were 49 men and 95 women. The mean age was 58.5 years, and mean follow-up period was 7.9 years. Eight cases had died during follow-up (hepatic insufficiency in one, renal insufficiency in one, suicide in one, intracerebral hemorrhage (ICH) in two, SAH in one, and pneumonia after stroke in two). Therefore, the cause of death was stroke and late effects of stroke. Twelve symptomatic cerebrovascular events (cerebral infarction in seven, ICH in four, and SAH in one) occurred in ten patients. Consequently, annual risk of SAH after clipping of unruptured aneurysms was 0.085 %. Besides, annual risk of stroke in those patients was 1.06 %, and this incidence was higher than that in the general population. Although this study confirmed the good surgical result, annual risk of stroke after clipping of unruptured aneurysms was much higher than that in the general population. The long-term periodic examination to detect recurrent aneurysms and appropriate management to prevent stroke should be performed for patients with surgically treated unruptured aneurysm.

Totally Ossified Metaplastic Spinal Meningioma
Chang Il Ju, Kazutoshi Hida, Tomohiro Yamauchi, Kiyohiro Houkin
JOURNAL OF KOREAN NEUROSURGICAL SOCIETY, 54, 3, 257, 260, KOREAN NEUROSURGICAL SOC, 2013年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, A 61-year-old woman with a very rare case of totally ossified large thoracic spinal metaplastic meningioma, showing progressing myelopathy is presented. Computed tomographic images showed a large totally ossfied intradural round mass occupying the spinal canal on T9-10 level. Magnetic resonance imaging revealed a large T9-10 intradural extramedullary mass that was hypointense to spinal cord on T1- and T2-weighted sequences, partial enhancement was apparent after Gadolinium administration. The spinal cord was severely compressed and displaced toward the right at the level of T9-10. Surgical removal of the tumor was successfully accomplished via the posterior midline approach and the histological diagnosis verified an ossified metaplastic meningioma. The clinical neurological symptoms of patient were improved postoperatively. In this article we discuss the surgical and pathological aspects of rare case of spinal totally ossified metaplastic meningioma.

Diagnosis of moyamoya disease on magnetic resonance imaging: are flow voids in the basal ganglia an essential criterion for definitive diagnosis?
Takeshi Mikami, Toshiya Sugino, Shunya Ohtaki, Kiyohiro Houkin, Nobuhiro Mikuni
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 22, 6, 862, 8, 2013年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Flow voids in the basal ganglia cannot always be recognized on magnetic resonance imaging, even in patients with typical moyamoya disease. In this report, flow voids in the basal ganglia and cisternal flow voids of the sylvian valley were evaluated in patients with moyamoya disease, and their diagnostic value was verified. A total of 41 consecutive patients with moyamoya disease were included in this analysis. The number of flow voids in the basal ganglia and the sylvian valley were counted on each side by 3 observers. Then the numbers of flow voids were compared between the patients with moyamoya disease and controls. The patients with moyamoya disease had a significantly higher mean number of flow voids in the basal ganglia and the sylvian valley (P < .0001); however, the number of flow voids in the basal ganglia was 0 or 1 in 69 sides (28.0%) in patients with moyamoya disease. Comparative analysis using the area under the receiver operating curve indicated that the evaluation of flow voids in the sylvian valley was significantly superior method to that in the basal ganglia (P < .0001). The cutoff value for the number of cisternal flow voids in the sylvian valley for the diagnosis of moyamoya disease was 6. Based on these findings, we recommend a definitive diagnosis of moyamoya disease should include assessment for abnormal vessels around the terminal portions of the internal carotid arteries.

Arterial Spin-Labeling Magnetic Resonance Imaging After Revascularization of Moyamoya Disease
Toshiya Sugino, Takeshi Mikami, Kei Miyata, Kengo Suzuki, Kiyohiro Houkin, Nobuhiro Mikuni
JOURNAL OF STROKE & CEREBROVASCULAR DISEASES, 22, 6, 811, 816, ELSEVIER SCIENCE BV, 2013年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Arterial spin labeling (ASL) magnetic resonance imaging (MRI) is a technique for depicting cerebral perfusion without contrast medium. The purpose of this study was to determine whether ASL can be used to detect hyperperfusion after revascularization for moyamoya disease as effectively as N-isopropyl-[123I]beta-iodoamphetamine (I-123-IMP) single-photon emission computed tomography (SPECT). Fifteen consecutive patients with moyamoya disease were included in the study. All patients underwent surgical revascularization. Postoperatively, regional cerebral blood flow (rCBF) was measured by flow-sensitive alternating inversion recovery (FAIR) ASL and I-123-IMP SPECT during the acute stage, and rCBF of the operative side was compared with the other side. The asymmetry ratio (AR) was then calculated from the rCBF as measured using each modality. The postoperative AR of ASL was moderately correlated with that of I-123-IMP SPECT (y = 0.180x 1 0.819; R = 0.80; P = .0003). In this series, 2 patients (13.3%) suffered symptomatic hyperperfusion after revascularization and accordingly exhibited increased AR of ASL. Our data indicate that early increases in rCBF in patients with hyperperfusion could be detected using FAIR ASL supplemental to I-123-IMP SPECT after revascularization. Our data indicate that FAIR ASL is a convenient method for evaluating hyperperfusion that can be performed repeatedly without the use of contrast medium or radioisotopes.

Assessment of moyamoya disease using multidetector row computed tomography.
Toshiya Sugino, Takeshi Mikami, Shunya Ohtaki, Tohru Hirano, Satoshi Iihoshi, Kiyohiro Houkin, Nobuhiro Mikuni
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 22, 5, 644, 9, 2013年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The recent introduction of multidetector row computed tomography (MDCT) scanners has enabled high-resolution 3-dimensional reconstruction. The purpose of this study was to establish a method to evaluate moyamoya disease using computed tomography angiography (CTA), specifically MDCT. Twenty-four patients (48 sides total) with moyamoya disease diagnosed by magnetic resonance angiography (MRA) were evaluated by means of CTA using MDCT by 3 independent observers, and the resulting 144 sides were analyzed. CTA and MRA were compared in terms of the steno-occlusive changes exhibited in each vessel. CTA and MRA scores were assigned on the basis of the severity of occlusive changes in the internal carotid artery, middle cerebral artery, anterior cerebral artery, and posterior cerebral artery. CTA scores were significantly correlated with MRA scores (P < .0001), and the 2 scores were in complete agreement in 57 sides (39.6%). The mean CTA score was significantly lower than the mean MRA score (P < .0001). Compared with CTA, MRA overestimated occlusion in 115 of the 576 vessels assessed. The mean MRA score was significantly higher in the overestimation group than in the good correlation group (P < .0001). CTA had a significantly higher rate of detection of moyamoya-affected vessels (P = .0001). Our data indicate that CTA using MDCT is a more reliable technique than MRA for diagnosing moyamoya disease. The ability to perform CTA quickly is a significant benefit for patients with moyamoya disease, particularly in pediatric and emergency cases.

A modified Essen stroke risk score for predicting recurrent cardiovascular events: development and validation
Shigeki Sumi, Hideki Origasa, Kiyohiro Houkin, Yasuo Terayama, Shinichiro Uchiyama, Hiroyuki Daida, Hiroshi Shigematsu, Shinya Goto, Kortaro Tanaka, Susumu Miyamoto, Kazuo Minematsu, Masayasu Matsumoto, Yasushi Okada, Motoki Sato, Norihiro Suzuki
INTERNATIONAL JOURNAL OF STROKE, 8, 4, 251, 257, WILEY-BLACKWELL, 2013年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background The Essen stroke risk score is widely applied to predict the risk of recurrent ischemic stroke. We developed a modified Essen stroke risk score and validated it using a large prospective Effective Vascular Event REduction after STroke (EVEREST) registry including 3588 patients with ischemic stroke in Japan. Patients with cardioembolic stroke were excluded, and follow-up was one-year. Methods The modified Essen stroke risk score was calculated from scores for waist circumference, stroke subtype by etiology, and gender in addition to age, hypertension, diabetes mellitus, previous myocardial infarction, other cardiovascular diseases except myocardial infarction and atrial fibrillation, peripheral artery disease, smoking, and previous stroke or transient ischemic attack. A multiple logistic regression model identified the predictors (each assigned one or two points) and provided c-statistics for the modified Essen stroke risk score. We considered two outcomes, recurrent ischemic stroke and cardiovascular events (defined as the combined outcomes of fatal or nonfatal stroke, myocardial infarction, nonfatal unstable angina, and cardiac death). Results Recurrent ischemic stroke occurred in 121 patients (37%) and cardiovascular events occurred in 133 (40%) within a year. The c-statistic (used for discrimination) was 0632 for recurrent stroke and 0640 for cardiovascular events. Patients scoring 6 or greater were classified as high risk, otherwise were classified as low risk. KaplanMeier analysis revealed that the modified risk score was more predictive than the Essen stroke risk score in both men and women. Conclusions The modified Essen stroke risk score increased the ability of the Essen stroke risk score to predict recurrent cardiovascular events. Patients with a high modified Essen stroke risk score should be candidates for intensified secondary prevention strategies.

Primary intracranial yolk sac tumor in the posterior fossa: Case report of a child with Down syndrome
Shogo Endo, Hiroyuki Kobayashi, Shunsuke Terasaka, Akihiro Iguchi, Yuko Cho, Junjiro Ohshirma, Kanako Kubota, Kiyohiro Houkin
CLINICAL NEUROLOGY AND NEUROSURGERY, 115, 6, 811, 813, ELSEVIER SCIENCE BV, 2013年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Reversible isolated accessory nerve palsy due to a large thrombosed vertebral aneurysm
Hisayasu Saito, Satoshi Kuroda, Shunsuke Terasaka, Takeshi Asano, Naoki Nakayama, Kiyohiro Houkin
Case Reports in Neurology, 5, 2, 135, 138, 2, 2013年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Objective: Isolated accessory nerve palsy due to intracranial disorders is uncommon because intracranial accessory nerve injury usually occurs in case of a skull base tumor or trauma, resulting in one of multiple cranial nerve palsies. We report a very rare case of isolated accessory nerve palsy due to a large thrombosed aneurysm of the intracranial vertebral artery. Full recovery was achieved after surgery. Case Report: A patient complaining of transient numbness in the right side was referred to our hospital. An MRI indicated a large thrombosed aneurysm of the right vertebral artery. The aneurysm severely compressed the medulla oblongata. First, the proximal vertebral artery (VA) was clipped with an aneurysm clip to reduce the pressure inside the aneurysm. However, cerebral angiography revealed a partial recanalization of the right VA. The patient then underwent coil embolization of the right VA just proximal to the aneurysm clip. Subsequently, the right VA was completely obliterated. The patient was discharged without any neurological deficit. Two weeks later, however, she complained of right shoulder pain. Physical and neurological examinations demonstrated atrophy of the right trapezius and sternocleidomastoid muscle, leading to a deepening of the right supraclavicular fossa. The symptoms were considered to result from the right isolated accessory nerve palsy. Follow-up MRI showed that the VA aneurysm gradually decreased in size over a period of several months. At the same time, her symptoms disappeared completely. Conclusion: We should keep in mind that isolated accessory nerve palsy can be caused by a large or giant vertebral aneurysm. © 2013 S. Karger AG, Basel.

Sarpogrelate Dilates Cerebral Arteries in the Absence of Exogenous Serotonin
Maiko Kawamura, Masanori Ishiguro, Takashi Nagamine, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 53, 5, 291, 298, JAPAN NEUROSURGICAL SOC, 2013年05月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Vasoconstriction of arteries induced by serotonin (5-hydroxytryptamine: 5-HT) is mediated by 5-HT2A and 5-HT1B receptors localized on smooth muscle. The present study investigated the impact of sarpogrelate, a 5-HT2A receptor antagonist, on cerebral artery diameter in the presence and absence of exogenous 5-HT. Diameter measurements were obtained in vitro from rabbit cerebral arteries pressurized to 60 mmHg. In the absence of 5-HT, arteries exhibiting pressure-induced myogenic tone dilated to sarpogrelate in a concentration-dependent manner (half maximal inhibitory concentration [IC50] approximate to 2.3 mu M). In a separate experimental series, exogenous application of 5-HT (0.01 mu M) caused further constriction of myogenically active arteries, decreasing cerebral artery diameter by an additional 25%. In the presence of 5-HT, sarpogrelate caused concentration-dependent vasodilation (IC50 approximate to 2.3 mu M) that was similar to that observed in the absence of exogenous 5-HT. Dilation induced by sarpogrelate was not affected by physical removal of the endothelium or inhibition of nitric oxide synthase with N omega-nitro L-arginine. The highest concentration of sarpogrelate (100 mu M) induced near maximal dilation, comparable to dilation induced by the L-type voltage-dependent calcium channel antagonist diltiazem. These findings suggest that in rabbit cerebral arteries, sarpogrelate has direct vasodilator effects on vascular smooth muscle.

Thoracolumbar intramedullary subependymoma with multiple cystic formation: a case report and review
Motoyuki Iwasaki, Kazutoshi Hida, Takeshi Aoyama, Kiyohiro Houkin
EUROPEAN SPINE JOURNAL, 22, S317, S320, SPRINGER, 2013年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background An intramedullary subependymoma is rare, particularly in the thoracolumbar region. Moreover, a radiographical obvious cystic formation of subependymoma of spinal cord rarely occurs in comparison to ependymoma.
Case report A 57-year-old woman presented with paraparesis. MRI revealed a multinodular and multicystic lesion in the spinal cord that was difficult to diagnose correctly. Intraoperative observation via midline myelotomy revealed a grayish, gelatinous solid mass with an eccentric localization. In addition, DREZtomy on the caudal side of the tumor revealed cystic formation. The cyst was punctured and xanthochromic fluid was collected. Attenuation of motor evoked potential (MEP) resulted in the partial removal of tumor. A pathological examination revealed the mass to be a subependymoma. The patient experienced transient worsening of symptoms, but improved gradually. No adjuvant radiosurgery was administered. Follow-up estimation 30 months after surgery revealed no evidences of regrowth.
Conclusions This report presents this rare case, a review of the literature associated with thoracolumbar subependymomas, and a discussion of the clinical and radiographical characteristics.

IDH1 mutation as a potential novel biomarker for distinguishing pseudoprogression from true progression in patients with glioblastoma treated with temozolomide and radiotherapy
Hiroaki Motegi, Yuuta Kamoshima, Shunsuke Terasaka, Hiroyuki Kobayashi, Shigeru Yamaguchi, Mishie Tanino, Junichi Murata, Kiyohiro Houkin
BRAIN TUMOR PATHOLOGY, 30, 2, 67, 72, SPRINGER JAPAN KK, 2013年04月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The purpose of this study was to distinguish pseudoprogression (PP) from early true progression in patients with glioblastoma (GBM) based on the presence of a mutation in isocitrate dehydrogenase 1 (IDH1). We retrospectively surveyed 32 patients with GBM or GBM with oligodendroglioma component (GBMO) who underwent biopsy or maximal tumor resection followed by concurrent radiotherapy and temozolomide (TMZ). We then selected patients with early radiological progression in magnetic resonance imaging within 6 months after concurrent radiotherapy and TMZ treatment. DNA was extracted from their tumor blocks. The IDH1 mutation was analyzed in the genomic region by direct sequencing as a biomarker for PP. Twenty-eight patients were diagnosed with GBM and four with GBMO. Eleven patients were discovered to have early radiological progression. PP was detected in two patients (6.3 %) diagnosed with GBMO and one patient with GBM. Both of the GBMO patients with PP had the IDH1 mutation, the one GBM patient with PP and the other eight patients with early true progression with wild type. The sensitivity and specificity of the IDH1 mutation for detecting PP were 66.7 and 100 %, respectively. This study suggests the IDH1 mutation may become a novel molecular biomarker for PP. Analyzing the IDH1 mutation, in the case of recognizing early radiological progression, may enable distinction of PP from early true progression, and we could determine the need for second-look surgery.

Primary rhabdoid tumor with low grade glioma component of the central nervous system in a young adult
Shogo Endo, Shunsuke Terasaka, Shigeru Yamaguchi, Hitoshi Ikeda, Tsutomu Kato, Hiroyuki Kobayashi, Shinya Tanaka, Kiyohiro Houkin
NEUROPATHOLOGY, 33, 2, 185, 191, WILEY-BLACKWELL, 2013年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, In the CNS, primary tumors with rhabdoid components are classified as atypical teratoid/rhabdoid tumor, rhabdoid meningioma or rhabdoid glioblastoma. The authors present a young adult patient with supratentorial rhabdoid tumor incidentally found after head trauma as a small pre-existing lesion in the parahippocampal gyrus. MRI demonstrated an area of hypointensity on T1-weighted images and hyperintensity on T2-weighted and fluid attenuated inversion recovery images. A serial MR scan revealed no change 3 months after the initial examination but drastic changes at 6 months. As the tumor and accompanying intratumoral hemorrhage enlarged rapidly, resection of the tumor was performed. Histopathology revealed that the main component of the tumor was typical rhabdoid cells with some necrotic areas. There were also pathological features consistent with oligoastrocytoma. The specimen had neither vascular proliferation usually seen in high-grade glioma nor the meningothelial pattern that suggests meningioma. Immunohistochemical findings revealed that cells were strongly positive for vimentin, epithelial membrane antigen and INI-1 antibody throughout the specimen. Further, monosomy 22 was detected by fluorescence in situ hybridization. The tumor was finally thought to be an unclassifiable primitive rhabdoid tumor with oligoastrocytoma that arose in the CNS. The patient died within 5 months of detection of the tumor, regardless of surgical resection, radiotherapy and chemotherapy.

Timing and cell dose determine therapeutic effects of bone marrow stromal cell transplantation in rat model of cerebral infarct
Masahito Kawabori, Satoshi Kuroda, Masaki Ito, Hideo Shichinohe, Kiyohiro Houkin, Yuji Kuge, Nagara Tamaki
NEUROPATHOLOGY, 33, 2, 140, 148, WILEY-BLACKWELL, 2013年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Stereotactic transplantation of bone marrow stromal cells (BMSCs) enables efficient delivery to the infarct brain. This study was aimed to assess its optimal timing and cell dose for ischemic stroke. The BMSCs were harvested from the green fluorescent protein-transgenic rats and were labeled with quantum dots. The BMSCs (1x105 or 1x106) were stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion at 1 or 4 weeks post-ischemia. Motor function was serially assessed. Using in vivo near infrared (NIR) fluorescence imaging, the engrafted BMSCs were visualized at 3 weeks post-transplantation. Immunohistochemistry was performed to evaluate their fate. Functional recovery was significantly enhanced when both low and high doses of BMSCs were transplanted at 1 week post-ischemia, but such therapeutic effects were observed only when the high-dose BMSCs were transplanted at 4 weeks post-ischemia. Both optical imaging and immunohistochemistry revealed their better engraftment in the peri-infarct area when the high-dose BMSCs were transplanted at 1 or 4 weeks post-ischemia. These findings strongly suggest the importance of timing and cell dose to yield therapeutic effects of BMSC transplantation for ischemic stroke. Earlier transplantation requires a smaller number of donor cells for beneficial effects.

Semiquantitative analysis of indocyanine green videoangiography for cortical perfusion assessment in superficial temporal artery to middle cerebral artery anastomosis
Haruto Uchino, Toshitaka Nakamura, Kiyohiro Houkin, Jun-ichi Murata, Hisatoshi Saito, Satoshi Kuroda
ACTA NEUROCHIRURGICA, 155, 4, 599, 605, SPRINGER WIEN, 2013年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Postoperative hyperperfusion may lead to severe neurological complications after superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis. However, there are no reliable modalities to predict the occurrence of postoperative hyperperfusion during surgery. The purpose of this study is to evaluate whether a semiquantitative analysis of indocyanine green (ICG) videoangiography could be useful in predicting postoperative hyperperfusion after STA-MCA anastomosis.
This study included seven patients who underwent STA-MCA anastomosis due to occlusive carotid artery diseases. During surgery, ICG videoangiography was performed before and after bypass procedures, and ICG intensity-time curves were semiquantitatively analyzed to evaluate hemodynamic changes by calculating maximum intensity, time to peak (TTP), and blood flow index (BFI).
Maximum intensity significantly increased from 252.6 +/- 132.5 to 351.7 +/- 151.9 after bypass (p < 0.001). TTP was significantly shortened from 12.9 +/- 4.4 s to 9.8 +/- 3.7 s (p < 0.001). Furthermore, BFI significantly increased from 33.9 +/- 28.1 to 74.6 +/- 88.4 (p < 0.05). Postoperative hyperperfusion was observed in five of seven patients 1 day after surgery. The ratio of BFI before and after bypass procedures was significantly higher in patients with postoperative hyperperfusion than those without, 2.5 +/- 1.1 and 1.5 +/- 0.4, respectively (p = 0.013).
These findings suggest that semiquantitative analysis of ICG videoangiography is helpful in predicting occurrence of hyperperfusion after STA-MCA anastomosis in patients with occlusive carotid artery diseases.

Microvascular decompression for hemifacial spasm associated with the vertebral artery.
Takeshi Mikami, Yoshihiro Minamida, Yukinori Akiyama, Masahiko Wanibuchi, Toshiya Sugino, Kiyohiro Houkin, Nobuhiro Mikuni
Neurosurgical review, 36, 2, 303, 8, 2013年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, In patients with vascular compression syndromes, the preoperative recognition of the cranial nerves and compressed vessels will contribute to improved surgical results. The aim of this study was to clarify the pathophysiology of hemifacial spasm (HFS) associated with the vertebral artery (VA) and to assess the value of preoperative imaging. Fifty-three consecutive patients with HFS underwent microvascular decompression (MVD). Of these, 18 cases of HFS were associated with the VA; this case series was compared with the remaining non-VA-associated HFS. For preoperative assessment, magnetic resonance imaging (MRI) was performed. Since January 2006, fusion imaging has been performed by combining MRI and computed tomography angiography. Of the 18 cases of VA-associated HFS, 17 (94.4 %) were on the left side; this was significantly higher than in the non-VA-associated HFS cases (p < 0.0001). The VA was attached to the root exit zone (REZ) directly in three cases. In the other 15 cases, the VA was compressing the REZ indirectly as a result of other intervening vessels. In all cases, preoperative imaging fully simulated the status of the REZ. The symptom disappeared in 17 cases (94.4 %) after MVD, and there was no significant difference in the surgical results between the VA-associated group and the non-VA-associated group (p = 0.9925). HFS associated with VA is not a rare condition. Preoperative recognition is thus important to the improvement of surgical results. Fusion imaging is useful to determine the status of the REZ, especially in indirect VA-associated HFS.

難治性慢性硬膜下血腫で再発した嗅神経芽細胞腫の一例
伊師 雪友, 寺坂 俊介, 茂木 洋晃, 栗栖 宏多, 小林 浩之, 寳金 清博, 山田 洋介, 畑中 佳奈子
北海道医学雑誌, 88, 2-3, 111, 111, 北海道医学会, 2013年04月, ［査読有り］
日本語

くも膜下出血と脳動脈瘤の最新情報 未破裂脳動脈瘤の治療適応と合併症
中山若樹, 寳金清博
Clin Neurosci, 31, 4, 408, 410, 2013年04月01日
日本語

骨髄間質細胞移植によるラクナ梗塞モデルの中枢神経再生
七戸秀夫, 黒田敏, 宮本倫行, 山内朋裕, 斎藤久泰, 新保大輔, 数又研, 中山若樹, 寶金清博
再生医療, 12, 237, 2013年02月28日
日本語

内頚動脈海綿静脈洞部巨大・大型動脈瘤の治療戦略
大瀧隼也, 三上毅, 飯星智史, 宮田圭, 野中雅, 寳金清博, 三國信啓
Neurological Surgery, 41, 2, 107, 115, 2, 2013年02月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, The treatment of a large-giant aneurysm in the cavernous portion of an internal carotid artery (ICA) requires occlusion of the ICA, with or without extracranial-intracranial (EC-IC) bypass surgery Although a balloon occlusion test (BOT) is used to determine the need for bypass surgery and select the bypass type, the criteria are not well established In this study, we retrospectively analyzed 10 consecutive patients (11 sides) with cavernous large and giant aneurysms treated during the past 8 years. Therapeutic strategies for each patient were selected according to the results of neurological and radiological examinations, and regional cerebral oxygen saturation A total of 6 high-flow bypasses were placed before ICA occlusions Three patients had STA-MCA bypasses before ICA occlusions, and two underwent endovascular ICA occlusion without bypass surgery. Favorable outcomes were obtained in all cases with respect to cranial nerve palsy, but one patient had insufficient ipsilateral cerebral blood flow postoperatively, and hemiparesis was revealed. An emergent STA-MCA bypass was performed in this case, which minimized the hemiparesis. Despite radiological evaluation during the BOT procedures, we had one false negative result. This indicates that the BOT requires increased sensitivity and specificity, and that a safety margin should be adopted when determining indications for bypass surgeries.

Long-term clinical and radiological results of endovascular internal trapping in vertebral artery dissection
Daina Kashiwazaki, Satoshi Ushikoshi, Takeshi Asano, Satoshi Kuroda, Kiyohiro Houkin
NEURORADIOLOGY, 55, 2, 201, 206, SPRINGER, 2013年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Previous reports have suggested that endovascular parent artery occlusion is an effective and safe procedure for the treatment of vertebral artery dissection (VAD). However, the results of long-term outcomes are still unclear. This study reviewed the clinical and imaging outcomes of patients with VAD treated by endovascular internal trapping.
A total of 73 patients were treated for VAD by endovascular internal trapping between March 1998 and March 2011. Patients were regularly followed up by magnetic resonance imaging, magnetic resonance angiography, and clinical examinations. Clinical outcomes were evaluated using the modified Rankin Scale.
Forty-five patients had ruptured VADs, and 28 had unruptured VADs. Clinical follow-up of at least 6 months data was obtained for 61 patients (83.6 %). The follow-up period ranged from 6 to 145 months (mean +/- SD, 55.6 +/- 8.9 months). Two patients with ruptured VADs had recurrence (2.74 %). Cranial nerve paresis (CNP) was observed in six patients (8.21 %), spinal cord infarction in two patients (2.74 %), and a perforating artery ischemia was diagnosed in seven patients (9.59 %); all patients with CNP and five of the patients with partial Wallenberg syndrome experienced only temporary symptoms; two of the patients with partial Wallenberg syndrome had permanent neurological deficits. Despite their symptoms, most patients were in good general condition, as shown by their clinical scores.
The results of this study have proven that endovascular internal trapping is a stable and durable treatment for closure of VADs. Recanalization is rather rare and occurred only in ruptured cases, both within 3 months after initial treatment without rupture. CNPs were observed in 8.21 %, perforating ischemia in 9.59 %, and spinal cord infarction in 2.74 %. The former two are temporary, while the last can be a factor that affects the modified Rankin Scale. Patients rated their quality of life as good, as corroborated by their posttreatment clinical score. Endovascular internal trapping for VAD is a therapy with a satisfactory long-term outcome.

Incidence, Locations, and Longitudinal Course of Silent Microbleeds in Moyamoya Disease A Prospective T2*-Weighted MRI Study
Satoshi Kuroda, Daina Kashiwazaki, Tatsuya Ishikawa, Naoki Nakayama, Kiyohiro Houkin
STROKE, 44, 2, 516, 518, LIPPINCOTT WILLIAMS & WILKINS, 2013年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose-Clinical significance of silent microbleeds is unknown in moyamoya disease. This study was aimed to clarify the incidence, locations, and longitudinal course.
Methods-This prospective cohort study included 78 nontreated patients with moyamoya disease. The incidence and locations of silent microbleeds were evaluated on T2*-weighted MRI. MR examinations were repeated every 6 or 12 months during a mean follow-up period of 43.1 months.
Results-T2*-weighted MRI identified silent microbleeds in 17 (29.3%) of 58 adult patients with moyamoya disease, but in none of 20 pediatric patients. During follow-up periods, de novo silent microbleeds developed in 4 (6.9%) of 58 adult patients. Hemorrhagic stroke occurred in 4 patients (6.9%), all of who had silent microbleeds on initial examination. The presence of silent microbleeds was a significant predictor for subsequent hemorrhagic stroke in adult moyamoya disease (P<0.001).
Conclusions-Careful and long-term follow-up of silent microbleeds would be essential to improve their outcome in adult patients with moyamoya disease. (Stroke. 2013;44:516-518.)

Post-ischemic Intra-arterial Infusion of Liposome-encapsulated Hemoglobin Can Reduce Ischemic Reperfusion Injury
Shimbo Daisuke, Abumiya Takeo, Shichinohe Hideo, Nakayama Naoki, Kazumata Ken, Houkin Kiyohiro, Ishizuka Takanobu
STROKE, 44, 2, 2013年02月, ［査読有り］

Predictors Of Effective Indirect Bypass In Adult Moyamoya Disease
Miyamoto Michiyuki, Kuroda Satoshi, Nakayama Naoki, Kazumata Ken, Houkin Kiyohiro
STROKE, 44, 2, 2013年02月, ［査読有り］

Impaired Cerebrovascular Reactivity to Acetazolamide in Parent Arterial Territory of Major Artery Aneurysms in Adult Patients with Moyamoya Disease
Ito Masaki, Houkin Kiyohiro, Niiya Yoshimasa, Uchino Haruto, Mabuchi Shoji, Nakayama Naoki, Kazumata Ken, Shichinohe Hideo, Sugiyama Taku, Ishii Nobuaki, Nomura Mikio
STROKE, 44, 2, 2013年02月, ［査読有り］

Bone marrow stromal cell transplantation enhances recovery of motor function after lacunar stroke in rats
Hideo Shichinohe, Tomohiro Yamauchi, Hisayasu Saito, Kiyohiro Houkin, Satoshi Kuroda
Acta Neurobiologiae Experimentalis, 73, 3, 354, 363, 3, 2013年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, This study was aimed to clarify if the bone marrow stromal cells (BMSCs) significantly improve functional outcome after lacunar stroke when stereotactically transplanted into the brain. Ouabain, a Na/K ATPase pump inhibitor, was stereotactically injected into the right striatum of Wistar rats. One week later, the superparamagnetic iron oxide (SPIO)-labeled rat BMSCs (n+AD0-7) or vehicle (n+AD0-8) were stereotactically transplanted into the left striatum. Using rotarod test, motor function was serially evaluated through the experiment. A 7.0-T MR apparatus was employed to serially monitor the migration of BMSCs in the host brain. Histological analysis was performed at 7 weeks after ouabain injection, i.e., 6 weeks after BMSC transplantation. Ouabain injection yielded the reproducible, focal lesion in the right striatum, causing continuous motor dysfunction throughout the experiment. BMSC transplantation significantly enhanced the recovery of motor function after ouabain injection. MR imaging demonstrated that the BMSCs aggressively migrated towards the lesion through the corpus callosum. Histological analysis supported the findings on MRI. The BMSCs significantly enhanced the neurogenesis in the subventricular zone (SVZ) on both sides. Some of them also expressed neuronal or astrocytic phenotypes in the neocortex, SVZ, corpus callosum, and peri-lesion area. These findings strongly suggest that the BMSCs may serve therapeutic impacts on lacunar stroke when stereotactically transplanted at clinically relevant timing. +ACY-copy+ADs. © 2013 by Polish Neuroscience Society - PTBUN, Nencki Institute of Experimental Biology.

Translational challenge for bone marrow stroma cell therapy after stroke
Satoshi Kuroda, Kiyohiro Houkin
Frontiers of Neurology and Neuroscience, 32, 62, 68, S. Karger AG, 2013年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, There is increasing evidence that the transplanted bone marrow stromal cells (BMSC) significantly promote functional recovery after central nervous system (CNS) damage in the animal models of various kinds of CNS disorders, including cerebral infarct. However, there remain several challenges before considering BMSC transplantation for patients with ischemic stroke. In this review, therefore, the authors discuss what should be clarified to establish cell transplantation therapy in the clinical setting and describe their scientific contributions in this matter. The BMSC have the ability to alter their gene expression profile and phenotype in response to the surrounding environment and to protect the neurons by producing certain neurotrophic factors. They also promote neurite extension and rebuild the neural circuits in the injured CNS. The BMSC can be expanded in vitro using the animal serum-free medium. Pharmacological modulation may accelerate the in vitro proliferation of the BMSC. Using in vivo optical imaging technique and MRI, the transplanted BMSC can noninvasively be tracked in the living animal for at least 8 weeks after transplantation. It is urgent to develop a clinical imaging technique to track the transplanted cells in the CNS and evaluate the therapeutic significance of BMSC transplantation in order to establish it as a definite therapeutic strategy in the clinical setting in the future.

Validity of Dual MRI and F-18-FDG PET Imaging in Predicting Vulnerable and Inflamed Carotid Plaque
Hisayasu Saito, Satoshi Kuroda, Kenji Hirata, Keiichi Magota, Tohru Shiga, Nagara Tamaki, Daisuke Yoshida, Satoshi Terae, Naoki Nakayama, Kiyohiro Houkin
CEREBROVASCULAR DISEASES, 35, 4, 370, 377, KARGER, 2013年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Vulnerable and inflamed plaques in the carotid artery are at high risk of ischemic stroke, suggesting the importance of diagnostic modalities to detect them in patients with carotid stenosis with high sensitivity and specificity. Although many investigators have reported that magnetic resonance imaging (MRI) is a useful tool to predict the vulnerable components of carotid plaque, its validity is not established. On the other hand, F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) may be an alternative modality to directly identify the inflamed plaque in carotid artery stenosis. Therefore, this study aimed at evaluating the validity of MRI and FDG-PET to predict vulnerable and inflamed carotid plaque. Methods: This prospective study totally included 25 patients who underwent carotid endarterectomy (CEA) for carotid artery stenosis at our institute between January 2009 and January 2012. Prior to CEA, FDG-PET, black-blood T1-weighted imaging (BB-T1WI), and 3-dimensional time-of-flight (TOF) imaging were performed. The specimens were stained with hematoxylin-eosin to assess the different plaque components (lipid, hemorrhage, calcification, and fibrous tissue). In addition, they were stained with primary antibodies against CD68 (activated macrophages) and matrix metalloproteinase (MMP)-9. Results: High FDG uptake was detected in 13 (52.0%) of 25 patients. All of them had lipid-rich plaque. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) to identify the lipid-rich plaques were all 100% for FDG-PET. More importantly, all of the FDG-positive plaques had strong immunoreactivity against both CD68 and MMP-9. There was a significant correlation between the findings on FDG-PET and those on immunohistochemistry against CD68 and MMP-9 (p = 0.006 and 0.004, respectively). On the other hand, 16 (64.0%) of 25 patients had high signal intensity plaque on BB-T1WI. In 7 of these 16 patients, the lesions also showed high signal intensity on TOF imaging. All of them had a large intraplaque hemorrhage. The sensitivity, specificity, PPV, and NPV to identify a large intraplaque hemorrhage were 70, 100, 100, and 83%, respectively, for MRI. Conclusions: These findings suggest that FDG-PET and MRI are complementary to predict high-risk carotid plaque, such as lipid-rich or hemorrhagic plaque. FDG-PET can accurately predict the lipid-rich and inflamed plaque. MRI is valuable to identify unstable plaque with a large intraplaque hemorrhage. The combination of these two modalities may play an important role in predicting carotid plaque at high risk of ischemic stroke. Copyright (C) 2013 S. Karger AG, Basel

Transformation from asymptomatic to symptomatic of lower cervical spinal dural arteriovenous fistula.
Toru Sasamori, Kazutoshi Hida, Takeshi Asano, Toshiya Osanai, Syunsuke Yano, Takeshi Aoyama, Yoshinobu Iwasaki, Kiyohiro Houkin
Neurologia medico-chirurgica, 53, 2, 103, 6, 2, 2013年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 60-year-old woman presented with a spinal dural arteriovenous fistula (SDAVF) located in the lower cervical region, which had been asymptomatic for 56 months after the initial detection. She underwent embolization of the SDAVF when she became symptomatic, but her neurological recovery was only partial. Cervical SDAVF is rare but sometimes discovered in an asymptomatic state. The natural history and validity of preventive treatment for asymptomatic SDAVF have not been fully established. Her unfavorable outcome demonstrates the potential advantages of adequate treatment at an early stage even for asymptomatic SDAVF.

Clinical features of patients bearing central nervous system hemangioblastoma in von Hippel-Lindau disease
Hiroshi Kanno, Jun-ichi Kuratsu, Ryo Nishikawa, Kazuhiko Mishima, Atushi Natsume, Toshihiko Wakabayashi, Kiyohiro Houkin, Shunsuke Terasaka, Taro Shuin
ACTA NEUROCHIRURGICA, 155, 1, 1, 7, SPRINGER WIEN, 2013年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Central nervous system (CNS) hemangioblastoma (HB) is one of the most common manifestations in von Hippel-Lindau disease (VHL), but large-scale studies on clinical features of CNS HB in VHL are scarce.
On the basis of the results of a questionnaire, we collected data of VHL patients with CNS HB.
The total number of CNS HBs in 111 VHL patients (male 59, female 52) was 264 with the following distributions: cerebellar, 65.4 %; brainstem, 9.9 %; spinal cord, 23.9 %; and pituitary, 1. 1 %. The follow-up period was 0.6 to 39.2 years, with the mean 12.5 years. Patients bearing brainstem or spinal cord HB also had another HB significantly more frequently than those bearing cerebellar HBs (P < 0.05). The mean onset age of CNS HB was 29.1 years, and that of patients bearing a single HB (mean 34.4 years) was significantly greater than that of multiple HBs (mean 25.7 years). Patients with multiple HBs under 40 years are more dominant than those with a single HB. The distribution rate of brainstem HB is significantly smaller in patients below 30 years than patients above 29 years. Although ECOG PS score increased along with number of operations, the onset age decreased with increasing number of operations. The mean ECOG PS score of patients below 20 years is significantly smaller than patients above 19 years.
When the onset age of CNS HB is under 40 years, and CNS HB is located at the brainstem or spinal cord HB, the probability of multiple occurrence can be predicted. Since patients with an onset age under 20 years old preserve a high performance status, early detection of CNS HB would be important. In addition, since a multiple operations aggravate performance status, number of operations should be reduced.

