Researcher Profile and Settings

Master

Affiliation (Master)

• Hokkaido University Hospital　Division of Child Maternal and Female medicine

Affiliation (Master)

• Hokkaido University Hospital　Division of Child Maternal and Female medicine

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Profile and Settings

Profile and Settings

• Name (Japanese)

  Egawa

• Name (Kana)

  Kiyoshi

• Name

  201701018882291534

Achievement

Research Interests

• 神経生理学   小児科   

Research Areas

• Life sciences / Clinical pharmacy
• Life sciences / Physiology
• Life sciences / Fetal medicine/Pediatrics

Awards

• 日本てんかん学会 JUHN AND MARY WADA奨励賞
   

  受賞者: 江川 潔

Published Papers

• Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment.

  Hideo Hagihara, Hirotaka Shoji, Satoko Hattori, Giovanni Sala, Yoshihiro Takamiya, Mika Tanaka, Masafumi Ihara, Mihiro Shibutani, Izuho Hatada, Kei Hori, Mikio Hoshino, Akito Nakao, Yasuo Mori, Shigeo Okabe, Masayuki Matsushita, Anja Urbach, Yuta Katayama, Akinobu Matsumoto, Keiichi I Nakayama, Shota Katori, Takuya Sato, Takuji Iwasato, Haruko Nakamura, Yoshio Goshima, Matthieu Raveau, Tetsuya Tatsukawa, Kazuhiro Yamakawa, Noriko Takahashi, Haruo Kasai, Johji Inazawa, Ikuo Nobuhisa, Tetsushi Kagawa, Tetsuya Taga, Mohamed Darwish, Hirofumi Nishizono, Keizo Takao, Kiran Sapkota, Kazutoshi Nakazawa, Tsuyoshi Takagi, Haruki Fujisawa, Yoshihisa Sugimura, Kyosuke Yamanishi, Lakshmi Rajagopal, Nanette Deneen Hannah, Herbert Y Meltzer, Tohru Yamamoto, Shuji Wakatsuki, Toshiyuki Araki, Katsuhiko Tabuchi, Tadahiro Numakawa, Hiroshi Kunugi, Freesia L Huang, Atsuko Hayata-Takano, Hitoshi Hashimoto, Kota Tamada, Toru Takumi, Takaoki Kasahara, Tadafumi Kato, Isabella A Graef, Gerald R Crabtree, Nozomi Asaoka, Hikari Hatakama, Shuji Kaneko, Takao Kohno, Mitsuharu Hattori, Yoshio Hoshiba, Ryuhei Miyake, Kisho Obi-Nagata, Akiko Hayashi-Takagi, Léa J Becker, Ipek Yalcin, Yoko Hagino, Hiroko Kotajima-Murakami, Yuki Moriya, Kazutaka Ikeda, Hyopil Kim, Bong-Kiun Kaang, Hikari Otabi, Yuta Yoshida, Atsushi Toyoda, Noboru H Komiyama, Seth G N Grant, Michiru Ida-Eto, Masaaki Narita, Ken-Ichi Matsumoto, Emiko Okuda-Ashitaka, Iori Ohmori, Tadayuki Shimada, Kanato Yamagata, Hiroshi Ageta, Kunihiro Tsuchida, Kaoru Inokuchi, Takayuki Sassa, Akio Kihara, Motoaki Fukasawa, Nobuteru Usuda, Tayo Katano, Teruyuki Tanaka, Yoshihiro Yoshihara, Michihiro Igarashi, Takashi Hayashi, Kaori Ishikawa, Satoshi Yamamoto, Naoya Nishimura, Kazuto Nakada, Shinji Hirotsune, Kiyoshi Egawa, Kazuma Higashisaka, Yasuo Tsutsumi, Shoko Nishihara, Noriyuki Sugo, Takeshi Yagi, Naoto Ueno, Tomomi Yamamoto, Yoshihiro Kubo, Rie Ohashi, Nobuyuki Shiina, Kimiko Shimizu, Sayaka Higo-Yamamoto, Katsutaka Oishi, Hisashi Mori, Tamio Furuse, Masaru Tamura, Hisashi Shirakawa, Daiki X Sato, Yukiko U Inoue, Takayoshi Inoue, Yuriko Komine, Tetsuo Yamamori, Kenji Sakimura, Tsuyoshi Miyakawa

  eLife 12 2024/03/26 

  Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer's disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.
• Ommaya reservoir placement using ultrasound guidance via anterior fontanelle combined with frameless electromagnetic neuronavigation in patients with mucopolysaccharidosis type 2: Case reports and review of the literature.

  Makoto Mizushima, Masahito Kawabori, Kazuyoshi Yamazaki, Kiyoshi Egawa, Miki Fujimura

  Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 2024/01/02 

  Mucopolysaccharidosis type II (MPS II) results from the genetic deficiency of a lysosomal enzyme and is associated with central nervous system (CNS) dysfunction. In Japan, in addition to intravenous enzyme administration, intracerebroventricular enzyme delivery through the Ommaya reservoir has recently gained approval. Nevertheless, the ideal approach for safely implanting the reservoir into the narrow ventricles of infantile MPS II patients remains uncertain. In this report, we present two cases of successful reservoir placement in infantile MPS II patients using ultrasound guidance via the anterior fontanelle, coupled with flameless electromagnetic neuronavigation.
• Nusinersen induces detectable changes in compound motor action potential response in spinal muscular atrophy type 1 patients with severe impairment of motor function.

  Yuki Ueda, Kiyoshi Egawa, Kentaro Kawamura, Noriki Ochi, Takeru Goto, Shuhei Kimura, Masashi Narugami, Sachiko Nakakubo, Midori Nakajima, Atsushi Manabe, Hideaki Shiraishi

  Brain & development 2023/12/15 

  BACKGROUND: Most long-term affected spinal muscular atrophy (SMA) type 1 patients have severe impairment of motor function and are dependent on mechanical ventilation with tracheostomy. The efficacy and safety of nusinersen in these patients have not been established. METHODS: We retrospectively evaluated the efficacy of intrathecal nusinersen treatment in patients with SMA type 1 who continued treatment for at least 12 months. There were three patients enrolled in our study (3, 4 and 16 years of age) who had severe impairment of gross motor function without head control or the ability to roll over. All three needed mechanical ventilation with tracheostomy and tube feeding. Motor function was assessed using the Children s Hospital of Philadelphia infant test of neuromuscular disorders (CHOP-INTEND) and the caregivers' evaluations. Concurrently, we examined nerve conduction longitudinally and compared compound motor action potential (CMAP) amplitudes. RESULTS: All patients continued nusinersen administration without significant adverse events for more than three years. While CHOP-INTEND scores did not remarkably increase, according to the caregivers, all three patients had improved finger or facial muscle movements that enabled them to make their intentions understood. Some CMAPs before treatment were not identified but became traces after nusinersen administration. CONCLUSIONS: The improvement in motor function that leads to smoother communication could be a basis for continuing nusinersen treatment. Currently available motor function scorings are not efficient for assessing therapeutic interventions in SMA patients with medical care complexity. Longitudinal nerve conduction studies could be an objective indicator.
• Use of lacosamide for focal epilepsy in a child with kidney failure undergoing peritoneal dialysis.

  Yuki Ueda, Ayako Furugen, Masaki Kobayashi, Yasuyuki Sato, Yasuhiro Ueda, Asako Hayashi, Takeru Goto, Shuhei Kimura, Masashi Narugami, Sachiko Nakakubo, Midori Nakajima, Kiyoshi Egawa, Takayuki Okamoto, Atsushi Manabe, Hideaki Shiraishi

  Brain & development 2023/10/30 

  BACKGROUND: Lacosamide (LCM) has become commonly used for focal onset seizures due to its high tolerability and low drug interactions. Unlike patients on hemodialysis (HD), pharmacokinetic data and dosing recommendations for patients undergoing peritoneal dialysis (PD) are scant. CASE REPORT: A 2-year-old girl with end-stage kidney disease undergoing PD suffered prolonged focal onset seizures. The patient had congenital anomalies of the kidney and urinary tract associated with branchio-oto-renal syndrome due to an EYA1 gene mutation. She also had neurological sequelae from post-resuscitation encephalopathy at the age of one month. Antiseizure medication with few drug interactions, less impact on the neurodevelopmental state and possibility of intravenous administration was preferred. LCM met those criteria and was carefully administered. Although the patient had recurrent prolonged seizures during the titration periods, LCM could be continued without any apparent side effects. The blood levels of LCM increased linearly to the optimal level. We confirmed excretion of LCM in the PD fluid. Kidney transplantation was done three months after and her seizures were well controlled. CONCLUSIONS: LCM might be a promising option for patients undergoing PD. Due to the lower removal efficacy in PD compared with in HD, close attention should be paid to possible drug excess.
• Transcutaneous auricular vagus nerve stimulation therapy in patients with cognitively preserved structural focal epilepsy: A case series report.

  Hideaki Shiraishi, Kiyoshi Egawa, Kaoru Murakami, Midori Nakajima, Yuki Ueda, Sachiko Nakakubo, Masashi Narugami, Shuhei Kimura, Takeru Goto, Yasuyoshi Hiramatsu, Masaaki Murakami

  Brain & development 2023/08/30 

  OBJECTIVE: Transcutaneous auricular vagus nerve stimulation (taVNS) was performed in two patients suffering structural focal epilepsy with preserved intellectual ability to show the feasibility of taVNS for specific patient groups. CASE PRESENTATIONS: Patient 1 was a 24-year-old woman with frontal lobe epilepsy who had weekly hyperkinetic seizures despite multiple anti-seizure medications. Patient 2 was a 27-year-old woman with parietal lobe epilepsy and focal cortical dysplasia in the vicinity of the lipoma in the corpus callosum. She experienced weekly focal-impaired awareness seizures even with anti-seizure medication. taVNS was applied to the left earlobe of both patients at 1.5 mA, 25 Hz, 250 μs pulse width, and 30 s stimulation with 30 s rest for 4 h per day. Over an 8-week baseline and 20 weeks of stimulation, the rate of reduction in seizure frequency was evaluated, along with quality-of-life using the Short-Form 36-Item Health survey. RESULTS: At baseline, we measured up to 11 and 12 focal seizures per week in Patient 1 and 2, respectively, with both patients achieving seizure freedom after 4 and 20 weeks taVNS, respectively. Patient 1 and 2 were observed for 18 and 14 months, respectively, including the clinical trial and follow-up observation period. Quality-of-life ratings increased in both patients, and no significant adverse events occurred during the study period. During the maintenance period after 20 weeks, seizures remained absent in Patient 1, and seizures remained reduced in Patient 2. CONCLUSION: Our results demonstrate that taVNS may be a promising tool for structural focal epilepsy with preserved cognitive function. A multicenter double-blind clinical trial is needed to confirm the role of taVNS as an anti-seizure tool.
• Video-based detection of epileptic spasms in West syndrome using a deep neural network: A pilot case study.

