Faculty Profiles - AKIYAMA Tomoyuki

Papers - AKIYAMA Tomoyuki

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Pyridoxal in the Cerebrospinal Fluid May Be a Better Indicator of Vitamin B6-dependent Epilepsy Than Pyridoxal 5'-Phosphate. Reviewed International journal

Tomoyuki Akiyama, Yuki Hyodo, Kosei Hasegawa, Taikan Oboshi, Katsumi Imai, Naoko Ishihara, Yuri Dowa, Takayoshi Koike, Toshiyuki Yamamoto, Jun Shibasaki, Hiroko Shimbo, Tetsuhiro Fukuyama, Kyoko Takano, Hiroshi Shiraku, Saoko Takeshita, Tohru Okanishi, Shimpei Baba, Masaya Kubota, Shin-Ichiro Hamano, Katsuhiro Kobayashi

Pediatric neurology 113 33 - 41 2020.9

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

BACKGROUND: We aimed to demonstrate the biochemical characteristics of vitamin B6-dependent epilepsy, with a particular focus on pyridoxal 5'-phosphate and pyridoxal in the cerebrospinal fluid. METHODS: Using our laboratory database, we identified patients with vitamin B6-dependent epilepsy and extracted their data on the concentrations of pyridoxal 5'-phosphate, pyridoxal, pipecolic acid, α-aminoadipic semialdehyde, and monoamine neurotransmitters. We compared the biochemical characteristics of these patients with those of other epilepsy patients with low pyridoxal 5'-phosphate concentrations. RESULTS: We identified seven patients with pyridoxine-dependent epilepsy caused by an ALDH7A1 gene abnormality, two patients with pyridoxal 5'-phosphate homeostasis protein deficiency, and 28 patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Cerebrospinal fluid pyridoxal and pyridoxal 5'-phosphate concentrations were low in patients with vitamin B6-dependent epilepsy but cerebrospinal fluid pyridoxal concentrations were not reduced in most patients with other epilepsies with low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. Increase in 3-O-methyldopa and 5-hydroxytryptophan was demonstrated in some patients with vitamin B6-dependent epilepsy, suggestive of pyridoxal 5'-phosphate deficiency in the brain. CONCLUSIONS: Low cerebrospinal fluid pyridoxal concentrations may be a better indicator of pyridoxal 5'-phosphate deficiency in the brain in vitamin B6-dependent epilepsy than low cerebrospinal fluid pyridoxal 5'-phosphate concentrations. This finding is especially helpful in individuals with suspected pyridoxal 5'-phosphate homeostasis protein deficiency, which does not have known biomarkers.

DOI： 10.1016/j.pediatrneurol.2020.08.020

Identification of new biomarkers of pyridoxine-dependent epilepsy by GC/MS-based urine metabolomics. Reviewed International journal

Tomiko Kuhara, Tomoyuki Akiyama, Morimasa Ohse, Takayoshi Koike, Jun Shibasaki, Katsumi Imai, ArthurJ L Cooper

Analytical biochemistry 604 113739 - 113739 2020.9

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

α-Aminoadipic semialdehyde and its cyclic form (Δ1-piperideine-6-carboxylate) accumulate in patients with α-aminoadipic semialdehyde dehydrogenase (AASADH; antiquitin; ALDH7A1) deficiency. Δ1-Piperideine-6-carboxylate is known to react with pyridoxal 5'-phosphate (PLP) to form a Knoevenagel condensation product, resulting in pyridoxine-dependent epilepsy. Despite dramatic clinical improvement following pyridoxine supplementation, many patients still suffer some degree of intellectual disability due to delayed diagnosis. In order to expedite the diagnosis of patients with suspected AASADH deficiency and minimize the delay in treatment, we used gas chromatography-mass spectrometry-based metabolomics to search for potentially diagnostic biomarkers in urine from four patients with ALDH7A1 mutations, and identified Δ2-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate as candidate biomarkers. In a patient at postnatal day six, but before pyridoxine treatment, Δ2-piperideine-6-carboxylate and pipecolate were present at very high concentrations, indicating that these compounds may be good biomarkers for untreated AASADH deficiency patients. On the other hand, following pyridoxine/PLP treatment, 6-oxopipecolate was shown to be greatly elevated. We suggest that noninvasive urine metabolomics screening for Δ2-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate will be useful for prompt and reliable diagnosis of AASADH deficiency in patients within any age group. The most appropriate combination among Δ2-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate as biomarkers for AASADH deficiency patients appears to depend on the age of the patient and whether pyridoxine/PLP supplementation has been implemented. We anticipate that the present bioanalytical information will also be useful to researchers studying glutamate, proline, lysine and ornithine metabolism in mammals and other organisms.

DOI： 10.1016/j.ab.2020.113739

Pyridoxal 5'-phosphate and related metabolites in hypophosphatasia: Effects of enzyme replacement therapy. Reviewed International journal

Tomoyuki Akiyama, Takuo Kubota, Keiichi Ozono, Toshimi Michigami, Daisuke Kobayashi, Shinji Takeyari, Yuichiro Sugiyama, Masahiro Noda, Daisuke Harada, Noriyuki Namba, Atsushi Suzuki, Maiko Utoyama, Sachiko Kitanaka, Mitsugu Uematsu, Yusuke Mitani, Kunihiro Matsunami, Shigeru Takishima, Erika Ogawa, Katsuhiro Kobayashi

Molecular genetics and metabolism 125 ( 1-2 ) 174 - 180 2018.9

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

OBJECTIVE: To investigate the utility of serum pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) as a diagnostic marker of hypophosphatasia (HPP) and an indicator of the effect of, and patient compliance with, enzyme replacement therapy (ERT), we measured PLP, PL, and PA concentrations in serum samples from HPP patients with and without ERT. METHODS: Blood samples were collected from HPP patients and serum was frozen as soon as possible (mostly within one hour). PLP, PL, and PA concentrations were analyzed using high-performance liquid chromatography with fluorescence detection after pre-column derivatization by semicarbazide. We investigated which metabolites are associated with clinical phenotypes and how these metabolites change with ERT. RESULTS: Serum samples from 20 HPP patients were analyzed. The PLP-to-PL ratio and PLP concentration were elevated in all HPP patients. They correlated negatively with serum alkaline phosphatase (ALP) activity and showed higher values in more severe phenotypes (perinatal severe and infantile HPP) compared with other phenotypes. PL concentration was reduced only in perinatal severe HPP. ERT reduced the PLP-to-PL ratio to mildly reduced or low-normal levels and the PLP concentration was reduced to normal or mildly elevated levels. Urine phosphoethanolamine (PEA) concentration did not return to normal levels with ERT in most patients. CONCLUSIONS: The serum PLP-to-PL ratio is a better indicator of the effect of ERT for HPP than serum PLP and urine PEA concentrations, and a PLP-to-PL ratio of <4.0 is a good indicator of the effect of, and patient compliance with, ERT.

DOI： 10.1016/j.ymgme.2018.07.006

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

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

Brain & development 10 339 - 343 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

Alectinib maintenance therapy following cord blood transplantation for relapsed pediatric anaplastic large cell lymphoma with central nervous system involvement. Reviewed International journal

Kosuke Tamefusa, Hisashi Ishida, Daisuke Miyahara, Takahiro Shiwaku, Motoharu Ochi, Kiichiro Kanamitsu, Kaori Fujiwara, Yasuhisa Tatebe, Kana Washio, Tomoyuki Akiyama, Hirokazu Tsukahara

Annals of hematology 103 ( 11 ) 4805 - 4809 2024.9

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

Pediatric ALK-positive anaplastic large cell lymphoma is a rare subtype of non-Hodgkin lymphoma, and approximately 30% of patients relapse following treatment with conventional chemotherapy. Alectinib monotherapy has demonstrated excellent activity in relapsed and refractory ALCL, but its role as a maintenance therapy after hematopoietic cell transplantation is unclear. We experienced a relapse case of pediatric ALK-positive ALCL with central nervous system involvement treated with alectinib maintenance therapy following cord blood transplantation. The patient has maintained complete remission for more than 3 years after transplantation. There were no remarkable adverse effects that led to discontinuation of alectinib.

DOI： 10.1007/s00277-024-06000-7

Editorial comments on “Two cases of cerebrospinal fluid hypovolemia that had been interpreted as orthostatic dysregulation” Reviewed

Tomoyuki Akiyama, Shinji Saitoh

Brain and Development Case Reports 2 ( 3 ) 100033 - 100033 2024.9

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

脳腫瘍摘出術後に発作の完全抑制を得られた乳児てんかん性スパズム症候群の男児例

塚原理恵, 土屋弘樹, 秋山麻里, 佐々木達也, 秋山倫之, 小林勝弘

てんかん研究 42 ( 1 ) 77 - 77 2024.6

広範な脳形成異常に伴う新生児期発症難治てんかんに対して緩和的半球離断術を施行した1乳児例

兵頭勇紀, 松田奈央子, 金聖泰, 秋山麻里, 佐々木達也, 秋山倫之, 小林勝弘

てんかん研究 42 ( 1 ) 58 - 58 2024.6

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

髄液グリシン濃度の解釈におけるいくつかのpit fall

土屋弘樹, 住友裕美, 島崎敦, 榎本早也香, 大野友香子, 塚原理恵, 時岡礼恵, 竹中暁, 道上理絵, 秋山倫之, 小林勝弘

脳と発達 56 ( Suppl. ) S217 - S217 2024.5

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

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

Epilepsy research 202 107359 - 107359 2024.5

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

低ホスファターゼ症患児における成長障害の臨床的特性

藤原誠, 植田郁実, 石見壮史, 山田知絵子, 中野由佳子, 山本賢一, 中山尋文, 大幡泰久, 北岡太一, 秋山倫之, 大薗恵一, 窪田拓生

日本内分泌学会雑誌 100 ( 1 ) 390 - 390 2024.5

A case report of odonto-hypophosphatasia with a novel variant in the ALPL gene. Reviewed International journal

Yuji Oto, Daiki Suzuki, Tsubasa Morita, Takeshi Inoue, Akihisa Nitta, Nobuyuki Murakami, Yuuka Abe, Yoshinobu Hamada, Tomoyuki Akiyama, Tomoyo Matsubara

Journal of pediatric endocrinology & metabolism : JPEM 37 ( 3 ) 276 - 279 2024.3

Language：English

OBJECTIVES: Hypophosphatasia (HPP) is a rare skeletal dysplasia caused by variants in the alkaline phosphatase (ALPL) gene. More than 400 pathogenic variants of the ALPL gene have been registered in the ALPL gene variant database. Here, we describe the case of a Japanese child with odonto-hypophsphatasia (odonto-HPP) and a novel ALPL variant. CASE PRESENTATION: At the age of 2 years and 1 month, he prematurely lost one deciduous tooth, with the root intact, when he fell and hit his face lightly. Three months later, he lost another adjacent deciduous tooth without incentive. His serum alkaline phosphatase (ALP) level was 72 U/L. His urine phosphoethanolamine (PEA) level was extremely high at 938 μmol/mg·Cre. The serum pyridoxal 5'-phosphaye (PLP) level was 255.9 nmol/L. Based on the clinical symptoms and laboratory findings, the patient was clinically diagnosed with odonto-HPP. Genetic analysis of the ALPL gene revealed a heterozygous variant (NM_000478.6:c.1151C>A, p.Thr384Lys). CONCLUSIONS: We report a case of odonto-HPP with a novel variant in the ALPL gene. HPP is a rare disease, and the heterozygous mutation in the ALPL gene highlights the novelty of this case.

DOI： 10.1515/jpem-2023-0549

眼球運動障害で発症した多発性ミトコンドリア機能障害症候群type3の乳児例

時岡礼恵, 土屋弘樹, 秋山倫之, 高梨潤一, 才津浩智, 小林勝弘

日本小児科学会雑誌 128 ( 2 ) 253 - 253 2024.2

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

Epileptic Seizure Detection Using a Recurrent Neural Network With Temporal Features Derived From a Scale Mixture EEG Model Reviewed

Akira Furui, Ryota Onishi, Tomoyuki Akiyama, Toshio Tsuji

IEEE Access 12 162814 - 162824 2024

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

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. Reviewed International journal

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

Brain & development 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. Reviewed 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

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

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

一次運動野付近にてんかん原性領域を疑われ,術式選択に苦慮したWest症候群の1例

時岡礼恵, 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. ) S281 - S281 2023.5

マイクロアレイ染色体検査にてCharcot-Marie-Tooth病責任領域の重複が認められたMiller-Dieker症候群の遺伝カウンセリング

十川麗美, 秋山倫之, 衛藤英理子, 二川摩周, 加藤芙美乃, 山本英喜, 平沢晃, 大守伊織, 小林勝弘

脳と発達 55 ( Suppl. ) S302 - S302 2023.5

一次運動野付近にてんかん原性領域を疑われ,術式選択に苦慮したWest症候群の1例

時岡礼恵, 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. ) S281 - S281 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

青年期発症進行性ミオクローヌスてんかんを呈しMECP2遺伝子変異が判明した一例

秋山麻里, 秋山倫之, 時岡礼恵, 塚原理恵, 浦田奈生子, 竹中暁, 才津浩智, 小林勝弘

脳と発達 55 ( Suppl. ) S336 - S336 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

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

Simultaneous assay of urine sepiapterin and creatinine in patients with sepiapterin reductase deficiency. Reviewed International journal

Yuki Hyodo, Tomoyuki Akiyama, Tetsuhiro Fukuyama, Masakazu Mimaki, Keiko Watanabe, Tadayuki Kumagai, Katsuhiro Kobayashi

Clinica chimica acta; international journal of clinical chemistry 534 167 - 172 2022.9

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

OBJECTIVES: Sepiapterin reductase deficiency (SRD) causes central nervous system symptoms due to dopamine and serotonin depletion because sepiapterin reductase plays an important role in tetrahydrobiopterin biosynthesis. SRD cannot be detected by newborn screening because of the absent hyperphenylalaninemia. To diagnose SRD biochemically, confirmation of reduced monoamine metabolites and elevated sepiapterin in the cerebrospinal fluid (CSF) has been considered necessary, because a past study showed no elevation of urine sepiapterin. Recently, however, the elevation of urine sepiapterin in SRD was reported. METHODS: We developed a fast method to measure sepiapterin and creatinine simultaneously using high-performance liquid chromatography with fluorescence and ultraviolet detection. Urine sepiapterin and creatinine were measured in three SRD patients, two SRD carriers, four SRD siblings, and 103 non-SRD patients. RESULTS: In the three SRD cases, concentrations of urine sepiapterin were 1086, 914, and 575 µmol/mol creatinine (upper limit: 101.7 µmol/mol creatinine), and were markedly higher than those in other groups. CSF sepiapterin concentration was also measured in one SRD case and it was 4.1 nmol/L (upper limit: 0.5 nmol/L). CONCLUSIONS: The simultaneous determination of urine sepiapterin and creatinine appears helpful for the diagnosis of SRD. This assay system can also be used to measure sepiapterin in the CSF.

DOI： 10.1016/j.cca.2022.07.016

Folic acid inhibits 5‐methyltetrahydrofolate transport across the blood–cerebrospinal fluid barrier: Clinical biochemical data from two cases Reviewed International journal

Tomoyuki Akiyama, Ichiro Kuki, Kiyohiro Kim, Naohiro Yamamoto, Yumi Yamada, Kazuya Igarashi, Tomohiko Ishihara, Yuya Hatano, Katsuhiro Kobayashi

JIMD Reports 63 ( 6 ) 529 - 535 2022.8

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

Objective: The use of folic acid (FA) has been discouraged in cerebral folate deficiency (CFD) because, theoretically, it could inhibit the transport of 5-methyltetrahydrofolic acid (5MTHF) across the blood-cerebrospinal fluid (CSF) barrier. We present the clinical biochemical data of two cases with CFD to support this hypothesis. Methods: We measured CSF and serum 5MTHF concentrations in a patient with Kearns-Sayre syndrome (KSS) and a patient homozygous for MTHFR C677T polymorphism before and during folate supplementation therapy. To evaluate these 5MTHF concentrations, we also analyzed CSF and serum samples in pediatric patients without folate supplementation. Results: Both patients had low CSF 5MTHF before treatment and high-dose FA therapy did not normalize CSF 5MTHF. There was a dissociation between serum total folate and 5MTHF concentrations during FA therapy, which was considered to be due to the appearance of unmetabolized FA. The addition of folinic acid did not improve low CSF 5MTHF in the KSS patient and the cessation of FA resulted in the normalization of CSF 5MTHF. In the patient homozygous for MTHFR C677T, minimization of the FA dosage resulted in the normalization of CSF 5MTHF and an increased CSF-to-serum 5MTHF ratio. Conclusions: Our data suggest that excess supplementation of FA impaired 5MTHF transport across the blood-CSF barrier. In the treatment of CFD, supplementation of folinic acid or 5MTHF (in cases of impaired 5MTHF synthesis) is preferred over the use of FA. The reference values of CSF 5MTHF concentration based on 600 pediatric cases were also provided.

DOI： 10.1002/jmd2.12321

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jmd2.12321

当院における小児のてんかん外科の手術 focal epilepsyとepileptic spasmの治療方針の決定について

佐々木達也, 細本翔, 岡崎洋介, 谷本駿, 皮居巧嗣, 佐々田晋, 安原隆雄, 土屋弘樹, 秋山倫之, 小林勝弘, 伊達勲

てんかん研究 40 ( 2 ) 401 - 401 2022.8

当院における小児のてんかん外科の手術 focal epilepsyとepileptic spasmの治療方針の決定について

佐々木達也, 細本翔, 岡崎洋介, 谷本駿, 皮居巧嗣, 佐々田晋, 安原隆雄, 土屋弘樹, 秋山倫之, 小林勝弘, 伊達勲

てんかん研究 40 ( 2 ) 401 - 401 2022.8

低ホスファターゼ症患児における成長障害とALP活性低下の影響の解析

藤原誠, 石見壮史, 山田知絵子, 中野由佳子, 武鑓真司, 山本賢一, 中山尋文, 大幡泰久, 北岡太一, 秋山倫之, 窪田拓生, 大薗恵一

日本骨粗鬆症学会雑誌 8 ( Suppl.1 ) 195 - 195 2022.8

前児染色体異常症がde novo発生と判明しながらも次子に出生前診断を希望する両親への遺伝カウンセリング

衛藤英理子, 三苫智裕, 横畑理美, 三島桜子, 大平安希子, 桐野智江, 谷和祐, 牧尉太, 早田桂, 増山寿, 秋山倫之, 大守伊織, 十川麗美, 河内麻里子, 平沢晃

日本遺伝カウンセリング学会誌 43 ( 2 ) 95 - 95 2022.6

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

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

日本におけるビタミンB6依存性てんかんの実態

倉橋宏和, 秋山倫之, 高木みずき, 沼本真吾, 岩山秀之, 東慶輝, 白石秀明, 本田涼子, 奥村彰久

脳と発達 54 ( Suppl. ) S273 - S273 2022.5

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のための予備研究

秋山倫之, 三枝大輔, 秋山麻里, 兵頭勇紀, 道上理絵, 井上拓志, 所谷知穂, 森篤志, 小林勝弘

脳と発達 54 ( Suppl. ) S274 - S274 2022.5

A Japanese single-center experience of the efficacy and safety of asfotase alfa in pediatric-onset hypophosphatasia. Reviewed International journal

Yohei Sugiyama, Taijiro Watanabe, Makiko Tajika, Tetsuro Matsuhashi, Masaru Shimura, Takuya Fushimi, Keiko Ichimoto, Ayako Matsunaga, Tomohiro Ebihara, Tomoko Tsuruoka, Tomoyuki Akiyama, Kei Murayama

Orphanet journal of rare diseases 17 ( 1 ) 78 - 78 2022.2

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

BACKGROUND: Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by mutations in the ALPL gene, which encodes tissue nonspecific alkaline phosphatase. The severity of HPP is widely diverse from the perinatal form to the adult mild form. The former represents the most severe form and was earlier associated with high mortality due to pneumonia which was caused by severe hypomineralization of the bones-such as chest deformity and fractured ribs-and muscle weakness. Enzyme replacement therapy using asfotase alfa (AA) was approved in 2015 in Japan for treating patients with HPP and has improved their pulmonary function and life prognosis. There are several practical and ethical challenges related to using orphan drugs for a rare disorder in a publicly funded healthcare system. Sharing experiences about their application is essential towards formulating guidelines to assist clinicians with decisions about their initiation and withdrawal. We report the details of AA experience in ten cases of pediatric-onset HPP in nine families from January 2015 to November 2019 (median [interquartile range] age 11.0 [7.6-12.5] years; 60% male). This is a study of a single-center cohort describing the clinical course of patients with HPP, mainly consisting of the mild childhood form of HPP, treated with AA in Japan. RESULTS: One case of perinatal form of HPP, two cases of benign prenatal form, and seven cases of childhood form were observed. The most common symptom at onset was pain. All patients had low serum alkaline phosphatase levels as compared to the age-matched reference range before the commencement of AA. All HPP patients seem to have responded to AA treatment, as evidenced by pain alleviation, increased height standard deviation, improvement in respiratory condition and 6-min walk test result improvement, disappearance of kidney calcification, alleviation of fatigue, and/or increases in bone mineralization. There were no serious adverse events, but all patients had an injection site reaction and skin changes at the injection sites. Genetic analysis showed that eight out of ten patients had compound heterozygosity. CONCLUSIONS: AA may be effective in patients with mild to severe pediatric-onset forms of HPP.