Bone marrow stromal cell transplantation enhances recovery of local glucose metabolism after cerebral infarction in rats: A serial 18F-FDG PET study
Michiyuki Miyamoto, Satoshi Kuroda, Songji Zhao, Keiichi Magota, Hideo Shichinohe, Kiyohiro Houkin, Yuji Kuge, Nagara Tamaki
Journal of Nuclear Medicine, 54, 1, 145, 150, 2013年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, This study aimed to assess whether 18F-FDG PET could serially monitor the beneficial effects of bone marrow stromal cells (BMSC) on cerebral glucose metabolism when transplanted into the infarct brain of rats. Methods: The BMSC from green fluorescent protein transgenic rats or vehicle was stereotactically transplanted into the ipsilateral striatum at 7 d after permanent middle cerebral artery occlusion of rats. Local glucose metabolism was semiquantitatively measured at 6 and 35 d after ischemia using 18F-FDG PET. Motor function was serially evaluated throughout the experiments. At 35 d after ischemia, immunohistochemistry was performed to evaluate the phenotype of BMSC and their effects on the expression of brain-type glucose transporters. Results: BMSC transplantation not only enhanced functional recovery but also promoted the recovery of glucose utilization in the periinfarct area when stereotactically transplanted at 1 wk after ischemia. The engrafted cells were widely distributed, and most expressed a neuron-specific protein, NeuN. BMSC transplantation also prevented the pathologic upregulation of glucose transporters in the periinfarct neocortex. Conclusion: The present findings strongly suggest that the BMSC may enhance functional recovery by promoting the recovery of local glucose metabolism in the periinfarct area when directly transplanted into the infarct brain at clinically relevant timing. The BMSC also inhibit the pathologic upregulation of brain-isoform glucose transporters type 1 and 3. 18F-FDG PET may be a valuable modality to scientifically prove the beneficial effects of BMSC transplantation on the host brain in clinical situations. COPYRIGHT © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

北海道版脳卒中地域連携クリティカルパス「脳卒中あんしん連携ノート」の施行状況
齊藤正樹, 板本孝治, 中村正弘, 三國信啓, 中川原譲二, 三浦哲嗣, 寳金清博, 深津恵美
北海道医報, 1134, 2013年

脊髄動静脈奇形と脊髄硬膜動静脈瘻における病態と外科治療
飛騨一利, 長内俊也, 青山剛, 矢野俊介, 関敏孝, 岩崎喜信, 寳金清博
脳神経外科ジャーナル, 22, Supplement, 2013年

Platelet lysateで培養した骨髄間質細胞移植による脳梗塞再生医療
七戸秀夫, 寳金清博
血液事業, 36, 2, 2013年

モヤモヤ病と脳循環代謝-Sense of Wonder-
寳金清博
脳循環代謝, 25, 1, 2013年

骨髄間質細胞移植による脳梗塞再生医療:治療機序の分子細胞レベルでの検討
七戸秀夫, 山内朋裕, 斎藤久泰, 寳金清博, 黒田敏
脳循環代謝, 25, 1, 2013年

自家骨髄間質細胞移植による脳梗塞再生医療をめざして
七戸秀夫, 寳金清博
神経治療学, 30, 5, 2013年

嗅神経芽細胞腫に対する治療成績と治療戦略
茂木洋晃, 寺坂俊介, 小林浩之, 本間明宏, 加納里志, 畠山博充, 水町貴諭, 福田諭, 寳金清博
日本脳腫瘍の外科学会プログラム・抄録集, 18th, 2013年

松果体部に生じた原発性横紋筋肉腫の一例
伊師雪友, 寺坂俊介, 山崎和義, 茂木洋晃, 小林浩之, 寳金清博, 井口晶裕, 長祐子, 大島淳二郎, 佐藤智信
日本脳腫瘍の外科学会プログラム・抄録集, 18th, 2013年

脳梗塞治療のための自己骨髄間質細胞移植
七戸秀夫, 寳金清博
週刊日本医事新報, 4663, 2013年

初期治療に難渋した未熟奇形腫の1例
寺坂俊介, 小林浩之, 茂木洋晃, 金子貞洋, 遠藤将吾, 寳金清博, 石津桂, 白土博樹
日本小児血液・がん学会雑誌, 50, 2, 2013年

5年の経過で髄腔外への転移を認めた退形成性上衣腫の1症例
遠藤将吾, 寺坂俊介, 金子貞洋, 小林浩之, 浅岡克行, 鴨嶋雄大, 山口秀, 茂木洋晃, 畑中佳奈子, 寳金清博
小児の脳神経, 38, 1, 2013年

Intraoperative Dual Monitoring During Carotid Endarterectomy Using Motor Evoked Potentials and Near-Infrared Spectroscopy
Haruto Uchino, Toshitaka Nakamura, Satoshi Kuroda, Kiyohiro Houkin, Jun-ichi Murata, Hisatoshi Saito
WORLD NEUROSURGERY, 78, 6, 651, 657, ELSEVIER SCIENCE INC, 2012年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Carotid endarterectomy (CEA) is a useful procedure to prevent subsequent ischemic stroke in patients with severe stenosis of internal carotid artery. However, lowering of morbidity is still essential to keep its clinical significance. This study aimed to evaluate the validity of dual monitoring using transcranial motor evoked potential (MEP) and near-infrared spectroscopy (NIRS) during CEA.
METHODS: Transcranial MEP and NIRS monitoring were conducted in 20 consecutive CEAs. MEP was recorded in the contralateral extremities. Regional cerebral saturation of oxygen (rSO(2)) was continuously measured in the ipsilateral forehead. The changes of MEP amplitudes and rSO(2) during cross-clamping of carotid artery were compared in each case.
RESULTS: The amplitudes of MEP significantly decreased when rSO(2) reduced to more than 20% during carotid clamping. There was a significant correlation between the changes of MEP amplitude and rSO(2) during carotid clamping in a quadratic manner (P < .001, r = 0.821). However, NIRS could not detect critical cerebral ischemia in 1 patient with cerebral infarction in the ipsilateral frontal lobe. On the other hand, MEP could not identify it in 1 patient with severe motor deficit. No perioperative complication occurred.
CONCLUSIONS: These findings strongly suggest that both MEP and NIRS can detect critical cerebral ischemia during CEA in most patients. Dual MEP and NIRS monitoring may further increase the sensitivity to identify it, being valuable to prevent perioperative complications due to cerebral ischemia during CEA.

Inadequate Communication Between Patients With Unruptured Cerebral Aneurysms and Neurosurgeons
Makoto Saito, Yoshimitsu Takahashi, Yayoi Yoshimura, Ayako Shima, Akio Morita, Kiyohiro Houkin, Takeo Nakayama, Kazuhiko Nozaki
NEUROLOGIA MEDICO-CHIRURGICA, 52, 12, 873, 877, JAPAN NEUROSURGICAL SOC, 2012年12月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Communication between patients with cerebral aneurysms and consulting neurosurgeons remains unstudied in Japan. The present clinical study surveyed patients with unruptured cerebral aneurysms and their neurosurgeons after explanation of the disease and its treatment options and expected outcomes in clinic visits using a one-page written questionnaire about treatment options and decisions given to patients and their neurosurgeons. The numbers of participating patients and neurosurgeons were 42 and 9, respectively, and 42 paired patient-neurosurgeon responses were obtained. Agreement was quite low (kappa = 0.17-0.31 for 6-point Likert scale and kappa = 0.44-0.67 for 2 category scale) regarding the "best" treatment for each patient as agreed on by the patient and neurosurgeon. Agreement in the understanding of treatment options and general application was unexpectedly low (kappa = 0.12 and 0.01 for 6-point Likert scale and kappa = not applicable and -0.03, respectively, for 2 category scale). Agreement tended to be higher between experienced neurosurgeons and patients than non-experienced neurosurgeons and patients. Patients estimated much higher risks of stroke or death after surgical intervention (p < 0.001) or no intervention (p = 0.006) compared with the estimates offered by their neurosurgeons.

Spontaneous Echo Contrast and Thrombus Formation at the Carotid Bifurcation After Carotid Endarterectomy
Masahito Kawabori, Tetsuyuki Yoshimoto, Masaki Ito, Shin Fujimoto, Taisei Mikami, Mutsuko Muraki, Sadao Kaneko, Naoki Nakayama, Satoshi Kuroda, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 52, 12, 885, 891, JAPAN NEUROSURGICAL SOC, 2012年12月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Spontaneous echo contrast (SEC) consists of numerous microechoes swirling in the cardiovascular lumen and is usually seen during blood stasis in dysfunctional left atrium. However, SEC and consecutive local thrombus formation at the carotid artery early after carotid endarterectomy (CEA) have not been reported. This study retrospectively investigated the clinical importance and therapeutic strategy of postoperative SEC and thrombus formation in 113 consecutive patients who underwent CEA between 2001 and 2009. Ultrasonography was routinely performed preoperatively, intraoperatively, and 1 day and 1 week after the operation. If SEC and/or thrombus was detected at any time after the operation, follow-up ultrasonography was performed at short intervals, once a week for inpatients and once every 1-2 months for outpatients. Eight of the 113 patients (7%) had SEC after the operation from Day 1 to 12 (mean 7.2 days), and 6 of these 8 patients developed local de novo thrombus formation at the site of SEC from Day 6 to 33 (mean 14.7 days). The maximum luminal narrowing by the thrombi were 26-62% (mean 37%). After administering anticoagulant therapy, all thrombi disappeared from Day 13 to 190 (mean 57 days) from CEA. SEC seen after CEA is highly associated with consecutive local thrombus formation. Postoperative geometric blood stasis with the absence of intima may be the causative factor for its development.

Experience of I-123-iomazenil SPECT study for crossed cerebellocerebral diaschisis: Report of two cases
Kota Kurisu, Masahito Kawabori, Yoshimasa Niiya, Yuzuru Ohta, Naoki Nakayama, Satoshi Kuroda, Shoji Mabuchi, Kiyohiro Houkin
CLINICAL NEUROLOGY AND NEUROSURGERY, 114, 9, 1274, 1276, ELSEVIER SCIENCE BV, 2012年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Bilateral Chronic Subdural Hematomas of the Posterior Fossae -Case Report-
Kota Kurisu, Masahito Kawabori, Yoshimasa Niiya, Yuzuru Ohta, Shoji Mabuchi, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 52, 11, 822, 825, JAPAN NEUROSURGICAL SOC, 2012年11月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, An 86-year-old female presented with rare bilateral chronic subdural hematomas (CSHs) of the posterior fossae which were successfully treated by surgical intervention. She had experienced mild head trauma one month before admission. She was transferred to our hospital because of consciousness disturbance and tetraparesis. Magnetic resonance (MR) imaging showed simultaneous occurrence of supratentorial and infratentorial CSHs. We tried to evacuate the CSHs of the bilateral posterior fossae because brainstem compression was markedly severe. Through bilateral burr-hole trepanations, chocolate-colored fluid, not containing clotted components, gushed out under great pressure. Postoperative course was uneventful. MR imaging revealed that the CSHs of the posterior fossae had completely disappeared and brainstem compression had also improved. The patient's neurological deficits were immediately improved after the operation. The patient was discharged one month after the operation for further rehabilitation. Trepanation and evacuation of the hematoma through the posterior fossa might be one of the therapeutic options for posterior fossa CSH, which is similar to supratentorial CSH. However, we considered that the emergency of this rare entity and the method of anesthesia were quite different from supratentorial CSH.

人工酸素運搬体Liposome-encapsulated hemoglobinを用いた虚血再灌流傷害の治療戦略
新保 大輔, 鐙谷 武雄, 七戸 秀夫, 中山 若樹, 数又 研, 宝金 清博, 石塚 隆伸
脳循環代謝, 24, 1, 178, 178, (一社)日本脳循環代謝学会, 2012年11月
日本語

Predictors and Clinical Features of Postoperative Hyperperfusion after Surgical Revascularization for Moyamoya Disease A Serial Single Photon Emission CT/Positron Emission Tomography Study
Haruto Uchino, Satoshi Kuroda, Kenji Hirata, Tohru Shiga, Kiyohiro Houkin, Nagara Tamaki
STROKE, 43, 10, 2610, 2616, LIPPINCOTT WILLIAMS & WILKINS, 2012年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose-Clinical features and pathophysiology of postoperative hyperperfusion in moyamoya disease are still unclear. This study was aimed to clarify the incidence and time course of postoperative hyperperfusion and to determine the independent predictors of postoperative hyperperfusion in moyamoya disease.
Methods-This prospective study included 41 patients who underwent surgical revascularization for moyamoya disease. Using O-15-gas positron emission tomography, hemodynamic and metabolic parameters were quantified before surgery. Using single photon emission computed tomography, cerebral blood flow was serially measured just after surgery and on 2 and 7 days postsurgery. A multivariate logistic regression analysis was conducted to test the effect of multiple variables on postoperative hyperperfusion.
Results-Postoperative hyperperfusion was observed in 29 (50.0%) of 58 operated hemispheres. The incidence of both radiological and symptomatic hyperperfusion was significantly higher in adult patients than in pediatric ones (P=0.026 and P=0.0037, respectively). Hyperperfusion just after surgery more often led to subsequent neurological deficits (P=0.033). A multivariate analysis revealed that preoperative cerebral blood volume increase was an independent predictor of both radiological and symptomatic hyperperfusion after surgery in adult moyamoya disease (OR, 6.6 and 12.3, respectively).
Conclusions-Postoperative hyperperfusion after surgical revascularization is not rare in moyamoya disease. Adult patients with a cerebral blood volume increase may be at high risk for radiological and symptomatic hyperperfusion after surgery. Careful perioperative management would reduce surgical complications and improve long-term outcome in moyamoya disease. (Stroke. 2012; 43:2610-2616.)

Transplanted bone marrow stromal cells protect neurovascular units and ameliorate brain damage in stroke-prone spontaneously hypertensive rats
Masaki Ito, Satoshi Kuroda, Taku Sugiyama, Katsuhiko Maruichi, Masahito Kawabori, Naoki Nakayama, Kiyohiro Houkin, Yoshinobu Iwasaki
NEUROPATHOLOGY, 32, 5, 522, 533, WILEY-BLACKWELL, 2012年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, This study was aimed to assess whether bone marrow stromal cells (BMSC) could ameliorate brain damage when transplanted into the brain of stroke-prone spontaneously hypertensive rats (SHR-SP). The BMSC or vehicle was stereotactically engrafted into the striatum of male SHR-SP at 8 weeks of age. Daily loading with 0.5% NaCl-containing water was started from 9 weeks. MRIs and histological analysis were performed at 11 and 12 weeks, respectively. Wistar-Kyoto rats were employed as the control. As a result, T2-weighted images demonstrated neither cerebral infarct nor intracerebral hemorrhage, but identified abnormal dilatation of the lateral ventricles in SHR-SP. HE staining demonstrated selective neuronal injury in their neocortices. Double fluorescence immunohistochemistry revealed that they had a decreased density of the collagen IV-positive microvessels and a decreased number of the microvessels with normal integrity between basement membrane and astrocyte end-feet. BMSC transplantation significantly ameliorated the ventricular dilatation and the breakdown of neurovascular integrity. These findings strongly suggest that long-lasting hypertension may primarily damage neurovascular integrity and neurons, leading to tissue atrophy and ventricular dilatation prior to the occurrence of cerebral stroke. The BMSC may ameliorate these damaging processes when directly transplanted into the brain, opening the possibility of prophylactic medicine to prevent microvascular and parenchymal-damaging processes in hypertensive patients at higher risk for cerebral stroke.

Hemorrhagic onset of rhabdoid meningioma after initiating treatment for infertility
Hiroaki Motegi, Hiroyuki Kobayashi, Shunsuke Terasaka, Nobuaki Ishii, Masaki Ito, Daisuke Shimbo, Kanako Kubota, Kiyohiro Houkin
BRAIN TUMOR PATHOLOGY, 29, 4, 240, 244, SPRINGER JAPAN KK, 2012年10月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Rhabdoid meningioma (RM) is a rare aggressive phenotype and is classified as a grade III neoplasm by the World Health Organization. A 29-year-old woman initiated treatment with clomiphene citrate for infertility. Two weeks later, she presented with acute headache and nausea. Brain computed tomography and magnetic resonance imaging demonstrated a tumor with hematoma in the left frontoparietal region. Surgical resection was performed, and the tumor was subtotally removed. The tumor was diagnosed as a rhabdoid meningioma (RM). Despite radiation and chemotherapy, she experienced regrowth and dissemination to the spinal cord. She died 11 months after onset of symptoms. Spontaneous hemorrhage is an unusual presentation of RM. In our case, infertility treatment may have triggered progression and bleeding because of an imbalance of sex hormones.

Systematic review of complications for proper informed consent (4) cerebrospinal fluid shunts for hydrocephalus and related disorders
Masaki Ito, Kiyohiro Houkin, Hisayasu Saito, Daisuke Shimbo, Hiroaki Motegi, Masahito Kawabori, Michiyuki Miyamoto, Tomohiro Yamauchi
Neurological Surgery, 40, 10, 923, 945, 10, 2012年10月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Cerebrospinal fluid (CSF) shunts are commonly employed to treat patients with hydrocephalus. A large number of papers have been published focusing on complications and failures of CSF shunts. However, there appears to be a paucity of knowledge comprehensively covering both common complications and rare ones. In this systematic review, we surveyed articles about surgical complications of CSF shunts as comprehensively as possible. Quantitative analysis was performed to determine the frequency of well-known complications, mortality and revision rates of CSF shunts. Furthermore, rare complications of CSF shunts have also been reviewed.

Hemophilic Pseudotumor of the Temporal Bone With Conductive Hearing Loss : Case Report
KASHIWAZAKI Daina, TERASAKA Shunsuke, KAMOSHIMA Yuuta, KUBOTA Kanako, ASANO Takeshi, HOUKIN Kiyohiro
Neurologia medico-chirurgica = 神経外科, 52, 10, 745, 747, 一般社団法人 日本脳神経外科学会, 2012年10月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 46-year-old man with factor VIII deficiency presented with a rare case of hemophilic pseudotumor in the temporal bone manifesting as severe conductive hearing loss and external ear bleeding. The pseudotumor expanded and destroyed the temporal bone and skin of the external ear over the course of 8 years. The pseudotumor was surgically excised, and the patient's symptoms improved. Histological examination of a specimen collected from inside the pseudotumor demonstrated blood products in various stages of evolution and showed that the outer membrane consisted of a collagen layer. Hemophilic pseudotumors are rare complications occurring in 1-2% of patients with mild or severe hemophilia. Pseudotumors are chronic, slowly expanding, encapsulated cystic masses, and most are located in the long bones and pelvis. The present case suggests that cranial pseudotumor should be considered in the differential diagnosis of cranial lesion in a patient with hemophilia.

Radiation induced intraparenchymal meningioma occurring 6 years after CNS germinoma: Case report
Yuuta Kamoshima, Shunsuke Terasaka, Hiroyuki Kobayashi, Sadahiro Kaneko, Kanako Kubota, Shinya Tanaka, Kiyohiro Houkin
CLINICAL NEUROLOGY AND NEUROSURGERY, 114, 7, 1077, 1080, ELSEVIER SCIENCE BV, 2012年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Favorable Outcome After Radical Resection and Subsequent Local Irradiation of Malignant Peripheral Nerve Sheath Tumor in the Cervical Spine
SASAMORI Toru, HIDA Kazutoshi, YANO Shunsuke, AOYAMA Takeshi, ASANO Takeshi, KUBOTA Kanako, ITO Manabu, ABUMI Kuniyoshi, IWASAKI Yoshinobu, SAITO Hisatoshi, HOUKIN Kiyohiro
Neurologia medico-chirurgica = 神経外科, 52, 9, 670, 674, 一般社団法人 日本脳神経外科学会, 2012年09月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 25-year-old man presented with malignant transformation to malignant peripheral nerve sheath tumor (MPNST) in the cervical spine associated with neurofibromatosis type 1. He presented with a 3-week history of rapidly increasing weakness and numbness in all four extremities. Magnetic resonance (MR) imaging of the cervical spine demonstrated a dumbbell-shaped tumor, which compressed the spinal cord at the C2-3 level. The tumor was excised, mainly within the spinal canal to decompress the spinal cord. The histological diagnosis was benign neurofibroma. Three months after surgery, he rapidly developed progressive tetraparesis and MR imaging revealed marked regrowth of an extradural mass into the spinal canal. At reoperation, the regrown mass in the spinal canal was totally excised. The histological diagnosis revealed MPNST. He underwent radiation therapy, with a total dose of 32 Gy, for approximately 3 weeks after the second surgery, but MR imaging showed tumor regrowth within the spinal canal, and his condition deteriorated. The decision was made to remove the tumor radically, including the involved facet and extradural lesion. Posterior fusion using a pedicle screw was performed one month later. He manifested no additional neurological deficits. He has been free of relapse for 46 months. Radical resection remains the most effective treatment for MPNST, although complete removal with a clear tumor margin is often impossible in practice.

[The Multi-detector-row CT angiography for diagnosis of spinal dural arteriovenous fistula].
Toshiya Osanai, Kazutoshi Hida, Takeshi Asano, Takeshi Aoyama, Kiyohiro Houkin
No shinkei geka. Neurological surgery, 40, 8, 695, 703, 8, 2012年08月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, PURPOSE: Multi-detector-row CT angiography (MDCTA) is useful for diagnosis of spinal arteriovenous (AV) shunt. So we reported the role and pitfall of MDCTA based on our experience. SUBJECTS: From January 2007 to September 2011, 57 cases used MDCTA in our institution. We investigated 22 case of spinal dural AVF and 5 cases of epidural AVF. METHODS: All cases were performed by Toshiba Aquilion 64. FOV was the whole spine, curved planar reconstruction along the spinal canal, sagittal and axial view obtained by multi-planar reconstruction. RESULTS: MDCTA detected dilated the perimedullary vein in all cases and identified the level of segmental artery matching the result of DSA in 16 cases of spinal dural AVF (73%) and 1 cases of epidural AVF (20%). CONCLUSION: MDCTA is useful for screening, and identifying the shunt point, but care needs to be taken concerning the particular pitfall of MDCTA.

Bilateral abducens nerve palsies in treated cases of subarachnoid hemorrhage
Hisayasu Saito, Naoki Nakayama, Shugo Takikawa, Satoshi Ushikoshi, Daisuke Shinbo, Satoshi Kuroda, Kiyohiro Houkin
Neurological Surgery, 40, 8, 717, 722, 8, 2012年08月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Isolated abducens nerve palsies associated with the rupture of intracranial aneurysms have rarely been reported. We report two cases of isolated bilateral abducens nerve palsies occurring after subarachnoid hemorrhage due to the rupture of an intracranial aneurysm. Case 1 : A 49-year-old woman had bilateral abducens nerve palsies following subarachnoid hemorrhage due to the rupture of the left vertebral artery-posterior inferior cerebellar artery aneurysm. Case 2: A 55-year-old man had bilateral abducens nerve palsies following subarachnoid hemorrhage due to dissecting aneurysm of the right vertebral artery. Case 1 and 2 were treated with surgical clipping of the aneurysm and internal occlusion of the parent artery. In both cases, bilateral abducens nerve palsies achieved almost full recovery several months after treatment. It is speculated that the main causes of palsies are compression and stretching of the bilateral abducens nerves by a thick clot in the prepontine cistern. Although most of the abducens palsies may be reversible and have good prognosis, it is important that they are kept in mind as isolated symptoms of subarachnoid hemorrhage.

Systematic review of complications for proper informed consent (3) surgery for unruptured middle cerebral artery aneurysm
Masahito Kawabori, Ken Kazumata, Kosuke Ohnishi, Taku Sugiyama, Masaki Itoh, Naoki Nakayama, Kiyohiro Houkin
Neurological Surgery, 40, 8, 731, 740, 8, 2012年08月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Although a large number of patients with unruptured middle cerebral artery (MCA) aneurysms (AN) have been treated by surgical clipping in Japan, there has yet been no comprehensive study investigating the surgical risks based on a quantitative evaluation of the extensive existing body of patient records. This systematic review was conducted to determine morbidity of the procedure by performing a meta-analysis of the literature. The authors used a PubMed and J-stage search from 2000 to 2011 for studies containing the surgical clipping of the unruptured MCA AN. There were 21 articles, containing a total 1.323 cases of unruptured AN with morbidity specifically located in the MCA. 54 cases indicated significant neurological deficits for a morbidity rate of 4.1% (95% CI
3.0-5.1). A limited number of studies disclosed an incremental increase in morbidity with the size of the aneurysm. Smaller MCA AN (7±3 mm) presented a lower morbidity of 1.48%. whereas giant MCA AN (>
25 mm) corresponded with a higher morbidity of 27.8%. Factors consistently associated with high morbidity included incorporated MCA branches, plaque at the neck of the AN, an unclippable configuration, and M1 superior wall AN. Complex aneurysms required a wide array of intracranial bypass procedures, yielding morbidity of 23.4% (95% CI
20.9-25.9). This is the first systematic review and quantitative meta-analysis of the surgical complications related to unruptured MCA AN.

Pituitary Apoplexy Manifesting as Massive Intracerebral Hemorrhage -Case Report-
Kota Kurisu, Masahito Kawabori, Yoshimasa Niiya, Yuzuru Ohta, Shoji Mabuchi, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 52, 8, 587, 590, JAPAN NEUROSURGICAL SOC, 2012年08月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 68-year-old man presented with severe conscious disturbance caused by pituitary apoplexy resulting in massive intracerebral hemorrhage (ICH). He had been periodically followed up for asymptomatic pituitary adenoma at another hospital for 8 years. Neuroimaging examination revealed pituitary apoplexy and massive ICH located in the left frontal lobe, and the ICH was directly connected to the intratumoral hemorrhage. The diagnosis was massive ICH from pituitary apoplexy. The patient underwent emergent evacuation of hematoma and removal of the pituitary adenoma via bi-frontal craniotomy. Postoperatively, he continued to exhibit deep consciousness disturbance and died 1 month after the operation. Pituitary apoplexy is usually characterized by intra-tumoral hemorrhage. The treatment strategy for asymptomatic pituitary adenoma is still controversial. This case shows that we should always consider the risk of pituitary apoplexy manifesting as ICH which may cause a fatal outcome.

[A novel adherent culture method of glioblastoma cells expressing CD133 using collagen-1-coated plates].
Motegi H, Kamoshima Y, Terasaka S, Kobayashi H, Houkin K
[Hokkaido igaku zasshi] The Hokkaido journal of medical science, 87, 4-5, 147, 151, 4-5, 2012年08月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, BACKGROUND AND AIMS: Glioblastoma is one of the most malignant brain tumors, causing death within two years despite maximal tumor resection and concurrent radio-chemotherapy. Tumor stem cells are thought to be closely related to tumor progression and recurrence and are attractive therapeutic targets. It is common to culture cell lines in serum-free medium with growth factors to stimulate spheres of enriched tumor stem cells. To avoid spontaneous differentiation and cell death in the sphere environment, Pollard et al. formulated an adherent culture method using laminin-coated plates. We here evaluated collagen-1-coated plates, which are superior to laminin-coated plates in handling and cost, as an alternative adherent culture method of CD133 expressing glioblastoma cells. MATERIALS AND METHODS: We cultured the human glioblastoma cell line, U87MG, under serum contained medium (SCM) or serum free medium with EGF, FGF2, LIF, B27 and N2 supplements (SFM) in non-coated, laminin or collagen-1-coated plates. The growth morphology in various cultures was evaluated, and the number of living cells in each plate on day 5 after cell seeding was calculated. The RNA expression level of CD133 as a stem cell marker in each plate was examined. Semi-quantitative measurement of CD133 positive cells by immunocytochemistry was performed. RESULTS: In collagen-1-coated plates with SFM, cell lines were cultured in an adherent monolayer. Cell proliferation was statistically encouraged in collagen-1-coated plates. Both laminin-coated plates and collagen-1-coated plates with SFM enhanced the RNA expression of CD133 compared to non-coated plates with SCM. Immunocytochemistry showed a statistically significant increase of CD133 positive cells in collagen-1-coated plates with SFM. CONCLUSION: Collagen-1-coated plates with SFM was used for cell morphology and cell proliferation of CD133 expression in the U87MG malignant glioma cell line.

クリッピング後長期間経過した後に再発した前交通動脈瘤とその臨床的意義
穂刈 正昭, 中山 若樹, 黒田 敏, 長内 俊也, 濱内 祝嗣, 遠藤 将吾, 宝金 清博
脳神経外科速報, 22, 8, 938, 942, (株)メディカ出版, 2012年08月
日本語, 46歳女。前交通動脈瘤破裂に対してクリッピング術を行い、術後の脳血管撮影でcomplete clippingを確認していたが、19年後に動脈瘤の再発を認めた。初回治療時には右A1-2 bifurcation typeの動脈瘤に対してpterional approachで前交通動脈(AcomA)に平行に過不足ないクリッピングが行われていたが、AcomA側に及んでいた壁の薄い部分(クリップブレード上側脇)から動脈瘤が再発し、前および上向きに伸展したと考えられた。両側前開頭interhemisphaericアプローチでクリッピング術を行い、以前のクリップを外すことなく母動脈に対して直交するかたちで余すことなくクリッピングできた。

Giant Calcified Thrombosed Varices Secondary to a Pial Arteriovenous Fistula Associated With Hereditary Hemorrhagic Telangiectasia -Case Report of Surgical Removal-
Taku Sugiyama, Naoki Nakayama, Shunsuke Terasaka, Satoshi Kuroda, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 52, 7, 506, 509, JAPAN NEUROSURGICAL SOC, 2012年07月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 28-year-old woman presented with an unusual case of giant thrombosed varix with calcified walls that had mass effects secondary to a pial single-channel arteriovenous fistula (AVF) associated with hereditary hemorrhagic telangiectasia (HHT). She consulted our hospital for chronic headache. She had been diagnosed with HHT based on genetic testing when her 3-year-old son presented with subarachnoid hemorrhage due to spinal AVF. Imaging studies revealed pial single-channel AVF with multiple varices. The varices in the right frontal lobe were over 6 cm in diameter and had laminar thromboses and calcified walls. Because of the mass effect, direct surgical flow disconnection was performed followed by removal of the varices using an internal decompression technique. Postoperatively, the patient was discharged with no neurological symptoms and no longer suffered chronic headache. Intracerebral varices are occasionally associated with high-flow AVF, and usually treated by interrupting the feeding arteries leaving the varices intact. This extremely rare case of intracerebral giant thrombosed varices with calcified wall and mass effect indicates that surgical removal of varices should be considered.

[The utility and efficacy of preoperative embolization for hypervascular tumor by NBCA].
Toshiya Osanai, Takeshi Asano, Shunsuke Terasaka, Kiyohiro Houkin
No shinkei geka. Neurological surgery, 40, 7, 599, 606, 7, 2012年07月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Preoperative embolization for hypervascular tumors is typically performed using particle agents such as polyvinyl alcohol, gelfoam powder, and fibrin glue. Furthermore, n-butyl-2-cyanoacrylate (NBCA) is used in patients with cerebral arteriovenous malformation (AVM) or an AV shunt. However, few reports have described the efficacy of NBCA in treating hypervascular tumors. Here, we report cases of hypervascular tumors in which preoperative embolization was performed using NBCA. We also discuss the difference between the efficacy of a liquid agent and a particle agent for hypervascular tumor embolization. We analyzed 10 cases encountered at our institution since 2004 in which preoperative embolization was performed using NBCA. In all cases, NBCA was injected through the tumor-feeding artery. In eight of these cases, preoperative embolization decreased intraoperative bleeding and markedly reduced the tumor stain. In the remaining two cases, complications occurred but without any permanent sequel. Thus, NBCA is useful for preoperative embolization.

Primary clear cell carcinoma of the skull base and paranasal cavity: A case report
Kengo Suzuki, Masahiko Wanibuchi, Yukinori Akiyama, Jun Ikeda, Yoshihiro Minamida, Tadashi Hasegawa, Kiyohiro Houkin, Nobuhiro Mikuni
Neurological Surgery, 40, 7, 617, 621, 7, 2012年07月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, We described a case of primary clear cell carcinoma (CCC) of the paranasal cavity and skull base. A 59-year-old female experienced chronic nasal obstruction and double vision. Computed tomography (CT) scan revealed a mass lesion of the paranasal cavity, reaching the skull base and intracranial zone. We performed a biopsy by endonasal endoscopic surgery and pathological examinations revealed the tumor was a clear cell carcinoma. No primary tumor was identified on evaluation of the whole body by CT scan and FDG-PET ( 18fluorodeoxy glucose positron emission tomography) scan, so we diagnosed a primary CCC of the paranasal cavity. We decided to use stereotactic radiation therapy. Neurologically, her diplopia was improved. The patient is well at 2 years of follow-up with no evidence of local enlargement. There are some reports about the metastatic sinonasal CCC, but there are few reports about primary nasal and sinonasal CCC. This is the fourth case report of primary nasal and sinonasal CCC.

[Treatment strategy of a patient who has multiple cerebral aneurysms caused by subarachnoid hemorrhage: possibility of coil embolization for aortic aneurysms].
Hokari M, Nagauchi T, Nakayama N, Hamauchi S, Ito Y, Shimoda Y, Houkin K
No shinkei geka. Neurological surgery, 40, 651, 655, 7, 2012年07月, ［査読有り］

[Treatment strategy of a patient with multiple cerebral aneurysms and subarachnoid hemorrhage: a case with both coil embolization suitable aneurysm and the unsuitable one].
Masaaki Hokari, Toshiya Osanai, Naoaki Nakayama, S Hamauchi, Yasuhiro Ito, Yusuke Shimoda, Kiyohiro Houkin
No shinkei geka. Neurological surgery, 40, 7, 651, 5, 2012年07月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）

【神経・筋疾患の病態と診断・治療(I)】脳動静脈奇形
中山 若樹, 宝金 清博
医学と薬学, 68, 1, 30, 40, (株)自然科学社, 2012年07月
日本語

A case of vein of galen aneurysmal malformation with a newly developed dural arteriovenous fistula after successful embolization
Takeshi Asano, Satoshi Kuroda, Kiyohiro Houkin, Daisuke Yoshida, Kazutoshi Cho, Hideaki Shiraishi, Shinji Saito
Neurological Surgery, 40, 6, 519, 525, 6, 2012年06月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, We report a case of vein of Galen aneurysmal malformation (VGAM) with a newly developed dural arteriovenous fistula (AVF) subsequent to successful embolization. A male neonate diagnosed as VGAM with prenatal ultrasonography and MRI presented severe cardiac and respiratory failure soon after birth. Five sessions of transarterial embolization using NBCA were performed during the first 6 months of his life. The shunt flow was effectively reduced and heart failure was resolved after the treatment. Follow-up angiography performed 2.5 years after the last embolization revealed complete obliteration of VGAM and newly developed small dural AVF on the wall of the thrombosed falcorial sinus. We believe that the dural AVF in this case was caused by local venous hypertension or induction of angiogenic factor during the thrombosing process of VGAM.

[Surgery for unruptured anterior cerebral artery aneurysms].
Sugiyama T, Houkin K, Ito M, Hokari M, Nakayama N, Kazumata K, Kuroda S
No shinkei geka. Neurological surgery, 40, 6, 555, 565, 6, 2012年06月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, In Japan, a large number of surgical treatments for unruptured intracranial aneurysms have been performed. On the other hands, it is known that surgical treatment for unruptured intracranial aneurysms is the most frequent source of lawsuits in the neurosurgical field. Neurosurgeons have the duty to disclose all risks and consequences of a proposed surgical procedure to each patient. Moreover, precise knowledge of surgical risks would be helpful in preventing complications from occurring. However, it is almost impossible that a single surgeon or an institute have experiences with all possible surgical complications because there is limitation of the number of surgery. In this review series, we attempted an exhaustive bibliographic survey of the possible surgical complications including exceptional ones, and then, determined the frequency of each complications as far as possible quantitatively. In this paper, we focused on the complications of surgical treatment for anterior cerebral artery aneurysms.

Intracerebral, but not intravenous, transplantation of bone marrow stromal cells enhances functional recovery in rat cerebral infarct: An optical imaging study
Masahito Kawabori, Satoshi Kuroda, Taku Sugiyama, Masaki Ito, Hideo Shichinohe, Kiyohiro Houkin, Yuji Kuge, Nagara Tamaki
NEUROPATHOLOGY, 32, 3, 217, 226, WILEY-BLACKWELL, 2012年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Recent studies have indicated that bone marrow stromal cells (BMSC) may improve neurological function when transplanted into an animal model of CNS disorders, including cerebral infarct. However, there are few studies that evaluate the therapeutic benefits of intracerebral and intravenous BMSC transplantation for cerebral infarct. This study was aimed to clarify the favorable route of cell delivery for cerebral infarct in rats. The rats were subjected to permanent middle cerebral artery occlusion. The BMSC were labeled with near infrared (NIR)-emitting quantum dots and were transplanted stereotactically (1 x 10(6) cells) or intravenously (3 x 10(6) cells) at 7 days after the insult. Using in vivo NIR fluorescence imaging technique, the behaviors of BMSC were serially visualized during 4 weeks after transplantation. Motor function was also assessed. Immunohistochemistry was performed to evaluate the fate of the engrafted BMSC. Intracerebral, but not intravenous, transplantation of BMSC significantly enhanced functional recovery. In vivo NIR fluorescence imaging could clearly visualize their migration toward the cerebral infarct during 4 weeks after transplantation in the intracerebral group, but not in the intravenous, group. The BMSC were widely distributed in the ischemic brain and some of them expressed neural cell markers in the intracerebral group, but not in the intravenous group. These findings strongly suggest that intravenous administration of BMSC has limited effectiveness at clinically relevant timing and intracerebral administration should be chosen for patients with ischemic stroke, although further studies would be warranted to establish the treatment protocol.

自家頭蓋分層骨と側頭部疎性輪紋状結合織遊離移植を併用した頭蓋形成術
鴨嶋雄大, 寺坂俊介, 小山明彦, 蕨雄大, 下田祐介, 寳金清博
Neurological Surgery, 40, 5, 407, 412, 5, 2012年05月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, We report a new simple method of cranial reconstruction using an autologous split calvarial bone, combined with free graft of temporal loose areolar tissue. A 58-year-old woman suffered from a cranium defect on her left side. The originating bone infection happened after initial brain tumor surgery. Part of the left side of her scalp just above the damaged cranial area had become very thin due to previous cranioplasty, which involved a titanium mesh plate and postoperative infections. We performed a cranial reconstruction with an autologous split calvarial bone, combined with loose areolar tissue free graft, for the damaged area with skin from the inner side. In our case, we expect that the addition of the free graft of loose areolar tissue to the autologous calvarial bone graft will effectively contribute to the skin's healing and provide good cosmetic results in our short follow-up period. A free graft of loose areolar tissue for the damaged skin area may be a new optional method for cranial reconstruction in a patient with skin trouble.