  Katsuki Eguchi, Hiroaki Yaguchi, Sachiko Nakakubo, Midori Nakajima, Yuki Ueda, Kiyoshi Egawa, Hideaki Shiraishi, Ichiro Yabe

  Journal of the neurological sciences 449 120671 - 120671 2023/06/15
• Efficacy of sirolimus for epileptic seizures in childhood associated with focal cortical dysplasia type II

  Hideaki Shiraishi, Tsuyoshi Teramoto, Saki Yokoshiki, Jun Tohyama, Yuki Ueda, Kiyoshi Egawa, Norihiro Sato, Atsushi Manabe, Mitsuhiro Kato

  BRAIN & DEVELOPMENT 45 (6) 343 - 347 0387-7604 2023/06 

  Objective: The efficacy of the mechanistic target of rapamycin inhibitor, sirolimus, was recently reported for patients more than 6 years of age by Kato et al. We evaluated the efficacy and safety of sirolimus in a 2-year-old patient with recurrent focal seizures with impaired consciousness after focal cortical dysplasia (FCD) type IIa resection. Methods: The patient was a 2-year-old girl who had recurrent seizures after undergoing FCD resection at 4 months of age. The initial dose of sirolimus was 0.5 mg/day and was gradually increased using the trough blood concentration before oral administration as an index, and evaluation was performed at 92 weeks. Results: The trough blood level of sirolimus was increased to 6.1 ng/mL and maintenance therapy was started at 40 weeks. Focal seizures with impairment of consciousness with tonic extension of the limbs decreased. No critically serious adverse events occurred. Conclusion: Sirolimus was effective against epileptic seizures from FCD type II even for a child under 5 years of age. There were no critically serious adverse events and administration could be continued. (c) 2023 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. This is an open access article under the CC BY-NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
• Ndufs4機能欠失マウスを用いたLeigh脳症に対する5-ALAの有効性の評価

  木村 修平, 後藤 健, 中久保 佐千子, 苅部 冬紀, 山田 勇磨, 藤山 文乃, 白石 秀明, 江川 潔, 平松 泰好, 鳴神 雅史, 中島 翠, 植田 佑樹, 佐々木 大輔

  脳と発達 (一社)日本小児神経学会 55 (Suppl.) S315 - S315 0029-0831 2023/05
• Imbalanced expression of cation-chloride cotransporters as a potential therapeutic target in an Angelman syndrome mouse model.

  Kiyoshi Egawa, Miho Watanabe, Hideaki Shiraishi, Daisuke Sato, Yukitoshi Takahashi, Saori Nishio, Atsuo Fukuda

  Scientific reports 13 (1) 5685 - 5685 2023/04/17 

  Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the maternally expressed UBE3A gene. Treatments for the main manifestations, including cognitive dysfunction or epilepsy, are still under development. Recently, the Cl- importer Na+-K+-Cl- cotransporter 1 (NKCC1) and the Cl- exporter K+-Cl- cotransporter 2 (KCC2) have garnered attention as therapeutic targets for many neurological disorders. Dysregulation of neuronal intracellular Cl- concentration ([Cl-]i) is generally regarded as one of the mechanisms underlying neuronal dysfunction caused by imbalanced expression of these cation-chloride cotransporters (CCCs). Here, we analyzed the regulation of [Cl-]i and the effects of bumetanide, an NKCC1 inhibitor, in Angelman syndrome models (Ube3am-/p+ mice). We observed increased NKCC1 expression and decreased KCC2 expression in the hippocampi of Ube3am-/p+ mice. The average [Cl-]i of CA1 pyramidal neurons was not significantly different but demonstrated greater variance in Ube3am-/p+ mice. Tonic GABAA receptor-mediated Cl- conductance was reduced, which may have contributed to maintaining the normal average [Cl-]i. Bumetanide administration restores cognitive dysfunction in Ube3am-/p+ mice. Seizure susceptibility was also reduced regardless of the genotype. These results suggest that an imbalanced expression of CCCs is involved in the pathophysiological mechanism of Ube3am-/p+ mice, although the average [Cl-]i is not altered. The blockage of NKCC1 may be a potential therapeutic strategy for patients with Angelman syndrome.
• An integrated genetic analysis of epileptogenic brain malformed lesions.

  Atsushi Fujita, Mitsuhiro Kato, Hidenori Sugano, Yasushi Iimura, Hiroharu Suzuki, Jun Tohyama, Masafumi Fukuda, Yosuke Ito, Shimpei Baba, Tohru Okanishi, Hideo Enoki, Ayataka Fujimoto, Akiyo Yamamoto, Kentaro Kawamura, Shinsuke Kato, Ryoko Honda, Tomonori Ono, Hideaki Shiraishi, Kiyoshi Egawa, Kentaro Shirai, Shinji Yamamoto, Itaru Hayakawa, Hisashi Kawawaki, Ken Saida, Naomi Tsuchida, Yuri Uchiyama, Kohei Hamanaka, Satoko Miyatake, Takeshi Mizuguchi, Mitsuko Nakashima, Hirotomo Saitsu, Noriko Miyake, Akiyoshi Kakita, Naomichi Matsumoto

  Acta neuropathologica communications 11 (1) 33 - 33 2023/03/02 

  Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway.
• Therapeutic effects of KRM-II-81, positive allosteric modulator for α2/3 subunit containing GABAA receptors, in a mouse model of Dravet syndrome.

  Sachiko Nakakubo, Yasuyoshi Hiramatsu, Takeru Goto, Syuhei Kimura, Masashi Narugami, Midori Nakajima, Yuki Ueda, Hideaki Shiraishi, Atsushi Manabe, Dishary Sharmin, James M Cook, Kiyoshi Egawa

  Frontiers in pharmacology 14 1273633 - 1273633 2023 

  Introduction: Dravet syndrome (DS) is an intractable epilepsy syndrome concomitant with neurodevelopmental disorder that begins in infancy. DS is dominantly caused by mutations in the SCN1A gene, which encodes the α subunit of a voltage-gated Na channel. Pre-synaptic inhibitory dysfunction is regarded as the pathophysiological mechanism, but an effective strategy for ameliorating seizures and behavioral problems is still under development. Here, we evaluated the effects of KRM-II-81, a newly developed positive allosteric modulator for α 2/3 subunit containing GABAA receptors (α2/3-GABAAR) in a mice model of DS both in vivo and at the neuronal level. Methods: We used knock-in mice carrying a heterozygous, clinically relevant SCN1A mutation (background strain: C57BL/6 J) as a model of the DS (Scn1a WT/A1783V mice), knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V). Seizure threshold and locomotor activity was evaluated by using the hyperthermia-induced seizure paradigm and open filed test, respectively. Anxiety-like behavior was assessed by avoidance of the center region in locomotor activity. We estimated a sedative effect by the total distance traveled in locomotor activity and grip strength. Inhibitory post synaptic currents (IPSCs) were recorded from a hippocampal CA1 pyramidal neuron in an acutely prepared brain slice. Results: KRM-II-81 significantly increased the seizure threshold of Scn1a WT/A1783V mice in a dose-dependent manner. A low dose of KRM-II-81 specifically improved anxiety-like behavior of Scn1a WT/A1783V mice. A sedative effect was induced by relatively high dose of KRM-II-81 in Scn1a WT/A1783V mice, the dose of which was not sedative for WT mice. KRM-II-81 potentiated IPSCs by increasing its decay time kinetics. This effect was more prominent in Scn1a WT/A1783V mice. Discussion: Higher activation of α2/3-GABAAR by KRM-II-81 suggests a compensatory modification of post synaptic inhibitory function against presynaptic inhibitory dysfunction in Scn1a WT/A1783V. The increased sensitivity for KRM-II-81 may be relevant to the distinct dose-dependent effect in each paradigm of Scn1a WT/A1783V mice. Conclusion: Selective activation for α2/3-GABAAR by KRM-II-81 could be potential therapeutic strategy for treating seizures and behavioral problems in DS.
• 問題症例のMEG 構造的焦点てんかんを呈した乳児例に対する後頭葉切除と側頭葉切除(Occipital lobe dissection and temporal lobectomy for an infantile case with structural focal epilepsy.)

  平松 泰好, 中島 翠, 江川 潔, 江夏 怜, 三國 信啓, 鳴神 雅史, 植田 佑樹, 中久保 佐千子, 木村 修平, 後藤 健, 白石 秀明

  臨床神経生理学 50 (5) 344 - 344 1345-7101 2022/10
• Adrenal function during long-term ACTH therapy for patients with developmental and epileptic encephalopathy.

  Yuki Ueda, Shuta Fujishige, Takeru Goto, Shuhei Kimura, Noriko Namatame, Masashi Narugami, Sachiko Nakakubo, Midori Nakajima, Kiyoshi Egawa, Naoya Kaneko, Kanako Nakayama, Nozomi Hishimura, Takeshi Yamaguchi, Akie Nakamura, Hideaki Shiraishi

  Epilepsia open 7 (1) 194 - 200 2021/12/04 

  Some patients with developmental and epileptic encephalopathy (DEE) respond to adrenocorticotropic hormone (ACTH) therapy but relapse soon after. While long-term ACTH therapy (LT-ACTH) has been attempted for these patients, no previous studies have carefully assessed adrenal function during LT-ACTH. We evaluated the effectiveness of LT-ACTH, as well as adverse effects (AE), including their adrenal function in three DEE patients. Patients underwent a corticotropin-releasing hormone (CRH) stimulation test during LT-ACTH, and those with peak serum cortisol below 15 μg/dL were considered to be at high risk of adrenal insufficiency (AI). Two of three responded, and their life-threatening seizures with postgeneralized electroencephalogram (EEG) suppression decreased. Although no individuals had serious AE, CRH stimulation test revealed relatively weak responses, without reaching normal cortisol peak level (18 μg/dL). Hydrocortisone replacement during stress was prepared in a case with lower cortisol peak than our cutoff level. LT-ACTH could be a promising treatment option for cases of DEE that relapse soon after effective ACTH treatment. The longer duration and larger cumulative dosage in LT-ACTH than in conventional ACTH could increase the relative risk of AI. Careful evaluation with pediatric endocrinologists, including hormonal stimulation tests, might be useful for continuing this treatment safely.
• Selective Eating in Autism Spectrum Disorder Leading to Hair Color Change.

  Yuji Maruo, Kimiaki Uetake, Kiyoshi Egawa, Hideaki Shiraishi

  Pediatric neurology 120 1 - 2 2021/07
• Flurothyl-induced seizure paradigm revealed higher seizure susceptibility in middle-aged Angelman syndrome mouse model.

