Faculty Profiles - SHIBATA Takashi

Papers - SHIBATA Takashi

Division display >> ／ All the affair displays 1 - 75 of about 75

A retrospective study on post-operative recovery of daily living activity after total corpus callosotomy. International journal

Hiroki Tsuchiya, Takashi Shibata, Tatsuya Sasaki, Mari Akiyama, Tomoyuki Akiyama, Katsuhiro Kobayashi

Brain & development 2024.9

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Post-operative complications of corpus callosotomy (CC) in children, prolonged hospitalization due to inactivity as acute disconnection syndrome is occasionally experienced. We aimed to clarify this issue and its risk factors with a hypothesis that electroencephalogram (EEG) findings as measures of functional lateralization may be among prognostic factors for post-operative recovery. MATERIALS AND METHODS: Twenty-three patients with childhood-onset drug-resistant epilepsy who underwent total CC between April 2017 and December 2023 were included in the study and they were divided into two groups based on the duration of post-operative hospitalization as an indicator of recovery of daily living activity. We compared scalp EEG findings and the other factors including clinical characteristics between the two groups. RESULTS: Of 22 patients (14 males) without specific complications, post-operative hospitalization clustered in 9-14 days in 15 patients (Group A) with range 16-118 days in seven patients (Group B). The ratios of patients with non-lateralized spikes on pre-operative EEG and that of patients with symmetric background activity on post-operative EEG were significantly greater in Group B (7/7, 100 %; 6/7, 86 %, respectively) than in Group A (8/15, 53 %; 4/15, 27 %, respectively) (p = 0.038; p = 0.020, respectively, by Fisher's exact test), while other factors were not significantly different between the two groups. CONCLUSIONS: Delayed recovery of living activity should be anticipated, especially in patients with non-lateralized epileptic discharges on pre-operative EEG.

DOI： 10.1016/j.braindev.2024.09.006

8歳MRI陰性側頭葉てんかんの一手術例

佐々木達也, 井本良二, 松田奈央子, 柴田敬, 秋山麻里, 亀田雅博, 安原隆雄, 秋山倫之, 小林勝弘, 伊達勲

てんかん研究 42 ( 1 ) 58 - 59 2024.6

新生児低血糖症による両側後頭葉病変を背景としたWest症候群の1手術例

竹中暁, 土屋弘樹, 柴田敬, 所谷知穂, 佐々木達也, 伊達勲, 秋山倫之, 小林勝弘

てんかん研究 42 ( 1 ) 64 - 64 2024.6

Modulation index predicts the effect of ethosuximide on developmental and epileptic encephalopathy with spike-and-wave activation in sleep. International journal

Takashi Shibata, Hiroki Tsuchiya, Mari Akiyama, Tomoyuki Akiyama, Katsuhiro Kobayashi

Epilepsy research 202 107359 - 107359 2024.5

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

PURPOSE: In developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS), the thalamocortical network is suggested to play an important role in the pathophysiology of the progression from focal epilepsy to DEE-SWAS. Ethosuximide (ESM) exerts effects by blocking T-type calcium channels in thalamic neurons. With the thalamocortical network in mind, we studied the prediction of ESM effectiveness in DEE-SWAS treatment using phase-amplitude coupling (PAC) analysis. METHODS: We retrospectively enrolled children with DEE-SWAS who had an electroencephalogram (EEG) recorded between January 2009 and September 2022 and were prescribed ESM at Okayama University Hospital. Only patients whose EEG showed continuous spike-and-wave during sleep were included. We extracted 5-min non-rapid eye movement sleep stage N2 segments from EEG recorded before starting ESM. We calculated the modulation index (MI) as the measure of PAC in pair combination comprising one of two fast oscillation types (gamma, 40-80 Hz; ripples, 80-150 Hz) and one of five slow-wave bands (delta, 0.5-1, 1-2, 2-3, and 3-4 Hz; theta, 4-8 Hz), and compared it between ESM responders and non-responders. RESULTS: We identified 20 children with a diagnosis of DEE-SWAS who took ESM. Fifteen were ESM responders. Regarding gamma oscillations, significant differences were seen only in MI with 0.5-1 Hz slow waves in the frontal pole and occipital regions. Regarding ripples, ESM responders had significantly higher MI in coupling with all slow waves in the frontal pole region, 0.5-1, 3-4, and 4-8 Hz slow waves in the frontal region, 3-4 Hz slow waves in the parietal region, 0.5-1, 2-3, 3-4, and 4-8 Hz slow waves in the occipital region, and 3-4 Hz slow waves in the anterior-temporal region. SIGNIFICANCE: High MI in a wider area of the brain may represent the epileptic network mediated by the thalamus in DEE-SWAS and may be a predictor of ESM effectiveness.

DOI： 10.1016/j.eplepsyres.2024.107359

Exploration of urine metabolic biomarkers for new-onset, untreated pediatric epilepsy: A gas and liquid chromatography mass spectrometry-based metabolomics study. Reviewed International journal

Tomoyuki Akiyama, Daisuke Saigusa, Takushi Inoue, Chiho Tokorodani, Mari Akiyama, Rie Michiue, Atsushi Mori, Eiji Hishinuma, Naomi Matsukawa, Takashi Shibata, Hiroki Tsuchiya, Katsuhiro Kobayashi

Brain & development 2024.1

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The discovery of objective indicators for recent epileptic seizures will help confirm the diagnosis of epilepsy and evaluate therapeutic effects. Past studies had shortcomings such as the inclusion of patients under treatment and those with various etiologies that could confound the analysis results significantly. We aimed to minimize such confounding effects and to explore the small molecule biomarkers associated with the recent occurrence of epileptic seizures using urine metabolomics. METHODS: This is a multicenter prospective study. Subjects included pediatric patients aged 2 to 12 years old with new-onset, untreated epilepsy, who had had the last seizure within 1 month before urine collection. Controls included healthy children aged 2 to 12 years old. Those with underlying or chronic diseases, acute illnesses, or recent administration of medications or supplements were excluded. Targeted metabolome analysis of spot urine samples was conducted using gas chromatography (GC)- and liquid chromatography (LC)-tandem mass spectrometry (MS/MS). RESULTS: We enrolled 17 patients and 21 controls. Among 172 metabolites measured by GC/MS/MS and 41 metabolites measured by LC/MS/MS, only taurine was consistently reduced in the epilepsy group. This finding was subsequently confirmed by the absolute quantification of amino acids. No other metabolites were consistently altered between the two groups. CONCLUSIONS: Urine metabolome analysis, which covers a larger number of metabolites than conventional biochemistry analyses, found no consistently altered small molecule metabolites except for reduced taurine in epilepsy patients compared to healthy controls. Further studies with larger samples, subjects with different ages, expanded target metabolites, and the investigation of plasma samples are required.

DOI： 10.1016/j.braindev.2023.12.004

尿中メタボローム解析を用いた未治療てんかんのバイオマーカー探索

秋山倫之, 三枝大輔, 秋山麻里, 柴田敬, 土屋弘樹, 道上理絵, 小林勝弘

脳と発達 56 ( 1 ) 71 - 71 2024.1

Effective Epilepsy Surgery for Post-Traumatic West Syndrome Following Abusive Head Trauma.

Hiroki Tsuchiya, Takashi Shibata, Tatsuya Sasaki, Takushi Inoue, Isao Date, Tomoyuki Akiyama, Katsuhiro Kobayashi

Acta medica Okayama 77 ( 5 ) 561 - 566 2023.10

Language：English

West syndrome, an infantile developmental and epileptic encephalopathy with a deleterious impact on long-term development, requires early treatment to minimize developmental abnormality; in such cases, epilepsy surgery should be considered a powerful therapeutic option. We describe a 10-month-old female admitted with West syndrome associated with a hemispheric lesion following abusive head trauma. Her seizures were suppressed by hemispherotomy at 12 months of age, leading to developmental improvement. Surgical treatment of West syndrome following traumatic brain injury has not been reported previously but is worth considering as a treatment option, depending on patient age and brain plasticity.

DOI： 10.18926/AMO/65980

West症候群に対するVGBの6年間の使用経験

道上理絵, 土屋弘樹, 柴田敬, 秋山麻里, 秋山倫之, 小林勝弘

てんかん研究 41 ( 2 ) 403 - 403 2023.9

A female patient with adolescent-onset progressive myoclonus epilepsy carrying a truncating MECP2 mutation. International journal

Mari Akiyama, Tomoyuki Akiyama, Hirotomo Saitsu, Yukie Tokioka, Rie Tsukahara, Hiroki Tsuchiya, Takashi Shibata, Katsuhiro Kobayashi

Brain & development 45 ( 10 ) 597 - 602 2023.8

Language：English

BACKGROUND: MECP2 is a well-known causative gene for Rett syndrome but other phenotypes have also been reported. Here, we report a case of a female patient with adolescent-onset progressive myoclonus epilepsy (PME) carrying a novel truncating mutation in the MECP2 gene. CASE REPORT: The patient was a 29-year-old woman with infantile-onset intellectual disability of unspecified cause. She had demonstrated slow but steady development with moderate intellectual disability until the age of 16, when she started having epileptic seizures. Her epilepsy progressed intractably with multiple seizure types accompanied by myoclonus, tremor, and gradual regression. She is currently apathetic and requires extensive assistance in all aspects of life. After an extensive work-up for underlying diseases for PME turned out negative, whole-exome sequencing revealed a de novo 113-bp deletion and 3-bp insertion in MECP2, a variant of NM_004992.4:c.1099_1211delinsGGG, p.(His367Glyfs*32). CONCLUSIONS: The clinical presentation of this case was inconsistent with Rett syndrome, and the rapid regression in the patient's twenties was considered characteristic. Mutations of MECP2 may result in variable neurodevelopmental phenotypes and may also be considered a causative gene for adolescent-onset PME.