DOI： 10.1186/s13023-022-02230-y

Sirolimus for epileptic seizures associated with focal cortical dysplasia type II. Reviewed International journal

Mitsuhiro Kato, Akiko Kada, Hideaki Shiraishi, Jun Tohyama, Eiji Nakagawa, Yukitoshi Takahashi, Tomoyuki Akiyama, Akiyoshi Kakita, Noriko Miyake, Atsushi Fujita, Akiko M Saito, Yushi Inoue

Annals of clinical and translational neurology 9 ( 2 ) 181 - 192 2022.2

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

OBJECTIVE: To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II. METHODS: Sixteen patients (aged 6-57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS-01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5-15 ng/mL, followed by a 12-week maintenance therapy period. The primary endpoint was a lower focal seizure frequency during the maintenance therapy period. Further, we also conducted a prospective cohort study (RES-FCD) in which 60 patients with FCD type II were included as an external control group. RESULTS: The focal seizure frequency reduced by 25% in all patients during the maintenance therapy period and by a median value of 17%, 28%, and 23% during the 1-4-, 5-8-, and 9-12-week periods. The response rate was 33%. The focal seizure frequency in the external control group reduced by 0.5%. However, the background characteristics of external and sirolimus-treated groups differed. Adverse events were consistent with those of mTOR inhibitors reported previously. The blood KL-6 level was elevated over time. INTERPRETATION: The reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations.

DOI： 10.1002/acn3.51505

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

Two Cases of Monozygotic Twins with Early-onset Isolated (DYT1) Dystonia Effectively Treated with Bilateral Globus Pallidus Internus Stimulation. Reviewed

Yosuke Okazaki, Tatsuya Sasaki, Kouji Kawai, Kakeru Hosomoto, Susumu Sasada, Takao Yasuhara, Tomoyuki Akiyama, Yoshiyuki Hanaoka, Isao Date

NMC case report journal 9 307 - 312 2022

Language：English

Early-onset isolated (DYT1) dystonia is one of the most common forms of primary dystonia in childhood, and deep brain stimulation of the globus pallidus internus (GPi-DBS) is a highly effective treatment for it. However, the effectiveness of GPi-DBS in monozygotic twins with DYT1 dystonia has never been reported globally. Here, we report the cases of monozygotic twins with DYT1 dystonia who were treated using GPi-DBS, and we include a literature review. The younger brother showed an abnormal gait, with external rotation of the right lower leg at 6 years old. The symptoms gradually became so severe that he had difficulty walking on his own at 9 years of age. Treatment with levodopa-carbidopa partially resolved his symptoms, but most of the symptoms remained. Meanwhile, the older brother developed dystonia in both upper limbs at 8 years of age, with gradual symptom progression. At 13 years of age, they were diagnosed with DYT1 dystonia. Bilateral GPi-DBS was performed in both patients at 16 years of age. Their symptoms remarkably improved after surgery. The Burke-Fahn-Marsden dystonia rating scale (BFMDRS) movement score was reduced from 52 to 2 points for the younger brother and from 35 to 1 point for the older brother. Even if monozygotic twins have the same genes, the onset and severity of symptoms might vary in accordance with differences in epigenomic profiles. However, GPi-DBS treatment was very effective for the two cases; thus, we should consider the surgical interventions for each patient.

DOI： 10.2176/jns-nmc.2022-0084

A Time-Series Scale Mixture Model of EEG with a Hidden Markov Structure for Epileptic Seizure Detection. International journal

Akira Furui, Tomoyuki Akiyama, Toshio Tsuji

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference 2021 5832 - 5836 2021.11

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

In this paper, we propose a time-series stochastic model based on a scale mixture distribution with Markov transitions to detect epileptic seizures in electroencephalography (EEG). In the proposed model, an EEG signal at each time point is assumed to be a random variable following a Gaussian distribution. The covariance matrix of the Gaussian distribution is weighted with a latent scale parameter, which is also a random variable, resulting in the stochastic fluctuations of covariances. By introducing a latent state variable with a Markov chain in the background of this stochastic relationship, time-series changes in the distribution of latent scale parameters can be represented according to the state of epileptic seizures. In an experiment, we evaluated the performance of the proposed model for seizure detection using EEGs with multiple frequency bands decomposed from a clinical dataset. The results demonstrated that the proposed model can detect seizures with high sensitivity and outperformed several baselines.

DOI： 10.1109/EMBC46164.2021.9630840

Case Report: High-Gamma Oscillations on an Ictal Electroencephalogram in a Newborn Patient With Hypoxic–Ischemic Encephalopathy Reviewed International journal

Akihito Takeuchi, Takushi Inoue, Makoto Nakamura, Misao Kageyama, Tomoyuki Akiyama, Katsuhiro Kobayashi

Frontiers in Pediatrics 9 679771 - 679771 2021.10

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

Fast oscillations (FOs) &gt;40 Hz in electroencephalograms (EEGs) are associated with ictogenesis and epileptogenesis in adults and children with epilepsy. However, only a few previous studies showed FOs in neonates. Reported frequencies of such neonatal FOs were in the low-gamma (&lt;60 Hz) band and, therefore, they were not high compared to those in pediatric patients. We herein report a newborn patient with severe hypoxic–ischemic encephalopathy (HIE), who showed pathological FOs with a frequency in the high-gamma band. She was born at a gestational age of 39 weeks 4 days by emergency cesarean section because of non-reassuring fetal status. She had focal motor seizures involving unilateral upper and lower limbs lasting for tens of seconds on days 0, 1, 4, 5, 8, and 9 and subclinical seizures on days 4–11. Phenobarbital (PB) was intravenously administered on days 0, 2, 4, 5, and 6. We found FOs that were superimposed on the ictal delta activities using visual inspection and time–frequency analysis on 8–11 days of age. Among them, we detected high-gamma (71.4–100 Hz) oscillations that appeared to be temporally independent of low-gamma activities in the ictal EEG on 11 days of age. To the best of our knowledge, this is one of the earliest reports showing pathological FOs with a frequency of &gt;60 Hz in the high-gamma band in human neonatal seizures, which were previously observed in animal studies. Further studies are needed to elucidate the pathophysiology of ictal FOs in neonatal seizures.

DOI： 10.3389/fped.2021.679771

A Single-Arm Open-Label Clinical Trial on the Efficacy and Safety of Sirolimus for Epileptic Seizures Associated with Focal Cortical Dysplasia Type II: A Study Protocol. Reviewed

Akiko Kada, Jun Tohyama, Hideaki Shiraishi, Yukitoshi Takahashi, Eiji Nakagawa, Tomoyuki Akiyama, Akiko M Saito, Yushi Inoue, Mitsuhiro Kato

The Kurume medical journal 66 ( 2 ) 115 - 120 2021.7

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

Epileptic seizures are core symptoms in focal cortical dysplasia (FCD), a disease that often develops in infancy. Such seizures are refractory to conventional antiepileptic drugs (AED) and temporarily disappear in response to AED in only 17% of patients. Currently, surgical resection is an important option for the treatment of epileptic seizures in FCD. In 2015, Korean and Japanese groups independently reported that FCD is caused by somatic mosaic mutation of the MTOR gene in the brain tissue. Based on these results we decided to test a novel treatment using sirolimus, an mTOR inhibitor, for epileptic seizures in patients with FCD type II. A single arm open-label clinical trial for FCD type II patients is being conducted in order to evaluate the efficacy and safety of sirolimus. The dose of sirolimus is fixed for the first 4 weeks and dose adjustment is achieved to maintain a blood level of 5 to 15 ng/mL during 8 to 24 weeks after initiation of administration, and it is kept within this level during a maintenance therapy period of 12 weeks. Primary endpoint is a reduction in the rate of incidence of focal seizures (including focal to bilateral tonic-clonic seizures) per 28 days during the maintenance therapy period from the observation period. To evaluate the frequency of epileptic seizures, registry data will be used as an external control group. We hope that the results of this trial will lead to future innovative treatments for FCD type II patients.

DOI： 10.2739/kurumemedj.MS662007

Monozygotic twins with DYT-TOR1A showing jerking movements and levodopa responsiveness Reviewed International journal

Hanaoka Y, Akiyama T, Yoshinaga H, Kobayashi K

Brain Dev 43 ( 7 ) 783 - 788 2021.7

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

BACKGROUND: DYT-TOR1A is caused by a GAG deletion in the TOR1A gene. While it usually manifests as early-onset dystonia, its phenotype is extremely diverse, even within one family. Recent reports have revealed that some DYT-TOR1A cases have novel mutations in the TOR1A gene while others have mutations in both TOR1A and another DYT gene (THAP1 or SGCE). Our understanding of the correlation between genotype and phenotype is becoming increasingly complicated. CASE PRESENTATIONS: Here, we report on monozygotic twins who developed dystonia in childhood. The two children had different presentations in terms of onset age and dominant disturbances, but both exhibited marked diurnal fluctuation and jerking movements of the limbs as well as levodopa/levodopa-carbidopa responsiveness. These features are commonly associated with DYT/PARK-GCH1 and DYT-SGCE, yet these twins had no mutations in the GCH1 or SGCE genes. Whole exome sequencing eventually revealed a single GAG deletion in the TOR1A gene. CONCLUSION: Monozygotic twins whose only mutation was a GAG deletion in TOR1A exhibited DYT/PARK-GCH1-asssociated features and jerking movements reminiscent of myoclonus. This finding may expand the spectrum of phenotypes associated with DYT-TOR1A, and suggests that levodopa has potential as a treatment for DYT-TOR1A with DYT/PARK-GCH1-associated features.

DOI： 10.1016/j.braindev.2021.03.005

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

Authorship：Last author 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

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 & development 43 ( 9 ) 904 - 911 2021.5

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

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

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

Isolated cortical tuber in an infant with genetically confirmed tuberous sclerosis complex 1 presenting with symptomatic West syndrome. Reviewed International journal

Hajime Miyata, Soichiro Fushimi, Yoko Ota, Harry V Vinters, Kaori Adachi, Eiji Nanba, Tomoyuki Akiyama

Neuropathology : official journal of the Japanese Society of Neuropathology 41 ( 1 ) 58 - 64 2021.2

Language：English

Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary disorder caused by mutations in either TSC1 on chromosome 16 or TSC2 on chromosome 9, clinically characterized mainly by facial angiofibroma, epilepsy, and intellectual disability. Cortical dysplasias, subependymal nodules, and subependymal giant cell astrocytoma are characteristic central nervous system lesions among 11 major features in the current clinical diagnostic criteria for TSC. We encountered an unusual case of genetically confirmed TSC1 presenting with symptomatic West syndrome due to an isolated cortical dysplasia in the left occipital lobe of a six-month-old male infant who did not meet the clinical diagnostic criteria for TSC. The patient underwent left occipital lesionectomy at age 11 months and has been seizure-free for nearly six years since then. Histological examination of the resection specimen revealed cortical neuronal dyslamination with abundant dysmorphic neurons and ballooned cells, consistent with focal cortical dysplasia (FCD) type IIb. However, the lesion was also accompanied by unusual features, including marked calcifications, dense fibrillary gliosis containing abundant Rosenthal fibers, CD34-positive glial cells with abundant long processes confined to the dysplastic cortex, and multiple nodular lesions occupying the underlying white matter, consisting exclusively of ballooned cell and/or balloon-like astrocytes with focal calcifications. Genetic testing for TSC1 and TSC2 using the patient's peripheral blood revealed a germline heterozygous mutation in exon 7 (NM_000368.5: c.526dupT, p.Tyr176fs) in TSC1. Isolated FCD with unusual features such as calcification, dense fibrillary gliosis, Rosenthal fibers and/or subependymal nodule-like lesions in the white matter may indicate the possibility of a cortical tuber even without a clinical diagnosis of TSC. Identification of such histopathological findings has significant implications for early and accurate diagnosis and treatment of TSC, and is likely to serve as an important supplementary feature for the current clinical diagnostic criteria for TSC.

DOI： 10.1111/neup.12700

急性散在性脳脊髄炎との鑑別に苦慮した中枢神経原発悪性リンパ腫の1例

宮原大輔, 嶋田明, 道上理絵, 兵頭勇紀, 花岡義行, 秋山倫之, 塚原宏一, 小林勝弘

日本小児科学会雑誌 125 ( 2 ) 271 - 271 2021.2

Marked motor function improvement in a 32-year-old woman with childhood-onset hypophosphatasia by asfotase alfa therapy: Evaluation based on standardized testing batteries used in Duchenne muscular dystrophy clinical trials. Reviewed International journal

Hitomi Nishizawa, Yoshihiko Sato, Masumi Ishikawa, Yuko Arakawa, Mari Iijima, Tomoyuki Akiyama, Kyoko Takano, Atsushi Watanabe, Tomoki Kosho

Molecular genetics and metabolism reports 25 100643 - 100643 2020.12

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

Hypophosphatasia (HPP) is a rare disorder resulting from biallelic loss-of-function variants or monoallelic dominant negative variants in the ALPL gene. We herein describe the clinical outcome of a 32-year-old woman with childhood-onset HPP caused by compound heterozygous variants in ALPL. Her chief complaints were severe musculoskeletal pain, muscle weakness, and impaired daily activities necessitating assistance in housework and child-rearing in addition to a history of early tooth loss and mildly short stature. Asfotase alfa therapy produced a remarkable increase in muscle strength and daily activities and markedly reduced musculoskeletal pain. Drug efficacy was clearly demonstrated through multiple test batteries (muscle strength test using microFET®2, six-minute walking test, Stair Climb Test, rising-from-floor-time test, and number-of-steps test using Actigraph®) currently adopted as standardized evaluations in Duchenne muscular dystrophy clinical trials since no test batteries for HPP have been established to date. These tests may also be promising for the assessment of HPP.

DOI： 10.1016/j.ymgmr.2020.100643

両側淡蒼球内節刺激術が有効であったDYT1ジストニアの一卵性双胎例

岡崎洋介, 佐々木達也, 細本翔, 亀田雅博, 安原隆雄, 秋山麻里, 秋山倫之, 小林勝弘, 伊達勲

日本定位・機能神経外科学会プログラム・抄録集 60回 110 - 110 2020.12

Longitudinal correspondence of epilepsy and scalp EEG fast (40-200 Hz) oscillations in pediatric patients with tuberous sclerosis complex. Reviewed International journal

Hiroki Tsuchiya, Fumika Endoh, Tomoyuki Akiyama, Masao Matsuhashi, Katsuhiro Kobayashi

Brain & development 42 ( 9 ) 663 - 674 2020.10

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

INTRODUCTION: Epilepsy associated with tuberous sclerosis complex (TSC) has very complex clinical characteristics. Scalp electroencephalogram (EEG) fast (40-200 Hz) oscillations (FOs) were recently suggested to indicate epilepsy severity. Epileptic FOs may undergo age-dependent longitudinal change in individual patients, however, and the typical pattern of such change is not yet fully clarified. We therefore investigated the age-related correspondence between clinical courses and FOs in pediatric patients with TSC-associated epilepsy. SUBJECTS AND METHODS: FOs were semi-automatically detected from scalp sleep EEG data recorded from 23 children (15 boys, 8 girls; initial data obtained at <10 years of age) with TSC-associated epilepsy. RESULTS: The number of FOs per patient that were associated with spikes was significantly greater than that of FOs unassociated with spikes (median 145 and 5, respectively; p = 0.0001 by the Wilcoxon signed-rank test). In the eight patients who had West syndrome (WS) in infancy, FOs associated with spikes were abundant during the WS period prior to adrenocorticotropic hormone therapy, with significantly greater numbers of FOs compared to the post-WS period (median 242 and 0, respectively; p = 0.0078). As there was no such time-dependent difference regarding FOs unassociated with spikes, FOs associated with spikes were identified as epileptic. The detected FOs included both gamma and ripple oscillations with no consistent age-dependent shifts in dominant frequency. There were no apparent age-related changes in FO duration. CONCLUSIONS: Epileptic scalp FOs are confirmed to correspond to severity of epileptic encephalopathy, particularly in WS, even during the long-term evolutional courses of TSC-associated epilepsy.

DOI： 10.1016/j.braindev.2020.06.001

神経発達症診療におけるスクリーニング脳波の意義

秋山麻里, 岡牧郎, 遠藤文香, 秋山倫之, 花岡義之, 道上理恵, 宮原大輔, 諸岡輝子, 兵頭勇紀, 金聖泰, 藤代定志, 小林勝弘

脳と発達 52 ( Suppl. ) S239 - S239 2020.8

筋緊張低下と眼球上転発作を呈したチロシン水酸化酵素欠損症の1例

佐藤亮, 渋谷守栄, 宮林拓矢, 大久保幸宗, 遠藤若葉, 乾健彦, 菊池敦生, 福與なおみ, 冨樫紀子, 秋山倫之, 萩野谷和裕

脳と発達 52 ( Suppl. ) S325 - S325 2020.8

A case of dramatic improvement of lennox―gastaut syndrome in both seizures and aggressive behaviors by perampanel

Naoko Maura, Fumika Endoh, Mari Akiyama, Yoshiyuki Hanaoka, Tomoyuki Akiyama, Katsuhiro Kobayashi

Journal of the Japan Epilepsy Society 38 ( 1 ) 36 - 42 2020.7

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Epilepsy Society

Perampanel (PER) is a new antiepileptic drug (AED) and a selective non―competitive antagonist against the α―amino―3―hydroxy―5―methyl―4―isoxazolepropionic acid (AMPA) receptor. The effects of PER on Lennox―Gastaut syndrome (LGS) have not been established, and because of its adverse effects of irritability, detrimental effects on cognition and behavior should be anticipated upon its usage for LGS. We report a 22―year―old male patient who had West syndrome at 5 months of age and whose epilepsy was thereafter very resistant to ACTH therapy and numerous AEDs. Tonic seizures began to occur at 2 years of age with the appearance of slow spike―wave complexes and generalized paroxysmal fast activity on electroencephalogram (EEG), which indicated a transition from West syndrome to LGS. At 5 years of age, behavior disorders such as irritability and violent aggressiveness emerged. Occasional focal impaired awareness seizures and myoclonic seizures began at 9 years of age. At 18 years of age, PER was cautiously introduced with a dramatic reduction of seizure frequency and associated improvement of behavioral disorders. In this case, we believe that the amelioration of irritability and aggressive behavior was brought about by the decrease of seizure frequency through the antiepileptic effects of PER, despite its potential to cause irritability.

DOI： 10.3805/JJES.38.36

Non-Gaussianity Detection of EEG Signals Based on a Multivariate Scale Mixture Model for Diagnosis of Epileptic Seizures. Reviewed International journal

Akira Furui, Ryota Onishi, Akihito Takeuchi, Tomoyuki Akiyama, Toshio Tsuji

IEEE transactions on bio-medical engineering PP ( 2 ) 515 - 525 2020.7

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

OBJECTIVE: The detection of epileptic seizures from scalp electroencephalogram (EEG) signals can facilitate early diagnosis and treatment. Previous studies suggested that the Gaussianity of EEG distributions changes depending on the presence or absence of seizures; however, no general EEG signal models can explain such changes in distributions within a unified scheme. METHODS: This paper describes the formulation of a stochastic EEG model based on a multivariate scale mixture distribution that can represent changes in non-Gaussianity caused by stochastic fluctuations in EEG. In addition, we propose an EEG analysis method by combining the model with a filter bank and introduce a feature representing the non-Gaussianity latent in each EEG frequency band. RESULTS: We applied the proposed method to multichannel EEG data from twenty patients with focal epilepsy. The results showed a significant increase in the proposed feature during epileptic seizures, particularly in the high-frequency band. The feature calculated in the high-frequency band allowed highly accurate classification of seizure and non-seizure segments [area under the receiver operating characteristic curve (AUC) = 0.881] using only a simple threshold. CONCLUSION: This paper proposed a multivariate scale mixture distribution-based stochastic EEG model capable of representing non-Gaussianity associated with epileptic seizures.Experiments using simulated and real EEG data demonstrated the validity of the model and its applicability to epileptic seizure detection. SIGNIFICANCE: The stochastic fluctuations of EEG quantified by the proposed model can help detect epileptic seizures with high accuracy.

