Elucidation of the pathophysiology of refractory status epilepticus by comprehensive inflammation analysis and development of new diagnosis and treatment methods

• Project/Area Number: 18K08918
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55060:Emergency medicine-related
• Research Institution: Kobe University
• Principal Investigator: Nagase Hiroaki 神戸大学, 医学研究科, 特命教授 (80571968)
• Co-Investigator(Kenkyū-buntansha): 森岡 一朗 日本大学, 医学部, 教授 (80437467) ; 篠原 正和 神戸大学, 医学研究科, 准教授 (80437483)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 熱性けいれん / てんかん重積状態 / 急性脳症 / 炎症 / サイトカイン / GDF-15 / てんかん重積 / けいれん重積 / 炎症性サイトカイン

Outline of Final Research Achievements

Febrile status epilepticus (FSE) and refractory FSE (fRSE) are common in pediatric emergency, and are often diagnosed as acute encephalopathy with serious outcomes such as death and sequelae. In this study, we found that in pediatric patients with fRSE, inflammatory cytokines peaked within 24 hours of onset and then decreased, regardless of the final diagnosis or outcome. We also revealed that the inflammation-related protein GDF15 reported as an excellent pathological and prognostic markers such as sepsis was also significantly elevated in FSE, peaked out within 12 hours of onset. Furthermore, the peak value of GDF-15 within 6 hours of onset was shown to be associated with the neurological sequelae in children with FSE.

Academic Significance and Societal Importance of the Research Achievements

FSE, fRSEと炎症性サイトカインが関連することはこれまでにも報告されており，抗炎症治療が行われているが，発症24時間以内にはすでにピークアウトしていることが本研究で初めて明らかになった．さらに炎症関連蛋白であるGDF-15は発症12時間以内にピークアウトしていること，発症6時間以内の値が転帰と関連することも今回初めて明らかとなった．炎症のピークとなる時間が6－12時間であることが明らかになったことで，今後fRSEに対する抗炎症治療の有効性、ゴールデンタイムの解明につながる成果であると考えた。