DOI： 10.1016/j.braindev.2023.07.006

Epilepsy in Children With Congenital Heart Disease: Risk Factors and Characteristic Presentations. International journal

Takashi Shibata, Maiko Kondo, Yosuke Fukushima, Mari Akiyama, Tomoyuki Akiyama, Teruko Morooka, Kenji Baba, Shinichi Ohtsuki, Hirokazu Tsukahara, Shingo Kasahara, Katsuhiro Kobayashi

Pediatric neurology 147 28 - 35 2023.7

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Children with a congenital heart disease (CHD) are at a higher risk of developing epilepsy than the general population, but detailed characteristics of CHD-associated epilepsy have not been clarified. The purposes of this study were to determine the risk factors for developing epilepsy associated with CHD and to elucidate the characteristics of such epilepsy. METHODS: We performed a retrospective cohort study based on medical records of pediatric patients with CHD who were born between January 2006 and December 2016, underwent cardiac surgery at Okayama University Hospital, and were followed up until at least age three years. Multivariate logistic regression analysis was used to determine factors particularly associated with epilepsy occurrence. In patients who developed epilepsy, clinical data on seizure characteristics were further investigated. RESULTS: We collected data from 1024 patients, and 41 (4.0%) developed epilepsy. The presence of underlying disease (odds ratio [OR]: 2.413; 95% confidence interval [CI]: 1.150 to 4.883) and the Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery score category 2 (OR: 4.373; 95% CI: 1.090 to 29.150) and category 5 (OR: 10.385; 95% CI: 1.717 to 89.016) were significantly related to epilepsy occurrence. Of the 41 patients with epilepsy, 15 (including nine with hypoplastic left heart syndrome) had focal impaired awareness seizures specified as autonomic seizures with vomiting, which tends to escape detection. CONCLUSIONS: We clarified the risk factors for developing epilepsy in children with CHD. We also found that autonomic seizure with vomiting is an important symptom in these children.

DOI： 10.1016/j.pediatrneurol.2023.07.004

結節性硬化症を背景とした焦点てんかんの生後2ヵ月児に対する早期てんかん外科治療の1例

竹中暁, 品川穣, 秋山麻里, 柴田敬, 土屋弘樹, 秋山倫之, 佐々木達也, 伊達勲, 小林勝弘

脳と発達 55 ( Suppl. ) S423 - S423 2023.5

皮膚所見を伴い鑑別に苦慮したCerebral proliferative angiopathyの男児例

塚原理恵, 柴田敬, 土屋弘樹, 春間純, 竹内章人, 井上拓志, 石黒友也, 小林勝弘

脳と発達 55 ( Suppl. ) S389 - S389 2023.5

脳梁離断術後の活動性低下,食思不振が長期化しうる要因とは

土屋弘樹, 大野友香子, 道上理絵, 柴田敬, 秋山麻里, 佐々木達也, 伊達勲, 秋山倫之, 小林勝弘

脳と発達 55 ( Suppl. ) S281 - S281 2023.5

大家族における発達性ディスレクシアの病因遺伝子解析

岡牧郎, 禅正和真, 柴田敬, 宮崎育子, 浅沼幹人, 小林勝弘

脳と発達 55 ( Suppl. ) S353 - S353 2023.5

脳梁離断術後の活動性低下,食思不振が長期化しうる要因とは

土屋弘樹, 大野友香子, 道上理絵, 柴田敬, 秋山麻里, 佐々木達也, 伊達勲, 秋山倫之, 小林勝弘

脳と発達 55 ( Suppl. ) S281 - S281 2023.5

結節性硬化症を背景とした焦点てんかんの生後2ヵ月児に対する早期てんかん外科治療の1例

竹中暁, 品川穣, 秋山麻里, 柴田敬, 土屋弘樹, 秋山倫之, 佐々木達也, 伊達勲, 小林勝弘

脳と発達 55 ( Suppl. ) S423 - S423 2023.5

皮膚所見を伴い鑑別に苦慮したCerebral proliferative angiopathyの男児例

塚原理恵, 柴田敬, 土屋弘樹, 春間純, 竹内章人, 井上拓志, 石黒友也, 小林勝弘

脳と発達 55 ( Suppl. ) S389 - S389 2023.5

Comprehensive study of metabolic changes induced by a ketogenic diet therapy using GC/MS- and LC/MS-based metabolomics Reviewed

Mari Akiyama, Tomoyuki Akiyama, Daisuke Saigusa, Eiji Hishinuma, Naomi Matsukawa, Takashi Shibata, Hiroki Tsuchiya, Atsushi Mori, Yuji Fujii, Yukiko Mogami, Chiho Tokorodani, Kozue Kuwahara, Yurika Numata-Uematsu, Kenji Inoue, Katsuhiro Kobayashi

Seizure 107 52 - 59 2023.4

【てんかん診療update-診断,治療,社会整備,基礎研究の最新情報-】デジタル脳波がもたらす新時代

小林勝弘, 柴田敬, 土屋弘樹

日本臨床 80 ( 12 ) 1895 - 1899 2022.12

Artificial intelligence-based detection of epileptic discharges from pediatric scalp electroencephalograms: a pilot study Reviewed

Katsuhiro Kobayashi, Takashi Shibata, Hiroki Tsuchiya, Tomoyuki Akiyama

Acta Medica Okayama 76 ( 6 ) 617 - 624 2022.12

Language：English Publishing type：Research paper (scientific journal)

We developed an artificial intelligence (AI) technique to identify epileptic discharges (spikes) in pediatric scalp electroencephalograms (EEGs). We built a convolutional neural network (CNN) model to automatically classify steep potential images into spikes and background activity. For the CNN model' training and validation, we examined 100 children with spikes in EEGs and another 100 without spikes. A different group of 20 children with spikes and 20 without spikes were the actual test subjects. All subjects were ≥ 3 to < 18 years old. The accuracy, sensitivity, and specificity of the analysis were >0.97 when referential and combination EEG montages were used, and < 0.97 with a bipolar montage. The correct classification of background activity in individual patients was significantly better with a referential montage than with a bipolar montage (p=0.0107). Receiver operating characteristic curves yielded an area under the curve > 0.99, indicating high performance of the classification method. EEG patterns that interfered with correct classification included vertex sharp transients, sleep spindles, alpha rhythm, and low-amplitude ill-formed spikes in a run. Our results demonstrate that AI is a promising tool for automatically interpreting pediatric EEGs. Some avenues for improving the technique were also indicated by our findings.

DOI： 10.18926/AMO/64111

AIにより小児頭皮脳波からてんかん発射を検出するための試験的研究

小林勝弘, 柴田敬, 土屋弘樹, 秋山倫之

臨床神経生理学 50 ( 5 ) 417 - 417 2022.10

A Case of a Solitary Cortical Tuber with No Other Manifestations of Tuberous Sclerosis Complex Mimicking Focal Cortical Dysplasia Type II with Calcification.

Kakeru Hosomoto, Tatsuya Sasaki, Koji Kawai, Yosuke Okazaki, Yuki Hyodo, Takashi Shibata, Susumu Sasada, Takao Yasuhara, Katsuhiro Kobayashi, Hiroyuki Yanai, Isao Date

Acta medica Okayama 76 ( 3 ) 323 - 328 2022.6

Language：English

Cortical tubers are one of the typical intracranial manifestations of tuberous sclerosis complex (TSC). Multiple cortical tubers are easy to diagnose as TSC; however, a solitary cortical tuber without any other cutaneous or visceral organ manifestations can be confused with other conditions, particularly focal cortical dysplasia. We report a surgical case of refractory epilepsy caused by a solitary cortical tuber mimicking focal cortical dysplasia type II, and describe the radiological, electrophysiological, and histopathological findings of our case.