  Kiyoshi Egawa, Sachiko Nakakubo, Shuhei Kimura, Takeru Goto, Atsushi Manabe, Hideaki Shiraishi

  Brain & development 43 (4) 515 - 520 2021/04 

  INTRODUCTION: Epilepsy is one of the main clinical problems in Angelman syndrome (AS). Seizures typically start in early childhood then decrease or are often alleviated by young adulthood. Several studies using AS model mice showed comparable seizure susceptibility during young adulthood. In contrast, the course of epilepsy post young adulthood differs from persistently relieved to rerising among reports. To elucidate this, we evaluated the seizure susceptibility of AS model mice of two different ages. METHODS: Mice lacking maternal Ube3a gene (Ube3am-/p+) of C57BL/6 background or their littermate wild type (WT) were divided into two groups by age, 2 to 3 months (2-3 M) and 6 to 12 months (6-12 M), corresponding to adolescent to young adult aged and middle aged humans, respectively. Seizure susceptibility was evaluated by flurothyl inhalation or intraperitoneal injection of pentylenetetrazole (PTZ IP)-induced acute seizure protocol. RESULTS: In the flurothyl-induced seizure paradigm, the latency to seizure occurrence had a significant interaction with genotype and age. Post-hoc analysis revealed that the latency was significantly shorter at 6-12 M than at 2-3 M in Ube3am-/p+ mice, and in Ube3am-/p+ mice than in WT mice at 6-12 M. No significant interaction or difference was observed by PTZ IP. CONCLUSION: The flurothyl-induced seizure paradigm revealed that seizure susceptibility of Ube3am-/p+ mice increased with age, similar to clinical studies reporting the reappearance of epilepsy in older age. The flurothyl-induced seizure paradigm applied to middle-aged Ube3am-/p+ mice could be a suitable protocol for screening drugs against seizures in AS.
• Variance in the pathophysiological impact of the hemizygosity of gamma-aminobutyric acid type A receptor subunit genes between Prader-Willi syndrome and Angelman syndrome.

  Kiyoshi Egawa, Shinji Saitoh, Naoko Asahina, Hideaki Shiraishi

  Brain & development 43 (4) 521 - 527 2021/04 

  INTRODUCTION: Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are neurodevelopmental disorders caused by loss of function of maternally expressed UBE3A and paternally expressed contiguous genes on chromosome 15q11-13, respectively. A majority of these syndromes suffer from a large deletion of the relevant chromosome (AS Del or PWS Del), which includes biallelically expressed gamma-aminobutyric acid type A receptor subunit (GABAaR) genes, while remaining individuals present without the deletion (AS non-Del or PWS non-Del). We previously reported that AS Del, but not AS non-Del individuals, show aberrantly desynchronized somatosensory-evoked magnetic fields (SEFs) and speculated that it might reflect GABAergic dysfunction due to the hemizygosity of GABAaR genes. To verify its pathophysiological impact on PWS and AS, we analyzed the SEFs of PWS individuals. METHOD: SEFs were recorded from eight PWS Del and two PWS non-Del individuals. The latency and strength of the first peak (N1m) were compared with those of AS Del/non-Del individuals and controls, most of which were obtained earlier. RESULTS: In contrast to AS, both PWS Del and PWS non-Del showed normal SEF waveforms. Desynchronized response with delayed N1m peak latency was exclusively indicated in AS Del. N1m strength was statistically higher in AS Del and AS non-Del, but not in PWS Del and PWS non-Del. CONCLUSIONS: Our results indicate that the pathophysiological impact of the hemizygosity of GABAaR genes is lower in PWS than AS. UBE3A deficiency and the hemizygosity of GABAaR genes could synergistically deteriorate neuronal function, resulting in aberrant SEFs in AS Del.
• Short-latency somatosensory-evoked potentials demonstrate cortical dysfunction in patients with Angelman syndrome.

  Kiyoshi Egawa, Shinji Saitoh, Naoko Asahina, Hideaki Shiraishi

  eNeurologicalSci 22 100298 - 100298 2021/03 

  Background: Angelman syndrome (AS) is neurodevelopmental disorder, causal gene of which is maternally expressed UBE3A. A majority of patients results from the large deletion of relevant chromosome which includes GABAA receptor subunit genes (GABARs) as well as UBE3A (AS Del). We previously reported aberrantly desynchronized primary somatosensory response in AS Del by using magnetoencephalography. The purpose of this study is to estimate cortical and subcortical involvement in the deficit of primary somatosensory processing in AS. Methods: We analyzed short-latency somatosensory-evoked potentials (SSEPs) in 8 patients with AS Del. SSEPs were recorded on a 4-channel system comprising of two cortical electrodes which were placed on the frontal and centro-parietal areas. The peak and onset latency of each component were measured to compare latency and interval times. Results: The first-cortical peak latency (N20, P20), and N13-N20 peak interval times were significantly prolonged in AS Del compared to healthy controls. In contrast, there was no difference in latencies between subcortical components up to N20 onset or for N11-N20 onset interval times. Conclusion: Highly desynchronized first-cortical SSEP components and normal latencies of subcortical components indicated cortical dysfunction rather than impairment of afferent pathways in AS Del patients, which might be attributed to GABAergic dysfunction due to loss of UBE3A function and heterozygosity of GABARs.
• Selective Eating in Autism Spectrum Disorder Leading to Kwashiorkor and Brain Edema.

  Yuji Maruo, Kiyoshi Egawa, Hidefumi Tonoki, Satoshi Terae, Yuki Ueda, Hideaki Shiraishi

  Pediatric neurology 116 55 - 56 2021/03
• Reply to the letter: "Perampanel may be beneficial in leigh syndrome by its anti-oxidative but not anti-epileptic effect".

  Shuhei Kimura, Hideaki Shiraishi, Kiyoshi Egawa, Masaya Uchida, Michihiko Ueno

  Brain & development 43 (2) 361 - 362 2021/02
• Efficacy of bezafibrate for preventing myopathic attacks in patients with very long-chain acyl-CoA dehydrogenase deficiency.

  Hideaki Shiraishi, Kenji Yamada, Kiyoshi Egawa, Mika Ishige, Fumihiro Ochi, Asami Watanabe, Sanae Kawakami, Kazuyo Kuzume, Kenji Watanabe, Koji Sameshima, Kiyotaka Nakamagoe, Akira Tamaoka, Naoko Asahina, Saki Yokoshiki, Keiko Kobayashi, Takashi Miyakoshi, Koji Oba, Toshiyuki Isoe, Hiroshi Hayashi, Seiji Yamaguchi, Norihiro Sato

  Brain & development 43 (2) 214 - 219 2021/02 [Refereed][Not invited]
   

  BACKGROUND: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks. PATIENTS AND METHODS: We conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions. RESULTS: The number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients' ability to conduct everyday activities was also improved by the treatment. CONCLUSION: Our findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.
• Reinterpretation of magnetic resonance imaging findings with magnetoencephalography can improve the accuracy of detecting epileptogenic cortical lesions.

  Kosuke Otsuka, Kiyoshi Egawa, Noriyuki Fujima, Kohsuke Kudo, Satoshi Terae, Midori Nakajima, Tomoshiro Ito, Kazuyori Yagyu, Hideaki Shiraishi

  Epilepsy & behavior : E&B 114 (Pt A) 107516 - 107516 2021/01 

  OBJECTIVE: This study examined whether the application of magnetoencephalography (MEG) to interpret magnetic resonance imaging (MRI) findings can aid the diagnosis of intractable epilepsy caused by organic brain lesions. METHODS: This study included 51 patients with epilepsy who had MEG clusters but whose initial MRI findings were interpreted as being negative for organic lesions. Three board-certified radiologists reinterpreted the MRI findings, utilizing the MEG findings as a guide. The degree to which the reinterpretation of the imaging results identified an organic lesion was rated on a 5-point scale. RESULTS: Reinterpretation of the MRI data with MEG guidance helped detect an abnormality by at least one radiologist in 18 of the 51 patients (35.2%) with symptomatic localization-related epilepsy. A surgery was performed in 7 of the 51 patients, and histopathological analysis results identified focal cortical dysplasia in 5 patients (Ia: 1, IIa: 2, unknown: 2), hippocampal sclerosis in 1 patient, and dysplastic neurons/gliosis in 1 patient. CONCLUSIONS: The results of this study highlight the potential diagnostic applications of MEG to detect organic epileptogenic lesions, particularly when radiological visualization is difficult with MRI alone.
• Efficacy of perampanel for epileptic seizures and daily behavior in a patient with Leigh syndrome: A case report.

  Shuhei Kimura, Hideaki Shiraishi, Kiyoshi Egawa, Masaya Uchida, Michihiko Ueno

  Brain & development 43 (1) 157 - 159 2021/01 [Refereed][Not invited]
   

  BACKGROUND: Leigh syndrome (LS) is a mitochondrial disorder that shows abnormal basal ganglia lesion and psychomotor regression. Although vitamins have been used for LS, we have not found any effective drug. CASE PRESENTATION: A 26-year-old man who showed psychomotor delay and short stature at the age of 1 year was diagnosed with LS according to the results of cerebrospinal fluid and high signal intensity in the bilateral striatum on T2-weighted magnetic resonance imaging. He demonstrated psychomotor delay and breathing disorders, but the progression was very slow. His symptoms suddenly worsened at the age of 24 years after acute epididymitis. He showed epileptic seizures simultaneously and his activities of daily living (ADL) significantly worsened. Several antiepileptic drugs were ineffective, but his seizures were suppressed by a low dose of perampanel and his ADL improved. CONCLUSION AND DISCUSSION: Our case showed that low-dose perampanel could be a drug for epileptic seizures and improvement of ADL in patients with LS.
• アンジェルマン症候群の病態生理と治療に関する最近の話題

  江川 潔, 白石 秀明

  てんかんをめぐって 日本てんかん学会-北海道地方会 38 11 - 19 1349-3078 2020/12 

  アンジェルマン症候群は、母性発現遺伝子UBE3Aを原因因子とする遺伝性疾患で、精神運動発達遅滞、言語障害、運動機能障害、特徴的な顔貌を主要症状とする。アンジェルマン症候群を発症する遺伝的メカニズムを紹介し、その病態生理の一つとして、GABA抑制系機能障害に関する著者らの研究を紹介した。また、アンジェルマン症候群のてんかんと治療に関する最近のトピックスを紹介した。
• Perampanel for nonepileptic myoclonus in Angelman syndrome.

