托珠单抗在热性感染相关性癫痫综合征中的应用现状

doi:10.12372/jcp.2026.25e0509

摘要/Abstract

摘要：

热性感染相关性癫痫综合征（FIRES）是一种罕见的严重癫痫性脑病。FIRES主要累及学龄期儿童，表现为前驱发热感染后迅速进展为难治性癫痫持续状态，病程呈双相性。该病预后差，急性期病死率约10%，慢性期幸存者常遗留难治性癫痫及认知障碍。FIRES发病机制尚不明确，以白细胞介素-6（IL-6）为代表的细胞因子参与的神经炎症可能起关键作用。托珠单抗（tocilizumab）是一种人源化的IL-6受体单克隆抗体，可通过抑制IL-6信号通路发挥抗炎作用，对于常规抗癫痫发作药物、一线免疫治疗及生酮饮食等无效的FIRES患者，托珠单抗目前被推荐用于二线免疫治疗选项。本文就托珠单抗在FIRES中应用的背景、机制、现状、安全性及挑战等方面进行综述，以帮助临床医师了解该领域的最新进展。

Abstract:

Febrile infection-related epilepsy syndrome (FIRES) is a rare and catastrophic epileptic encephalopathy that predominantly affects school-aged children.Characterized by a biphasic clinical course, FIRES manifests as rapid progression to refractory status epilepticus following a preceding febrile infection. The prognosis of FIRES is dismal: the acute-phase mortality rate is approximately 10%, and survivors often develop chronic refractory epilepsy and cognitive impairment. The pathogenesis of FIRES remains unclear, but neuroinflammation involving cytokines such as IL-6 may play a key role. Tocilizumab, a humanized monoclonal antibody targeting the IL-6 receptor, exerts anti-inflammatory effects by blocking IL-6 signaling. For FIRES patients unresponsive to conventional anti-seizure medications (ASMs), first-line immunotherapies, or ketogenic diet, tocilizumab is currently recommended as a second-line immunotherapeutic option. This review summarizes the background, mechanisms, clinical applications, safety profile, and challenges associated with tocilizumab in FIRES management, aiming to update clinicians on the latest advances in this field..

Key words: febrile infection-related epilepsy syndrome, refractory status epilepticus, interleukin-6, tocilizumab

中图分类号:

陈哲, 洪思琦. 托珠单抗在热性感染相关性癫痫综合征中的应用现状[J]. 临床儿科杂志, 2026, 44(3): 264-269.

CHEN Zhe, HONG Siqi. Clinical application of tocilizumab in febrile infection-related epilepsy syndrome[J]. Journal of Clinical Pediatrics, 2026, 44(3): 264-269.

