Efficacy and safety of the ketogenic diet in genetic developmental and epileptic encephalopathy_Journal of Epilepsy

Authors：

ZHANG Huan , ZHANG Tong , HU Wandong , LIU Yong , REN Ying , JIN Ruifeng ,  ZHANG Hongwei

Department of Neurology, Shandong University Affiliated Children’s Hospital (Jinan Children’s Hospital), Jinan 250022, China;

Corresponding?author：

ZHANG Hongwei, Email: zhw850510@163.com

Keywords：

Ketogenic diet; Developmental and epileptic encephalopathy; Genetic; Efficacy; Safety

DOI：

10.7507/2096-0247.202503010

Video：

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Objective To explore the efficacy and safety of the ketogenic diet (KD) in the treatment of genetic developmental and epileptic encephalopathy (DEE). Methods Clinical data from 42 children with genetically confirmed refractory epileptic encephalopathy treated in the Department of Neurology, Jinan Children’s Hospital, between January 2021 and October 2023 were retrospectively analyzed. A classic KD protocol was implemented, and outcomes including seizure frequency, electroencephalogram (EEG) improvement, and adverse reactions were observed at 3, 6, and 12 months post-treatment. Results Among the 42 children, the seizure-free rates at 3, 6, and 12 months of KD treatment were 16.7%, 16.7%, and 14.3%, respectively, while the effective seizure control rates were 69.0%, 52.4%, and 35.7%. At 3 months, comparison of baseline characteristics between the effective and ineffective groups showed no statistically significant differences in gender (P=0.095), age at onset (P=0.648), age at KD initiation(P=0.768), disease duration before KD (P=0.519), presence of abnormal brain MRI findings (P=0.226), epilepsy syndrome classification(P=0.344), or ion channel gene involvement (P=0.066). EEG improvement rates at 6 and 12 months were 54.2% (24 cases) and 42.8% (14 cases), respectively. Retention rates for KD at 3, 6, and 12 months were 100.0%, 71.4%, and 42.8%. Adverse reactions occurred in 7 patients (16.7%), primarily gastrointestinal symptoms (vomiting, constipation, diarrhea; 6 cases) and elevated uric acid (1 case), with no severe adverse events reported. Conclusion KD is an effective treatment for genetic DEE with favorable short-term safety, though long-term adherence requires attention.

Citation： ZHANG Huan, ZHANG Tong, HU Wandong, LIU Yong, REN Ying, JIN Ruifeng, ZHANG Hongwei. Efficacy and safety of the ketogenic diet in genetic developmental and epileptic encephalopathy. Journal of Epilepsy, 2025, 11(3): 220-225. doi: 10.7507/2096-0247.202503010 Copy

