研究者詳細 - 秋山　倫之

論文 - 秋山　倫之

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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年8月

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年8月

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年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：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

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Non-Gaussianity Detection of EEG Signals Based on a Multivariate Scale Mixture Model for Diagnosis of Epileptic Seizures. 査読国際誌

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

IEEE transactions on bio-medical engineering PP ( 2 ) 515 - 525 2020年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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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年6月

記述言語：日本語出版者・発行元：(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)

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その他リンク： 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. 査読国際誌

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年5月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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年3月

A case of pyridoxine-dependent epilepsy with novel ALDH7A1 mutations 査読国際誌

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

Oxford Medical Case Reports 3 ( 3 ) 99 - 103 2020年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

<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

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Metabolic Profiling of the Cerebrospinal Fluid in Pediatric Epilepsy. 査読

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

Acta medica Okayama 74 ( 1 ) 65 - 72 2020年2月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

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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年2月

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年2月

Laboratory changes during ACTH therapy associated with renal calcified lesions. 査読国際誌

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年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

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年

記述言語：英語

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

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Clinical and genetic aspects of mild hypophosphatasia in Japanese patients. 査読国際誌

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年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders. 査読国際誌

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年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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

Ohuchi Y, Akiyama T, Matsuhashi M, Kobayashi K

Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology 130 ( 10 ) 1971 - 1980 2019年10月

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

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年9月

Findings of amplitude-integrated electroencephalogram recordings and serum vitamin B6 metabolites in perinatal lethal hypophosphatasia during enzyme replacement therapy. 査読国際誌

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年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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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年9月

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年9月

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