DOI： 10.18926/AMO/63742

難治性てんかん患者におけるケトン食による代謝変化の網羅的検討

秋山麻里, 秋山倫之, 三枝大輔, 井上賢治, 森篤志, 最上友紀子, 藤井裕士, 所谷知穂, 桑原こずえ, 植松有里佳, 土屋弘樹, 柴田敬, 小林勝弘

脳と発達 54 ( Suppl. ) S222 - S222 2022.5

【脳波の読み方-up to date】疾患別の脳波睡眠時持続性棘徐波(CSWS)を示すてんかん性脳症およびLandau-Kleffner症候群 Invited

小林勝弘, 柴田敬, 土屋弘樹

Clinical Neuroscience 40 ( 4 ) 492 - 498 2022.4

Prolonged Video-EEG and Heart Rate Variability can Elucidate Autonomic Dysregulation in Infantile Apneic Seizures. Reviewed International journal

Shinsuke Maruyama, Puneet Jain, Kaajal Parbhoo, Cristina Go, Takashi Shibata, Hiroshi Otsubo

Pediatric neurology 127 48 - 55 2022.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Infantile apneic seizures (IASs) are unexpected life-threatening events. We aimed to determine the utility of prolonged video-electroencephalography (vEEG) and heart rate variability (HRV) in IAS. METHODS: The study included seven infants with apneic seizures captured by vEEG, percutaneous oxygen saturation (SpO2), and electrocardiography (ECG). Interictal, preictal, and postictal HRV of patients and N2 sleep HRV of 10 age-matched controls were determined. RESULTS: We analyzed seven vEEGs (duration = 17 to 87 hours) of seven patients aged three to 13 months (mean onset age of apneic event = 6.3 months). Fifteen apneic seizures (one to five per infant) were captured. The initial apneic seizure was captured at 7.5 to 76 hours (mean = 36.6 hours) after vEEG initiation. Ictal rhythmic delta/theta/fast waves were seen over temporal (five patients), central (one), and diffuse areas (one). Ictal SpO2 decreased between 1.5% and 90% (mean = 47.9%). Ictal decreased heart rate (HR) (six seizures) and ictal increased HR (14) was detected. Both decreased and increased HR was observed (five). The preictal low-frequency (LF)/high-frequency (HF) ratio was significantly higher than the interictal LF/HF ratio (P = 0.048). Preictal (P = 0.048), and postictal (P = 0.019) root mean square of successive differences (RMSSDs) of patients were lower than the sleep RMSSD of controls. These results indicated dominant sympathetic activity. RMSSD from interictal to preictal periods tended to be higher in IAS with decreased HR than in IAS with increased HR alone (P = 0.066). The postictal RMSSD showed tendency to be higher in IAS with decreased HR than in IAS with increased HR alone (P = 0.088). The decreased HR and increased RMSSD suggested not only sympathetic activity but also escalated parasympathetic activity in IAS. CONCLUSIONS: Infants with unexpected apneic events should be monitored with prolonged vEEG, SpO2, and ECG. Abnormal HRV in infants with apneic seizures might indicate additional autonomic dysregulation in IAS.

DOI： 10.1016/j.pediatrneurol.2021.11.007

先天性心疾患の児に発症したてんかんの検討

柴田敬, 近藤麻衣子, 秋山麻里, 秋山倫之, 諸岡輝子, 馬場健児, 大月審一, 塚原宏一, 笠原真悟, 小林勝弘

日本小児科学会雑誌 126 ( 2 ) 303 - 303 2022.2

一酸化炭素中毒に対して高気圧酸素療法を施行した2例

浦田奈生子, 土屋弘樹, 柴田敬, 塚原紘平, 嶋泰樹, 小林勝弘

日本小児科学会雑誌 126 ( 2 ) 337 - 337 2022.2

一酸化炭素中毒に対して高気圧酸素療法を施行した2例

浦田奈生子, 土屋弘樹, 柴田敬, 塚原紘平, 嶋泰樹, 小林勝弘

脳と発達 53 ( 6 ) 469 - 469 2021.11

A study on the relationship between non-epileptic fast (40 – 200 Hz) oscillations in scalp EEG and development in children Reviewed International journal

Makio Oka, Katsuhiro Kobayashi, Takashi Shibata, Hiroki Tsuchiya, Yoshiyuki Hanaoka, Mari Akiyama, Teruko Morooka, Masao Matsuhashi, Tomoyuki Akiyama

Brain and Development 43 ( 9 ) 904 - 911 2021.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

OBJECTIVE: Physiological gamma and ripple activities may be linked to neurocognitive functions. This study investigated the relationship between development and non-epileptic, probably physiological, fast (40-200 Hz) oscillations (FOs) including gamma (40 - 80 Hz) and ripple (80 - 200 Hz) oscillations in scalp EEG in children with neurodevelopmental disorders. METHODS: Participants were 124 children with autism spectrum disorder (ASD) and/or attention deficit/hyperactivity disorder (ADHD). Gamma and ripple oscillations were explored from 60-second-long sleep EEG data in each subject using a semi-automatic detection tool supplemented with visual confirmation and time-frequency analysis. RESULTS: Gamma and ripple oscillations were detected in 25 (20.2%) and 22 (17.7%) children, respectively. The observation of one or more occurrence(s) of ripple oscillations, but not gamma oscillations, was significantly related to lower age at EEG recording (odds ratio, OR: 0.727 [95% confidence interval, CI: 0.568-0.929]), higher intelligence/developmental quotient (OR: 1.041, 95% CI: 1.002-1.082), and lack of a diagnosis with ADHD (OR: 0.191, 95% CI: 0.039 - 0.937) according to a binominal logistic regression analysis that included diagnosis with ASD, sex, history of perinatal complications, history of febrile seizures, and use of a sedative agent for the EEG recording as the other non-significant parameters. Diagnostic group was not related to frequency or power of spectral peaks of FOs. CONCLUSION: The production of non-epileptic scalp ripples was confirmed to be associated with brain development and function/dysfunction in childhood. Further investigation is necessary to interpret all of the information on higher brain functions that may be embedded in scalp FOs.

DOI： 10.1016/j.braindev.2021.05.004

Exclusion of the Possibility of “False Ripples” From Ripple Band High-Frequency Oscillations Recorded From Scalp Electroencephalogram in Children With Epilepsy Reviewed International journal

Katsuhiro Kobayashi, Takashi Shibata, Hiroki Tsuchiya, Tomoyuki Akiyama

Frontiers in Human Neuroscience 15 696882 - 696882 2021.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers Media SA

<sec><title>Aim</title>Ripple-band epileptic high-frequency oscillations (HFOs) can be recorded by scalp electroencephalography (EEG), and tend to be associated with epileptic spikes. However, there is a concern that the filtration of steep waveforms such as spikes may cause spurious oscillations or “false ripples.” We excluded such possibility from at least some ripples by EEG differentiation, which, in theory, enhances high-frequency signals and does not generate spurious oscillations or ringing.

</sec><sec><title>Methods</title>The subjects were 50 pediatric patients, and ten consecutive spikes during sleep were selected for each patient. Five hundred spike data segments were initially reviewed by two experienced electroencephalographers using consensus to identify the presence or absence of ripples in the ordinary filtered EEG and an associated spectral blob in time-frequency analysis (Session A). These EEG data were subjected to numerical differentiation (the second derivative was denoted as EEG″). The EEG″ trace of each spike data segment was shown to two other electroencephalographers who judged independently whether there were clear ripple oscillations or uncertain ripple oscillations or an absence of oscillations (Session B).

</sec><sec><title>Results</title>In Session A, ripples were identified in 57 spike data segments (Group A-R), but not in the other 443 data segments (Group A-N). In Session B, both reviewers identified clear ripples (strict criterion) in 11 spike data segments, all of which were in Group A-R (<italic>p</italic> &lt; 0.0001 by Fisher’s exact test). When the extended criterion that included clear and/or uncertain ripples was used in Session B, both reviewers identified 25 spike data segments that fulfilled the criterion: 24 of these were in Group A-R (<italic>p</italic> &lt; 0.0001).

</sec><sec><title>Discussion</title>We have demonstrated that real ripples over scalp spikes exist in a certain proportion of patients. Ripples that were visualized consistently using both ordinary filters and the EEG″ method should be true, but failure to clarify ripples using the EEG″ method does not mean that true ripples are absent.

</sec><sec><title>Conclusion</title>The numerical differentiation of EEG data provides convincing evidence that HFOs were detected in terms of the presence of such unusually fast oscillations over the scalp and the importance of this electrophysiological phenomenon.

</sec>

DOI： 10.3389/fnhum.2021.696882

Rituximab Was Effective for Treatment of Anti–N-Methyl-d-Aspartate Receptor Encephalitis in Early Adolescence in Initially Suspected Dissociative Disorder Reviewed

Takashi Shibata, Hiroki Kawai, Shinji Sakamoto, Ko Tsutsui, Takashi Kanbayashi, Keiko Tanaka, Manabu Takaki

Clinical Neuropharmacology 44 ( 3 ) 99 - 100 2021.5

Phase-amplitude coupling of interictal fast activities modulated by slow waves on scalp EEG and its correlation with seizure outcomes of disconnection surgery in children with intractable nonlesional epileptic spasms Reviewed International journal

Takehiro Uda, Ichiro Kuki, Takeshi Inoue, Noritsugu Kunihiro, Hiroharu Suzuki, Hiroshi Uda, Toshiyuki Kawashima, Kosuke Nakajo, Yoko Nakanishi, Shinsuke Maruyama, Takashi Shibata, Hiroshi Ogawa, Shin Okazaki, Hisashi Kawawaki, Kenji Ohata, Takeo Goto, Hiroshi Otsubo

Journal of Neurosurgery: Pediatrics 27 ( 5 ) 572 - 580 2021.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Neurosurgery Publishing Group (JNSPG)

<sec>
<title>OBJECTIVE</title>
Epileptic spasms (ESs) are classified as focal, generalized, or unknown onset ESs. The classification of ESs and surgery in patients without lesions apparent on MRI is challenging. Total corpus callosotomy (TCC) is a surgical option for diagnosis of the lateralization and possible treatment for ESs. This study investigated phase-amplitude coupling (PAC) of fast activity modulated by slow waves on scalp electroencephalography (EEG) to evaluate the strength of the modulation index (MI) before and after disconnection surgery in children with intractable nonlesional ESs. The authors hypothesize that a decreased MI due to surgery correlates with good seizure outcomes.