DOI： 10.1109/TBME.2020.3006246

ペランパネルが発作および行動異常に共に著効したLennox-Gastaut症候群の1例

間浦奈央子, 遠藤文香, 秋山麻里, 花岡義行, 秋山倫之, 小林勝弘

てんかん研究 38 ( 1 ) 36 - 42 2020.6

Language：Japanese Publisher：(一社)日本てんかん学会

ペランパネル(PER)は選択的AMPA受容体拮抗作用を有する新規抗てんかん薬であるが、Lennox-Gastaut症候群(LGS)に対する効果は未確定で、易刺激性の副作用もあり精神・行動に対する影響が危惧される。本症例は22歳男性で、生後5ヵ月にWest症候群を発症した。ACTH療法や各種抗てんかん薬の治療に抵抗した。2歳頃から強直発作が出現し、脳波で緩徐性棘徐波複合、全般性突発性速律動を認めLGSへの変容を示した。5歳より易興奮性、攻撃的行動異常が出現し、9歳より焦点意識減損発作、ミオクロニー発作も認めた。18歳時にPERを副作用に注意しつつ慎重に開始した所、発作は著減し脳波も改善し、同時に易興奮性、攻撃的行動異常も著明に軽減した。易刺激性が懸念されるPERであるが、本症例では激しいてんかん発作に伴い増悪していた易興奮性や行動異常が本剤による発作改善を通して改善したと思われる。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01742&link_issn=&doc_id=20200715050005&doc_link_id=10.3805%2Fjjes.38.36&url=https%3A%2F%2Fdoi.org%2F10.3805%2Fjjes.38.36&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Vitamin B6 in acute encephalopathy with biphasic seizures and late reduced diffusion. Reviewed International journal

Tomoyuki Akiyama, Soichiro Toda, Nobusuke Kimura, Yukiko Mogami, Yoshiyuki Hanaoka, Chiho Tokorodani, Tomoshiro Ito, Hiroyuki Miyahara, Yuki Hyodo, Katsuhiro Kobayashi

Brain & development 42 ( 5 ) 402 - 407 2020.5

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

BACKGROUND: The initial presentation of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is indistinguishable from that of complex febrile seizures (FS), which poses a great diagnostic challenge for clinicians. Excitotoxicity is speculated to be the pathogenesis of AESD. Vitamin B6 (VB6) is essential for the biosynthesis of gamma-aminobutyric acid, an inhibitory neurotransmitter. The aim of this study is to investigate our hypothesis that VB6 deficiency in the brain may play a role in AESD. METHODS: We obtained cerebrospinal fluid (CSF) samples from pediatric patients with AESD after early seizures and those with FS. We measured pyridoxal 5'-phosphate (PLP) and pyridoxal (PL) concentrations in the CSF samples using high-performance liquid chromatography with fluorescence detection. RESULTS: The subjects were 5 patients with AESD and 17 patients with FS. Age did not differ significantly between AESD and FS. In AESD, CSF PLP concentration was marginally lower (p = 0.0999) and the PLP-to-PL ratio was significantly (p = 0.0417) reduced compared to those in FS. CONCLUSIONS: Although it is impossible to conclude that low PLP concentration and PLP-to-PL ratio are causative of AESD, this may be a risk factor for developing AESD. When combined with other markers, this finding may be useful in distinguishing AESD from FS upon initial presentation.

DOI： 10.1016/j.braindev.2020.02.002

Effect of Asfotase Alfa on Muscle Weakness in a Japanese Adult Patient of Hypophosphatasia with Low ALP Levels Reviewed

Hiroyuki Koyama, Satoshi Yasuda, Shota Kakoi, Yasuhisa Ohata, Yuki Shimizu, Chie Hasegawa, Akiko Hayakawa, Tomoyuki Akiyama, Takashi Yagi, Daisuke Aotani, Kenro Imaeda, Keiichi Ozono, Hiromi Kataoka, Tomohiro Tanaka

Internal Medicine 59 ( 6 ) 811 - 815 2020.3

A case of pyridoxine-dependent epilepsy with novel ALDH7A1 mutations Reviewed International journal

Yuri Dowa, Takashi Shiihara, Tomoyuki Akiyama, Kosei HASEGAWA, Fumitaka Inoue, Mio Watanabe

Oxford Medical Case Reports 3 ( 3 ) 99 - 103 2020.3

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

<jats:title>Abstract</jats:title>
<jats:p>Pyridoxine-dependent epilepsy (PDE) is a rare autosomal-recessive disorder typically presenting with neonatal seizures and is sometimes difficult to diagnose, because the clinical features mimic those of birth asphyxia. A Japanese newborn boy presented with pulmonary haemorrhage and convulsions on the day of birth. Brain computed tomography showed diffuse, but mild, low-density cerebral white matter and a thin subdural hematoma in the posterior fossa. He did not have thrombocytopenia or coagulopathy. His respiratory status improved with conservative treatment, but his convulsions were persistent even after prescription of several antiepileptic drugs. His serum and cerebrospinal fluid showed decreased vitamin B6 vitamers and increased upstream metabolites of α-aminoadipic semialdehyde dehydrogenase, strongly suggesting a diagnosis of PDE; the epileptic spasms ceased after administration of intravenous pyridoxal phosphate hydrate. Gene analysis revealed novel compound heterozygous mutations in ALDH7A1 that included NM_001182.4:[c.1196G &gt; T] and [c.1200 + 1G &gt; A]. Atypical birth asphyxia with persistent neonatal seizure should prompt vitamin B6/metabolite screening.</jats:p>

DOI： 10.1093/omcr/omaa008

Metabolic Profiling of the Cerebrospinal Fluid in Pediatric Epilepsy. Reviewed

Tomoyuki Akiyama, Daisuke Saigusa, Yuki Hyodo, Keiko Umeda, Reina Saijo, Seizo Koshiba, Katsuhiro Kobayashi

Acta medica Okayama 74 ( 1 ) 65 - 72 2020.2

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

To characterize metabolic profiles within the central nervous system in epilepsy, we performed gas chromatography-tandem mass spectrometry (GC-MS/MS)-based metabolome analysis of the cerebrospinal fluid (CSF) in pediatric patients with and without epilepsy. The CSF samples obtained from 64 patients were analyzed by GC-MS/MS. Multivariate analyses were performed for two age groups, 0-5 years of age and 6-17 years of age, to elucidate the effects of epilepsy and antiepileptic drugs on the metabolites. In patients aged 0-5 years (22 patients with epilepsy, 13 without epilepsy), epilepsy patients had reduced 2-ketoglutaric acid and elevated pyridoxamine and tyrosine. In patients aged 6-17 years (12 with epilepsy, 17 without epilepsy), epilepsy patients had reduced 1,5-anhydroglucitol. Valproic acid was associated with elevated 2-aminobutyric acid, 2-ketoisocaproic acid, 4-hydroxyproline, acetylglycine, methionine, N-acetylserine, and serine. Reduced energy metabolism and alteration of vitamin B6 metabolism may play a role in epilepsy in young children. The roles of 1,5-anhydroglucitol in epilepsy in older children and in levetiracetam and zonisamide treatment remain to be explained. Valproic acid influenced the levels of amino acids and related metabolites involved in the metabolism of serine, methionine, and leucine.

DOI： 10.18926/AMO/57955

片側のジストニアを主症状とする抗NMDA受容体脳炎の1例

兵頭勇紀, 花岡義行, 金聖泰, 秋山倫之, 三谷納, 佐久間啓, 小林勝弘

日本小児科学会雑誌 124 ( 2 ) 365 - 365 2020.2

神経発達症診療におけるスクリーニング脳波の意義

秋山麻里, 藤代定志, 宮原大輔, 道上理恵, 岡牧郎, 遠藤文香, 秋山倫之, 小林勝弘

日本小児科学会雑誌 124 ( 2 ) 270 - 270 2020.2

Laboratory changes during ACTH therapy associated with renal calcified lesions. Reviewed International journal

Hiroyuki Miyahara, Tomoyuki Akiyama, Kosei Hasegawa, Mari Akiyama, Makio Oka, Katsuhiro Kobayashi, Hirokazu Tsukahara

Pediatrics international : official journal of the Japan Pediatric Society 62 ( 5 ) 587 - 592 2020.1

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

BACKGROUND: Renal calcified lesions are known as one of the complications during adrenocorticotropic hormone (ACTH) therapy for intractable epilepsy. However, laboratory changes during the therapy or laboratory features of high-risk cases with renal calcified lesions are yet to be clarified. METHODS: In this study, 43 patients with West syndrome ≤2 years were included. We retrospectively reviewed age and body mass index at the beginning of ACTH therapy, as well as the amount of fluid intake, daily urinary volume, and laboratory data during therapy. In addition, we studied the urinary sediment of the cases with renal calcified lesions diagnosed by computed tomography. RESULTS: After initiating ACTH treatment, urinary calcium (Ca)/creatinine ratio and urinary pH increased within 2 weeks. Urinary crystals and renal tubular epithelial cells (RTECs) in urinary sediment were frequently found in most cases. Urinary Ca levels, proteinuria or frequency of urinary crystals, and number of RTECs in the urinary sediment were significantly higher in patients with epithelial casts (ECs) or hematuria than in patients without these findings. Among the 7 patients who underwent abdominal CT, ECs or hematuria were found only those with renal calcified lesions. These findings suggested that patients with ECs or hematuria were more likely to have calcified lesions. CONCLUSIONS: The risk of renal calcified lesions increases after 2 weeks of ACTH treatment. Abnormal findings in urinary sediments might be an early sign of renal calcification during ACTH therapy.

DOI： 10.1111/ped.14158

Odontohypophosphatasia treated with asfotase alfa enzyme replacement therapy in a toddler: a case report. Reviewed

Mizuki Takagi, Shunsuke Kato, Taichiro Muto, Yoshimi Sano, Tomoyuki Akiyama, Junko Takagi, Akihisa Okumura, Hideyuki Iwayama

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 29 ( 3 ) 115 - 118 2020

Language：English

Hypophosphatasia (HPP) is a rare skeletal disorder caused by loss-of-function mutations in Alkaline Phosphatase, Biomineralization associated (ALPL) gene that encodes tissue-nonspecific alkaline phosphatase. Odontohypophosphatasia (odonto-HPP), a mild form of HPP, is characterized only by oral manifestations including premature exfoliation of deciduous teeth. Enzyme replacement therapy (ERT) is effective in severe HPP cases; however, information about its efficacy for odonto-HPP is limited. A 2-yr-old girl was referred to our hospital for mobility of her deciduous teeth with low serum alkaline phosphatase (ALP) level of 253 U/L (reference range: 410-1,150 U/L) and high urine phosphoethanolamine level of 1,419.9 µmol/g·Cre (7-70 µmol/g·Cre). She had no history of bone fractures; however, several members of her family had low serum ALP levels with a history of pathological fractures. She had a novel heterozygous missense mutation (c.1183A>T, p.Ile395Phe) in ALPL, and therefore, was diagnosed with odonto-HPP. After she was provided ERT to prevent premature exfoliation, no tooth mobility was observed. However, two deciduous teeth exfoliated two months after starting ERT, which was possibly triggered by a bout of common cold. Starting ERT following tooth mobility might be relatively late. Previous studies on experimental mice showed that starting ERT at birth may be effective in preventing premature exfoliation of deciduous teeth.

DOI： 10.1297/cpe.29.115

Clinical and genetic aspects of mild hypophosphatasia in Japanese patients. Reviewed International journal

Katsuyuki Yokoi, Yoko Nakajima, Yasuko Shinkai, Yoshimi Sano, Mototaka Imamura, Tomoyuki Akiyama, Tetsushi Yoshikawa, Tetsuya Ito, Hiroki Kurahashi

Molecular genetics and metabolism reports 21 100515 - 100515 2019.12

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

Background: Hypophosphatasia (HPP) is a rare inborn error of metabolism that results from a dysfunctional tissue non-specific alkaline phosphatase enzyme (TNSALP). Although genotype-phenotype correlations have been described in HPP patients, only sparse information is currently available on the genetics of mild type HPP. Methods: We investigated 5 Japanese patients from 3 families with mild HPP (patients 1 and 2 are siblings; patient 4 is a daughter of patient 5) who were referred to Fujita Health University due to the premature loss of deciduous teeth. Physical and dental examinations, and blood, urine and bone density tests were conducted. Genetic analysis of the ALPL gene was performed in all patients with their informed consent. Results: After a detailed interview and examination, we found characteristic symptoms of HPP in some of the study cases. Mobile teeth or the loss of permanent teeth were observed in 2 patients, and 3 out of 5 patients had a history of asthma. The serum ALP levels of all patients were 30% below the lower limit of the age equivalent normal range. ALPL gene analysis revealed compound heterozygous mutations, including Ile395Val and Leu520Argfs in family 1, Val95Met and Gly491Arg in family 2, and a dominant missense mutation (Gly456Arg) in family 3. The 3D-modeling of human TNSALP revealed three mutations (Val95Met, Ile395Val and Gly456Arg) at the homodimer interface. Severe collisions between the side chains were predicted for the Gly456Arg variant. Discussion: One of the characteristic findings of this present study was a high prevalence of coexisting asthma and a high level serum IgE level. These characteristics may account for the fragility of tracheal tissues and a predisposition to asthma in patients with mild HPP. The genotypes of the five mild HPP patients in our present study series included 1) compound heterozygous for severe and hypomorphic mutations, and 2) dominant-negative mutations. All of these mutations were at the homodimer interface, but only the dominant-negative mutation was predicted to cause a severe collision effect between the side chains. This may account for varying mechanisms leading to different effects on TNSALP function.

DOI： 10.1016/j.ymgmr.2019.100515

Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders. Reviewed International journal

Toshiyuki Yamamoto, Taichi Imaizumi, Keiko Yamamoto-Shimojima, Yongping Lu, Tomoe Yanagishita, Shino Shimada, Pin Fee Chong, Ryutaro Kira, Riyo Ueda, Akihiko Ishiyama, Eri Takeshita, Ken Momosaki, Shiro Ozasa, Tomoyuki Akiyama, Katsuhiro Kobayashi, Hiroo Oomatsu, Hikaru Kitahara, Tokito Yamaguchi, Katsumi Imai, Hirokazu Kurahashi, Akihisa Okumura, Hirokazu Oguni, Toshiyuki Seto, Nobuhiko Okamoto

Brain & development 41 ( 9 ) 776 - 782 2019.10

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

BACKGROUND: Recently, many genes related to neurodevelopmental disorders have been identified by high-throughput genomic analysis; however, a comprehensive understanding of the mechanism underlying neurodevelopmental disorders remains to be established. To further understand these underlying mechanisms, we performed a comprehensive genomic analysis of patients with undiagnosed neurodevelopmental disorders. METHODS: Genomic analysis using next-generation sequencing with a targeted panel was performed for a total of 133 Japanese patients (male/female, 81/52) with previously undiagnosed neurodevelopmental disorders, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy. Genomic copy numbers were also analyzed using the eXome Hidden Markov Model (XHMM). RESULTS: Thirty-nine patients (29.3%) exhibited pathogenic or likely pathogenic findings with single-gene variants or chromosomal aberrations. Among them, 20 patients were presented here. Pathogenic or likely pathogenic variants were identified in 18 genes, including ACTG1, CACNA1A, CHD2, CDKL5, DNMT3A, EHMT1, GABRB3, GABRG2, GRIN2B, KCNQ3, KDM5C, MED13L, SCN2A, SHANK3, SMARCA2, STXBP1, SYNGAP1, and TBL1XR1. CONCLUSION: A diagnostic yield of 29.3% in this study was nearly the same as that previously reported from other countries. Thus, we suggest that there is no difference in genomic backgrounds in Japanese patients with undiagnosed neurodevelopmental disabilities. Although most of the patients possessed de novo variants, one of the patients showed an X-linked inheritance pattern. As X-linked recessive disorders exhibit the possibility of recurrent occurrence in the family, comprehensive molecular diagnosis is important for genetic counseling.

DOI： 10.1016/j.braindev.2019.05.007

High-frequency oscillations in a spectrum of pediatric epilepsies characterized by sleep-activated spikes in scalp EEG. Reviewed

Ohuchi Y, Akiyama T, Matsuhashi M, Kobayashi K

Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology 130 ( 10 ) 1971 - 1980 2019.10

The Effect of S-Adenosylmethionine Treatment on Neurobehavioral Phenotypes in Lesch-Nyhan Disease: A Case Report. Reviewed

Momosaki K, Kido J, Matsumoto S, Taniguchi A, Akiyama T, Sawada T, Ozasa S, Nakamura K

Case reports in neurology 11 ( 3 ) 256 - 264 2019.9

Publishing type：Research paper (scientific journal)

© 2019 The Author(s). Published by S. Karger AG, Basel. Lesch-Nyhan disease (LND) is an X-linked recessive disorder caused by a deficiency in hypoxanthine-guanine phosphoribosyl transferase. Patients with LND experience involuntary movements, including dystonia, choreoathetosis, opisthotonos, ballismus, and self-injury. Alleviating these involuntary movements is important to improve the quality of life in patients with LND. Many clinicians have difficulty controlling these involuntary movements in their patients, and there are no established and effective treatments. A 6-month-old boy with LND presented with generalized dystonia and self-injury behavior that was alleviated after receiving S-adenosylmethionine (SAMe). His self-injury behavior completely resolved after he received SAMe and risperidone. Although he had often experienced inspiratory stridor because of laryngeal dystonia and frequently developed aspiration pneumonitis and bronchitis, no inspiratory stridor was noted after SAMe treatment. The patient is continuing to receive SAMe and risperidone. SAMe treatment alleviates dystonic movements and improves quality of life in pediatric patients with LND. Additional research is needed to determine the long-term safety and efficacy of SAMe and its appropriate dosage.

DOI： 10.1159/000502568

Findings of amplitude-integrated electroencephalogram recordings and serum vitamin B6 metabolites in perinatal lethal hypophosphatasia during enzyme replacement therapy. Reviewed International journal

Tomonori Ishiguro, Yuichiro Sugiyama, Kazuto Ueda, Yukako Muramatsu, Hiroyuki Tsuda, Tomomi Kotani, Toshimi Michigami, Kanako Tachikawa, Tomoyuki Akiyama, Masahiro Hayakawa

Brain & development 41 ( 8 ) 721 - 725 2019.9

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

Hypophosphatasia (HPP) is a rare disorder caused by low serum tissue non-specific alkaline phosphatase (ALP) activity due to hypomorphic mutations in the ALPL gene. HPP is characterized by defective bone mineralization. It frequently accompanies pyridoxine-responsive seizures. Because alkaline phosphatase change pyridoxal 5' phosphate (PLP) into pyridoxal (PL), which can cross the blood brain barrier and regulates inhibitory neurotransmitter gamma-aminobutyric acid. The female patient was born at a gestational age of 37 weeks 2 days. She presented severe respiratory disorder due to extreme thoracic hypoplasia. With the extremely low serum ALP value (14 IU/L), she was clinically diagnosed as HPP. The diagnosis was confirmed with genetic testing. On day1, the subclinical seizures were detected by aEEG. Together with enzyme replacement therapy by asfotase alfa, pyridoxine hydrochloride was administered, then the seizures were rapidly controlled. While confirming that there was no seizure by aEEG monitoring, pyridoxine hydrochloride was gradually discontinued after 1 month. Before administration of pyridoxine hydrochloride, PL was extremely low (4.7 nM) and PLP was increased (1083 nM). After the withdrawal, PL was increased to 84.9 nM only by enzyme replacement. Monitoring with aEEG enabled early intervention for pyridoxine responsive seizures. Confirming increased serum PL concentration is a prudent step in determining when to reduce or discontinue pyridoxine hydrochloride during enzyme replacement therapy.

DOI： 10.1016/j.braindev.2019.03.015

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症候群における髄液中ビタミンB6化合物の解析

秋山倫之, 兵頭勇紀, 花岡義行, 秋山麻里, 小林勝弘, 池本智, 松浦隆樹, 小一原玲子, 浜野晋一郎, 岡西徹

てんかん研究 37 ( 2 ) 590 - 590 2019.9

Action of antiepileptic drugs on neurons. Reviewed

Kobayashi K, Endoh F, Ohmori I, Akiyama T

Brain & development 42 ( 1 ) 2 - 5 2019.7

A case of dihydropyrimidinase deficiency incidentally detected by urine metabolome analysis. Reviewed International journal

Hiroki Tsuchiya, Tomoyuki Akiyama, Tomiko Kuhara, Yoko Nakajima, Morimasa Ohse, Hiroki Kurahashi, Takema Kato, Yasuhiro Maeda, Harumi Yoshinaga, Katsuhiro Kobayashi

Brain & development 41 ( 3 ) 280 - 284 2019.3

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

Dihydropyrimidinase deficiency is a rare autosomal recessive disease affecting the second step of pyrimidine degradation. It is caused by mutations in the DPYS gene. Only approximately 30 cases have been reported to date, with a phenotypical variability ranging from asymptomatic to severe neurological illness. We report a case of dihydropyrimidinase deficiency incidentally detected by urine metabolome analysis. Gas chromatography-mass spectrometry-based urine metabolomics demonstrated significant elevations of dihydrouracil and dihydrothymine, which were subsequently confirmed by a quantitative analysis using liquid chromatography-tandem mass spectrometry. Genetic testing of the DPYS gene revealed two mutations: a novel mutation (c.175G > T) and a previously reported mutation (c.1469G > A). Dihydropyrimidinase deficiency is probably underdiagnosed, considering its wide phenotypical variability, nonspecific neurological presentations, and an estimated prevalence of 2/20,000. As severe 5-fluorouracil-associated toxicity has been reported in patients and carriers of congenital pyrimidine metabolic disorders, urinary pyrimidine analysis should be considered for those who will undergo 5-fluorouracil treatment.

