Advances in pharmacotherapy for pediatric epilepsy syndromes

doi:10.12092/j.issn.1009-2501.2026.02.002

Abstract

Abstract:

Epilepsy is one of the most prevalent neurological disorders in children. While pediatric epilepsy is characterized by a diverse range of causes and intricate pathological processes, roughly 30% of affected children exhibit resistance to existing pharmacological treatments. It can be classified into distinct epilepsy syndromes based on characteristic clinical and electroencephalographic (EEG) features. Among these, developmental and epileptic encephalopathy (DEE) represents the most severe subtype. Over recent decades, there have been significant advancements in new anti-seizure medications (ASM), yet the rate of drug-resistant epilepsy cases has not significantly declined. To systematically evaluate therapeutic strategies for pediatric epilepsy syndromes, this review primarily focuses on several relatively common pediatric epilepsy syndromes, including Dravet syndrome, infantile epileptic spasm syndrome (IESS), as well as rare etiology-specific DEEs (e.g. KCNQ2-, SCN2A-, SCN8A-, and CDKL5-related DEE), and febrile infection-related epilepsy syndrome (FIRES). We summarize current pharmacological management and emerging therapeutic advances in these conditions, aiming to support evidence-based clinical decisions.

Key words: pediatric, epilepsy syndromes, developmental and epileptic encephalopathy (DEE), antiseizure medications

CLC Number:

R742.1

Tianshuang WANG, Xinhua WANG, Yuanfeng ZHOU. Advances in pharmacotherapy for pediatric epilepsy syndromes[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(2): 154-161.