</sec>
<sec>
<title>METHODS</title>
The authors studied 10 children with ESs without lesions on MRI who underwent disconnection surgeries. Scalp EEG was obtained before and after surgery. The authors collected 20 epochs of 3 minutes each during non–rapid eye movement sleep. The MI of the gamma (30–70 Hz) amplitude and delta (0.5–4 Hz) phase was obtained in each electrode. MIs for each electrode were averaged in 4 brain areas (left/right, anterior/posterior quadrants) and evaluated to determine the correlation with seizure outcomes.

</sec>
<sec>
<title>RESULTS</title>
The median age at first surgery was 2.3 years (range 10 months–9.1 years). Two patients with focal onset ESs underwent anterior quadrant disconnection (AQD). TCC alone was performed in 5 patients with generalized or unknown onset ESs. Two patients achieved seizure freedom. Three patients had residual generalized onset ESs. Disconnection surgeries in addition to TCC consisted of TCC + posterior quadrant disconnection (PQD) (1 patient); TCC + AQD + PQD (1 patient); and TCC + AQD + hemispherotomy (1 patient). Seven patients became seizure free with a mean follow-up period of 28 months (range 5–54 months). After TCC, MIs in 4 quadrants were significantly lower in the 2 seizure-free patients than in the 6 patients with residual ESs (p < 0.001). After all 15 disconnection surgeries in 10 patients, MIs in the 13 target quadrants for each disconnection surgery that resulted in freedom from seizures were significantly lower than in the 26 target quadrants in patients with residual ESs (p < 0.001).

</sec>
<sec>
<title>CONCLUSIONS</title>
In children with nonlesional ESs, PAC for scalp EEG before and after disconnection surgery may be a surrogate marker for control of ESs. The MI may indicate epileptogenic neuronal modulation of the interhemispheric corpus callosum and intrahemispheric subcortical network for ESs. TCC may be a therapeutic option to disconnect the interhemispheric modulation of epileptic networks.

</sec>

DOI： 10.3171/2020.9.peds20520

Other Link： https://thejns.org/downloadpdf/journals/j-neurosurg-pediatr/27/5/article-p572.xml

小児神経疾患患者における尿中メタボローム解析の経験

秋山倫之, 久原とみ子, 大瀬守眞, 秋山麻里, 柴田敬, 花岡義行, 土屋弘樹, 兵頭勇紀, 小林勝弘

脳と発達 53 ( Suppl. ) S240 - S240 2021.5

小児神経疾患患者における尿中メタボローム解析の経験

秋山倫之, 久原とみ子, 大瀬守眞, 秋山麻里, 柴田敬, 花岡義行, 土屋弘樹, 兵頭勇紀, 小林勝弘

脳と発達 53 ( Suppl. ) S240 - S240 2021.5

Phase-amplitude coupling of delta brush unveiling neuronal modulation development in the neonatal brain Reviewed

Takashi Shibata, Hiroshi Otsubo

Neuroscience Letters 735 135211 - 135211 2020.9

Autonomic dysregulation in children with epilepsy with postictal generalized EEG suppression following generalized convulsive seizures Reviewed

Kazuo Okanari, Shinsuke Maruyama, Hiroharu Suzuki, Takashi Shibata, Elizabeth Pulcine, Elizabeth J. Donner, Hiroshi Otsubo

Epilepsy & Behavior 102 106688 - 106688 2020.1

Novel AVPR2 variant in a male infant with nephrogenic diabetes insipidus who showed delayed head control Reviewed

Kosei Hasegawa, Hiromi Ihoriya, Natsuko Futagawa, Yousuke Higuchi, Hiroki Tsuchiya, Takashi Shibata, Yumiko Hayashi, Katsuhiro Kobayashi, Hirokazu Tsukahara

Clinical Pediatric Endocrinology 28 ( 4 ) 155 - 158 2019.10

Anti-NMDA-receptor antibody in initial diagnosis of mood disorder Reviewed

Hiroki Kawai, Manabu Takaki, Shinji Sakamoto, Takashi Shibata, Ayaka Tsuchida, Bunta Yoshimura, Yuji Yada, Namiko Matsumoto, Kota Sato, Koji Abe, Yuko Okahisa, Yoshiki Kishi, Soshi Takao, Ko Tsutsui, Takashi Kanbayashi, Keiko Tanaka, Norihito Yamada

European Neuropsychopharmacology 29 ( 9 ) 1041 - 1050 2019.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

Anti-NMDAR encephalitis is increasingly recognized as one etiology of psychiatric symptoms, but there is not enough evidence on patients with mood disorder. We assayed anti-NR1/NR2B IgG antibodies in serum and/or cerebrospinal fluid of 62 patients initially diagnosed with mood disorder by a cell-based assay. We also investigated the specific patient characteristics and psychotic symptoms. At first admission, the patients showed only psychiatric symptoms without typical neurological signs or abnormal examination findings. Four of the 62 patients had anti-NR1/NR2B IgG antibodies. The anti-NR1/NR2B IgG antibody-positive patients showed more super- or abnormal sensitivity (P = 0.00088), catatonia (P = 0.049), and more conceptual disorganization (P < 0.0001), hostility (P = 0.0010), suspiciousness (P < 0.0001), and less emotional withdrawal (P < 0.0001) and motor retardation (P < 0.0001) on the Brief Psychiatric Rating Scale than the antibody-negative patients. During the clinical course, anti-NR1/NR2B IgG antibody-positive patients showed more catatonia (P = 0.0042) and met Graus's criteria for diagnosis of anti-NMDAR encephalitis, but negative patients did not. Immunotherapy was effective for anti-NR1/NR2B IgG antibody-positive patients, and there was the weak relationship (R² = 0.318) between the anti-NR1/NR2B IgG antibody titer in the cerebrospinal fluid and the Brief Psychiatric Rating Scale score.

DOI： 10.1016/j.euroneuro.2019.07.137

Infantile spasmsにおける初回ACTH療法後の再発に関する検討

金聖泰, 小林勝弘, 兵頭勇紀, 藤代定志, 水野むつみ, 道上理絵, 宮原大輔, 花岡義行, 柴田敬, 秋山麻里, 岡牧郎, 遠藤文香, 秋山倫之

てんかん研究 37 ( 2 ) 574 - 574 2019.9

West症候群を発症した結節性硬化症症例のてんかんの経過と幼児期早期の発達について

遠藤文香, 土屋弘樹, 兵頭勇紀, 水野むつみ, 金聖泰, 花岡義行, 柴田敬, 秋山麻里, 小林勝弘

脳と発達 51 ( Suppl. ) S279 - S279 2019.5

難治性てんかんで発症したinsular pilocytic astrocytomaの一例

佐々木達也, 細本翔, 岡崎三保子, 水野むつみ, 柴田敬, 秋山麻里, 亀田雅博, 安原隆雄, 小林勝弘, 伊達勲

てんかん研究 36 ( 1 ) 88 - 89 2018.6

Ethosuximide-induced Stevens-Johnson syndrome: Beneficial effect of early intervention with high-dose corticosteroid therapy. Reviewed International journal

Kota Tachibana, Toshihisa Hamada, Hiroki Tsuchiya, Takashi Shibata, Kazuyasu Fujii, Katsuhiro Kobayashi, Keiji Iwatsuki

The Journal of dermatology 45 ( 5 ) 592 - 595 2018.5

Language：English Publishing type：Research paper (scientific journal)

We report two rare cases of childhood epilepsy patients who developed ethosuximide-induced Stevens-Johnson syndrome (SJS). Unlike typical SJS, the initial eruption of both patients presented well-demarcated, infiltrating firm papules mainly on the cheeks and the extensor aspects of the arms (case 1), and multiple vesicles on the soles and oral aphthosis (case 2), which closely mimicked viral exanthema. We diagnosed both patients with ethosuximide-induced SJS, based on the dosing period and the positive results of drug-induced lymphocyte stimulation test. Systemic corticosteroids are usually selected as a standard therapy for SJS, despite controversial results regarding their effectiveness. In case 1, an i.v. pulse therapy of methylprednisolone (30 mg/kg, 3 days consecutively) was initiated on day 7 from the onset of illness, and an i.v. immunoglobulin (400 mg/kg, 5 days consecutively) was added the following day. In case 2, an i.v. prednisone treatment (1 mg/kg, for 1 week) was initiated on day 4 from the onset. Eventually, the early therapeutic interventions resulted in good outcomes in both patients.