Research Products

• [Journal Article] Elevated cytokine, chemokine, and growth and differentiation factor-15 levels in hemorrhagic shock and encephalopathy syndrome: A retrospective observational study (2021)
  • Author(s): Yamaguchi Hiroshi、Nishiyama Masahiro、Tokumoto Shoichi、Ishida Yusuke、Tomioka Kazumi、Aoki Kazunori、Seino Yusuke、Toyoshima Daisaku、Takeda Hiroki、Kurosawa Hiroshi、Sakuma Hiroshi、Tada Hiroko、Nozu Kandai、Maruyama Azusa、Tanaka Ryojiro、Iijima Kazumoto、Nagase Hiroaki
  • Journal Title: Cytokine Volume: 137 Pages: 155324-155324
  • DOI: 10.1016/j.cyto.2020.155324
  • Peer Reviewed
• [Journal Article] Prediction of AESD and neurological sequelae in febrile status epilepticus (2021)
  • Author(s): Nishiyama M, Ishida Y, Yamaguchi H, Tokumoto S, Tomioka K, Hongo H, Toyoshima D, Maruyama A, Kurosawa H, Tanaka R, Nozu K, Iijima K, Nagase H
  • Journal Title: Brain Dev Volume: 43 Issue: 5 Pages: 616-625
  • DOI: 10.1016/j.braindev.2021.01.004
  • NAID: 120007028964
  • Peer Reviewed
• [Journal Article] Early non-convulsive seizures are associated with the development of acute encephalopathy with biphasic seizures and late reduced diffusion (2021)
  • Author(s): Maruyama A, Tokumoto S, Yamaguchi H, Ishida Y, Tanaka T, Tomioka K, Nishiyama M, Fujita K, Toyoshima D, Nagase H
  • Journal Title: Brain Dev Volume: 43 Issue: 4 Pages: 548-555
  • DOI: 10.1016/j.braindev.2020.11.012
  • NAID: 120007002555
  • Peer Reviewed
• [Journal Article] Detailed characteristics of acute encephalopathy with biphasic seizures and late reduced diffusion: 18-year data of a single-center consecutive cohort. (2020)
  • Author(s): Yamaguchi H, Nishiyama M, Tokumoto S, Ishida Y, Tomioka K, Aoki K, Seino Y, Toyoshima D, Takeda H, Kurosawa H, Nozu K, Maruyama A, Tanaka R, Iijima K, Nagase H.
  • Journal Title: J Neurol Sci. Volume: 411 Pages: 116684-116684
  • DOI: 10.1016/j.jns.2020.116684
  • NAID: 120006846525
  • Peer Reviewed
• [Journal Article] Detailed clinical course of fatal acute encephalopathy in children. (2019)
  • Author(s): Tomioka K, Nishiyama M, Nagase H, Ishida Y, Tanaka T, Tokumoto S, Yamaguchi H, Toyoshima D, Maruyama A, Fujita K, Aoki K, Seino Y, Nozu K, Nishimura N, Kurosawa H, Iijima K.
  • Journal Title: Brain Dev. Volume: 41 Issue: 8 Pages: 691-698
  • DOI: 10.1016/j.braindev.2019.04.012
  • NAID: 120006894043
  • Peer Reviewed
• [Journal Article] Predicting the outcomes of targeted temperature management for children with seizures and/or impaired consciousness accompanied by fever without known etiology (2019)
  • Author(s): Tanaka Tsukasa、Nagase Hiroaki、Yamaguchi Hiroshi、Ishida Yusuke、Tomioka Kazumi、Nishiyama Masahiro、Toyoshima Daisaku、Maruyama Azusa、Fujita Kyoko、Nozu Kandai、Nishimura Noriyuki、Kurosawa Hiroshi、Tanaka Ryojiro、Iijima Kazumoto
  • Journal Title: Brain and Development Volume: 印刷中 Issue: 7 Pages: 604-613
  • DOI: 10.1016/j.braindev.2019.03.007
  • NAID: 120006733176
  • Peer Reviewed
• [Journal Article] Acute encephalopathy with biphasic seizures and late reduced diffusion accompanied by Takotsubo cardiomyopathy (2019)
  • Author(s): Yamaguchi Hiroshi、Nagase Hiroaki、Yoshida Shinobu、Tokumoto Shoichi、Hayashi Ken、Toyoshima Daisaku、Kurosawa Hiroshi、Tanaka Toshikatsu、Maruyama Azusa、Iijima Kazumoto