Figures/Tables 1

References 57

1	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
2	Zuberi SM, Wirrell E, Yozawitz E, et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE task force on nosology and definitions[J]. Epilepsia, 2022, 63 (6): 1349- 1397. doi: 10.1111/epi.17239
3	Lagae L, Sullivan J, Knupp K, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial[J]. Lancet, 2019, 394 (10216): 2243- 2254. doi: 10.1016/S0140-6736(19)32500-0
4	Guerrini R, Chiron C, Vandame D, et al. Comparative efficacy and safety of stiripentol, cannabidiol and fenfluramine as first‐line add‐on therapies for seizures in Dravet syndrome: a network meta‐analysis[J]. Epilepsia Open, 2024, 9 (2): 689- 703. doi: 10.1002/epi4.12923
5	Sills GJ. Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies[J]. Ther Adv Neurol Disord, 2023, 16, 1- 27. doi: 10.1177/17562864231191000
6	Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the dravet syndrome[J]. N Engl J Med, 2017, 376 (21): 2011- 2020. doi: 10.1056/NEJMoa1611618
7	Scheffer IE, Halford JJ, Miller I, et al. Add‐on cannabidiol in patients with Dravet syndrome: Results of a long‐term open‐label extension trial[J]. Epilepsia, 2021, 62 (10): 2505- 2517. doi: 10.1111/epi.17036
8	Bacq A, Depaulis A, Castagné V, et al. An update on stiripentol mechanisms of action: a narrative review[J]. Adv Ther, 2024, 41 (4): 1351- 1371. doi: 10.1007/s12325-024-02813-0
9	Frampton JE. Stiripentol: a review in dravet syndrome[J]. Drugs, 2019, 79 (16): 1785- 1796. doi: 10.1007/s40265-019-01204-y
10	Vasquez A, Wirrell EC, Youssef PE. Stiripentol for the treatment of seizures associated with Dravet syndrome in patients 6 months and older and taking clobazam[J]. Expert Rev Neurother, 2023, 23 (4): 297- 309. doi: 10.1080/14737175.2023.2195550
11	Sullivan J, Lagae L, Cross JH, et al. Fenfluramine in the treatment of Dravet syndrome: results of a third randomized, placebo‐controlled clinical trial[J]. Epilepsia, 2023, 64 (10): 2653- 2666. doi: 10.1111/epi.17737
12	Jensen MP, Gammaitoni AR, Salem R, et al. Fenfluramine treatment for Dravet syndrome: caregiver- and clinician-reported benefits on the quality of life of patients, caregivers, and families living in Germany, Spain, Italy, and the United Kingdom[J]. Epilepsy Res, 2023, 190, 107091. doi: 10.1016/j.eplepsyres.2023.107091
13	Wirrell EC, Lagae L, Scheffer IE, et al. Practical considerations for the use of fenfluramine to manage patients with Dravet syndrome or Lennox–Gastaut syndrome in clinical practice[J]. Epilepsia Open, 2024, 9 (5): 1643- 1657. doi: 10.1002/epi4.12998
14	Nabbout R, Mistry A, Zuberi S, et al. Fenfluramine for treatment-resistant seizures in patients with Dravet syndrome receiving stiripentol-inclusive regimens[J]. JAMA Neurol, 2020, 77 (3): 300- 308. doi: 10.1001/jamaneurol.2019.4113
15	Frampton JE. Fenfluramine: A review in dravet and lennox-gastaut syndromes[J]. Drugs, 2023, 83 (10): 923- 934. doi: 10.1007/s40265-023-01881-w
16	Cross JH, Galer BS, Gil-Nagel A, et al. Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome[J]. Seizure, 2021, 93, 154- 159. doi: 10.1016/j.seizure.2021.10.024
17	Lattanzi S, Trinka E, Russo E, et al. Pharmacotherapy for dravet syndrome: a systematic review and network meta-analysis of randomized controlled trials[J]. Drugs, 2023, 83 (15): 1409- 1424. doi: 10.1007/s40265-023-01936-y
18	Hahn CD, Jiang Y, Villanueva V, et al. A phase 2, randomized, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox–Gastaut syndrome (ELEKTRA)[J]. Epilepsia, 2022, 63 (10): 2671- 2683. doi: 10.1111/epi.17367
19	Prezioso G, Chiarelli F, Matricardi S. Efficacy and safety of vigabatrin in patients with tuberous sclerosis complex and infantile epileptic spasm syndrome: a systematic review[J]. Expert Rev Neurother, 2023, 23 (7): 661- 671. doi: 10.1080/14737175.2023.2216385
20	Moloney PB, Delanty N. An overview of the value of mTOR inhibitors to the treatment of epilepsy: the evidence to date[J]. Expert Rev Neurother, 2025, 25 (3): 281- 297. doi: 10.1080/14737175.2025.2462280
21	Prezioso G, Carlone G, Zaccara G, et al. Efficacy of ketogenic diet for infantile spasms: A systematic review[J]. Acta Neurol Scand, 2018, 137 (1): 4- 11. doi: 10.1111/ane.12830
22	Osborne JP, Edwards SW, Alber FD, et al. Prednisolone or tetracosactide depot for infantile epileptic spasms syndrome? A prospective analysis of data embedded within two randomised controlled trials[J]. Eur J Paediatr Neurol, 2023, 42, 110- 116. doi: 10.1016/j.ejpn.2022.12.007
23	Paprocka J, Malkiewicz J, Palazzo-Michalska V, et al. Effectiveness of ACTH in patients with infantile spasms[J]. Brain Sci, 2022, 12 (2): 254. doi: 10.3390/brainsci12020254
24	Reyes Valenzuela G, Gallo A, Calvo A, et al. Purified cannabidiol as add-on therapy in children with treatment-resistant infantile epileptic spasms syndrome[J]. Seizure, 2024, 115, 94- 99. doi: 10.1016/j.seizure.2024.01.010
25	Biton V. Clinical pharmacology and mechanism of action of zonisamide[J]. Clin Neuropharmacol, 2007, 30 (4): 230- 240. doi: 10.1097/wnf.0b013e3180413d7d
26	Panda PK, Sharawat IK, Panda P, et al. Efficacy, tolerability, and safety of zonisamide in children with epileptic spasms: a systematic review and meta-analysis[J]. Seizure, 2021, 91, 374- 383. doi: 10.1016/j.seizure.2021.07.017
27	Falsaperla R, Criscione R, Cimino C, et al. KCNQ2-related epilepsy: Genotype–phenotype relationship with tailored antiseizure medication (ASM)—A systematic review[J]. Neuropediatrics, 2023, 54 (5): 297- 307. doi: 10.1055/a-2060-4576
