研究者詳細 - 秋山　倫之

論文 - 秋山　倫之

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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年5月

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年5月

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年5月

A Japanese single-center experience of the efficacy and safety of asfotase alfa in pediatric-onset hypophosphatasia. 査読国際誌

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年2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 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

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Sirolimus for epileptic seizures associated with focal cortical dysplasia type II. 査読国際誌

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年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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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年2月

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

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年

記述言語：英語

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

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

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年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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Case Report: High-Gamma Oscillations on an Ictal Electroencephalogram in a Newborn Patient With Hypoxic–Ischemic Encephalopathy 査読国際誌

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

Frontiers in Pediatrics 9 679771 - 679771 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

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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. 査読

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年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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Monozygotic twins with DYT-TOR1A showing jerking movements and levodopa responsiveness 査読国際誌

Hanaoka Y, Akiyama T, Yoshinaga H, Kobayashi K

Brain Dev 43 ( 7 ) 783 - 788 2021年7月

Exclusion of the Possibility of “False Ripples” From Ripple Band High-Frequency Oscillations Recorded From Scalp Electroencephalogram in Children With Epilepsy 査読国際誌

Katsuhiro Kobayashi, Takashi Shibata, Hiroki Tsuchiya, Tomoyuki Akiyama

Frontiers in Human Neuroscience 15 696882 - 696882 2021年6月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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

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A study on the relationship between non-epileptic fast (40 - 200 Hz) oscillations in scalp EEG and development in children. 査読国際誌

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年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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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年5月

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年5月

Isolated cortical tuber in an infant with genetically confirmed tuberous sclerosis complex 1 presenting with symptomatic West syndrome. 査読国際誌

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年2月

記述言語：英語

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

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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年2月

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. 査読国際誌

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年12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 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

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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年12月

Longitudinal correspondence of epilepsy and scalp EEG fast (40-200 Hz) oscillations in pediatric patients with tuberous sclerosis complex. 査読国際誌

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

Brain & development 42 ( 9 ) 663 - 674 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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