小児脳炎における疫学調査および自己抗体の網羅的解析

• Project/Area Number: 19K10613
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 58020:Hygiene and public health-related: including laboratory approach
• Research Institution: Kyushu University (2021-2023); Fukuoka Children’s Hospital (2019-2020)
• Principal Investigator: Chong Pin・Fee (チョン ピンフィー) 九州大学, 大学病院, 医員 (90835167)
• Co-Investigator(Kenkyū-buntansha): 酒井 康成 九州大学, 医学研究院, 准教授 (10380396)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 急性脳炎 / 自己免疫性脳炎 / 中枢脱髄性疾患 / 抗MOG抗体 / 小児 / 急性脳症 / 中枢性脱髄性疾患 / 疫学調査 / 小児脳炎 / 自己抗体

Outline of Research at the Start

本研究の概要は、福岡県を中心とした九州内の小児医療機関の多施設、前向きコホート研究を基盤とした小児脳炎の疫学調査である。感染性脳炎、自己免疫性脳炎、中枢脱髄性疾患の割合、発症頻度を始め、異なる病態ごと脳炎の予後の相違等を明らかにするために行う研究である。

Outline of Annual Research Achievements

小児期発症の脳炎は神経学的後遺症を残す疾患であるが、原因不明な症例が多く、疫学に関する知見も限定的である。我々は、ウイルスや細菌に起因する感染性脳炎、特異的自己抗体による自己免疫性脳炎や中枢脱髄性疾患を系統的に分類するために、GFP検出システムを用いた細胞ベースアッセイ法とFilmArray髄膜炎・脳炎パネルを組み合わせた実験系を確立した。
この実験系を用いて、研究期間中に福岡県内の医療機関との共同研究を行った。原因の特定されていない小児脳炎患者の髄液検体より、原因ウイルス5例、NMDA受容体抗体6例を同定できました。主に成人患者に見られるLGI1抗体、CASPR2抗体、DPPX抗体、AMPA1/2受容体抗体、GABAB受容体抗体を検出することができなかった。また、自己免疫性脳炎や中枢脱髄性疾患が疑われている患者の血液検体からは、MOG抗体15例を検知し、MOG抗体関連疾患と確定診断することができた。自己抗体を迅速に探知し、各医療機関にフィードバックすることで、迅速に病態に応じた特異的治療を始めることができた。
小児脳炎において最も検出頻度の多い自己抗体であるMOG抗体の病態解明はいまだに不明である。我々はMOG抗体関連疾患の髄液検体を用いて、網羅的脂質代謝とサイトカイン解析を行った。非脱髄性疾患と比較し、異なる脂質プロファイルを呈することを明らかにした。今後は特異的代謝経路が判明できれば、MOG抗体関連疾患の病態解明や新規治療の検討に展開が期待される。