参考文献 38

[1]	Van Baalen A, Häusler M, Boor R, et al. Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood[J]. Epilepsia, 2010, 51(7): 1323-1328. doi: 10.1111/j.1528-1167.2010.02535.x pmid: 20345937
[2]	Hirsch LJ, Gaspard N, Van Baalen A, et al. Proposed consensus definitions for new‐onset refractory status epilepticus (NORSE), febrile infection‐related epilepsy syndrome (FIRES), and related conditions[J]. Epilepsia, 2018, 59(4): 739-744. doi: 10.1111/epi.2018.59.issue-4
[3]	Specchio N, Wirrell EC, Scheffer IE, et al. International league against epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE task force on nosology and definitions[J]. Epilepsia, 2022, 63(6): 1398-1442. doi: 10.1111/epi.17241 pmid: 35503717
[4]	Rachfalska N, Pietruszewski J, Paprocka J. Dramatic course of paediatric cryptogenic febrile infection-related epilepsy syndrome with unusual chronic phase presentation—a case report with literature study[J]. Brain Sci, 2021, 11(8): 1030. doi: 10.3390/brainsci11081030
[5]	Van Baalen A, Häusler M, Plecko-Startinig B, et al. Febrile infection-related epilepsy syndrome without detectable autoantibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES[J]. Neuropediatrics, 2012, 43(4): 209-216. doi: 10.1055/s-0032-1323848 pmid: 22911482
[6]	Soler Wenglein J, Kluger G, Leypoldt F, et al. No evidence of neuronal/glial autoantibodies in febrile infection-related epilepsy syndrome (FIRES): a prospective clinic-serologic analysis[J]. Front Neurosci, 2023, 17: 1221761. doi: 10.3389/fnins.2023.1221761
[7]	deCampo D, Xian J, Karlin A, et al. Investigating the genetic contribution in febrile infection-related epilepsy syndrome and refractory status epilepticus[J]. Front Neurol, 2023, 14: 1161161. doi: 10.3389/fneur.2023.1161161
[8]	Helbig I, Barcia G, Pendziwiat M, et al. Whole‐exome and HLA sequencing in febrile infection‐related epilepsy syndrome[J]. Ann Clin Transl Neurol, 2020, 7(8): 1429-1435. doi: 10.1002/acn3.v7.8
[9]	Van Baalen A. Febrile infection-related epilepsy syndrome in childhood: a clinical review and practical approach[J]. Seizure, 2023, 111: 215-222. doi: 10.1016/j.seizure.2023.09.008 pmid: 37703593
[10]	Farias‐Moeller R, Bartolini L, Staso K, et al. Early ictal and interictal patterns in FIRES: the sparks before the blaze[J]. Epilepsia, 2017, 58(8): 1340-1348. doi: 10.1111/epi.13801 pmid: 28555777
[11]	Pavone P, Corsello G, Raucci U, et al. Febrile infection- related epilepsy syndrome (FIRES): a severe encephalopathy with status epilepticus. Literature review and presentation of two new cases[J]. Ital J Pediatr, 2022, 48(1): 199. doi: 10.1186/s13052-022-01389-1 pmid: 36527084
[12]	Culleton S, Talenti G, Kaliakatsos M, et al. The spectrum of neuroimaging findings in febrile infection- related epilepsy syndrome (FIRES): a literature review[J]. Epilepsia, 2019, 60(4): 585-592. doi: 10.1111/epi.14684 pmid: 30854647
[13]	Wickström R, Taraschenko O, Dilena R, et al. International consensus recommendations for management of new onset refractory status epilepticus (NORSE) including febrile infection‐related epilepsy syndrome (FIRES): summary and clinical tools[J]. Epilepsia, 2022, 63(11): 2827-2839. doi: 10.1111/epi.v63.11
[14]	Sakuma H, Tanuma N, Kuki I, et al. Intrathecal overproduction of proinflammatory cytokines and chemokines in febrile infection-related refractory status epilepticus[J]. J Neurol Neurosurg Psychiatry, 2015, 86(7): 820-822. doi: 10.1136/jnnp-2014-309388 pmid: 25398790
[15]	Kothur K, Bandodkar S, Wienholt L, et al. Etiology is the key determinant of neuroinflammation in epilepsy: Elevation of cerebrospinal fluid cytokines and chemokines in febrile infection‐related epilepsy syndrome and febrile status epilepticus[J]. Epilepsia, 2019, 60(8): 1678-1688. doi: 10.1111/epi.v60.8
[16]	Steinborn B, Żarowski M, Winczewska-Wiktor A, et al. Concentration of Il-1β, Il-2, Il-6, TNFα in the blood serum in children with generalized epilepsy treated by valproate[J]. Pharmacol Rep, 2014, 66(6): 972-975. doi: 10.1016/j.pharep.2014.06.005
[17]	Grebenciucova E, VanHaerents S. Interleukin 6: at the interface of human health and disease[J]. Front Immunol, 2023, 14: 1255533. doi: 10.3389/fimmu.2023.1255533
[18]	Nakamura Y, Ueda M, Kodama S, et al. Treatment of cryptogenic new-onset refractory status epilepticus (C-NORSE) with tocilizumab[J]. Intern Med, 2024, 63(24): 3377-3382. doi: 10.2169/internalmedicine.3392-23