  • Journal Title: Brain and Development Volume: 41 Issue: 3 Pages: 305-309
  • DOI: 10.1016/j.braindev.2018.10.002
  • NAID: 120006846523
  • Peer Reviewed
• [Journal Article] Lipid and thyroid hormone levels in children with epilepsy treated with levetiracetam or carbamazepine: A prospective observational study (2019)
  • Author(s): Nishiyama Masahiro、Takami Yuichi、Ishida Yusuke、Tomioka Kazumi、Tanaka Tsukasa、Nagase Hiroaki、Nakagawa Taku、Tokumoto Shoichi、Yamaguchi Hiroshi、Toyoshima Daisaku、Maruyama Azusa、Nozu Kandai、Nishimura Noriyuki、Iijima Kazumoto
  • Journal Title: Epilepsy & Behavior Volume: 90 Pages: 15-19
  • DOI: 10.1016/j.yebeh.2018.11.003
  • NAID: 120006599198
  • Peer Reviewed
• [Journal Article] Nonconvulsive Seizure Detection by Reduced-Lead Electroencephalography in Children with Altered Mental Status in the Emergency Department (2019)
  • Author(s): Yamaguchi Hiroshi、Nagase Hiroaki、Nishiyama Masahiro、Tokumoto Shoichi、Ishida Yusuke、Tomioka Kazumi、Tanaka Tsukasa、Fujita Kyoko、Toyoshima Daisaku、Nishimura Noriyuki、Kurosawa Hiroshi、Nozu Kandai、Maruyama Azusa、Tanaka Ryojiro、Iijima Kazumoto
  • Journal Title: The Journal of Pediatrics Volume: 207 Pages: 213-219
  • DOI: 10.1016/j.jpeds.2018.11.019
  • Peer Reviewed
• [Journal Article] Clinical time course of pediatric acute disseminated encephalomyelitis (2019)
  • Author(s): Nishiyama Masahiro、Nagase Hiroaki、Tomioka Kazumi、Tanaka Tsukasa、Yamaguchi Hiroshi、Ishida Yusuke、Toyoshima Daisaku、Fujita Kyoko、Maruyama Azusa、Sasaki Kaori、Oyazato Yoshinobu、Nakagawa Taku、Takami Yuichi、Nozu Kandai、Nishimura Noriyuki、Nakashima Ichiro、Iijima Kazumoto
  • Journal Title: Brain and Development Volume: 41 Issue: 6 Pages: 531-537
  • DOI: 10.1016/j.braindev.2019.02.011
  • NAID: 120006645705
  • Peer Reviewed
• [Journal Article] Acute focal bacterial nephritis characterized by acute encephalopathy with biphasic seizures and late reduced diffusion (2018)
  • Author(s): Yamaguchi Hiroshi、Nagase Hiroaki、Ito Yusuke、Matsunoshita Natsuki、Mizutani Makoto、Matsushige Takeshi、Ishida Yusuke、Toyoshima Daisaku、Kasai Masashi、Kurosawa Hiroshi、Maruyama Azusa、Iijima Kazumoto
  • Journal Title: Journal of Infection and Chemotherapy Volume: 24 Issue: 11 Pages: 932-935
  • DOI: 10.1016/j.jiac.2018.04.007
  • NAID: 120006846522
  • Peer Reviewed
• [Journal Article] Early risk factors for mortality in children with seizure and/or impaired consciousness accompanied by fever without known etiology (2018)
  • Author(s): Tomioka Kazumi、Nagase Hiroaki、Tanaka Tsukasa、Nishiyama Masahiro、Yamaguchi Hiroshi、Ishida Yusuke、Toyoshima Daisaku、Maruyama Azusa、Fujita Kyoko、Taniguchi-Ikeda Mariko、Nozu Kandai、Morioka Ichiro、Nishimura Noriyuki、Kurosawa Hiroshi、Uetani Yoshiyuki、Iijima Kazumoto
  • Journal Title: Brain and Development Volume: 印刷中 Issue: 7 Pages: 552-557
  • DOI: 10.1016/j.braindev.2018.02.015
  • NAID: 120006629313
  • Peer Reviewed
• [Journal Article] Diurnal occurrence of complex febrile seizure and their severity in pediatric patients needing hospitalization (2018)