  Osamu Kawano, Kiyoshi Egawa, Hideaki Shiraishi

  Brain & development 42 (5) 389 - 392 2020/05 [Refereed][Not invited]
   

  BACKGROUND: Angelman syndrome (AS) is a neurodegenerative disorder caused by functional loss of the maternal ubiquitin-protein ligase 3A gene. Nonepileptic myoclonus, also described as tremulous movement, often occurs during puberty and increases in adulthood. The involuntary movement in AS has not been defined patho-physiologically and the drugs used such as levetiracetam and piracetam are not always effective. Recently, the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist, perampanel (PER), was used to alleviate myoclonus in progressive myoclonus epilepsy. Herein, we tested the efficacy of PER for nonepileptic myoclonus. METHODS AND RESULTS: Four patients with AS, aged from 20 to 40 years at the beginning of treatment, were enrolled in our study. All patients reported disruption to their daily lives from the myoclonus movement. They experienced mild to moderate improvement with the starting dose of 2 mg. The dose was increased to 4 mg in one patient to achieve sufficient efficacy, while two had their dose reduced to 1 mg due to dizziness or possible exacerbation of myoclonus. The last patient continued to take the starting dose. Follow-up over 16-20 months revealed a significant reduction in the severity of nonepileptic myoclonus in all patients. CONCLUSION: Our study suggests that PER could be one of the promising drugs for nonepileptic myoclonus in AS.
• A neonatal case of spinal muscular atrophy type I treated with nusinersen from 55 days of age

  Eri Nishino, Noriko Namatame, Osamu Kawano, Kiyoshi Egawa, Takashi Ogasawara, Makoto Kaneda, Hideaki Shiraishi

  No To Hattatsu 52 (1) 38 - 40 0029-0831 2020 

  Herein we report a neonatal case of spinal muscular atrophy (SMA) typeⅠ treated by the antisense oligonucleotide drug, nusinersen, from 55 days after birth. A male infant showed no abnormalities at birth, but demonstrated hypotonia at his 1-month checkup. He was diagnosed as SMA typeⅠ by genetic test at 48 days after birth and treated by nusinersen from day 55. He required no respiratory assistance, could feed orally, and move his upper and lower limbs against gravity during early treatment however, the quantity of oral feeding gradually decreased from 4 months following an upper respiratory tract infection. He subsequently experienced aspiration pneumonia and required tube feeding. With no improvement in his paradoxical breathing at 6 months, the infant was started on noninvasive positive-pressure ventilation during sleep and a cough-assist device. Thus, early administration of nusinersen for a neonate with SMA typeⅠ recovered limb movement, but did not fully stabilize his respiratory condition and oral feeding. This patient was considered as having SMA typeⅠa if subcategorized, and we predict that the efficacy of nusinersen could vary depending on the SMAⅠ subcategory, with typeⅠa showing only partial response to treatment.
• 日齢55よりnusinersenによる治療を開始した脊髄性筋萎縮症I型の1例

  西野 瑛理, 生田目 紀子, 河野 修, 江川 潔, 小笠原 卓, 金田 眞, 白石 秀明

  脳と発達 (一社)日本小児神経学会 52 (1) 38 - 40 0029-0831 2020/01 

  脊髄性筋萎縮症(spinal muscular atrophy;SMA)I型に対しアンチセンス核酸であるnusinersenを日齢55より開始した症例を経験した。症例は男児で、胎児期、生直後に異常を認めなかったが、1ヵ月健診で筋緊張低下を指摘された。日齢48に遺伝学的検査にて脊髄性筋萎縮症I型と診断し、日齢55よりnusinersenの投与を開始した。同剤導入4ヵ月時点で呼吸補助を必要とせず、全量経口哺乳、上下肢の抗重力運動が可能となった。しかし、生後4ヵ月時の上気道感染症罹患を契機に経口哺乳量は減少し、誤嚥性肺炎を来して再度全量経管栄養となった。呼吸に関しては奇異性呼吸の改善を認めず、生後6ヵ月頃より夜間の非侵襲的陽圧換気およびカフアシストを導入した。Nusinersen投与を乳児期極早期に施行し、四肢の運動発達に改善傾向が認められたが、哺乳、呼吸に関しては期待したほど大きな改善を認めなかった。本症例はSMAの亜分類においてSMAIa型と考えられ、nusinersenの治療効果はI型の中でも亜分類によって治療効果に差異があることが示唆された。(著者抄録)
• アンジェルマン症候群モデルマウスにおける脳波・発作閾値の検討

  江川 潔, 白石 秀明

  てんかんをめぐって 日本てんかん学会-北海道地方会 37 49 - 54 1349-3078 2019/12 

  アンジェルマン症候群(AS)は、母性発現遺伝子UBE3Aを原因遺伝子とする疾患で、その約8割に癲癇を合併するとされている。今回、ASモデルマウス(Ube3aを機能欠失させたC57/BL6系マウス)における癲癇発作の客観的評価を試みた。頭蓋内電極を埋め込み、24時間ビデオ脳波記録を行ったところ、癲癇性放電と徐波成分の増強が認められたものの、自発癲癇発作は認められず、自発発作の頻度による癲癇の評価は困難と考えられた。次にGABA受容体拮抗薬Pentylenetetrazolを腹腔内投与し、痙攣発作の観察を30分間行ったが、個体毎のバラツキが大きく、野生型マウス(WT)との有意差は認められなかった。そこで、揮発性のGABA受容体拮抗薬Fluorothylを密閉したチャンバー内に持続注入し、マウスが揮発ガスを吸入し痙攣に至るまでの潜時を調べることで発作閾値を評価した。結果、ASモデルマウスの発作閾値はWTに比べて有意に低く、本法はASモデルマウスにおける発作閾値評価法として優れていることが示唆された。
• Down症候群の発達と療育 合併症の有無による検討

  生田目 紀子, 江川 潔, 須藤 章, 石川 丹

  脳と発達 (一社)日本小児神経学会 51 (6) 373 - 379 0029-0831 2019/11 

  【目的】Down症候群患者の発達と患者背景、リハビリテーション、合併症との関連性を検討することを目的とした。【方法】1997年1月から2016年12月に初診し当院で療育を行ったDown症候群患者の患者背景、当院のリハビリテーション、合併症の有無と、粗大運動および有意語の獲得時期、IQ/DQについて診療録を元に後方視的に調査し、関連性について検討した。【結果】成人期初診例、モザイク症例を除いたDown症候群患者58症例を対象とした。調査時年齢は9.8±4.8歳、初診時月齢は22.3±15.5ヵ月であった。合併症は54例(93%)で確認でき、心疾患37例、眼疾患17例、甲状腺疾患11例、難聴9例、血液疾患5例、消化器疾患3例、てんかん2例であった。難聴、てんかん合併群は粗大運動発達、有意語獲得時期ともに遅い傾向にあり、IQ/DQもより低値であった。患者背景とその他の合併症は概ね発達に影響を及ぼさなかった。生後12ヵ月以前に理学療法を開始した群の独歩獲得までの理学療法期間は、生後24ヵ月以降に開始した群に比し有意に短かった。【結論】てんかん合併群は発達遅滞がより顕著となる傾向にあり、治療、療育の早期介入が重要である。難聴合併群も同様の傾向が疑われるが他の合併症の影響も否定できず、今後詳細な検討が必要となる。Down症候群における理学療法早期開始は早期の独歩獲得に有用である。(著者抄録)
• Diverse Actions of Astrocytes in GABAergic Signaling.

  Masaru Ishibashi, Kiyoshi Egawa, Atsuo Fukuda

  International journal of molecular sciences 20 (12) 2019/06/18 [Refereed][Not invited]
   

  An imbalance of excitatory and inhibitory neurotransmission leading to over excitation plays a crucial role in generating seizures, while enhancing GABAergic mechanisms are critical in terminating seizures. In recent years, it has been reported in many studies that astrocytes are deeply involved in synaptic transmission. Astrocytes form a critical component of the "tripartite" synapses by wrapping around the pre- and post-synaptic elements. From this location, astrocytes are known to greatly influence the dynamics of ions and transmitters in the synaptic cleft. Despite recent extensive research on excitatory tripartite synapses, inhibitory tripartite synapses have received less attention, even though they influence inhibitory synaptic transmission by affecting chloride and GABA concentration dynamics. In this review, we will discuss the diverse actions of astrocytic chloride and GABA homeostasis at GABAergic tripartite synapses. We will then consider the pathophysiological impacts of disturbed GABA homeostasis at the tripartite synapse.
• クロバザムにより自覚的発作コントロール良好な眼瞼ミオクロニアを伴う欠神てんかんの1例

  河野 修, 中島 翠, 伊藤 智城, 植田 佑樹, 江川 潔, 岡嶋 覚, 白石 秀明

  てんかん研究 (一社)日本てんかん学会 37 (1) 85 - 86 0912-0890 2019/06
• Psychomotor development and rehabilitation in down syndrome: Investigations with complications

  Noriko Namatame, Kiyoshi Egawa, Akira Sudo, Akashi Ishikawa

  No To Hattatsu 51 (6) 373 - 379 0029-0831 2019 

  Objective: The present study aimed to investigate the association among psychomotor development, patient profiles, rehabilitation in our clinic, and complications in Down syndrome. Methods: We investigated the profiles, rehabilitation, complications, acquisition of motor developmental milestones, age at utterance of the first specific word, intelligence quotient（IQ）or developmental quotient（DQ）of patients with Down syndrome who first visited to our clinic from January 1997 to December 2016. We also examined the associations among the aforementioned factors. Results: Fifty eight patients with Down syndrome were included in this study but a patient whose first visit was in adulthood and a patient with mosaic trisomy were excluded. The average age of investigation and the first visit of them were 9.8 years and 22.3 months old, respectively. Fifty four patients （93%）had medical complications heart defects 37 patients, eye disorder 17, thyroid disease 11, hearing loss 9, hematologic diseases 5, gastrointestinal disease 3, and epilepsy 2. Hearing loss and epilepsy were related to motor developmental delay and the delayed utterance of the first specific word. Results of IQ or DQ in patients with hearing loss and epilepsy were lower than those in patients without these conditions. In contrast, patients' profiles and the other medical complications mostly were not related to the developmental levels. The patients who started physical therapy before 12 months old needed significantly shorter physical therapy periods to acquire independent walking than those who started physical therapy after 24 months old. Conclusion: Because epilepsy showed negative effects for patients' development, early intervention by treatment and rehabilitation would be important. Hearing loss also showed similar effect however, a final conclusion would require further considerations due to existence of other possible complications which might show some effects. In conclusion, early physical therapy would be important for early acquisition of independent walking for patients with Down syndrome.
• Long-term follow up of an adult with alternating hemiplegia of childhood and a p.Gly755Ser mutation in the ATP1A3 gene.

  Tomoshiro Ito, Masashi Narugami, Kiyoshi Egawa, Hiroyuki Yamamoto, Naoko Asahina, Shinobu Kohsaka, Atsushi Ishii, Shinichi Hirose, Hideaki Shiraishi

  Brain & development 40 (3) 226 - 228 0387-7604 2018/03 [Refereed][Not invited]
   

  Alternating hemiplegia of childhood (AHC) is a rare neurological disease mainly caused by mutations in the ATP1A3 gene and showing varied clinical severity according to genotype. Patients with a p.Gly755Ser (p.G755S) mutation, one of minor genotypes for AHC, were recently described as having a mild phenotype, although their long-term outcomes are still unclear due to the lack of long-term follow up. Here, we demonstrate the full clinical course of a 43-year-old female AHC patient with p.G755S mutation. Although her motor dysfunction had been relatively mild into her 30 s, she showed a subsequent severe aggravation of symptoms that left her bedridden, concomitant with a recent recurrence of seizure status. The seizures were refractory to anti-epileptic drugs, but administration of flunarizine improved seizures and the paralysis. Our case suggests that the phenotype of AHC with p.G755S mutation is not necessarily mild, despite such a presentation during the patient's younger years.
• 皮質形成異常由来の症候性局在関連てんかん2乳児例の初期病像

  高橋 美智, 小川 泰弘, 小野 暁, 信太 知, 梶井 直文, 河野 修, 伊藤 智城, 江川 潔, 白石 秀明, 山本 晃代, 福村 忍, 管野 彩, 江夏 怜, 越智 さと子, 三國 信啓

  日本小児科学会雑誌 (公社)日本小児科学会 121 (11) 1890 - 1890 0001-6543 2017/11
• Minimum Norm Estimateを用いた広汎性脳磁場解析

  田中 雅大, 山本 啓之, 河野 修, 伊藤 智城, 江川 潔, 香坂 忍, 朝比奈 直子, 江夏 怜, 越智 さと子, 三國 信啓, 白石 秀明

  てんかん研究 (一社)日本てんかん学会 35 (1) 74 - 74 0912-0890 2017/06
• Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential.