DOI： 10.1016/j.braindev.2018.10.005

A case of vitamin B6-responsive West syndrome caused by severe traumatic brain injury Reviewed International journal

Inoue T, Akiyama T, Hanaoka Y, Oka M, Kobayashi K

Epilepsy & Seizure 10 ( 1 ) 114 - 119 2019.2

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

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 B.V.

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

Strong coupling between slow oscillations and wide fast ripples in children with epileptic spasms: Investigation of modulation index and occurrence rate Reviewed

Yasushi Iimura, Kevin Jones, Lynne Takada, Itsuki Shimizu, Misaki Koyama, Kyoko Hattori, Yushi Okazawa, Yutaka Nonoda, Eishi Asano, Tomoyuki Akiyama, Cristina Go, Ayako Ochi, O. Carter Snead, Elizabeth J. Donner, James T. Rutka, James M. Drake, Hiroshi Otsubo

Epilepsia 59 ( 3 ) 544 - 554 2018.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Inc.

Objective: Epileptic spasms (ES) often become drug-resistant. To reveal the electrophysiological difference between children with ES (ES+) and without ES (ES−), we compared the occurrence rate (OR) of high-frequency oscillations (HFOs) and the modulation index (MI) of coupling between slow and fast oscillations. In ES+, we hypothesized that (1) pathological HFOs are more widely distributed and (2) slow oscillations show stronger coupling with pathological HFOs than in ES−. Methods: We retrospectively reviewed 24 children with drug-resistant multilobar onset epilepsy, who underwent intracranial video electroencephalography prior to multilobar resections. We measured the OR of HFOs and determined the electrodes with a high rate of HFOs by cluster analysis. We calculated MI, which reflects the degree of coupling between HFO (ripple/fast ripple [FR]) amplitude and 5 different frequency bands of delta and theta activities (0.5-1 Hz, 1-2 Hz, 2-3 Hz, 3-4 Hz, 4-8 Hz). Results: In ES+ (n = 10), the OR( FR s), the number of electrodes with high-rate FRs, and the MI( FR s &amp
3-4 Hz) in all electrodes were significantly higher than in ES− (n = 14). In both the ES+ and ES− groups, MI(ripples/ FR s &amp
3-4 Hz) was the highest among the 5 frequency bands. Within the good seizure outcome group, the OR( FR s) and the MI( FR s &amp
3-4 Hz) in the resected area in ES+ were significantly higher than in ES− (OR[FR s], P =.04
MI[ FR s &amp
3-4 Hz], P =.04). Significance: In ES+, the larger number of high-rate FR electrodes indicates more widespread epileptogenicity than in ES−. High values of OR( FR s) and MI( FR s &amp
3-4 Hz) in ES+ compared to ES− are a signature of the severity of epileptogenicity. We proved that ES+ children who achieved seizure freedom following multilobar resections exhibited strong coupling between slow oscillations and FRs.

DOI： 10.1111/epi.13995

A case of perinatal hypophosphatasia with a novel mutation in the ALPL gene: clinical course and review of the literature. Reviewed

Oyachi M, Harada D, Sakamoto N, Ueyama K, Kondo K, Kishimoto K, Izui M, Nagamatsu Y, Kashiwagi H, Yamamuro M, Tamura M, Kikuchi S, Akiyama T, Michigami T, Seino Y, Namba N

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 27 ( 3 ) 179 - 186 2018

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

Hypophosphatasia (HPP) is a metabolic bone disease characterized by failure of bone calcification and vitamin B6 dependent seizures. It is caused by loss-of-function mutations in the ALPL gene. A newborn girl required respiratory support by nasal-directional positive airway pressure at birth, and pyridoxine hydrochloride administration for vitamin B6-dependent seizures observed from day two. Umbilical cord blood showed low alkaline phosphatase (ALP) activity and high pyridoxal phosphate levels. Radiographs showed severe rickets-like appearance of the bones. Genetic analysis of the ALPL gene revealed compound heterozygous mutations, c.1559delT/p.Ser188Pro. We diagnosed her with perinatal severe HPP, and started the patient on asfotase alfa from day six. Following enzyme replacement therapy (ERT), skeletal mineralization and respiratory insufficiency improved with no remarkable side-effects. Crying vital capacity (CVC) was used to evaluate respiratory status, which continuously improved from 13.3 mL/kg (day 22) to 20.6 mL/kg (day 113). Since no seizures occurred, pyridoxine hydrochloride was tapered off at one year of age. Strategies to manage perinatal severe HPP cases following ERT have not been established till date. A review of the literature shows that CVC may be a good indicator for weaning from ventilatory support. In addition, ERT will most likely enable withdrawal of pyridoxine treatment.

DOI： 10.1297/cpe.27.179

Differential diagnosis of nonepileptic twilight state with convulsive manifestations after febrile seizures Reviewed

Hiroyuki Miyahara, Tomoyuki Akiyama, Kenji Waki, Yoshio Arakaki

Brain and Development 40 ( 9 ) 781 - 785 2018

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier B.V.

Background: Nonepileptic twilight state with convulsive manifestations (NETC) is a nonepileptic state following a febrile seizure (FS), which may be misdiagnosed as a prolonged seizure and result in overtreatment. We aimed to describe clinical manifestations of NETC and to determine characteristics that are helpful to distinguish NETC from other pathological conditions. Methods: We conducted a retrospective chart review from January 2010 to December 2016 and selected the patients who presented with symptoms resembling status epilepticus with fever and a confirmed diagnosis using an electroencephalogram (EEG). We compared the NETC clinical features and venous blood gas analysis results with those of other conditions that mimic NETC. We also compared the characteristics of NETC with past reports. Results: Our NETC patients presented with short durations of the preceding generalized convulsions followed by tonic posturing, closed eyes, no cyanosis, responsiveness to painful stimulation, and no accumulation of CO2 in the venous blood gas. Most of these characteristics were consistent with past reports. Prolonged FS or acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) showed several of these features, but all the characteristics were not consistent with our study. Conclusions: Prolonged FS and AESD need to be differentiated from NETC, and close clinical observation makes it possible to partially distinguish NETC from the other conditions. EEG is recommended for patients with symptoms that are inconsistent with these features.

DOI： 10.1016/j.braindev.2018.05.014

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

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 SCIENCE 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 (< 1.2 nmo1/1). 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-toserum 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

Epileptogenic high-frequency oscillations skip the motor area in children with multilobar drug-resistant epilepsy Reviewed

Yasushi Iimura, Kevin Jones, Kyoko Hattori, Yushi Okazawa, Atsuko Noda, Kana Hoashi, Yutaka Nonoda, Eishi Asano, Tomoyuki Akiyama, Cristina Go, Ayako Ochi, O. Carter Snead, Elizabeth J. Donner, James T. Rutka, James M. Drake, Hiroshi Otsubo

CLINICAL NEUROPHYSIOLOGY 128 ( 7 ) 1197 - 1205 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Objective: Subtotal hemispherectomy involves the resection of multiple lobes in children with drug-resistant epilepsy, skipping the motor area (MA). We determined epileptogenicity using the occurrence rate (OR) of high-frequency oscillations (HFOs) and the modulation index (MI), demonstrating strength of coupling between HFO and slow wave. We hypothesized that epileptogenicity increased over the multiple lobes but skipped the MA.
Methods: We analyzed 23 children (14 subtotal hemispherectomy; 9 multilobar resections). Scalp video-EEG and magnetoencephalography were performed before surgery. We analyzed the OR(HFO) and MI(5 (phases= 0.5-8) (Hz)) on electrodes of total area, resection areas, and MA. We compared the data between good [International League Against Epilepsy (ILAE) class I-II] and poor (III-VI) seizure outcome groups.
Results: ILAE class Ia outcome was achieved in 18 children. Among the MI(5 phases) in the resection areas, MI(3-4 (Hz)) was the highest. The OR(HFO) and MI(3-4 (Hz)) in both total area and resection areas were significantly higher in the good seizure outcome group than in the poor outcome group. The OR(HFO) and MI(3-4 (Hz)) in resection areas were significantly higher than in the MA.
Conclusions: Our patients with multilobar drug-resistant epilepsy showed evidence of multifocal epileptogenicity that specifically skipped the MA. (C) 2017 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.clinph.2017.03.031

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

Kobayashi K, Endoh F, Agari T, Akiyama T, Akiyama M, Hayashi Y, Shibata T, Hanaoka Y, Oka M, Yoshinaga H, Date I

Epilepsia open 2 ( 2 ) 260 - 266 2017.6

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

We investigated the relationship between the scalp distribution of fast (40-150 Hz) oscillations (FOs) and epileptogenic lesions in West syndrome (WS) and related disorders. Subjects were 9 pediatric patients with surgically confirmed structural epileptogenic pathology (age at initial electroencephalogram [EEG] recording: mean 7.1 months, range 1-22 months). The diagnosis was WS in 7 patients, Ohtahara syndrome in 1, and a transitional state from Ohtahara syndrome to WS in the other. In the scalp EEG data of these patients, we conservatively detected FOs, and then examined the distribution of FOs. In five patients, the scalp distribution of FOs was consistent and concordant with the lateralization of cerebral pathology. In another patient, FOs were consistently dominant over the healthy cerebral hemisphere, and the EEG was relatively low in amplitude over the pathological atrophic hemisphere. In the remaining 3 patients, the dominance of FOs was inconsistent and, in 2 of these patients, the epileptogenic hemisphere was reduced in volume, which may result from atrophy or hypoplasia. The correspondence between the scalp distribution of FOs and the epileptogenic lesion should be studied, taking the type of lesion into account. The factors affecting scalp FOs remain to be elucidated.

DOI： 10.1002/epi4.12043

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

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

Background: We quantified pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) in the cerebrospinal fluid (CSF) of children and to investigate the effect of age, sex, epilepsy, and anti-epileptic drug (AED) therapy on these vitamers.
Methods: CSF samples prospectively collected from 116 pediatric patients were analyzed. PLP, PI, and PA were measured using high-performance liquid chromatography with fluorescence detection, using pre-column derivatization by semicarbazide. Effects of age, sex, epilepsy, and AEDs on these vitamers and the PLP/PL ratio were evaluated using multiple linear regression models.
Results: The PLP, PL, and PA concentrations were correlated negatively with age and the PLP/PL ratio was correlated positively with age. Multiple regression analysis revealed that the presence of epilepsy was associated with lower PLP concentrations and PLP/PL ratios but sex and AED therapy had no influence on these values. The observed ranges of these vitamers in epileptic and non-epileptic patients were demonstrated.
Conclusions: We showed the age dependence of PLP and PL in CSF from pediatric patients. Epileptic patients had lower PLP concentrations and PLP/PL ratios than non-epileptic patients, but it is unknown whether this is the cause, or a result, of epilepsy. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.cca.2016.12.027

Severe leukoencephalopathy with cortical involvement and peripheral neuropathy due to FOLR1 deficiency Reviewed

Yu Kobayashi, Jun Tohyama, Tomoyuki Akiyama, Shinichi Magara, Hideshi Kawashima, Noriyuki Akasaka, Mitsuko Nakashima, Hirotomo Saitsu, Naomichi Matsumoto

BRAIN & DEVELOPMENT 39 ( 3 ) 266 - 270 2017.3

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

Cerebral folate deficiency due to folate receptor 1 gene (FOLR1) mutations is an autosomal recessive disorder resulting from a brain-specific folate transport defect. It is characterized by late infantile onset, severe psychomotor regression, epilepsy, and leukodystrophy. We describe a consanguineous girl exhibiting severe developmental regression, intractable epilepsy, polyneuropathy, and profound hypomyelination with cortical involvement. Magnetic resonance imaging showed cortical disturbances in addition to profound hypomyelination and cerebellar atrophy. Nerve conduction studies revealed both axonal degeneration and demyelinating features. A diagnosis of cerebral folate deficiency was confirmed by a homozygous c.466T>G (p.W156G) mutation in FOLR1, coupled with extremely low cerebrospinal fluid levels of 5-methyltetrahydrofolate. Her symptoms, neuroradiological findings, and polyneuropathy were alleviated by oral folinic acid treatment in conjunction with intravenous and intramuscular administration therapy. Our patient shows that folinic acid therapy can ameliorate the clinical symptoms, white matter disturbances, cortical insults, and peripheral neuropathy of cerebral folate deficiency caused by FOLR1 mutation. It is important to recognize these clinical symptoms and make a precise diagnosis early on, because cerebral folate deficiency is treatable. (C) 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2016.09.011

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

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 SCIENCE BV

Background: We describe a new method for simultaneous measurement of monoamine metabolites (3-0-methyldopa [3-0MD],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 10 min. They showed linearity from the limit of detection to 1024 nmol/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 alpha 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. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.cca.2016.12.005

A Japanese case of beta-ureidopropionase deficiency with dysmorphic features Reviewed

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

BRAIN & DEVELOPMENT 39 ( 1 ) 58 - 61 2017.1

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

beta-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 P-ureidopropionic acid and beta-ureidoisobutyric acid, strongly suggesting a diagnosis of P-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. P-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. (C) 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2016.08.001

Importance of the multisystem follow-up in patients with tuberous sclerosis complex. Reviewed

Yoshinaga H, Oka M, Akiyama T, Endoh F, Akiyama M, Hayashi Y, Shibata T, Hanaoka Y, Kobayashi K

No to hattatsu = Brain and development 5-9 ( 1 ) 5 - 9 2017.1

Language：Japanese Publisher：The Japanese Society of Child Neurology

<p> Objective: Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by the formation of hamartoma in multiple organ systems of the body. However, without a well-established cooperative system involving related departments, some organ lesions might be overlooked until symptoms appear or even until the disorder progresses. Therefore, the purpose of this study is to investigate the current status of follow-ups in the TSC patients in the Department of Child Neurology at Okayama University Medical Hospital. Methods: We performed a retrospective chart review of 38 patients with TSC who visited our hospital at least twice between January 2005 and December 2014. Patients were between 3 years and 48 years of age at their latest visit. We divided the patients into a child group and an adult group, and investigated the patients' follow-up data while focusing on the various multiorgan systems. Results: The follow-ups were well conducted in the child group in terms of every organ. In the adult group, neuroimaging tests were unsatisfactorily performed. The kidney has not been examined in seven patients more than five years even though these patients all had kidney lesions. The lung was not been examined in 7 out of 14 female patients over 18 years of age who are most at risk for lymphangioleiomyomatosis (LAM). In 12 out of 18 child patients, echocardiograms were performed every few years, while electrocardiograms to assess underlying conduction defects were rarely performed in either age group. Conclusions: In Europe, guidelines for the management of TSC have been well established. However, in our hospital, the multiorgan system follow-up is not satisfactorily performed especially in adult patients. We decided the establishment of a TSC board in our hospital for the management of this multiorgan disorder.</p>

DOI： 10.11251/ojjscn.49.5

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

Shibata T, Yoshinaga H, Akiyama T, Kobayashi K

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

Fast (40-150 Hz) oscillations are associated with positive slow waves in the ictal EEGs of epileptic spasms in West syndrome Reviewed

Katsuhiro Kobayashi, Tomoyuki Akiyama, Makio Oka, Fumika Endoh, Harumi Yoshinaga

BRAIN & DEVELOPMENT 38 ( 10 ) 909 - 914 2016.11

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

Objective: To elucidate the generative mechanisms of epileptic spasms (ESs) in West syndrome, we investigated the temporal relationship between scalp fast (40-150 Hz) oscillations (FOs) and slow waves in the ictal electroencephalograms (EEGs) of ESs.
Methods: In 11 infants with WS, ictal FOs were detected in a bipolar montage based on spectral and waveform criteria. Their temporal distribution was analyzed in terms of the positive peaks (trough point, TT) of identical EEG data in a referential montage. Among six EEG data sections defined according to TT, the number of FOs, peak power values, and peak frequencies were compared.
Results: We identified a total of 1014 FOs (946 gamma and 68 ripple oscillations), which clustered closely at TT. The number of gamma oscillations in the 1 s epoch including TT was significantly higher than those in the prior and subsequent phases. Peak power values and frequencies tended to be higher in these positive phase sections.
Conclusions: The temporal association of FO clustering and positive slow waves in the ictal EEGs of ES indicated that active neuronal firing related to FOs underlies the generation of ESs and their ictal slow waves. (C) 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights

DOI： 10.1016/j.braindev.2016.05.005

Magnetoencephalography spike sources interrelate the extensive epileptogenic zone of tuberous sclerosis complex Reviewed

Tohru Okanishi, Tomoyuki Akiyama, Ellen Mayo, Yasunori Honda, Chihiro Ueda-Kawada, Midori Nakajima, Yoichiro Homma, Ayako Ochi, Cristina Go, Elysa Widjaja, Sylvester H. Chuang, James T. Rutka, James Drake, O. Carter Snead, Hiroshi Otsubo

EPILEPSY RESEARCH 127 302 - 310 2016.11

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

Objective: We hypothesized that the extensive epileptic network in patients with tuberous sclerosis complex (TSC) manifests as clustered and scattered distributions of magnetoencephalography spike sources (MEGSS).
Methods: We retrospectively analyzed pre-surgical MEG in 15 patients with TSC. We performed single moving dipole analysis to localize and classify clustered and scattered MEGSS. We compared the number of electrodes within the resected area (RA) and the proportions of clustered and scattered MEGSS within RA with the seizure outcome.
Results: The number of electrodes within RA ranged from 29 to 83 (mean = 51). The MEGSS were distributed over multiple lobes (3-8; mean = 5.9) and bilaterally in 14 patients. Clusters of MEGSS ranged from 1 to 4 (mean = 1.4). The number of MEGSS ranged in total from 28 to 139 (mean = 70); in the clusters, 10-128 (mean = 49); and in the scatters, 0-45 (mean = 21). Four patients achieved an Engel class I surgical outcome, four, a class II outcome; five, a class III outcome; and two, a class IV outcome. The proportion of MEGSS ranged in total from 0 to 92% (mean = 57%) within RA; 0-100% (mean = 67%) in the resection hemisphere; 0-100% (mean = 63%) in the clusters; and 0-81% (mean = 28%) in the scatters. Univariate ordinal logistic regression analyses showed that the proportion of scattered MEGSS within RA (p = 0.049) significantly correlated with seizure outcomes. Multivariate analyses using three covariates (number of electrodes, proportions of clustered and scattered MEGSS within RA) showed that only the proportion of scattered MEGSS within RA significantly correlated with seizure outcomes (p = 0.016).
Significance: MEG data showed a wide distribution of multilobar MEGSS in patients with TSC. The seizure outcome was not related to the clustered MEGSS within RA, since the grids were essentially planned to cover and resect the clustered MEGSS surrounding tubers. The maximal possible resection of scattered MEGSS correlated with improved seizure outcome in TSC. Some parts of the epileptogenic zone disrupted by multiple tubers did not have a sufficiently large area to produce clustered MEGSS. Although the wide distribution of scattered MEGSS is not interpreted as epileptogenic, they might be interrelated with clustered MEGSS to project a complex epilepsy network and be part of the extensive epileptogenic zones found in TSC. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.eplepsyres.2016.09.007

SSADH deficiency possibly associated with enzyme activity-reducing SNPs Reviewed

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

BRAIN & DEVELOPMENT 38 ( 9 ) 871 - 874 2016.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE 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 (approximate to 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. (C) 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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

Determination of CSF 5-methyltetrahydrofolate in children and its application for defects of folate transport and metabolism Reviewed

Mari Akiyama, Tomoyuki Akiyama, Kaoruko Kanamaru, Mutsuko Kuribayashi, Hiroko Tada, Tsugumi Shiokawa, Soichiro Toda, Katsumi Imai, Yu Kobayashi, Jun Tohyama, Takafumi Sakakibara, Harumi Yoshinaga, Katsuhiro Kobayashi

CLINICA CHIMICA ACTA 460 120 - 125 2016.9

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

Objective: To describe an assay of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid (CSF) of children, to determine reference values, and to report the clinical significance of this assay in metabolic disorders affecting folate transport and metabolism.
Methods: CSF 5MTHF was determined by high-performance liquid chromatography with fluorescent detection in pediatric patients including one with FOLR1 gene mutation and one with methylenetetrahydrofolate reductase (MTHFR) deficiency. CSF total folate was measured using an automated analyzer.
Results: 5MTHF and total folate were determined in 188 and 93 CSF samples, respectively. CSF 5MTHF was high throughout the first six months of life and subsequently declined with age. Reference values of CSF 5MTHF and total folate were determined from 162 and 82 samples, respectively. The patient with FOLR1 gene mutation had extremely low CSF 5MTHF and total folate, though these values normalized after folinic acid supplementation. The patient with MTHFR deficiency had extremely low 5MTHF and moderately low total folate; these values were not associated and showed no significant change after folic acid supplementation.
Conclusions: This 5MTHF assay is simple, rapid, sensitive, reliable, and cost-effective. It will aid in the diagnosis and therapeutic monitoring of metabolic disorders affecting folate transport and metabolism. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.cca.2016.06.032

A Japanese case of hereditary chin trembling responsive to arotinolol Reviewed

Tomoyuki Akiyama, Hiroyuki Miyahara, Kenji Waki, Harumi Yoshinaga, Katsuhiro Kobayashi

PARKINSONISM & RELATED DISORDERS 29 133 - 134 2016.8

Predictive factors for relapse of epileptic spasms after adrenocorticotropic hormone therapy in West syndrome Reviewed