DOI： 10.1111/1346-8138.14253

Ethosuximide-induced Stevens-Johnson syndrome: Beneficial effect of early intervention with high-dose corticosteroid therapy Reviewed International journal

Kota Tachibana, Toshihisa Hamada, Hiroki Tsuchiya, Takashi Shibata, Kazuyasu Fujii, Katsuhiro Kobayashi, Keiji Iwatsuki

The Journal of Dermatology 45 ( 5 ) 592 - 595 2018.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Wiley

We report two rare cases of childhood epilepsy patients who developed ethosuximide-induced Stevens-Johnson syndrome (SJS). Unlike typical SJS, the initial eruption of both patients presented well-demarcated, infiltrating firm papules mainly on the cheeks and the extensor aspects of the arms (case 1), and multiple vesicles on the soles and oral aphthosis (case 2), which closely mimicked viral exanthema. We diagnosed both patients with ethosuximide-induced SJS, based on the dosing period and the positive results of drug-induced lymphocyte stimulation test. Systemic corticosteroids are usually selected as a standard therapy for SJS, despite controversial results regarding their effectiveness. In case 1, an i.v. pulse therapy of methylprednisolone (30 mg/kg, 3 days consecutively) was initiated on day 7 from the onset of illness, and an i.v. immunoglobulin (400 mg/kg, 5 days consecutively) was added the following day. In case 2, an i.v. prednisone treatment (1 mg/kg, for 1 week) was initiated on day 4 from the onset. Eventually, the early therapeutic interventions resulted in good outcomes in both patients.

DOI： 10.1111/1346-8138.14253

Detection of fast (40–150 Hz) oscillations from the ictal scalp EEG data of myoclonic seizures in pediatric patients Reviewed International journal

Katsuhiro Kobayashi, Yuji Ohuchi, Takashi Shibata, Yoshiyuki Hanaoka, Mari Akiyama, Makio Oka, Fumika Endoh, Tomoyuki Akiyama

Brain and Development 40 ( 5 ) 397 - 405 2018.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

OBJECTIVE: We explored fast (40-150 Hz) oscillations (FOs) from the ictal scalp electroencephalogram (EEG) data of myoclonic seizures in pediatric patients to obtain insight into the pathophysiological mechanisms involved in the generation of myoclonic seizures. SUBJECTS AND METHODS: The participants were 21 children (11 boys, 10 girls; age ranging from 5 months to 17 years 2 months) with myoclonic seizures associated with generalized (poly)spike-wave bursts in the ictal EEG data. The patients had heterogeneous etiologies and epilepsy diagnoses. In the ictal data, we detected FOs that clearly showed oscillatory morphology in filtered EEG traces and an outstanding spectral blob in time-frequency analysis. RESULTS: We identified FOs in 61 (88.4%) of all 69 myoclonic seizures. Every patient had at least one myoclonic seizure-associated FO. The observed FOs were embedded in the spike component of (poly)spike-wave discharges, and they had a focal distribution with frontal predominance. They ranged in frequency from 41.0 to 123.0 Hz and involved both the gamma and ripple bands, and their spectral peak frequencies were higher in the group of patients with a genetic background free of apparent fundamental brain pathology than in the group of other patients (p = 0.019). CONCLUSION: FOs were found to represent at least part of the cortical pathophysiological process in the generation of myoclonic seizures that should involve the thalamocortical network system.

DOI： 10.1016/j.braindev.2018.01.004

Loss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders Reviewed

Takeshi Mizuguchi, Mitsuko Nakashima, Mitsuhiro Kato, Nobuhiko Okamoto, Hirokazu Kurahashi, Nina Ekhilevitch, Masaaki Shiina, Gen Nishimura, Takashi Shibata, Muneaki Matsuo, Tae Ikeda, Kazuhiro Ogata, Naomi Tsuchida, Satomi Mitsuhashi, Satoko Miyatake, Atsushi Takata, Noriko Miyake, Kenichiro Hata, Tadashi Kaname, Yoichi Matsubara, Hirotomo Saitsu, Naomichi Matsumoto

Human Molecular Genetics 27 ( 8 ) 1421 - 1433 2018.4

Epileptic high-frequency oscillations in scalp electroencephalography

Takashi Shibata, Katsuhiro Kobayashi

Acta Medica Okayama 72 ( 4 ) 325 - 329 2018

Language：English Publishing type：Research paper (scientific journal) Publisher：Okayama University

Electroencephalography (EEG) examines the functional state of the brain. High-frequency oscillations (HFOs) in the ripple (80-200/250 Hz) and fast ripple (200/250-500/600 Hz) bands have recently been attracting attention, and their recording has been enabled by advancements in digital EEG techniques. The detection of HFOs was previously limited to intracranial EEG, but fast oscillations (FOs) in the gamma (40-80 Hz) and ripple bands can now be detected over the scalp. HFOs and FOs have been shown to be related to epileptogenicity in intracranial EEG and scalp EEG, respectively. A large number of FOs are found in the scalp EEGs of pediatric patients with various epileptic encephalopathies, particularly West syndrome. FOs are suggested to be a biomarker of the epileptogenic cortical region in epilepsy surgery. FOs are detectable even in patients with idiopathic focal epilepsies, including benign epilepsy with centrotemporal spikes and Panayiotopoulos syndrome, who are not generally candidates for operation. The detection of HFOs and FOs may provide clues to the pathophysiology of epilepsy and the relationship between HFOs and cognitive dysfunction.

SCN8A遺伝子異常を認めた早期発症てんかん性脳症の1例

柴田敬, 岡牧郎, 小林勝弘, 高見勇一

脳と発達 49 ( 6 ) 429 - 429 2017.11

Another Case of Glucose Transporter 1 Deficiency Syndrome with Periventricular Calcification, Cataracts, Hemolysis, and Pseudohyperkalemia Reviewed

Katsuhiro Kobayashi, Harumi Yoshinaga, Hiroaki Ono, Michiko Shinpo, Kuriko Kagitani-Shimono, Takashi Shibata

Neuropediatrics 48 ( 05 ) 390 - 393 2017.10

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Georg Thieme Verlag KG

<title>Abstract</title>Glucose transporter 1 (GLUT1) deficiency syndrome (GLUT1DS) is a disorder resulting from shortage of energy in the brain caused by reduced GLUT1 activity. Its common clinical symptoms include seizures, microcephaly, intellectual disability, abnormal ocular movements, ataxia, and dystonia. We report a case of GLUT1DS with unusual symptoms, including periventricular calcification. The patient is a Japanese girl, whose seizures had always evolved into status epilepticus since she was 4 months old. She also had cataracts and horizontal nystagmus. Neuroimaging studies showed periventricular calcification and brain atrophy. Laboratory data revealed pseudohyperkalemia, reticulocyte increase, and hypoglycorrhachia. A mutation of c1306_1308delATC (p.Ile436del) was identified in the SLC2A1 gene, and she was thus diagnosed with GLUT1DS. A case with the identical SLC2A1 gene mutation and similar clinical findings was previously reported by Bawazir et al (2012). The leak of monovalent cations through the red cell membrane causes hemolysis in such patients, and a similar phenomenon may occur at the blood–brain barrier and the lens epithelium. After commencing ketogenic diet therapy, the electroencephalogram (EEG) abnormalities improved markedly and the patient's development advanced. Clinicians should be aware of atypical GLUT1DS.

DOI： 10.1055/s-0037-1603520

Pyridoxal 5′-phosphate, pyridoxal, and 4-pyridoxic acid in the paired serum and cerebrospinal fluid of children Reviewed International journal

Tomoyuki Akiyama, Yumiko Hayashi, Yoshiyuki Hanaoka, Takashi Shibata, Mari Akiyama, Hiroki Tsuchiya, Tokito Yamaguchi, Katsuhiro Kobayashi

Clinica Chimica Acta 472 118 - 122 2017.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

BACKGROUND: We quantified pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) in paired serum and cerebrospinal fluid (CSF) samples from children and investigated the effect of age on the concentrations and CSF-to-serum ratios of these vitamers. METHODS: Serum and CSF samples prospectively collected from 49 pediatric patients were analyzed. PLP, PL, and PA were measured using high-performance liquid chromatography with fluorescence detection, using pre-column derivatization by semicarbazide. Effects of age on these vitamers, the PLP-to-PL ratio, CSF-to-serum PLP ratio, and CSF-to-serum PL ratio were evaluated using correlation analysis. RESULTS: The PLP, PL, and PA concentrations in the serum and CSF were higher at younger ages, except for CSF PA concentrations that were mostly below the limit of detection (<1.2nmol/l). The PLP-to-PL ratios in the serum and CSF correlated positively with age. The CSF-to-serum PLP ratio and CSF-to-serum PL ratio were independent of age. CONCLUSIONS: Age-related changes in PLP, PL, and PA in serum and in CSF from pediatric patients and CSF-to-serum ratios of PLP and PL demonstrated in this study will provide valuable information for evaluating PLP supply to the central nervous system from the peripheral blood.