Research Products

• [Journal Article] Persistent intracranial hyper-inflammation in ruptured cerebral aneurysm after COVID-19: case report and review of the literature (2024)
  • Author(s): Chong PF, Higashi K, Matsuoka W, Arimura K, Sangatsuda Y, Iwaki K, Sonoda Y, Ichimiya Y, Kamori A, Kawakami A, Mizuguchi S, Kaku N, Sakai Y, Ohga S.
  • Journal Title: BMC Neurol Volume: 2 Issue: 1 Pages: 17-17
  • DOI: 10.1186/s12883-023-03493-z
  • Peer Reviewed / Open Access
• [Journal Article] The Etiology and Outcome of Area Postrema Syndrome in Childhood: Two Cases and a Literature Review (2024)
  • Author(s): Tomari Y, Igata Y, Chong PF, Kajiwara K, Hatai E, Sonoda Y, Oba U, Kaku N, Koga Y, Sakai Y, Ohga S.
  • Journal Title: Pediatr Neurol Volume: 152 Pages: 11-15
  • DOI: 10.1016/j.pediatrneurol.2023.12.010
  • Peer Reviewed
• [Journal Article] Divergent neurodevelopmental profiles of very-low-birth-weight infants (2024)
  • Author(s): Ogata R, Watanabe K, Chong PF, Okamoto J, Sakemi Y, Nakashima T, Ohno T, Nomiyama H, Sonoda Y, Ichimiya Y, Inoue H, Ochiai M, Yamashita H, Sakai Y, Ohga S.
  • Journal Title: Pediatr Res Volume: 95 Issue: 1 Pages: 233-240
  • DOI: 10.1038/s41390-023-02778-w
  • Peer Reviewed
• [Journal Article] Long-lasting pain and somatosensory disturbances in children with myelin oligodendrocyte glycoprotein antibody-associated disease (2023)
  • Author(s): Ichimiya Yuko、Chong Pin Fee、Sonoda Yuri、Tocan Vlad、Watanabe Mitsuru、Torisu Hiroyuki、Kira Ryutaro、Takahashi Toshiyuki、Kira Jun-Ichi、Isobe Noriko、Sakai Yasunari、Ohga Shouichi
  • Journal Title: European Journal of Pediatrics Volume: 182 Issue: 7 Pages: 3175-3185
  • DOI: 10.1007/s00431-023-04989-z
  • Peer Reviewed / Open Access
• [Journal Article] Critical vitamin deficiencies in autism spectrum disorder: Reversible and irreversible outcomes (2022)
  • Author(s): P. F. Chong, M. Torio, F. Fujii, Y. Hirata, W. Matsuoka, Y. Sonoda, et al.
  • Journal Title: Eur J Clin Nutr Volume: 76 Issue: 11 Pages: 1618-1621
  • DOI: 10.1038/s41430-022-01170-x
  • Peer Reviewed
• [Journal Article] Clinical and electrophysiological features of acute flaccid myelitis: A national cohort study. (2021)
  • Author(s): Chong PF, Torisu H, Yasumoto S, Okumura A, Mori H, Sato T, Kimura J, Ohga S, Tanaka-Taya K, Kira R
  • Journal Title: Clin Neurophysiol. Volume: 132 Issue: 10 Pages: 2456-2463
  • DOI: 10.1016/j.clinph.2021.07.013
  • Peer Reviewed / Open Access
• [Journal Article] Acute flaccid myelitis: cause, diagnosis, and management (2021)
  • Author(s): Murphy OC, Messacar K, Benson L, et al.
  • Journal Title: The Lancet Volume: 397 Issue: 10271 Pages: 334-346
  • DOI: 10.1016/s0140-6736(20)32723-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Three-Year Longitudinal Motor Function and Disability Level of Acute Flaccid Myelitis (2021)
  • Author(s): Chong Pin Fee、Kira Ryutaro、Torisu Hiroyuki、Yasumoto Sawa、Okumura Akihisa、Mori Harushi、Tanaka-Taya Keiko.
  • Journal Title: Pediatric Neurology Volume: 116 Pages: 14-19
  • DOI: 10.1016/j.pediatrneurol.2020.11.019
  • Peer Reviewed
• [Journal Article] Infantile spasms and early-onset progressive polycystic renal lesions associated with TSC2/PKD1 contiguous gene deletion syndrome (2021)
  • Author(s): Matsubara Yoshie、Akamine Satoshi、Chong Pin Fee、Kawakami Saori、Maehara Kenji、Kaku Yoshitsugu、Kurokawa Mari、Morisada Naoya、Iijima Kazumoto、Kira Ryutaro