Yumiko Hayashi, Harumi Yoshinaga, Tomoyuki Akiyama, Fumika Endoh, Yoko Ohtsuka, Katsuhiro Kobayashi

BRAIN & DEVELOPMENT 38 ( 1 ) 32 - 39 2016.1

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

Purpose: To investigate whether serial electroencephalographic (EEG) findings can predict relapse of epileptic spasms after synthetic adrenocorticotropic hormone (ACTH) therapy in patients with West syndrome (WS).
Subjects and methods: Thirty-nine WS patients (8 cryptogenic and 31 symptomatic) were included in this study. These patients received ACTH therapy for the first time and were regularly followed up for more than three years at our hospital. Sixteen patients (41.0%) showed seizure relapse (relapse group) and 23 patients (59.0%) did not show relapse (non-relapse group). We used survival analysis to investigate the influence of etiology and presence of epileptic discharges after the ACTH therapy on seizure outcome.
Results: Immediately after the ACTH therapy, etiology was associated with seizure outcome (p = 0.003). In the early stage (1 month after the ACTH therapy), only the presence of epileptic discharges (p = 0.001) had a significant association with seizure outcome, regardless of etiology. Because all relapsed patients were in the symptomatic group, we performed the same statistical analysis on symptomatic WS patient data only. We found that the group with no epileptic discharges on EEG showed a significantly higher seizure-free rate than those with epileptic discharges in the early stage (p = 0.0091).
Conclusion: This study demonstrated that serial EEG findings after ACTH therapy are significantly related to relapse of epileptic spasms. (c) 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2015.05.012

Total folate and 5-methyltetrahydrofolate in the cerebrospinal fluid of children: correlation and reference values Reviewed

Tomoyuki Akiyama, Hiroko Tada, Tsugumi Shiokawa, Katsuhiro Kobayashi, Harumi Yoshinaga

CLINICAL CHEMISTRY AND LABORATORY MEDICINE 53 ( 12 ) 2009 - 2014 2015.11

Language：English Publishing type：Research paper (scientific journal) Publisher：WALTER DE GRUYTER GMBH

Background: Cerebral folate deficiency (CFD) may be underdiagnosed, as it manifests with various non-specific neurological symptoms. The diagnosis of CFD requires a determination of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid (CSF), which is available in a limited number of specialized laboratories. In clinical biochemistry laboratories, total folate (TF) determination in serum or plasma is routinely performed by automated analyzers. The aim of this study is to determine whether the automated assay of CSF TF is a helpful screening tool for CFD.
Methods: We analyzed CSF samples collected from 73 pediatric patients. We measured CSF TF, serum TF, and CSF 5MTHF in 73, 70, and 48 patients, respectively. The assay of 5MTHF was conducted by a newly developed system utilizing liquid chromatography-tandem mass spectrometry (LC-MS/ MS). We investigated the correlation between TF and 5MTHF in the CSF.
Results: There was a strong positive correlation between CSF TF and 5MTHF (rho=0.930, p<0.0001, n=48). Age was negatively correlated with CSF TF (rho=-0.557, p<0.0001, n=51), serum TF (rho=-0.457, p=0.0008, n=51), and CSF 5MTHF (rho=-0.387, p=0.0263, n=33), but not with the CSF/serum TF ratio.
Conclusions: The automated assay of CSF TF is helpful to estimate CSF 5MTHF. The CSF TF assay may have a significant impact on the early diagnosis of CFD, because clinicians have better access to it than the 5MTHF assay.

DOI： 10.1515/cclm-2015-0208

Spatial relationship between fast and slow components of ictal activities and interictal epileptiform discharges in epileptic spasms Reviewed

Tomoyuki Akiyama, Mari Akiyama, Katsuhiro Kobayashi, Tohru Okanishi, Cyrus G. Boelman, Dragos A. Nita, Ayako Ochi, Cristina Y. Go, O. Carter Snead, James T. Rutka, James M. Drake, Sylvester Chuang, Hiroshi Otsubo

CLINICAL NEUROPHYSIOLOGY 126 ( 9 ) 1684 - 1691 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Objective: We analyzed the spatial distribution and concordance of fast (>10 Hz) and slow (<5 Hz) electroencephalogram (EEG) components of ictal activities and interictal epileptiform discharges (IIED) recorded by intracranial video EEG (IVEEG) in children with epileptic spasms (ES).
Methods: We studied eight children with ES, who underwent IVEEG before resective surgery for epilepsy. We quantified the root-mean-square (RMS) amplitude of the fast and slow components of ictal activities during ES and IIED. We compared the concordance between the spatial distributions of the fast and slow components of ES and IIED.
Results: There was a larger concordance between the spatial distributions of the fast and slow components in IIED than in ES (p = 0.0206 and 0.0401).
Conclusions: The spatial concordance between the fast and slow EEG components was significantly different between ES and IIED.
Significance: The mechanisms underlying the generation of slow EEG components may differ between ES and IIED. The slow EEG components of ES might indicate an extensive epileptic network involving remote symptomatic zones for ES in either the cortical or subcortical areas. The high spatial concordance between the fast and slow components of IIED suggests the involvement of a local inhibitory process within the epileptic cortex. (C) 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.clinph.2014.12.005

Progressive brain atrophy in Schinzel-Giedion syndrome with a SETBP1 mutation Reviewed

Akihito Takeuchi, Nobuhiko Okamoto, Shoko Fujinaga, Hirosuke Morita, Junya Shimizu, Tomoyuki Akiyama, Shinsuke Ninomiya, Jun-ichi Takanashi, Toshihide Kubo

EUROPEAN JOURNAL OF MEDICAL GENETICS 58 ( 8 ) 369 - 371 2015.8

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

Schinzel-Giedion syndrome is a rare congenital malformation syndrome. Recently, SETBP1 was identified as the causative gene. Herein, we present a Japanese boy with Schinzel-Giedion syndrome resulting from a novel mutation in SETBP1 in order to establish the clinical features and serial MRI findings associated with the syndrome. On the third day of life, the boy was referred to our hospital because of facial abnormalities and feeding difficulty. Midfacial retraction, frontal bossing, deep groove under the eyes, upturned nose, low-set ears, bilateral cryptorchidism, and generalized hypertrichosis were identified on admission. At the age of 7 months, epileptic spasms in series occurred. Based on characteristic facial and skeletal abnormalities and severe developmental delay, we clinically diagnosed him with Schinzel-Giedion syndrome. Direct sequencing of the SETBP1 gene revealed a heterozygous mutation (p.Ile871Ser) in exon 4. Although neither cardiac defect nor choanal stenosis were present in our case, the phenotype of our case was nearly identical to those of previously reported cases confirmed by genetic analysis. Serial MRI from the age of 1 month-3 years revealed progressive brain atrophy, especially in the white matter and basal ganglia. However, myelination was age-appropriate and no obvious abnormal signals in the white matter were seen. Diffusion weighted imaging revealed no abnormal findings. Accumulation of MRI data including diffusion weighted imaging from Schinzel-Giedion syndrome cases is needed to understand the mechanism underlying progressive brain atrophy in this syndrome. (C) 2015 Elsevier Masson SAS. All rights reserved.

DOI： 10.1016/j.ejmg.2015.05.006

Action potentials contribute to epileptic high-frequency oscillations recorded with electrodes remote from neurons Reviewed

Katsuhiro Kobayashi, Tomoyuki Akiyama, Iori Ohmori, Harumi Yoshinaga, Jean Gotman

CLINICAL NEUROPHYSIOLOGY 126 ( 5 ) 873 - 881 2015.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Objective: The importance of epileptic high-frequency oscillations (HFOs) in electroencephalogram (EEG) is growing. Action potentials generating some HFOs are observed in the vicinity of neurons in experimental animals. However electrodes that are remote from neurons, as in case of clinical situations, should not record action potentials. We propose to resolve this question by a realistic simulation of epileptic neuronal network.
Methods: The rat dentate gyrus with sclerosis was simulated in silico. We computed the current dipole moment generated by each granule cell and the field potentials in a measurement area far from neurons.
Results: The dentate gyrus was stimulated through synaptic input to evoke discharges resembling interictal epileptiform discharges, which had superimposed HFOs <= 295 Hz that were recordable with remote electrodes and represented bursts of action potentials of granule cells. The increase in power of HFOs was associated with the progression of sclerosis, the reduction of GABAergic inhibition, and the increase in cell connectivity. Spectral frequency of HFOs had similar tendencies.
Conclusions: HFOs recorded with electrodes remote from neurons could actually be generated by clusters of action potentials. Significance: The phenomenon of action potentials recorded with remote electrodes can possibly extend the clinical meaning of EEG. (C) 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.clinph.2014.08.010

Phenotypic Variability in Childhood of Skeletal Muscle Sodium Channelopathies Reviewed

Harumi Yoshinaga, Shunichi Sakoda, Takashi Shibata, Tomoyuki Akiyama, 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

Trend figures assist with untrained emergency electroencephalogram interpretation Reviewed

Katsuhiro Kobayashi, Kosuke Yunoki, Kazumasa Zensho, Tomoyuki Akiyama, Makio Oka, Harumi Yoshinaga

BRAIN & DEVELOPMENT 37 ( 5 ) 487 - 494 2015.5

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

Objective: Acute electroencephalogram (EEG) findings are important for diagnosing emergency patients with suspected neurological disorders, but they can be difficult for untrained medical staff to interpret. In this research, we will develop an emergency EEG trend figure that we hypothesize will be more easily understood by untrained staff compared with the raw original traces. Methods: For each of several EEG patterns (wakefulness, sleep, seizure activity, and encephalopathy), trend figures incorporating information on both amplitude and frequency were built. The accuracy of untrained reviewers' interpretation was compared with that of the raw EEG trace interpretation. Results: The rate of correct answers was significantly higher in response to the EEG trend figures than to the raw traces showing wakefulness, sleep, and encephalopathy, but there was no difference when seizure activity patterns were viewed. The rates of misjudging normal or abnormal findings were significantly lower with the trend figures in the wakefulness pattern; in the other patterns, misjudgments were equally low for the trend figures and the raw traces. Conclusion: EEG trend figures improved the accuracy with which untrained medical staff interpreted emergency EEGs. Emergency EEG figures that can be understood intuitively with minimal training might improve the accuracy of emergency EEG interpretation. However, additional studies are required to confirm these results because there may be many types of clinical EEGs that are difficult to interpret. (C) 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2014.08.006

A Storm of Fast (40-150Hz) Oscillations during Hypsarrhythmia in West Syndrome Reviewed

Katsuhiro Kobayashi, Tomoyuki Akiyama, Makio Oka, Fumika Endoh, Harumi Yoshinaga

ANNALS OF NEUROLOGY 77 ( 1 ) 58 - 67 2015.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

ObjectiveFast oscillations (FOs) were first explored from scalp electroencephalographic (EEG) data from hypsarrhythmia in West syndrome (infantile spasms) to investigate the meaning of FOs in this epileptic encephalopathy.
MethodsIn 17 infants with West syndrome, we conservatively detected fast frequency peaks that stood out from the time-frequency spectral background with square root power>1 mu V (spectral criterion) and corresponded to clear FOs with at least 4 oscillations in the filtered EEG traces (waveform criterion) in sleep EEGs.
ResultsWe found a total of 1,519 interictal FOs that fulfilled both the spectral and waveform criteria. The FOs with a median frequency of 56.6Hz (range=41.0-140.6Hz) were dense, with a median rate of 66 (range=24-171) per minute before adrenocorticotropic hormone (ACTH) treatment, which was significantly higher than that in control infants without seizures (median=1, p<0.001). The FOs were reduced by treatment. The mean gamma and ripple oscillation rates that were detected using the waveform criterion alone were 40.62/min and 15.75/min, respectively, per channel; these results were 112.8 and 98.4 times higher, respectively, than the previously reported corresponding rates in adult epilepsy patients.
InterpretationThe observed FOs corresponded to epileptogenicity because of their close relation to the severity of hypsarrhythmia during the course of ACTH treatment. The very high epileptic FO rates in hypsarrhythmia are thought to affect the process of neurodevelopment by interfering with physiological functions in West syndrome, taking into account that high frequencies are also important in physiological higher brain functions. ANN NEUROL 2015;77:58-67

DOI： 10.1002/ana.24299

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

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

Yamamoto T, Shimojima K, Shibata T, Akiyama M, Oka M, Akiyama T, Yoshinaga H, Kobayashi K

Human genome variation 2 15048 - 15048 2015

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

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

Interictal high frequency oscillations correlating with seizure outcome in patients with widespread epileptic networks in tuberous sclerosis complex Reviewed

Tohru Okanishi, Tomoyuki Akiyama, Shin-Ichi Tanaka, Ellen Mayo, Ayu Mitsutake, Cyrus Boelman, Cristina Go, O. Carter Snead, James Drake, James Rutka, Ayako Ochi, Hiroshi Otsubo

EPILEPSIA 55 ( 10 ) 1602 - 1610 2014.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

ObjectiveMultiple tubers in patients with tuberous sclerosis complex (TSC) often are responsible for drug-resistant epilepsy. The complexity of the epileptic network formed by multiple tubers complicates localization of the epileptogenic zone that is needed to design a surgical treatment strategy. High frequency oscillations (HFOs) on intracranial video-electroencephalography (IVEEG) may be a valuable surrogate marker for the localization of the epileptogenic zone. The purpose of this study was to test the hypothesis that high occurrence rate (OR) of interictal HFOs can guide the localization of the epileptogenic zone.
MethodsWe analyzed the OR of interictal HFOs at 80-200Hz (ripples) and >200Hz (fast ripples, FRs). We divided OR of interictal HFOs between high and low rates by thresholding. We analyzed the correlation between seizure outcomes using Engel classification and the resection ratio of the seizure onset zone (SOZ), and high-OR HFOs using ordinal logistic regression analysis.
ResultsWe collected 10 patients. The seizure outcomes resulted in Engel classification I in three patients, II in four, III in one, and IV in two. High-OR ripples (5-57 [mean 29] channels, 1-4 [2.8] lobes) and high-OR FRs (9-66 [mean 27] channels, 1-4 [2.6] lobes) were widely distributed. The resection ratio of SOZ did not show statistically significant correlation with the seizure outcome. The resection ratio of high-OR ripples showed statistically significant correlation with the seizure outcome (p=0.038). The resection ratio of high-OR FRs showed statistically significant correlation with the seizure outcome (p=0.048).
SignificanceThe multiple extensive zones with high-OR HFOs suggest a complex and widespread epileptic network in patients with TSC. In a subset of TSC patients with drug-resistant epilepsy, resection of cortex with both interictal high-OR FRs and ripples on IVEEG correlated with a good seizure outcome.

DOI： 10.1111/epi.12761

Five pediatric cases of ictal fear with variable outcomes Reviewed

Mari Akiyama, Katsuhiro Kobayashi, Takushi Inoue, Tomoyuki Akiyama, Harumi Yoshinaga

BRAIN & DEVELOPMENT 36 ( 9 ) 758 - 763 2014.10

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

Purpose: Ictal fear is an uncommon condition in which fear manifests as the main feature of epileptic seizures. The literature has suggested that ictal fear is generally associated with poor seizure outcomes. We wanted to clarify the variability in seizure outcome of children with ictal fear. Subjects and methods: We identified five pediatric patients with ictal fear who were followed up on at Okayama University Hospital between January 2003 and December 2012. We retrospectively reviewed their clinical records and EEG findings. Results: The onset age of epilepsy ranged from 8 months to 9 years and 10 months. The common ictal symptoms were sudden fright, clinging to someone nearby, and subsequent impairment of consciousness, which were often accompanied by complex visual hallucinations and psychosis-like complaints. Ictal fear, in four patients, was perceived as a nonepileptic disorder by their parents. Ictal electroencephalograms (EEG) of ictal fear were obtained in all patients. Three showed frontal onset, while the other two showed centrotemporal or occipital onsets. Two patients were seizure free at last follow-up, while seizures persisted in the other three. A patient with seizure onset during infancy had a favorable outcome, which was considered to be compatible with benign partial epilepsy with affective symptoms. Conclusion: Ictal fear is not always associated with a symptomatic cause or a poor seizure outcome. It is quite important to make a correct diagnosis of ictal fear as early as possible to optimize treatment. (C) 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2013.11.011

極めて難治のてんかん重積状態を来たし、外科的介入が成功した皮質形成異常の1例

井上拓志, 林裕美子, 岡牧郎, 秋山倫之, 中尻智史, 吉永治美, 小林勝弘

てんかん研究 32 ( 1 ) 57 - 58 2014.6

緊急少数電極脳波のトレンド表示は脳波非習熟者における判読精度を向上させるか?

柚木宏介, 禅正和真, 小林勝弘, 秋山倫之, 吉永治美

日本小児科学会雑誌 118 ( 5 ) 849 - 849 2014.5

Genotype-phenotype correlations in alternating hemiplegia of childhood Reviewed

Masayuki Sasaki, Atsushi Ishii, Yoshiaki Saito, Naoya Morisada, Kazumoto Iijima, Satoshi Takada, Atsushi Araki, Yuko Tanabe, Hidee Arai, Sumimasa Yamashita, Tsukasa Ohashi, Yoichiro Oda, Hiroshi Ichiseki, Shininchi Hirabayashi, Akihiro Yasuhara, Hisashi Kawawaki, Sadami Kimura, Masayuki Shimono, Seiro Narumiya, Motomasa Suzuki, Takeshi Yoshida, Yoshinobu Oyazato, Shuichi Tsuneishi, Shiro Ozasa, Kenji Yokochi, Sunao Dejima, Tomoyuki Akiyama, Nobuyuki Kishi, Ryutaro Kira, Toshio Ikeda, Hirokazu Oguni, Bo Zhang, Shoji Tsuji, Shinichi Hirose

NEUROLOGY 82 ( 6 ) 482 - 490 2014.2

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Objective:Clinical severity of alternating hemiplegia of childhood (AHC) is extremely variable. To investigate genotype-phenotype correlations in AHC, we analyzed the clinical information and ATP1A3 mutations in patients with AHC.Methods:Thirty-five Japanese patients who were clinically diagnosed with AHC participated in this study. ATP1A3 mutations were analyzed using Sanger sequencing. Detailed clinical information was collected from family members of patients with AHC and clinicians responsible for their care.Results:Gene analysis revealed 33 patients with de novo heterozygous missense mutations of ATP1A3: Glu815Lys in 12 cases (36%), Asp801Asn in 10 cases (30%), and other missense mutations in 11 cases. Clinical information was compared among the Glu815Lys, Asp801Asn, and other mutation groups. Statistical analysis revealed significant differences in the history of neonatal onset, gross motor level, status epilepticus, and respiratory paralysis in the Glu815Lys group compared with the other groups. In addition, 8 patients who did not receive flunarizine had severe motor deteriorations.Conclusions:The Glu815Lys genotype appears to be associated with the most severe AHC phenotype. Although AHC is not generally seen as a progressive disorder, it should be considered a disorder that deteriorates abruptly or in a stepwise fashion, particularly in patients with the Glu815Lys mutation.

DOI： 10.1212/WNL.0000000000000102

グアニジノ酢酸メチルトランスフェラーゼ欠損症の一症例治療経過報告

秋山倫之, 小坂仁, 新保裕子, 中尻智史, 小林勝弘, 岡牧郎, 遠藤文香, 吉永治美

日本小児科学会雑誌 118 ( 2 ) 258 - 258 2014.2

Dynamic modulation of epileptic high frequency oscillations by the phase of slower cortical rhythms Reviewed

George M. Ibrahim, Simeon M. Wong, Ryan A. Anderson, Gabrielle Singh-Cadieux, Tomoyuki Akiyama, Ayako Ochi, Hiroshi Otsubo, Tohru Okanishi, Taufik A. Valiante, Elizabeth Donner, James T. Rutka, O. Carter Snead, Sam M. Doesburg

EXPERIMENTAL NEUROLOGY 251 30 - 38 2014.1

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

Pathological high frequency oscillations (pHFOs) have been proposed to be robust markers of epileptic cortex. Oscillatory activity below this frequency range has been shown to be modulated by phase of lower frequency oscillations. Here, we tested the hypothesis that dynamic cross-frequency interactions involving pHFOs are concentrated within the epileptogenic cortex. Intracranial electroencephalographic recordings from 17 children with medically-intractable epilepsy secondary to focal cortical dysplasia were obtained. A time-resolved analysis was performed to determine topographic concentrations and dynamic changes in cross-frequency amplitude-to-phase coupling (CFC). CFC between pHFOs and the phase of theta and alpha rhythms was found to be significantly elevated in the seizure-onset zone compared to non-epileptic regions (p < 0.01). Data simulations showed that elevated CFC could not be attributed to the presence of sharp transients or other signal properties. The phase of low frequency oscillations at which pHFO amplitudes were maximal was inconsistent at seizure initiation, yet consistently at the trough of the low frequency rhythm at seizure termination. Amplitudes of pHFOs were most significantly modulated by the phase of alpha-band oscillations (p < 0.01). These results suggest that increased CFC between pHFO amplitude and alpha phase may constitute a marker of epileptogenic brain areas and may be relevant for understanding seizure dynamics. (C) 2013 Elsevier Inc All rights reserved.