28	Millichap JJ, Harden CL, Dlugos DJ, et al. Capturing seizures in clinical trials of antiseizure medications for KCNQ2‐DEE[J]. Epilepsia Open, 2021, 6 (1): 38- 44. doi: 10.1002/epi4.12466
29	Kuersten M, Tacke M, Gerstl L, et al. Antiepileptic therapy approaches in KCNQ2 related epilepsy: a systematic review[J]. Eur J Med Genet, 2020, 63 (1): 103628. doi: 10.1016/j.ejmg.2019.02.001
30	Chow CK, Luk HM, Wong SN. KCNQ2 Encephalopathy and responsiveness to pyridoxal-5′-phosphate[J]. J Paediatr Genet, 2020, 12 (1): 90- 94. doi: 10.1055/s-0040-1721384
31	Knight D, Mahida S, Kelly M, et al. Ezogabine impacts seizures and development in patients with KCNQ2 developmental and epileptic encephalopathy[J]. Epilepsia, 2023, 64 (7): e143- e147. doi: 10.1111/epi.17627
32	Zhang YM, Xu HY, Hu HN, et al. Discovery of HN37 as a potent and chemically stable antiepileptic drug candidate[J]. J Med Chem, 2021, 64 (9): 5816- 5837. doi: 10.1021/acs.jmedchem.0c02252
33	French JA, Porter RJ, Perucca E, et al. Efficacy and safety of XEN1101, a novel potassium channel opener, in adults with focal epilepsy[J]. JAMA Neurol, 2023, 80 (11): 1145- 1154. doi: 10.1001/jamaneurol.2023.3542
34	Gardella E, Marini C, Trivisano M, et al. The phenotype of SCN8A developmental and epileptic encephalopathy[J]. Neurology, 2018, 91 (12): e1112- e1124.
35	Liu Y, Schubert J, Sonnenberg L, et al. Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability[J]. Brain, 2019, 142 (2): 376- 390.
36	Wagnon JL, Barker BS, Ottolini M, et al. Loss-of-function variants of SCN8A in intellectual disability without seizures[J]. Neurology Genet, 2017, 3 (4): e170. doi: 10.1212/NXG.0000000000000170
37	Johannesen KM, Liu Y, Koko M, et al. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications[J]. Brain, 2022, 145 (9): 2991- 3009. doi: 10.1093/brain/awab321
38	Baker EM, Thompson CH, Hawkins NA, et al. The novel sodium channel modulator GS‐458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy[J]. Epilepsia, 2018, 59 (6): 1166- 1176.
39	Wengert ER, Saga AU, Panchal PS, et al. Prax330 reduces persistent and resurgent sodium channel currents and neuronal hyperexcitability of subiculum neurons in a mouse model of SCN8A epileptic encephalopathy[J]. Neuropharmacol, 2019, 158, 107699. doi: 10.1016/j.neuropharm.2019.107699
40	Müller P, Draguhn A, Egorov AV. Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers[J]. Pflugers Arch, 2024, 476 (10): 1445- 1473. doi: 10.1007/s00424-024-02980-7
41	Kahlig KM, Scott L, Hatch RJ, et al. The novel persistent sodium current inhibitor PRAX‐562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers[J]. Epilepsia, 2022, 63 (3): 697- 708. doi: 10.1111/epi.17149
42	Mangatt M, Wong K, Anderson B, et al. Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome[J]. Orphanet J Rare Dis, 2016, 11 (1): 39. doi: 10.1186/s13023-016-0418-y
43	Hong W, Haviland I, Pestana-Knight E, et al. CDKL5 deficiency disorder-related epilepsy: a review of current and emerging treatment[J]. CNS Drugs, 2022, 36 (6): 591- 604. doi: 10.1007/s40263-022-00921-5
44	Valente KD, Melo F, Marin R, et al. The long odyssey for the DEE‐CDKL5 diagnosis: a call for action[J]. Epilepsia Open, 2024, 9 (6): 2164- 2172. doi: 10.1002/epi4.13031
45	Aledo-Serrano Á, Gómez-Iglesias P, Toledano R, et al. Sodium channel blockers for the treatment of epilepsy in CDKL5 deficiency disorder: findings from a multicenter cohort[J]. Epilepsy Behav, 2021, 118, 107946. doi: 10.1016/j.yebeh.2021.107946
46	Devinsky O, King L, Schwartz D, et al. Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder[J]. Epilepsia, 2021, 62 (7): e98- e102. doi: 10.1111/epi.16923
47	Knight EMP, Amin S, Bahi-Buisson N, et al. Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial[J]. Lancet Neurol, 2022, 21 (5): 417- 427. doi: 10.1016/S1474-4422(22)00077-1
48	Specchio N, Pietrafusa N. New-onset refractory status epilepticus and febrile infection-related epilepsy syndrome[J]. Dev Med Child Neurol, 2020, 62 (8): 897- 905.
49	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.17391
50	Yamanaka G, Ishida Y, Kanou K, et al. Towards a treatment for neuroinflammation in epilepsy: interleukin-1 receptor antagonist, anakinra, as a potential treatment in intractable epilepsy[J]. Int J Mol Sci, 2021, 22 (12): 6282. doi: 10.3390/ijms22126282
51	Lai YC, Muscal E, Wells E, et al. Anakinra usage in febrile infection related epilepsy syndrome: an international cohort[J]. Ann Clin Transl Neurol, 2020, 7 (12): 2467- 2474. doi: 10.1002/acn3.51229
52	Dilena R, Mauri E, Aronica E, et al. Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection–related epilepsy syndrome[J]. Epilepsia Open, 2019, 4 (2): 344- 350. doi: 10.1002/epi4.12317
53	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
54	Koh S, Wirrell E, Vezzani A, et al. Proposal to optimize evaluation and treatment of Febrile infection‐related epilepsy syndrome (FIRES): a report from FIRES workshop[J]. Epilepsia Open, 2021, 6 (1): 62- 72. doi: 10.1002/epi4.12447
55	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.25374
56	Mantoan Ritter L, Nashef L. New-onset refractory status epilepticus (NORSE)[J]. Prac Neurol, 2021, 21 (2): 119- 127. doi: 10.1136/practneurol-2020-002534
57	Klein P, Kaminski RM, Koepp M, et al. New epilepsy therapies in development[J]. Nat Rev Drug Discov, 2024, 23 (9): 682- 708. doi: 10.1038/s41573-024-00981-w