  • Author(s): Yamaguchi Hiroshi、Nagase Hiroaki、Ishida Yusuke、Toyoshima Daisaku、Maruyama Azusa、Tomioka Kazumi、Tanaka Tsukasa、Nishiyama Masahiro、Fujita Kyoko、Mariko Taniguchi-Ikeda、Nozu Kandai、Morioka Ichiro、Nishimura Noriyuki、Kurosawa Hiroshi、Takada Satoshi、Uetani Yoshiyuki、Iijima Kazumoto
  • Journal Title: Epilepsy & Behavior Volume: 80 Pages: 280-284
  • DOI: 10.1016/j.yebeh.2018.01.015
  • Peer Reviewed
• [Journal Article] Infantile spasms related to a 5q31.2-q31.3 microdeletion including PURA (2018)
  • Author(s): Shimojima Keiko、Okamoto Nobuhiko、Ohmura Kayo、Nagase Hiroaki、Yamamoto Toshiyuki
  • Journal Title: Human Genome Variation Volume: 5 Issue: 1 Pages: 18007-18007
  • DOI: 10.1038/hgv.2018.7
  • Peer Reviewed
• [Journal Article] Fosphenytoin vs. continuous midazolam for pediatric febrile status epilepticus (2018)
  • Author(s): Nishiyama Masahiro、Nagase Hiroaki、Tomioka Kazumi、Tanaka Tsukasa、Yamaguchi Hiroshi、Ishida Yusuke、Toyoshima Daisaku、Fujita Kyoko、Maruyama Azusa、Kurosawa Hiroshi、Uetani Yoshiyuki、Nozu Kandai、Taniguchi-Ikeda Mariko、Morioka Ichiro、Takada Satoshi、Iijima Kazumoto
  • Journal Title: Brain and Development Volume: 40 Issue: 10 Pages: 884-890
  • DOI: 10.1016/j.braindev.2018.08.001
  • NAID: 120006599197
  • Peer Reviewed
• [Presentation] 急性脳症の予測基準の有用性の検証(第1報) AESD予測のために開発された基準の別コホートにおける再検証 (2020)
  • Author(s): 石田 悠介, 西山 将広, 徳元 翔一, 山口 宏, 冨岡 和美, 豊嶋 大作, 丸山 あずさ, 飯島 一誠, 永瀬 裕朗
  • Organizer: 第62回日本小児神経学会
• [Presentation] 急性脳症の予測基準の有用性の検証(第2報) 後遺症またはAESD予測のために開発された基準の比較 (2020)
  • Author(s): 西山 将広, 石田 悠介, 徳元 翔一, 冨岡 和美, 山口 宏, 豊嶋 大作, 丸山 あずさ, 飯島 一誠, 永瀬 裕朗
  • Organizer: 第62回日本小児神経学会
• [Presentation] 有熱時けいれん/意識障害の発症6時間以内のサイトカインによる予後予測 血清IL-1RA,IL-10の可能性 (2020)
  • Author(s): 冨岡 和美, 西山 将広, 山口 宏, 石田 悠介, 徳元 翔一, 豊嶋 大作, 丸山 あずさ, 服部 有香, 親里 嘉展, 中川 卓, 高見 勇一, 多田 弘子, 佐久間 啓, 飯島 一誠, 永瀬 裕朗
  • Organizer: 第62回日本小児神経学会
• [Presentation] 小児けいれん重積に対する脳波モニタリング下ミダゾラム昏睡療法の有効性と安全性 (2019)
  • Author(s): 石田悠介、冨岡和美、田中 司、西山将広、 永瀬裕朗、徳元翔一、山口 宏、豊嶋大作、丸山あずさ、黒澤寛史、飯島一誠
  • Organizer: 第61回日本小児神経学会
• [Presentation] 時間単位で評価した急性脳症のサイトカイン動態解析:第1報 (2019)
  • Author(s): 冨岡和美、西山将広、永瀬裕朗 、石田悠介、田中司、徳元翔一、山口宏、豊嶋大作、丸山あずさ、黒澤寛史、多田弘子、佐久間啓、飯島一誠
  • Organizer: 第61回日本小児神経学会
• [Presentation] 時間単位で評価した急性脳症のサイトカイン動態解析:第2報 (2019)
  • Author(s): 西山将広、冨岡和美、永瀬裕朗 、石田悠介、田中司、徳元翔一、山口宏、豊嶋大作、丸山あずさ、起塚庸、親里嘉展 、高見勇一、多田弘子、佐久間啓、飯島一誠
  • Organizer: 第61回日本小児神経学会
• [Presentation] 出血性ショック脳症症候群(HSES)7 症例の詳細な臨床経過の検討 (2019)
  • Author(s): 山口宏、徳元翔一、西山将広、豊嶋大作、永瀬裕朗 、丸山あずさ、飯島一誠
  • Organizer: 第61回日本小児神経学会
• [Presentation] 有熱性難治性けいれん重積の治療プロトコル変遷による短期的予後の検討 (2019)
  • Author(s): 徳元翔一、山口宏、豊嶋大作、丸山あずさ、石田悠介、冨岡和美、田中司、西山将広、永瀬裕朗、飯島一誠
  • Organizer: 第61回日本小児神経学会
• [Presentation] 出血性ショック脳症症候群（HSES）7症例の詳細な臨床経過の検討 (2019)
  • Author(s): 山口宏，徳元翔一，西山将広，豊嶋大作，永瀬裕朗，丸山あずさ，飯島一誠
  • Organizer: 第61回日本小児神経学会学術集会
• [Presentation] 時間単位で評価した急性脳症のサイトカイン動態解析：第1報 (2019)
  • Author(s): 冨岡和美，西山将広，永瀬裕朗，石田悠介，田中司，徳元翔一，山口宏，豊嶋大作，丸山あずさ，黒澤寛史，多田弘子，佐久間啓，飯島一誠
  • Organizer: 第61回日本小児神経学会学術集会
• [Presentation] 小児けいれん重積に対する脳波モニタリング下ミダゾラム昏睡療法の有効性と安全性 (2019)
  • Author(s): 石田悠介，冨岡和美，田中司，西山将広，永瀬裕朗，徳元翔一，山口宏，豊嶋大作，丸山あずさ，黒澤寛史，飯島一誠
  • Organizer: 第61回日本小児神経学会学術集会
• [Presentation] 有熱性難治性けいれん重積の治療プロトコル変遷による短期的予後の検討 (2019)
  • Author(s): 徳元翔一，山口宏，豊嶋大作，丸山あずさ，石田悠介，冨岡和美，田中司，西山将広，永瀬裕朗，飯島一誠
  • Organizer: 第61回日本小児神経学会学術集会