DOI： 10.1016/j.cca.2017.07.032

Complex observation of scalp fast (40-150 Hz) oscillations in West syndrome and related disorders with structural brain pathology Reviewed

Katsuhiro Kobayashi, Fumika Endoh, Takashi Agari, Tomoyuki Akiyama, Mari Akiyama, Yumiko Hayashi, Takashi Shibata, Yoshiyuki Hanaoka, Makio Oka, Harumi Yoshinaga, Isao Date

Epilepsia Open 2 ( 2 ) 260 - 266 2017.6

Measurement of pyridoxal 5′-phosphate, pyridoxal, and 4-pyridoxic acid in the cerebrospinal fluid of children Reviewed

Tomoyuki Akiyama, Mari Akiyama, Yumiko Hayashi, Takashi Shibata, Yoshiyuki Hanaoka, Soichiro Toda, Katsumi Imai, Shin-ichiro Hamano, Tohru Okanishi, Harumi Yoshinaga, Katsuhiro Kobayashi

Clinica Chimica Acta 466 1 - 5 2017.3

Simultaneous measurement of monoamine metabolites and 5-methyltetrahydrofolate in the cerebrospinal fluid of children Reviewed International journal

Tomoyuki Akiyama, Yumiko Hayashi, Yoshiyuki Hanaoka, Takashi Shibata, Mari Akiyama, Kazuyuki Nakamura, Yu Tsuyusaki, Masaya Kubota, Harumi Yoshinaga, Katsuhiro Kobayashi

Clinica Chimica Acta 465 5 - 10 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

BACKGROUND: We describe a new method for simultaneous measurement of monoamine metabolites (3-O-methyldopa [3-OMD], 3-methoxy-4-hydroxyphenylethyleneglycol [MHPG], 5-hydroxyindoleacetic acid [5-HIAA], and homovanillic acid [HVA]) and 5-methyltetrahydrofolate (5-MTHF) and its use on cerebrospinal fluid (CSF) samples from pediatric patients. METHODS: Monoamine metabolites and 5-MTHF were measured by high-performance liquid chromatography with fluorescence detection. CSF samples were prospectively collected from children according to a standardized collection protocol in which the first 1-ml fraction was used for analysis. RESULTS: Monoamine metabolites and 5-MTHF were separated within 10min. They showed linearity from the limit of detection to 1024nmol/l. The limit of quantification of each metabolite was sufficiently low for the CSF sample assay. In 42 CSF samples after excluding cases with possibly altered neurotransmitter profiles, the concentrations of 3-OMD, MHPG, 5-HIAA, HVA, and 5-MTHF showed significant age dependence and their ranges were comparable with the reference values in the literature. The metabolite profiles of aromatic l-amino acid decarboxylase deficiency, Segawa disease, and folate receptor α defect by this method were compatible with those in the literature. CONCLUSIONS: This method is a simple means of measuring CSF monoamine metabolites and 5-MTHF, and is especially useful for laboratories not equipped with electrochemical detectors.

DOI： 10.1016/j.cca.2016.12.005

A Japanese case of β-ureidopropionase deficiency with dysmorphic features Reviewed International journal

Tomoyuki Akiyama, Takashi Shibata, Harumi Yoshinaga, Tomiko Kuhara, Yoko Nakajima, Takema Kato, Yasuhiro Maeda, Morimasa Ohse, Makio Oka, Misao Kageyama, Katsuhiro Kobayashi

Brain and Development 39 ( 1 ) 58 - 61 2017.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

β-Ureidopropionase deficiency is a rare autosomal recessive disease affecting the last step of pyrimidine degradation, and it is caused by a mutation in the UPB1 gene. Approximately 30 cases have been reported to date, with a phenotypical variability ranging from asymptomatic to severe neurological illness. Non-neurological symptoms have been rarely reported. We describe a case of this disease with developmental delay and dysmorphic features. Gas chromatography-mass spectrometry-based urine metabolomics demonstrated significant (⩾+4.5 standard deviation after logarithmic transformation) elevations of β-ureidopropionic acid and β-ureidoisobutyric acid, strongly suggesting a diagnosis of β-ureidopropionase deficiency. Subsequent quantitative analysis of pyrimidines by liquid chromatography-tandem mass spectrometry supported this finding. Genetic testing of the UPB1 gene confirmed compound heterozygosity of a novel mutation (c.976C>T) and a previously-reported mutation (c.977G>A) that is common in East Asians. β-Ureidopropionase deficiency is probably underdiagnosed, considering a wide phenotypical variability, non-specific neurological presentations, and an estimated prevalence of 1/5000-6000. Urine metabolomics should be considered for patients with unexplained neurological symptoms.

DOI： 10.1016/j.braindev.2016.08.001

Significance of High-frequency Electrical Brain Activity Reviewed

Katsuhiro Kobayashi, Tomoyuki Akiyama, Takashi Agari, Tatsuya Sasaki, Takashi Shibata, Yoshiyuki Hanaoka, Mari Akiyama, Fumika Endoh, Makio Oka, Isao Date

ACTA MEDICA OKAYAMA 71 ( 3 ) 191 - 200 2017

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Electroencephalogram (EEG) data include broadband electrical brain activity ranging from infra-slow bands (<0.1 Hz) to traditional frequency bands (e.g., the approx. 10 Hz alpha rhythm) to high-frequency bands of up to 500 Hz. High-frequency oscillations (HFOs) including ripple and fast ripple oscillations (80-200 Hz and >200/250 Hz, respectively) are particularly of note due to their very close relationship to epileptogenicity, with the possibility that they could function as a surrogate biomarker of epileptogenicity. In contrast, physiological high-frequency activity plays an important role in higher brain functions, and the differentiation between pathological/epileptic and physiological HFOs is a critical issue, especially in epilepsy surgery. HFOs were initially recorded with intracranial electrodes in patients with intractable epilepsy as part of a long-term invasive seizure monitoring study. However, fast oscillations (FOs) in the ripple and gamma bands (40-80 Hz) are now noninvasively detected by scalp EEG and magnetoencephalography, and thus the scope of studies on HFOs/FOs is rapidly expanding.

DOI： 10.18926/AMO/55201

A study on spike focus dependence of high-frequency activity in idiopathic focal epilepsy in childhood Reviewed

Takashi Shibata, Harumi Yoshinaga, Tomoyuki Akiyama, Katsuhiro Kobayashi

Epilepsia Open 1 ( 3-4 ) 121 - 129 2016.12

PRRT2遺伝子変異を認めたepisodic ataxiaの女児

柴田敬, 岡牧郎, 小林勝弘, 大内田守, 大守伊織

脳と発達 48 ( 6 ) 446 - 446 2016.11

SSADH deficiency possibly associated with enzyme activity-reducing SNPs Reviewed International journal

Tomoyuki Akiyama, Hitoshi Osaka, Hiroko Shimbo, Tomiko Kuhara, Takashi Shibata, Katsuhiro Kobayashi, Kenji Kurosawa, Harumi Yoshinaga

Brain and Development 38 ( 9 ) 871 - 874 2016.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

BACKGROUND: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder that affects the degradation of gamma-aminobutyric acid and leads to the accumulation of gamma-hydroxybutyric acid (GHB) in body fluids. Diagnosis of SSADH deficiency is challenging, since the neurological symptoms are non-specific. CASE: The patient is a nine-year-old Japanese boy who presented with developmental delay, autism, epilepsy, and episodic gait disturbance. Brain magnetic resonance imaging showed hyperintense lesions in the bilateral thalami, globus pallidi, substantia nigra, and dentate nuclei. Urine metabolome analysis revealed elevated GHB, which led to a biochemical diagnosis of SSADH deficiency. Genetic analysis of the ALDH5A1 gene revealed a novel missense mutation c.1586G>A inherited from his father. It also demonstrated three single nucleotide polymorphisms (SNPs) (c.106G>C, c.538C>T, and c.545C>T), all of which were inherited from his mother and are known to reduce SSADH enzyme activity. There were no duplications or deletions in other exons in the patient or his parents. No variants in the upstream, intronic, or downstream regions of the ALDH5A1 gene were found in the patient. Enzymatic assay revealed a marked reduction of SSADH enzyme activity (≈2% of the lower limit of the normal range). CONCLUSION: Although other mechanisms cannot be fully excluded, the clinical manifestation of SSADH deficiency in this patient may be attributed to the combined effect of the mutation and the three enzyme activity-reducing SNPs. Urine metabolome analysis effectively detected his elevated GHB and is thus considered to be a good screening method for this underdiagnosed and potentially manageable metabolic disorder.