Review of Past Research and Current Concepts on the Etiology of Moyamoya Disease
Kiyohiro Houkin, Masaki Ito, Taku Sugiyama, Hideo Shichinohe, Naoki Nakayama, Ken Kazumata, Satoshi Kuroda
NEUROLOGIA MEDICO-CHIRURGICA, 52, 5, 267, 277, JAPAN NEUROSURGICAL SOC, 2012年05月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Research on moyamoya disease has progressed remarkably in the past several decades. Indeed, many new facts concerning the epidemiology of the disease have been revealed and surgical treatments have been drastically improved. However, despite extensive research, the mechanism of moyamoya disease is still unknown. Consequently, the cardinal treatment of this disease has not yet been developed. For further clarification of its etiology, innovative studies are therefore indispensable. The aim of this paper is to review research on the pathogenesis of moyamoya disease to identify milestones in the direction of its true solution. Many hypotheses of the pathogenesis of moyamoya disease have been proposed in the past half century, including infection (viral and bacterial), autoimmune disorders, proteins abnormality, and gene abnormality. Some of these are now considered to be historical achievements. Others, however, can be still subjected to contemporary research. Currently, several genetic abnormalities are considered to offer the most probable hypothesis. In addition, interesting papers have been presented on the role of the endothelial progenitor cell on the pathogenesis of moyamoya disease. Intuitively, however, it appears that a single theory cannot always explain the pathogenesis of this disease adequately. In other words, the complex mechanism of several factors may comprehensively explain the formation of moyamoya disease. The "double hit hypothesis" is probably the best explanation for the complicated pathology and epidemiology of this disease.

Bypass Surgery for Moyamoya Disease -Concept and Essence of Surgical Techniques
Satoshi Kuroda, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 52, 5, 287, 294, JAPAN NEUROSURGICAL SOC, 2012年05月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, This review describes the basic concepts of surgical revascularization for moyamoya disease, including direct and indirect bypass surgery. Direct bypass surgery can improve cerebral hemodynamics and reduce further ischemic events immediately after surgery, but may be technically challenging in some pediatric patients. Indirect bypass surgery is simple and has widely been used. However, its beneficial effects can be achieved 3 to 4 months after surgery, and surgical design is quite important to determine the extent of surgical collateral pathways. Combined bypass procedure, especially superficial temporal artery (STA) to middle cerebral artery anastomosis and indirect bypass, encephalo-duro-myo-arterio-pericranial synangiosis, is a safe and effective option to improve the short- and long-term outcome in patients with moyamoya disease. Alternative techniques are also described for specific cases with profound cerebral ischemia in the anterior cerebral artery or posterior cerebral artery territory. Special techniques to safely complete bypass surgery and avoid perioperative complications are presented, including methods to prevent delayed wound healing, to avoid facial nerve palsy after surgery, and to preserve the STA and middle meningeal artery during skin incision and craniotomy. Finally, the importance of careful management of patients is emphasized to reduce the incidence of perioperative complications, including ischemic stroke and hyperperfusion syndrome.

Transient Crossed Cerebellar Diaschisis Due to Cerebral Hyperperfusion Following Surgical Revascularization for Moyamoya Disease -Case Report
Masaaki Hokari, Satoshi Kuroda, Yusuke Simoda, Haruto Uchino, Kenji Hirata, Tohru Shiga, Naoki Nakayama, Kiyohiro Houkin, Nagara Tamaki
NEUROLOGIA MEDICO-CHIRURGICA, 52, 5, 350, 353, JAPAN NEUROSURGICAL SOC, 2012年05月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Crossed cerebellar diaschisis (CCD) often occurs after ischemic or hemorrhagic stroke that damages the cortico-ponto-cerebellar pathway. However, CCD due to cerebral hyperperfusion following cerebrovascular reconstruction is rare. A 61-year-old woman presented with transient CCD due to cerebral hyperperfusion following bypass surgery for adult moyamoya disease. She developed transient weakness of the right extremities and was diagnosed with moyamoya disease. First, she underwent superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis with indirect synangiosis on the left. Postoperative course was uneventful. Subsequently, she underwent STA-MCA anastomosis with indirect synangiosis on the right. She complained of mild headache on the right, and single photon emission computed tomography (SPECT) performed on the 7th postoperative day demonstrated hyperperfusion in the right frontal and temporal lobes associated with hypoperfusion in the left cerebellum. Magnetic resonance (MR) imaging demonstrated no new lesions and MR angiography showed patent STA-MCA bypass. Subsequent SPECT showed disappearance of both hyperperfusion and CCD. This case strongly suggests that cerebral hyperperfusion after bypass surgery for moyamoya disease may cause transient CCD. Although the clinical significance is still obscure, this phenomenon indicates the cortico-ponto-cerebellar pathway is interrupted due to hyperperfusion, suggesting the development of hyperperfusion syndrome. Careful observation of cerebral hemodynamics after bypass surgery is warranted to avoid hyperperfusion-related complications.

ヨード過敏症を有する右鎖骨下動脈閉塞症例に対してガドリニウム造影剤を用いてステント治療を行った1例
宮本倫行, 浅野剛, 長内俊也, 遠藤将吾, 中山若樹, 黒田敏, 寳金清博
Neurological Surgery, 40, 5, 415, 20, 5, 2012年05月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, The authors reported a subclavian artery stenting (SAS) using gadolinium contrast medium. The patient was a 65-year-old female who presented dizziness and right upper extremity pain with movement. Digital subtraction angiography revealed right subclavian artery occlusion with subclavian steal phenomenon. We tried to treat this lesion using SAS. However, iodinated contrast medium caused the allergy in this patient and the treatment was discontinued. Therefore, SAS was performed with gadolinium contrast medium. Using gadolinium contrast medium, it is possible to confirm large arteries like innominate artery and subclavian artery. The stenting procedure was performed without complication. The usage of gadolinium contrast medium has the limit and some strategies are important to reduce the usage of gadolinium contrast medium in SAS. First, PercuSurge GuardWire® was placed in the right internal carotid artery to confirm the anatomy, to decide working angle, and to treat the common carotid artery in case of dissection. Second, a "U" shaped guide wire was placed in the distal end from the brachial artery. Guide wire from femoral side was able to pass the lesion at midpoint of the "U" shaped one. SAS using gadolinium contrast medium may be an alternative treatment if a patient with subclavian artery stenosis or occlusion is allergic to iodinated contrast medium.

¹⁸F-Fluoromisonidazole positron emission tomography may differentiate glioblastoma multiforme from less malignant gliomas.
Hirata K, Terasaka S, Shiga T, Hattori N, Magota K, Kobayashi H, Yamaguchi S, Houkin K, Tanaka S, Kuge Y, Tamaki N
European journal of nuclear medicine and molecular imaging, 39, 5, 760, 770, 5, 2012年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Purpose Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor and its prognosis is significantly poorer than those of less malignant gliomas. Pathologically, necrosis is one of the most important characteristics that differentiate GBM from lower grade gliomas; therefore, we hypothesized that F-18 fluoromisonidazole (FMISO), a radiotracer for hypoxia imaging, accumulates in GBM but not in lower grade gliomas. We aimed to evaluate the diagnostic value of FMISO positron emission tomography (PET) for the differential diagnosis of GBM from lower grade gliomas.
Methods This prospective study included 23 patients with pathologically confirmed gliomas. All of the patients underwent FMISO PET and 18F-fluorodeoxyglucose (FDG) PET within a week. FMISO images were acquired 4 h after intravenous administration of 400 MBq of FMISO. Tracer uptake in the tumor was visually assessed. Lesion to normal tissue ratios and FMISO uptake volume were calculated. Results Of the 23 glioma patients, 14 were diagnosed as having GBM (grade IV glioma in the 2007 WHO classification), and the others were diagnosed as having non-GBM (5 grade III and 4 grade II). In visual assessment, all GBM patients showed FMISO uptake in the tumor greater than that in the surrounding brain tissues, whereas all the non-GBM patients showed FMISO uptake in the tumor equal to that in the surrounding brain tissues (p <= 0.001). One GBM patient was excluded from FDG PET study because of hyperglycemia. All GBM patients and three of the nine (33%) non-GBM patients showed FDG uptake greater than or equal to that in the gray matter. The sensitivity and specificity for diagnosing GBM were 100 and 100% for FMISO, and 100 and 66% for FDG, respectively. The lesion to cerebellum ratio of FMISO uptake was higher in GBM patients (2.74 +/- 0.60, range 1.71-3.81) than in non-GBM patients (1.22 +/- 0.06, range 1.09-1.29, p <= 0.001) with no overlap between the groups. The lesion to gray matter ratio of FDG was also higher in GBM patients (1.46 +/- 0.75, range 0.91-3.79) than in non-GBM patients (1.07 +/- 0.62, range 0.66-2.95, p <= 0.05); however, overlap of the ranges did not allow clear differentiation between GBM and non-GBM. The uptake volume of FMISO was larger in GBM ( 27.18 +/- 10.46%, range 14.02- 46.67%) than in non- GBM ( 6.07 +/- 2.50%, range 2.12- 9.22%, p <= 0.001).
Conclusion These preliminary data suggest that FMISO PET may distinguish GBM from lower grade gliomas.

One-Year Atherothrombotic Vascular Events Rates in Outpatients with Recent Non-Cardioembolic Ischemic Stroke: The EVEREST (Effective Vascular Event REduction after STroke) Registry
Norihiro Suzuki, Motoki Sato, Kiyohiro Houkin, Yasuo Terayama, Shinichiro Uchiyama, Hiroyuki Daida, Hiroshi Shigematsu, Shinya Goto, Kortaro Tanaka, Hideki Origasa, Susumu Miyamoto, Kazuo Minematsu, Masayasu Matsumoto, Yasushi Okada
JOURNAL OF STROKE & CEREBROVASCULAR DISEASES, 21, 4, 245, 253, ELSEVIER SCIENCE BV, 2012年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Patients with recent ischemic stroke may have higher risk of atherothrombosis than stable patients with established vascular events. Our aims were to investigate 1-year atherothrombotic vascular event rates and to assess the risk factors for recurrent ischemic stroke in this population. Methods: This prospective cohort study was conducted between January 2007 and July 2009 at 313 hospitals in Japan. Outpatients who were at least 45 years of age and who had received oral antiplatelet therapy were enrolled within 2 weeks to 6 months from the last onset of noncardioembolic ischemic stroke. At 12 +/- 3 months after enrollment, data on presence/absence of atherothrombotic vascular events were collected. The primary endpoint was the occurrence of fatal or nonfatal ischemic stroke. Results: A total of 3452 patients were enrolled, and 3411 patients who had baseline data were included in the analysis. The 1-year event rate was 3.81% (9.5% confidence interval 3.15-4.48%) for fatal or nonfatal ischemic stroke and 0.84% (95% confidence interval 0.52-1.15%) for all-cause mortality. The annual rate of recurrent ischemic stroke was significantly higher in patients who had ischemic stroke at least twice than in patients who had first-ever ischemic stroke (5.02% vs 3.59%; P = .0313). In the multivariable Cox regression analysis, recurrent ischemic stroke was significantly associated with age (P = .0033), the presence of diabetes (P = .0129), and waist circumference >= 80 cm (P = .0056). Conclusions: Patients with recent ischemic stroke have a higher risk of stroke recurrence than stable patients enrolled in the REduction of Atherothrombosis for Continued Health (REACH) registry even though they received antiplatelet therapy. The rigorous management of risk factors is needed.

Systematic review of complications for proper informed consent (1) surgery for unruptured internal carotid artery aneurysm
Kiyohiro Houkin, Masaki Ito, Michiyuki Miyamoto, Masaaki Hokari, Ken Kazumata, Naoki Nakayama, Satoshi Kuroda
Neurological Surgery, 40, 4, 365, 375, 4, 2012年04月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）

合併症のシステマティック・レビュー—適切なInformed Consentのために(1)未破裂内頚動脈瘤の外科治療
寳金清博, 伊東雅基, 宮本倫行, 穂刈正昭, 数又研, 中山若樹, 黒田敏
Neurol Surg, 40, 4, 365-375, 2012年04月10日
日本語

The Impact of Extent of Resection and Histological Subtype on the Outcome of Adult Patients with High-grade Gliomas
Shigeru Yamaguchi, Hiroyuki Kobayashi, Shunsuke Terasaka, Nobuaki Ishii, Jun Ikeda, Hiromi Kanno, Hiroshi Nishihara, Shinya Tanaka, Kiyohiro Houkin
JAPANESE JOURNAL OF CLINICAL ONCOLOGY, 42, 4, 270, 277, OXFORD UNIV PRESS, 2012年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We reviewed the relationship between extent of resection and survival of patients with high-grade gliomas with special consideration of an oligodendroglial component.A retrospective review was performed on 160 adult patients with histological diagnosis of high-grade gliomas since 2000. All histological slides were categorized as high-grade astrocytomas or oligodendroglial tumors. Extent of resection was assessed by early post-operative magnetic resonance imaging and classified as complete resection, incomplete resection and biopsy. Measured outcomes were overall survival and progression-free survival. The independent association of extent of resection and survival was analyzed by the multivariate proportional hazard model adjusting for prognostic factors.The lesions were classified as high-grade astrocytomas in 93 patients and high-grade oligodendroglial tumors in 67 patients. In high-grade astrocytomas, the median survival after complete resection (n 36), incomplete resection (n 36) and biopsy (n 21) was 23.4, 15.3 and 12.6 months, respectively. Complete resection was independently associated with increased overall survival (P 0.001) and progression-free survival (P 0.002) compared with incomplete resection, while incomplete resection was not associated with survival benefit compared with biopsy by multivariate analysis. On the other hand, in high-grade oligodendroglial tumors, the majority of patients were still alive and there is no significant difference in the survival between complete resection (n 24) and incomplete resection (n 33), while even incomplete resection had a significantly longer overall survival (P 0.001) and progression-free survival (P 0.006) compared with biopsy (n 10).Maximal cytoreduction improves the survival of high-grade gliomas, although our data indicated that the impact of extent of resection in high-grade astrocytomas is different from that in high-grade oligodendroglial tumors.

Impact of ageing on biological features of bone marrow stromal cells (BMSC) in cell transplantation therapy for CNS disorders: functional enhancement by granulocyte-colony stimulating factor (G-CSF).
Yasuhiro Chiba, Satoshi Kuroda, Toshiya Osanai, Hideo Shichinohe, Kiyohiro Houkin, Yoshinobu Iwasaki
Neuropathology : official journal of the Japanese Society of Neuropathology, 32, 2, 139, 48, 2, 2012年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, This study was designed to clarify the effects of donor age on biological features of bone marrow stromal cells (BMSC), one of the candidates for cell transplantation therapy for CNS disorders, because many aged patients might require such therapy. This study was also aimed to test whether ex vivo treatments with granulocyte-colony stimulating factor (G-CSF) could modify biological properties of BMSC from aged donors and enhance its therapeutic effects in an animal model of traumatic brain injury. The BMSC were harvested from young (6-week-old) and aged (100-week-old) rats. The ageing significantly increased the senescence-associated β-galactosidase (SA-β-gal) activity of the cultured BMSC, and decreased their proliferative capacity and production of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). As the next step, the rats were subjected to brain freezing injury by applying liquid nitrogen onto the neocortex through the thinned skull. The 6-week BMSC, 100-week BMSC, G-CSF-treated 100-week BMSC or vehicle were stereotactically injected into the ipsilateral striatum at 7 days post-injury. Transplantation of the 6-week BMSC, but not 100-week BMSC, significantly improved locomotor function. However, treatment of the 100-week BMSC with 0.1 µmol of G-CSF significantly improved their proliferation activity and growth factor production, and recovered therapeutic effects in the injured brain. In conclusion, donor age may largely determine biological aspects of BMSC. G-CSF may contribute to improve the outcome of BMSC transplantation therapy for CNS disorders in aged patients.

巨大延髄背側血管芽腫の1治療例
鴨嶋雄大, 寺坂俊介, 下田祐介, 小林浩之, 黒田敏, 浅野剛, 山口秀, 村田純一, 寳金清博
Neurological Surgery, 40, 3, 229, 234, 3, 2012年03月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Hemangioblastoma in the medulla oblongata is a relatively rare tumor. We present the case of a giant hemangioblastoma occurring in the dorsal medulla oblongata. A 33-year-old man with no neurological symptoms was diagnosed with a hemangioblastoma in the dorsal medulla oblongata, and opted for observation in the outpatient department. After 22 months of observation time, MRI scans showed rapid local tumor progression and obstructive hydrocephalus. At this point, he presented with mild dysphagia as a preoperative neurological deficit. Total surgical removal of the tumor was performed after temporary ventricle drainage and preoperative embolization of the feeding artery. Postoperatively, he became fully conscious but developed bulbar palsy followed by tracheostomy. During the 12 months of postoperative follow-up, severe dysphagia was still present.

くも膜下出血で発症した特発性内頚動脈海綿静脈洞瘻の1例
淺野剛, 寳金清博, 森脇拓也, 新谷好正, 馬渕正二
Neurological Surgery, 40, 3, 235, 239, 3, 2012年03月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, We report a case of longstanding asymptomatic direct carotid-cavemous fistula (CCF) which caused fatal subarachnoid hemorrhage (SAH). A 91-year-old female with no history of previous head trauma and optic symptoms presented acute subarachnoid hemorrhage. Angiography revealed a left direct carotid-cavernous fistula draining only into the contralateral cavernous sinus with leptomeningeal venous reflux and small varix on the pontine bridging vein. The affected cavernous sinus was markedly dilated and there was no septum between the left cavernous sinus and the internal carotid artery. The patient underwent transvenous coil embolization for intercavernous sinus and leptomeningeal venous reflux was successfully obliterated and opacification of the varix was diminished. The past history of this patient and angiographical findings strongly suggest long standing asymptomatic CCF caused SAH.

Early Diagnosis and Surgical Revascularization for a Predictive Case of Moyamoya Disease in a Boy Born to a Moyamoya Mother
Hongyan Han, Satoshi Kuroda, Yusuke Shimoda, Kiyohiro Houkin
JOURNAL OF CHILD NEUROLOGY, 27, 3, 408, 413, SAGE PUBLICATIONS INC, 2012年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Among patients with moyamoya disease, familial occurrence is observed in about 20%, suggesting the involvement of genetic factors. In this report, we describe the first predictive case of moyamoya disease in a boy born to a woman who underwent surgical revascularization for moyamoya disease when she was 3 years old. We educated the mother and her family not to miss his initial signs of the disease. His family could easily notice his brief episode of ischemic attack when he was 6 years old. He underwent superficial temporal artery-to-middle cerebral artery anastomosis and indirect bypass on both sides. The postoperative course was uneventful. In conclusion, it is quite important to educate the family not to miss the initial signs of disease in their offspring, at least when they have a genetic background of the disease, because early diagnosis and effective treatment are essential to improve the long-term outcome in pediatric patients.

甲状腺機能亢進症に合併した類もやもや病
三上 毅, 杉野 寿哉, 菅野 彩, 宝金 清博, 三國 信啓
脳卒中, 34, 2, 82, 88, (一社)日本脳卒中学会, 2012年03月
日本語, 著者らは2007年1月〜2010年12月にかけ甲状腺機能亢進症に併発した類もやもや病4例(男性2例、女性2例、年齢14〜43歳、平均年齢27.5歳)に対し血行再建術を行った。今回、その病態や治療方針について検討した結果、1)脳血管撮影所見やMRA所見では一定の傾向はみられなかった。2)手術は直接血行再建術と間接血行再建術が行われ、TIAは全例で消失し、1例で認められた舞踏病様の不随意運動も消失した。だが、1例では甲状腺機能の悪化みられた。

Visualization of the Superparamagnetic Iron Oxide (SPIO)-Labeled Bone Marrow Stromal Cells Using a 3.0-T MRI-a Pilot Study for Clinical Testing of Neurotransplantation
Hideo Shichinohe, Satoshi Kuroda, Kohsuke Kudo, Masaki Ito, Masahito Kawabori, Michiyuki Miyamoto, Mitsuhiro Nakanishi, Satoshi Terae, Kiyohiro Houkin
Translational Stroke Research, 3, 1, 99, 106, 2012年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Recent studies have elucidated that transplantation of the bone marrow stromal cells (BMSC) has therapeutic potential for the central nervous system (CNS) disorders. However, no imaging modalities have been established to track the engrafted cells in the CNS in clinical situation. This study aimed to investigate the ability of magnetic resonance imaging (MRI) to visualize the BMSC labeled with superparamagnetic iron oxide (SPIO). The BMSC of mice were labeled with SPIO. Various numbers of the cells were injected into the agar phantom and were visualized using a 3. 0-T MR apparatus. The SPIO-labeled cells were injected into the temperature-sensitive gelation polymer (TGP) hydrogel and were cultured for 7 days. They were also visualized just after the injection and at 7 days postinjection. After a 7-day culture, they were stained with Turnbull blue technique. T2-, T2*-, and susceptibility-weighted imaging could identify minimally 1,000 cells in the agar or TGP hydrogel, although it was difficult to quantify their number on MRI. All of these sequences could track the SPIO-labeled BMSC for at least 7 days when injected into the TGP. Turnbull blue staining revealed the survival and proliferation of the SPIO-labeled BMSC in the TGP for 7 days. The findings strongly suggest that the SPIO labeling may enable to track minimally 1,000 cells engrafted in the CNS on clinical MR apparatus. These data would be valuable to consider the application of imaging technique into cell transplantation therapy for CNS disorders. © 2011 Springer Science+Business Media, LLC.

膠芽腫患者長期生存5例の検討-特にIDH1遺伝子変異,MGMT遺伝子プロモーターメチル化に関して
鴨嶋雄大, 茂木洋晃, 寺坂俊介, 小林浩之, 山口秀, 村田純一, 田中伸哉, 寳金清博
Neurological Surgery, 40, 2, 129, 135, 2, 2012年02月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with an extremely poor prognosis in spite of multimodal treatment approaches. The median survival time of patients with GBM is 15 months, and only 3-5% of patients survive longer than 36 months. Those patients who survive over 36 months after the initial diagnosis are defined as long-term survivors. In this study, we retrospectively performed clinical and molecular analyses of five long-term survivors of GBM (>
36 months) and twenty four GBM patients with poor survival time as control group (<
36 months) to identify any prognostic factors that potentially contribute to survival. The O 6- methylguanine-DNA methyltransferase (MGMT) gene methylation status was evaluated by performing methylation specific polymerase chain reaction assays. The mutation of isocitrate dehydrogenase 1 and 2 were evaluated by the direct sequencing method. All five cases were primary GBMs and the coexistence of the oligodendroglioma component was checked for each case as GBM with oligodendroglioma component. All five cases showed MGMT promoter methylation (5/5). IDH1 mutation was detected in two of the long-term survivors with oligodendroglioma component (2/5) while no IDH1 mutation was detected in the control group. All patients were treated by gross total removal followed by radiotherapy and various chemotherapies including temozolomide. MGMT promoter methylation and IDH1 mutation might be favorable factors for long-term survival in GBM patients.

Reoxygenation of Glioblastoma Multiforme Treated with Fractionated Radiotherapy Concomitant with Temozolomide: Changes Defined by F-18-fluoromisonidazole Positron Emission Tomography: Two Case Reports
Takuhito Narita, Hidefumi Aoyama, Kenji Hirata, Shunsuke Onodera, Tohru Shiga, Hiroyuki Kobayashi, Junichi Murata, Shunsuke Terasaka, Shinya Tanaka, Kiyohiro Houkin
JAPANESE JOURNAL OF CLINICAL ONCOLOGY, 42, 2, 120, 123, OXFORD UNIV PRESS, 2012年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Two glioblastoma multiforme patients underwent F-18-FMISO (fluoromisonidazole) positron emission tomography study to access the tumor oxygenation status before and immediately after fractionated radiotherapy concomitant with temozolomide chemotherapy. In both cases, a prominent F-18-FMISO tumor accumulation observed in the first study was notably decreased in the second study, which was supposed to be a reoxygenation of the tumor. As far as we investigated, this is the first report of the changes of oxygenation status in glioblastoma multiforme treated through radiation therapy with temozolomide.

Therapeutic effects of intra-arterial delivery of bone marrow stromal cells in traumatic brain injury of rats--in vivo cell tracking study by near-infrared fluorescence imaging.
Toshiya Osanai, Satoshi Kuroda, Taku Sugiyama, Masahito Kawabori, Masaki Ito, Hideo Shichinohe, Yuji Kuge, Kiyohiro Houkin, Nagara Tamaki, Yoshinobu Iwasaki
Neurosurgery, 70, 2, 435, 44, 2, 2012年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: A noninvasive and effective route of cell delivery should be established to yield maximal therapeutic effects for central nervous system (CNS) disorders. OBJECTIVE: To elucidate whether intra-arterial delivery of bone marrow stromal cells (BMSCs) significantly promotes functional recovery in traumatic brain injury (TBI) in rats. METHODS: Rat BMSCs were transplanted through the ipsilateral internal carotid artery 7 days after the onset of cortical freezing injury. The BMSCs were labeled with fluorescent dye, and in vivo optical imaging was employed to monitor the behaviors of cells for 4 weeks after transplantation. Motor function was assessed for 4 weeks, and the transplanted BMSCs were examined using immunohistochemistry. RESULTS: In vivo optical imaging and histologic analysis clearly demonstrated that the intra-arterially injected BMSCs were engrafted during the first pass without systemic circulation, and the transplanted BMSCs started to migrate from the cerebral capillary bed to the injured CNS tissue within 3 hours. Intra-arterial BMSC transplantation significantly promoted functional recovery after cortical freezing injury. A subgroup of BMSCs expressed the phenotypes of neurons, astrocytes, and endothelial cells around the injured neocortex 4 weeks after transplantation. CONCLUSION: Intra-arterial transplantation may be a valuable option for prompt, noninvasive delivery of BMSCs to the injured CNS tissue, enhancing functional recovery after TBI. In vivo optical imaging may provide important information on the intracerebral behaviors of donor cells by noninvasive, serial visualization.

Giant frontal mucocele occurring 32 years after frontal bone fracture: A case report
Yuuta Kamoshima, Shunsuke Terasaka, Yuji Nakamaru, Dai Takagi, Satoshi Fukuda, Kiyohiro Houkin
Case Reports in Neurology, 4, 1, 34, 37, 1, 2012年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Giant mucoceles of the frontal sinus are rare but their recognition is important in the differential diagnosis of proptosis and fronto-orbital lesions. The authors describe a patient with frontal giant mucocele with intracranial as well as orbit and ethmoid sinus involvement. Thirty-two years after a frontal sinus fracture, a 51-year-old female presented with headache, and left exophthalmos and ophthalmoplegia. Computed tomography and magnetic resonance imaging demonstrated a giant frontal sinus mucocele with extension into the left anterior cranial fossa. The mucocele was treated with a transcranial and endoscopic transnasal approach. The frontal sinus was then cranialized with reconstruction of the posterior wall, and finally a wide nasal drainage was performed. The clinical symptoms disappeared immediately after surgery. Copyright © 2012 S. Karger AG, Basel.

Neurohypophyseal germinoma with abundant fibrous tissue
Shunsuke Terasaka, Masahito Kawabori, Hiroyuki Kobayashi, Junichi Murata, Hiromi Kanno, Shinya Tanaka, Kiyohiro Houkin
BRAIN TUMOR PATHOLOGY, 29, 1, 58, 62, SPRINGER TOKYO, 2012年01月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, We report an unusual case of neurohypophyseal germinoma with abundant fibrous tissue and clival invasion that was initially misdiagnosed as lymphocytic hypophysitis. A 40-year-old woman presented with diabetes insipidus and panhypopituitarism after delivering her second son and which lasted for 4 years. Magnetic resonance imaging showed the intrasellar mass extending to the suprasellar region with enlarged pituitary stalk. The mass was heterogeneously enhanced and invaded the clivus. Biopsy of the intrasellar mass was performed via the trans-sphenoidal route, and histological examination revealed marked fibrous tissue and infiltration of lymphocytes, with no evidence of tumor cells. Lymphocytic hypophysitis was the initial diagnosis, and corticosteroid therapy was begun. Despite intensive treatment, the lesion enlarged and clinical symptoms worsened 2 weeks after surgery. Subtotal removal of the mass was performed, and a second histological examination revealed typical findings of the germinoma. Subsequently, the patient underwent chemoradiotherapy, and complete remission was achieved. Histological diagnosis is sometimes incorrect in fibrous tumors at the sellar region, and biopsy from several points is strongly recommended for this entity.

Cerebrovascular Accident in Patients with Ventricular Assist Device
Shimoda Yusuke, Nakayama Naoki, Hokari Masaaki, Shitinohe Hideo, Kuroda Satoshi, Hokin Kiyohiro, Sakakibara Mamoru, Tsutsui Hiroyuki, Ooka Tomonori, Matsui Yoshiro
CEREBROVASCULAR DISEASES, 34, 109, 110, 2012年, ［査読有り］

Small but Severe Residual Hypoperfusion Relates to Symptomatic Hemorrhage Even after Early Perfusion Improvement in Tissue Plasminogen Activator Therapy
Takeo Abumiya, Masahito Katoh, Takuya Moriwaki, Masami Yoshino, Takeshi Aoki, Hiroyuki Imamura, Toshimitsu Aida, Naoki Nakayama, Kiyohiro Houkin
CEREBROVASCULAR DISEASES, 34, 5-6, 446, 447, KARGER, 2012年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

多発性頭蓋骨縫合早期癒合における導出静脈の同定における超音波検査の有用性
下田祐介, 黒田敏, 小山明彦, 浜内祝嗣, 山崎和義, 寳金清博
小児の脳神経, 37, 2, 2012年

骨髄間質細胞移植による中枢神経再生医療のトランスレーショナルリサーチ
七戸秀夫, 黒田敏, 山内朋裕, 齋藤久泰, 新保大輔, 寳金清博
脳循環代謝, 24, 1, 2012年

骨髄間質細胞移植による“Nursing Effect”-神経栄養因子の分泌による神経保護作用
七戸秀夫, 石原武, 黒田敏, 高橋浩治, 田中嘉一, 宮本倫行, 山内朋裕, 斎藤久泰, 武本浩, 寳金清博
再生医療, 11, 2012年

Blood Flow Metabolism Mismatch Triggers Postoperative Hyperperfusion after Carotid Endarterectomy: A Serial SPECT/PET Study
Shimbo Daisuke, Kuroda Satoshi, Nakayama Naoki, Kazumata Ken, Hirata Kenji, Shiga Tohru, Houkin Kiyohiro, Tamaki Nagara
CEREBROVASCULAR DISEASES, 34, 19, 2012年, ［査読有り］

Full Exposure of Ruptured Cerebral Aneurysm Preceding Clip Application: A Novel Surgical Concept and Its Advantages in 118 Case Series
Nakayama Naoki, Houkin Kiyohiro, Ishikawa Tatsuya, Hokari Masaaki, Kazumata Ken, Ito Masaki, Sugiyama Taku, Yasuda Hiroshi
CEREBROVASCULAR DISEASES, 34, 20, 2012年, ［査読有り］

Topography of Hemorrhage and Microbleeds in Adult Moyamoya Disease
Kazumata Ken, Houkin Kiyohiro, Nakayama Naoki, Shichinohe Hideo, Osanai Toshiya, Shinpo Daisuke, Saito Hisayasu
CEREBROVASCULAR DISEASES, 34, 32, 2012年, ［査読有り］

Endovascular Treatment of Ruptured Arterial Dissection of the Vertebral Artery
Osanai Toshiya, Ushikoshi Satoshi, Ken Kazumata, Nakayama Naoki, Houkin Kiyohiro
CEREBROVASCULAR DISEASES, 34, 92, 2012年, ［査読有り］

Irregular Neointimal Lining with Prominent Proliferative Activity in a Patient Underwent Patch Angioplasty for Carotid Endarterectomy - An Autopsy Case Report
Ito Masaki, Niiya Yoshimasa, Uchino Haruto, Itosaka Hiroyuki, Shichinohe Hideo, Kazumata Ken, Nakayama Naoki, Mabuchi Syoji, Houkin Kiyohiro
CEREBROVASCULAR DISEASES, 34, 102, 2012年, ［査読有り］

骨髄間質細胞移植は脳梗塞周囲の神経受容体機能を改善させる―¹²³I‐iomazenil SPECTによる検討　　　　　　　　　　　　　　　
齋藤久泰, 黒田敏, 宮本倫行, 山内朋裕, 七戸秀夫, 趙松吉, 孫田惠一, 久保直樹, 久下裕司, 玉木長良, 寶金清博
脳循環代謝, 24, 1, 216, 2012年
英語, 研究論文（その他学術会議資料等）

脳梗塞をターゲットとした骨髄間質細胞移植―新たな培養・移植・イメージング技術による展開　　　　　　　　　　　　　　　
黒田敏, 宮本倫行, 山内朋裕, 斉藤久泰, 伊東雅基, 川堀真人, 杉山拓, 千葉泰弘, 七戸秀夫, 宝金清博, 久下裕司, 趙松吉, 玉木長良
再生医療, 11, 136, 2012年
日本語, 研究論文（その他学術会議資料等）

A possible mechanism of isolated oculomotor nerve palsy by apoplexy of pituitary adenoma without cavernous sinus invasion: a report of two cases
Hiroyuki Kobayashi, Masahito Kawabori, Shunsuke Terasaka, Junichi Murata, Kiyohiro Houkin
ACTA NEUROCHIRURGICA, 153, 12, 2453, 2456, SPRINGER WIEN, 2011年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Isolated oculomotor nerve palsy occasionally occurs in patients with cavernous sinus invasion with or without pituitary apoplexy. We describe two cases of pituitary apoplexy without cavernous sinus invasion presenting with isolated oculomotor palsy. In both cases, computed tomography (CT) showed erosion of the right posterior clinoid process. Magnetic resonance imaging (MRI) depicted pituitary adenoma with apoplexy protruding latero-posteriorly to the right cavernous sinus. The medio-posterior wall of the cavernous sinus was markedly displaced latero-posteriorly by the tumor, and there was no evidence of cavernous sinus invasion. Oculomotor palsy may be caused first by unilateral erosion of the posterior clinoid process, resulting in latero-posterior protrusion of the adenoma. Hemorrhage may result in sudden kinking of the oculomotor nerve at the entrance of the oculomotor trigone.

Suprahepatic spaceへの脳室腹腔シャント腹腔端の再建
伊師雪友, 伊東雅基, 寺坂俊介, 茂木洋晃, 新保大輔, 金子貞洋, 寳金清博
Neurological Surgery, 39, 11, 1061, 1066, 11, 2011年11月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Complications arising from the placement of ventriculoperitoneal shunts are common. These complications may be related to a number of causes and present with various symptoms. Of these, abdominal complications such as formation of intraperitoneal pseudocysts and abdominal abscesses possibly recur, but, alternative sites for placing the peritoneal catheter of ventriculoperitoneal shunts are limited. We present two cases of ventriculoperitoneal shunt malfunctioning due to repeated abdominal complications. The location of the peritoneal end of the shunt was successfully revised to the suprahepatic space in the peritoneal cavity. We describe the clinical course of these two cases in this report, along with a precise technique of placing the peritoneal end of the shunt into the suprahepatic space. In addition, we will discuss the validity of this space as an alternative site for the placement of the peritoneal end of the ventriculoperitoneal shunt.

脊髄前角に偏在する特発性脊髄空洞症に対して空洞くも膜下腔短絡術を行った1例
栗栖宏多, 飛騨一利, 青山剛, 寳金清博
Neurological Surgery, 39, 11, 1079, 1084, 11, 2011年11月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Idiopathic syringomyelia not associated with Chiari malformation, tumor, nor tetherd cord syndrome has not been frequently reported. So the clinical significance and optimum treatment strategy for this disease remains unclear. We report a 37-year-old man who was diagnosed as having idiopathic syringomyelia and was treated successfully using implantation of a syringo-subarachnoid shunt. The patient suffered gradual worsening of sensory disturbance in the upper extremities, and Magnetic resonance imaging demonstrated a large syrinx located in the cervical spinal cord (C2-3), located mainly at the left anterior horn. We performed syringo-subarachnoid shunt for syringomyelia under partial hemilaminectomy. During the surgery, the spinal cord was markedly rotated and dorsal root entry had shifted to the midline because of the large syrinx. In order to perform myelotomy at the dorsal root entry zone, we needed additional drilling to the medial portion of the lamina. After this procedure, we were able to perform implantation of the syringo-subarachnoid shunt safely. After the operation, the syrinx collapsed immediately and no neurological deficit was observed. The patient was discharged 2 weeks after the operation. Idiopathic syringomyelia in which the syrinx has deviated to the anterior horn is rare. In those cases, we consider that sufficient hemilaminectomy for the midline should be performed.

頚静脈孔部腫瘍患者に生じた同側顔面痙攣に微小血管減圧術が有用であった1例
鴨嶋雄大, 寺坂俊介, 下田祐介, 福田聡, 寳金清博
Neurological Surgery, 39, 11, 1099, 1103, 11, 2011年11月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Hemifacial spasm is a movement disorder characterized by involuntary paroxysmal chronic contractions of the facial musculature. The usual cause is simple vascular compression of the facial nerve, at its root exit zone of the brain stem. Previously only a case of hemifacial spasm associated with a juglar foramen tumor has been reported in the literature. In this article, we report a case in which hemifacial spasm accompanied an ipsilateral juglar foramen tumor in a 62-year-old woman. The sole use of arterial decompression of the facial nerve at the root exit zone resulted in complete resolution of the patient's symptoms.

Bone Marrow-Derived Endothelial Progenitor Cells Participate in the Initiation of Moyamoya Disease
Taku Sugiyama, Satoshi Kuroda, Naoki Nakayama, Shinya Tanaka, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 51, 11, 767, 773, JAPAN NEUROSURGICAL SOC, 2011年11月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The mechanisms through which moyamoya disease occurs and progresses remain unknown. Recent studies have indicated the involvement of circulating endothelial progenitor cells (EPCs) in the development of moyamoya disease. This study directly investigated the participation of EPCs in moyamoya disease, using specimens of the supraclinoid internal carotid artery collected from two adult patients. The specimens were stained with primary antibodies against CD34, CD133, and vascular endothelial growth factor receptor-2 (VEGFR2) to localize the circulating EPCs in the thickened intima of occlusive arterial lesion. The CD34- and VEGFR2-positive cells were densely found in the thickened intima of occlusive arterial lesion, particularly clustered in the superficial layer of thickened intima. However, the number of CD34- and CD133-positive cells was very small. The CD34-positive cells also expressed von Willebrand factor on the surface of thickened intima and were also positive for a-smooth muscle actin in the deeper layer. These findings suggest that circulating EPCs may be involved in the development of occlusive arterial lesion in moyamoya disease.