DOI： 10.1016/j.expneurol.2013.10.019

CSF/plasma ratios of amino acids: Reference data and transports in children Reviewed

Tomoyuki Akiyama, Katsuhiro Kobayashi, Akihito Higashikage, Junko Sato, Harumi Yoshinaga

BRAIN & DEVELOPMENT 36 ( 1 ) 3 - 9 2014.1

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

Objective: We intended to investigate the effects of age, gender, and medications on amino acid cerebrospinal fluid (CSF)/plasma ratios in children, and to determine whether amino acid transports across the blood CSF barrier in children differ from those in adults. Patients and methods: Amino acid concentrations measured by ion-exchange high-performance liquid chromatography were used (CSF from 99 children, simultaneously collected plasma from 76 children). Influence of age, gender, and medications on the amino acid CSF concentrations and CSF/plasma ratios were analyzed by linear multiple regression. Interactions of amino acid transports were analyzed by correlation analysis of CSF/plasma ratios. Results: CSF/plasma ratios of serine, valine, histidine, and arginine were higher in younger children. The glutamate CSF/plasma ratio was higher in older children. Serine, alanine, threonine, valine, and histidine CSF/plasma ratios were lower in females. Glutamine, methionine, tyrosine, and phenylalanine CSF/plasma ratios were elevated with valproate therapy. Serine, threonine, valine, leucine, and tyrosine CSF/plasma ratios were lower with clobazam therapy. The asparagine CSF/plasma ratio was elevated with pyridoxal phosphate therapy. Transports of most essential neutral amino acids interacted with each other, as did neutral amino acids with low molecular weights. Cationic amino acids interacted with each other and some essential neutral amino acids. Acidic amino acids had no interactions with other amino acids. Conclusions: Age, gender, and anti-epileptic drugs affect amino acid CSF/plasma ratios in children. Transport interactions between amino acids in children showed no remarkable difference from those of adults and generally followed the substrate specificities of multiple amino acid transport systems. (C) 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2012.12.001

A Japanese adult case of guanidinoacetate methyltransferase deficiency. Reviewed International journal

Akiyama T, Osaka H, Shimbo H, Nakajiri T, Kobayashi K, Oka M, Endoh F, Yoshinaga H

JIMD reports 12 65 - 69 2014

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

Guanidinoacetate methyltransferase (GAMT) deficiency is a rare disorder of creatine synthesis resulting in cerebral creatine depletion. We present a 38-year-old patient, the first Japanese case of GAMT deficiency. Developmental delay started after a few months of age with a marked delay in language, which resulted in severe intellectual deficit. She showed hyperactivity and trichotillomania from childhood. Epileptic seizures appeared at 18 months and she had multiple types of seizures including epileptic spasms, brief tonic seizures, atypical absences, complex partial seizures with secondary generalization, and "drop" seizures. They have been refractory to multiple antiepileptic drugs. Although there have been no involuntary movements, magnetic resonance imaging revealed T2 hyperintense lesions in bilateral globus pallidi. Motor regression started around 30 years of age and the patient is now able to walk for only short periods. Very low serum creatinine levels measured by enzymatic method raised a suspicion of GAMT deficiency, which was confirmed by proton magnetic resonance spectroscopy and urinary guanidinoacetate assay. GAMT gene analysis revealed that the patient is a compound heterozygote of c.578A>G, p.Gln193Arg and splice site mutation, c.391G>C, p.Gly131Arg, neither of which have been reported in the literature. We also identified two aberrant splice products from the patient's cDNA analysis. The patient was recently started on supplementation of high-dose creatine and ornithine, the effects of which are currently under evaluation. Although rare, patients with developmental delay, epilepsy, behavioral problems, and movement disorders should be vigorously screened for GAMT deficiency, as it is a treatable disorder.

DOI： 10.1007/8904_2013_245

Neocortical pathological high-frequency oscillations are associated with frequency-dependent alterations in functional network topology Reviewed

George M. Ibrahim, Ryan Anderson, Tomoyuki Akiyama, Ayako Ochi, Hiroshi Otsubo, Gabrielle Singh-Cadieux, Elizabeth Donner, James T. Rutka, O. Carter Snead, Sam M. Doesburg

JOURNAL OF NEUROPHYSIOLOGY 110 ( 10 ) 2475 - 2483 2013.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

Synchronization of neural oscillations is thought to integrate distributed neural populations into functional cell assemblies. Epilepsy is widely regarded as a disorder of neural synchrony. Knowledge is scant, however, regarding whether ictal changes in synchrony involving epileptogenic cortex are expressed similarly across various frequency ranges. Cortical regions involved in epileptic networks also exhibit pathological high-frequency oscillations (pHFOs, >80 Hz), which are increasingly utilized as biomarkers of epileptogenic tissue. It is uncertain how pHFO amplitudes are related to epileptic network connectivity. By calculating phase-locking values among intracranial electrodes implanted in children with intractable epilepsy, we constructed ictal connectivity networks and performed graph theoretical analysis to characterize their network properties at distinct frequency bands. Ictal data from 17 children were analyzed with a hierarchical mixed-effects model adjusting for patient-level covariates. Epileptogenic cortex was defined in two ways: 1) a hypothesis-driven method using the visually defined seizure-onset zone and 2) a data-agnostic method using the high-frequency amplitude of each electrode. Epileptogenic cortex exhibited a logarithmic decrease in interregional functional connectivity at high frequencies (>30 Hz) during seizure initiation and propagation but not at termination. At slower frequencies, conversely, epileptogenic cortex expressed a relative increase in functional connectivity. Our findings suggest that pHFOs reflect epileptogenic network interactions, yielding theoretical support for their utility in the presurgical evaluation of intractable epilepsy. The view that abnormal network synchronization plays a critical role in ictogenesis and seizure dynamics is supported by the observation that functional isolation of epileptogenic cortex at high frequencies is absent at seizure termination.

DOI： 10.1152/jn.00034.2013

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

Cortical contribution to scalp EEG gamma rhythms associated with epileptic spasms Reviewed

Katsuhiro Kobayashi, Kazushi Miya, Tomoyuki Akiyama, Fumika Endoh, Makio Oka, Harumi Yoshinaga, Yoko Ohtsuka

BRAIN & DEVELOPMENT 35 ( 8 ) 762 - 770 2013.9

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

The cortical contribution for the generation of gamma rhythms detected from scalp ictal EEG was studied in unique cases of epileptic spasms and a review of the related literature was conducted. Ictal scalp gamma rhythms were investigated through time frequency analysis in two cases with a combination of focal seizures and spasms and another case with spasms associated with cortical dysplasia. In the two patients with combined seizures, the scalp distribution of ictal gamma rhythms was related to that of focal seizure activity. In the third patient, an asymmetric distribution of the ictal scalp gamma rhythms was transiently revealed in correspondence to the dysplasic cortex during hormonal treatment. Therefore, the dominant region of scalp gamma rhythms may correspond to the epileptogenic cortical area. The current findings have reinforced the possibility of the cortical generation of ictal scalp gamma rhythms associated with spasms The detection of high frequencies through scalp EEG is a technical challenge, however, and the clinical significance of scalp gamma rhythms may not be the same as that of invasively recorded high frequencies. Further studies on the pathophysiological mechanisms related to the generation of spasms involving high frequencies are necessary in the future, and the development of animal models of spasms will play an important role in this regard. (C) 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2012.12.012

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

後方1/4離断術が奏功した大田原症候群の一例

上利崇, 近藤聡彦, 秋山倫之, 林裕美子, 桃木恵美子, 井上拓志, 岡牧郎, 小林勝弘, 佐々木達也, 金恭平, 伊達勲

てんかん研究 31 ( 1 ) 90 - 91 2013.6

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

Disruption of Rolandic Gamma-Band Functional Connectivity by Seizures is Associated with Motor Impairments in Children with Epilepsy Reviewed

George M. Ibrahim, Tomoyuki Akiyama, Ayako Ochi, Hiroshi Otsubo, Mary Lou Smith, Margot J. Taylor, Elizabeth Donner, James T. Rutka, O. Carter Snead, Sam M. Doesburg

PLOS ONE 7 ( 6 ) e39326 2012.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Although children with epilepsy exhibit numerous neurological and cognitive deficits, the mechanisms underlying these impairments remain unclear. Synchronization of oscillatory neural activity in the gamma frequency range (>30 Hz) is purported to be a mechanism mediating functional integration within neuronal networks supporting cognition, perception and action. Here, we tested the hypothesis that seizure-induced alterations in gamma synchronization are associated with functional deficits. By calculating synchrony among electrodes and performing graph theoretical analysis, we assessed functional connectivity and local network structure of the hand motor area of children with focal epilepsy from intracranial electroencephalographic recordings. A local decrease in inter-electrode phase synchrony in the gamma bands during ictal periods, relative to interictal periods, within the motor cortex was strongly associated with clinical motor weakness. Gamma-band ictal desychronization was a stronger predictor of deficits than the presence of the seizure-onset zone or lesion within the motor cortex. There was a positive correlation between the magnitude of ictal desychronization and impairment of motor dexterity in the contralateral, but not ipsilateral hand. There was no association between ictal desynchronization within the hand motor area and non-motor deficits. This study uniquely demonstrates that seizure-induced disturbances in cortical functional connectivity are associated with network-specific neurological deficits.

DOI： 10.1371/journal.pone.0039326

Occipital lobe epilepsy in children: Characterization, evaluation and surgical outcomes Reviewed

George M. Ibrahim, Aria Fallah, Gregory W. Albert, Teresa Withers, Hiroshi Otsubo, Ayako Ochi, Tomoyuki Akiyama, Elizabeth J. Donner, Shelly Weiss, O. Carter Snead, James M. Drake, James T. Rutka

EPILEPSY RESEARCH 99 ( 3 ) 335 - 345 2012.5

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

Introduction: Occipital lobe epilepsy (OLE) poses a diagnostic challenge to clinicians. Here, we present our experience in the surgical management of OLE in children using magnetoencephalography (MEG) in the pre-operative evaluation.
Methods: Retrospective chart review was performed from 2000 to 2010 to identify patients with OLE. Patients were analyzed in two categories: isolated OLE (11 patients) and extended OLE (parietooccipital, temporooccipital, and temporoparietooccipital; 30 patients). Survival analysis and multivariate Cox proportional hazards regression were used to identify independent predictors of seizure outcome.
Results: Forty-one patients with a mean follow-up of 3.1 years were identified with an overall 68% rate of satisfactory seizure outcome. Patients with extended OLE had younger ages at seizure onset and different seizure semiologies compared with those with isolated OLE. None of the latter underwent insertion of subdural grid electrodes for localization of the epileptogenic zone compared with 77% of the former (p < 0.001). On multivariate analysis, the strongest independent predictor of unsatisfactory outcome was MEG dipoles in the occipital lobe contralateral to resection.
Conclusion: Here, we find similar seizure outcomes for isolated and extended OLE foci despite the use of less invasive strategies for the former. Furthermore, we describe the role of MEG in evaluation, surgical planning and prognostication of children with OLE. (C) 2012 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.eplepsyres.2011.12.015

Histopathology of cortex and white matter in pediatric epileptic spasms: Comparison with those of partial seizures Reviewed

Yukiko Inage, William C. Halliday, Cristina Go, Ayako Ochi, Tomoyuki Akiyama, Mari Akiyama, Elysa Widjaja, Hiroshi Otsubo

BRAIN & DEVELOPMENT 34 ( 2 ) 118 - 123 2012.2

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

Epileptic spasms in older children have increasingly been recognized as a distinct seizure type and subset of these patients are considered for surgical resection. This study compares histopathology and magnetic resonance imaging (MRI), especially focusing the difference between the cortical grey matter and the subcortical white matter to understand the extensive epileptic brain in patients with epileptic spasms. We examined 22 patients consisting of 11 patients with epileptic spasms and 11 with partial seizures. Scalp video electroencephalography (EEG) showed interictal generalized epileptiform discharges (9 patients with epileptic spasms vs. 1 with partial seizures) and ictal generalized epileptiform discharges (10 vs. 3). We found MRI abnormalities in a single lobe (6 vs. 7) and multiple lobes (2 vs. 1). Surgical resections were performed across multiple lobes (9 vs. 2), comparing within a single lobe (2 vs. 9), (p < 0.001). Histopathology showed abnormal cortical organizations as FCD (2 vs. 5) and microdysgenesis (4 vs. 4), normal (4 vs. 1). Two patients with epileptic spasms showed hyaline proteoplasmic astrocytopathy. There were heterotopic neurons (10 vs. 10), cluster of oligodendroglia (8 vs. 7), balloon cells (2 vs. 5) and blurred myelination (1 vs. 4), in the white matter. Seizure-free outcomes were seen in seven patients with epileptic spasms (64%) and four with partial seizures (36%). The multilobar epileptogenic zones existed in patients with epileptic spasms, compared with the focal epileptogenic zone in patients with partial seizures. There was no difference of MRI and histopathology findings in cortex and subcortical white matter between two groups. (C) 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2011.03.009

High kurtosis of intracranial electroencephalogram as a marker of ictogenicity in pediatric epilepsy surgery Reviewed

Tomoyuki Akiyama, Makoto Osada, Masahide Isowa, Cristina Y. Go, Ayako Ochi, Irene M. Elliott, Mari Akiyama, O. Carter Snead, James T. Rutka, James M. Drake, Hiroshi Otsubo

CLINICAL NEUROPHYSIOLOGY 123 ( 1 ) 93 - 99 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Objective: We determined whether kurtosis analysis of intracranial electroencephalogram (EEG) can estimate the localization of the epileptogenic zone.
Methods: We analyzed 29 pediatric epilepsy patients who underwent intracranial EEG before focal resective surgery. We localized the brain regions with high kurtosis, the seizure onset zone (SOZ) and the regions with high-rate, high-amplitude and long-duration interictal paroxysms >= 20 Hz. We tested correlations between the surgical resection of those regions and post-surgical seizure outcome, and correlations between kurtosis and the rate/amplitude/duration of interictal paroxysms.
Results: The resection of the regions with high kurtosis correlated with 1-year post-surgical seizure outcome (p = 0.028) but not with 2-year outcome. Kurtosis showed more significant correlation with 1-year seizure outcome than the SOZ and the rate/amplitude/duration of interictal paroxysms. Kurtosis showed positive, independent correlations with the amplitude and duration of interictal paroxysms (p < 0.0001) but not with the rate (p = 0.4).
Conclusions: The regions with high kurtosis provide more reliable information to predict seizure outcome than the SOZ and the regions with high-rate/amplitude and long-duration interictal paroxysms. Kurtosis reflects combined effects of the amplitude and duration of the interictal paroxysms.
Significance: High kurtosis suggests the regions with acquired ictogenicity within the irritative zone. (C) 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.clinph.2011.05.026

Lateralized interictal epileptiform discharges during rapid eye movement sleep correlate with epileptogenic hemisphere in children with intractable epilepsy secondary to tuberous sclerosis complex Reviewed

Ayako Ochi, Ryan Hung, Shelly Weiss, Elysa Widjaja, Tonia To, Yoshihiro Nawa, Taiki Shima, Cristina Go, Tomoyuki Akiyama, Elizabeth Donner, James Drake, James T. Rutka, O. Carter Snead, Hiroshi Otsubo

EPILEPSIA 52 ( 11 ) 1986 - 1994 2011.11

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Purpose: We assessed lateralization of interictal epileptiform discharges (IEDs) in children with intractable epilepsy secondary to tuberous sclerosis complexes (TSCs) during rapid eye movement sleep (R), compared with non-rapid eye movement sleep (NR) and wakefulness (W), to determine epileptogenicity of R-IEDs.
Methods: We retrospectively studied 23 children with TSC, who underwent prolonged scalp video-electroencephalography (EEG) and magnetic resonance imaging (MRI). We determined the lateralization of ictal EEG, clinical semiology, and the largest tuber on MRI. We analyzed a minimum of 100 IEDs during R, NR, and W to classify right/left/generalized spikes to compare the lateralization with ictal EEG, clinical semiology, and MRI.
Key Findings: R-IEDs were lateralized in 22 patients (96%), W-IEDs in 19 (83%), and NR-IEDs in 16 (70%). Ictal EEGs were lateralized in 15 patients (65%) and clinical semiology in 5 (22%). Ictal EEG lateralization was concordant to R-IEDs in 14 patients (93%), W-IEDs in 11 (73%), and NR-IEDs in 10 (67%). The lateralization of clinical semiology was concordant with R-IEDs in 4 (80%), W-IEDs in 3 (60%), and NR-IEDs in 2 (40%). MRI lateralization of the largest tuber was concordant with R-IEDs in 16 (70%), W-IEDs in 12 (52%), and NR-IEDs in 11 (48%). Thirteen patients (57%) underwent resective surgery, the hemisphere of which was concordant with R-IEDs in 13 (100%), W-IEDs in 8 (62%), and NR-IEDs in 8 (62%). Nine (69%) of them achieved good seizure control after surgery.
Significance: R provoked the most lateralized IEDs compared to NR and W in children with TSC. Lateralization of R-IEDs corresponded with the hemisphere of ictal EEG and largest tuber, and can be used to identify surgical candidacy in TSC children with intractable epilepsy.

DOI： 10.1111/j.1528-1167.2011.03198.x

Fast activity during EEG seizures in neonates Reviewed

Lakshmi Nagarajan, Soumya Ghosh, Linda Palumbo, Tomoyuki Akiyama, Hiroshi Otsubo

EPILEPSY RESEARCH 97 ( 1-2 ) 162 - 169 2011.11

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

Introduction: Paroxysmal fast activity (FA) has been proposed as a marker for epileptic networks. We explore the presence and significance of ictal FA on scalp video EEG seizures (EEG Sz) recorded in neonates.
Methodology: Forty two babies had 159 EEG Szs. The seizures were analysed for ictal FA, using a low frequency filter of 30 Hz. We explored the relationship of ictal FA to the occurrence of electroclinical and electrographic seizures, the use of phenobarbitone and to neurodevelopmental outcomes.
Results: Ictal FA occurred in 62 (39%) of the 159 EEG Szs. In the 62 seizures with ictal FA, 34 (55%) were electroclinical seizures (ECSz) and 28 (45%) were electrographic (ESz). In the remaining 97 seizures without ictal FA, 27 (28%) were ECSz and 70 (72%) ESz. There was a significant correlation (p=0.0006) between ictal FA and electroclinical seizures. There was no relationship between phenobarbitone and presence of ictal FA. There was no significant difference in the background EEG, neuroimaging abnormalities, neurodevelopmental impairment or post neonatal seizures between those with and without ictal FA.
Conclusions: Ictal FA is highly correlated to the occurrence of clinical features during an EEG seizure. The presence of ictal FA does not appear to influence neurodevelopmental outcomes. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.eplepsyres.2011.08.003

Focal resection of fast ripples on extraoperative intracranial EEG improves seizure outcome in pediatric epilepsy Reviewed

Tomoyuki Akiyama, Blathnaid McCoy, Cristina Y. Go, Ayako Ochi, Irene M. Elliott, Mari Akiyama, Elizabeth J. Donner, Shelly K. Weiss, O. Carter Snead, James T. Rutka, James M. Drake, Hiroshi Otsubo

EPILEPSIA 52 ( 10 ) 1802 - 1811 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Purpose: High-frequency oscillations (HFOs), termed ripples at 80-200 Hz and fast ripples (FRs) at >200/250 Hz, recorded by intracranial electroencephalography (EEG), may be a valuable surrogate marker for the localization of the epileptogenic zone. We evaluated the relationship of the resection of focal brain regions containing high-rate interictal HFOs and the seizure-onset zone (SOZ) determined by visual EEG analysis with the postsurgical seizure outcome, using extraoperative intracranial EEG monitoring in pediatric patients and automated HFO detection.
Methods: We retrospectively analyzed 28 pediatric epilepsy patients who underwent extraoperative intracranial video-EEG monitoring prior to focal resection. Utilizing the automated analysis, we identified interictal HFOs during 20 min of sleep EEG and determined the brain regions containing high-rate HFOs. We investigated spatial relationships between regions with high-rate HFOs and SOZs. We compared the size of these regions, the surgical resection, and the amount of the regions with high-rate HFOs/SOZs within the resection area with seizure outcome.
Key Findings: Ten patients were completely seizure-free and 18 were not at 2 years after surgery. The brain regions with high-rate ripples were larger than those with high-rate FRs (p = 0.0011) with partial overlap. More complete resection of the regions with high-rate FRs significantly correlated with a better seizure outcome (p = 0.046). More complete resection of the regions with high-rate ripples tended to improve seizure outcome (p = 0.091); however, the resection of SOZ did not influence seizure outcome (p = 0.18). The size of surgical resection was not associated with seizure outcome (p = 0.22-0.39).
Significance: The interictal high-rate FRs are a possible surrogate marker of the epileptogenic zone. Interictal ripples are not as specific a marker of the epileptogenic zone as interictal FRs. Resection of the brain regions with high-rate interictal FRs in addition to the SOZ may achieve a better seizure outcome.