[19]	Foiadelli T, Santangelo A, Costagliola G, et al. Neuroinflammation and status epilepticus: a narrative review unraveling a complex interplay[J]. Front Pediatr, 2023, 11: 1251914. doi: 10.3389/fped.2023.1251914
[20]	El-Haggar SM, Hegazy SK, Mustafa W, et al. Possible immuno-modulatory effects of tocilizumab in patients with refractory status epilepticus[J]. Eur Rev Med Pharmacol Sci, 2023, 27(4): 1512-1521.
[21]	Soltani Khaboushan A, Yazdanpanah N, Rezaei N. Neuroinflammation and proinflammatory cytokines in epileptogenesis[J]. Mol Neurobiol, 2022, 59(3): 1724-1743. doi: 10.1007/s12035-022-02725-6 pmid: 35015252
[22]	Lattanzi S, Leitinger M, Rocchi C, et al. Unraveling the enigma of new‐onset refractory status epilepticus: a systematic review of aetiologies[J]. Eur J Neurol, 2022, 29(2): 626-647. doi: 10.1111/ene.v29.2
[23]	Ohsugi Y. The immunobiology of humanized anti-IL6 receptor antibody: from basic research to breakthrough medicine[J]. J Transl Autoimmun, 2020, 3: 100030. doi: 10.1016/j.jtauto.2019.100030
[24]	Hanin A, Muscal E, Hirsch LJ. Second‐line immunotherapy in new onset refractory status epilepticus[J]. Epilepsia, 2024, 65(5): 1203-1223. doi: 10.1111/epi.17933
[25]	Jun JS, Lee ST, Kim R, et al. Tocilizumab treatment for new onset refractory status epilepticus[J]. Ann Neurol, 2018, 84(6): 940-945. doi: 10.1002/ana.v84.6
[26]	Cantarín-Extremera V, Jiménez-Legido M, Duat-Rodríguez A, et al. Tocilizumab in pediatric refractory status epilepticus and acute epilepsy: Experience in two patients[J]. J Neuroimmunol, 2020, 340: 577142. doi: 10.1016/j.jneuroim.2019.577142
[27]	Wickstrom R, Taraschenko O, Dilena R, et al. International consensus recommendations for management of new onset refractory status epilepticus including febrile infection related epilepsy syndrome: Statements and supporting evidence[J]. Epilepsia, 2022, 63(11): 2840-2864. doi: 10.1111/epi.v63.11
[28]	Gaspard N, Hirsch LJ, Sculier C, et al. New‐onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): state of the art and perspectives[J]. Epilepsia, 2018, 59(4): 745-752. doi: 10.1111/epi.2018.59.issue-4
[29]	Chee YC, Lim CH, Halim SA, et al. Extinguishing FIRES using tocilizumab[J]. Neurol Clin Neurosci, 2020, 8(4): 192-195. doi: 10.1111/ncn3.v8.4
[30]	李凡, 黄先杰, 范亚珍, 等. 托珠单抗治疗儿童热性感染相关性癫痫综合征2例并文献复习[J]. 临床儿科杂志, 2025, 43(7): 532-538.
	LI F, Huang XJ, Fan YZ, et al. Tocilizumab treatment for febrile infection-related epilepsy syndrome in children: 2 cases report and literature review[J]. Linchuang Erke Zazhi, 2025, 43(7): 532-538.
[31]	王营, 马燕丽, 王媛, 等. 托珠单抗成功治疗儿童发热感染相关癫痫综合征1例及文献复习[J]. 中华神经科杂志, 2022, 55(11): 1277-1285.
	Wang Y, Ma YL, Wang Y, et al. A case of febrile infection-related epilepsy syndrome in children successfully treated with tocilizumab and literature review[J]. Zhonghua Shenjingke Zazhi, 2022, 55(11): 1277-1285.
[32]	Wan L, Liu J, Wang J, et al. Favorable outcomes and FDG-PET changes following tocilizumab treatment for febrile infection-related epilepsy syndrome in a child[J]. Int Immunopharmacol, 2025, 146: 113872. doi: 10.1016/j.intimp.2024.113872
[33]	Stredny CM, Case S, Sansevere AJ, et al. Interleukin-6 blockade with tocilizumab in anakinra-refractory febrile infection-related epilepsy syndrome (FIRES)[J]. Child Neurol Open, 2020, 7: 2329048X2097925.
[34]	Goh Y, Tay SH, Yeo LLL, et al. Bridging the gap: tailoring an approach to treatment in febrile infection-related epilepsy syndrome[J]. Neurology, 2023, 100(24): 1151-1155. doi: 10.1212/WNL.0000000000207068 pmid: 36797068
[35]	Aledo-Serrano A, Hariramani R, Gonzalez-Martinez A, et al. Anakinra and tocilizumab in the chronic phase of febrile infection-related epilepsy syndrome (FIRES): effectiveness and safety from a case-series[J]. Seizure, 2022, 100: 51-55. doi: 10.1016/j.seizure.2022.06.012 pmid: 35759951
[36]	Kurimoto T, Matsuoka T, Ami Y, et al. Anti-inflammatory and immune-mediated therapy for a case of febrile infection-related epilepsy syndrome with rapid recurrence[J]. Clin Case Rep, 2022, 10(6): e5952. doi: 10.1002/ccr3.v10.6
[37]	Girardin ML, Flamand T, Roignot O, et al. Treatment of new onset refractory status epilepticus/febrile infection-related epilepsy syndrome with tocilizumab in a child and a young adult[J]. Epilepsia, 2023, 64(6): e87-e92.
[38]	Sheppard M, Laskou F, Stapleton P, et al. Tocilizumab (actemra)[J]. Hum Vaccin Immunother, 2017, 13(9): 1972-1988. doi: 10.1080/21645515.2017.1316909