  • Journal Title: Seizure Volume: 86 Pages: 82-84
  • DOI: 10.1016/j.seizure.2021.01.016
  • Peer Reviewed
• [Journal Article] Disseminated cortical and subcortical lesions in neonatal enterovirus 71 encephalitis (2020)
  • Author(s): Nakamura Ryoko、Chong Pin Fee、Haraguchi Kohei、Katano Harutaka、Tanaka-Taya Keiko、Kira Ryutaro
  • Journal Title: Journal of NeuroVirology Volume: 26 Issue: 5 Pages: 790-792
  • DOI: 10.1007/s13365-020-00843-2
  • Peer Reviewed
• [Journal Article] Acute Flaccid Myelitis With Neuroradiological Finding of Brachial Plexus Swelling (2020)
  • Author(s): Chong Pin Fee、Yoshida Takeshi、Yuasa Shota、Mori Harushi、Tanaka-Taya Keiko、Kira Ryutaro
  • Journal Title: Pediatric Neurology Volume: 109 Pages: 85-88
  • DOI: 10.1016/j.pediatrneurol.2020.04.004
  • Peer Reviewed
• [Journal Article] Influenza-associated encephalopathy with focal late reduced diffusion circumscribing a pre-existing cortical lesion (2020)
  • Author(s): Maeda Kenichi、Chong Pin Fee、Yamashita Fumiya、Akamine Satoshi、Kawakami Saori、Lee Sooyoung、Kira Ryutaro
  • Journal Title: Journal of Neuroradiology Volume: 47 Issue: 3 Pages: 241-243
  • DOI: 10.1016/j.neurad.2020.01.086
  • Peer Reviewed
• [Journal Article] Isolated cranial neuritis of the oculomotor nerve: Expanding the MOG phenotype? (2020)
  • Author(s): Kawakami Saori、Akamine Satoshi、Chong Pin Fee、Yamashita Fumiya、Maeda Kenichi、Takahashi Toshiyuki、Kira Ryutaro
  • Journal Title: Multiple Sclerosis and Related Disorders Volume: 41 Pages: 102040-102040
  • DOI: 10.1016/j.msard.2020.102040
  • Peer Reviewed
• [Journal Article] Disseminated cortical and subcortical lesions in neonatal enterovirus 71 encephalitis (2020)
  • Author(s): Nakamura Ryoko, Chong Pin Fee, Haraguchi Kohei, Katano Harutaka, Tanaka-Taya Keiko, Kira Ryutaro
  • Journal Title: Journal of NeuroVirology Volume: -
  • Peer Reviewed
• [Journal Article] West Syndrome in an Infant With Vitamin B12 Deficiency Born to Autoantibodies Positive Mother (2019)
  • Author(s): Chong Pin Fee、Matsukura Masaru、Fukui Kaoru、Watanabe Yoriko、Matsumoto Naomichi、Kira Ryutaro
  • Journal Title: Frontiers in Pediatrics Volume: 7
  • DOI: 10.3389/fped.2019.00531
  • Peer Reviewed / Open Access
• [Journal Article] Cytotoxic lesion of the corpus callosum exclusively at the genu in a case of callosal hypogenesis (2019)
  • Author(s): Tsuji Moeri、Chong Pin Fee、Yamashita Fumiya、Maeda Kenichi、Kira Ryutaro
  • Journal Title: Journal of Neuroradiology Volume: 46 Issue: 3 Pages: 222-223
  • DOI: 10.1016/j.neurad.2018.11.001
  • Peer Reviewed
• [Journal Article] The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype (2019)
  • Author(s): Yigit Gokhan、Saida Ken、DeMarzo Danielle、Miyake Noriko、Fujita Atsushi、Yang Tan Tiong、White Susan M.、Wadley Alexandrea、Toliat Mohammad R.、Motameny Susanne、Franitza Marek、Stutterd Chloe A.、Chong Pin F.、Kira Ryutaro、et al.
  • Journal Title: Human Mutation Volume: 41 Issue: 3 Pages: 591-599
  • DOI: 10.1002/humu.23964
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders (2019)
  • Author(s): Yamamoto Toshiyuki、Imaizumi Taichi、Yamamoto-Shimojima Keiko、Kurahashi Hirokazuら,
  • Journal Title: Brain and Development Volume: 41 Issue: 9 Pages: 776-782
  • DOI: 10.1016/j.braindev.2019.05.007
  • Peer Reviewed
• [Journal Article] Global Central Nervous System Atrophy in Spinal Muscular Atrophy Type 0 (2019)