DOI： 10.1111/j.1528-1167.2011.03199.x

非定型良性小児部分てんかん診断における脳磁図検査の有用性 Reviewed

白石秀明, 萩野谷和裕, 中川栄二, 香坂忍, 金子裕, 須貝研司, 植松貢, 柿坂庸介, 中里信和, 花谷亮典, 秋山倫之, 齋藤伸治, 大坪宏

てんかん研究 29 ( 2 ) 337 - 337 2011.9

Jeavons syndrome existing as occipital cortex initiating generalized epilepsy Reviewed

Sorawit Viravan, Cristina Go, Ayako Ochi, Tomoyuki Akiyama, O. Carter Snead, Hiroshi Otsubo

EPILEPSIA 52 ( 7 ) 1273 - 1279 2011.7

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Purpose: Jeavons syndrome (JS) is one of the underreported epileptic syndromes characterized by eyelid myoclonia (EM), eye closure-induced seizures/electroencephalography (EEG) paroxysms, and photosensitivity. JS has been proposed as idiopathic generalized epilepsy (IGE) because of normal posterior dominant background activity and paroxysmal generalized ictal epileptiform discharges (EDs). However, we noticed subtle occipital EDs preceding EM and interictal posterior EDs using digital video-EEG. We studied clinical and EEG findings in JS to determine the specific occipital lobe relation to this "eye closure-induced'' reflex IGE.
Methods: We identified 12 children who met the diagnostic criteria of JS from January 2004 to April 2009 at the Hospital for Sick Children, Toronto, Canada. All patients had EM captured by video-EEG. We reviewed and described ictal EEG patterns, interictal abnormalities, and demographics, clinical, and neuroimaging findings.
Key Findings: All patients but one were female (92%). Age at seizure onset ranged from 1.5 to 9 years, with a mean age of 4.9 years. Six patients (50%) were previously diagnosed as having absence epilepsy and 10 patients were on antiepileptic medications. All 12 patients had normal posterior dominant alpha rhythm, reactive to eye opening and closure. Spiky posterior alpha activity was noted with sustained eye closure in six patients (50%). Interictally, there were generalized EDs found in 10 patients (83%); four of them also had focal interictal EDs over the posterior head region. Eleven patients (92%) had evidence of focal posterior ictal EDs. EM and/or paroxysmal EDs were induced by photic stimulation in 9 (75%) and hyperventilation in 7 (58%).
Significance: We observed two neurophysiologic findings in JS: (1) focal interictal EDs from posterior head region; and (2) predominant focal posterior ictal EDs preceding generalized EDs. Further clinical observations of seizures induced by eye closure, photic stimulation, and hyperventilation along with EEG paroxysms would raise the possibility of the occipital cortex initiating generalized epilepsy network involving the brainstem, and thalamocortical and transcortical pathways in JS.

DOI： 10.1111/j.1528-1167.2011.03068.x

Focal-onset myoclonic seizures and secondary bilateral synchrony Reviewed

Tomoyuki Akiyama, Elizabeth J. Donner, Cristina Y. Go, Ayako Ochi, O. Carter Snead, James T. Rutka, Hiroshi Otsubo

EPILEPSY RESEARCH 95 ( 1-2 ) 168 - 172 2011.6

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

We present a child with myoclonic seizures, epileptic spasms and generalized epileptiform discharges on scalp EEG. Magnetoencephalography and coherence-phase analysis for scalp EEG suggested focal onset in the left hemisphere. Intracranial video EEG confirmed seizure onset in the left frontal lobe with ictal high-frequency oscillations. Left frontal lobectomy suppressed his seizures. Subsets of myoclonic seizures can be focal in origin despite bilaterally synchronized epileptiform discharges on scalp EEG. (c) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.eplepsyres.2011.02.006

Autoimmune Limbic Encephalitis as an Emerging Pediatric Condition: Case Report and Review of the Literature Reviewed

Blathnaid McCoy, Tomoyuki Akiyama, Elysa Widjaja, Cristina Go

JOURNAL OF CHILD NEUROLOGY 26 ( 2 ) 218 - 222 2011.2

Language：English Publisher：SAGE PUBLICATIONS INC

Limbic encephalitis, first described in the 1960s as a paraneoplastic condition, has emerged as an autoimmune condition, occurring often without evidence of an underlying tumor. Many novel autoantibodies have been identified, and this diagnosis is increasingly being made in the pediatric population. This article reports the case of a 16-year-old boy who presented following gastrointestinal illness with subacute evolution of neuropsychiatric symptoms. Brain magnetic resonance imaging revealed progressive hippocampal signal abnormality and swelling. N-methyl-D-aspartate (NMDA) receptor antibody was detected in serum. The patient responded well to pharmacological immunotherapy but has residual cognitive deficits. The available literature on this condition is reviewed. Limbic encephalitis should be considered in the differential diagnosis in children presenting with encephalopathy, particularly with neuropsychiatric manifestations. Long-term surveillance and close follow-up are required to accurately clarify tumor risk and natural history of this condition in children and balance these factors with risks of radiation exposure through imaging.

DOI： 10.1177/0883073810378536

Topographic movie of intracranial ictal high-frequency oscillations with seizure semiology: Epileptic network in Jacksonian seizures Reviewed

Tomoyuki Akiyama, Derrick W. Chan, Cristina Y. Go, Ayako Ochi, Irene M. Elliott, Elizabeth J. Donner, Shelly K. Weiss, O. Carter Snead, James T. Rutka, James M. Drake, Hiroshi Otsubo

EPILEPSIA 52 ( 1 ) 75 - 83 2011.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

P>Purpose:
We developed a technique to produce images of dynamic changes in ictal high-frequency oscillations (HFOs) > 40 Hz recorded on subdural electroencephalography (EEG) that are time-locked to the ictal EEG and ictal semiology video. We applied this technique to Jacksonian seizures to demonstrate ictal HFO propagation along the homunculus in the primary sensory-motor cortex to visualize the underlying epileptic network.
Methods:
We analyzed intracranial ictal EEGs from two patients with intractable Jacksonian seizures who underwent epilepsy surgery. We calculated the degrees of increase in amplitude within 40-80, 80-200, and 200-300 Hz frequency bands compared to the interictal period and converted them into topographic movies projected onto the brain surface picture. We combined these data with the ictal EEGs and video of the patient demonstrating ictal semiology.
Key Findings:
The ictal HFOs began in the sensory cortex and appeared concomitantly with the sensory aura. They then propagated to the motor cortex at the same time that focal motor symptoms evolved. As the seizure progressed, the ictal HFOs spread or reverberated in the rolandic region. However, even when the seizure became secondarily generalized, the ictal HFOs were confined to the rolandic region. In both cases, there was increased amplitude of higher frequency bands during seizure initiation compared to seizure progression.
Significance:
This combined movie showed the ictal HFO propagation corresponding to the ictal semiology in Jacksonian seizures and revealed the epileptic network involved in seizure initiation and progression. This method may advance understanding of neural network activities relating to clinical seizure generation and propagation.

DOI： 10.1111/j.1528-1167.2010.02776.x

Cortical Gamma-Oscillations Modulated by Auditory-Motor Tasks-Intracranial Recording in Patients With Epilepsy Reviewed

Tetsuro Nagasawa, Robert Rothermel, Csaba Juhasz, Miho Fukuda, Masaaki Nishida, Tomoyuki Akiyama, Sandeep Sood, Eishi Asano

HUMAN BRAIN MAPPING 31 ( 11 ) 1627 - 1642 2010.11

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Human activities often involve hand-motor responses following external auditory verbal commands It has been believed that hand movements are predominantly driven by the contralateral primary sensorimotor cortex, whereas auditory-verbal information is processed in both superior temporal gyn. It remains unknown whether cortical activation in the superior temporal gyrus during an auditory motor task is affected by laterality of hand-motor responses Here, event-related gamma-oscillations were intracranially recorded as quantitative measures of cortical activation; we determined how cortical structures were activated by auditory-cued movement Using each hand in 15 patients with focal epilepsy. Auditory-verbal stimuli elicited augmentation of gamma-oscillations in a posterior portion of the superior temporal gyrus, whereas hand-motor responses elicited gamma-augmentation in the pre- and postcentral gyn. The magnitudes of such gamma-augmentation in the superior temporal, precentral, and postcentral gyn were significantly larger when the hand contralateral to the recorded hemisphere was required to be used for motor responses, compared with when the ipsilateral hand was. The superior temporal gyrus in each hemisphere might play a greater pivotal role when the contralateral hand needs to be used for motor responses, compared with when the ipsilateral hand does. Hum Brain Mapp 31 1627-1642, 2010. (C) 2010 Wiley-Liss, Inc.

DOI： 10.1002/hbm.20963

Rapid oscillatory activity in delta brushes of premature and term neonatal EEG Reviewed

Derrick W. S. Chan, Madoka Yamazaki, Tomoyuki Akiyama, Bill Chu, Elizabeth J. Donner, Hiroshi Otsubo

BRAIN & DEVELOPMENT 32 ( 6 ) 482 - 486 2010.6

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

We compared frequency and power of neonatal EEG delta brush rapid oscillatory activity (ROA) using multiple band frequency analysis (MBFA) in three groups; pre-term (PT, post-conceptional age 33-35.6 weeks, n = 5); full-term (FT, 39.4-40.6 weeks, n = 5) and pre-term or full-term with phenobarbital exposure (PB, n = 5). Mean number of delta brushes analyzed was 29.4 (range 26-47) in PT, 20.8 (14-33) in FT and 20 (7-37) in PB. Mean frequency +/- standard deviation (s.d.) was 16.9 +/- 2.1 Hz (range 15-20 Hz) in PT, 17.3 +/- 1.9 Hz (15-20 Hz) in FT and 16.1 +/- 1.6 Hz (14-19 Hz) in PB. Mean power +/- s.d. was 22.9 +/- 6.2 mu V(2) (range 16-39 mu V(2)) in PT, 11.9 +/- 4.1 mu V(2) (7-19 mu V(2)) in FT and 17.1 +/- 6.2 mu V(2) (9-26 mu V(2)) in PB. Power was significantly higher in PT than FT (p < 0.005). Power after merging PB into respective PT (PT', n = 8) and FT (FT', n = 7) groups, remained significantly higher in PT' (mean +/- s.d. 21.8 +/- 7.4 mu V(2)) than FT' (11.4 +/- 3.6 mu V(2)) (p < 0.05). We characterise ROA in delta brushes in maturing neonates using MBFA, which may provide additional information for assessing future seizure recurrence and epilepsy risk. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2009.07.006

[Antiepileptic drugs in North America]. Reviewed

Akiyama T, Otsubo H

Brain and nerve = Shinkei kenkyu no shinpo 62 ( 5 ) 519 - 526 2010.5

What is the point of specifying Panayiotopoulos syndrome from a practical point of view? Reviewed

Eishi Asano, Tomoyuki Akiyama

BRAIN & DEVELOPMENT 32 ( 1 ) 2 - 3 2010.1

Localization of epileptic foci in children with intractable epilepsy secondary to multiple cortical tubers by using synthetic aperture magnetometry kurtosis Clinical article Reviewed

Ichiro Sugiyama, Katsumi Imai, Yu Yamaguchi, Ayako Ochi, Yoko Akizuki, Cristina Go, Tomoyuki Akiyama, O. Carter Snead, Tames T. Rutka, James M. Drake, Elysa Widjaja, Sylvester H. Chuang, Doug Cheyne, Hiroshi Otsubo

JOURNAL OF NEUROSURGERY-PEDIATRICS 4 ( 6 ) 515 - 522 2009.12

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC NEUROLOGICAL SURGEONS

Object. Magnetoencephalography (MEG) has been typically used to localize epileptic activity by modeling interictal activity as equivalent current dipoles (ECDs). Synthetic aperture magnetometry (SAM) is a recently developed adaptive spatial filtering algorithm for MEG that provides some advantages over the ECD approach. The SAM-kurtosis algorithm (also known as SAM[g2]) additionally provides automated temporal detection of spike sources by using excess kurtosis value (steepness of epileptic spike on virtual sensors). To evaluate the efficacy of the SAM(g2) method, the authors applied it to readings obtained in children with intractable epilepsy secondary to tuberous sclerosis complex (TSC), and compared them to localizations obtained with ECDs.
Methods. The authors studied 13 children with TSC (7 girls) whose ages ranged from 13 months to 16.3 years (mean 7.3 years). Video electroencephalography, MR imaging, and MEG studies were analyzed. A single ECD model was applied to localize ECD clusters. The SAM(g2) value was calculated at each SAM(g2) virtual voxel in the patient's MR imaging-defined brain volume. The authors defined the epileptic voxels of SAM(g2) (evSAM[g2]) as those with local peak kurtosis values higher than half of the maximum. A clustering of ECDs had to contain a 6 ECDs within 1 cm of each other, and a grouping of evSAM(g2)s had to contain a 3 evSAM(g2)s within 1 cm of each other. The authors then compared both ECD clusters and evSAM(g2) groups with the resection area and correlated these data with seizure outcome.
Results. Seizures started when patients were between 6 weeks and 8 years of age (median 6 months), and became intractable secondary to multiple tubers in all cases. Ictal onset on scalp video electroencephalography was lateralized in 8 patients (62%). The MEG studies showed multiple ECD clusters in 7 patients (54%). The SAM(g2) method showed multiple groups of epileptic voxels in 8 patients (62%). Colocalization of grouped evSAM(g2) with ECD clusters ranged from 20 to 100%, with a mean of 82%. Eight patients underwent resection of single (1 patient) and multiple (7 patients) lobes, with 6 patients achieving freedom from seizures. Of 8 patients who underwent surgery, in 7 the resection area covered ECD clusters and grouped evSAM(g2)s. In the remaining patient the resection area partially included the ECD cluster and grouped evSAM(g2)s. Six of the 7 patients became seizure free.
Conclusions. The combination of SAM(g2) and ECD analyses succeeded in localizing the complex epileptic zones in children with TSC who had intractable epilepsy secondary to multiple cortical tubers. For the subset of children with TSC who present with early-onset and nonlateralized seizures, MEG studies in which SAM(g2) and ECD are used might identify suitable candidates for resection to control seizures. (DOI: 10.3171/2009.7.PEDS09198)

DOI： 10.3171/2009.7.PEDS09198

High-frequency oscillations of ictal muscle activity and epileptogenic discharges on intracranial EEG in a temporal lobe epilepsy patient Reviewed

Hiroshi Otsubo, Ayako Ochi, Katsumi Imai, Tomoyuki Akiyama, Ayataka Fujimoto, Cristina Go, Peter Dirks, Elizabeth J. Donner

CLINICAL NEUROPHYSIOLOGY 119 ( 4 ) 862 - 868 2008.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Objective: During seizures, intracranial EEG electrodes can record ictal muscle movements. Our purpose was to differentiate the high-frequency oscillations (HFOs) of extracranial muscle contractions from those of intracranial epileptogenic discharges.
Methods: Using intracranial video-EEG (IVEEG), we recorded seizures in a 17-year-old boy with left mesial-temporal lobe epilepsy. We used multiple band frequency analysis (MBFA) to differentiate extracranial HFOs of craniofacial muscle activities from intracranial HFOs recorded ictally and interictally.
Results: During I I seizures, IVEEG showed low-amplitude fast waves (similar to 60 Hz) starting at the left mesial-temporal electrodes. Ictal facial grimacing projected low-amplitude (similar to 20 mu V) fast waves (similar to 160 Hz) on inferior lateral-temporal electrodes. Interictal chewing projected medium-amplitude (similar to 100 mu V) fast waves (similar to 140 Hz) correlating to mouth movements. MBFA topographic power spectrograms revealed a sustained, consistent ictal fast-frequency band from electrodes in the seizure-onset zone and randomly scattered HFOs without a specific frequency band from ictal and interictal extracranial muscle contractions.
Conclusions: MBFA power spectrograms differentiated randomly scattered muscle HFOs without a specific frequency band at electrodes close to temporal muscles from ictal epileptic HFOs with a sustained, fast-frequency band in the seizure-onset zone.
Significance: The pattern and distribution of frequency power spectrograms of extracranial HFOs differ from those of intracranial HFOs. (c) 2008 Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology.

DOI： 10.1016/j.clinph.2007.12.014

Epileptic spasms in older pediatric patients: MEG and ictal high-frequency oscillations suggest focal-onset seizures in a subset of epileptic spasms Reviewed

Rajesh RamachandranNair, Ayako Ochi, Katsumi Imai, Mony Benifla, Tomoyuki Akiyama, Stephanie Holowka, James T. Rutka, O. Carter Snead, Hiroshi Otsubo

EPILEPSY RESEARCH 78 ( 2-3 ) 216 - 224 2008.2

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

Objectives: To elucidate the pathophysiology of intractable epileptic spasms in older children by describing the interictal. magnetoencephalography spike sources (MEGSSs), intracranial EEG ictal-onset zones (IOZs) and their ictal high-frequency oscillations (HFOs) and surgical outcomes.
Methods: We studied five patients (4.5-14 years) who underwent surgery following intracranial video-EEG (VEEG) monitoring. We analyzed clinical profiles, MRIs, scalp and intracranial. VEEGs, and MEGSSs. We localized ictal. HFOs using a sampling rate of 1000 Hz and multiple band frequency analysis (MBFA).
Results: Seizure onset ranged from 0.4 to 8 years. Three patients presented with asymmetrical spasms. Interictal scalp VEEG recorded predominantly unilateral epileptiform discharges in four; generalized and multifocal in one. Ictal. scalp VEEG showed generalized high-amplitude slow waves with superimposed fast waves in four patients; hemispheric electrodecremental episodes in one. MRI findings were normal in three, hemispheric polymicrogyria and periventricular heterotopia in one each. All. patients had unilateral MEGSS clusters. Ictal. HFOs, ranging from 150 to 250 Hz, localized over Rolandic and frontal regions in four, with one also having extensive temporo-occipital HFOs. After cortical resection, three patients were seizure free; one had >90% reduction in seizure frequency. One patient experienced residual seizures after resection of the hemispheric ictal HFO region.
Conclusion: Unilateral clusters of MEGSSs overlapped regional IOZs in older patients with epileptic spasms. High spatio-temporal MBFA before and during spasms revealed the regional ictal HFOs. Seizure-free outcomes following resection of zone with MEGSS clusters and ictal HFOs suggested that a subset of epileptic spasms was focal-onset seizures. (C) 2007 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.eplepsyres.2007.12.007

Dynamic changes of ictal high-frequency oscillations in neocortical epilepsy: Using multiple band frequency analysis Reviewed

Ayako Ochi, Hiroshi Otsubo, Elizabeth J. Donner, Irene Elliott, Ryoichi Iwata, Takanori Funaki, Yoko Akizuki, Tomoyuki Akiyama, Katsumi Imai, James T. Rutka, O. Carter Snead

EPILEPSIA 48 ( 2 ) 286 - 296 2007.2

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

Purpose: To characterize the spatial and temporal course of ictal high-frequency oscillations (HFOs) recorded by subdural EEG in children with intractable neocortical epilepsy.
Methods: We retrospectively studied nine children (four girls, five boys; 4-17 yr) who presented with intractable extrahippocampal localization-related epilepsy and who underwent extraoperative video subdural EEG (1000 Hz sampling rate) and cortical resection. We performed multiple band frequency analysis (MBFA) to evaluate the frequency, time course, and distribution of ictal HFOs. We compared ictal HFO changes before and after clinical onset and postsurgical seizure outcomes.
Results: Seventy-eight of 79 seizures showed HFOs. We observed wide-band HFOs (similar to 250Hz, similar to 120 electrodes) in six patients either with partial seizures alone (three patients) or with epileptic spasms (three patients). Three patients with partial seizures that secondarily generalized had wide-band HFOs (similar to 170 Hz) before clinical onset and sustained narrow-band HFOs (60-164 Hz) with electrodecremental events after clinical onset (similar to 28 electrodes). In four postoperatively seizure-free patients, more electrodes recorded higher-frequency HFOs inside the resection area than outside before and after clinical seizure onset. In five patients with residual seizures, electrodes recorded more HFOs that were of higher or equal frequency outside the surgical area than inside after clinical onset.
Conclusion: For partial seizures alone and epileptic spasms, more electrodes recorded only wide-band HFOs; for partial seizures that secondarily generalized, fewer electrodes recorded wide-band HFOs, but in these seizures electrodes also recorded subsequent sustained narrow-band ictal HFOs. Resection of those brain regions having electrodes with ictal, higher HFOs resulted in postsurgical seizure-free outcomes.