  Joseph Glykys, Volodymyr Dzhala, Kiyoshi Egawa, Kristopher T Kahle, Eric Delpire, Kevin Staley

  Trends in neurosciences 40 (5) 276 - 294 0166-2236 2017/05 [Refereed][Not invited]
   

  Pharmacoresistant seizures and cytotoxic cerebral edema are serious complications of ischemic and traumatic brain injury. Intraneuronal Cl- concentration ([Cl-]i) regulation impacts on both cell volume homeostasis and Cl--permeable GABAA receptor-dependent membrane excitability. Understanding the pleiotropic molecular determinants of neuronal [Cl-]i - cytoplasmic impermeant anions, polyanionic extracellular matrix (ECM) glycoproteins, and plasmalemmal Cl- transporters - could help the identification of novel anticonvulsive and neuroprotective targets. The cation/Cl- cotransporters and ECM metalloproteinases may be particularly druggable targets for intervention. We establish here a paradigm that accounts for recent data regarding the complex regulatory mechanisms of neuronal [Cl-]i and how these mechanisms impact on neuronal volume and excitability. We propose approaches to modulate [Cl-]i that are relevant for two common clinical sequela of brain injury: edema and seizures.
• Efficacy of perampanel for controlling seizures and improving neurological dysfunction in a patient with dentatorubral-pallidoluysian atrophy (DRPLA).

  Hideaki Shiraishi, Kiyoshi Egawa, Tomoshiro Ito, Osamu Kawano, Naoko Asahina, Shinobu Kohsaka

  Epilepsy & behavior case reports 8 44 - 46 2213-3232 2017 [Refereed][Not invited]
   

  We administered perampanel (PER) to a bedridden 13-year-old male patient with dentatorubral-pallidoluysian atrophy (DRPLA). The DRPLA diagnosis was based on the presence of a CAG trinucleotide repeat in the ATN1 gene. The patient experienced continuous myoclonic seizures and weekly generalized tonic-clonic seizures (GTCs). PER stopped the patient's myoclonic seizures and reduced the GTCs to fragmented clonic seizures. The patient recovered his intellectual abilities and began to walk again with assistance. We suggest that PER be considered as one of the key drugs used to treat patients with DRPLA.
• 新鮮凍結血漿アレルギーに対する選択的血漿交換の経験

  松本 剛直, 太田 稔, 岩見 大基, 千葉 裕基, 佐々木 元, 白石 秀明, 江川 潔, 伊藤 智城, 鳴神 雅史, 篠原 信雄

  日本アフェレシス学会雑誌 (一社)日本アフェレシス学会 35 (Suppl.) 155 - 155 1340-5888 2016/11
• てんかん脳磁図の最前線 発作時脳磁図のdynamic statistical parametric mapping(dSPM)解析

  山本 啓之, 柳生 一自, 鳴神 雅史, 伊藤 智城, 江川 潔, 眞鍋 智代, 高橋 香代子, 中根 進児, 白石 秀明

  日本生体磁気学会誌 日本生体磁気学会 29 (1) 12 - 13 0915-0374 2016/06
• 器質的疾患により思春期早発症を来した2例

  山口 健史, 森川 俊太郎, 石津 桂, 江川 潔, 白石 秀明, 田島 敏広, 有賀 正

  日本小児科学会雑誌 (公社)日本小児科学会 120 (2) 346 - 346 0001-6543 2016/02
• The presence of short and sharp MEG spikes implies focal cortical dysplasia.

  Yuki Ueda, Kiyoshi Egawa, Tomoshiro Ito, Fumiya Takeuchi, Midori Nakajima, Kosuke Otsuka, Naoko Asahina, Kayoko Takahashi, Shingo Nakane, Shinobu Kohsaka, Hideaki Shiraishi

  Epilepsy research 114 141 - 6 0920-1211 2015/08 [Refereed][Not invited]
   

  PURPOSE: This study focused on the characteristic needle-like epileptic spikes of short duration and steep shape seen on magnetoencephalography (MEG) in patients diagnosed with focal cortical dysplasia (FCD) morphologically. We aimed to validate the analysis of MEG spike morphology as a noninvasive method of identifying the presence and location of FCD. METHODS: MEG was collected by 204-channel helmet-shaped gradiometers. We analyzed MEG spike sources for 282 patients with symptomatic localization-related epilepsy. MEG showed clustered equivalent current dipoles when superimposed on their three-dimensional-magnetic resonance images (MRI) in 85 patients. Fifty-seven patients were excluded from our study, because they had destructive brain lesions or an insufficient number of spikes for statistical analysis. Twenty-eight patients (18 males, 10 females; aged 1-34 years) were finally matched to our inclusion criteria, and were categorized into three groups: FCD (7 patients), non-FCD (10 patients), and non-lesion (11 patients), based on the MRI findings. We measured the duration, amplitude, and tilt manually for at least 15 spikes per patient, and compared the three groups using a one-way analysis of variance, followed by the Tukey test when statistically significant (p < 0.05). In 17 patients with visible MRI lesions, we investigated the correlation between the depth of the lesion and the tilt using the Pearson product moment correlation. RESULTS: The average spike duration was significantly shorter in the FCD and non-lesion groups than in the non-FCD group (p < 0.05). The average amplitude was not significantly different between the three groups. The average spike tilt was significantly steeper in the FCD group than in the non-FCD group (p = 0.0058). There was no significant difference between FCD and non-lesion patients in both duration and tilt. Our additional study revealed a significant negative correlation between the depth of the lesion and the average tilt (p = 0.0009). SIGNIFICANCE: MEG epileptiform discharges of short duration and steep tilt characterize FCD, especially when located at the superficial neocortical gyrus. We speculate that this particular spike morphology results from the intrinsic epileptogenicity of FCD. Morphological analysis of MEG spikes can evaluate the etiology of epileptogenic lesions and detect a strong, localized epileptogenic focus such as that typically observed in FCD.
• 【神経症候群(第2版)-その他の神経疾患を含めて-】てんかん症候群 その他の重要な病態 Angelman症候群

  白石 秀明, 江川 潔, 細木 華奈

  日本臨床 (株)日本臨床社 別冊 (神経症候群VI) 436 - 440 0047-1852 2014/12
• Response to Comments on "Local impermeant anions establish the neuronal chloride concentration"

  J. Glykys, V. Dzhala, K. Egawa, T. Balena, Y. Saponjian, K. V. Kuchibhotla, B. J. Bacskai, K. T. Kahle, T. Zeuthen, K. J. Staley

  SCIENCE 345 (6201) 0036-8075 2014/09 [Refereed][Not invited]
  
• Local Impermeant Anions Establish the Neuronal Chloride Concentration

  J. Glykys, V. Dzhala, K. Egawa, T. Balena, Y. Saponjian, K. V. Kuchibhotla, B. J. Bacskai, K. T. Kahle, T. Zeuthen, K. J. Staley

  SCIENCE 343 (6171) 670 - 675 0036-8075 2014/02 [Refereed][Not invited]
   

  Neuronal intracellular chloride concentration [Cl-](i) is an important determinant of gamma-aminobutyric acid type A (GABA(A)) receptor (GABA(A)R)-mediated inhibition and cytoplasmic volume regulation. Equilibrative cation-chloride cotransporters (CCCs) move Cl- across the membrane, but accumulating evidence suggests factors other than the bulk concentrations of transported ions determine [Cl-](i). Measurement of [Cl-](i) in murine brain slice preparations expressing the transgenic fluorophore Clomeleon demonstrated that cytoplasmic impermeant anions ([A](i)) and polyanionic extracellular matrix glycoproteins ([A](o)) constrain the local [Cl-]. CCC inhibition had modest effects on [Cl-] i and neuronal volume, but substantial changes were produced by alterations of the balance between [A](i) and [A](o). Therefore, CCCs are important elements of Cl- homeostasis, but local impermeant anions determine the homeostatic set point for [Cl-], and hence, neuronal volume and the polarity of local GABA(A)R signaling.
• Cl⁻ homeodynamics in gap junction-coupled astrocytic networks on activation of GABAergic synapses.

  Kiyoshi Egawa, Junko Yamada, Tomonori Furukawa, Yuchio Yanagawa, Atsuo Fukuda

  The Journal of physiology 591 (16) 3901 - 17 0022-3751 2013/08/15 [Refereed][Not invited]
   

  The electrophysiological properties and functional role of GABAergic signal transmission from neurons to the gap junction-coupled astrocytic network are still unclear. GABA-induced astrocytic Cl⁻ flux has been hypothesized to affect the driving force for GABAergic transmission by modulating [Cl⁻]o. Thus, revealing the properties of GABA-mediated astrocytic responses will deepen our understanding of GABAergic signal transmission. Here, we analysed the Cl⁻ dynamics of neurons and astrocytes in CA1 hippocampal GABAergic tripartite synapses, using Cl⁻ imaging during GABA application, and whole cell recordings from interneuron-astrocyte pairs in the stratum lacunosum-moleculare. Astrocytic [Cl⁻]i was adjusted to physiological conditions (40 mm). Although GABA application evoked bidirectional Cl⁻ flux via GABAA receptors and mouse GABA transporter 4 (mGAT4) in CA1 astrocytes, a train of interneuron firing induced only GABAA receptor-mediated inward currents in an adjacent astrocyte. A GAT1 inhibitor increased the interneuron firing-induced currents and induced bicuculline-insensitive, mGAT4 inhibitor-sensitive currents, suggesting that synaptic spillover of GABA predominantly induced the astrocytic Cl⁻ efflux because GABAA receptors are localized near the synaptic clefts. This GABA-induced Cl⁻ efflux was accompanied by Cl⁻ siphoning via the gap junctions of the astrocytic network because gap junction inhibitors significantly reduced the interneuron firing-induced currents. Thus, Cl⁻ efflux from astrocytes is homeostatically maintained within astrocytic networks. A gap junction inhibitor enhanced the activity-dependent depolarizing shifts of reversal potential of neuronal IPSCs evoked by repetitive stimulation to GABAergic synapses. These results suggest that Cl⁻ conductance within the astrocytic network may contribute to maintaining GABAergic synaptic transmission by regulating [Cl⁻]o.
• Deteriorated degradation of GAT1 by Ube3 a deficiency causes a decrement of tonic inhibition in cerebellar granule cells and a cerebellar ataxia

  Fukuda Atsuo, Egawa Kiyoshi, Kitagawa Kyoko, Takayama Masakazu, Takayama Chitoshi, Saitoh Shinji, Kishino Tatsuya, Kitagawa Masatoshi

  JOURNAL OF PHYSIOLOGICAL SCIENCES 63 S125  1880-6546 2013 [Refereed][Not invited]
  
• Pathophysiological power of improper tonic GABA(A) conductances in mature and immature models.