  • Author(s): Maeda Kenichi、Chong Pin Fee、Yamashita Fumiya、Akamine Satoshi、Kawakami Saori、Saito Kayoko、Takahata Yasushi、Kira Ryutaro
  • Journal Title: Annals of Neurology Volume: 86 Issue: 5 Pages: 801-802
  • DOI: 10.1002/ana.25596
  • Peer Reviewed
• [Journal Article] Long surviving classical Menkes disease treated with weekly intravenous copper therapy (2019)
  • Author(s): Ogata Reina、Chong Pin Fee、Maeda Kenichi、Imagi Toru、Nakamura Ryoko、Kawamura Nobuko、Kira Ryutaro
  • Journal Title: Journal of Trace Elements in Medicine and Biology Volume: 54 Pages: 172-174
  • DOI: 10.1016/j.jtemb.2019.04.020
  • Peer Reviewed
• [Journal Article] Sequential radiologic findings in osteopathia striata with cranial sclerosis. (2019)
  • Author(s): Tomita Y, Chong P-F, Yamamoto T, Akaminea S, Imaizumi T, Kira R.
  • Journal Title: Diagn Interv Imaging. Volume: 100 Issue: 9 Pages: 529-531
  • DOI: 10.1016/j.diii.2019.04.001
  • Peer Reviewed
• [Presentation] The utility of multiplex assay in the differential diagnosis of pediatric CNS infection (2023)
  • Author(s): Chong Pin Fee
  • Organizer: World Meningitis Day Forum 2023
  • Invited
• [Presentation] 小児の炎症性脊髄疾患 (2023)
  • Author(s): チョン ピンフィー
  • Organizer: 第65回日本小児神経学会学術集会
  • Invited
• [Presentation] AFPの全国調査の概要と臨床的な視点 (2023)
  • Author(s): チョン ピンフィー
  • Organizer: 第27回日本ワクチン学会・第64回日本臨床ウイルス学会合同学術集会
  • Invited
• [Presentation] COVID-19感染後に発症した脳動脈瘤破裂によるくも膜下出血の男児例 (2023)
  • Author(s): チョン ピンフィー、東加奈子、松岡若利、有村公一、三月田祐平、岩城克馬、家守章子、川上晶子、園田有里、一宮優子、水口壮一、賀来典之、酒井康成、大賀正一
  • Organizer: 第65回日本小児神経学会学術集会
• [Presentation] Pediatric and transitional MOGAD: distinctive features and pathogenesis (2022)
  • Author(s): Chong Pin Fee
  • Organizer: 14th Pan-Asian Committee for Treatment and Research in Multiple Sclerosis Congress
  • Int'l Joint Research / Invited
• [Presentation] A patient with West syndrome and autistic spectrum disorder with SCN2A gene deletion without SCN1A involvement (2020)
  • Author(s): Pin Fee Chong, Saori Kawakami, Satoshi Akamine, Ryutaro Kira
  • Organizer: 21st Annual Meeting of Infantile Seizure Society
  • Int'l Joint Research
• [Presentation] RHOA体細胞モザイク変異認めた伊藤白斑の１症例 (2020)
  • Author(s): チョン ピンフィー、川上 沙織、山下 文也、前田 謙一、赤峰 哲、才田 謙、藤田 京志、三宅 紀子、松本 直通、吉良龍太郎
  • Organizer: 第62回日本小児神経学会学術集会
• [Presentation] Restrictively defined acute flaccid myelitis: stricter definition for diagnosing acute flaccid myelitis (2019)
  • Author(s): Chong Pin Fee
  • Organizer: 15th Asian & Oceanian Congress of Child Neurology
  • Int'l Joint Research
• [Presentation] An infant with dietary vitamin B12 deficiency due to maternal antibodies presenting with West syndrome (2019)
  • Author(s): Pin Fee Chong, Fumiya Yamashita, Kenichi Maeda, Satoshi Akamine, Ryutaro Kira
  • Organizer: 20th Annual Meeting of Infantile Seizure Society
  • Int'l Joint Research
• [Presentation] 急性弛緩性脊髄炎の臨床像：2018-2019の動向 (2019)
  • Author(s): チョン ピンフィー、吉良龍太郎
  • Organizer: 第61回日本小児神経学術集会
  • Invited
• [Presentation] 尿中マルベリー細胞を認めた腎機能正常な古典型ファブリー病男児例 (2019)
  • Author(s): チョン ピンフィー
  • Organizer: Conference of Fabry disease
  • Invited
• [Presentation] 成人期まで経静脈的銅補充を行った古典型メンケス病の一例 (2019)
  • Author(s): チョン ピンフィー、緒方怜奈、前田謙一、中村涼子、今城透、山下文也、赤峰哲、吉良龍太郎
  • Organizer: 第61回日本小児神経学会学術集会
• [Presentation] 憤怒けいれんのmimickers (2019)
  • Author(s): チョン ピンフィー、川上沙織、山下文也、前田謙一、赤峰哲、吉良龍太郎
  • Organizer: 第53回日本てんかん学会学術集会