Giant Skull Base Atypical Meningioma Presenting With Rapidly Progressive Impaired Consciousness Caused by Severe Venous Congestion-Case Report
Shigeru Yamaguchi, Shunsuke Terasaka, Hiroyuki Kobayashi, Katsuyuki Asaoka, Junichi Murata, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 51, 11, 789, 792, JAPAN NEUROSURGICAL SOC, 2011年11月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 43-year-old female presented with a giant skull base atypical meningioma manifesting as rapid progression of impaired consciousness. The meningioma was located in the ethmoid sinus, sphenoid sinus, nasal cavity, and left middle temporal fossa, and the intracranial portion of the tumor involved the left temporal region with massive surrounding brain edema in the left temporal lobe and basal ganglia. She underwent emergent fronto-temporo-parietal decompressive craniectomy, and the intracranial portion of the tumor was resected to control intracranial pressure. She recovered consciousness and neurological function dramatically, and subsequently underwent radical tumor resection via combined extended transbasal and left lateral transzygomatic infratemporal fossa approaches one month after the initial surgery. The extensive brain edema completely disappeared after tumor resection, and the patient fully recovered without neurological deficits except anosmia and small visual field defect. Rapid neurological deterioration and disturbance of consciousness caused by extensive peritumoral brain swelling are unusual in meningioma. In this case, the extemporaneous decompressive craniectomy was highly useful in the management of increased intracranial pressure.

Giant Cell Tumor of the Frontal Bone in a Girl : Case Report
KAMOSHIMA Yuuta, SAWAMURA Yutaka, IMAI Tetsuaki, FURUKAWA Hiroshi, KUBOTA Kanako, HOUKIN Kiyohiro
Neurologia medico-chirurgica = 神経外科, 51, 11, 798, 800, 一般社団法人 日本脳神経外科学会, 2011年11月, ［査読有り］
英語, 研究論文（学術雑誌）, A 2-year-old female presented with a rare case of recurrent giant cell tumor affecting the frontal bone. She had already undergone partial removal twice at the ages of 14 and 18 months. The tumor was located in the frontal bone, expanding to the ethmoid and orbital bones, and invading the frontal base dura mater. The tumor was totally removed including the surrounding bone and frontal base dura mater. No local recurrence and metastasis were observed at 18 months after the last operation. Most giant cell tumors occur in the epiphyses of long bones and are rare in the cranio-facial bone. These tumors usually affect young adults and few pediatric cases are reported.

慢性血行力学的脳虚血病変に対するEC-IC bypassの長期成績 PETを用いた治療選択における10年間の検討
川堀 真人, 黒田 敏, 中山 若樹, 石川 達哉, 宝金 清博
脳循環代謝, 23, 1, 155, 155, (一社)日本脳循環代謝学会, 2011年11月
日本語

高度に脳灌流圧が低下した領域における脳血液量の意義 OEFとAcetazolamideに対するCBV反応性
伊東 雅基, 黒田 敏, 穂刈 正昭, 中山 若樹, 志賀 哲, 玉木 長良, 宝金 清博
脳循環代謝, 23, 1, 117, 117, (一社)日本脳循環代謝学会, 2011年11月
日本語

もやもや病における血行再建術後過環流 PET/SPECTを用いた検討
内野 晴登, 黒田 敏, 中山 若樹, 宝金 清博
脳循環代謝, 23, 1, 157, 157, (一社)日本脳循環代謝学会, 2011年11月
日本語

頸動脈内膜剥離術後の過灌流の予測因子 acetazolamideか? OEFか?
新保 大輔, 黒田 敏, 中山 若樹, 宝金 清博
脳循環代謝, 23, 1, 123, 123, (一社)日本脳循環代謝学会, 2011年11月
日本語

ヨード過敏症を有する右鎖骨下動脈CTOに対してstent治療を行った1例
宮本 倫行, 長内 俊也, 浅野 剛, 中山 若樹, 黒田 敏, 宝金 清博
JNET: Journal of Neuroendovascular Therapy, 5, 4, 219, 219, (NPO)日本脳神経血管内治療学会, 2011年11月
日本語

骨髄間質細胞移植は脳梗塞後の局所糖代謝を改善する 小動物用PET/CTによる検討　　　　　　　　　　　　　　　
宮本 倫行, 黒田 敏, 七戸 秀夫, 伊東 雅基, 川堀 真人, 趙 松吉, 孫田 恵一, 久下 裕司, 玉木 長良, 宝金 清博
脳循環代謝, 23, 1, 142, 142, (一社)日本脳循環代謝学会, 2011年11月
日本語

胆管細胞癌よりの脈絡叢転移性腫瘍の1例
栗栖宏多, 鴨嶋雄大, 寺坂俊介, 小林浩之, 久保田佳奈子, 寳金清博
Neurological Surgery, 39, 10, 991, 997, 10, 2011年10月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Metastatic intraventricular tumor located in the choroid plexus is very rare. Only a few cases have been reported in the past. According to past reports, these tumors originated from lung, colon, and so on, but not from the bile duct. This is the first case report of choroid plexus metastasis from cholangiocellular carcinoma. A 57-year-old woman who had a history of cholagiocellular carcinoma, demonstrated intraventricular tumor. Although sufficient examination was performed, the tumor was difficult to diagnose as being a metastatic tumor or a choroid plexus carcinoma. Because of this, we performed endoscopic biopsy of the intraventricular tumor. However intraoperative findings were not helpful in distinguishing metastatic tumor and choroid plexus carcinoma. Postoperatively, histological examination was performed. However it was still difficult to differentiate this rare tumor from choroid plexus carcinoma by only hematoxylin and eosin stain. For further examination, Ber EP-4 stain was performed. Ber EP-4 showed strongly positive which indicates metastatic tumor. This method led us to make an appropriate diagnosis of this extremely rare tumor. We considered that in order to diagnose this rare tumor, appropriate histopathological examination, including immunohistopathological examination should be performed.

腎癌原発症候性下垂体転移の1例
鴨嶋雄大, 寺坂俊介, 浜内祝嗣, 小林浩之, 遠藤将吾, 菅野由岐子, 来海公彦, 寳金清博
Neurological Surgery, 39, 10, 999, 1004, 10, 2011年10月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Symptomatic metastases to the pituitary from renal cell carcinoma are rare. We present a case of pituitary metastases from renal cell carcinoma showing panhypopituitarism. A 50-year-old man who had renal cell carcinoma with distant metastases in skin, bone and lymph nodes was referred to our department. Clinically he showed severe cognitive function disorder. Endocrinological evaluation revealed central adrenal and gonadal insufficiencies. Brain magnetic resonance imaging demonstrated a hemorrhagic mass in left frontal lobe and a sellar mass with supra sellar cistern extension. After hormonal replacement and surgical removal of the frontal tumor, he immediately recovered from his cognitive function disorder. Subsequently, whole brain radiotherapy for metastatic pituitary tumor was performed. At present, he is being treated with molecular targeting drugs for other distant metastases and he presents no neurological deficit. Palliative therapy for CNS metastases from renal cell carcinoma may result in better quality of life for patients with advanced stage of renal cell carcinoma.

Xanthogranuloma of the Sellar Region of Children : Series of Five Cases and Literature Review
KAMOSHIMA Yuuta, SAWAMURA Yutaka, MOTEGI Hiroaki, KUBOTA Kanako, HOUKIN Kiyohiro
Neurologia medico-chirurgica = 神経外科, 51, 10, 689, 693, 一般社団法人 日本脳神経外科学会, 2011年10月, ［査読有り］
英語, Five Japanese children presented with rare xanthogranuloma located in the sellar region between 2000 and 2010 at the Department of Neurosurgery, Hokkaido University Hospital. Endocrinological examination disclosed central diabetes in four patients. Preoperative magnetic resonance (MR) imaging and computed tomography (CT) demonstrated clearly defined intra- or suprasellar masses appearing as isointense or hyperintense on T₁-weighted MR imaging with no calcification on CT. The tumor was totally removed under preoperative diagnosis of craniopharyngioma in all cases. Histological examination found fibrous tissue with abundant cholesterol clefts and hemosiderin deposits, but no or only tiny amounts of epithelial cells in each case. Therefore, the histological diagnoses were xanthogranuloma of the sellar region, not adamantinomatous craniopharyngioma. Postoperatively, no patient recovered from endocrinological deficits, whereas visual disturbances were improved immediately after operation. Currently, whether xanthogranuloma is distinct from adamantinomatous craniopharyngioma remains unclear. Only a few clinical reports of xanthogranuloma of the sellar region have been reported in pediatric patients. Our series shows that xanthogranuloma should be included in the differential diagnosis of pediatric tumor of the sellar region.

Midsubtemporal Ridge as a Predictor of the Lateral Loop Formed by the Maxillary Nerve and Mandibular Nerve: A Cadaveric Morphological Study
Masahiko Wanibuchi, Gen Murakami, Taro Yamashita, Yoshihiro Minamida, Takanori Fukushima, Allan H. Friedman, Mineko Fujimiya, Kiyohiro Houkin
NEUROSURGERY, 69, 1 Suppl Operative, 95, 98, LIPPINCOTT WILLIAMS & WILKINS, 2011年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The lateral loop formed by the maxillary nerve (V2) and the mandibular nerve (V3) consists of a part of the far lateral triangle of the cavernous sinus. Because this triangle becomes a surgical corridor of the preauricular infratemporal fossa approach and a landmark of the extradural approach for the ganglion-type trigeminal schwannomas, identification of the lateral loop has important implications at the early stage of middle cranial base surgery. We realized that a bony ridge usually existed just lateral to the lateral loop.
OBJECTIVE: To nominate midsubtemporal ridge (MSR) as the name for this anatomically unnamed bony ridge and to clarify its features.
METHODS: Using 35 cadaver heads, we measured the shape of the MSR on both sides and the distance between the MSR and the adjacent structures.
RESULTS: The MSR was recognized in 60 of 70 specimens (85.7%). The bony protrusion was 2.9 +/- 1.1 mm in height, 6.0 +/- 2.1 mm in width, and 9.1 +/- 3.2 mm in length. A single peak with anteroposterior length was common in 47 of 60 specimens (78.3%). The MSR was located at the midpoint of the V2 and V3 in 28 specimens (46.7%) and existed 10.7 +/- 3.6 mm lateral from the line that bound the foramen rotundum and the foramen ovale.
CONCLUSION: We demonstrate morphological characteristics of the MSR. These data on the MSR will assist the surgeon in identifying the lateral loop as a surgical landmark during middle cranial base surgery.

Sonodynamic therapy using water-dispersed TiO2-polyethylene glycol compound on glioma cells: Comparison of cytotoxic mechanism with photodynamic therapy
Shigeru Yamaguchi, Hiroyuki Kobayashi, Takuhito Narita, Koki Kanehira, Shuji Sonezaki, Nobuki Kudo, Yoshinobu Kubota, Shunsuke Terasaka, Kiyohiro Houkin
ULTRASONICS SONOCHEMISTRY, 18, 5, 1197, 1204, ELSEVIER SCIENCE BV, 2011年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Sonodynamic therapy is expected to be a novel therapeutic strategy for malignant gliomas. The titanium dioxide (TiO2) nanoparticle, a photosensitizer, can be activated by ultrasound. In this study, by using water-dispersed TiO2 nanoparticles, an in vitro comparison was made between the photodynamic and sonodynamic damages on U251 human glioblastoma cell lines. Water-dispersed TiO2 nanoparticles were constructed by the adsorption of chemically modified polyethylene glycole (PEG) on the TiO2 surface (TiO2/PEG). To evaluate cytotoxicity, U251 monolayer cells were incubated in culture medium including 100 mu g/ml of TiO2/PEG for 3 h and subsequently irradiated by ultraviolet light (5.0 mW/cm(2)) or 1.0 MHz ultrasound (1.0 W/cm(2)). Cell survival was estimated by MTT assay 24 h after irradiation. In the presence of TiO2/PEG, the photodynamic cytotoxic effect was not observed after 20 min of an ultraviolet light exposure, while the sonodynamic cytotoxicity effect was almost proportional to the time of sonication. In addition, photodynamic cytotoxicity of TiO2/PEG was almost completely inhibited by radical scavenger, while suppression of the sonodynamic cytotoxic effect was not significant. Results of various fluorescent stains showed that ultrasound-treated cells lost their viability immediately after irradiation, and cell membranes were especially damaged in comparison with ultraviolet-treated cells. These findings showed a potential application of TiO2/PEG to sonodynamic therapy as a new treatment of malignant gliomas and suggested that the mechanism of TiO2/PEG mediated sonodynamic cytotoxicity differs from that of photodynamic cytotoxicity. (C) 2011 Elsevier B.V. All rights reserved.

Validity of Bone Marrow Stromal Cell Expansion by Animal Serum-Free Medium for Cell Transplantation Therapy of Cerebral Infarct in Rats—A Serial MRI Study
Masaki Ito, Satoshi Kuroda, Taku Sugiyama, Hideo Shichinohe, Yukari Takeda, Mitsufumi Nishio, Takao Koike, Kiyohiro Houkin
Translational Stroke Research, 2, 3, 294, 306, Springer Science and Business Media LLC, 2011年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, This study was aimed to test the hypothesis that human bone marrow stromal cells (hBMSC) expanded in fetal calf serum (FCS)-free, platelet lysate (PL)-containing medium would retain their capacity of migration, survival, and neural differentiation when transplanted into the infarct brain, using serial in vivo magnetic resonance imaging (MRI). Cell growth kinetic analysis revealed that hBMSC maintain their proliferative activity when cultured either in conventional FCS-containing medium or FCS-free, PL-containing medium. Subsequently, hBMSC were labeled with a superparamagnetic iron oxide agent and were stereotactically transplanted into the ipsilateral striatum of rats at 7 days after permanent middle cerebral artery occlusion. Serial MRI performed over 8 weeks revealed that they retain their migratory capacity towards the cerebral infarct. Moreover, double fluorescence immunohistochemistry also revealed that they preserve their capacity of differentiation into the neural cells in the peri-infarct area. The hBMSC expanded in the FCS-free, PL-containing medium retain their capacity of migration, survival, and differentiation when stereotactically transplanted into the infarct brain. The present findings strongly suggest the clinical utility of PL as a substitute to expand autologous hBMSC for cerebral infarct in the future.

Biological Features of Human Bone Marrow Stromal Cells (hBMSC) Cultured with Animal Protein-Free Medium-Safety and Efficacy of Clinical Use for Neurotransplantation
Hideo Shichinohe, Satoshi Kuroda, Taku Sugiyama, Masaki Ito, Masahito Kawabori, Mitsufumi Nishio, Yukari Takeda, Takao Koike, Kiyohiro Houkin
Translational Stroke Research, 2, 3, 307, 315, 2011年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The donor cell culture in animal serum-free medium is quite important for the clinical application of cell transplantation therapy. This study was aimed to test the hypothesis that the human bone marrow stromal cells (hBMSC) expanded with fetal calf serum (FCS)-free, platelet lysate (PL)-containing medium retain their biological features favoring central nervous system regeneration. The hBMSC were cultured with 5% PL or 10% FCS. Their phenotypes were analyzed with flow cytometry, and their production of growth factors was quantified with enzyme-linked immunosorbent assay. Their capacity of neural differentiation was verified by immunocytochemistry. There was no significant difference in morphology and cell surface marker between the hBMSC-FCS and hBMSC-PL. Both of them were positive for CD44, CD90, CD105, and CD166 and were negative for CD34, CD45, and CD271. The production of human brain-derived neurotrophic factor, human hepatocyte growth factor, human β-nerve growth factor, and human platelet-derived growth factor-BB did not differ between the two groups, although the hBMSC-PL produced significantly more amount of TGF-β1 than the hBMSC-FCS. There was no significant difference in their in vitro differentiation into the neurons and astrocytes between the two groups. The hBMSC expanded with PL-containing medium retain their biological capacity of neural differentiation and neuroprotection. The PL may be a clinically valuable and safe substitute for FCS in expanding the hBMSC for cell therapy. © 2011 Springer Science+Business Media, LLC.

Intramedullary Cavernous Angiomas of the Spinal Cord : Clinical Characteristics of 13 Lesions
AOYAMA Takeshi, HIDA Kazutoshi, HOUKIN Kiyohiro
Neurologia medico-chirurgica = 神経外科, 51, 8, 561, 566, 一般社団法人 日本脳神経外科学会, 2011年08月15日, ［国内誌］
英語, 研究論文（学術雑誌）, Magnetic resonance imaging has increased the incidence of the diagnosis of intramedullary cavernous angioma. Surgical therapy tends not to be recommended for asymptomatic lesions, but symptomatic lesions that bleed recurrently should be treated. The natural course of intramedullary cavernous angioma remains unknown and arguments have been raised against the surgical treatment of symptomatic lesions. We reviewed the clinical features of 13 intramedullary cavernous angiomas in 12 patients surgically treated between 1988 and 2009. The 7 men and 5 women were aged from 14 to 60 years, the preoperative interval ranged from 0 to 161 months, and the mean number of hemorrhages in the 13 lesions was 2.5. Sixteen operations were performed to treat the 13 lesions. The surgical approach depended on the lesion location. The outcome of patients with mild to moderate preoperative symptoms (McCormick grades I-III) was significantly better than that of patients with severe symptoms (McCormick grade IV) (p < 0.05). Symptomatic intramedullary cavernous angioma tends to bleed repeatedly. The lesion should be surgically removed to avoid further deterioration due to recurrent hemorrhages. The shortest path approach should be selected based on preoperative images and complete removal should be attempted. Residual lesion may be masked by surrounding gliosis, so careful postoperative follow up is necessary.

外傷性髄液漏に対する前頭洞有茎疎性輪紋状結合織選択的充填および骨膜弁被覆併用修復術
鴨嶋雄大, 寺坂俊介, 浜内祝嗣, 金子貞洋, 村上博基, 寳金清博
Neurological Surgery, 39, 8, 783, 788, 8, 2011年08月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, We report a case of cerebrospinal fluid (CSF) leak repair using loose areolar connective tissue insertion into the frontal sinus and pericranial flap covering. A 61-years-old man suffered from skull fracture including frontal sinus fracture in violence inflicted by others. Fifty days later, he presented rhinorrhea and pneumocephalus caused by a bone defect site of the frontal sinus and anterior skull base. We performed CSF leak repair with insertion of pedunculated loose areolar connective tissue into his frontal sinus, covering the leak point using pericranial flap. In general, frontal sinus obliteration has been accomplished with autologous grafts such as fat, muscle, or bone. These avascular grafts carry an increased risk of resorption and infection. The use of loose areolar tissue insertion into the frontal sinus was able to increase stability of the construct and caused no cosmetic troubles in our short follow up period. The combined use of these two autologous materials may be useful for repair of CSF leak from an anterior skull base fracture.

Primary Central Nervous System Mucosa-Associated Lymphoid Tissue Lymphoma : Case Report
KAMOSHIMA Yuuta, SAWAMURA Yutaka, SUGIYAMA Taku, YAMAGUCHI Shigeru, HOUKIN Kiyohiro, KUBOTA Kanako
Neurologia medico-chirurgica = 神経外科, 51, 7, 527, 530, 一般社団法人 日本脳神経外科学会, 2011年07月15日, ［国内誌］
英語, 研究論文（学術雑誌）, A 55-year-old woman presented with an extremely rare primary central nervous system mucosa-associated lymphoid tissue (MALT) lymphoma manifesting as seizure and was subsequently diagnosed with dural MALT lymphoma in the cranium. Magnetic resonance imaging revealed a left frontal dural mass with peritumoral edema. Histological examination of the dural mass confirmed MALT lymphoma and revealed infiltration of small cells with irregular nuclear borders and expression of a B cell marker (CD20) but absence of CD5, CD10, CD23, and cyclinD1. Reactive T-cell infiltration was also seen. Subsequently, local irradiation (40 Gy/20 fractions) was performed. Magnetic resonance imaging showed complete remission just after irradiation was completed. There was no evidence of systemic MALT lymphoma. There has been no recurrence for 3 years without additional therapy.

Threshold levels of intracranial pressure as determinants of survival from diffuse brain injury. An observational study
Kei Miyata, Takeshi Mikami, Yasufumi Asai, Kazuhisa Mori, Izumi Koyanagi, Nobuhiro Mikuni, Kiyohiro Houkin
Neurological Surgery, 39, 7, 657, 662, 7, 2011年07月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Objective: Intracranial pressure (ICP) is frequently monitored in patients with severe head injuries. In this study of a series of diffuse brain injury patients, we investigated whether there are significant threshold levels that determine the outcome. Method: Data were obtained from 17 patients with severe head injuries (adults aged≥ 15-years-old). The outcome was categorized using the Glasgow Outcome Scale and survival or death. Patients were also grouped according to the Traumatic Coma Data Bank (TCDB) CT classification for diffuse injury: type I (n=0)
II(n = 5)
III(n=10)
IV (n=2). Conclusion and result: The mortality rate was 29% (5 of 17 patients). The average initial ICP within 24 hours (14.08 mmHg) and the peak ICP (26.75 mmHg) were lower in the survivors than that in the patients who died (57.60 mmHg and 91.00 mmHg, respectively
p = 0.0006 and 0.0002, respectively). Patients with an initial ICP score>
35 mmHg did not survive, and patients with a peak ICP<
35 mmHg, except one who died of a traumatic brainstem hemorrhage, did survive. Using an X-bar chart, a threshold value for the initial ICP within 24 hours of 27 mmHg and for the peak ICP 46 mmHg appear to be the survival predictors in patients with diffuse brain injury.

Association of Recurrent Cerebral Infarction With Adenosine Diphosphate- and Collagen-Induced Platelet Aggregation in Patients Treated With Ticlopidine and/or Aspirin
Takeo Abumiya, Kiyohiro Houkin
JOURNAL OF STROKE & CEREBROVASCULAR DISEASES, 20, 4, 319, 323, ELSEVIER SCIENCE BV, 2011年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Although the platelet aggregation test is the most common method for evaluating response to antiplatelet therapy, little is known about the association of recurrent cerebral infarction with platelet aggregation in the presence of various different antiplatelet drugs. We prospectively evaluated adenosine diphosphate (ADP)- and collagen-induced platelet aggregation and followed the incidence of recurrent infarction in patients categorized into 3 groups based on treatment; aspirin (n = 144), ticlopidine (n = 100), and aspirin + ticlopidine (n = 96). The patients in each treatment group were stratified into quartiles according to platelet aggregation, and the association of recurrent infarction with platelet aggregation was investigated. ADP-induced platelet aggregation values were significantly lower in the ticlopidine group and the aspirin + ticlopidine group compared with the aspirin group (P <.001), and collagen-induced platelet aggregation values were significantly lower in the aspirin group and the aspirin + ticlopidine group compared with the ticlopidine group (P <.001). In the aspirin group, the recurrence rate was somewhat higher in the higher aggregation quartiles than in the lower aggregation quartiles of 2 mu g/mL collagen, the differences were not statistically significantly (P =.243). In the ticlopidine group, the recurrence rate was significantly higher in the lower aggregation quartiles compared with the higher aggregation quartiles of 1 mu mol/L ADP (P =.025). No tendencies were found in the aspirin + ticlopidine group. Although the study is limited by its small sample size, the results suggest a possible difference between aspirin therapy and ticlopidine therapy in the pattern of association of recurrent infarction with platelet aggregation.

Surgical approach for the tuberculum sellae meningioma: High and low?
Shunsuke Terasaka, Hiroyuki Kobayashi, Kiyohiro Houkin
Neurological Surgery, 39, 6, 553, 562, 6, 2011年06月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）

生体肝移植後に自然消失した脳動静脈奇形の1例
下田祐介, 黒田敏, 柏崎大奈, 浅野剛, 山下健一郎, 谷口雅彦, 鈴木友己, 嶋村剛, 古川博之, 中山若樹, 寳金清博
Neurological Surgery, 39, 6, 589, 594, 6, 2011年06月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, In this report, the authors describe a 35-year-old male whose intracranial arteriovenous malformation (AVM) spontaneously disappeared about 2 years after successful living-donor liver transplantation for alcohol-induced liver cirrhosis. Preoperative screening MRI revealed intracranial arteriovenous malformation (AVM) around the midbrain. Cerebral angiography demonstrated that the AVM was fed by the paramedian mesencephalic arteries and was drained via the vein of Galen. He successfully underwent living-donor liver transplantation, and his postoperative course was uneventful. Follow-up MRI and MRA revealed spontaneous disappearance of the AVM 27 months after surgery. The authors discuss precisely the underlying mechanism of this rare phenomenon, based on thorough literature review.

蝶形骨洞内異所性下垂体腺腫の1例
鴨嶋雄大, 寺坂俊介, 内田和希, 牛越聡, 曹圭龍, 寳金清博
Neurological Surgery, 39, 6, 601, 605, 6, 2011年06月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Ectopic pituitary adenomas are relatively rare tumors. We present a case of ectopic pituitary adenoma occurring in the sphenoid sinus. A 63-year-old woman was referred to our hospital complaining of headache. She had no endocrinological abnormalities. Magnetic resonance imaging showed a tumor in the sphenoid sinus, adjacent to the sellar floor and appearing as a low-signal on T1-weighetd image and a high signal on T2-weighted image. No connection between the normal pituitary gland and tumor was observed. Using an endonasal- transsphenoidal approach assisted with neuro-endoscopy, we performed total removal of the tumor. No connection between the normal pituitary gland and the tumor was found. Histopathological analysis showed a pituitary adenoma. As demonstrated by our case report, differential diagnosis of a tumor occurring in the sphenoid sinus must include consideration of the existence of an ectopic pituitary adenoma.

Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke
Osamu Honmou, Kiyohiro Houkin, Takuya Matsunaga, Yoshiro Niitsu, Sumio Ishiai, Rie Onodera, Stephen G. Waxman, Jeffery D. Kocsis
BRAIN, 134, Pt 6, 1790, 1807, OXFORD UNIV PRESS, 2011年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Transplantation of human mesenchymal stem cells has been shown to reduce infarct size and improve functional outcome in animal models of stroke. Here, we report a study designed to assess feasibility and safety of transplantation of autologous human mesenchymal stem cells expanded in autologous human serum in stroke patients. We report an unblinded study on 12 patients with ischaemic grey matter, white matter and mixed lesions, in contrast to a prior study on autologous mesenchymal stem cells expanded in foetal calf serum that focused on grey matter lesions. Cells cultured in human serum expanded more rapidly than in foetal calf serum, reducing cell preparation time and risk of transmissible disorders such as bovine spongiform encephalomyelitis. Autologous mesenchymal stem cells were delivered intravenously 36-133 days post-stroke. All patients had magnetic resonance angiography to identify vascular lesions, and magnetic resonance imaging prior to cell infusion and at intervals up to 1 year after. Magnetic resonance perfusion-imaging and 3D-tractography were carried out in some patients. Neurological status was scored using the National Institutes of Health Stroke Scale and modified Rankin scores. We did not observe any central nervous system tumours, abnormal cell growths or neurological deterioration, and there was no evidence for venous thromboembolism, systemic malignancy or systemic infection in any of the patients following stem cell infusion. The median daily rate of National Institutes of Health Stroke Scale change was 0.36 during the first week post-infusion, compared with a median daily rate of change of 0.04 from the first day of testing to immediately before infusion. Daily rates of change in National Institutes of Health Stroke Scale scores during longer post-infusion intervals that more closely matched the interval between initial scoring and cell infusion also showed an increase following cell infusion. Mean lesion volume as assessed by magnetic resonance imaging was reduced by > 20% at 1 week post-cell infusion. While we would emphasize that the current study was unblinded, did not assess overall function or relative functional importance of different types of deficits, and does not exclude placebo effects or a contribution of recovery as a result of the natural history of stroke, our observations provide evidence supporting the feasibility and safety of delivery of a relatively large dose of autologous mesenchymal human stem cells, cultured in autologous human serum, into human subjects with stroke and support the need for additional blinded, placebo-controlled studies on autologous mesenchymal human stem cell infusion in stroke.

自家頭蓋分層骨とリン酸カルシウムペーストを併用した頭蓋形成術
鴨嶋雄大, 寺坂俊介, 小山明彦, 寳金清博
Neurological Surgery, 39, 5, 491, 495, 5, 2011年05月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, We report a case of cranial reconstruction using autologous split calvarial bone combined with calcium phosphate bone cement (CPC). A 19-years-old man suffered from cranium defect and rhinorrhea originating from frontal skull base fracture in a traffic accident. After CSF hydration treatment had finished, continuously we performed cranial reconstruction with autologous split calvarial bone so that the patient could return to work at an early stage. The use of autologous split calvarial bone with CPC was able to increase stability of the construct and provide excellent cosmetic result in our short follow up period. The combination use of these two materials may be useful for cranial reconstruction in patients with cranium defect.

仙骨部硬膜動静脈瘻の4例
笹森徹, 飛騨一利, 浅野剛, 青山剛, 山内朋裕, 岩崎素之, 矢野俊介, 岩崎喜信, 寳金清博
Neurological Surgery, 39, 5, 505, 511, 5, 2011年05月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Spinal dural arteriovenous fistula (SDAVF) in the sacral region is relatively rare and remains difficult to diagnose because of the uncommon origin of its feeder. It also has higher incidence of recurrence than usual thoraco-lumbar lesion and needs subsequent treatment. We reviewed 51 cases of SDAVF over the past 10 years. Especially in patients with sacral lesion, clinical features and the findings on spinal angiography were analyzed. Four patients (7.8%) had SDAVF in the sacral region. In all cases, SDAVF were supplied by the lateral sacral artery. Multiple feeders were observed in 3 (75%) out of 4 patients and 2 patients (50%) had multiple fistulas. Endovascular embolizations were performed in all patients, and neurological symptoms were improved in two patients (50%) and the other two were stabilized (50%). There was no recurrence during a follow-up period of 3 months to 8 years. We should keep in mind that SDAVF in the sacral region can have multiple shunts and feeders derived from the lateral sacral artery.

神経皮膚黒色症と鑑別を要した巨大色素性有毛性母斑と星細胞腫が合併した稀な1例
鴨嶋雄大, 澤村豊, 斉藤伸治, 川堀真人, 寳金清博, 久保田佳奈子
Neurological Surgery, 39, 5, 479, 83, 5, 2011年05月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, A 1-year-old female infant presented with congenital giant, hairy and pigmented nevi. MRI scan as screening test revealed a cerebellar tumor. A diagnosis of provisional neurocutaneous melanosis was made on the basis of the patient's MRI and physical findings. At her 6 years of age, MRI revealed the tumor grown up to 3 cm diameter in 5 years. The cerebellar tumor was removed partially using the occipital transtentorial approach for tissue diagnosis. The color of the cerebellar tumor was whitish and contained neither benign nor malignant melanocyte. Pathological examination revealed diffuse astrocytoma. Finally residual cerebellar tumor was totally removed at a second surgical resection. To our knowledge, this is the first patient to be reported with astrocytoma complicated giant skin nevus except neurocutaneous syndrome cases.

仙骨部硬膜動静脈瘻の4例
笹森 徹, 飛騨 一利, 浅野 剛, 青山 剛, 山内 朋裕, 岩崎 素之, 矢野 俊介, 岩崎 喜信, 寳金 清博
Neurological Surgery, 39, 5, 505, 511, (株)医学書院, 2011年05月
日本語, 過去10年間に脊髄硬膜動静脈瘻(SDAVF)の診断で治療した51例中仙骨部病変の4例(全例男性、57〜76歳)を対象に、臨床経過、脊髄血管造影検査所見について検討した。初発症状は両下肢しびれ2例、歩行障害2例で、いずれも緩徐進行性であった。再発で紹介の1例を除き発症から平均20.7ヵ月でSDAVFと診断した。脊髄血管造影検査では、仙骨部病変はS2レベル:3例、S1レベル:1例、全例で外側仙骨動脈からfeederを認め、拡張したfilm terminale上のdraining veinへの頭側方向に環流を認めた。また、3例で両側の外側仙骨動脈から複数のfeederを、2例に複数のfistulaを認めた。全例でN-butyl cyanoacrylateを用いた血管内塞栓術を行い、3ヵ月〜8年のフォローアップ期間で2例に神経症状の改善、2例に神経症状の進行抑制を認め、全例で再発は認めていない。

脊髄円錐部および馬尾に複数のAV shuntを形成した脊髄辺縁部動静脈瘻の1例
齋藤久泰, 飛騨一利, 浅野剛, 矢野俊介, 青山剛, 岩崎喜信, 寳金清博
Neurological Surgery, 39, 4, 375, 380, 4, 2011年04月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Penmedullary arteriovenous fistula (AVF) is usually located on the surface of the spinal cord and is fed by the anterior spinal artery and/or the posterior spinal artery. We report a rare case of Conus penmedullary AVF with multiple shunt points including the cauda equina. A 68-year-old man presented with leg pain when walking long distances. Magnetic resonance imaging at the thoracic and lumbar level revealed multiple signal voids with marked cord signal change. Angiography showed the penmedullary AVF fed by the anterior spinal artery from the right T9 intercostal artery at the level of the conus medullaris and the fistula fed by the left lateral sacral artery from the left internal iliac artery at the level of the cauda equina. In the first surgery, we performed surgical interruption of feeding arteries from the filum terminale and coagulated AV shunt of the conus medullaris. However residual perimedullary AVF was found at the conus medullaris in the postoperative angiography. Secondary surgery was carried out to treat residual AVF. Follow-up angiography showed complete disappearance of all AVFs. Postoperatively, the patient's symptoms were improved. Because the Conus perimedullary AVF has the characteristics of multiple feeding arteies. multiple shunt points, and complex venous drainage, it must be kept in mind that other fistula could exist in the cauda equina or filum terminale.

中大脳動脈瘤の術野展開とclipping work
中山若樹, 石川達哉, 宝金清博, 黒田敏, 上山博康
脳神経外科ジャーナル, 20, Supplement, 46, 2011年04月10日
日本語

頭蓋形成術後感染症例に対する自家頭蓋骨およびチタンメッシュプレートを併用した頭蓋形成術
鴨嶋雄大, 澤村豊, 川嶋邦弘, 長内俊也, 柏崎大奈, 山内朋裕, 寳金清博
Neurological Surgery, 39, 4, 351, 8, 4, 2011年04月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, We present a modified method for reconstruction of calvarial bone defects for patients with a history of infectious complications. Three patients who had experienced implanted bone infections underwent reconstruction of calvarial bone defect. For reconstruction of the calvarial bone defects, autologous split calvarial bone grafts were used to cover the calvarial bone defect. The full or half layered fronto-parietal bone used as implants were fixed with titanium mini-plates for primary bone defect site, while the new bone defect site caused by getting autologous bone graft were covered with titanium mesh plates assisted by residual half layered calvarias. The average follow-up span of patients was 64 months. Evaluated clinical and radiologic results are stable, showing no measurable side effects. Split calvarial bone graft in combination with titanium mesh plates is recommended in patients with a history of infection or high risk of infection.

Intraoperative Indocyanine Green Videoangiography for Spinal Vascular Lesions: Case Report
Tomohiro Murakami, Izumi Koyanagi, Takahisa Kaneko, Satoshi Iihoshi, Kiyohiro Houkin
NEUROSURGERY, 68, 3, E241, E245, LIPPINCOTT WILLIAMS & WILKINS, 2011年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND IMPORTANCE: In surgery of spinal vascular lesions such as spinal arteriovenous fistula or vascular tumors, assessment of feeding arteries and draining veins is important. Intraoperative digital subtraction angiography is useful but is invasive and sometimes technically demanding. Near-infrared indocyanine green (ICG) video-angiography is less invasive and has been reported as an intraoperative diagnosis of arterial patency during clipping surgery of cerebral aneurysms or bypass surgeries. We present our experience with intraoperative ICG videoangiography in 3 cases of spinal vascular lesions.
CLINICAL PRESENTATION: Two patients had spinal arteriovenous fistula (perimedullary, n = 1; dural, n = 1), and 1 patient had spinal cord hemangioblastoma at the thoracic or thoracolumbar level. The surgical microscope was an OPMI Pentero (Carl Zeiss, Oberkochen, Germany). After laminectomy and opening of the dura, ICG (5 mg) was injected intravenously. The ICG angiography clearly demonstrated feeding and draining vessels. The ICG findings greatly helped successful interruption of arteriovenous fistula and total removal of the tumor.
CONCLUSION: Intraoperative ICG videoangiography for spinal vascular lesions was useful by providing information on vascular dynamics directly. However, the diagnostic area is limited to the field of the surgical microscope. Although intraoperative digital subtraction angiography is still needed in cases of complex spinal vascular lesions, ICG videoangiography will be an important diagnostic modality in the field of spinal vascular surgeries.

Intraoperative Indocyanine Green Videoangiography for Spinal Vascular Lesions: Case Report
Tomohiro Murakami, Izumi Koyanagi, Takahisa Kaneko, Satoshi Iihoshi, Kiyohiro Houkin
NEUROSURGERY, 68, LIPPINCOTT WILLIAMS & WILKINS, 2011年03月, ［査読有り］
英語, 研究論文（学術雑誌）, BACKGROUND AND IMPORTANCE: In surgery of spinal vascular lesions such as spinal arteriovenous fistula or vascular tumors, assessment of feeding arteries and draining veins is important. Intraoperative digital subtraction angiography is useful but is invasive and sometimes technically demanding. Near-infrared indocyanine green (ICG) videoangiography is less invasive and has been reported as an intraoperative diagnosis of arterial patency during clipping surgery of cerebral aneurysms or bypass surgeries. We present our experience with intraoperative ICG videoangiography in 3 cases of spinal vascular lesions.
CLINICAL PRESENTATION: Two patients had spinal arteriovenous fistula (perimedullary, n = 1; dural, n = 1), and 1 patient had spinal cord hemangioblastoma at the thoracic or thoracolumbar level. The surgical microscope was an OPMI Pentero (Carl Zeiss, Oberkochen, Germany). After laminectomy and opening of the dura, ICG (5 mg) was injected intravenously. The ICG angiography clearly demonstrated feeding and draining vessels. The ICG findings greatly helped successful interruption of arteriovenous fistula and total removal of the tumor.
CONCLUSION: Intraoperative ICG videoangiography for spinal vascular lesions was useful by providing information on vascular dynamics directly. However, the diagnostic area is limited to the field of the surgical microscope. Although intraoperative digital subtraction angiography is still needed in cases of complex spinal vascular lesions, ICG videoangiography will be an important diagnostic modality in the field of spinal vascular surgeries.