  Kiyoshi Egawa, Atsuo Fukuda

  Frontiers in neural circuits 7 170 - 170 1662-5110 2013 [Refereed][Not invited]
   

  High-affinity extrasynaptic gamma-aminobutyric acid A (GABA(A)) receptors are tonically activated by low and consistent levels of ambient GABA, mediating chronic inhibition against neuronal excitability (tonic inhibition) and the modulation of neural development. Synaptic (phasic) inhibition is spatially and temporally precise compared with tonic inhibition, which provides blunt yet strong integral inhibitory force by shunting electrical signaling. Although effects of acute modification of tonic inhibition are known, its pathophysiological significance remains unclear because homeostatic regulation of neuronal excitability can compensate for long-term deficit of extrasynaptic GABA(A) receptor activation. Nevertheless, tonic inhibition is of great interest for its pathophysiological involvement in central nervous system (CNS) diseases and thus as a therapeutic target. Together with the development of experimental models for various pathological states, recent evidence demonstrates such pathological involvements of tonic inhibition in neuronal dysfunction. This review focuses on the recent progress of tonic activation of GABA(A) conductance on the development and pathology of the CNS. Findings indicate that neuronal function in various brain regions are exacerbated with a gain or loss of function of tonic inhibition by GABA spillover. Disturbance of tonic GABA(A) conductance mediated by non-synaptic ambient GABA may result in brain mal-development. Therefore, various pathological states (epilepsy, motor dysfunctions, psychiatric disorders, and neurodevelopmental disorders) may be partly attributable to abnormal tonic GABA(A) conductances. Thus, the tone of tonic conductance and level of ambient GABA may be precisely tuned to maintain the regular function and development of the CNS. Therefore, receptor expression and factors for regulating the ambient GABA concentration are highlighted to gain a deeper understanding of pathology and therapeutic strategy for CNS diseases.
• Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome.

  Kiyoshi Egawa, Kyoko Kitagawa, Koichi Inoue, Masakazu Takayama, Chitoshi Takayama, Shinji Saitoh, Tatsuya Kishino, Masatoshi Kitagawa, Atsuo Fukuda

  Science translational medicine 4 (163) 163ra157  1946-6234 2012/12/05 [Refereed][Not invited]
   

  Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the UBE3A gene encoding a ubiquitin E3 ligase. Motor dysfunction is a characteristic feature of Angelman syndrome, but neither the mechanisms of action nor effective therapeutic strategies have yet been elucidated. We report that tonic inhibition is specifically decreased in cerebellar granule cells of Ube3a-deficient mice, a model of Angelman syndrome. As a mechanism underlying this decrease in tonic inhibition, we show that Ube3a controls degradation of γ-aminobutyric acid (GABA) transporter 1 (GAT1) and that deficiency of Ube3a induces a surplus of GAT1 that results in a decrease in GABA concentrations in the extrasynaptic space. Administering low doses of 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridin-3-ol (THIP), a selective extrasynaptic GABA(A) receptor agonist, improves the abnormal firing properties of a population of Purkinje cells in cerebellar brain slices and reduces cerebellar ataxia in Ube3a-deficient mice in vivo. These results suggest that pharmacologically increasing tonic inhibition may be a useful strategy for alleviating motor dysfunction in Angelman syndrome.
• GABAergic dysfunction in Ube3a deficient mice, models of Angelman syndrome

  Egawa Kiyoshi, Inoue Koichi, Saitoh Shinji, Kishino Tatsuya, Fukuda Atsuo

  Neuroscience Research Elsevier 71 e400  0168-0102 2011 [Refereed][Not invited]
  
• Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay.

  Hirotomo Saitsu, Jun Tohyama, Tatsuro Kumada, Kiyoshi Egawa, Keisuke Hamada, Ippei Okada, Takeshi Mizuguchi, Hitoshi Osaka, Rie Miyata, Tomonori Furukawa, Kazuhiro Haginoya, Hideki Hoshino, Tomohide Goto, Yasuo Hachiya, Takanori Yamagata, Shinji Saitoh, Toshiro Nagai, Kiyomi Nishiyama, Akira Nishimura, Noriko Miyake, Masayuki Komada, Kenji Hayashi, Syu-Ichi Hirai, Kazuhiro Ogata, Mitsuhiro Kato, Atsuo Fukuda, Naomichi Matsumoto

  American journal of human genetics 86 (6) 881 - 91 0002-9297 2010/06/11 [Refereed][Not invited]
   

  A de novo 9q33.3-q34.11 microdeletion involving STXBP1 has been found in one of four individuals (group A) with early-onset West syndrome, severe hypomyelination, poor visual attention, and developmental delay. Although haploinsufficiency of STXBP1 was involved in early infantile epileptic encephalopathy in a previous different cohort study (group B), no mutations of STXBP1 were found in two of the remaining three subjects of group A (one was unavailable). We assumed that another gene within the deletion might contribute to the phenotype of group A. SPTAN1 encoding alpha-II spectrin, which is essential for proper myelination in zebrafish, turned out to be deleted. In two subjects, an in-frame 3 bp deletion and a 6 bp duplication in SPTAN1 were found at the initial nucleation site of the alpha/beta spectrin heterodimer. SPTAN1 was further screened in six unrelated individuals with WS and hypomyelination, but no mutations were found. Recombinant mutant (mut) and wild-type (WT) alpha-II spectrin could assemble heterodimers with beta-II spectrin, but alpha-II (mut)/beta-II spectrin heterodimers were thermolabile compared with the alpha-II (WT)/beta-II heterodimers. Transient expression in mouse cortical neurons revealed aggregation of alpha-II (mut)/beta-II and alpha-II (mut)/beta-III spectrin heterodimers, which was also observed in lymphoblastoid cells from two subjects with in-frame mutations. Clustering of ankyrinG and voltage-gated sodium channels at axon initial segment (AIS) was disturbed in relation to the aggregates, together with an elevated action potential threshold. These findings suggest that pathological aggregation of alpha/beta spectrin heterodimers and abnormal AIS integrity resulting from SPTAN1 mutations were involved in pathogenesis of infantile epilepsy.
• Electroclinical features of epilepsy in patients with juvenile type dentatorubral-pallidoluysian atrophy.

  Kiyoshi Egawa, Yukitoshi Takahashi, Yuko Kubota, Hideki Kubota, Yushi Inoue, Takeki Fujiwara, Osamu Onodera

  Epilepsia 49 (12) 2041 - 9 0013-9580 2008/12 [Refereed][Not invited]
   

  PURPOSE: To clarify the electroclinical characteristics of epileptic seizures in patients with juvenile type dentatorubral-pallidoluysian atrophy (DRPLA). METHODS: Seventeen patients with juvenile type DRPLA confirmed by genetic analysis were studied retrospectively. The clinical records of all 17 patients and the ictal video electroencephalography (EEG) recordings from 12 of the 17 patients were reviewed. RESULTS: Electroclinical studies in 12 patients identified 11 habitual seizures in 6 patients as partial seizures on ictal video EEG recordings. Clinical manifestations composed mainly of versions of the head and loss of consciousness. These partial seizures were persistently recorded throughout the clinical course. Brief generalized seizures (atypical absence and myoclonic seizure) were observed in 6 of 12 patients at the early stage. In contrast, generalized tonic-clonic seizures (GTCS) were recorded in four advanced stage patients who were almost bedridden. Semiological studies in 17 patients showed that the prevalence of partial seizures was significantly higher in patients with younger epilepsy onset (below 10 years of age; chi(2) test, p < 0.05) and that the age of epilepsy onset was significantly lower in patients with partial seizures than in those without partial seizures (Mann-Whitney U test, p = 0.02). However, the number of CAG repeats and age at clinical onset were not significantly different between two groups. DISCUSSION: Partial seizure is one of the common epileptic features in juvenile type DRPLA, especially in patients with younger epilepsy onset. Seizure types may be affected in an age-dependent manner and change evolutionally during progression of the clinical stage.
• [(11)C]flumazenil positron emission tomography analyses of brain gamma-aminobutyric acid type A receptors in Angelman syndrome.

  Naoko Asahina, Tohru Shiga, Kiyoshi Egawa, Hideaki Shiraishi, Shinobu Kohsaka, Shinji Saitoh

  The Journal of pediatrics 152 (4) 546 - 9 0022-3476 2008/04 [Refereed][Not invited]
   

  OBJECTIVE: To evaluate the role of the gamma-aminobutyric acid type A (GABA(A)) receptor in Angelman syndrome (AS). STUDY DESIGN: We performed [(11)C]flumazenil positron emission tomography (PET) and examined GABA(A) receptor expression in 7 patients with AS of various genotypes (5 with the deletion, 1 with an imprinting defect [ID], and 1 with a UBE3A mutation) and 4 normal control healthy volunteers. RESULTS: Relative to the control subjects, the [(11)C]flumazenil binding potentials (BPs) were significantly higher in the cerebral cortex and cerebellum in the 5 patients with the deletion and in the 1 patient with a UBE3A mutation, and were less frequently or barely increased in adult patients with the deletion and in the patient with IDs. CONCLUSIONS: Total GABA(A) receptor expression was increased in patients with AS with various genotypes. We suggest that a developmental dysregulation of the GABA(A) receptor subunits occurs in patients with AS.
• Aberrant somatosensory-evoked responses imply GABAergic dysfunction in Angelman syndrome.

  Kiyoshi Egawa, Naoko Asahina, Hideaki Shiraishi, Kyousuke Kamada, Fumiya Takeuchi, Shingo Nakane, Akira Sudo, Shinobu Kohsaka, Shinji Saitoh

  NeuroImage 39 (2) 593 - 9 1053-8119 2008/01/15 [Refereed][Not invited]
   

  A role for gamma-aminobutyric acid (GABA)ergic inhibition in cortical sensory processing is one of the principle concerns of brain research. Angelman syndrome (AS) is thought to be one of the few neurodevelopmental disorders with GABAergic-related genetic involvement. AS results from a functional deficit of the imprinted UBE3A gene, located at 15q11-q13, resulting mainly from a 4-Mb deletion that includes GABA(A) receptor subunit genes. These genes are believed to affect the GABAergic system and modulate the clinical severity of AS. To understand the underlying cortical dysfunction, we have investigated the primary somatosensory-evoked responses in AS patients. Subjects included eleven AS patients with a 15q11-q13 deletion (AS Del), two AS patients without a 15q11-q13 deletion, but with a UBE3A mutation (AS non-Del), six epilepsy patients (non-AS) and eleven normal control subjects. Somatosensory-evoked fields (SEFs) in response to median nerve stimulation were measured by magnetoencephalography. The N1m peak latency in AS Del patients was significantly longer (34.6+/-4.8 ms) than in non-AS patients (19.5+/-1.2 ms, P<0.001) or normal control subjects (18.4+/-1.8 ms, P<0.001). The next component, P1m, was prolonged and ambiguous and was only detected in patients taking clonazepam. In contrast, SEF waveforms of AS non-Del patients were similar to those of control individuals, rather than to AS Del patients. Thus, GABAergic dysfunction in AS Del patients is likely due to hemizygosity of GABA(A) receptor subunit genes, suggesting that GABAergic inhibition plays an important role in synchronous activity of human sensory systems.
• Graded Magnetoencephalographic Analysis for Patients with Epilepsy : For Universal Application for Every Patient with Epilepsy

