Elucidation of the Neurological Damage Mechanism in Non-Convulsive Seizures Utilizing Continuous EEG Data from Emergency Departments

• Project/Area Number: 20K17894
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55060:Emergency medicine-related
• Research Institution: Kobe University
• Principal Investigator: Yamaguchi Hiroshi 神戸大学, 医学研究科, 特命助教 (80851849)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 非けいれん性てんかん重積 / 非けいれん性発作 / 熱性けいれん / 意識障害 / 救急外来 / 脳波 / 急性脳症 / てんかん / 急性脳炎 / 簡易脳波 / てんかん重積 / 小児 / 集中治療室 / 神経障害 / 非けいれん性てんかん重積状態 / 簡易脳波モニタリングシステム

Outline of Research at the Start

意識障害を伴い集中治療室（ICU）に入室する小児患者のうち約40%に非けいれん性てんかん
重積状態(non-convulsive status epilepticus:以下NCSE)を認め、NCSEが神経学的後遺症と関連するとされる。しかし救急診療初期から連続的に脳波を評価できる環境は稀で、NCSEのどのような波形がどのように神経傷害を引き起こすのかは不明である。本研究では意識障害を主訴に救急外来を受診した小児を対象とし、蓄積してきた救急外来からICUまでの持続脳波データと診療情報を包括的に解析する。さらに血清・髄液の炎症性サイトカイン・酸化ストレスマーカー・神経傷害マーカーもあわせて解析する。

Outline of Final Research Achievements

We conducted a reduced-lead electroencephalogram (EEG) analysis for pediatric patients with altered mental status in the emergency department (ED). We classified 51 cases into three groups: febrile seizures (FS), acute encephalopathy/encephalitis (AE/AES), and epilepsy, and described the EEG patterns using the ACNS Standardized Critical Care EEG Terminology 2021. The results showed that the EEG patterns of the FS and AE/AES groups were similar. However, intermittent rhythmic theta activity was observed in only about one-fourth of the FS group. Furthermore, we compared the levels of NSE, S100B, GFAP, Tau protein, and GDF-15 in the cerebrospinal fluid within 24 hours of onset in three cases of the FS group and five cases of the AE/AES group. S100B, GFAP, and GDF-15 were higher in the AE/AES group compared to the FS group. Combining EEG in ED with markers of neurological injury may offer the potential to differentiate between FS and AE/AES at an early stage.

Academic Significance and Societal Importance of the Research Achievements

救急外来（ED）で意識障害を呈する小児患者では、熱性けいれん（FS）、急性脳症/脳炎（AE/AES）およびてんかんが原因として多い。FSは後遺症を残すことは稀だが、AE/AESは後遺症を残す可能性が高く、遅れて診断されることがある。しかしEDではこれらを早期に鑑別することは難しい。EDの脳波(EEG)解析は，EDでEEGを実施できる施設が限られており報告は少ない。本研究はEDでの小児の意識障害患者において，詳細な簡易EEGの非けいれん性発作のEEGパターンを記述し、神経傷害バイオマーカーと組み合わせて評価した初めての研究である。

Research Products

• [Journal Article] Time course of serum cytokine level changes within 72?h after onset in children with acute encephalopathy and febrile seizures (2023)
  • Author(s): Tomioka Kazumi、Nishiyama Masahiro、Tokumoto Shoichi、Yamaguchi Hiroshi、Aoki Kazunori、Seino Yusuke、Toyoshima Daisaku、Kurosawa Hiroshi、Tada Hiroko、Sakuma Hiroshi、Nozu Kandai、Maruyama Azusa、Tanaka Ryojiro、Iijima Kazumoto、Nagase Hiroaki
  • Journal Title: BMC Neurology Volume: 23 Issue: 1 Pages: 7-7
  • DOI: 10.1186/s12883-022-03048-8
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and laboratory characteristics of complex febrile seizures in the acute phase: a case-series study in Japan (2023)
  • Author(s): Tanaka Tsukasa、Yamaguchi Hiroshi、Ishida Yusuke、Tomioka Kazumi、Nishiyama Masahiro、Toyoshima Daisaku、Maruyama Azusa、Takeda Hiroki、Kurosawa Hiroshi、Tanaka Ryojiro、Nozu Kandai、Nagase Hiroaki
  • Journal Title: BMC Neurology Volume: 23 Issue: 1 Pages: 28-28
  • DOI: 10.1186/s12883-023-03051-7
  • Peer Reviewed / Open Access
• [Journal Article] Dravet syndrome and hemorrhagic shock and encephalopathy syndrome associated with an intronic deletion of SCN1A (2023)
  • Author(s): Hanafusa H, Yamaguchi H, Kondo H, Nagasaka M, Juan Ye M, Oikawa S, Tokumoto S, Tomioka K, Nishiyama M, Morisada N, Matsuo M, Nozu K, Nagase H.
  • Journal Title: Brain Dev. Volume: 45 Issue: 6 Pages: 317-323
  • DOI: 10.1016/j.braindev.2023.01.008
  • Peer Reviewed
• [Journal Article] Timing of therapeutic interventions against infection-triggered encephalopathy syndrome: a scoping review of the pediatric literature (2023)
  • Author(s): Nagase Hiroaki、Yamaguchi Hiroshi、Tokumoto Shoichi、Ishida Yusuke、Tomioka Kazumi、Nishiyama Masahiro、Nozu Kandai、Maruyama Azusa
  • Journal Title: Frontiers in Neuroscience Volume: 17 Pages: 1150868-1150868
  • DOI: 10.3389/fnins.2023.1150868
  • Peer Reviewed / Open Access
• [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] 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] Thiamylal anaesthetic therapy for febrile refractory status epilepticus in children (2020)
  • Author(s): Ishida Y, Nishiyama M, Yamaguchi H, Tomioka K, Tanaka T, Takeda H, Tokumoto S, Toyoshima D, Maruyama A, Seino Y, Aoki K, Nozu K, Nishimura N, Kurosawa H, Iijima K, Nagase H
  • Journal Title: Seizure Volume: 80 Pages: 12-17
  • DOI: 10.1016/j.seizure.2020.03.012
  • 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
• [Presentation] 意識障害を呈した小児に対する救急外来簡易脳波の原因疾患別特徴 (2023)
  • Author(s): 山口宏、上田拓耶、老川静香、徳元翔一、西山将広、丸山あずさ、野津寛大、永瀬裕朗
  • Organizer: 第56回日本てんかん学会学術集会
• [Presentation] 意識障害を呈した小児に対する救急外来簡易脳波の原因疾患別特徴 (2023)
  • Author(s): 山口 宏、上田 拓耶、老川 静香、徳元 翔一、西山 将広、丸山 あずさ、野津 寛大、永瀬 裕朗
  • Organizer: 第56回日本てんかん学会学術集会
• [Presentation] A comparison of clinical features of acute encephalopathy with biphasic seizures and late reduced diffusion between short and prolonged first seizure duration (2020)
  • Author(s): Hiroshi Yamaguchi; Masahiro Nishiyama; Shoichi Tokumoto; Yusuke Ishida; Daisaku Toyoshima; Azusa Maruyama, Kazumoto Iijima; Hiroaki Nagase
  • Organizer: The International Symposium on Pathophysiology of Developmental and Epileptic Encephalopathy 2020
  • Int'l Joint Research
• [Presentation] けいれん重積型（二相性）急性脳症の初回けいれん時間による臨床像の比較検討 (2020)
  • Author(s): 山口 宏、西山 将広、徳元 翔一、石田 悠介、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学術集会