The Incidence And Mechanisms Of Postoperative Cerebral Infarction After Clipping Surgery For Non-ruptured Intracranial Aneurysms - A Multivariate Analysis Study
Miyamoto Michiyuki, Kuroda Satoshi, Nakayama Naoki, Hokari Masaaki, Yasuda Hiroshi, Saito Hisatoshi, Houkin Kiyohiro
STROKE, 42, 3, E172, 2011年03月, ［査読有り］

Validity of F-18-fluorodeoxyglucose PET in Identifying Inflamed and Vulnerable Carotid Plaque - A Radiological and Pathological Study
Kuroda Satoshi, Maruichi Katsuhiko, Nakayama Naoki, Houkin Kiyohiro, Hirata Kenji, Shiga Tohru, Tamaki Nagara
STROKE, 42, 3, E183, 2011年03月, ［査読有り］

眼窩先端部症候群で発症し内頚動脈浸潤した副鼻腔真菌症の3症例
杉山拓, 黒田敏, 中山若樹, 寳金清博
Neurological Surgery, 39, 2, 155, 161, 2, 2011年02月10日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Fungal infection is an increasing problem in patients treated with intensive chemotherapy or immunosuppressive therapy. Of these, invasive aspergillosis or mucormycosis on rare occasions, infiltrate the internal carotid artery (ICA) by contiguous spread from an infected paranasal sinus. Here, we report three cases of ICA infiltration secondary to the fungal infections of the paranasal sinus. All cases developed orbital apex syndrome when the lesion spread to the orbital apex or cavernous sinus, and aggressive progression led to ICA invasion causing life-threatening cerebral infarction or hemorrhage. In this case report, we describe the aggressive clinical course of the fungal ICA invasion from the paranasal sinus, and then discuss the clinical feature, diagnostic methods, and current treatment of intracranial fungal infection.

Flow diversion by double-overlapping-stent for fusiform vertebral artery aneurysm: A case report
Haruto Uchino, Takeshi Asano, Naoki Nakayama, Satoshi Kuroda, Kiyohiro Houkin
Neurological Surgery, 39, 1, 59, 63, 1, 2011年01月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, The authors present the case of a 61-year-old male with a de novo fusiform vertebral artery aneurysm, probably due to non-traumatic dissection. He underwent flow diversion therapy, using a double overlapping technique, because the origin of the contralateral vertebral artery was stenotic. Placement of two stents resulted in marked reduction of blood flow in the aneurysm. Postoperative course was uneventful. Follow-up 3D-CT angiography revealed a patent blood flow in the stent and a gradual progression of intra-aneurysmal thrombosis. Flow diversion therapy can potentially obliterate the complicated cerebral aneurysm with the preservation of blood flow in the parent artery, and would be one of the important therapeutic options in patients with complicated aneurysms in which conventional strategies such as neck clipping, endovascular coiling and parent artery occlusion are not feasible or contraindicated.

Susceptibility-weighted Imaging and Magnetic Resonance Angiography during Migraine Attack: A Case Report
Yusuke Shimoda, Kohsuke Kudo, Satoshi Kuroda, Yuri Zaitsu, Nobuyuki Fujima, Satoshi Terae, Makoto Sasaki, Kiyohiro Houkin
MAGNETIC RESONANCE IN MEDICAL SCIENCES, 10, 1, 49, 52, JPN SOC MAGNETIC RESONANCE IN MEDICINE, 2011年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, We performed magnetic resonance angiography (MRA) and susceptibility-weighted imaging (SWI) to observe cerebral changes during a migraine attack in a 28-year-old man. MRA revealed regional arterial spasm, and findings of SWI were consistent with decreased blood flow and/or venous dilatation. Because these noninvasive techniques can be performed repeatedly at short intervals, they can be useful for evaluating hemodynamic changes during and after migraine attacks.

Multiple infectious intracranial lesions of Mycobacterium genavense in an immunocompromised patient
Haruto Uchino, Shunsuke Terasaka, Shigeru Yamaguchi, Hiroyuki Kobayashi, Kagari Kawai, Kanako Kubota, Shinji Ooe, Kiyohiro Houkin
Brain and Nerve, 63, 1, 79, 83, 1, 2011年01月01日, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Nontuberculous mycobacteria rarely infect the central nervous system. Recently, Mycobacterium genavense, nontuberculous mycobacterium (NTM), has been identified as a significant pathogen in patients. In this report, we describe multiple intracranial lesions caused by M. genavense in an immunocompromised host. A 50-year-old man presented with dysarthria, aphasia, and right hemiparesis. He had a primary immunodeficiency and a M. genavense infection in the thoracic and abdominal lymph nodes. Magnetic resonance imaging revealed multiple intracranial masses in the subcortical regions with extensive perifocal edema. Laboratory investigations and cultures of cerebrospinal fluid provided no evidence of disseminated infection. We obtained a biopsy sample via a small craniotomy using neuronavigation, and NTM infection was confirmed on analysis of the specimen. He was treated with antimycobacterial agents, and the clinical symptoms and radiological findings improved. Although a surgical procedure bears the potential risk of infection, especially in an immunocompromised patient, a brain biopsy was necessary for definitive diagnosis in this case and it aided in the administration of appropriate treatment.

日本脳卒中協会主催PCEC/PSLS講習の意義
大里俊明, 大里俊明, 齊藤正樹, 齊藤正樹, 齊藤正樹, 奈良理, 奈良理, 宮田圭, 宮田圭, 浅井康文, 浅井康文, 中川原譲二, 中川原譲二, 寳金清博, 寳金清博
日本脳神経外科救急学会プログラム・抄録集, 16th (CD-ROM), 2011年

解剖を中心とした脳神経手術手技 鞍結節髄膜腫に対する手術到達法の選択:高位か低位か?
寺坂俊介, 小林浩之, 寳金清博
Neurological Surgery, 39, 6, 2011年

急速に進行する虚血性もやもや病に対する早期血行再建術の有用性
栗栖宏多, 黒田敏, 中山若樹, 内野晴登, 中村俊孝, 寶金清博
脳循環代謝, 23, 1, 157, 2011年
日本語

脳虚血・臨床・モヤモヤ病 もやもや病術後症例に対する追加脳血行再建術 その実際と脳循環代謝
黒田 敏, 中山 若樹, 平田 健司, 志賀 哲, 玉木 長良, 宝金 清博
脳循環代謝, 22, 1, 78, 78, (一社)日本脳循環代謝学会, 2010年11月
日本語

脳虚血・臨床・モヤモヤ病 小児モヤモヤ病における頭痛と脳血行動態の関係について
川堀 真人, 黒田 敏, 中山 若樹, 宝金 清博
脳循環代謝, 22, 1, 80, 80, (一社)日本脳循環代謝学会, 2010年11月
日本語

強直性脊椎炎に伴う頚椎骨折の1例
金子高久, 小柳泉, 村上友宏, 寳金清博
Neurological Surgery, 38, 9, 839, 843, 9, 2010年09月10日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, We report a case of a 61-year-old man with ankylosing spondylitis who showed cervical spine fracture. The patient had fallen down on the floor and presented with severe neck pain. He was treated conservatively with a hard neck collar in an emergency hospital because of C7 body fracture without dislocation. However, the follow-up radiographs demonstrated a progressive C6-7 anterior dislocation. He was referred to our hospital 6 weeks after the trauma. The 3D-CT reconstruction imaging revealed that the fracture extended from the C7 vertebral body to the C6 lamina via the bilateral C6/7 facet joints. The patient underwent C2-Th3 posterior fixation using pedicle and lateral mass screw techniques. The postoperative course was uneventful. He was discharged without any complication at 1 month postoperatively. The radiograph 3 months after surgery showed good bone fusion. Spine fracture with ankylosing spondylitis usually shows significant instability because of the long lever-arm of the fused vertebrae at the fracture level. Solid spinal fusions such as long posterior fusion or anterior-posterior simultaneous fusion are needed in such cases.

Glioblastoma simultaneously present with adjacent meningioma: case report and review of the literature
Kengo Suzuki, Hiroyuki Momota, Akiko Tonooka, Hiroko Noguchi, Kouhei Yamamoto, Masahiko Wanibuchi, Yoshihiro Minamida, Tadashi Hasegawa, Kiyohiro Houkin
JOURNAL OF NEURO-ONCOLOGY, 99, 1, 147, 153, SPRINGER, 2010年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The simultaneous occurrence of multiple primary intracranial tumors has been reported previously. However, most of these tumors arise after cranial radiotherapy or in association with familial tumor syndromes. Double tumors of different histologies that are unrelated to radiotherapy or genetic disorders are very rare. We present a case of two primary intracranial tumors occurring simultaneously at adjacent sites. Preoperative gadolinium-enhanced magnetic resonance imaging of these tumors revealed a single continuous lesion. Postoperative histological examination revealed the presence of two distinct tumors, meningioma and glioblastoma multiforme. To elucidate the mechanism of synchronous tumor formation, we performed immunohistochemical analysis of the proteins involved in the receptor tyrosine kinase, Wnt, and Notch signaling pathways. These analyses showed that platelet-derived growth factor (PDGF) receptors-alpha and beta were overexpressed in both tumors, thereby indicating the oncogenic effects of activated signaling of these receptors. The PDGF-mediated paracrine system may induce one tumor from another.

Protein deacetylase SIRT1 in the cytoplasm promotes nerve growth factor-induced neurite outgrowth in PC12 cells.
Toshiya Sugino, Mitsuhisa Maruyama, Masaya Tanno, Atsushi Kuno, Kiyohiro Houkin, Yoshiyuki Horio
FEBS letters, 584, 13, 2821, 6, 13, 2010年07月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, SIRT1, a NAD(+)-dependent protein deacetylase, is known to have neural functions. However, despite its cytoplasmic expression in some neural cells, its cytoplasmic function, if any, is unknown. Here we found that PC12 (pheochromocytoma) cells expressed SIRT1 in the cytoplasm. Nerve growth factor (NGF)-induced neurite outgrowth of these cells was promoted by activators of SIRT1, while inhibitors of SIRT1 or SIRT1-siRNA significantly inhibited it. The overexpression of a mutant SIRT1 that localised to the cytoplasm but not the nucleus enhanced the NGF-dependent neurite outgrowth, and a cytoplasmic dominant-negative SIRT1 suppressed it. Thus, cytoplasmic SIRT1 increases the NGF-induced neurite outgrowth of PC12 cells.

Pathogenesis of syringomyelia associated with Chiari type 1 malformation: review of evidences and proposal of a new hypothesis
Izumi Koyanagi, Kiyohiro Houkin
NEUROSURGICAL REVIEW, 33, 3, 271, 284, SPRINGER, 2010年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The exact pathogenesis of syringomyelia associated with Chiari type 1 malformation is unknown, although a number of authors have reported their theories of syrinx formation. The purpose of this review is to understand evidences based on the known theories and to create a new hypothesis of the pathogenesis. We critically review the literatures on clinicopathological, radiological, and clinical features of this disorder. The previously proposed theories mainly focused on the driven mechanisms of the cerebrospinal fluid (CSF) into the spinal cord. They did not fully explain radiological features or effects of surgical treatment such as shunting procedures. Common findings of the syrinx in clinicopathological studies were the communication with the central canal and extracanalicular extension to the posterior gray matter. Most of the magnetic resonance imaging studies demonstrated blockade and alternated CSF dynamics at the foramen magnum, but failed to show direct communication of the syrinx with the CSF spaces. Pressure studies revealed almost identical intrasyrinx pressure to the subarachnoid space and decreased compliance of the spinal CSF space. Recent imaging studies suggest that the extracellular fluid accumulation may play an important role. The review of evidences promotes a new hypothesis of syrinx formation. Decreased absorption mechanisms of the extracellular fluid may underlie the pathogenesis of syringomyelia. Reduced compliance of the posterior spinal veins associated with the decreased compliance of the spinal subarachnoid space will result in disturbed absorption of the extracellular fluid through the intramedullary venous channels and formation of syringomyelia.

Pulsatile wall movement of spinal arachnoid cyst deteriorates spinal cord symptoms: report of three cases
Takeo Baba, Izumi Koyanagi, Kazuhisa Yoshifuji, Tomohiro Murakami, Kiyohiro Houkin
ACTA NEUROCHIRURGICA, 152, 7, 1245, 1249, SPRINGER WIEN, 2010年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Symptomatic spinal arachnoid cyst is a rare disease and the pathophysiology causing spinal cord symptoms has not been well clarified.
The authors report three symptomatic cases of spinal arachnoid cyst at the thoracic level. These patients, aged from 70 to 73 years, showed progressive gait disturbance for a few months before admission. Phase-contrast cine magnetic resonance imaging demonstrated significant compression at the rostral side of the cyst during the diastolic phase of the cardiac cycle. Intraoperative ultrasonography demonstrated that the maximum expansion of the cyst and compression of the dorsal spinal cord occurred when the cerebrospinal fluid moved rostrally during diastole. All patients showed good improvement of their symptoms after surgical removal of the arachnoid cyst.
This report proposes the pathophysiology that the pulsatile enlargement of the arachnoid cyst during diastolic cardiac phase can be an important factor for deterioration of spinal cord symptoms.

Intravenous administration of mesenchymal stem cells derived from bone marrow after contusive spinal cord injury improves functional outcome
Misuzu Osaka, Osamu Honmou, Tomohiro Murakami, Tadashi Nonaka, Kiyohiro Houkin, Hirofumi Hamada, Jeffery D. Kocsis
BRAIN RESEARCH, 1343, 226, 235, ELSEVIER SCIENCE BV, 2010年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Transplantation of mesenchymal stem cells (MSCs) derived from bone marrow has been shown to improve functional outcome in spinal cord injury (SCI). Systemic delivery of MSCs results in therapeutic benefits in a number of experimental central nervous system disorders. In the present study we intravenously administered rat MSCs derived from bone marrow at various time points after induction of a severe contusive SCI in rat to study their therapeutic effects. MSCs were systemically delivered at varied time points (6 h to 28 days after SCI). The spinal cords were examined histologically 6 weeks after SCI. Stereological quantification was performed on the spinal cords to determine donor cell (MSCs transduced with the LacZ gene) density in the lesions. Light microscopic examination revealed that cavitation in the contused spinal cords was less in the MSC-treated rats. A limited number of cells derived from MSCs (LacZ(+)) in the injury site expressed neural or glial markers. Functional outcome measurements using the Basso-Beattie-Bresnehan (BBB) score were performed periodically up to 6 weeks post-SCI. Locomotor recovery improvement was greater in the MSC-treated groups than in sham controls with greatest improvement in the earlier post-contusion infusion times. The availability of autologous MSCs in large number and the potential for systemically delivering cells to target lesion areas without neurosurgical intervention suggests the potential utility of intravenous cell delivery as a prospective therapeutic approach in acute and subacute SCI. (C) 2010 Elsevier B.V. All rights reserved.

Protein deacetylase SIRT1 in the cytoplasm promotes nerve growth factor-induced neurite outgrowth in PC12 cells
Toshiya Sugino, Mitsuhisa Maruyama, Masaya Tanno, Atsushi Kuno, Kiyohiro Houkin, Yoshiyuki Horio
FEBS LETTERS, 584, 13, 2821, 2826, WILEY, 2010年07月, ［査読有り］
英語, 研究論文（学術雑誌）, SIRT1, a NAD(+)-dependent protein deacetylase, is known to have neural functions. However, despite its cytoplasmic expression in some neural cells, its cytoplasmic function, if any, is unknown. Here we found that PC12 (pheochromocytoma) cells expressed SIRT1 in the cytoplasm. Nerve growth factor (NGF)-induced neurite outgrowth of these cells was promoted by activators of SIRT1, while inhibitors of SIRT1 or SIRT1-siRNA significantly inhibited it. The overexpression of a mutant SIRT1 that localised to the cytoplasm but not the nucleus enhanced the NGF-dependent neurite outgrowth, and a cytoplasmic dominant-negative SIRT1 suppressed it. Thus, cytoplasmic SIRT1 increases the NGF-induced neurite outgrowth of PC12 cells. (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Novel bypass surgery for moyamoya disease using pericranial flap: Its impacts on cerebral hemodynamics and long-term outcome
Satoshi Kuroda, Kiyohiro Houkin, Tatsuya Ishikawa, Naoki Nakayama, Yoshinobu Iwasaki
Neurosurgery, 66, 6, 1093, 1101, 6, 2010年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Objective: We reviewed our 11-year experience with a novel bypass procedure, superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis and encephalo-duro-myo-arterio-pericranio-synangiosis (EDMAPS), for moyamoya disease regarding cerebral hemodynamics and long-term outcome. Methods: This prospective study included 75 patients with moyamoya disease, including 28 children and 47 adults. We performed STA-MCA anastomosis and EDMAPS on 123 hemispheres of 75 patients. In addition to conventional STA-MCA anastomosis and indirect bypass for the MCA territory, the medial frontal lobe was revascularized using the frontal pericranial flap through medial frontal craniotomy. Surgical results were analyzed with magnetic resonance imaging, cerebral angiography, and single-photon emission computed tomography/positron emission tomography. Results: Overall incidences of mortality and morbidity were 0% and 5.7%, respectively. The annual risk of cerebrovascular events during the follow-up periods was very low: 0% in pediatric patients and 0.4% in adults over approximately 67 months. Postoperative cerebral angiography showed that the pericranial flap functioned well as donor tissue for indirect bypass, especially in pediatric patients. Follow-up single-photon emission computed tomography/positron emission tomography studies revealed that cerebral blood flow and its reactivity to acetazolamide markedly improved in both the MCA and anterior cerebral artery territories. Conclusion: These findings strongly suggest that STA-MCA anastomosis and EDMAPS using a frontal pericranial flap is a safe and effective surgical procedure to further improve the long-term prognosis in moyamoya disease by improving cerebral hemodynamics in both the MCA and anterior cerebral artery territories. Copyright © 2010 by the Congress of Neurological Surgeons.

Stem cell therapy for cerebral ischemia
Osamu Honmou, Kiyohiro Houkin
Neurological Surgery, 38, 6, 515, 520, 6, 2010年06月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）

前脈絡叢動脈と後交通動脈の起始に関する検討
飯星智史, 野中雅, 宮田圭, 寳金清博
Neurological Surgery, 38, 6, 523, 530, 6, 2010年06月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Object: The anterior choroidal artery (AchoA) is a very important artery for neurosurgeons and neuroendovascular surgeons. In fact the AchoA not only supplies the ventricles but also has important branches to the diencephalon, mesencephalon and cerebrum and also supplies motor and visual pathways. Review of the cerebrovascular embryology explains this vanability in the anatomy of the developing AchoA and posterior communicating artery (PcomA)-posterior cerebral artery (PCA) distributions. Case 1: A 47-year-old woman, with an unruptured left internal carotid artery (ICA) aneurysm. For the cerebral arterial aneurysm approximately 7 mm in size, we performed coil embolization with an assist balloon under general anaesthesia. Case 2: A 63-year-old woman, with an unruptured right ICA aneurysm. Endeavouring to preserve the branch vessels, we undertook a craniotomy neck clipping operation. Discussion and Conclusion: It is thought that, usually. AchoA has its origin at the supraclinoid ICA distal to the PcomA. Our analysis of these two cases may be helpful for a better understanding of the vascular relations and anatomy of the AchoA and PcomA-PCA distributions. We emphasize the importance of recognizing such anomalies in planning surgical and interventional treatment.

Therapeutic time window of mesenchymal stem cells derived from bone marrow after cerebral ischemia
Katsuya Komatsu, Osamu Honmou, Junpei Suzuki, Kiyohiro Houkin, Hirofumi Hamada, Jeffery D. Kocsis
BRAIN RESEARCH, 1334, 84, 92, ELSEVIER SCIENCE BV, 2010年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Intravenous transplantation of mesenchymal stem cells (MSCs) prepared from bone marrow ameliorates functional deficits in rat cerebral infarction models. Although several hypotheses to account for these therapeutic effects have been suggested, angiogenesis is thought to be largely responsible. MSCs were intravenously infused into rats in the relatively later time points after permanent middle cerebral artery occlusion (MCAO) to determine if they could contribute to neovascularization and functional recovery. Although MRI analysis revealed that only rats receiving MSCs 7 days after MCAO exhibited decreased ischemic lesion volume than the control group, all MSCs treated rats receiving MSCs up to 1 month after MCAO had greater angiogenesis near the border of the ischemic lesions and showed greater functional recovery in the treadmill stress test than did control rats. Thus, these results suggest that the time window of MSC therapy is at least over 1 month after cerebral infarction in the rat permanent MCAO model, and systemic delivery of MSCs in the later phase after cerebral ischemia may have beneficial effect through an angiogenic mechanism. (c) 2010 Elsevier B.V. All rights reserved.

Skull base training and education using an artificial skull model created by selective laser sintering
Masahiko Wanibuchi, Masafumi Ohtaki, Takanori Fukushima, Allan H. Friedman, Kiyohiro Houkin
ACTA NEUROCHIRURGICA, 152, 6, 1055, 1060, SPRINGER WIEN, 2010年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Practicing skull base approaches on cadavers affords the surgeon a chance to learn complex anatomical relationships and to practice surgical skills. However, there are ethical or legal problems in obtaining cadaver material in some countries. In addition, there is always risk of transmitting infections with cadaveric material. In order to get around these problems, we created a whole skull model which reproduces the detailed anatomy within the skull base using a selective laser sintering (SLS) technique.
The first author's head was scanned using multidetector-row computed tomography. The data were reconstructed and converted into the standard triangulation language file system. Powdered material comprised of polyamide nylon and glass beads was laser-sintered in accord with the data derived from the head CT. The model was dissected under a surgical microscope using a high-speed drill, suction, and other surgical instruments.
The appearance of both inner and outer cranial surfaces, including sutures, foramens, fissures, and protrusions, were clearly demonstrated. The artificial mastoid did not melt from the heat of the drill when a mastoidectomy was performed. The anatomical structures inside the mastoid and of paranasal sinuses were accurately reproduced in the model.
The model created using SLS should be very useful for the teaching skull base approaches avoiding the ethical, legal, and infection problems inherent in cadavers.

Novel Bypass Surgery for Moyamoya Disease Using Pericranial Flap: Its Impacts on Cerebral Hemodynamics and Long-term Outcome
Satoshi Kuroda, Kiyohiro Houkin, Tatsuya Ishikawa, Naoki Nakayama, Yoshinobu Iwasaki
NEUROSURGERY, 66, 6, 1093, 1101, LIPPINCOTT WILLIAMS & WILKINS, 2010年06月, ［査読有り］
英語, 研究論文（学術雑誌）, OBJECTIVE: We reviewed our 11-year experience with a novel bypass procedure, superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis and encephalo-duro-myo-arterio-pericranio-synangiosis (EDMAPS), for moyamoya disease regarding cerebral hemodynamics and long-term outcome.
METHODS: This prospective study included 75 patients with moyamoya disease, including 28 children and 47 adults. We performed STA-MCA anastomosis and EDMAPS on 123 hemispheres of 75 patients. In addition to conventional STA-MCA anastomosis and indirect bypass for the MCA territory, the medial frontal lobe was revascularized using the frontal pericranial flap through medial frontal craniotomy. Surgical results were analyzed with magnetic resonance imaging, cerebral angiography, and single-photon emission computed tomography/positron emission tomography.
RESULTS: Overall incidences of mortality and morbidity were 0% and 5.7%, respectively. The annual risk of cerebrovascular events during the follow-up periods was very low: 0% in pediatric patients and 0.4% in adults over approximately 67 months. Postoperative cerebral angiography showed that the pericranial flap functioned well as donor tissue for indirect bypass, especially in pediatric patients. Follow-up single-photon emission computed tomography/positron emission tomography studies revealed that cerebral blood flow and its reactivity to acetazolamide markedly improved in both the MCA and anterior cerebral artery territories.
CONCLUSION: These findings strongly suggest that STA-MCA anastomosis and EDMAPS using a frontal pericranial flap is a safe and effective surgical procedure to further improve the long-term prognosis in moyamoya disease by improving cerebral hemodynamics in both the MCA and anterior cerebral artery territories.

小児もやもや病の治療戦略 小児もやもや病の外科治療 今後の課題
黒田 敏, 笹森 徹, 川堀 真人, 中山 若樹, 宝金 清博, 石川 達哉
小児の脳神経, 35, 2, 183, 183, (一社)日本小児神経外科学会, 2010年04月
日本語

Cysteinyl leukotriene receptor antagonists inhibit tumor metastasis by inhibiting capillary permeability
Masako Nozaki, Masanobu Yoshikawa, Kunihiko Ishitani, Hiroyuki Kobayashi, Kiyohiro Houkin, Kohzoh Imai, Yoichiro Ito, Takamura Muraki
Keio Journal of Medicine, 59, 1, 10, 18, 1, 2010年03月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, We explored the possibility of the cysteinyl leukotriene receptor antagonists, pranlukast and montelukast, preventing tumor cell migration through both cerebral and peripheral capillaries. To study tumor cell migration through brain capillaries, male Fisher rats were cannulated via the cisterna magna under pentobarbital anesthesia. RCN9 cells labeled with a fluorescent marker PKH67 were intravenously administered following arachidonic acid administration into the subarachnoid space, and specimens of the central nervous system were collected every 30 min for 8 h. Arachidonic acid increased the fluid volume with elevated white blood cell and RCN9 cell counts. When given 2 h before arachidonic acid administration, pranlukast, but not montelukast, reduced the fluid volume and inhibited white blood cell and RCN9 cell extravasation through the brain capillary. In addition, a Lewis lung carcinoma metastasis model in mice was used to study the inhibitory effect of pranlukast and montelukast against cancer cell extravasation through general capillaries. When mice were given food containing either pranlukast or montelukast, immediately after paw amputation, tumor metastasis was prevented by both drugs, and their survival was prolonged. These results show that pranlukast can inhibit tumor cell migration through both the brain and peripheral capillaries, whereas montelukast inhibits tumor cell migration only in the peripheral capillaries.

Practical Decision-Making in the Treatment of Unruptured Cerebral Aneurysm in Japan: The U-CARE Study
Yukinori Akiyama, Kiyohiro Houkin, Kazuhiko Nozaki, Nobuo Hashimoto
CEREBROVASCULAR DISEASES, 30, 5, 491, 499, KARGER, 2010年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Decision-making during the management of unruptured cerebral aneurysms is a delicate process for both neurosurgeons and patients. Guidelines are evidence-based references that can aid in making decisions. However, neurosurgeons do not always follow guidelines in clinical practice. The purpose of this study is to verify the hypothesis that there is substantial dissociation between treatment guidelines and practical decision-making due to a bias in treatment selection for unruptured cerebral aneurysms. This bias is dependent upon clinician-driven factors such as experience and specialty, and patient-driven factors such as patient preference. Methods: This study was performed using internet questionnaires. A total of 282 randomly selected, qualified Japanese neurosurgeons (out of approx. 6,000 registered neurosurgeons), including 45 endovascular specialists, participated in this study. Radiological and demographic data from 88 cases of unruptured cerebral aneurysm were opened on the Web. Participating neurosurgeons decided on the treatment for each case (clipping, coiling or observation). Results: Variations in treatment selection were not significant between neurosurgeons and endovascular specialists, except for aneurysms such as anterior choroidal artery aneurysm. However, contrary to the guidelines, aneurysms larger than 10 mm tended to be treated conservatively because the risk of treatment is high, while aneurysms smaller than 5 mm in diameter were often selected for intervention (clipping or coiling). Conclusions: This study revealed that in real-world clinical practice, physicians are not always faithful to the current guidelines. In making practical treatment decisions for unruptured cerebral aneurysms, the patient's will and the recognition of unavoidable, treatment-related risks seriously influence neurosurgeons' decisions. Copyright (C) 2010 S. Karger AG, Basel

Therapeutic benefits of human mesenchymal stem cells derived from bone marrow after global cerebral ischemia
Wei Zheng, Osamu Honmou, Kei Miyata, Kuniaki Harada, Junpei Suzuki, He Liu, Kiyohiro Houkin, Hirofumi Hamada, Jeffery D. Kocsis
BRAIN RESEARCH, 1310, 8, 16, ELSEVIER SCIENCE BV, 2010年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Although intravenous delivery of mesenchymal stem cells (MSCs) prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat middle cerebral artery occlusion models, there are few reports of MSC treatment in global cerebral ischemia. We utilized a global cerebral ischemia model induced by arresting the heart with a combination of hypovolemia and intracardiac injections of a cold potassium chloride solution in order to study the potential therapeutic benefits of human mesenchymal. stem cells (hMSCs) on global cerebral ischemia. hMSCs were intravenously injected into the rats 3 h after resuscitation from cardiac arrest. The effects on structural and functional outcome of hMSC were assessed at 5 h and 1, 3, and 7 days using magnetic resonance spectroscopy (MRS), histology, and cognitive functional analysis. intravenous delivery of hMSCs reduced the Lac/Cr ratios, nuclear DNA fragmentation, neuronal loss, and elicited functional improvement compared with the control sham group. Enzyme-linked immunosorbent assay (ELISA) of the hippocampus revealed an increase in BDNF in hMSC-treated group. These data suggest that intravenous delivery of hMSC may have a therapeutic effect in global cerebral ischemia. (C) 2009 Elsevier B.V. All rights reserved.

Hyperperfusion syndrome after clipping an unruptured cerebral aneurysm: two case reports.
Toshiya Sugino, Masafumi Ohtaki, Masahiko Wanibuchi, Sonen Kin, Kiyohiro Houkin
Neurologia medico-chirurgica, 50, 4, 306, 9, 4, 2010年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 68-year-old woman presented with severe headache 9 days after undergoing successful clipping of a right middle cerebral artery aneurysm. Postoperative imaging revealed increased perfusion and diffuse edema in the right frontotemporal cortex. A 57-year-old woman exhibited perseveration soon after undergoing successful clipping of an anterior communicating artery aneurysm. Postoperative imaging studies revealed increased perfusion and diffuse edema in the left frontal and insular cortex. The symptoms and diffuse edema gradually resolved in both patients. These two cases of hyperperfusion syndrome occurred in a series of 190 patients treated by clipping of unruptured cerebral aneurysms. Hyperperfusion syndrome is a rare complication following aneurysm surgery, especially surgery for unruptured cerebral aneurysms without temporary clipping.

脳虚血に対する幹細胞移植
本望修, 本望修, 寳金清博
Neurological Surgery, 38, 6, 2010年

多椎間後方固定を必要とした腰椎破壊性脊椎関節症の1例
村上友宏, 小柳泉, 金子高久, 寳金清博, 恩田敏之, 八巻稔明
日本脊髄外科学会プログラム・抄録集, 25th, 2010年

脳卒中教育としてのNIH stroke scaleの卒前医学教育とOSCE導入,卒業試験実施報告
齊藤正樹, 山本和利, 寳金清博, 米増保之, 高橋明, 小松克也, 小松克也, 三上毅, 三上毅, 今井富裕, 矢坂正弘, 岡田靖, 佐藤利夫, 下濱俊
日本神経学会総会プログラム・抄録集, 51st, 2010年

穿通性頭蓋底損傷について
三上毅, 秋山幸功, 宮田圭, 南田善弘, 寳金清博
日本脳神経外科救急学会プログラム・抄録集, 15th, 2010年

Preoperative and postoperative MRA
Takeshi Mikami, Satoshi Iihoshi, Kiyohiro Houkin
Moyamoya Disease Update, 150, 157, Springer Japan, 2010年, ［査読有り］
英語, 論文集(書籍)内論文, Magnetic resonance angiography (MRA) has opened the door to noninvasive evaluation of the intracranial major arteries. The contemporary MRA can clearly disclose the major intracranial arteries and has become an indispensable modality for the management of cerebrovascular stroke. Based on this dramatic technical evolution, since 1994 new diagnostic guidelines for moyamoya disease have included good MRA as the definitive diagnostic technique for moyamoya disease [1-4]. Nowadays, MRA can be an alternative to conventional angiography in moyamoya disease, and has been acknowledged as a reliable diagnostic tool with high sensitivity and specificity as a result of the remarkable development of MR imaging technology [5-13]. Moreover, MRA is useful not only for the diagnosis but also for follow-up of moyamoya disease in a noninvasive way. © 2010 Springer-Verlag Tokyo.

Overview of image diagnosis of moyamoya disease
Kiyohiro Houkin, Satoshi Iihoshi, Takeshi Mikami
Moyamoya Disease Update, 141, 149, Springer Japan, 2010年, ［査読有り］
英語, 論文集(書籍)内論文, As mentioned in the Introduction, when the original concept of moyamoya disease is reviewed, digital subtraction angiography (DSA) is still the most reliable diagnostic modality. However, as mentioned in the following sections, as far as the depiction of the steno-occlusive change of the Willis ring is concerned, other modalities such as magnetic resonance angiography (MRA) and 3-dimensional computed tomography angiography (3D-CTA) with best quality is quite compatible with DSA. However, the depiction of the moyamoya vessels and the collateral circulation is not always clear in MRA and magnetic resonance imaging (MRI). In addition, 3D-CTA essen tially depicts the morphological aspect of vasculature that is not necessarily identical to the true circulation of the blood flow. In addition, the collateral circulation such as (1) basal moyamoya, and (2) transdural anastomosis of the meningeal artery including the vault moyamoya and ethmoidal moyamoya is not well demonstrated in other modalities (Figs.1 and 2). © 2010 Springer-Verlag Tokyo.

BDNF-Hypersecreting Human Mesenchymal Stem Cells Promote Functional Recovery, Axonal Sprouting, and Protection of Corticospinal Neurons after Spinal Cord Injury
Masanori Sasaki, Christine Radtke, Andrew M. Tan, Peng Zhao, Hirofumi Hamada, Kiyohiro Houkin, Osamu Honmou, Jeffery D. Kocsis
JOURNAL OF NEUROSCIENCE, 29, 47, 14932, 14941, SOC NEUROSCIENCE, 2009年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Transplantation of mesenchymal stem cells (MSCs) derived from bone marrow has been shown to improve functional outcome in spinal cord injury (SCI). We transplanted MSCs derived from human bone marrow (hMSCs) to study their potential therapeutic effect in SCI in the rat. In addition to hMSCs, we used gene-modified hMSCs to secrete brain-derived neurotrophic factor (BDNF-hMSCs). After a dorsal transection lesion was induced at T9, cells were microinjected on each side of the transection site. Fluorogold (FG) was injected into the epicenter of the lesion cavity to identify transected corticospinal tract (CST) neurons. At 5 weeks after transplantation, the animals were perfused. Locomotor recovery improvement was observed for the BDNF-hMSC group, but not in the hMSC group. Structurally there was increased sprouting of injured corticospinal tract and serotonergic projections after hMSC and BDNF-hMSC transplantation. Moreover, an increased number of serotonergic fibers was observed in spinal gray matter including the ventral horn at and below the level of the lesion, indicating increased innervation in the terminal regions of a descending projection important for locomotion. Stereological quantification was performed on the brains to determine neuronal density in primary motor (M1) cortex. The number of FG backfilled cells demonstrated an increased cell survival of CST neurons in M1 cortex in both the hMSC and BDNF-hMSC groups at 5 weeks, but the increase for the BDNF-hMSC group was greater. These results indicate that transplantation of hMSCs hypersecreting BDNF results in structural changes in brain and spinal cord, which are associated with improved functional outcome in acute SCI.

Prior Ethanol Injection Promotes Brain Edema after Traumatic Brain Injury
Ryuichi Katada, Yoko Nishitani, Osamu Honmou, Shunichiro Okazaki, Kiyohiro Houkin, Hiroshi Matsumoto
JOURNAL OF NEUROTRAUMA, 26, 11, 2015, 2025, MARY ANN LIEBERT INC, 2009年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Alcohol consumption prior to traumatic brain injury (TBI) promotes morbidity and mortality although the mechanisms involved remain unclear. The morbidity and mortality caused by TBI, especially brain contusion, are known to be closely associated with brain edema. Here we examined the effects of ethanol pretreatment on brain edema, inflammatory responses, and oxidative stress after brain contusion. Male Wistar rats were given 3g/kg ethanol intraperitoneally and 1 h later were subjected to brain contusion. The ethanol-pretreated group had a significantly decreased survival rate. Magnetic resonance imaging showed ethanol pretreatment significantly augmented the volume of cytotoxic brain edema after contusion. In the ethanol-pretreated rat, the activities of NF-kappa B and AP-1 were reduced 6 h after contusion and COX-2 mRNA expression was increased 24 h after contusion. These findings suggest that ethanol augmented cerebral edema and mortality in rats with brain contusion, possibly through actions on cell survival pathways or COX-2 expression. In addition, antioxidant treatment at 3 h post-injury significantly attenuated some markers of oxidative stress, mortality, and volume of edema at 24 h after ethanol treatment and contusion.

QUANTITATIVE ANALYSIS OF ADVERSE EVENTS IN NEUROSURGERY
Kiyohiro Houkin, Takeo Baba, Yoshihiro Minamida, Tadashi Nonaka, Izumi Koyanagi, Satoshi Iiboshi
NEUROSURGERY, 65, 3, 587, 594, LIPPINCOTT WILLIAMS & WILKINS, 2009年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: it is well recognized that the occurrence rate of adverse events related to surgical procedures is considerably high in neurosurgery compared with other specialties. The purpose of this study was to quantitatively determine the occurrence rate of adverse events related to surgery and endovascular intervention in neurosurgery.
METHODS: A conference on adverse events related to treatments (morbidity and mortality conference) has been held every month for the past 2 years in our department. At these conferences, all adverse events are evaluated and discussed. Adverse events include not only the unexpected complications, but also the neurological and general deterioration predicted before surgery. All the adverse events are discussed in terms of the conceivable causes, their association with the procedures, and the possibility of prediction and avoidance.
RESULTS: One hundred eighty-two events (28.3%) among 643 neurosurgical interventions over 2 years were recognized as adverse events. Among these 182 adverse events, 165 (90.7%) were closely related to procedures and 125 events (68.7%) were predictable before or during the procedures. However, even when retrospectively reviewed, only 6 (3.3%) of events were deemed avoidable. Of these 6 avoidable events, there were only 2 (1.1%) that were considered to have been caused by error.
CONCLUSION: Adverse events are not invariably rare in neurosurgery. Most of them are predictable; however, their avoidance is not necessarily easy. Avoidable adverse events caused by medical errors were observed in only 1.1% of cases.