DOI： 10.1111/j.1528-1167.2007.00923.x

Rivabirin治療を行った亜急性硬化性全脳炎の1例

遠藤文香, 岡牧郎, 秋山倫之, 大塚頌子

脳と発達 39 ( 1 ) 72 - 72 2007.1

内側側頭葉てんかんの小児例の術前評価

井上拓志, 秋山倫之, 岡牧郎, 吉永治美, 大塚頌子

脳と発達 39 ( 1 ) 73 - 73 2007.1

Topographic movie of ictal high-frequency oscillations on the brain surface using subdural EEG in neocortical epilepsy Reviewed

Tomoyuki Akiyama, Hiroshi Otsubo, Ayako Ochi, Elaine Z. Galicia, Shelly K. Weiss, Elizabeth J. Donner, James T. Rutka, O. Carter Snead

EPILEPSIA 47 ( 11 ) 1953 - 1957 2006.11

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

Purpose: To understand the rapid dynamic changes of ictal intracranial high-frequency oscillations (HFOs) in neocortical epilepsy.
Methods: We integrated multiple band frequency analysis and brain-surface topographic maps of HFOs from ictal subdural EEG (SDEEG) recordings. We used SDEEG to record partial seizures consisting of right-arm jerks with secondary generalization in a 17-year-old right-handed girl. We selected 20-s EEG sections that included preclinical seizure recordings. We averaged the HFO power between 60 and 120 Hz for 25 selected electrodes, made topographic maps from these averaged powers, and superimposed the maps on the brain-surface image. We filmed consecutive HFO maps at a 10-ms frame rate.
Results: Before clinical seizure onset, high-power HFOs emerged at the superior portion of the left precentral gyrus, then appeared in the middle of the left postcentral gyrus, and subsequently reverberated between both regions as well as the posterior portion of the left postcentral gyrus. Right-arm extension and facial grimacing started as the HFO power decreased. As generalized tonic-clonic seizures evolved, HFO power increased but remained within the central region.
Conclusions: Topographic movies of intracranial HFOs on the brain surface allow visualization of the dynamic ictal changes in neocortical epilepsy.

DOI： 10.1111/j.1528-1167.2006.00823.x

Proposed diagnostic scheme for the classification of epileptic seizures and epilepsies (ILAE, 2001): Proposal from Japan Epilepsy Society Reviewed

Kazuie Iinuma, Kiyoshi Morimoto, Tomoyuki Akiyama, Akio Ikeda, Mana Kurihara

EPILEPSIA 47 ( 9 ) 1588 - 1589 2006.9

The mildest known case of Fukuyama-type congenital muscular dystrophy Reviewed

Tomoyuki Akiyama, Yoko Ohtsuka, Tsutomu Takata, Junri Hattori, Yukiko Kawakita, Kayoko Saito

BRAIN & DEVELOPMENT 28 ( 8 ) 537 - 540 2006.9

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

We present a 14-year-old boy with Fukuyama-type congenital muscular dystrophy (FCMD) who shows the mildest muscle weakness ever reported with this affliction and exceptionally mild mental retardation, but who has intractable epilepsy. Magnetic resonance imaging showed the typical abnormalities of FCMD. Molecular genetic analyses revealed a 3 kb insertion mutation in the fukutin gene heterozygously. We could find no mutation in the coding region of the fukutin gene in the chromosome without a 3 kb insertion. The most probable mechanism of clinical manifestation in this patient could be either a mutation in the noncoding regions of the fukutin gene on the chromosome without the ancestral founder haplotype of FCMD, or an error in the process of transcription or translation. Another possibility is the abnormalities in other genes involved in the glycosylation of alpha-dystroglycan, such as Fukutin-related protein and LARGE genes. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.braindev.2006.02.003

A population-based survey of childhood epilepsy in Okayama Prefecture, Japan: Reclassification by a newly proposed diagnostic scheme of epilepsies in 2001 Reviewed

Tomoyuki Akiyama, Katsuhiro Kobayashi, Tatsuya Ogino, Harumi Yoshinaga, Eiji Oka, Makio Oka, Minako Ito, Yoko Ohtsuka

EPILEPSY RESEARCH 70 S34 - S40 2006.8

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

The purpose of this study is to clarify the usefulness and problems of the newly proposed classification of epilepsies (International League Against Epilepsy: ILAE, 2001) in the epidemiological studies of epilepsy.
We previously conducted an epidemiological study in Okayama Prefecture, Japan, in 1999, using the ILAE 1989 classification. Among 250,997 children under 13 years of age, 2220 epileptic patients were ascertained. In this study, we reclassified them according to the ILAE 2001 classification, focusing on axes 2 (seizure types) and 3 (syndromes).
We were able to classify 1803 (95.0%) seizure types out of 1899 with detailed clinical information. In focal seizures, the most common were secondarily generalized seizures (88.6%), which generally do not represent a unique anatomic substrate. In generalized seizures, topic-clonic seizures (40.7%) and spasms (21.0%) were the most common. We identified only 269 (12.1%) patients with specific epilepsy syndromes out of the 2220. We classified 1761 patients without specific syndromic diagnoses only by axis 2, but the new concept of epileptic seizure types, representing a unique pathophysiologic mechanism and anatomic substrate, was not very meaningful in most cases, even in those with focal seizures. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.eplepsyres.2005.11.017

小児神経留学ネットワーク活動報告

山本俊至, 加藤光広, 作田亮一, 新島新一, 友田明美, 秋山倫之, 福水道郎, 高橋和俊, 稲葉雄二, 福山幸夫

脳と発達 38 ( Suppl. ) S312 - S312 2006.5

臨床脳波を基礎から学ぶ人のために正常脳波の年齢的変化小児(新生児を含む)

大塚頌子, 秋山倫之, 岡牧郎

臨床神経生理学 34 ( 2 ) 97 - 106 2006.4

EEG and seizure exacerbation induced by carbamazepine in Panayiotopoulos syndrome Reviewed

K Kikumoto, H Yoshinaga, M Oka, M Ito, F Endoh, T Akiyama, Y Ohtsuka

EPILEPTIC DISORDERS 8 ( 1 ) 53 - 56 2006.3

Language：English Publishing type：Research paper (scientific journal) Publisher：JOHN LIBBEY EUROTEXT LTD

We report on a 4-year 8-month-old boy with Panayiotopoulos syndrome who showed atypical evolution with newly developed absence seizures and EEG exacerbation induced by carbamazepine. Soon after the introduction of carbamazepine, EEGs began to worsen, and finally absence seizures and myoclonic seizures appeared. Immediately after we discontinued carbamazepine, the seizures disappeared and the EEG improved. Carbamazepine may induce unusual electroclinical features, electrophysiologically explained by bilateral synchrony. This case provides more evidence of the close links between Panayiotopoulos syndrome and benign childhood epilepsy with centrotemporal spikes.

Partial seizures triggering infantile spasms in the presence of a basal ganglia glioma Reviewed

R RamachandranNair, A Ochi, T Akiyama, DJ Buckley, TB Soman, SK Weiss, H Otsubo

EPILEPTIC DISORDERS 7 ( 4 ) 378 - 382 2005.12

Language：English Publishing type：Research paper (scientific journal) Publisher：JOHN LIBBEY EUROTEXT LTD

Infantile spasms associated with brain tumors have been reported. A focal cortical lesion can induce infantile spasms by triggering the brainstem and basal ganglia in this vulnerable age group. We report the case of a female infant with a low-grade glioma in the right basal ganglia, spreading to the cortical area. She presented at the age of five months with left hemiparesis and partial seizures. She developed infantile spasms at the age of 12 months. This is the first video clip report of partial seizures triggering symmetrical spasms in series, secondary to a basal ganglia glioma extending to the cortex.

Focal cortical high-frequency oscillations trigger epileptic spasms: Confirmation by digital video subdural EEG Reviewed

T Akiyama, H Otsubo, A Ochi, T Ishiguro, G Kadokura, R RamachandranNair, SK Weiss, JT Rutka, O Snead

CLINICAL NEUROPHYSIOLOGY 116 ( 12 ) 2819 - 2825 2005.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Objective: To localize high-frequency oscillations (HFOs) on the cortex during epileptic spasms using video subdural EEG and Multiple Band Frequency Analysis (MBFA).
Methods: Using video subdural EEG sampled at 1 kHz, we studied a 14-year-old boy with asymmetric epileptic spasms of possible left frontal origin. We identified HFOs, then analyzed and localized their distributions by MBFA. We correlated HFO distribution to clinical spasm intensity.
Results: Ictal subdural EEG recorded HFOs at 60-150 Hz lasting 0.3-4 s. MBFA showed extensive but noncontiguous distribution of HFOs predominantly over the left frontal and temporal regions. HFOs began and became quasiperiodic before manifestation of clinical spasms. As clinical spasms intensified, HFOs persisted in regions where they initiated subclinically but were of higher frequency and greater power than HFOs in other regions. We performed cortical resections over the left frontal and temporal regions with predominant HFOs. Six months after surgery, the patient remained seizure free.
Conclusions: HFOs were present over the ictal onset zone during epileptic spasms. Periodic spasms in this patient had the characteristics of partial seizures.
Significance: We show that HFOs occurred over the cerebral cortex during epileptic spasms, and we suggest that these focal cortical HFOs triggered the spasms. (c) 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.clinph.2005.08.029

Kinesigenic attacks with ictal electroencephalographic abnormalities Reviewed

T Akiyama, Y Ohtsuka, K Kobayashi, E Oka

PEDIATRIC NEUROLOGY 31 ( 5 ) 357 - 359 2004.11

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

We report on a 14-year 5-month-old male who had attacks similar to those of paroxysmal kinesigenic choreoathetosis. The attacks were elicited exclusively by sudden movements. On several occasions, these attacks were immediately followed by loss of consciousness or a seizure. Ictal electroencephalograms of his attacks without loss of consciousness or a seizure indicated 1.5-3.0 Hz activity in the left hemisphere. A small dosage of carbamazepine was remarkably effective in stopping the attacks. This case demonstrates that a thorough ictal electroencephalographic examination is indispensable for clarifying the pathophysiology of kinesigenic attacks. The relationship between paroxysmal kinesigenic choreoathetosis and supplementary motor area seizures is also discussed. (C) 2004 by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pediatrneurol.2004.05.006

Epileptic spasmsの発作時脳波における極高周波律動のシリーズ中の一定性に関する研究

井上拓志, 小林勝弘, 岡牧郎, 秋山倫之, 中堀智之, 大塚頌子

臨床神経生理学 32 ( 5 ) 599 - 599 2004.10

Very fast rhythmic activity on scalp EEG associated with epileptic spasms Reviewed

K Kobayashi, M Oka, T Akiyama, T Inoue, K Abiru, T Ogino, H Yoshinaga, Y Ohtsuka, E Oka

EPILEPSIA 45 ( 5 ) 488 - 496 2004.5

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING INC

Purpose: Very fast activity was investigated on the ictal EEGs of epileptic spasms to elucidate the pathophysiology of West syndrome (WS) and related disorders from a novel point of view.
Methods: The traces of scalp ictal EEG of spasms temporally were expanded in 11 patients whose clinical diagnosis was symptomatic WS in six, cryptogenic WS in two, Aicardi syndrome in one, and symptomatic generalized epilepsy after WS in the remaining two. Time evolution of averaged power spectra of the ictal fast activity also was analyzed in each patient.
Results: Rhythmic gamma activity with frequency ranging from 50 to 100 Hz was detected in a total of 345 of 537 spasms. Fast activity was seen bilaterally in nine patients, was lateralized to one hemisphere in another, and appeared independently on each hemisphere in the remaining infant with Aicardi syndrome. Power spectra showed a clear peak corresponding to spasm-associated gamma rhythm, with frequency centering similar to65 Hz and ranging from 51 to 98 Hz. The morphology and spectral characteristics of ictal gamma rhythm were completely different from those of muscle activity or alternating current (AC) artifacts.
Conclusions: Spasm-associated gamma activity was clearly detected on the scalp. This observation may provide a clue to the pathophysiology of spasms.

DOI： 10.1111/j.0013-9580.2004.45703.x

A study of spike-density on EEG in West syndrome Reviewed

M Oka, K Kobayashi, T Akiyama, T Ogino, E Oka

BRAIN & DEVELOPMENT 26 ( 2 ) 105 - 112 2004.3

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

To elucidate the pathophysiology of spasms in series, the distribution and density of spikes on hypsarrhythmia were studied in 13 patients with West syndrome by excluding slow waves from EEG using a digital filter. (1) Interictal spikes were mostly multifocal and dominant over the bilateral posterior head area with very few diffuse discharges. Therefore, spikes on hypsarrhythmia were demonstrated to occur actually depending on the brain regions although they appeared random. (2) The dominant region of interictal spikes did not correspond to the underlying focal cortical lesion in many patients, and was indicated to reflect the general process of cerebral maturation in infancy. (3) There were far fewer inter-spasm spikes, especially during the middle phase of a series of spasms, than interictal spikes. It was implied that the cortical activity of hypsarrhythmia was interfered with by the abnormal subcortical function, which might be related to the generation of spasms. (4) The dominant region of inter-spasm spikes tended to coincide with a focal cortical lesion shown by MRI and the focus of associated partial seizures. (C) 2003 Elsevier B.V. All rights reserved.

DOI： 10.1016/S0387-7604(03)00101-3

Initiation of treatment and selection of antiepileptic drugs in childhood epilepsy Reviewed

E Oka, T Murakami, T Ogino, T Kobayashi, Ohmori, I, T Akiyama, M Ito

EPILEPSIA 45 17 - 19 2004

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Purpose: A retrospective study was carried out on 53 cases with childhood epilepsy to evaluate the validity of the initial selection of antiepileptic drug (AED).
Methods: We investigated the AEDs selected at the beginning of the treatment from the medical records of 53 untreated cases. A follow-up study was undertaken to evaluate the effects of the AEDs. In the second study, we investigated the AEDs of 10 cases with atypical benign partial epilepsy (ABPE), to clarify whether the initial AEDs selected for rolandic epilepsy were related to the appearance of ABPE.
Results: The AEDs used at the initial stage consisted of carbamazepine (CBZ), valproic acid (VPA), phenobarbital (PB), and vitamin B-6. The main AEDs were CBZ and VPA for localization-related epilepsy, and VPA for generalized epilepsy. The initial selection of AEDs in 41 (85.4%) of 48 cases treated with AEDs were considered to be correct from the results of follow-up. We could not specify any AEDs that related to the appearance of ABPE.
Conclusions: The selection of AED in this series was considered to be most appropriate. We proposed a criterion to determine whether to begin the AED treatment immediately at the initial seizure.

DOI： 10.1111/j.0013-9580.2004.458004.x

Panayiotopoulos症候群のdipole分析による検討

吉永治美, 小林勝弘, 秋山倫之, 岡牧郎, 伊藤美奈子

脳と発達 35 ( Suppl. ) S116 - S116 2003.5

Epileptic spasmsを示すてんかんにおける棘波の出現に関する研究

岡牧郎, 小林勝弘, 秋山倫之, 太田穂高, 中野広輔, 岡えい次

脳と発達 34 ( Suppl. ) S105 - S105 2002.6

Systematic source estimation of spikes by a combination of independent component analysis and RAP-MUSIC II: Preliminary clinical application Reviewed

K Kobayashi, T Akiyama, T Nakahori, H Yoshinaga, J Gotman

CLINICAL NEUROPHYSIOLOGY 113 ( 5 ) 725 - 734 2002.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

Objectives: We tried to estimate epileptic sources by a combination of independent component analysis (ICA) and recursively applied and projected multiple signal classification (RAP-MUSIC) in real epileptiform EEG discharges.
Methods: EEG data including an array of spikes from 3 patients were decomposed by ICA, and source estimation was performed by applying RAP-MUSIC to the spatial information defined by the set of ICA components that showed epileptiform activity in their waveform. Sources were also estimated from the same data using RAP-MUSIC based on eigen-decomposition of the covariance matrix of averaged spikes, and common spatial pattern decomposition for comparison.
Results: RAP-MUSIC based on ICA could estimate generally correct epileptic sources in the 3 patients, and its results were better than those of the other methods, when compared to intracerebral data. The present analysis proceeded without introduction of subjective decision after data selection. The separation of epileptiform discharges from the background is essential for this analysis, and was successfully performed in the real EEG data.
Conclusions: RAP-MUSIC based on ICA appears promising for estimation of epileptic sources with minimal dependence on subjective decisions in the process of analysis. In particular, it was not necessary to select the number of sources. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S1388-2457(02)00047-0

Systematic source estimation of spikes by a combination of independent component analysis and RAP-MUSIC I: Principles and simulation study Reviewed

K Kobayashi, T Akiyama, T Nakahori, H Yoshinaga, J Gotman

CLINICAL NEUROPHYSIOLOGY 113 ( 5 ) 713 - 724 2002.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

Objectives: We propose a combination of independent component analysis (ICA) and recursively applied and projected multiple signal classification (RAP-MUSIC) as a new approach to dipole source estimation of epileptiform discharges. The method is minimally dependent on subjective decisions.
Methods: Ten electroencephalographic (EEG) data matrices were generated by computer, each matrix including real background activity from a normal subject and an array of added simulated spikes. Each spike was a summation of two transients originating from slightly different 'original dipole sources'. The unaveraged EEG matrices were decomposed by ICA, and source estimation was performed by applying RAP-MUSIC to the spatial information defined by the ICA components showing epileptiform activity in their waveform. For comparison, dipoles were also estimated from the same matrices using two existing methods: RAP-MUSIC based on eigen-decomposition of the covariance matrices of averaged spikes and common spatial pattern decomposition.
Results: In every simulated EEG data matrix, two dipoles close to the original sources were estimated by the present method. Their unaveraged activities were also similar to those of the original sources. The two existing methods gave less precise results than the proposed method.
Conclusions: RAP-MUSIC based on ICA thus proved promising for source estimation of unaveraged epileptiform discharges. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S1388-2457(02)00046-9

Source estimation of spikes by a combination of independent component analysis and RAP-MUSIC Reviewed

Katsuhiro Kobayashi, Tomoyuki Akiyama, Tomoyuki Nakahori, Harumi Yoshinaga, Yoko Ohtsuka, Jean Gotman, Eiji Oka

International Congress Series 1232 ( C ) 311 - 316 2002.4

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

We designed a combination of independent component analysis (ICA) and recursively applied and projected multiple signal classification (RAP-MUSIC) as a new approach to dipole source estimation of epileptiform discharges. The estimation is minimally influenced by subjective decisions in this analysis. A simulation study was performed by generating 10 EEG data matrices by means of a computer: each matrix included real background activity from a normal subject to which an array of simulated unaveraged spikes was added. Each discharge was a summation of two transients originating from slightly different “original dipole sources”. The simulated spikes in the unaveraged EEG data were extracted from the background by ICA as spatiotemporal components, each component having fixed potential field distribution and maximally independent waveform. The complete separation between spikes and background was objectively proven by reconstruction of the EEG from the decomposed components. RAP-MUSIC was performed based on the spatial information included in the epileptic ICA components. RAP-MUSIC does not involve subjective decisions such as selection of multiple local score peaks, determination of the number of dipoles or initial guesses of dipole parameters. In every simulated EEG data matrix, two dipoles close to the original sources were estimated. Their activities were also similar to those of the original sources. For comparison, the same simulated EEG data were averaged and subjected to RAP-MUSIC using eigen-decomposition of the covariance matrices. Only one dipole was estimated in every simulation by this conventional method and therefore the result of the present method was better. RAP-MUSIC based on ICA, thus, proved promising for source estimation of unaveraged epileptiform discharges. © 2002, Elsevier B.V.

DOI： 10.1016/S0531-5131(01)00713-0

Photosensitive fits elicited by TV animation: An electroencephalographic study Reviewed

Hideo Enoki, Tomoyuki Akiyama, Junri Hattori, E. D.I. Oka

Pediatrics International 40 ( 6 ) 626 - 630 1998

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

Background: We carried out a clinical and electroencephalographic (EEG) study to reveal the pathophysiology of acute symptoms elicited by a TV animation program. Methods: Clinical data and EEG were obtained from 20 patients ranging in age from 6 to 30 years. A pattern presentation and an intermittent photic stimulation were performed. Results: Of 20 patients, 13 had a convulsion and seven had other symptoms, mainly nausea and/or vomiting. A photoparoxysmal response (PPR) was confirmed in 12 of 13 patients (92.3%) who had a convulsion. Only one of seven patients (14.3%) without a convulsion showed a PPR. The incidence of PPR was significantly higher in patients with convulsion than those without convulsion. There were no significant differences in the family history of convulsion, gender, parameters associated with TV watching and basic EEG between the two groups. All patients with PPR had a convulsion or consciousness disturbance. Conclusion: Acute symptoms, such as convulsion and impairment of consciousness, are supposed to be based on photosensitivity. © 1998 Wiley. All rights reserved.

DOI： 10.1111/j.1442-200X.1998.tb02005.x

Electroclinical study of localization-related epilepsies in early infancy Reviewed

Ohmori, I, Y Ohtsuka, E Oka, T Akiyama, S Ohtahara

PEDIATRIC NEUROLOGY 16 ( 2 ) 131 - 136 1997.2

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

To clarify the characteristics of localization-related epilepsies in early infancy, we performed an electroclinical study of 28 epileptic patients whose first seizures occurred before 6 months of age. The patients were retrospectively divided into two groups: the seizure-controlled group (8 patients) and the refractory group (20 patients). The seizure-controlled group included the patients whose seizures were suppressed within 1 year after onset; the refractory group included all other patients. The characteristics of the refractory group were as follows: (1) most patients had serious underlying pathologies; (2) the seizure type in most cases was simple partial seizure or complex partial seizure without secondary generalization; (3) the interictal EEG showed focal abnormalities and severe dysrhythmia on the basic pattern associated with multifocal spikes in most cases; and (4) in some patients, West syndrome developed after localization- related epilepsies and generalized seizures appeared later in some cases. (C) 1997 by Elsevier Science Inc.

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