  SHIRAISHI Hideaki, TAKEUCHI Fumiya, EGAWA Kiyoshi, SUEDA Keitaro, ASAHINA Naoko, KOHSAKA Shinobu, NAKANE Shingo, SAITOH Shinji

  CI研究 : progress in computed imaging 日本脳神経CI学会 29 (1) 43 - 49 0918-7073 2007/06/30 [Not refereed][Not invited]
   

  小児のてんかん109症例を対象に、妥当性のある異常磁場活動に関する情報を得るための脳磁場(MEG)測定法を検討した。単一双極子法では、83症例でてんかん原性領域を特定でき、電流源が単一脳回に局在し、等価電流双極子(ECD)の局在に集積傾向を示した。残り26症例にdynamic statistical parametric mappingを用いた解析を行ったところ、16例で臨床発作対応の得られる磁場分布の表現が可能であった。これらの解析によっても解が得られなかった症候性局在関連てんかん10例に短時間フーリエ変換を用いた周波数解析を行ったところ、最頻出現周波数帯域の局在が求められ、臨床発作対応の得られる磁場分布であった。考え得る全てのてんかん性異常磁場活動の評価は、これらの捕捉された脳磁場波形を適切に適応することにより可能であると考えられた。
• Long-term sequential magnetoencephalographic analyses for patients with atypical benign partial epilepsy in childhood

  Hideaki Shiraishi, Kiyoshi Egawa, Naoko Asahina, Shinji Nakane, Yasuyo Udo, Akira Satake, Shinobu Kohsaka, Shinji Saitoh

  International Congress Series 1300 689 - 692 0531-5131 2007/06 [Refereed][Not invited]
   

  This study charted the magnetoencephalographic (MEG) findings with clinical course for atypical benign partial epilepsy in childhood (ABPE). We discuss the etiology and epileptogenesis of this condition. Three patients with ABPE (age: 8-10 years old) underwent MEG analysis using a 204ch helmet-shape MEG system. MEG showed unilateral epileptic activities over the frontal and temporal operculum and insular cortex during the worst seizures. The findings changed as the seizures were reduced by localized clustering of equivalent current dipoles (ECDs) at the unilateral temporal and frontal operculum near the primary motor area. We concluded that the localizations and directions of the ECDs in our patients during seizure remission resembled those of benign Rolandic epilepsy (BRE). We suggest a similar pathogenesis for ABPE and BRE. © 2007 Elsevier B.V. All rights reserved.
• 【抗てんかん薬による治療 新たな動向と展望】自己免疫反応から見たてんかん予防・治療の可能性

  高橋 幸利, 西村 成子, 角替 央野, 大谷 英之, 四家 達彦, 二階堂 弘輝, 小田 望, 江川 潔, 池田 浩子

  臨床精神薬理 (株)星和書店 10 (4) 607 - 616 1343-3474 2007/04 

  感染症に引き続いて発病するてんかんの一部などに、自己免疫がてんかん原性獲得に関係しているものがあることが明らかになってきた。Rasmussen症候群では細胞障害性T細胞を主体に、自己抗体・サイトカインの関与が考えられており、機能的半球切除が不可能な段階の症例では種々の免疫治療が行われている。血漿交換療法は主としててんかん重積時の適応があり、ガンマグロブリン療法(IVIG)は大きな副作用はなく比較的安全であるが、初回投与後明らかな有効例に絞って継続する。ステロイドパルス治療は初期に有効で、慢性期には重積時に適応となる。Tacrolimusはてんかん発作には無効であるが神経機能の退行を防く効果があるとされている。急性脳炎でも自己免疫の関与が明らかになりつつあり、急性期治療へそれらの知見を反映させることにより、後遺症としてのてんかんを予防・軽減できる可能性がある。(著者抄録)
• てんかん症例における律動波に対する脳磁図解析の試み

  白石 秀明, 竹内 文也, 江川 潔, 末田 慶太朗, 朝比奈 直子, 香坂 忍, 中根 進児, 斉藤 伸治

  てんかんをめぐって 日本てんかん学会-北海道地方会 XXVI 73 - 73 1349-3078 2007/03
• てんかん症例における脳磁律動波に対する周波数解析の試み

  白石 秀明, 竹内 文也, 江川 潔, 末田 慶太朗, 朝比奈 直子, 香坂 忍, 中根 進児, 斉藤 伸治

  てんかんをめぐって 日本てんかん学会-北海道地方会 XXVI 31 - 36 1349-3078 2007/03 

  15歳女児。10歳時に初発したが顕在化せず、12歳時に発作が出現し抗てんかん薬治療を開始したが発作は持続し、14歳時のMRIで左後頭葉・頭頂葉に限局性病変を認め、Dysembryoplastic neuroepithelial tumor(DNT)と診断した。発作間歇時SPECTで腫瘍像と一致した部位に集積欠損領域を認め、左前頭葉集積は右側より低下していた。頭皮上脳波・脳磁図は左半球性に出現する磁場活動上の多棘波に対応し、周波数解析では棘律動が腫瘍部分周辺および腫瘍前方の前頭葉領域に拡延して出現した。腫瘍摘出術は皮質脳波所見の腫瘍縁より一脳回広く脳回切除を施行し、病理所見はDNTであった。術後皮質脳波で前頭葉方向の拡延する棘律動は残存したが術後1年発作症状は認めていない。以上より、律動性棘波は脳磁場計測においても位相、周波数ともにほぼ相同な波形を示し周波数解析法のみが解析可能な方法と考えられた。また、基礎活動としての律動波に対しても磁場解析の可能性が示唆された。
• 肝膿瘍を契機に診断がついた慢性肉芽腫症の1例

  小林 穂高, 江川 潔, 藤田 祥二, 阿部 修司, 遠藤 満智子

  函館五稜郭病院医誌 函館五稜郭病院 14 20 - 23 1341-0687 2006/04 

  4歳4ヵ月男児.正常分娩で正常に出産したが生後6ヵ月から肛門周囲膿瘍,中耳炎,歯肉炎,口内炎,皮膚感染,麦粒腫などの細菌感染を反復した既往があった.腹部の圧痛の出現に続いて発熱を認め,腹部腫瘤が認められたことから入院となった.父親や姉に易感染性を疑う既往はなかったが,母親は小児期から傷が化膿しやすかった.腹部腫瘤は肝臓腫大であり,腹部CTにて肝膿瘍と診断し,肉芽腫性病変と考えられた.好中球機能検査の結果,貪食能は98.6%と正常であったが,殺菌能は16.7%と低下しており,慢性肉芽腫症と診断した
• 脊髄動静脈奇形を原因とするクモ膜下出血の1乳児例

  佐藤 泰征, 江川 潔, 朝比奈 直子, 白石 秀明, 斉藤 伸治, 有賀 正

  日本小児科学会雑誌 (公社)日本小児科学会 110 (4) 593 - 593 0001-6543 2006/04 [Not refereed][Not invited]
  
• Angelman症候群の再発危険率と遺伝カウンセリング

  斉藤 伸治, 江川 潔, 朝比奈 直子, 白石 秀明, 須藤 章

  北海道医学雑誌 北海道医学会 81 (2) 172 - 173 0367-6102 2006/03
• Panayiotopoulos症候群の長期経過と治療効果

  須藤 章, 佐竹 明, 梶井 直文, 江川 潔, 朝比奈 直子, 白石 秀明, 石川 信義, 斉藤 伸治

  てんかんをめぐって 日本てんかん学会-北海道地方会 XXV 26 - 35 1349-3078 2006/03 

  Panayiotopoulos症候群と診断確実な症例の全経過の臨床的特徴を詳細に明らかにするため,けいれん性疾患で2年以上脳波フォローができた440例中,条件を全て満たし,抗てんかん薬中止後2年以上観察できた17例を対象として診療録をもとに後方視的に検討した.熱性けいれんの既往を6例に認めた.両親または兄弟が熱性けいれんまたはてんかんとされた家族歴を有するものを6例で認めた.発作時の年齢は,4歳をピークとして年齢とともに発作症例が減少し,10歳以後の発作症例はなかった.抗てんかん薬使用前後の発作回数は,治療前後で有意差なく,17例中12例で投薬後にも再発した.17例全例で投薬終了後2年間経過観察したが,発作の再発例はなく,脳波異常の再現もなかった
• 非定型良性小児部分てんかん症例の経時的変化 脳磁図所見,治療経過を中心に

  白石 秀明, 江川 潔, 朝比奈 直子, 須藤 章, 香坂 忍, 斉藤 伸治, 中根 進児, 有働 康代

  てんかんをめぐって 日本てんかん学会-北海道地方会 XXV 65 - 66 1349-3078 2006/03
• Dynamic statistical parametric mapping for analyzing the magnetoencephalographic epileptiform activity in patients with epilepsy.

  Hideaki Shiraishi, Steven M Stufflebeam, Susanne Knake, Seppo P Ahlfors, Akira Sudo, Naoko Asahina, Kiyoshi Egawa, Keisaku Hatanaka, Shinobu Kohsaka, Shinji Saitoh, P Ellen Grant, Anders M Dale, Eric Halgren

  Journal of child neurology 20 (4) 363 - 9 0883-0738 2005/04 [Refereed][Not invited]
   

  Our current purpose is to evaluate the applicability of dynamic statistical parametric mapping, a novel method for localizing epileptiform activity recorded with magnetoencephalography in patients with epilepsy. We report four pediatric patients with focal epilepsies. Magnetoencephalographic data were collected with a 306-channel whole-head helmet-shaped sensor array. We calculated equivalent current dipoles and dynamic statistical parametric mapping movies of the interictal epileptiform discharges that were based in the minimum-L2 norm estimate, minimizing the square sum of the dipole element amplitudes. The dynamic statistical parametric mapping analysis of interictal epileptiform discharges can demonstrate the rapid change and propagation of interical epileptiform discharges. According to these findings, specific epileptogenic lesion-focal cortical dysplasia could be found and patients could be operated on successfully. The presurgical analysis of interictal epileptiform discharges using dynamic statistical parametric mapping seems to be promising in patients with a possible underlying focal cortical dysplasia and might help to guide the placement of invasive electrodes.
• Really sterile pyuria with Kawasaki disease?