Cerebral Ischemia Originating from Rotational Vertebral Artery Occlusion Caused by C5/6 Spondylotic Changes: A Case Report
Misuzu Ohsaka, Masayoshi Takigami, Izumi Koyanagi, Sangnyon Kim, Kiyohiro Houkin
NEUROLOGICAL SURGERY, 37, 8, 797, 802, IGAKU-SHOIN LTD, 2009年08月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, A 68-year-old man presented with sudden onset of left hemiparesis, diplopia and numbness of the left side of the body and was admitted to our hospital. MRI of the brain revealed no abnormality. However, neurological examination on admission strongly suggested ischemia of the brainstem. Under anticoagulation therapy his symptoms gradually disappeared by the fourth hospital day. He had a past history of bouts of unconsciousness caused by right rotation of the head, Dynamic plain roentgenograms of the cervical spine showed spondylotic changes and lateral osteophyte formation at C5/6 without instability. Computed tomography (CT)-angiography demonstrated narrowing of the right vertebral artery due to compression of the lateral osteophyte at C5/6. Vertebral angiography revealed complete occlusion of the right vertebral artery induced by right rotation of the head. The artery-to-artery embolism caused by repeated occlusion of the right vertebral artery due to the neck motion was suggested as the mechanism of ischemic attack in this patient, Osteophytectomy at C5/6 via the anterior approach successfully treated dynamic occlusion of the right vertebral artery. Occlusion of the vertebral artery at C1/2 by the head rotation is well known as Bow-Hunter's syndrome. However, dynamic occlusion due to spondylotic changes at C5/6 is rare. In case of ischemic attack of the posterior circulation with lateral osteophyte formation of the cervical spine, dynamic occlusion mechanisms of the vertebral artery at the lower cervical level should be considered.

Spinal cord infarct as the initial clinical presentation of intravascular malignant lymphomatosis
He Liu, Izumi Koyanagi, Hideki Chiba, Masahiro Wanibuchi, Osamu Honmou, Toshiaki Yamaki, Kiyohiro Houkin
JOURNAL OF CLINICAL NEUROSCIENCE, 16, 4, 570, 573, ELSEVIER SCI LTD, 2009年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Intravascular malignant lymphomatosis (IML) is an extremely rare form of lymphoproliferative disorder that is characterized by proliferation of the lymphoma cells in the vascular lumens. We report oil a 78-year-old man who initially presented with spinal cord infarct at the T1 1/12 level. Despite biopsies of the spinal cord and bone marrow from the sternum, the correct diagnosis was not made until autopsy. We identified 19 patients with IML showing spinal cord symptoms as the initial clinical manifestation, and considered the clinical and radiological characteristics as well as the limitations of biopsy. IML can be an important differential diagnosis of progressive paraparesis of unknown etiology. (c) 2008 Elsevier Ltd. All rights reserved.

Reversible Hyperintense Lesion after Balloon Occlusion Test
Koichi Haraguchi, Kiyohiro Houkin, Izumi Koyanagi, Tadashi Nonaka, Takeo Baba
JOURNAL OF NEUROIMAGING, 19, 2, 174, 178, WILEY-BLACKWELL PUBLISHING, INC, 2009年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We report a unique case of a reversible high signal intensity lesion observed on a magnetic resonance (MR) image accompanied by transient neurological deficits related to a balloon occlusion test. This abnormality was considered to be vasogenic edema caused by the disruption of the blood-brain barrier (BBB) due to a long history of uncontrolled hypertension and transient ischemia induced by the balloon occlusion test.
J Neuroimaging 2009;19:174-178.

Therapeutic benefits of angiogenetic gene-modified human mesenchymal stem cells after cerebral ischemia
Kentaro Toyama, Osamu Honmou, Kuniaki Harada, Junpei Suzuki, Kiyohiro Houkin, Hirofumi Hamada, Jeffery D. Kocsis
EXPERIMENTAL NEUROLOGY, 216, 1, 47, 55, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2009年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Intravenous transplantation of human mesenchymal stem cells (hMSCs) expanded from adult bone marrow ameliorates functional deficits in rat cerebral infarction models. Several hypotheses to account for the therapeutic mechanisms have been suggested, but angiogenesis is thought to be of critical importance. Recently, we have reported the therapeutic benefits of hMSCs which have been transfected with the angiopoietin-1 gene in a rat permanent middle cerebral artery occlusion (MCAO) model. To potentially enhance the therapeutic effects of angiopoietin-1 gene-modified hMSC (Ang-hMSC), we transfected hMSCs with the angiopoietin-1 gene and the VEGF gene, and investigated whether the combination of Ang-1 and VEGF gene-modified hMSCs (Ang-VEGF-hMSC) contribute to functional recovery in a rat MCAO model. We induced MCAO using intraluminal vascular occlusion, and hMSCs, Ang-hMSCs, VEGF-hMSCs or Ang-VEGF-hMSCs were intravenously infused 6 h later. MRI and behavioral analyses revealed that rats receiving Ang-VEGF-hMSCs showed the greatest structural-functional recovery as compared to the other groups. These results suggest that intravenous administration of hMSCs transfected with the angiopoietin-1 and VEGF gene using a fiber-mutant adenovirus vector may represent a new strategy for the treatment of ischemia. (C) 2008 Elsevier Inc. All rights reserved.

Susceptibility-weighted magnetic resonance imaging for the detection of cerebral microhemorrhage in patients with traumatic brain injury.
Akiyama Y, Miyata K, Harada K, Minamida Y, Nonaka T, Koyanagi I, Asai Y, Houkin K
Neurologia medico-chirurgica, 49, 3, 97, 99, 3, 2009年03月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The sensitivity of susceptibility-weighted magnetic resonance (MR) imaging was compared with conventional MR sequences, including T(2)*-weighted imaging, and computed tomography for the detection of cerebral hemorrhages in 15 patients with head injury. Susceptibility-weighted imaging detected a mean of 76+/-52 (total 1132) hypointense spotty lesions, compared to a mean of 21+/-19 (total 316) detected by T(2)*-weighted imaging (p<0.0001, paired t-test). Susceptibility-weighted imaging is extremely sensitive for the visualization and detection of microhemorrhages.

Susceptibility-Weighted Magnetic Resonance Imaging for the Detection of Cerebral Microhemorrhage in Patients With Traumatic Brain Injury
Yukinori Akiyama, Kei Miyata, Kuniaki Harada, Yoshihiro Minamida, Tadashi Nonaka, Izumi Koyanagi, Yasufumi Asai, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 49, 3, 97, 99, JAPAN NEUROSURGICAL SOC, 2009年03月, ［査読有り］
英語, 研究論文（学術雑誌）, The sensitivity of susceptibility-weighted magnetic resonance (MR) imaging was compared with conventional MR sequences, including T(2)*-weighted imaging, and computed tomography for the detection of cerebral hemorrhages in 15 patients with head injury. Susceptibility-weighted imaging detected a mean of 76 +/- 52 (total 1132) hypointense spotty lesions, compared to a mean of 21 +/- 19 (total 316) detected by T(2)*-weighted imaging (p < 0.0001, paired t-test). Susceptibility-weighted imaging is extremely sensitive for the visualization and detection of microhemorrhages.

ウイリス動脈輪閉塞症における病態・治療に関する研究 3DCT-Angioと3T-MRAによるもやもや病診断について
飯星智史, 寳金清博
ウィリス動脈輪閉塞症における病態・治療に関する研究 平成20年度 総括・分担研究報告書, 2009年

Stroke Teamによる,NIHSSとt-PAに関する医学部卒前教育と卒業試験の実施
齊藤正樹, 米増保之, 山本和利, 姉川敬裕, 高橋明, 岡村耕一, 矢坂正弘, 岡田靖, 下濱俊, 寳金清博
日本脳神経外科救急学会プログラム・抄録集, 14th, 2009年

後交通動脈と前脈絡叢動脈の起始に関する2症例の検討
飯星智史, 宮田圭, 斉藤正樹, 野中雅, 小柳泉, 寳金清博
日本神経放射線学会プログラム・抄録集, 38th, 2009年

Suprasellar Hemangioblastoma
Shiro Miyata, Takeshi Mikami, Yoshihiro Minamida, Yukinori Akiyama, Kiyohiro Houkin
JOURNAL OF NEURO-OPHTHALMOLOGY, 28, 4, 325, 326, LIPPINCOTT WILLIAMS & WILKINS, 2008年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, A 59-year-old woman presented with disturbance of consciousness and decreased visual acuity caused by a suprasellar mass identified on MRI. A bifrontal interhemispheric approach allowed removal of the top an d lateral sides of the tumor from the wall of the third ventricle. The hypothalamus appeared to be the origin of the mass, which proved to be hemangioblastoma, a rare tumor in this location.

Moyamoya disease: current concepts and future perspectives
Satoshi Kuroda, Kiyohiro Houkin
LANCET NEUROLOGY, 7, 11, 1056, 1066, ELSEVIER SCIENCE INC, 2008年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Moyamoya disease is an uncommon cerebrovascular disease that is characterised by progressive stenosis of the terminal portion of the internal carotid artery and its main branches. The disease is associated with the development of dilated, fragile collateral vessels at the base of the brain, which are termed moyamoya vessels. The incidence of moyamoya disease is high in east Asia, and familial forms account for about 15% of patients with this disease. Moyamoya disease has several unique clinical features, which include two peaks of age distribution at 5 years and at about 40 years. Most paediatric patients have ischaemic attacks, whereas adult patients can have ischaemic attacks, intracranial bleeding, or both. Extracranial-intracranial arterial bypass, including anastomosis of the superficial temporal artery to the middle cerebral artery and indirect bypass, can help prevent further ischaemic attacks, although the beneficial effect on haemorrhagic stroke is still not clear. In this Review, we summarise the epidemiology, aetiology, clinical features, diagnosis, surgical treatment, and outcomes of moyamoya disease. Recent updates and future perspectives for moyamoya disease will also be discussed.

Current knowledge on the genetic factors involved in moyamoya disease
Hirokuni Hashikata, Wanyang Liu, Yohei Mineharu, Kayoko Inoue, Katsunobu Takenaka, Hidetoshi Ikeda, Kiyohiro Houkin, Satoshi Kuroda, Kenji Kikuchi, Mitsuru Kimura, Takuyuu Taki, Makoto Sonobe, Sadahiko Ban, Hidekazu Nogaki, Akira Handa, Kenichiro Kikuta, Yasushi Takagi, Kazuhiko Nozaki, Nobuo Hashimoto, Akio Koizumi
Brain and Nerve, 60, 11, 1261, 1269, 11, 2008年11月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Moyamoya disease (MMD) is characterized by progressive stenosis and occlusion of the terminal portion of the bilateral carotid arteries as well as arterial collateral vessels. The etiology of MMD, however, remains unknown. Several pieces of evidence suggest the involvement of genetic factors in MMD: over 10% of MMD patients have affected blood relatives
concordance in the affection status has been proven in 80% of identical twins
and there is an ethnic predisposition to MMD, the incidence of the disease being the highest in the Asian population. With regard to genetic factor (s), transmission of MMD does not follow the classic Mendelian law, i, e., skipping of a generation and discordance in identical twins, thereby indicating that genetic influence is likely to determine the susceptibility to MMD. This study aimed to overview the recent findings related to the genetic determinants in MMD and to provide research perspectives for the next decade. Pathophysiological investigations at molecular levels have uncovered the upregulation of various growth and stress response factors that are associated with angiogenesis in occlusive cerebral arteries. Genetic studies have been conducted in the past 30 years. In the first phase, the association of MMD with HLA was investigated extensively, but the opinions remained equivocal. In the second phase, linkage analysis was performed, which demonstrated multiple loci-3p24.2-26, 6q, 8q23. 12p12, and 17q25. None of these studies were replicated. A large genome-wide linkage analysis using 3 generation families that has been performed in 2008 has resolved the enigma of MMD and revealed a single locus on17q25. This locus is expected to provide a clue to the genetic basis for MMD, paving a way to comprehensive understanding of molecular consequences in MMD.

もやもや病に対するSTA-MCA anastomosis+EDMAPSの治療成績
黒田 敏, 中山 若樹, 石川 達哉, 宝金 清博, 岩崎 喜信
脳循環代謝, 20, 1, 153, 153, (一社)日本脳循環代謝学会, 2008年11月
日本語

Optimization of a therapeutic protocol for intravenous injection of human mesenchymal stem cells after cerebral ischemia in adult rats
Yoshinori Omori, Osamu Honmou, Kuniaki Harada, Junpei Suzuki, Kiyohiro Houkin, Jeffery D. Kocsis
BRAIN RESEARCH, 1236, 30, 38, ELSEVIER SCIENCE BV, 2008年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The systemic injection of human mesenchymal stem cells (hMSCs) prepared from adult bone marrow has therapeutic benefits after cerebral artery occlusion in rats, and may have multiple therapeutic effects at various sites and times within the lesion as the cells respond to a particular pathological microenvironment. However, the comparative therapeutic benefits of multiple injections of hMSCs at different time points after cerebral artery occlusion in rats remain unclear. in this study, we induced middle cerebral artery occlusion (MCAO) in rats using intra-luminal vascular occlusion, and infused hMSCs intravenously at a single 6 h time point (low and high cell doses) and various multiple time points after MCAO. From MRI analyses lesion volume was reduced in all hMSC cell injection groups as compared to serum alone injections. However, the greatest therapeutic benefit was achieved following a single high cell dose injection at 6 h post-MCAO, rather than multiple lower cell infusions over multiple time points. Three-dimensional analysis of capillary vessels in the lesion indicated that the capillary volume was equally increased in all of the cell-injected groups. Thus, differences in functional outcome in the hMSC transplantation subgroups are not likely the result of differences in angiogenesis, but rather from differences in neuroprotective effects. (C) 2008 Elsevier B.V. All rights reserved.

Interstitial spinal-cord oedema in syringomyelia associated with Chiari type 1 malformations
Y. Akiyama, I. Koyanagi, K. Yoshifuji, T. Murakami, T. Baba, Y. Minamida, T. Nonaka, K. Houkin
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 79, 10, 1153, 1158, B M J PUBLISHING GROUP, 2008年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Object: The pathophysiology of syringomyelia in Chiari type 1 malformations has not been clarified. Oedema-like spinal-cord swelling was recently reported in several pathological conditions, including Chiari type 1 malformations as a pre-syrinx state. However, the role of the pre-syrinx state in the development of syringomyelia is unknown. The purpose of this study is to investigate the parenchymal changes of the spinal cord in syringomyelia associated with Chiari type 1 malformations.
Methods: Pre- and postoperative MRI findings in 14 patients who underwent foramen magnum decompression in our institute were reviewed. The analysis was focused on differences in visualisation of the syrinx between T1- and T2-weighted images and abnormal parenchymal signal changes. There were 6 men and 8 women, aged from 6 to 79 years. No patients showed hydrocephalus.
Results: Twelve patients had large and expansive syrinx, whereas 2 patients showed small syrinx confined to the centre of the spinal cord. T2-weighted images displayed significantly larger intramedullary abnormal signal areas. Nine patients showed parenchymal hyperintensity areas around the enlarged central canal or base of the posterior white columns adjacent to the syringomyelic cavity. Such parenchymal hyperintensity areas markedly diminished with reduction of the syrinx after surgery and were considered to be interstitial oedema.
Conclusions: From this study, the interstitial oedema of the spinal cord commonly accompanies syringomyelia with Chiari type 1 malformations. Accumulation of the extracellular fluid due to disturbed absorption mechanisms may play an important role in the pathophysiology of syringomyelia associated with Chiari type 1 malformations.

Radiological findings and clinical course of conus lipoma: Implications for surgical treatment
Izumi Koyanagi, Kazutoshi Hida, Yoshinobu Iwasaki, Toyohiko Isu, Masami Yoshino, Tomohiro Murakami, Kazuhisa Yoshifuji, Kiyohiro Houkin
NEUROSURGERY, 63, 3, 546, 551, LIPPINCOTT WILLIAMS & WILKINS, 2008年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: A significant variety in morphology of conus lipomas may underlie differences in clinical presentation of the patients and controversy in surgical management. We retrospectively studied 58 patients with conus lipomas at our institutions. The purpose of this study was to infer the clinical course from the radiological findings and to provide information for decision-making in planning for surgical treatment.
METHODS: The patients underwent untethering surgery between 1984 and 2005. There were 35 transitional and 23 dorsal lipomas. The age at surgery ranged from 1 month to 50 years (median, 4 yr). Preoperative clinical history, radiological findings, and postoperative results were analyzed.
RESULTS: Fifteen patients were asymptomatic, and 43 patients were symptomatic pre-operatively. Twenty-one patients presented with motor deficits of the lower extremities. In seven patients, motor deficits appeared early, before 1 year of age. Massive lipomas compressing the cord or herniation of the spinal cord into the subcutaneous tissue were characteristic findings of such early deterioration. Motor deficits were present in 73% of patients with lipomas extending to the lumbar level, whereas 88% of patients with lipomas confined to the sacral level had only urinary deficits. During a mean postoperative follow-up period of 7.9 years, 4 (27%) of the 15 asymptomatic patients developed urinary and/or motor deficits, and 12 (28%) of the 43 symptomatic patients showed further neurological deterioration.
CONCLUSION: This study demonstrates that the location and morphology of conus lipomas influence the neurological presentation of the patients. Early prophylactic surgery is a reasonable treatment option if early deterioration is predicted by imaging studies.

Novel epidemiological features of moyamoya disease
T. Baba, K. Houkin, S. Kuroda
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 79, 8, 900, 904, B M J PUBLISHING GROUP, 2008年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Many clinical features that are specific to moyamoya disease have been reported and cited in textbooks based on previous data. The purpose of this study is to investigate the present epidemiological features of moyamoya disease based on recently obtained regional all-inclusive data.
Methods: The authors performed an all-inclusive survey of moyamoya disease in Hokkaido, one of the major islands in Japan that has a population of 5.63 million. The epidemiological features were analysed based on the data from 267 newly registered patients with moyamoya disease in Hokkaido from 2002 to 2006. These analysed data were adjusted to the whole Japanese population at 2005.
Results: The detection rate of the disease per year was 0.94 patients per 100 000 people, and prevalence was 10.5 patients per 100 000 people. The incidence of ischaemia concerned with the disease was 0.53 patients per 100 000 people- years and haemorrhage was 0.2 patients per 100 000 people- years. The ratio of female to male patients was 2.18. The ratio of patients aged 10 years and above to under 10 years of age at onset was 6.18. Two peaks for age of onset were seen: the highest was observed between 45 and 49 years, and the second between 5 and 9 years. Asymptomatic patients comprised 17.8% of the total number of patients.
Conclusion: The epidemiological features of moyamoya disease determined by this survey varied considerably from previous data. The detection rate and prevalence of the disease were higher than those reported previously. The highest peak of onset age was older than those reported previously. In addition, it was revealed that asymptomatic moyamoya patients are not always rare in Japan.

Autosomal dominant moyamoya disease maps to chromosome 17q25.3.
Mineharu Y, Liu W, Inoue K, Matsuura N, Inoue S, Takenaka K, Ikeda H, Houkin K, Takagi Y, Kikuta K, Nozaki K, Hashimoto N, Koizumi A
Neurology, 70, 24 Pt 2, 2357, 2363, 2008年06月, ［査読有り］
英語

Evaluation of carotid plaque composition by computed tomographic angiography and black blood magnetic resonance images
K. Haraguchi, K. Houkin, I. Koyanagi, T. Nonaka, T. Baba
MINIMALLY INVASIVE NEUROSURGERY, 51, 2, 91, 94, GEORG THIEME VERLAG KG, 2008年04月, ［査読有り］
英語, 研究論文（学術雑誌）, The purpose of this study was to evaluate quantitatively the composition of carotid plaque by computed tomographic (CT) angiography and qualitatively by black blood magnetic resonance images (MRI). Thirty-eight patients with high-grade carotid artery stenosis were included in this study. Ultrasonography, CT angiography and black blood MRI of the cervical carotid artery were performed, and the CT number was measured in Hounsfield units (HU). The average CT number of the 15 unstable plaques (39.5%) was 27.7 +/- 7.5 HU and that of the 23 stable plaques (60.5%) was 60.4 +/- 20.8 HU (p=0.0001). In the 23 patients with stable plaque, 21 demonstrated isointensity in T-1- and T-2-weighted images in the black blood MRI (p = 0.0001). By using CT angiography and MRI, precise images of the pathology of the carotid arterial wall can be obtained. It is possible to evaluate the components of carotid artery plaque with high reliability by quantification of the CT number in CT angiography and performing black blood MRI as well as carotid ultrasonography.

Evaluation of Carotid Plaque Composition by Computed Tomography Angiography and Black Blood Magnetic Resonance Image
K. Haraguchi, K. Houkin, I. Koyanagi, T. Nonaka, T. Baba
INTERVENTIONAL NEURORADIOLOGY, 14, 1, 39, 43, EDIZIONI CENTAURO, 2008年03月, ［査読有り］
英語, 研究論文（学術雑誌）, The purpose of this study was to evaluate the composition of a carotid plaque quantitatively by computed tomography (CT) angiography and qualitatively by black blood magnetic resonance imaging (MRI). Thirty-eight patients with high-grade carotid artery stenosis were included in this study. Ultrasonography, CT angiography and black blood MRI of the cervical carotid artery were performed, and the CT number was measured in Hounsfield units (HU). The average CT number of the 15 unstable plaques (39.5%) was 27.7 +/- 7.5 HU and that of the 23 stable plaques (60.5%) was 60.4 +/- 20.8 HU (p <0.0001). In the 23 patients with stable plaque, 21 demonstrated isointensity in T1 and T2 in the black blood MRI (p <0.0001).
By using CT angiography and MRI, precise images of the pathology of the carotid arterial wall can be obtained. It is possible to evaluate the components of a carotid artery plaque with high reliability by quantification of the CT number in CT angiography and performing black blood MRI as well as in carotid ultrasonography.

Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia
Toshiyuki Onda, Osamu Honmou, Kuniaki Harada, Kiyohiro Houkin, Hirofumi Hamada, Jeffery D. Kocsis
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 28, 2, 329, 340, NATURE PUBLISHING GROUP, 2008年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Transplantation of human mesenchymal stem cells (hMSCs) prepared from adult bone marrow has been reported to ameliorate functional deficits after cerebral artery occlusion in rats. Although several hypotheses to account for these therapeutic effects have been suggested, current thinking is that both neuroprotection and angiogenesis are primarily responsible. In this study, we compared the effects of hMSCs and angiopoietin-1 gene-modified hMSCs (Ang-hMSCs) intravenously infused into rats 6 h after permanent middle cerebral artery occlusion. Magnetic resonance imaging and histologic analyses revealed that rats receiving hMSCs or Ang-hMSCs exhibited comparable reduction in gross lesion volume as compared with the control group. Although both cell types indeed improved angiogenesis near the border of the ischemic lesions, neovascularization and regional cerebral blood flow were greater in some border areas in Ang-hMSC group. Both hMSC- and Ang-hMSC-treated rats showed greater improved functional recovery in the treadmill stress test than did control rats, but the Ang-hMSC group was greater. These results indicate the intravenous administration of genetically modified hMSCs to express angiopoietin has a similar effect on reducing lesion volume as hMSCs, but the Ang-hMSC group showed enhanced regions of increased angiogenesis at the lesion border, and modest additional improvement in functional outcome.

Moyamoya disease presenting with subarachnoid hemorrhage localized over the frontal cortex: case report.
Toshiya Osanai, Satoshi Kuroda, Naoki Nakayama, Tomohiro Yamauchi, Kiyohiro Houkin, Yoshinobu Iwasaki
Surgical neurology, 69, 2, 197, 200, 2, 2008年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: In moyamoya disease, intracranial bleeding is known to occur because of the rupture of saccular aneurysms in the circle of Willis or because of the rupture of dilated, fragile moyamoya vessels. The former causes subarachnoid hemorrhage (SAH), and the latter causes intracerebral or intraventricular hemorrhage. CASE DESCRIPTION: In this report, we describe the case of a 34-year-old woman with moyamoya disease who suddenly developed headache and jacksonian seizure. Plain computed tomographic scans on admission revealed SAH localized over the left frontal cortex. The patient was diagnosed with moyamoya disease on cerebral angiography. However, no aneurysm was found on cerebral angiography. Positron emission tomography showed the reduction of CBF and its reactivity to acetazolamide and the elevation of CBV in the left hemisphere. She underwent STA to MCA anastomosis and indirect synangiosis. Intraoperative observations revealed that the pial arterioles were markedly dilated on the brain surface. The CBF in the left hemisphere significantly improved after surgery. The patient has experienced no further episode of cerebral ischemia or intracranial bleeding. CONCLUSIONS: Subarachnoid hemorrhage of unknown cause is quite rare in moyamoya disease. Based on the findings in the present case, the dilated collateral arteries on the brain surface may rupture and cause SAH over the cerebral cortex, which is the third cause of intracranial bleeding in patients with persistent cerebral ischemia due to moyamoya disease.

Autosomal dominant moyamoya disease maps to chromosome 17q25.3. Neurology. 2008 Jun 10;70(24 Pt 2):2357-63. Epub 2008 May 7.　　　　　　　　　　　　　　　
Mineharu Y, Liu W, Inoue K, Matsuura N, Inoue S, Takenaka K, Ikeda H, Houkin K, Takagi Y, Kikuta K, Nozaki K, Hashimoto N, Koizumi A
2008年, ［査読有り］
英語

Clinical manifestations and surgical results for paraclinoid cerebral aneurysms presenting with visual symptoms
Tadashi Nonaka, Koichi Haraguchi, Takeo Baba, Izumi Koyanagi, Kiyohiro Houkin
SURGICAL NEUROLOGY, 67, 6, 612, 619, ELSEVIER SCIENCE INC, 2007年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Clipping a paraclinoid aneurysm is difficult if the patient has a visual disturbance. Visual function sometimes deteriorates postoperatively for patients with a large aneurysm. In this study, we report the long-term follow-up of patients with visual impairments attributed to optic nerve compression when paraclinoid aneurysms are surgically treated.
Methods: Seventeen patients with optic nerve impairment induced by compression of paraclinoid ICA aneurysms were treated. All of the aneurysms were large, including 6 giant aneurysms. The aneurysms displayed partial thrombosis or calcification of the aneurysmal wall in 6 cases.
Results: Direct surgery such as neck clipping or wrapping of the aneurysm was performed in 9 aneurysms and indirect procedures in 8 others (ICA occlusion, 1; ICA occlusion + bypass, 7). Of 17 patients, 11 (65%) showed improvement in several dysfunctions of visual acuity or visual field. Of 6 patients, whose vision had not recovered well, 5 underwent direct surgery. Moreover, these 5 patients had an intra-aneurysmal thrombosis or calcification of the aneurysmal wall. Nevertheless, I patient whose aneurysm with partial thrombosis was treated via indirect procedure had good recovery of vision.
Conclusions: Direct clipping is the treatment of choice for patients with a mass effect on the optic nerve due to paraclinoid aneurysm. However, it is difficult to achieve sufficient decompression of the optic nerve when the aneurysm is accompanied by partial thrombosis or calcification of the aneurysmal wall. In those cases, an indirect procedure seems to be a relatively safe, effective treatment. (C) 2007 Elsevier Inc. All rights reserved.

Mesenchymal stem cells derived from peripheral blood protects against ischemia
Ryo Ukai, Osamu Honmou, Kuniaki Harada, Kiyohiro Houkin, Hirofumi Hamada, Jeffery D. Kocsis
JOURNAL OF NEUROTRAUMA, 24, 3, 508, 520, MARY ANN LIEBERT INC, 2007年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Intravenous delivery of mesenchymal stem cells (MSCs) prepared from bone marrow (BMSCs) reduces infarction volume and ameliorates functional deficits in a rat cerebral ischemia model. MSC-like multipotent precursor cells (PMSCs) have also been suggested to exist in peripheral blood. To test the hypothesis that treatment with PMSCs may have a therapeutic benefit in stroke, we compared the efficacy of systemic delivery of BMSCs and PMSCs. A permanent middle cerebral artery occlusion (MCAO) in rat was induced by intraluminal vascular occlusion with a microfilament. Rat BMSCs and PMSCs were prepared in culture and intravenously injected into the rats 6 h after MCAO. Lesion size was assessed at 6 h, and 1, 3, and 7 days using MR imaging and histology. The hemodynamic change of cerebral blood perfusion on stroke was assessed the same times using perfusion-weighted image (PWI). Functional outcome was assessed using the treadmill stress test. Both BMSCs and PMSCs treated groups had reduced lesion volume, improved regional cerebral blood flow, and functional improvement compared to the control group. The therapeutic benefits of both MSC-treated groups were similar. These data suggest that PMSCs derived from peripheral blood could be an important cell source of cell therapy for stroke.

Transorbital intracranial penetrating injury from impaling on an earpick
Taro Yamashita, Takeshi Mikami, Takeo Baba, Yoshihiro Minamida, Toshiya Sugino, Izumi Koyanagi, Tadashi Nonaka, Kiyohiro Houkin
JOURNAL OF NEURO-OPHTHALMOLOGY, 27, 1, 48, 49, LIPPINCOTT WILLIAMS & WILKINS, 2007年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, An inebriated 86-year-old man impaled himself on a wooden earpick that penetrated through the superior orbital fissure into the prepontine cistern. The patient underwent surgery immediately by a lateral suboccipital approach, and the earpick was pulled out through the wound with control of hemorrhage from the cavernous sinus. He survived this event with no neurologic deficits apart from complete ipsilateral ophthalmoplegia, and ptosis. Prompt imaging and surgical intervention allowing direct visualization of the foreign body and prevention of intracranial complications are part of proper management of this problem.

[Surgical site infections in neurosurgery: perioperative management].
Minamida Y, Houkin K
Nihon rinsho. Japanese journal of clinical medicine, 65 Suppl 3, 573, 578, 2007年03月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）

Magnetic resonance lactate and lipid signals in rat brain after middle cerebral artery occlusion model
Kuniaki Harada, Osamu Honmou, He Liu, Michio Bando, Kiyohiro Houkin, Jeffery D. Kocsis
BRAIN RESEARCH, 1134, 1, 206, 213, ELSEVIER SCIENCE BV, 2007年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Proton magnetic resonance spectroscopy (1-H MRS) has revealed changes of metabolites in acute cerebral infarction. Although the drastic changes of lactate and N-acetyl-aspartate have been reported to be useful indicators of the ischemic damage in both humans and experimental animals, lipid signals are also detected by the short echo time sequence 15 days after ischemia. The objective of this study was to find a novel technique to isolate lactate signals from lipid signals in the ischemic brain. First, MRS was used to study the lipid and lactate components of a spherical phantom in vitro, and parameters were established to separate these components in vitro. Then, MR measurements were obtained from the brains of middle cerebral artery occlusion rats. All MR measurements were performed using a 7-T (300 MHz), 18.3-cm-bore superconducting magnet (Oxford Magnet Technologies) interfaced to a Unity INOVA Imaging System (Varian Technologies). T-2-weighted images were obtained from a 1.0-mm-thick coronal section using a 3-cm field of view. It is well known that lipid has a shorter and lactate a longer T-2 relaxation time. These distinct magnetic characteristics allowed us to separate the lactate signal from the lipid signal. Thus, adjustment of the echo time is essential to analyze the metabolites in acute cerebral infarction, which maybe useful in both the clinic and laboratory. (c) 2006 Elsevier B.V. All rights reserved.

Free Flap Transfer for the Treatment of Intractable Postcraniotomy Subdural Empyemas and Epidural Abscesses
Takeshi Mikami, Yoshihiro Minamida, Toshiya Sugino, Izumi Koyanagi, Takatoshi Yotsuyanagi, Kiyohiro Houkin
Operative Neurosurgery, 60, suppl_2, ONS, 83, Oxford University Press (OUP), 2007年02月01日, ［査読有り］
研究論文（学術雑誌）,


Postcraniotomy subdural empyemas and epidural abscesses are uncommon, potentially lethal, complications of neurosurgery. Patients with these complications may be difficult to manage, and mortality can occur.





Between 1997 and 2006, the authors treated eight patients with recalcitrant postcraniotomy subdural empyema and epidural abscess with combinations of myocu-taneous free flap transfer. The free flap transfer was intended for patients who could not be cured with conventional surgical debridement and bone flap removal. Patient ages ranged from 15 to 67 years (mean, 41.5 yr). There were six men and two women. Treatment was required for cranial base tumors (n = :3), the result of trauma (n = :2), malignant tumors (n = :2), and cerebral hematoma (n = :1). In six patients (75%), an expanded polytetrafluoroethylene sheet was used as a dural substitute at the original surgery. We used three rectus abdominis myocutaneous flaps and five latissimus dorsi myocutaneous flaps. In six patients (75%), surgery was performed in the chronic stage of infection, and the other two patients were in the acute stage of infection.





Among all the patients, two failures occurred because of flap ischemia, but these were resolved after an additional procedure. However, one of these two patients, in whom surgery was performed at the acute stage of infection, died 4 weeks after the surgery. The postoperative course of the other six patients was uneventful. Isolated microorganisms were methicillin-resistant Staphylococcus aureus (four patients), Pseudomonas aeruginosa(three patients), and methicillin-sensitive Staphylococcus aureus(one patient).





Myocutaneous free flap transfer allows sufficient blood circulation and dead space control and is resistant to infection. Therefore, free flap transfer is useful for eliminating intractable empyema and abscess; however, it is important that the procedure be considered in the chronic stage of infection.

NOVEL BIPOLAR FORCEPS WITH PROTEIN REPELLENCE USING GOLD–POLYTETRAFLUOROETHYLENE COMPOSITE FILM
Takeshi Mikami, Yoshihiro Minamida, Izumi Koyanagi, Kiyohiro Houkin
Operative Neurosurgery, 60, 157, 161, Oxford University Press (OUP), 2007年02月, ［査読有り］
研究論文（学術雑誌）

Delayed thromboembolic infarction associated with reconfiguration of guglielmi detachable coils - Case report -
Koichi Haraguchi, Kiyohiro Houkin, Tadashi Nonaka, Takeo Baba
NEUROLOGIA MEDICO-CHIRURGICA, 47, 2, 79, 82, JAPAN NEUROSURGICAL SOC, 2007年02月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 77-year-old woman presented with delayed thromboembolic infarction of a basilar artery trunk aneurysm that occurred 2 weeks after coil embolization of the unruptured aneurysm. The postoperative course was uneventful until the patient suffered sudden onset of consciousness disturbance 13 days after the treatment. Computed tomography showed no abnormality, but digital subtraction angiography revealed a thrombus extending from the aneurysm neck to a point distal to the basilar artery. Thrombolysis was achieved by the infusion of urokinase. Reconfiguration of the coil at the aneurysm neck was revealed compared with the initial configuration of the coil immediately after embolization. Magnetic resonance imaging obtained after the thrombolysis showed hyperintense areas in the bilateral occipital lobes and thalami. Periprocedural thromboembolic complications associated with coil embolization of an aneurysm are well known. However, delayed thromboembolic complications may occur in some patients after successful coil packing of an aneurysm.

Free flap transfer for the treatment of intractable postcraniotomy subdural empyemas and epidural abscesses
Takeshi Mikami, Yoshihiro Minamida, Toshiya Sugino, Izumi Koyanagi, Takatoshi Yotsuyanagi, Kiyohiro Houkin
NEUROSURGERY, 60, 2, 83, 87, LIPPINCOTT WILLIAMS & WILKINS, 2007年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Postcraniotomy subdural empyemas and epidural abscesses are uncommon, potentially lethal, complications of neurosurgery. Patients with these complications may be difficult to manage, and mortality can occur.METHODS: Between 1997 and 2006, the authors treated eight patients with recalcitrant postcraniotomy subdural empyema and epidural abscess with combinations of myocutaneous free flap transfer. The free flap transfer was intended for patients who could not be cured with conventional surgical debridement and bone flap removal. Patient ages ranged from 15 to 67 years (mean, 41.5 yr). There were six men and two women. Treatment was required for cranial base tumors. (n = 3), the result of trauma (n = 2), malignant tumors (n = 2), and cerebral hematoma (n = 1). In six patients (75%), an expanded polytetrafluoroethylene sheet was used as a dural substitute at the original surgery. We used three rectus abdominis myocutaneous flaps and five latissimus dorsi myocutaneous flaps. In six patients (75%), surgery was performed in the chronic stage of infection, and the other two patients were in the acute stage of infection.RESULTS: Among all the patients, two failures occurred because of flap ischemia, but these were resolved after an additional procedure. However, one of these two patients, in whom surgery was performed at the acute stage of infection, died 4 weeks after the surgery. The postoperative course of the other six patients was uneventful. Isolated microorganisms were methicillin-resistant Staphylococcus aureus (four patients), Pseudomonas aeruginosa (three patients), and methicillin-sensitive Staphylococcus aureus (one patient).CONCLUSION: Myocutaneous free flap transfer allows sufficient blood circulation and dead space control and is resistant to infection. Therefore, free flap transfer is useful for eliminating intractable empyema and abscess; however, it is important that the procedure be considered in the chronic stage of infection.

Novel bipolar forceps with protein repellence using gold-polytetrafluoroethylene composite film
Takeshi Mikami, Yoshihiro Minamida, Izumi Koyanagi, Kiyohiro Houkin
NEUROSURGERY, 60, 2, 157, 160, LIPPINCOTT WILLIAMS & WILKINS, 2007年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Objective: Advancement in new technology has been necessary for the development of surgical hemostasis. The purpose of this study was to assess novel bipolar forceps plated with gold-polytetrafluoroethylene (PTEE) composite film.
Methods: Novel bipolar forceps with gold-PTFE composite film were invented and compared with commercially available forceps with 50-mu m gold-plated tips in terms of their physical properties and coagulation performance. The contact angle was measured to determine the degree of wetting tension. Then the surface roughness, electric resistance and changes in local temperature on the surface of the tip were recorded. Coagulation performance of the two sets of bipolar forceps was determined comparing the amount of protein in the adhered coagulum on the tips and comparing the ease with which the coagulum could be removed.
Results: This gold-PTFE composite film-plated metal has a significantly higher contact angle than conventional gold-plated metal, and the plating maintains the matrix metal property. The amount of coagulum sticking was smaller than with the ordinary gold-plated forceps. The ease of removal was also superior with the gold-PTFE composite film-plated forceps.
Conclusion: The concept of promotion protein repellence is important for achieving reduced adherence of protein to neurosurgical instruments. This protein repellent plating is indispensable to achieve safer and more accurate microneurosurgery.

Moyamoya disease and pregnancy: A prospective study
Kuroda Satoshi, Ishikawa Tatsuya, Nakayama Naoki, Houkin Kiyohiro, Iwasaki Yoshinobu
STROKE, 38, 2, 525, 526, 2007年02月, ［査読有り］

Alveolar soft part sarcoma in brain with cardiac metastasis. A case report
Yukinori Akiyama, Takeo Baba, Yukihiro Ibayashi, Yasufumi Asai, Kiyohiro Houkin
International Journal of Cardiology, 114, 3, E93, E95, 3, 2007年01月18日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Alveolar soft part sarcoma (ASPS) is a rare soft tissue neoplasm. The coexistence of ASPS with cardiac metastasis is quite rare, in particular. In general, the sarcoma is a malignant disease and grows very fast. However, the mean survival time of patients with ASPS is relatively long. Patients who are diagnosed with localized disease usually have a favorable prognosis, while those who present with widespread metastases usually have a poor prognosis and ultimately, succumb to their disease. The use of modern treatment modalities, such as combination of surgery, and radiotherapy, may significantly prolong the survival time in many patients. Because of the long-term period with symptomatic brain tumors in this disease, the patients should be treated even in the presence of multiple metastases in other organs. © 2006 Elsevier Ireland Ltd. All rights reserved.