[1]	GONG Yan, GONG Weijing, LI Jiaxin, QIN Yanjie, LUO Li. Population pharmacokinetics of high-dose methotrexate in pediatric patients with diverse malignancies [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2025, 30(1): 70-77.
[2]	BAI Yue, JIN Qiqi, CAI Weicha, LI Jianlin, ZHOU Yingfeng, YUAN Kaiming, LI Jun. Effects of the timing of satisfactory sedation with preoperative oral midazolam on anesthesia induction and recovery in children undergoing adenotonsillectomy [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2024, 29(3): 296-302.
[3]	JIN Baowei, GUO Jianrong. Pharmacological characteristics of esketamine and its application progress in pediatric anesthesia [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2024, 29(3): 328-333.
[4]	WU Xiongzhi, WANG Xuan, XU Siqi, JU Xia, WANG Shengbin, CHEN Yongquan. A comparative investigation of the impact of oral midazolam solution and dexmedetomidine nasal spray on preoperative anxiety in pediatric patients [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(6): 666-670.
[5]	LI Chenhao, YU Xihua, YAN Wenhao, CHAI Yuxia, LI Yanyan, LI Kun, LI Zeyun. Research progress on the relationship between pediatric epilepsy and vitamin D [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(11): 1299-1306.
[6]	DANG Yangbin, LIANG Yuxin, WANG Tiancheng. Research progress on the related treatment of progressive myoclonic epilepsy [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(10): 1184-1194.
[7]	ZHU Lili, ZHU Xiuxiu, WANG Wenjun, ZHANG Hailin, LIN Li. Clinical trials of inhalation in pediatric population in China [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(2): 178-183.
[8]	ZHANG Yu, HUANG Chaoqun, BAI Yue, LI Jianlin, ZHOU Yingfeng, YUAN Kaiming, LI Jun. Effects of preoperative single-dose of fentanyl on sedation and agitation during recovery after pediatric adenotonsillectomy day surgery [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(11): 1272-1277.
[9]	ZHANG Huimin, LIU Aiming, ZHU Wenfeng, YU Lingzhi, CHEN Fangliang. Scientific decision process and regulation requirements based on the current guidelines of data extrapolation from adult to pediatric population [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(1): 49-56.
[10]	YING Haifeng, ZHANG Weiping, YOU Kuangzhang, CHEN Lingyang. Analgesia effect of small amount of buprenorphine on children undergoing laparoscopic hernia repair under general anesthesia [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(8): 916-921.
[11]	WU Si-lian, CHENG Yong-quan, JIN Xiao-ju. Effects of compound lidocaine cream in the endotracheal tube extubation of pediatric abdominal surgery under general anesthesia [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(7): 801-804.
[12]	SHI Jun, Jeffrey S .Barrett. Pharmacometrics in pediatric drug development and rational dosage [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2010, 15(1): 1-10.
[13]	XIONG Bo, SHI Qi-qing, WANG Xuan. Efficacy of wound infiltration with ropivacaine on postoperative pain relief after acute appendectomy in children [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(5): 573-577.
[14]	SHI Qi-qing, XIONG Bo, ZHANG Xue-feng. Clinical research of ropivacaine supplemented with midazolam for sacral block in pediatric operation [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2007, 12(2): 228-231.