DOI： 10.1016/j.braindev.2016.03.008

Idiopathic focal epilepsies: the "lost tribe" Reviewed

Deb K. Pal, Colin Ferrie, Laura Addis, Tomoyuki Akiyama, Giuseppe Capovilla, Roberto Caraballo, Anne de Saint-Martin, Natalio Fejerman, Renzo Guerrini, Khalid Hamandi, Ingo Helbig, Andreas A. Ioannides, Katsuhiro Kobayashi, Dennis Lal, Gaetan Lesca, Hiltrud Muhle, Bernd A. Neubauer, Tiziana Pisano, Gabrielle Rudolf, Caroline Seegmuller, Takashi Shibata, Anna Smith, Pasquale Striano, Lisa J. Strug, Pierre Szepetowski, Thalia Valeta, Harumi Yoshinaga, Michalis Koutroumanidis

EPILEPTIC DISORDERS 18 ( 3 ) 252 - 288 2016.9

Language：English Publisher：JOHN LIBBEY EUROTEXT LTD

The term idiopathic focal epilepsies of childhood (IFE) is not formally recognised by the ILAE in its 2010 revision (Berg et al., 2010), nor are its members and boundaries precisely delineated. The IFEs are amongst the most commonly encountered epilepsy syndromes affecting children. They are fascinating disorders that hold many "treats" for both clinicians and researchers. For example, the IFEs pose many of the most interesting questions central to epileptology: how are functional brain networks involved in the manifestation of epilepsy? What are the shared mechanisms of comorbidity between epilepsy and neurodevelopmental disorders? How do focal EEG discharges impact cognitive functioning? What explains the age-related expression of these syndromes? Why are EEG discharges and seizures so tightly locked to slow-wave sleep? In the last few decades, the clinical symptomatology and the respective courses of many IFEs have been described, although they are still not widely appreciated beyond the specialist community. Most neurologists would recognise the core syndromes of IFE to comprise: benign epilepsy of childhood with centro-temporal spikes or Rolandic epilepsy (BECTS/RE); Panayiotopoulos syndrome; and the idiopathic occipital epilepsies (Gastaut and photosensitive types). The Landau-Kleffner syndrome and the related (idiopathic) epilepsy with continuous spikes and waves in sleep (CSWS or ESES) are also often included, both as a consequence of the shared morphology of the interictal discharges and their potential evolution from core syndromes, for example, CSWS from BECTS. Atypical benign focal epilepsy of childhood also has shared electro-clinical features-warranting inclusion. In addition, a number of less well-defined syndromes of IFE have been proposed, including benign childhood seizures with affective symptoms, benign childhood epilepsy with parietal spikes, benign childhood seizures with frontal or midline spikes, and benign focal seizures of adolescence.
The term "benign" is often used in connection with the IFEs and is increasingly being challenged. Certainly most of these disorders are not associated with the devastating cognitive and behavioural problems seen with early childhood epileptic encephalopathies, such as West or Dravet syndromes. However, it is clear that specific, and sometimes persistent, neuropsychological deficits in attention, language and literacy accompany many of the IFEs that, when multiplied by the large numbers affected, make up a significant public health problem. Understanding the nature, distribution, evolution, risk and management of these is an important area of current research.A corollary to such questions regarding comorbidities is the role of focal interictal spikes and their enduring impact on cognitive functioning. What explains the paradox that epilepsies characterised by abundant interictal epileptiform abnormalities are often associated with very few clinical seizures? This is an exciting area in both clinical and experimental arenas and will eventually have important implications for clinical management of the whole child, taking into account not just seizures, but also adaptive functioning and quality of life. For several decades, we have accepted an evidence-free approach to using or not using antiepileptic drugs in IFEs. There is huge international variation and only a handful of studies examining neurocognitive outcomes. Clearly, this is a situation ready for an overhaul in practice.
Fundamental to understanding treatment is knowledge of aetiology. In recent years, there have been several significant discoveries in IFEs from studies of copy number variation, exome sequencing, and linkage that prompt reconsideration of the "unknown cause" classification and strongly suggest a genetic aetiology. The IFE are strongly age-related, both with regards to age of seizure onset and remission. Does this time window solely relate to a similar age-related gene expression, or are there epigenetic factors involved that might also explain low observed twin concordance? The genetic (and epigenetic) models for different IFEs, their comorbidities, and their similarities to other neurodevelopmental disorders deserve investigation in the coming years. In so doing, we will probably learn much about normal brain functioning. This is because these disorders, perhaps more than any other human brain disease, are disorders of functional brain systems (even though these functional networks may not yet be fully defined). In June 2012, an international group of clinical and basic science researchers met in London under the auspices of the Waterloo Foundation to discuss and debate these issues in relation to IFEs. This Waterloo Foundation Symposium on the Idiopathic Focal Epilepsies: Phenotype to Genotype witnessed presentations that explored the clinical phenomenology, phenotypes and endophenotypes, and genetic approaches to investigation of these disorders. In parallel, the impact of these epilepsies on children and their families was reviewed. The papers in this supplement are based upon these presentations. They represent an updated state-of-the-art thinking on the topics explored.
The symposium led to the formation of internationalworking groups under the umbrella of "Luke's Idiopathic Focal Epilepsy Project" to investigate various aspects of the idiopathic focal epilepsies including: semiology and classification, genetics, cognition, sleep, high-frequency oscillations, and parental resources (see www.childhood-epilepsy.org). The next sponsored international workshop, in June 2014, was on randomised controlled trials in IFEs and overnight learning outcome measures.

DOI： 10.1684/epd.2016.0839

複雑脳動脈奇形により乳児期から脳梗塞を繰り返した女児例

林裕美子, 花岡義行, 柴田敬, 井上拓志, 岡牧郎, 吉永治美, 小林勝弘, 栄徳隆裕, 馬場健児

日本小児科学会雑誌 120 ( 2 ) 229 - 229 2016.2

Novel PLA2G6 mutations associated with an exonic deletion due to non-allelic homologous recombination in a patient with infantile neuroaxonal dystrophy Reviewed International journal

Toshiyuki Yamamoto, Keiko Shimojima, Takashi Shibata, Mari Akiyama, Makio Oka, Tomoyuki Akiyama, Harumi Yoshinaga, Katsuhiro Kobayashi

Human Genome Variation 2 ( 1 ) 15048 - 15048 2015.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Nature

Novel PLA2G6 mutations associated with p.Asp283Asn and a unique intragenic deletion of exons 4 and 5 due to non-allelic homologous recombination were identified in a Japanese female patient with typical infantile neuroaxonal dystrophy. The patient showed progressive tetraplegia beginning at 9 months. An electroencephalogram showed a diffuse increase in fast waves, and brain magnetic resonance imaging showed progressive brain atrophy and T2 hypointensity in the globus pallidus.

DOI： 10.1038/hgv.2015.48

Phenotypic Variability in Childhood of Skeletal Muscle Sodium Channelopathies Reviewed

Harumi Yoshinaga, Shunichi Sakoda, Takashi Shibata, Tomoyuld Aldyama, Makio Oka, Jun-Hui Yuan, Hiroshi Takashima, Masanori P. Takahashi, Tetsuro Kitamura, Nagako Murakami, Katsuhiro Kobayashi

PEDIATRIC NEUROLOGY 52 ( 5 ) 504 - 508 2015.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

BACKGROUND: Mutations of the SCN4A gene cause several skeletal muscle channelopathies and overlapping forms of these disorders. However, the variability of the clinical presentation in childhood is confusing and not fully understood among pediatric neurologists. PATIENTS: We found three different mutations (p.V445M, p.I693L, and a novel mutation, p.V1149L) in SCN4A but not in the CLCN1 gene. The patient with p.V445M showed the clinical phenotype of sodium channel myotonia, but her clear symptoms did not appear until 11 years of age. Her younger sister and mother, who have the same mutation, displayed marked intrafamilial phenotypic heterogeneity from mild to severe painful myotonia with persistent weakness. The patient with p.I693L exhibited various symptoms that evolved with age, including apneic episodes, tonic muscular contractions during sleep, fluctuating severe episodic myotonia, and finally episodic paralyses. The patient with the novel p.V1149L mutation exhibited episodic paralyses starting at 3 years of age, and myotonic discharges were detected at 11 years of age for the first time. CONCLUSION: The present cohort reveals the complexity, variability, and overlapping nature of the clinical features of skeletal muscle sodium channelopathies. These are basically treatable disorders, so it is essential to consider genetic testing before the full development of a patient's condition.

DOI： 10.1016/j.pediatrneurol.2015.01.014

Manifestation of both emetic seizures and sylvian seizures in the same patients with benign partial epilepsy Reviewed

Harumi Yoshinaga, Katsuhiro Kobayashi, Takashi Shibata, Takushi Inoue, Makio Oka, Tomoyuki Akiyama

BRAIN & DEVELOPMENT 37 ( 1 ) 13 - 17 2015.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Purpose: Benign childhood epilepsy with centro-temporal spikes (BECTS) and Panayiotopoulos syndrome (PS) have different pathophysiologies and show different types of seizures, yet they overlap in some important respects. In an attempt to understand the ways in which they differ from each other and overlap each other, we performed a detailed investigation on patients who had both characteristic types of seizure manifestations, namely, sylvian seizures and emetic seizures. Subjects and methods: We recruited consecutive subjects from the EEG database of outpatients who had visited our hospital between 2008 and 2010 and who had been diagnosed with BECTS or PS. As a result, 45 patients with BECTS and 50 patients with PS were selected from the database. Viewing the clinical records of these 95 patients, five patients were selected who had experienced both sylvian seizures and emetic seizures. Next, the clinical features and EEG findings of these five patients were retrospectively observed at the date of investigation: October 1, 2011. Results: We found that all the patients showed rolandic spikes when they had sylvian seizures, and occipital spikes or multifocal spikes when they had emetic seizures. We also report in detail on one patient who showed two different types of ictal EEG patterns: one of which started in the occipital area and the other of which was located in the rolandic area. Conclusion: Based on these findings, we conclude that widespread cortical hyperexcitability that includes the occipital area is necessary to produce the autonomic seizure manifestations seen in PS. (C) 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2014.01.013

West syndrome associated with epileptic negative myoclonus Reviewed

Takashi Shibata, Harumi Yoshinaga, Makio Oka, Katsuhiro Kobayashi

No To Hattatsu 46 ( 5 ) 354 - 358 2014.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Society of Child Neurology

We report a 10-month-oIcI girl who had brief epileptic negative myoclonus during the course of West syndrome. She began to have epileptic spasms in series at the age of 8 months. Video-elcctroencephalograph (EEG) monitoring revealed that she also had brief epileptic negative myoclonus when she was 10 months old. Brief atonia of limbs occurred in isolation or in a cluster during drowsiness or sleep. The ictal EEG exhibited diffuse polyspikes and waves or diffuse high-voltage slow waves that were overlapped by low-voltage fast waves. 3 to 4 hundred milliseconds of silent periods were observed in the bilateral deltoid electromyograms, which correspond to the EEG patterns.
The occurrence of other types of seizures, partial seizures in particular, accompanied by epileptic spasms has been fully investigated. This is the first case report of a patient with West syndrome whose coexisting epileptic negative myoclonus was confirmed by a silent electromyogram pattern.