Anatomical variations in pneumatization of the anterior clinoid process
Takesm Mikami, Yoshimro Minamma, Immi Koyanagi, Takeo Baba, Kiyomro Houkin
JOURNAL OF NEUROSURGERY, 106, 1, 170, 174, AMER ASSOC NEUROLOGICAL SURGEONS, 2007年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Object. An anterior clinoidectomy can provide enormous benefits, facilitating the management of paraclinoid and upper basilar artery lesions, but it also carries the potential risk of cerebrospinal fluid leaks. The aim of this study was to assess the variation in the pneumatization of the anterior clinoid process (ACP) in an attempt to reduce the complications associated with an anterior clinoidectomy.
Methods. The authors analyzed the anatomical variations in the pneumatization of the ACP and optical strut (OS) in 600 sides of 300 consecutive patients by using multidetector-row computed tomography (CT). Computed tomography scans with a 0.5-mm thickness were obtained, and coronal and sagittal reconstructions of the images were displayed in all cases. Pneumatization of the ACP was found in 9.2% of all sides. The origin of pneumatization was the sphenoid sinus in 81.8% of all the sides, the ethmoid sinus in 10.9%, and both of these sinuses in 7.3%. Pneumatized patterns were divided into three groups according to the route: 74.5% were Type I, in which pneumatization occurred via the OS; 14.5% were Type II, pneumatization via the anterior root (AR); and 10.9% were Type III, pneumatization via both the OS and the AR. The origin of pneumatization and the pneumatization pattern showed statistical dependence (p < 0.001). Pneumatization of the OS beyond its narrowest point was found in 6.8% of all sides.
Conclusions. An awareness of the different variations in pneumatization can prevent destruction of the mucous membrane and facilitate orientation during reconstruction with cranialization. During an anterior clinoidectomy, preoperative CT assessments are necessary to evaluate pneumatization of the ACP.

脳梗塞に対する骨髄幹細胞治療
本望修, 寳金清博
脳卒中, 29, 2, 2007年

Low Grade Gliomaの治療方針
秋山幸功, 南田善弘, 小柳泉, 野中雅, 寳金清博
日本脳神経外科学会総会抄録集(CD-ROM), 66th, 2007年

Neural differentiation potential of peripheral blood- and bone-marrow-derived precursor cells
Sangnyon Kim, Osamu Honmou, Kazunori Kato, Tadashi Nonaka, Kiyohiro Houkin, Hirufumi Amada, Jeffery D. Kocsis
BRAIN RESEARCH, 1123, 1, 27, 33, ELSEVIER SCIENCE BV, 2006年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Transplantation of mesenchymal stem cells (MSCs) prepared from adult bone marrow (BMSCs) has been reported to ameliorate functional deficits in several CNS diseases in experimental animal models. Bone marrow was enriched in MSCs by selecting for plastic-adherent cells that were grown to confluency in appropriate culture conditions as flattened fibroblast-like cells. Despite the fact that the stem/precursor cells in peripheral blood are widely used for reconstruction in the hematopoietic system, it is not fully understood whether peripheral blood-derived plastic-adherent precursor/stem cells (PMSCs) can differentiate into a neural lineage. To compare the potential of PMSCs and BMSCs for neural differentiation in vitro, BMSCs and PMSCs were prepared from the adult rat and expanded in culture. Although the growth rate of PMSCs was less than BMSCs, immunocytochemical and RT-PCR analyses indicated that both MSC types were successfully induced to nestin-positive neurospheres in the presence of EGF and bFGF. After withdrawal of the mitogens, these cells could differentiate into neurofilament-positive neurons or GFAP-positive glia. Thus, our findings suggest the potential use of PMSCs for a cell therapy in CNS diseases. (c) 2006 Elsevier B.V. All rights reserved.

[Stereotactic removal and thrombolysis of intracerebral hematoma].
Haraguchi K, Houkin K
Nihon rinsho. Japanese journal of clinical medicine, 64 Suppl 8, 361, 363, 2006年11月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）

Intravenous administration of glial cell line-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in the adult rat
Yoshifumi Horita, Osamu Honmou, Kuniaki Harada, Kiyohiro Houkin, Hirofumi Hamada, Jeffery D. Kocsis
JOURNAL OF NEUROSCIENCE RESEARCH, 84, 7, 1495, 1504, WILEY-LISS, 2006年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Intravenous administration of human mesenchymal stem cells (hMSCs) prepared from adult bone marrow has been reported to ameliorate functional deficits after cerebral artery occlusion in rats. Several hypotheses to account for these therapeutic effects have been suggested, and current thinking is that neuroprotection rather than neurogenesis is responsible. To enhance the therapeutic benefits of hMSCs potentially, we transfected hMSCs with the glial cell line-derived neurotrophic factor (GDNF) gene using a fiber-mutant F/RGD adenovirus vector and investigated whether GDNF gene-modified hMSCs (GDNF-hMSCs) could contribute to functional recovery in a rat permanent middle cerebral artery occlusion (MCAO) model. We induced MCAO by using intraluminal vascular occlusion, and GDNF-hMSCs were intravenously infused into the rats 3 hr later. MRI and behavioral analyses revealed that rats receiving GDNF-hMSCs or hMSCs exhibited increased recovery from ischemia compared with the control group, but the effect was greater in the GDNF-hMSC group. Thus, these results suggest that intravenous administration of hMSCs transfected with the GDNF gene using a fiber-mutant adenovirus vector may be useful in the cerebral ischemia and may represent a new strategy for the treatment of stroke. (c) 2006 Wiley-Liss, Inc.

Optimization of three-dimensional time-of-flight magnetic resonance angiography of the intracranial arteries
Kuniaki Harada, Osamu Honmou, Yoshihiro Odawara, Michio Bando, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 46, 11, 523, 528, JAPAN NEUROSURGICAL SOC, 2006年11月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The signal-to-noise ratio obtained from arteries in three-dimensional (3D) time-of-flight (TOF) magnetic resonance (MR) angiography is often too low to allow clinical diagnosis because the radiofrequency pulse decreases the magnetization of protons in the blood and suppresses the in-flow effect in the slab. The present study adjusted the position of the head coil to boost arterial signal intensity. Ten healthy volunteers, eight men and two women aged 24-78 years, underwent 3D TOF MR angiography of the intracranial arteries with the same standard GE transmit-receive birdcage head coil using both normal and half position (lower edge of the coil level with the mouth) methods. Our subjects were divided into Group 1 consisted of five relatively young volunteers aged 24-42 years (mean 31.2 years), and Group 2 consisted of five older volunteers aged 70-78 years (mean 73 years). The following four arteries were chosen for analysis: the internal carotid artery (ICA), the proximal middle cerebral artery segment (M-1), and the two distal middle cerebral artery segments (M-2, M-3). The half position method increased the signal-to-noise ratio in the ICA, M-1, M-2, and M-3 by 15%9 25%, 36%, and 44%, respectively. In general, this method resulted in the generation of stronger signals in the M-2 and M-3 in younger subjects and in all arteries examined in older subjects. The half position method can provide better MR angiograms in certain brain regions of younger people, and in all brain regions in older patients.

Marked saggital sinus dilatation and thrombi without thrombosis in a patient with systemic lupus erythematosus
Susumu Chiba, Takeshi Koizumi, Hiroyuki Matsumoto, Misuzu Ohsaka, Tadashi Nonaka, Kiyohiro Houkin
CLINICAL RHEUMATOLOGY, 25, 6, 911, 913, SPRINGER, 2006年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Superior saggital sinus thrombosis (SSST), which has a strong causal link with antiphospholipid syndrome, rarely occurs in patients with systemic lupus erythematosus (SLE). We describe a 34-year-old woman with SLE whose clinical problem was mild headache. Her serology indicated negative antiphospholipid, anticardiolipin antibodies and lupus anticoagulants. However, marked dilatation of the entire saggital sinus with scattered thrombi was observed in enhanced-, surface- and three-dimensional reconstructed CTs (3D-CTs) without abnormal intra-axial signal in brain MRI. The enhanced-, surface- and 3D-CTs are useful to detect silent dural sinus dilatation with scattered thrombi in a patient with SLE without any symptoms of SSST.

[A cell therapy for stroke].
Honmou O, Houkin K
Nihon rinsho. Japanese journal of clinical medicine, 64 Suppl 7, 664, 666, 2006年10月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）

False-negative cerebral infarction on diffusion magnetic resonance imaging
Yukinori Akiyama, Yasufumi Asai, Kiyohiro Houkin
AMERICAN JOURNAL OF EMERGENCY MEDICINE, 24, 6, 746, 748, W B SAUNDERS CO-ELSEVIER INC, 2006年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Neuroprotection by PIGF gene-modified human mesenchymal stem cells after cerebral ischaemia
H. Liu, Osamu Honmou, K. Harada, K. Nakamura, K. Houkin, H. Hamada, J. D. Kocsis
Brain, 129, 10, 2734, 2745, 2006年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Intravenous delivery of mesenchymal stem cells (MSCs) prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischaemia models. Placental growth factor (PlGF) is angiogenic to impaired non-neural tissue. To test the hypothesis that PlGF contributes to the therapeutic benefits of MSC delivery in cerebral ischaemia, we compared the efficacy of systemic delivery of human MSCs (hMSCs) and hMSCs transfected with a fibre-mutant F/RGD adenovirus vector with a PlGF gene (PlGF-hMSCs). A permanent middle cerebral artery occlusion (MCAO) was induced by intraluminal vascular occlusion with a microfilament. hMSCs and PlGF-hMSCs were intravenously injected into the rats 3 h after MCAO. Lesion size was assessed at 3 and 6 h, and 1, 3, 4 and 7 days using MR imaging and histology. Functional outcome was assessed using the limb placement test and the treadmill stress test. Both hMSCs and PlGF-hMSCs reduced lesion volume, induced angiogenesis and elicited functional improvement compared with the control sham group, but the effect was greater in the PlGF-hMSC group. Enzyme-linked immunosorbent assay of the infarcted hemisphere revealed an increase in PlGF in both hMSC groups, but a greater increase in the PlGF-hMSC group. These data support the hypothesis that PlGF contributes to neuroprotection and angiogenesis in cerebral ischaemia, and cellular delivery of PlGF to the brain can be achieved by intravenous delivery of hMSCs. © The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Lhermitte-Duclos disease with cervical paraspinal arteriovenous fistula - Case report
Yukinori Akiyama, Jun Ikeda, Yukihiro Ibayashi, Tadashi Nonaka, Yasufumi Asai, Kiyohiro Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 46, 9, 446, 449, JAPAN NEUROSURGICAL SOC, 2006年09月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 38-year-old man presented with a dysplastic cerebellar gangliocytoma associated with a paraspinal arteriovenous fistula (AVF) at the upper cervical portion. Neuroimaging examination indicated the diagnosis of Lhermitte-Duclos disease. The patient was treated by embolization of the AVF followed by partial resection of the cerebellar tumor. Genetic examination showed a mutation of the phosphatase and tensin homolog deleted on chromosome ten (PTEN) gene. Histological examination confirmed the diagnosis. Lhermitte-Duclos disease is a rare dysplastic gangliocytoma manifesting as a slowly growing mass in the cerebellum and is usually asymptomatic. This case of Lhermitte-Duclos disease associated with paraspinal AVF and mutation of the PTEN gene suggests a relationship between Lhermitte-Duclos disease and Cowden disease.

Cerebrospinal fluid leak due to inner ear malformations
Takeshi Mikami, Yoshihiro Minamida, Tetsuo Himi, Kiyohiro Houkin
NEUROLOGICAL SURGERY, 34, 9, 933, 937, IGAKU-SHOIN LTD, 2006年09月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, A case of inner ear anomalies associated with recurrent meningitis found in a 66-year-old female is reported.
The patient had had 2 episodes of meningitis in the previous one year period. Multidetector-row CT of the temporal bone and three-demensional fast imaging employing steady-state acquisition MRI revealed dysplasia of the bony labyrinth and enlarged fundus of the internal auditory canal (IAC). During surgical treatment, we confirmed the cerebrospinal fluid (CSF) leakage through a bony defect in the stapedial footplate. The inner ear was obliterated and contained small pieces of temporal fascia.
A meningitis or CSF leakage due to innar ear malformation is extreamly rear condition for neurosurgeon. Though we always have to take it into condideration as a cause of CSF leakage.

前床突起に発生したprimary intraosseous cavernous hemangiomaの1例
山下 太郎, 三上 毅, 南田 善弘, 馬場 雄大, 宝金 清博
Neurological Surgery, 34, 8, 833, 837, (株)医学書院, 2006年08月, ［国内誌］
日本語, 研究論文（学術雑誌）, 66歳女.頭痛,視力障害が出現した.視力は右0.1(0.5),左0.5(0.8)で,ゴールドマン視野検査で右眼外側下1/4盲を,眼底検査では右側の視神経萎縮を認めた.CTでは右前床突起内に等吸収の腫瘤を認めたが,骨肥厚や脱灰像はなく,病変のCT値は健側の脂肪髄よりも高値であった.MRIで同部位はT1,T2強調像で高信号を示し,造影剤により増強され,拡散強調像では高信号を呈した.視力障害が進行したため,右前頭側頭開頭にて腫瘍切除術を行った.前床突起表面は皮質骨が菲薄化して内部の腫瘍が透見され,drillingにて暗赤色の腫瘤性病変を認めた.腫瘍は前床突起に限局しており,皮膜の形成や腫瘍へのfeeder,drainerもなかった.腫瘍を前床突起ごと全摘出し,視束管開放を行った.術後経過は良好で,頭痛は消失したが,視力視野は改善しなかった.病理組織所見で骨梁間に拡張した腔を形成する血管の増生と脂肪の増生を認め,cavernous hemangiomaと診断した

STA-MCAバイパス術後のhyperperfusion 発生状況とその発生因子の検討
中山 若樹, 黒田 敏, 石川 達哉, 志賀 哲, 宝金 清博, 玉木 長良, 岩崎 喜信
脳循環代謝, 18, 2, 135, 135, (一社)日本脳循環代謝学会, 2006年08月
日本語

Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat
T. Honma, O. Honmou, S. Iihoshi, K. Harada, K. Houkin, H. Hamada, J. D. Kocsis
EXPERIMENTAL NEUROLOGY, 199, 1, 56, 66, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2006年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Intravenous infusion of bone marrow cells has demonstrated therapeutic efficacy in animal models of cerebral ischemia and spinal cord injury. We intravenously delivered human mesenchymal stem cells (SH2+, SH3+, CD34(-), and CD45(-)) immortalized with a human-telomerase gene (hTERT-MSCs) and transfected with eGFP or LacZ into rats 12 h after induction of transient middle cerebral artery occlusion (MCAO), to study their potential therapeutic benefit. hTERT-MSCs were delivered at 12 It after lesion induction. Lesion size was assessed using MR imaging and spectroscopy, and histological methods. Functional outcome was assessed using the Morris water maze and a treadmill test. Intravenous delivery of hTERT-MSCs reduced lesion volume and the magnitude of the reduction and functional improvement was positively correlated with the number of cells injected. The reduction of lesion size could be assessed in vivo with MRI and MRS and was correlated with subsequent histological examination of the brain. This work demonstrates that highly purified hTERT-MSCs reduce cerebral infarction volume and improve functional outcome. (c) 2005 Elsevier Inc. All rights reserved.

Clinical features of familial moyamoya disease
R Nanba, S Kuroda, M Tada, T Ishikawa, K Houkin, Y Iwasaki
CHILDS NERVOUS SYSTEM, 22, 3, 258, 262, SPRINGER, 2006年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Objects: This study aims to clarify the genetic background of moyamoya disease by comparing clinical features between familial and sporadic cases to reveal the responsible genes for familial moyamoya disease. Methods: This study included 155 Japanese patients with moyamoya disease, which included 24 familial cases (10 family pedigrees) and 131 sporadic cases. Clinical features were compared between the familial and sporadic cases. Results and conclusions: A female preponderance was significantly more prominent in the familial than in the sporadic group (P=0.0421). Mean age at onset was significantly lower in familial than in sporadic cases (P=0.004). In eight parent-offspring pairs, mean age at onset was significantly lower in the second than in the first generation (P < 0.0001). These results suggest that familial moyamoya disease is associated with genetic anticipation and female predominance and that a genetic analysis study focused on expanded triplet repeats may clarify the pathogenesis of the disease.

A case of moyamoya disease presenting with chorea
W Zheng, M Wanibuchi, T Onda, H Liu, Koyanagi, I, K Fujimori, K Houkin
CHILDS NERVOUS SYSTEM, 22, 3, 274, 278, SPRINGER, 2006年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Case report: We describe a 15-year-old girl with moyamoya disease whose initial manifestation was chorea-like involuntary movements. T2-weighted magnetic resonance imaging showed high signal intensity lesions in the left frontal lobe, right parieto-occipital lobes, and frontal subcortical white matter. Single-photon emission computed tomography (SPECT) showed diffuse hypoperfusion of the whole brain. Bilateral direct and indirect cerebrovascular bypass surgeries were performed. Chorea disappeared 2 days after the surgery. Follow-up SPECT demonstrated increased cerebral perfusion in the bilateral frontal, temporal, and parietal regions. Conclusions: Chorea accompanied with moyamoya disease can be properly managed by revascularization surgery. Moyamoya disease should be remembered as being one of the differential diagnoses of chorea, which is treatable by surgery.

Cerebral oxygen metabolism and neuronal integrity in patients with impaired vasoreactivity attributable to occlusive carotid artery disease
S Kuroda, T Shiga, K Houkin, T Ishikawa, C Katoh, N Tamaki, Y Iwasaki
STROKE, 37, 2, 393, 398, LIPPINCOTT WILLIAMS & WILKINS, 2006年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose-It is still unclear that impaired cerebrovascular reactivity (CVR) to acetazolamide is comparable to elevated oxygen extraction fraction (OEF) on positron emission tomography (PET) in patients with occlusive carotid diseases. Therefore, in this study, the authors aimed to clarify whether OEF is elevated in all patients with reduced cerebral blood flow (CBF) and CVR (type 3) on single photon emission computed tomography (SPECT), and, if not, to specify the underlying pathophysiology of type 3 but normal OEF.
Methods-This study included 46 patients who had decreased CBF and CVR on N-isopropyl-p-I-123-iodoamphetamine SPECT in the ipsilateral middle cerebral artery area attributable to occlusive carotid diseases. Hemodynamic and metabolism parameters were determined in all patients by O-15-gas PET, and neuronal integrity was evaluated in 19 patients using C-11-flumazenil (FMZ) PET.
Results-OEF was significantly elevated in 20 (43.5%) of 46 type 3 patients. Another 26 type 3 patients had normal OEF. Regression analysis showed that OEF significantly correlated with cerebral metabolic rate for oxygen and C-11-FMZ binding potential but not with other parameters. Subcortical infarction had no significant effect on OEF values.
Conclusions-The results strongly suggest that type 3 patients with reduced CBF and CVR may be divided into 2 pathophysiologically different subgroups: misery perfusion attributable to hemodynamic compromise and matched hypometabolism attributable to incomplete infarction. Type 3 but normal OEF may represent a transition stage from misery perfusion to matched hypometabolism.

Acute necrotizing encephaloplathy associated with human herpesvirus-6 infection
M Ohsaka, K Houkin, M Takigami, Koyanagi, I
PEDIATRIC NEUROLOGY, 34, 2, 160, 163, ELSEVIER SCIENCE INC, 2006年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, An extremely rare case of acute necrotizing encephalopathy caused by human herpesvirus-6 variant type B infection is reported. The patient, a 14-month-old previously healthy female, presented with high fever and generalized tonic convulsion followed by rapid deterioration of consciousness. On the second day of the illness, the protein level of the cerebrospinal fluid increased without pleocytosis. On the third day, magnetic resonance images demonstrated symmetric, abnormal signal intensity lesions in the bilateral thalamus, cerebellum, and brainstem. On the fourth day, characteristic maculopapular rash of exanthema subitum appeared on the trunk. Human herpesvirus-6 deoxyribonucleic acid was detected by the polymerase chain reaction in the serum, and immunoglobulin G and inummoglobulin M of serum human herpesvirus-6 were positive. On the twelfth day of illness, the patient died as a result of severe brain damage. Acute necrotizing encephalopathy should be included in the differential diagnosis when examining infants and young children with fulminating consciousness disturbance and intractable convulsion. In addition, as a causative virus, human herpesvirus-6 has to be considered at the pre-eruptive stage of exanthema subitum. Magnetic resonance images are useful because they reveal the characteristic distribution of lesions specific to acute necrotizing encephalopathy. (c) 2006 by Elsevier Inc. All rights reserved.

Neuronal cell injury in patients after cardiopulmonary resuscitation: evaluation by diffusion-weighted imaging and magnetic resonance spectroscopy
H Kano, K Houkin, K Harada, Koyanagi, I, S Nara, Y Itou, H Imaizumi, Y Asai, M Saitou
NEUROSURGICAL REVIEW, 29, 1, 88, 92, SPRINGER, 2006年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Neuronal cell injury after global cerebral ischemic insult is not well understood in humans. We performed serial examination of diffusion-weighted imaging and magnetic resonance spectroscopy in three patients after cardiopulmonary resuscitation. The presence of the signal for lactate in magnetic resonance spectroscopy in the acute stage after cardiopulmonary resuscitation was closely correlated to irreversible damage. In addition, high intensity in diffusion-weighted magnetic resonance image in the acute stage also predicted a poor outcome. Lesions that were positive for these factors in the acute stage led to serious brain damage in the subacute and chronic stages. The results indicated that after cardiopulmonary resuscitation, diffusion-weighted magnetic resonance imaging and magnetic resonance spectroscopy is an extremely useful modality to estimate the prognosis of patients, which is not always easy using conventional methods.

鼻内視鏡手術における未固定凍結遺体を用いたトレーニングシステム
南田善弘, 三上毅, 寳金清博, 村上弦
日本内分泌学会雑誌, 82, Suppl. (June), 2006年

脳血管障害総論 XI.治療動向 開発・研究中の遺伝子治療,再生医療 各論 脳梗塞の細胞療法(神経再生治療)-自家骨髄細胞の静脈内投与-
本望修, 寳金清博
日本臨床, 64, 2006年

Superior sagittal sinus thrombosis in a case of longstanding systemic lupus erythematosus
Misuzu Ohsaka, Tadashi Nonaka, Shinichi Oka, Yoshihiro Minamida, Takeshi Mikami, Kiyohiro Houkin
Brain and Nerve, 58, 1, 57, 61, 2006年01月, ［査読有り］
日本語, 研究論文（学術雑誌）, A 33-year-old female who had been on a steroid treatment for the past 14 years due to systemic lupus erythematosus (SLE) visited our hospital complaining of mild headache. No neurological deficit and no positive serologic tests for lupus anticoagulants (LAC) and anticardiolipin antibodies (aCL) were noted. Only a mild inflammatory change was observed on routine hematological examination. On neuroradiological examination, MRI revealed thickened falx cerebri and tentorium cerebelli, and an empty delta sign. These findings were suggestive of sinus thrombosis of superior sagittal sinus (SSS). Angiograms clearly demonstrated occlusion of the posterior part of superior sagittal sinus and transeverse sinus (TS). Conservative treatment was chosen because of no evidence of intracranial hypertension. There was no deterioration in her general and neurological status during her hospital stay and she was discharged. Long-standing vasculitis and pachymeningitis related to lupus erythematosus might be the probable cause of the sinus thrombosis in this case.

Risk factors of postprocedural hypotension following carotid artery stenting
T Nonaka, S Oka, S Miyata, T Baba, T Mikami, K Houkin
INTERVENTIONAL NEURORADIOLOGY, 12, 205, 210, EDIZIONI CENTAURO, 2006年01月, ［査読有り］
英語, 研究論文（学術雑誌）, This study is performed to investigate risk factors of hypotension in response to elective carotid stenting. Forty-four lesions of 40 consecutive patients (mean age 70.4 +/- 8.2 years) were retrospectively analyzed. Easy Wall stent was applied in 15 lesions and SMART stent in 29 lesions. We investigated correlations between the occurrence rate of postoperative hypotension below 90 mmHg and persisting over three hours and findings of preoperative angiograms, ultrasonograms and clinical characteristics. Postprocedural hypotension occurred in 19 patients (47.5%) and medical treatment (intravenous administration of catecholamines) was required in eleven patients (27.5%). Although there was no permanent neurological deficits related with postprocedural hypotension, transient neurological deficits were found in three patients. Risk factors of prolonged postprocedural hypotension were statistically analyzed. On angiographic characteristics; 1) distance between the carotid bifurcation and the lesion with maximum stenosis (<= 10 mm vs. > 10 mm: p = 0. 031), 2) type of stenosis (eccentric vs. concentric: p = 0. 014) On ultrasonographic characteristics; 1) calcifications at the carotid bifurcation (present vs. absent: p<0.001). Other variables, including age and degree of stenosis, were not associated with postprocedural hypotension after carotid stenting. These angiographic and ultrasonographic variables can be used to identify patients at risk for postprocedural hypotension after carotid stenting. Such identification may help in selection of patients who will benefit from appropriate pharmacological treatment.

The 5-hydroxytryptamine2A receptor antagonist sarpogrelate hydrochloride inhibits acute platelet aggregation in injured endothelium
K. Houkin, N. Nakayama, T. Nonaka, I. Koyanagi
Journal of International Medical Research, 34, 1, 65, 72, Cambridge Medical Publications, 2006年, ［査読有り］
英語, 研究論文（学術雑誌）, In this study, the effect of sarpogrelate hydrochloride, a 5-hydroxytryptamine2A receptor antagonist, on platelet aggregation at the site of injured carotid artery endothelium was examined. The rat common carotid artery was clamped for 30 min to induce endothelial injury. Sarpogrelate hydrochloride was administered before and after the injury, and the effects were compared with those in rats receiving sham operation only and those receiving clipping injury but no sarpogrelate hydrochloride. The animals were killed 24 h after the procedure. The common carotid artery was examined by scanning electron microscopy and stained immunochemically for factor VIII. Sarpogrelate hydrochloride treatment was associated with reduced aggregation of platelets on electron microscopy and lower expression of factor VIII at the injured intima. Sarpogrelate hydrochloride has an inhibitory effect on platelet aggregation at the intima in the acute stage after injury, suggesting that this drug may be used to prevent early ischaemic complications after surgical or endovascular arterial intervention. Copyright © 2006 Cambridge Medical Publications.

Entrapment neuropathy of the optic nerve due to hyperostosis associated with congenital anemia - Case report
T Baba, Y Minamida, T Mikami, Koyanagi, I, K Houkin
JOURNAL OF NEUROSURGERY, 103, 5, 917, 919, AMER ASSOC NEUROLOGICAL SURGEONS, 2005年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The authors report on the case of a 14-year-old boy who presented with bilateral visual impairment due to optic canal stenosis caused by hyperplasia of the bone marrow arising from anemia. The patient had hereditary hemolytic anemia with unstable hemoglobin of the Christchurch type. This congenital form of anemia caused hyperplasia of the bone marrow as well as hyperostosis of the entire calvarial bone, which in turn led to optic canal stenosis. The patient underwent surgical decompression of the optic canal, resulting in significant improvement in visual acuity. Pathological findings in the calvarial bone indicated hypertrophic bone mar-row with no other specific features such as neoplastic pattern or fibrous dysplasia. With the exception of objective hearing impairment, no other significant cranial neuropathy has been detected thus far.
On reviewing the published literature, this case was found to be the first in which hyperostosis due to congenital anemia resulted in symptomatic entrapment neuropathy of the optic nerve. The authors concluded that surgical decompression effectively improves visual acuity.

Incidence and clinical features of disease progression in adult moyamoya disease
S Kuroda, T Ishikawa, K Houkin, R Nanba, M Hokari, Y Iwasaki
STROKE, 36, 10, 2148, 2153, LIPPINCOTT WILLIAMS & WILKINS, 2005年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose - The progression of occlusive lesions in the major intracranial arteries was believed to be very rare in adult patients with moyamoya disease. The present study aims to clarify the incidence and clinical features of disease progression in adult moyamoya disease.
Methods - For the past 15 years, 120 adult Japanese patients were diagnosed with moyamoya disease. Of these, 63 patients were enrolled in this historical prospective cohort study on a total of 86 nonoperated hemispheres. All were followed up with a mean period of 73.6 months. MRI and magnetic resonance angiography were repeated every 6 to 12 months, and cerebral angiography was performed when disease progression was suspected on MRI and magnetic resonance angiography.
Results - Disease progression occurred in 15 of 86 nonoperated hemispheres (17.4% per hemisphere) or in 15 of 63 patients (23.8% per patient) during the follow-up period. Occlusive arterial lesions progressed in both anterior and posterior circulations, in both symptomatic and asymptomatic patients, and in both bilateral and unilateral types. Eight of 15 patients developed ischemic or hemorrhagic events in relation to disease progression. Multivariate analysis revealed that the odds ratio conferred by a male patient was 0.20 (95% CI, 0.04 to 0.97).
Conclusions - The incidence of disease progression in adult moyamoya disease is much higher than recognized before, and female patients may be at higher risk for it than male patients. Careful follow-up would be essential to prevent additional stroke occurrence in medically treated adult patients with moyamoya disease, even if they are asymptomatic or are diagnosed as having unilateral moyamoya disease.

Cranial nerve assessment in posterior fossa tumors with fast imaging employing steady-state acquisition (FIESTA)
T Mikami, Y Minamida, T Yamaki, Koyanagi, I, T Nonaka, K Houkin
NEUROSURGICAL REVIEW, 28, 4, 261, 266, SPRINGER, 2005年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Steady-state free precession is widely used for ultra-fast cardiac or abdominal imaging. The purpose of this work was to assess fast imaging employing steady-state acquisition (FIESTA) and to evaluate its efficacy for depiction of the cranial nerve affected by the tumor. Twenty-three consecutive patients with posterior fossa tumors underwent FIESTA sequence after contrast agent administration, and then displacement of the cranial nerve was evaluated. The 23 patients with posterior fossa tumor consisted of 12 schwannomas, eight meningiomas, and three cases of epidermoid. Except in the cases of epidermoid, intensity of all tumors increased on FIESTA imaging of the contrast enhancement. In the schwannoma cases, visualization of the nerve became poorer as the tumor increased in size. In cases of encapsulated meningioma, all the cranial nerves of the posterior fossa were depicted regardless of location. The ability to depict the nerves was also significantly higher in meningioma patients than in schwannoma patients (P < 0.05). In cases of epidermoid, extension of the tumors was depicted clearly. Although the FIESTA sequence offers similar contrast to other heavily T2-weighted sequences, it facilitated a superior assessment of the effect of tumors on cranial nerve anatomy. FIESTA sequence was useful for preoperative simulations of posterior fossa tumors.

Inadequate website disclosure of surgical outcome of intracranial aneurysms - Survey of 1225 sites in Japan
K Houkin, T Nonaka, S Oka, Koyanagi, I
NEUROLOGIA MEDICO-CHIRURGICA, 45, 9, 448, 453, JAPAN NEUROSURGICAL SOC, 2005年09月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Social demand for the disclosure of medical information is increasing, especially the treatment for unruptured intracranial aneurysms. This study investigated to what extent information on the treatment for unruptured intracranial aneurysms is disclosed on websites in Japan. We surveyed 1225 institutions authorized by The Japan Neurosurgical Society. The following factors were analyzed: percentage of institutions with websites, disclosure of number of surgeries, and disclosure of outcome of treatment for ruptured and unruptured intracranial aneurysms. Of the 1225 institutions surveyed, 1097 (89.6 %) had their own websites. The total number of websites was 1262 since some institutions have several homepages in different websites. The annual number of surgeries was shown in 274 of the 1225 institutions (22.4%). The outcome of treatment for ruptured intracranial aneurysms was disclosed in 104 of the 1225 institutions (8.5%). The outcome of treatment for unruptured intracranial aneurysms was shown in only 32 of the 1225 institutions (2.6%). Disclosure of outcome of treatment for unruptured intracranial aneurysms on websites is not common. To improve disclosure of the outcome on websites, guidelines should be established.

Acquired factor VIII inhibitors in a patient associated with neurosurgery: Case report and review of the literature
T Mikami, N Masauzi, J Niwa, K Houkin
NEUROSURGERY, 57, 3, 595, 595, LIPPINCOTT WILLIAMS & WILKINS, 2005年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE AND IMPORTANCE: Acquired factor VIII inhibitors in patients without hemophilia is rare event characterized by severe bleeding as a result of antibody against factor VIII. We describe a patient who developed subcutaneous and epidural bleeding after the clipping of an unruptured aneurysm. CLINICAL PRESENTATION: A 57-year-old man suddenly developed coagulopathy after undergoing a neurosurgical operation. Coagulation tests showed a prolongation of activated partial thromboplastin time and a marked reduction in factor VIII activity. Measurement of the factor VIII inhibitor level revealed 2 Bethesda units/ml. INTERVENTION: The hematoma was removed surgically, and bleeding was controlled with recombinant factor VIII. The patients then received prednisolone (80 mg/d) and cyclosporine. The laboratory tests normalized within 8 weeks. In the 5 years since cessation of corticosteroids, the clinical and laboratory courses of the patient have been uneventful. CONCLUSION: Autoimmune factor VIII inhibitors associated with a neurosurgical procedure are rare. Our case supports an association between surgery and the triggering of factor VIII inhibitors. This complication was probably the result of the surgical procedure or anesthetic agents or other drugs administrated during the perioperative period.

Prediction of prolonged postprocedural hypotension after carotid artery stenting
Tadashi Nonaka, Shinichi Oka, Kei Miyata, Takeshi Mikami, Izumi Koyanagi, Kiyohiro Houkin, Kazuhisa Yoshifuji, Toshio Imaizumi
Neurosurgery, 57, 3, 472, 476, 3, 2005年09月, ［査読有り］
英語, 研究論文（学術雑誌）, OBJECTIVE: Stent placement for the treatment of carotid artery stenosis may cause hemodynamic instability that induces ischemic complications for patients with bilateral carotid lesions. We carried out this study to define predictors of persistent hypotension after carotid stenting. METHODS: Thirty-three lesions in 31 consecutive patients (mean age, 69.2 ± 8.6 yr) who underwent stent deployment for carotid stenosis were studied. Fourteen lesions were treated with Easy Wall stents (Boston Scientific, Tokyo, Japan) and 19 lesions were treated with Smart stents (Johnson &
Johnson, Warren, NJ). We reviewed preoperative angiograms and ultrasonograms of the carotid artery and analyzed the predictive factors of postprocedural prolonged hypotension (systolic blood pressure <
90 mm Hg and periods >
3 h). RESULTS: Postprocedural hypotension was observed in 14 lesions (42.4%), of which medical treatment was necessary in seven (21.2%). A distance between carotid bifurcation and maximum stenotic lesion (≤10 mm
P = 0.0028) and type of stenosis (eccentric
P = 0.0287) on angiogram and fibrous plaque morphological features (P = 0.0008) and calcifications at carotid bifurcation (P = 0.0004) on ultrasonograms were determined to be independent risk factors of postprocedural hypotension. We introduced a scoring system for predicting prolonged hypotension that included factors such as the distance from carotid bifurcation to maximum stenotic lesion (≤10 mm), type of stenosis (eccentric), plaque morphological features (echogenic), and calcification at carotid bifurcation. The score was determined by adding one point for each of these factors. Three points or more on this score strongly suggested a high risk of prolonged hypotension. CONCLUSION: Our scoring system, which includes angiographic and ultrasonographic findings, may be a good index for the prediction of prolonged hypotension after carotid stenting and may contribute to the reduction of periprocedural ischemic events.

Prediction of prolonged postprocedural hypotension after carotid artery stenting
T Nonaka, S Oka, K Miyata, T Mikami, L Koyanagi, K Houkin, K Yoshifuji, T Imaizumi
NEUROSURGERY, 57, 3, 472, 476, LIPPINCOTT WILLIAMS & WILKINS, 2005年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Stent placement for the treatment of carotid artery stenosis may cause hemodynamic instability that induces ischemic complications for patients with bilateral carotid lesions. We carried out this study to define predictors of persistent hypotension after carotid stenting.
METHODS: Thirty-three lesions in 31 consecutive patients (mean age, 69.2 +/- 8.6 yr) who underwent stent deployment for carotid stenosis were studied. Fourteen lesions were treated with Easy Wall stents (Boston Scientific, Tokyo, Japan) and 19 lesions were treated with Smart stents (Johnson & Johnson, Warren, NJ). We reviewed preoperative angiograms and ultrasonograms of,the carotid artery and analyzed the predictive factors of postprocedural prolonged hypotension (systolic blood pressure < 90 mm Hg and periods > 3 h).
RESULTS: Postprocedural hypotension was observed in 14 lesions (42.4%), of which medical treatment was necessary in seven (21.2%). A distance between carotid bifurcation and maximum stenotic lesion (<= 10 mm; P = 0.0028) and type of stenosis (eccentric; P = 0.0287) on angiogram and fibrous plaque morphological features (P = 0.0008) and calcifications at carotid bifurcation (P = 0.0004) on ultrasonograms were determined to be independent risk factors of postprocedural hypotension. We introduced a scoring system for predicting prolonged hypotension that included factors such as the distance from carotid bifurcation to maximum stenotic lesion (<= 10 mm), type of stenosis (eccentric), plaque morphological features (echogenic), and calcification at carotid bifurcation. The score was determined by adding one point for each of these factors. Three points or more on this score strongly suggested a high risk of prolonged hypotension.
CONCLUSION: Our scoring system, which includes angiographic and ultrasonographic findings, may be a good index for the prediction of prolonged hypotension after carotid stenting and may contribute to the reduction of periprocedural ischemic events.

Metastatic renal cell carcinoma mimicking pituitary adenoma - Case report
H Liu, T Yamaki, S Oka, Koyanagi, I, K Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 45, 8, 418, 422, JAPAN NEUROSURGICAL SOC, 2005年08月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 54-year-old man, with a past history of renal cell carcinoma, presented with bitemporal visual field defect, hyponatremia, and diabetes insipidus. Endocrinological examination revealed panhypopituitarism. Computed tomography and magnetic resonance imaging showed an intrasellar mass with suprasellar extension. The initial radiological impression was pituitary adenoma. The tumor was decompressed via the transsphenoidal route. Histological examination revealed metastatic renal cell carcinoma. The clinical characteristics of metastatic pituitary carcinoma appear to be panhypopituitarism, and neuroimaging findings of strong enhancement of the tumor and bony destruction without marked sellar enlargement.