  Nobuko Shiono, Yasutsugu Koga, Hironobu Ito, Kiyoshi Egawa, Satoru Ono, Noritomo Itami

  Pediatric nephrology (Berlin, Germany) 19 (1) 124 - 124 0931-041X 2004/01 [Refereed][Not invited]
  

MISC

• 腹膜透析中に発症した焦点性てんかんに対してラコサミドを導入した小児例の経験

  植田 佑樹, 佐藤 泰征, 林 麻子, 上田 泰弘, 木村 修平, 後藤 健, 中久保 佐千子, 中島 翠, 江川 潔, 岡本 孝之, 白石 秀明, 古堅 彩子, 小林 正紀, 真部 淳  てんかん研究  40-  (2)  467  -467  2022/08
• 腹膜透析中に発症した焦点性てんかんに対してラコサミドを導入した小児例の経験

  植田 佑樹, 佐藤 泰征, 林 麻子, 上田 泰弘, 木村 修平, 後藤 健, 中久保 佐千子, 中島 翠, 江川 潔, 岡本 孝之, 白石 秀明, 古堅 彩子, 小林 正紀, 真部 淳  てんかん研究  40-  (2)  467  -467  2022/08
• 発達性てんかん性脳症に対するACTH週1回長期療法時の副腎機能の検討

  植田 佑樹, 木村 修平, 後藤 健, 中久保 佐千子, 生田目 紀子, 鳴神 雅史, 中山 加奈子, 菱村 希, 山口 健史, 中村 明枝, 江川 潔, 白石 秀明  てんかん研究  38-  (3)  223  -223  2021/01
• Angelman症候群患者iPS細胞由来神経細胞における電気生理学的検討

  江川 潔, 平田 快洋, 白石 秀明, 佐藤 大介, 齋藤 伸治, 高橋 幸利, 奥野 博庸, 石川 充, 岡野 栄之  脳と発達  52-  (4)  272  -272  2020/07
• 乳児期早期にてんかんを発症したHNRNPU遺伝子異常の1女児例

  河野 修, 生田目 紀子, 中島 翠, 伊藤 智城, 江川 潔, 岡嶋 覚, 板井 俊幸, 宮武 聡子, 松本 直通, 白石 秀明  脳と発達  52-  (4)  273  -273  2020/07
• 皮質下および深部白質に広範な病変を呈したJacobsen症候群の1例

  植田 佑樹, 河野 修, 中島 翠, 江川 潔, 澤井 彩織, 白石 秀明  脳と発達  52-  (4)  273  -274  2020/07
• ACTH治療で水頭症が増悪した症候性West症候群の1例

  植田 佑樹, 中島 翠, 鳴神 雅史, 中久保 佐千子, 江川 潔, 白石 秀明  日本小児科学会雑誌  124-  (7)  1165  -1165  2020/07
• 難治性の乳児てんかん性脳症に対するACTH週1回長期治療の試み

  植田 佑樹, 江川 潔, 中島 翠, 中久保 佐千子, 鳴神 雅史, 白石 秀明  日本小児科学会雑誌  124-  (2)  458  -458  2020/02
• AdSPMを使用した脳溝底に存在する限局性皮質形成異常の診断

  中島 翠, 植田 佑樹, 江川 潔, 越智 文子, 白石 秀明, 大坪 宏  脳と発達  51-  (Suppl.)  S246  -S246  2019/05
• 焦点性てんかんにおける片側性の律動性活動は脳磁図で見出されることがある

  植田 佑樹, 中島 翠, 江川 潔, 香坂 忍, 白石 秀明  脳と発達  51-  (Suppl.)  S379  -S379  2019/05
• アンジェルマン症候群患者由来iPS細胞を用いた興奮性神経細胞機能評価

  江川 潔, 平田 快洋, 白石 秀明, 佐藤 大介, 齋藤 伸治, 高橋 幸利, 奥野 博庸, 石川 充, 岡野 栄之  脳と発達  50-  (Suppl.)  S301  -S301  2018/05
• ASTROCYTIC RESPONSES TO GABA SPILL-OVER BY INTERNEURON FIRINGS IN CA1 STRATUM LACUNOSUM-MOLECULARE (SLM)

  Kiyoshi Egawa, Yamada Junko, Furukawa Tomonori, Yuchio Yanagawa, Atuo Fukuda  JOURNAL OF PHYSIOLOGICAL SCIENCES  59-  197  -197  2009  [Not refereed][Not invited]
  
• Evoked currents in CA1 stratum lacunosum-moleculare (SLM) astrocyte by adjacent interneuron firings

  Kiyoshi Egawa, Junko Yamada, Tomonori Furukawa, Atsuo Fukuda  NEUROSCIENCE RESEARCH  65-  S148  -S148  2009  [Not refereed][Not invited]
  
• Proliferation of GABAergic interneurons but not cortical plate cells was reduced by maternal stress in the fetal cerebral cortex

  Taku Uchida, Toshitaka Morishima, Tomonori Furukawa, Yutaka Oki, Kiyoshi Egawa, Tatsurou Kumada, Yuchio Yanagawa, Atsuo Fukuda  NEUROSCIENCE RESEARCH  65-  S185  -S185  2009  [Not refereed][Not invited]
  
• Evoked GABA currents and [Cl-](i) alterations in hippocampal CA1 astrocytes

  Kiyoshi Egawa, Junko Yamada, Tomonori Furukawa, Atsuo Fukuda  NEUROSCIENCE RESEARCH  61-  S226  -S226  2008  [Not refereed][Not invited]
  
• O1-19 Epilepsy in Patients with Juvenile type Dentatorubral-pallidoluysian Atrophy(The 41^ Congress of the Japan Epilepsy Society)

  江川 潔, 高橋 幸利, 久保田 裕子, 久保田 英幹, 井上 有史, 藤原建樹  Journal of the Japan Epilepsy Society  25-  (3)  262  -262  2007/09/30
• パニック障害を疑われた側頭葉てんかんの一例

  大谷 英之, 高橋 幸利, 久保田 裕子, 江川 潔, 池田 浩子, 井上 有史, 藤原 建樹  脳と発達  39-  (Suppl.)  S338  -S338  2007/06  [Not refereed][Not invited]
  
• Long-term clinical outcome and treatment efficacy of Panayiotopoulos syndrome.

  A Sudo, A Satake, A Kajii, K Egawa, N Asahina, H Shiraishi, N Ishikawa, S Saitoh  EPILEPSIA  46-  22  -22  2005  [Not refereed][Not invited]
  
• Longterm sequential magnetoencephalographic analysis for patients with atypical benign partial epilepsy in childhood

  H Shiraishi, K Egawa, N Asahina, A Sudo, S Nakane, Y Udo, A Satake, S Kohsaka, S Saitoh  EPILEPSIA  46-  175  -175  2005  [Not refereed][Not invited]
  

Books etc

• The Causes of Epilepsy, 2nd edition

  Kiyoshi Egawa (Chapter 46. Dentatorubral-Pallidoluysian atrophy (DRPLA).)
  Cambridge Press 2018/12

Research Projects

• ドラベ症候群におけるα2サブユニット選択的GABA(A)受容体賦活薬の有効性検証

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  Date (from‐to) : 2022/04 -2025/03 

  Author : 江川 潔
• なぜ概日リズム中枢はGABA作動性神経細胞から構成されるのか？

  日本学術振興会：科学研究費助成事業 基盤研究(B)

  Date (from‐to) : 2020/04 -2024/03 

  Author : 榎木 亮介, 江川 潔

   

  本研究課題では、哺乳類の概日時計中枢である視床下部の視交叉上核が何故GABA作動性神経細胞で構成されるのかを、光イメージング技術を駆使して解明することを目指している。本年度は特に、神経細胞のGABA応答性（脱分極-過分極）を決定するクロライドイオンに着目して研究を行った。アデノ随伴ウイルスを用いて遺伝子コード型クロライドを視交叉上核の神経細胞に感染発現させ、視交叉上核におけるプローブの発現パターンと機能動作の確認を行ったところ、プローブは視交叉上核の全領域において発現しており、その蛍光輝度は細胞内クロライド濃度の操作に伴い予測通りに変化することを確認した。蛍光-クロライド濃度の検量カーブを作成して細胞内クロライド濃度を計算し、パッチクランプ計測により報告されている従来のクロライド濃度とほぼ一致した。さらに長期蛍光イメージング顕微鏡システムにより数日間のタイムラプス計測を行ったところ、クロライドイオン濃度の24時間のリズムを細胞ネットワークレベルで観察した。リズム解析プログラムによりリズムの振幅、最低値、位相などを解析したところ、神経細胞ネットワークにおける特徴的な部位差とリズム位相パターンがあることを見いだした。またクロライドイオンとカルシウムイオンの同時イメージング計測を行い、既知のカルシウムリズムと比較することで"概日クロライドリズム"の位相を決定した。
• GABA持続抑制不全の多様性がもたらすアンジェルマン症候群の病態解明と治療法開発

  科学研究費助成事業 基盤研究B

  Date (from‐to) : 2018 -2021 

  Author : 江川 潔
• アンジェルマン症候群におけるてんかんの病態生理解明と治療法 の開発

  公益財団法人てんかん治療研究振興財団：研究助成

  Date (from‐to) : 2019/04 -2020/03
• 細胞発振現象と集団発振のモーダルシフト

  科学研究費助成事業 新学術領域

  Date (from‐to) : 2015 -2020 

  Author : 福田敦夫
• Pathophysiological impact of diverse deregulation of tonic inhibition in Angelman syndrome

  Angelman syndrome foundation：Research grant award

  Date (from‐to) : 2017/01 -2018/12 

  Author : Kiyoshi Egawa
• 自閉症スペクトラム、アンジェルマン症候群患者 iPS 細胞を用いた病態解析と治療法開発

  母子健康協会

  Date (from‐to) : 2017 -2018 

  Author : 江川 潔
• 自閉症スペクトラム、アンジェルマン症候群の認知機能障害メカニズムと治療法の探索

  小児医学研究振興財団

  Date (from‐to) : 2017 -2018 

  Author : 江川 潔
• アンジェルマン症候群の運動機能障害に対するモデルマウスおよびiPS細胞を用いた治療戦略の探索

  中冨健康科学振興財団

  Date (from‐to) : 2016 -2018 

  Author : 江川 潔
• 自閉症スペクトラムを示すアンジェルマン症候群の認知機能障害メカニズムと治療法の探索

  武田科学振興財団

  Date (from‐to) : 2016 -2018 

  Author : 江川 潔
• アンジェルマン症候群における認知記憶機能障害のメカニズムと治療法の探索

  科学研究費助成事業 基盤研究C

  Date (from‐to) : 2015 -2018 

  Author : 江川 潔
• 自閉症スペクトラム障害アンジェルマン症候群におけるケトン食糧法の有用性

  ひと・健康・未来研究財団

  Date (from‐to) : 2015 -2016 

  Author : 江川 潔
• Perturbation of developmental Cl^-homeodynamics may underlie fetal and neonatal brain disorders

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2011 -2011 

  Author : FUKUDA Atsuo, INOUE Koichi, EGAWA Kiyoshi, HATA Kenichiro

   

  The most major inhibitory neurotransmitter, GABA, induces synaptic inhibition in the adult brain. In immature neurons, however,[ Cl^-]_i is high due to balance of Cl^-transporters, promoting depolarizing GABA action by efflux of Cl^-along with its electrical gradient. Thus GABA evokes excitation and/or non-synaptic tonic depolarization in immature brain. Such multimodal GABA actions during development are necessary for neurogenesis, differentiation, migration, and synaptogenesis. Therfore, perturbation of the developmental Cl^-homeodynamics may underlie fetal and neonatal brain disorders. By using various pathological model mice, we have studied how Cl^-homeodynamics work in pathogenesis of fetal and neonatal disorders of cortical development.
• アンジェルマン症候群モデルマウスにおける小脳機能障害の電気生理学的検討

  科学研究費助成事業 若手Ｂ

  Date (from‐to) : 2011 -2011 

  Author : 江川 潔