当院で半球離断術を行った乳児期発症の難治てんかん6例の検討

柴田敬, 岡牧郎, 上利崇, 遠藤文香, 小林勝弘, 吉永治美, 伊達勲

日本小児科学会雑誌 118 ( 5 ) 854 - 855 2014.5

急激な経過で呼吸不全をきたした軸索型ギラン・バレー症候群の1例

柴田敬, 岡牧郎, 小林勝弘, 吉永治美

日本小児科学会雑誌 118 ( 5 ) 844 - 844 2014.5

外傷を契機に発見されたHunter症候群の1例

兵頭勇紀, 小林勝弘, 桃木恵美子, 柴田敬, 岡牧郎, 吉永治美

脳と発達 45 ( 6 ) 473 - 473 2013.11

乳児期早期に皮質性ミオクローヌスを認めたDravet症候群の一例

小林由典, 秋山倫之, 中尻智史, 柴田敬, 井上拓志, 小林勝弘, 大守伊織, 大内田守, 吉永治美

臨床神経生理学 41 ( 5 ) 490 - 490 2013.10

West症候群を発症した46,XY,der(16)t(2;16)(p22;p13.3)の一家系

柴田敬, 岡牧郎, 兵頭勇紀, 秋山倫之, 吉永治美, 小林勝弘

てんかん研究 31 ( 2 ) 474 - 474 2013.9

小児てんかんの診療実態に関する疫学調査(第1報)

花岡義行, 柴田敬, 岡牧郎, 秋山倫之, 小林勝弘, 吉永治美

脳と発達 45 ( Suppl. ) S236 - S236 2013.5

Clinical implications of preceding positive spikes in patients with benign partial epilepsy and febrile seizures Reviewed

Harumi Yoshinaga, Katsuhiro Kobayashi, Tomoyuki Akiyama, Takashi Shibata, Fumika Endoh, Yoko Ohtsuka

BRAIN & DEVELOPMENT 35 ( 4 ) 299 - 306 2013.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Purpose: To clarify the clinical implications of the preceding positive spikes (PPSs) observed primarily in rolandic spikes, we analyzed PPSs in the rolandic and occipital spikes observed in the electroencephalograms (EEGs) of patients with two types of benign partial epilepsies (benign childhood epilepsy with centro-temporal spikes [BECT] and Panayiotopoulos syndrome [PS]) and febrile seizures (FS). Subjects and methods: We identified patients from our outpatient EEG database that were seen between 2006 and 2008 that had BECT, PS, and FS with rolandic or occipital spikes. We generated an averaged spike for each patient from the rolandic and occipital spikes that were detected using an automatic spike detection and clustering system. We compared the presence rate of the averaged spikes with the PPS among the three groups (BECT vs. PS vs. FS) using sequential mapping. Results: We identified 25 BECT, 18 PS, and 15 FS patients with rolandic spikes. Fifteen BECT and nine PS patients exhibited a PPS in their averaged rolandic spikes, whereas only four FS patients did. Three of these four FS patients later developed afebrile seizures, and one of them was diagnosed as having PS. We analyzed eight PS and six FS patients with occipital spikes. Five PS patients exhibited a PPS in their averaged occipital spikes, whereas only one FS patient did. This FS patient later developed prolonged autonomic febrile seizures. Conclusion: PPSs are observed not only in rolandic spikes associated with BECT that is related strictly to sylvian seizures, but also in rolandic and occipital spikes associated with PS. Although PPSs are rare in such spikes observed in FS, patients with FS and PPSs may have an increased risk of developing afebrile seizures or prolonged autonomic febrile seizures. Further studies are warranted to determine the diagnostic utility of PPSs as a marker of the future development of epilepsy when they are observed in FS patients. (C) 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2012.06.006

小児期発症のナルコレプシーの2例

柴田敬, 岡牧郎, 井上拓志, 小林勝弘, 吉永治美

日本小児科学会雑誌 117 ( 3 ) 653 - 653 2013.3

Efficacy of topiramate for intractable childhood generalized epilepsy with epileptic spasms: With special reference to electroencephalographic changes

Fumika Endoh, Katsuhiro Kobayashi, Yumiko Hayashi, Takashi Shibata, Harumi Yoshinaga, Yoko Ohtsuka

Seizure 21 ( 7 ) 522 - 528 2012.9

Language：English Publishing type：Research paper (scientific journal)

Purpose: Epileptic spasms (ES) beyond infancy are a highly refractory type of seizures that require the development of an effective treatment. We therefore studied the efficacy and safety of topiramate (TPM), which is a drug that is indicated to be effective for intractable childhood epilepsy, for ES. Methods: Out of 58 children with ES, we enrolled 33 patients treated with TPM at ≤12 years of age. The administration of TPM was limited to cases of epilepsies that were resistant to any other potent treatment. We retrospectively investigated the efficacy of TPM for seizures and changes in electroencephalogram (EEG) findings. Results: The median age at the start of TPM treatment was 5 years, 8 months. All patients had ES and 28 also had tonic seizures. As for the efficacy of TPM for all seizures, five patients became seizure-free and two had a ≥50% reduction in seizures. Seizure aggravation was observed in six patients. Of 29 patients whose EEG findings were compared before and during TPM treatment, nine showed EEG improvement with reduced epileptic discharges. Adverse effects were observed in 13 patients and included somnolence, anorexia, and irritability. In general, TPM was well tolerated. Conclusions: TPM can be effective at suppressing very intractable ES in a proportion of patients who do not respond to any other treatment. The efficacy of TPM may be predictable based on EEG changes observed early in the course of treatment. TPM is promising for the treatment of extremely intractable childhood epilepsy and it has largely tolerable adverse effects. © 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.seizure.2012.05.009

Peculiar involuntary movements in premature babies with specific cerebellar injuries Reviewed

Harumi Yoshinaga, Katsuhiro Kobayashi, Fumika Endoh, Yumiko Ishizaki, Takashi Shibata, Yoko Ohtsuka

No To Hattatsu 44 ( 3 ) 239 - 243 2012.5

Language：Japanese Publishing type：Research paper (scientific journal)

We observed characteristic involuntary movements in premature babies during early infancy. These movements consisted of asymmetrical irregular banging of the extremities, similar to chorea, ballisms, or jitteriness. We investigated the clinical characteristics and neuroimaging findings of the patients with these peculiar involuntary movements to clarify their pathophysiological mechanisms and to find a treatment. In our sequential follow-up study on 90 premature infants with various pre-and perinatal brain insults, we found various types of cerebellar injuries in 28 patients. In 19 of these, the prominent injuries were observed in the inferior cerebellar hemispheres. These cerebellar injuries were often observed in patients born before the gestational age of 27 weeks. Fourteen of the 28 patients with cerebellar injuries displayed the above-mentioned characteristic involuntary movements. Twelve of these 14 patients with both cerebellar injury and involuntary movements were born before the gestational age of 27 weeks. On the contrary, 10 patients with cerebellar injury bom after the gestational age of 27 weeks did not display these peculiar involuntary movements. It is noteworthy that cerebral injuries were not associated with the occurrence of these involuntary movements. Two patients with asymmetrical cerebellar deformity caused by compression due to a cystic lesion did not show these involuntary movements. The movements appeared around the corrected age of 3 months, and they disturbed the patients' acquisition of sitting ability. Nine patients with these involuntary movements developed severe athetotic cerebral palsy. These movements showed drug resistance, however, benzodiazepines had a partial effect in some patients. Recently, cerebellar injury in premature infants has received a lot of attention. We believe that the peculiar involuntary movements we observed in the present patient group may be caused by a particular type of cerebellar damage specific to premature infants born before 27 weeks of gestational age.

脳梁離断術後に左右独立性のepileptic spasmsを認めたWest症候群の1例

東田好広, 柴田敬, 岡牧郎, 遠藤文香, 小林勝弘, 大塚頌子

てんかん研究 29 ( 2 ) 356 - 356 2011.9

多彩な発作症状を来した視床下部過誤腫による難治てんかん

柴田敬, 岡牧郎, 福島雅子, 小林勝弘, 大塚頌子

脳と発達 43 ( 1 ) 72 - 72 2011.1

　 PREV - NEXT 　

1