Surgical management of the recurrence and regrowth of craniopharyngiomas
Y Minamida, T Mikami, K Hashi, K Houkin
JOURNAL OF NEUROSURGERY, 103, 2, 224, 232, AMER ASSOC NEUROLOGICAL SURGEONS, 2005年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Object. The authors performed a retrospective analysis of a consecutive series of craniopharyngiomas and their recurrences, which were managed with surgery alone.
Methods. In the past 20 years, 37 consecutive patients with craniopharyngiomas underwent surgery without adjuvant radiotherapy. During that period there was a consistent strategy that surgical management was the first choice of treatment whenever possible.
Of these 37 patients, 11 experienced tumor recurrence (29.7%) during the mean follow-up period of 11.1 years. Of these 11 patients, seven experienced recurrence after neuroimaging-confirmed total removal, and four patients experienced recurrence after partial or incomplete removal. In these 11 patients, surgical removal was performed 17 times. Using a proper surgical approach (mainly a basal interhemispheric approach) and meticulous microsurgical techniques, total removal of the recurrent tumor was achieved in nine surgeries (52.9). The mortality and morbidity rates associated with these 17 surgeries were 0% and 9.1%, respectively. In most cases, visual function was preserved or improved and intellectual performance was also preserved.
Conclusions. Recurrence of craniopharyngioma can be safely managed by using meticulous contemporary microsurgical techniques without additional radiotherapy. The role of surgery and adjuvant radiotherapy for craniopharyngiomas may vary in the future, depending on innovations in treatment and technology. Nevertheless, surgery can be still a major therapeutic option in the management of recurrent craniopharyngiomas.

Clinical features and pathomechanisms of syringomyelia associated with spinal arachnoiditis
Koyanagi, I, Y Iwasaki, K Hida, K Houkin
SURGICAL NEUROLOGY, 63, 4, 350, 355, ELSEVIER SCIENCE INC, 2005年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Syringomyelia is a common intramedullary lesion associated with spinal arachnoiditis and obstruction of the foramen magnum such as in Chiari's malformation. Disturbance of cerebrospinal fluid flow around the spinal cord has an important role in the development of syringomyelia due to spinal arachnoiditis; however, the exact mechanisms have not been clarified. The purpose of this retrospective study is to understand the clinical features and pathomechanisms of syringomyelia secondary to spinal arachnoiditis and to provide the current choice of surgical treatment in this difficult clinical entity.
Methods: Clinical and radiological findings in 15 patients with syringomyelia associated with spinal arachnoiditis who underwent surgical treatment in our institutes between 1982 and 2000 were reviewed. All patients presented with paraparesis or tetraparesis on admission.
Results: Magnetic resonance imaging (MRI) or computed tomography-myelography revealed that the syrinx predominantly existed at the thoracic levels. Five patients showed complete block of the thoracic subarachnoid space by conventional myelography. T2-weighted MRI showed diffuse intramedullary hyperintensity at the level of arachnoiditis. As the first surgical treatment, 10 patients underwent syringo-peritoneal shunt placement. Three patients were treated with a syringo-subarachnoid shunt, and 2 patients were treated with a ventriculoperitoneal shunt. Eight patients required further shunting operations for syringomyelia 2 months to 12 years after the first surgery. Neurologic improvement was obtained in 9 patients (60%) with decreased size of the syrinx. One patient remained stable; 5 patients showed gradual deterioration.
Conclusions: The syrinx originated from the thoracic levels where severe adhesion of the subarachnoid space was present. The mechanisms of syrinx formation may be based on the increased interstitial fluid in the spinal cord. Shunting procedures were effective in some population of the patients. Decompression procedures of the spinal subarachnoid space may be an alternative primary surgical treatment except for patients with longitudinally extensive arachnoiditis. (c) 2005 Elsevier Inc. All rights reserved.

Carotid rete mirabile associated with subarachnoid hemorrhage - Case report
T Mikami, A Takahashi, K Houkin
NEUROLOGIA MEDICO-CHIRURGICA, 45, 4, 201, 204, JAPAN NEUROSURGICAL SOC, 2005年04月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, 47-year-old man presented with carotid rete mirabile manifesting as subarachnoid hemorrhage (SAH). Computed tomography showed SAH, and angiography disclosed an abnormal vascular network around the petrous and cavernous portions of the internal carotid artery. Single photon emission computed tomography (SPECT) with technetium-99m methyl cysteinate dimer revealed reduced regional cerebral blood How (CBF). Twelve months later, he was leading a normal life without neurological problems, hemorrhage, or ischemic manifestations. SPECT with iodine-123 N-isopropyl-p-iodoamphetamine and the acetazolamide challenge test showed the CBF had normalized.

BDNF産生ヒト間葉系幹細胞の経静脈的移植による脳梗塞治療の検討
野村 達史, 本望 修, 原田 邦明, 劉 赫, 寶金 清博, 中村 公則, 濱田 洋文
脳卒中, 27, 1, 203, 203, (一社)日本脳卒中学会, 2005年04月
日本語

Mesenchymal stem cells (MSC) as therapeutic cytoreagents for gene therapy
H Hamada, M Kobune, K Nakamura, Y Kawano, K Kato, O Honmou, K Houkin, T Matsunaga, YN Niitsu
CANCER SCIENCE, 96, 3, 149, 156, BLACKWELL PUBLISHING INC, 2005年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We developed human mesenchymal stem cell (MSC) lines that could differentiate into various tissue cells including bone, neural cells, bone marrow (BM) stromal cells supporting the growth of hematopoietic stem cell (HSC), and so-called 'tumor stromal cells' mixing with tumor cells. We investigated the applicability of MSC as therapeutic cell transplanting reagents (cytoreagents). Telomerized human BM derived stromal cells exhibited a prolonged lifespan and supported the growth of hematopoietic clonogenic cells. The gene transfer of Indian hedgehog (Ihh) remarkably enhanced the HSC expansion supported by the human BM stromal cells. Gene-modified MSC are useful as therapeutic tools for brain tissue damage (e.g. brain infarction) and malignant brain neoplasms. MSC transplantation protected the brain tissue from acute ischemic damage in the midcerebral artery occlusion (MCAO) animal model. Brain-derived neurotrophic factor (BDNF)-gene transduction further enhanced the protective efficacy against the ischemic damage. MSC possessed excellent migratory ability and exerted inhibitory effects on the proliferation of glioma cells. Gene-modification of MSC with therapeutic cytokines clearly augmented the antitumor effect and prolonged the survival of tumor-bearing animals. Gene therapy employing MSC as a tissue-protecting and targeting cytoreagent would be a promising approach.

Novel stent/CEA strategy for patients with bilateral carotid artery stenosis and coronary artery disease: Report of 2 cases
H Shichinohe, S Kuroda, T Asano, S Ushikoshi, T Ishikawa, K Houkin, T Murashita, Y Iwasaki
NEUROLOGICAL SURGERY, 33, 2, 149, 153, IGAKU-SHOIN LTD, 2005年02月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, Recently, there are increasing numbers of patients with occlusive carotid artery disease and coronary artery disease. Simultaneous or two-staged surgery for both lesions has been recommended for these patients to reduce the incidence of perioperative complications. However, therapeutic options for the patients with bilateral carotid artery stenosis and coronary artery disease have not been established. In this report, we describe two patients who a successfully underwent carotid endarterectomy (CEA) and carotid artery stenting (CAS) on each carotid artery in parallel with coronary artery bypass grafts (CABG). A 49-year-old male with severe stenosis of the bilateral internal carotid artery (ICA) and heart failure underwent CAS on the right side. Next day, he successfully under-went CABG and CEA on the left side at the same time. A 62-year-old male with severe stenosis of the bilateral ICA and coronary artery disease underwent CAS on the right side and CEA on the left side with an interval of 7 days. Subsequently, CABG was performed uneventfully. No perioperative complication occurred in either patient. The results suggest that combination therapy of CAS and CEA would be a valuable option for patients with complex carotid/coronary artery diseases.

Novel magnetic resonance angiography stage grading for Moyamoya disease
K Houkin, N Nakayama, S Kuroda, T Nonaka, T Shonai, T Yoshimoto
CEREBROVASCULAR DISEASES, 20, 5, 347, 354, KARGER, 2005年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Magnetic resonance angiography (MRA) has been acknowledged as a noninvasive diagnostic modality for moyamoya disease. However, in terms of staging of moyamoya disease, conventional angiography is still the gold standard. Therefore, the purpose of this study was to establish MRA grades for moyamoya disease as an alternative to conventional angiography. Methods: Twenty-two patients ( 44 sides) with moyamoya disease diagnosed by conventional angiography were evaluated by MRA during the past 5 years. MRA scores were assigned based on the severity of occlusive changes of the internal carotid artery, the horizontal portion of the middle cerebral artery, the anterior and the posterior cerebral arteries and the signals of the distal branches of these arteries. Total points ranged from 0 ( normal) to 10 ( most severe). Results: MRA scores ( 0 - 10) were significantly consistent with the conventional angiographic staging. Four grades based on this novel MRA scores correlated well with Suzuki's stages, with high sensitivity and specificity. Conclusions: These novel MRA grades can be a reliable alternative to conventional staging. By employing these novel MRA grades, the use of conventional angiography can be avoided for the purpose of evaluation of the stages of moyamoya disease. Copyright (C) 2005 S. Karger AG, Basel.

Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model
K Kurozumi, K Nakamura, T Tamiya, Y Kawano, K Ishii, M Kobune, S Hirai, H Uchida, K Sasaki, Y Ito, K Kato, O Honmou, K Houkin, Date, I, H Hamada
MOLECULAR THERAPY, 11, 1, 96, 104, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2005年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Mesenchymal stem cells (MSC) were reported to ameliorate functional deficits after stroke in rats, with some of this improvement possibly resulting from the action of cytokines secreted by these cells. To enhance such cytokine effects, we previously transfected the telomerized human MSC with the BDNF gene using a fiber-mutant adenovirus vector and reported that such treatment contributed to improved ischemic recovery in a rat transient middle cerebral artery occlusion (MCAO) model. In the present study, we investigated whether other cytokines in addition to BDNF, i.e., GDNF, CNTF, or NT3, might have a similar or greater effect in this model. Rats that received MSC-BDNF (P < 0.05) or MSC-GDNF (P < 0.05) showed significantly more functional recovery as demonstrated by improved behavioral test results and reduced ischemic damage on MRI than did control rats 7 and 14 days following MCAO. On the other hand, rats that received MSC-CNTF or MSC-NT3 showed neither functional recovery nor ischemic damage reduction compared to control rats. Thus, MSC transfected with the BDNF or GDNF gene resulted in improved function and reduced ischemic damage in a rat model of MCAO. These data suggest that gene-modified cell therapy may be a useful approach for the treatment of stroke.

Combined surgical and endovascular treatment of infected pseudoaneurysm after carotid endarterectomy - Case report
H Yasuda, S Kuroda, S Ushikoshi, T Kato, K Houkin, Y Iwasaki, H Abe
NEUROLOGIA MEDICO-CHIRURGICA, 45, 1, 37, 40, JAPAN NEUROSURGICAL SOC, 2005年01月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A 67-year-old male presented with a rare pseudoaneurysm caused by infection after carotid endarterectomy (CEA) performed for stenosis of the left internal carotid artery (ICA). Wound infection and recurrent bleeding from the operated ICA developed 1 month after surgery. Serial angiography showed that the post-CEA pseudoaneurysm gradually increased in size. The carotid balloon occlusion test revealed that the patient could not tolerate permanent ICA occlusion because of poorly developed collaterals. Direct surgical exposure of the aneurysm was impossible due to tight adhesion of the surrounding tissue, so common carotid to middle cerebral artery bypass using a radial artery graft was performed followed by ligation of the distal common carotid artery. Subsequently, retrograde blood flow from the ICA to the aneurysm was interrupted by embolization of the external carotid artery coil through the facial artery. Combined surgical and endovascular treatment is a therapeutic option for patients with post-CEA pseudoaneurysm, if either direct or endovascular surgery is unfeasible.

Sequence analysis and bioinformatics analysis of chromosome 17q25 in familial moyamoya disease
R Nanba, M Tada, S Kuroda, K Houkin, Y Iwasaki
CHILDS NERVOUS SYSTEM, 21, 1, 62, 68, SPRINGER, 2005年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Objects: The pathogenesis of moyamoya disease is still unknown. The present study aimed to find out the responsible genes that are located in the 17q25 locus. Methods: Considering the function, we selected nine genes as candidates from a total of 65 genes identified in the 9-cM region of D17S785 - D17S836 in chromosome 17q25, and performed sequence analysis on the DNA samples obtained from a pedigree of familial moyamoya disease, which showed a complete linkage to the region by a haplotype analysis. Also, we attempted to identify candidate genes that have not been known but might be functionally relevant to the disease among a total of 2,100 expressed sequence tag ( EST) sequences using bioinformatics techniques. Results and conclusion: The sequence analysis could detect no mutation in the nine genes. Nor could we identify a novel candidate gene by the EST analysis. Further studies using alternative approaches are warranted to clarify the pathogenesis of moyamoya disease.

I.v. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat
T Nomura, O Honmou, K Harada, K Houkin, H Hamada, JD Kocsis
NEUROSCIENCE, 136, 1, 161, 169, PERGAMON-ELSEVIER SCIENCE LTD, 2005年, ［査読有り］
英語, 研究論文（学術雑誌）, I.v. delivery of mesenchymal stem cells prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischemia models. Administration of the brain-derived neurotrophic factor to the infarction site has also been demonstrated to be neuroprotective. To test the hypothesis that brain-derived neurotrophic factor contributes to the therapeutic benefits of mesenchymal stem cell delivery, we compared the efficacy of systemic delivery of human mesenchymal stem cells and human mesenchymal stem cells transfected with a fiber-mutant F/RGD adenovirus vector with a brain-derived neurotrophic factor gene (brain-derived neurotrophic factor-human mesenchymal stem cells). A permanent middle cerebral artery occlusion was induced by intraluminal vascular occlusion with a microfilament. Human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells were i.v. injected into the rats 6 h after middle cerebral artery occlusion. Lesion size was assessed at 6 h, 1, 3 and 7 days using MR imaging, and histological methods. Functional outcome was assessed using the treadmill stress test. Both human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells reduced lesion volume and elicited functional improvement compared with the control sham group, but the effect was greater in the brain-derived neurotrophic factor-human mesenchymal stem cell group. ELISA analysis of the infarcted hemisphere revealed an increase in brain-derived neurotrophic factor in the human mesenchymal stem cell groups, but a greater increase in the brain-derived neurotrophic factor-human mesenchymal stem cell group. These data support the hypothesis that brain-derived neurotrophic factor contributes to neuroprotection in cerebral ischemia and cellular delivery of brain-derived neurotrophic factor can be achieved by i.v. delivery of human mesenchymal stem cells. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.

Increased expression of hepatocyte growth factor in cerebrospinal fluid and intracranial artery in moyamoya disease
R Nanba, S Kuroda, T Ishikawa, K Houkin, Y Iwasaki
STROKE, 35, 12, 2837, 2842, LIPPINCOTT WILLIAMS & WILKINS, 2004年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and Purpose-The etiology of moyamoya disease still remains unknown. This study was aimed to explore the role of hepatocyte growth factor (HGF), a strong inducer of angiogenesis, in development of moyamoya disease.
Methods-We studied cerebrospinal fluid (CSF) from 39 patients with moyamoya disease (24 children and 15 adults), 6 control patients with cervical spondylosis, and 7 control patients with internal carotid artery occlusion. CSF level of HGF was determined by enzyme-linked immunosorbent assay technique. We also evaluated the distribution of HGF and its cellular receptor c-Met in the carotid fork obtained from 2 patients with moyamoya disease and 2 control patients.
Results-CSF level of HGF was 408.2+/-201.6 pg/mL and 443.2+/-193.5 pg/mL in patients with cervical spondylosis and internal carotid artery occlusion, respectively (mean+/-SD). On the other hand, CSF level of HGF was 820.3+/-319.0 pg/mL in patients with moyamoya disease, being significantly higher than those in 2 control groups (P<0.01). Both HGF and c-Met were widely distributed in the media and thickened intima of the carotid fork in patients with moyamoya disease but not in control patients.
Conclusions-This study revealed that HGF is densely found in the carotid fork, and its CSF level is markedly elevated in moyamoya disease, suggesting that HGF may be a key protein for pathogenesis of moyamoya disease.

Autologous transplantation of expanded neural precursor cells into the demyelinated monkey spinal cord
S Oka, O Honmou, Y Akiyama, M Sasaki, K Houkin, K Hashi, JD Kocsis
BRAIN RESEARCH, 1030, 1, 94, 102, ELSEVIER SCIENCE BV, 2004年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The objective of this study was to establish if neural precursor cells could safely be developed from biopsy of the subventricular zone (SVZ) in the non-human primate (marmoset), and to determine their myelinating potential after autologous transplantation into a demyelinated lesion. Small amounts of tissue were safely collected from the subventricular-subependymal zone of the adult primate brain under ultrasonography without any neurological deficit. Neural precursor cells were isolated and expanded in the presence of mitogen in vitro. The dorsal columns of the adult marmoset spinal cord were demyelinated by X-irradiation and intraspinal injections of ethidium bromide in the center of the radiation field. Cell suspensions of the neural precursors were microinjected through a micropipette into the demyelinated lesion site in the spinal cord. Lesions were histologically examined 3 weeks after transplantation. Light and electron microscopic examination of plastic embedded sections revealed a significant number of myelinating profiles in the transplantation zone; no myelination was observed in control lesions. The myelinated axons had predominantly peripheral patterns of myelination. These results demonstrate that autologous transplantation of neural precursor cells in the adult nonhuman primate can remyelinate demyelinated central nervous system (CNS) axons, thus suggesting the potential utility of such an approach in demyelinating lesions in humans. (C) 2004 Elsevier B.V. All rights reserved.

Stereotactic irradiation for intracranial arteriovenous malformation using stereotactic radiosurgery or hypofractionated stereotactic radiotherapy
TC Chang, H Shirato, H Aoyama, S Ushikoshi, N Kato, S Kuroda, T Ishikawa, K Houkin, Y Iwasaki, K Miyasaka
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 60, 3, 861, 870, ELSEVIER SCIENCE INC, 2004年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Purpose: To investigate the appropriateness of the treatment policy of stereotactic irradiation using both hypofractionated stereotactic radiotherapy (HSRT) and stereotactic radiosurgery (SRS) for arteriovenous malformations (AVMs) located in an eloquent region or for large AVMs and using SRS alone for the other AVMs.
Methods and Materials: Included in this study were 75 AVMs in 72 patients, with a mean follow-up of 52 months. Of the 75 AVMs, 33 were located in eloquent regions or were >2.5 cm in maximal diameter and were given 25-35 Gy (mean, 32.4 Gy) in four daily fractions at a single isocenter if the patient agreed to prolonged wearing of the stereotactic frame for 5 days. The other 42 AVMs were treated with SRS at a dose of 15-25 Gy (mean, 24.1 Gy) at the isocenter. The 75 AVMs were classified according to the Spetzler-Martin grading system; 21, 23, 28, 2, and 1 AVM were Grade I, II, III, IV, V, and VI, respectively.
Results: The overall actuarial rate of obliteration was 43% (95% confidence interval [CI], 30-56%) at 3 years, 72% (95% CI, 58-86%) at 5 years, and 78% (95% CI, 63-93%) at 6 years. The actuarial obliteration rate at 5 years was 79% for the 42 AVMs <2.0 cm and 66% for the 33 AVMs >2 cm. The 5- and 6-year actuarial obliteration rate was 61% (95% Cl, 39-83%) and 71% (95% CI, 47-95%), respectively, after HSRT and 81% (95% CI, 66-96%) and 81% (95% CI, 66-96%), respectively, after SRS; the difference was not statistically significant. Radiation-induced necrosis was observed in 4 subjects in the SRS group and 1 subject in the HSRT group. Cyst formation occurred in 3 patients in the SRS group and no patient in the HSRT group. A permanent symptomatic complication was observed in 3 cases (4.2%), and 1 of the 3 was fatal. All 3 patients were in the SRS group. The annual intracranial hemorrhage rate was 5.5-5.6% for all patients.
Conclusion: Our treatment policy using SRS and HSRT was as effective as the policy involving SRS alone. The HSRT schedule was suggested to have a lower frequency of radiation necrosis and cyst formation than the high-dose SRS schedule. The benefit of HSRT compared with lower dose SRS has not yet been determined. (C) 2004 Elsevier Inc.

Spinal canal size in ossification of the posterior longitudinal ligament of the cervical spine
Koyanagi, I, H Imamura, S Fujimoto, K Hida, Y Iwasaki, K Houkin, DJ Maiman
SURGICAL NEUROLOGY, 62, 4, 286, 291, ELSEVIER SCIENCE INC, 2004年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND The size of the spinal canal is a factor that contributes to the neurologic deficits associated with cervical ossification of the posterior longitudinal ligament (OPLL).
METHODS Bone-window computed tomography (CT) examinations of the cervical spine in 64 patients with cervical OPLL were reviewed. Forty-two patients underwent surgical treatment (anterior decompression: 16 patients, posterior decompression: 26 patients). The remaining 22 patients were managed conservatively. Selection of the surgical approach, anterior or posterior, was based on the longitudinal extent of cord compression.
RESULTS The mean developmental size of the spinal canal in the posterior decompression group (10.7 mm at C4) was significantly smaller than the other 2 groups. The spinal canal was narrowed by OPLL to 2.9 to 10.0 mm. The proportion of the patients showing motor deficits of the lower extremities significantly increased when the sagittal canal diameter was narrowed to less than 8 mm.
CONCLUSIONS This study demonstrates critical values of CT-determined spinal canal stenosis. Developmental size of the spinal canal and the residual anterior-posterior canal diameters resulting from OPLL spinal cord compression are important factors influencing clinical management and the neurologic state. (C) 2004 Elsevier Inc. All rights reserved.

How does angiogenesis develop in pediatric moyamoya disease after surgery? A prospective study with MR angiography
K Houkin, N Nakayama, S Kuroda, T Ishikawa, T Nonaka
CHILDS NERVOUS SYSTEM, 20, 10, 734, 741, SPRINGER, 2004年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Object: The dynamic process of neovascularization seen in patients with moyamoya disease who have received bypass surgery has not been sufficiently elucidated. Magnetic resonance angiography (MRA) is expected to disclose this process since it can be conducted frequently because of its non-invasive nature. In this study, we prospectively investigated postoperative neovascularization using repeated MRA. Methods: We studied 14 pediatric patients ( 23 sides) who have received both direct bypass surgery of the superficial temporal artery (STA) to middle cerebral artery and indirect surgery of encephalo-duro-arterio-myo-synangiosis during the past 3 years. MRA was performed using a 1.5-T machine, image sequences of 512 x 256 resolution, and the time-of-flight method. MRA was prospectively performed preoperatively and repeated 1, 3, and 6 months after surgery. Conclusions: A tendency toward a decrease in moyamoya vessels and the development of the STA was observed 1 month after the surgery. Development of the deep temporal artery and the middle meningeal artery was observed 3 months after the surgery. The progression of stenotic change was apparently accelerated after the surgery. A reciprocal relation between neovascularization artificially induced by bypass surgery and moyamoya vessels, which are supposed to compensate for the stenotic change of the internal carotid artery, was disclosed.

Superior oblique myokymia caused by vascular compression
M Hashimoto, K Ohtsuka, Y Suzuki, Y Minamida, K Houkin
JOURNAL OF NEURO-OPHTHALMOLOGY, 24, 3, 237, 239, LIPPINCOTT WILLIAMS & WILKINS, 2004年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, A 49-year-old man had left superior oblique myokymia for eight years. Magnetic resonance images with enhanced spoiled gradient recalled acquisition in the steady state (SPGR) and flow imaging using steady acquisition (FIESTA) disclosed a branch of the superior cerebellar artery lying on the root exit zone of the left trochlear nerve.
Posterior fossa craniotomy confirmed the imaging findings. A Teflon pad was placed between the compressing artery and the trochlear nerve. The patient's superior oblique myokymia has completely resolved with a one-year follow-up. Only one such case has been previously reported. This is the first report to display the imaging findings.

In vivo quantification of the metabolites in normal brain and brain tumors by proton MR spectroscopy using water as an internal standard
ZY Tong, T Yamaki, K Harada, K Houkin
MAGNETIC RESONANCE IMAGING, 22, 7, 1017, 1024, ELSEVIER SCIENCE INC, 2004年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Metabolite concentrations in normal adult brains and in gliomas were quantitatively analyzed by in vivo proton magnetic resonance spectroscopy (MRS) using the fully relaxed water signal as an internal standard. Between January 1998 and October 2001, 28 healthy volunteers and 18 patients with gliomas were examined by in vivo proton MRS. Single voxel spectra were acquired using the point-resolved spectroscopic pulse sequence with a 1.5-T scanner (TR/TE/Ave = 3000 ms/30 ms/64). The calculated concentrations of N-acetyl-aspartate (NAA), creatine (Cre), choline (Cho), and water (H2O) in the normal hemispheric white matter were 23.59 +/- 2.62 mM (mean +/- SD), 13.06 +/- 1.8 mM, 4.28 +/- 0.8 mM, and 47280.96 +/- 5414.85 mM, respectively. The metabolite concentrations were not necessarily uniform in different parts of the brain. The concentrations of NAA and Cre decreased in all gliomas (p < 0.001). The NAA/Cho and NAA/H2O ratios can distinguish the normal brain from gliomas, and low-grade astrocytoma from high-grade group (p < 0.001). The concentration of taurine (Tau) in medulloblastomas was 29.64 +/- 5.76 mM. This is the first quantitative analysis of Tau in medulloblastoma in vivo and confirms earlier in vitro findings. (C) 2004 Elsevier Inc. All rights reserved.

Diacylglycerol kinase gamma serves as an upstream suppressor of Rac1 and lamellipodium formation
S Tsushima, M Kai, K Yamada, S Imai, K Houkin, H Kanoh, F Sakane
JOURNAL OF BIOLOGICAL CHEMISTRY, 279, 27, 28603, 28613, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2004年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Nine diacylglycerol kinase (DGK) isozymes have been identified. However, our knowledge of their individual functions is still limited. Here, we demonstrate the role of DGKgamma in regulating Rac1-governed cell morphology. We found that the expression of kinase-dead DGKgamma, which acts as a dominant-negative mutant, and inhibition of endogenous DGKgamma activity with R59949 induced lamellipodium and membrane ruffle formation in NIH3T3 fibroblasts in the absence of growth factor stimulation. Reciprocally, lamellipodium formation induced by platelet-derived growth factor was significantly inhibited upon expression of constitutively active DGKgamma. Moreover, the constitutively active DGKgamma mutant suppressed integrin-mediated cell spreading. These effects are isoform-specific because, in the same experiments, none of the corresponding mutants of DGKalpha and DGKbeta, closely related isoforms, affected cell morphology. These results suggest that DGKgamma specifically participates in the Rac1-mediated signaling pathway leading to cytoskeletal reorganization. In support of this, DGKgamma co-localized with dominant-active Rac1 especially in lamellipodia. Moreover, we found that endogenous DGKgamma was physically associated with cellular Rac1. Dominant-negative Rac1 expression blocked the lamellipodium formation induced by kinase-dead DGKgamma, indicating that DGKgamma acts upstream of Rac1. This model is supported by studies demonstrating that kinase-dead DGKgamma selectively activated Rac1, but not Cdc42. Taken together, these results strongly suggest that DGKgamma functions through its catalytic action as an upstream suppressor of Rac1 and, consequently, lamellipodium/ruffle formation.

Consequence of intellectual property and consortium project in neurosurgery
Osamu Honmou, Kiyohiro Houkin
Neurological Surgery, 32, 6, 571, 577, 6, 2004年06月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）

[Surgical treatment for cerebral aneurysm after incomplete Guglielmi detachable coil embolization].
Satoshi Kuroda, Satoshi Ushikoshi, Yoshimasa Niiya, Toshiya Osanai, Tatsuya Ishikawa, Shugo Takikawa, Kiyohiro Houkin, Yoshinobu Iwasaki
No shinkei geka. Neurological surgery, 32, 6, 645, 50, 6, 2004年06月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, The frequency of surgical treatment for intracranial aneurysms that have been incompletely treated by endovascular coiling will increase in time. The authors describe their experience in the following 3 patients. There was one non-ruptured aneurysm and two ruptured ones. The intervals between coiling and surgery were 1, 5, and 10 months. Surgery was indicated because of partial treatment and/or growth of residual neck. Observation during surgery revealed that coils were exposed to the subarachnoid space at the tip of the aneurysm in the cases of ruptured aneurysms. When the residual neck was large enough for the size of the clip blades, there was no need to remove the coils. The coils in the neck were able to be removed when the interval between coiling and surgery was very short, but could not be removed when the interval was prolonged. Intraoperative angiography and reconstructive bypass surgery may be essential in these complex cases. As pointed out previously, the operative approach should be determined by the need for coil removal and the duration since coiling.

Reduced blood flow and preserved vasoreactivity characterize oxygen hypometabolism due to incomplete infarction in occlusive carotid artery diseases
S Kuroda, T Shiga, T Ishikawa, K Houkin, T Narita, C Katoh, N Tamaki, Y Iwasaki
JOURNAL OF NUCLEAR MEDICINE, 45, 6, 943, 949, SOC NUCLEAR MEDICINE INC, 2004年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Recent studies have clarified that hemodynamically compromised patients are at high risk for subsequent stroke. The acetazolamide test is widely used to detect the patients with hemodynamic compromise due to occlusive carotid artery disease. Previous studies have suggested that patients with impaired reactivity to acetazolamide had an increased oxygen extraction fraction (OEF) on PET. However, the underlying pathophysiology has not been defined in patients with reduced blood flow and preserved reactivity to acetazolamide due to carotid occlusive diseases regardless of a normal appearance on MRI. This study aimed to clarify hemodynamic and metabolic parameters in such patients, using 150 gas and C-11-flumazenil (FMZ) PET. Methods: Our study included 15 patients who had reduced cerebral blood flow (CBF) and preserved cerebrovascular reactivity (CVR) to acetazolamide in the ipsilateral middle cerebral artery territory due to occlusive carotid diseases on N-isopropyl-p-I-123-iodoamphetamine (I-123-IMp) SPECT. We determined the CBF, cerebral metabolic rate for oxygen (CMRo(2)), cerebral blood volume (CBV), and OEF using 150 gas PET. The binding potential for C-11-FMZ was also measured in 5 patients. All patients were medically treated and followed-up during a mean period of 2.7 y. Results: 150 gas PET scans revealed that the ipsilateral CBF and CMRo(2) were reduced to 80% +/- 11% (P < 0.0001) and 78% +/- 8% (P < 0.0001) of the contralateral side, respectively. However, there was no significant side-to-side difference in the CBV and OEF The ipsilateral binding potential for C-11-FMZ was also significantly reduced to 82% +/- 2% of the contralateral side (P < 0.05), being very similar to the asymmetry of the CBF and CMRo(2). No patients suffered further ischemic stroke in the ipsilateral hemisphere during the follow-up period. Conclusion: Our results strongly suggest that a reduced CBF and a normal CVR characterize oxygen hypometabolism probably due to ischemia-related neuronal loss-namely, incomplete infarction. Such an ischemic lesion is not hemodynamically compromised and is at very low risk for a subsequent ischemic stroke even if the patient is medically treated.

Gradual recovery from dyslexia and related serial magnetoencephalographic changes in the lexicosemantic centers after resection of a mesial temporal astrocytoma - Case report
K Kamada, Y Sawamura, F Takeuchi, K Houkin, H Kawaguchi, Y Iwasaki, S Kuriki
JOURNAL OF NEUROSURGERY, 100, 6, 1101, 1106, AMER ASSOC NEUROLOGICAL SURGEONS, 2004年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Letter-perception centers are not held in as high regard as motor- and language-related cortices during planning of neurosurgical procedures, and there have been no reports suggesting cortical reorganization of reading ability. The authors describe a patient with a left mesial temporal glioma in whom two letter-perception centers (the anterior portion of the left superior temporal gyrus and the left fusiform gyrus) were successfully localized before surgery by performing magnetoencephalography (MEG) during reading tasks. Control MEG examinations of 15 healthy volunteers were also performed to assist in a careful interpretation of patient results. Although a radical resection of the mesial temporal glioma, which involved the left fusiform gyrus, caused severe dyslexia, the patient's impaired reading skills improved gradually during a 1-year postoperative period. In the meantime, the spared left superior temporal gyrus displayed an overshot recovery of MEG responses. During the postoperative period there was no obvious recovery in MEG signals and no compensatory activity in the contralateral fusiform gyrus. This case demonstrates that lexicosemantic centers involved in the reading process can be noninvasively localized using MEG and that the results obtained are highly reliable for surgical planning. The results of the repeated MEG reflected sequentially the patient's recovery from dyslexia. This is the first report in which MEG studies have been shown to predict preoperatively the risk of dyslexia and demonstrate its serial physiological recovery.

In vivo quantification of the metabolites in normal brain and brain tumors by proton MR spectroscopy using water as an internal standard
ZY Tong, T Yamaki, K Harada, K Houkin
MAGNETIC RESONANCE IMAGING, 22, 5, 735, 742, ELSEVIER SCIENCE INC, 2004年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Metabolite concentrations in normal adult brains and in gliomas were quantitatively analyzed by in vivo proton magnetic resonance spectroscopy (MRS) using the fully relaxed water signal as an internal standard. Between January 1998 and October 2001, 28 healthy volunteers and 18 patients with gliomas were examined by in vivo proton MRS. Single-voxel spectra were acquired using the point-resolved spectroscopic (PRESS) pulse sequence with a 1.5 T scanner (TR/TE/Ave = 3000 ms/30 ms/64). The calculated concentrations of N-acetyl-aspartate (NAA), creatine (Cre), choline (Cho), and water(H2O) in the normal hemispheric white matter were 23.59 +/- 2.62 mM (mean +/- SD), 13.06 +/- 1.8 mM, 4.28 +/- 0.8 mM, and,47280.96 +/- 5414.85 mM, respectively. The metabolite concentrations were not necessarily uniform in different parts of the brain. The concentrations of NAA and Cre decreased in all gliomas (p < 0.001). The NAA/Cho and NAA/H2O ratios can distinguish the normal brain from gliomas and low-grade from high-grade astrocytoma (p < 0.001). The concentration of taurine (Tau) in medulloblastomas was 29.64 +/- 5.76 mM. This is the first quantitative analysis of Tau in medulloblastoma in vivo and confirms earlier in vitro findings. (C) 2004 Elsevier Inc. All rights reserved.

Determinants of intellectual outcome after surgical revascularization in pediatric moyamoya disease: a multivariate analysis
S Kuroda, K Houkin, T Ishikawa, N Nakayama, J Ikeda, N Ishii, H Kamiyama, Y Iwasaki
CHILDS NERVOUS SYSTEM, 20, 5, 302, 308, SPRINGER-VERLAG, 2004年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Objects. The aim of this study was to clarify predictors for poor intellectual outcome in pediatric moyamoya disease. Methods. Fifty-two pediatric patients were included. Clinical diagnosis was transient ischemic attacks (TIA) in 35 and completed stroke in 17. Ten patients underwent indirect synangiosis through "small craniotomy," whereas the other 42 underwent superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis and indirect synangiosis through "large craniotomy." Full-scale IQ (FSIQ) was measured using the Wechsler intelligence scale for children (WISC) after surgery. Multivariate logistic regression models were applied to test the effect of clinical factors on intellectual outcome. Results and conclusion. Eight patients revealed mentally impaired status (FSIQ<70). Multivariate analysis revealed that completed stroke and "small craniotomy" surgery were significantly associated with poor intellectual outcome. Odds ratios of each factor were 33.4 (95% CI, 2.4-474) and 19.6 (95% CI, 1.8-215) respectively. Early diagnosis and the revascularization procedure over as wide an area as possible may be essential to improve their intellectual outcome.

A therapeutic window for intravenous administration of autologous bone marrow after cerebral ischemia in adult rats
S Iihoshi, O Honmou, K Houkin, K Hashi, JD Kocsis
BRAIN RESEARCH, 1007, 1-2, 1, 9, ELSEVIER SCIENCE BV, 2004年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The primary objective of this study was to test the hypothesis that intravenous administration of autologous bone marrow cells could improve functional recovery after middle cerebral artery occlusion (MCAO) for 45 min in the rat and to determine specific time windows for efficacy. Mononuclear cells from autologous bone marrow were transfected with the LacZ reporter gene, and injected intravenously into rats at 3-72 h after induction of MCAO. Histological analysis of the ischemic lesion at 14 days after transplantation revealed reduced ischemic lesion volume. Lesion volume was 250 +/- 45 mm(3) (n = 6) after MCAO without cell transplantation. Lesions were minimally detected by absence of 2,3,5-triphenyltetrazolium chloride (TTC) staining when bone marrow cells were infused 3 h after lesion induction. Lesions were clearly detected beginning with the 6-h postlesion group and became progressively larger at 12, 24 and 72 h (80 +/- 25, 140 +/- 18, and 180 +/- 22 mm(3), respectively; n=6 for each group). Transplanted LacZ(+) bone marrow cells accumulated extensively in and around the ischemic lesions, and immunohistochemistry suggests some neuronal and glial lineage differentiation. Behavioral testing (Morris water maze and Treadmill stress test) indicated greater functional recovery in the treated group. These findings suggest that early intervention with intravenous administration of autologous mononuclear cells from bone marrow can reduce lesion size in the MCAO model in the rat, and improve functional outcome. (C) 2004 Elsevier B.V. All rights reserved.

ラット脳梗塞モデルに対する経静脈的骨髄幹細胞移植療法
本間 敏美, 本望 修, 原田 邦明, 備前 明子, 劉 赫, 野村 達史, 中村 公則, 濱田 洋文, 寶金 清博
脳卒中, 26, 1, 185, 185, (一社)日本脳卒中学会, 2004年03月
日本語

Pitfalls in cerebral revascularization surgery
Kiyohiro Houkin
International Congress Series, 1259, C, 313, 320, 2004年02月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Cerebral revascularization surgery is an important surgical option for unclippable cerebral aneurysm and prevention of the cerebral ischemia. During the past 10 years, we have performed cerebral revascularization for a variety of diseases on 257 cases. Among these cases, there were several cases of surgical complications. In adult moyamoya disease, rebleeding after surgery was seen approximately 15% in 10 years experience. High flow bypass from the external carotid artery to the middle cerebral artery was mainly performed to the unclippable carotid artery aneurysm for 56 cases. Among them, acute occlusion of the bypass