1.	Wirrell EC, Nabbout R, Scheffer IE, et al. Methodology for classification and definition of epilepsy syndromes with list of syndromes: Report of the ILAE Task Force on Nosology and Definitions. Epilepsia, 2022, 63(6): 1333-1348.
2.	金良, 陳語婕, 陳勇軍. 發育性和癲癇性腦病遺傳學病因及診療的研究進展. 遺傳, 2023, 45(7): 553-567.
3.	孫琴, 郝金斗, 周啟新, 等. 生酮飲食對兒童難治性癲癇療效與安全性的Meta分析. 臨床神經病學雜志, 2023, 36(4): 300-304.
4.	Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 512-521.
5.	Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine, 2015, 17(5): 405-424.
6.	Scheffer IE, Zuberi S, Mefford HC, et al. Developmental and epileptic encephalopathies. Nature Reviews. Disease Primers, 2024, 10(1): 66.
7.	Ko A, Jung DE, Kim SH, et al. The efficacy of ketogenic diet for specific genetic mutation in developmental and epileptic encephalopathy. Front Neurol, 2018, 9: 530.
8.	Schoeler NE, Marston L, Lyons L, et al. Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial. Lancet Neurol, 2023, 22(12): 1113-1124.
9.	Devi N, Madaan P, Kandoth N, et al. Efficacy and safety of dietary therapies for childhood drug-resistant epilepsy: a systematic review and network meta-analysis. JAMA Pediatr, 2023, 177(3): 258-266.
10.	Paoli A, Tinsley GM, Mattson MP, et al. Common and divergent molecular mechanisms of fasting and ketogenic diets. Trends Endocrinol Metab, 2024, 35(2): 125-141.
11.	Ozcan E, Yu KB, Dinh L, et al. Dietary fiber content in clinical ketogenic diets modifies the gut microbiome and seizure resistance in mice. Nat Commun, 2025, 16(1): 987.
12.	Rho JM, Boison D. The metabolic basis of epilepsy. Nat Rev Neurol, 2022, 18(6): 333-347.
13.	Gao K, Lin Z, Wen S, et al. Potassium channels and epilepsy. Acta Neurol Scand, 2022, 146(6): 699-707.
14.	Ma W, Berg J, Yellen G. Ketogenic diet metabolites reduce firing in central neurons by opening K(ATP) channels. J Neurosci, 2007, 27(14): 3618-3625.
15.	Lin G, Lu P, Zeng T, et al. GAPDH-mediated posttranscriptional regulations of sodium channel Scn1a and Scn3a genes under seizure and ketogenic diet conditions. Neuropharmacology, 2017, 113(Pt A): 480-489.
16.	Dutton SBB, Sawyer NT, Kalume F, et al. Protective effect of the ketogenic diet in Scn1a mutant mice. Epilepsia, 2011, 52(11): 2050-2056.
17.	Song T, Deng J, Chen C, et al. Long-term effectiveness and tolerability of ketogenic diet therapy in patients with genetic developmental and epileptic encephalopathy onset within the first 6 months of life. Epilepsia Open, 2024, 9(2): 643-652.
18.	中國醫師協會神經內科醫師分會兒童神經專業委員會, 中華醫學會兒科學分會神經學組. 生酮飲食治療兒童癲癇性腦病循證指南. 中華實用兒科臨床雜志, 2019, 34(12): 881-888.
19.	Tian X, Chen J, Zhang J, et al. The efficacy of ketogenic diet in 60 chinese patients with dravet syndrome. Front Neurol, 2019, 10: 625.
20.	Lim Z, Wong K, Olson HE, et al. Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients. Epilepsia, 2017, 58(8): 1415-1422.
21.	蔣瓊, 朱會, 王齊艷, 等. COL4A1基因相關腦穿通畸形1例報告并文獻復習. 中國生育健康雜志, 2023, 34(4): 370-372,387.
22.	Mori T, Imai K, Oboshi T, et al. Usefulness of ketogenic diet in a girl with migrating partial seizures in infancy. Brain and Development, 2016, 38(6): 601-604.
23.	陳巖, 包新華, 章清萍, 等. KCNT1基因變異導致的早發性癲癇腦病患兒遺傳學和臨床分析. 中華兒科雜志, 2018, 56(11): 824-828.

1. Wirrell EC, Nabbout R, Scheffer IE, et al. Methodology for classification and definition of epilepsy syndromes with list of syndromes: Report of the ILAE Task Force on Nosology and Definitions. Epilepsia, 2022, 63(6): 1333-1348.
2. 金良, 陳語婕, 陳勇軍. 發育性和癲癇性腦病遺傳學病因及診療的研究進展. 遺傳, 2023, 45(7): 553-567.
3. 孫琴, 郝金斗, 周啟新, 等. 生酮飲食對兒童難治性癲癇療效與安全性的Meta分析. 臨床神經病學雜志, 2023, 36(4): 300-304.
4. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 512-521.
5. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine, 2015, 17(5): 405-424.
6. Scheffer IE, Zuberi S, Mefford HC, et al. Developmental and epileptic encephalopathies. Nature Reviews. Disease Primers, 2024, 10(1): 66.
7. Ko A, Jung DE, Kim SH, et al. The efficacy of ketogenic diet for specific genetic mutation in developmental and epileptic encephalopathy. Front Neurol, 2018, 9: 530.
8. Schoeler NE, Marston L, Lyons L, et al. Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial. Lancet Neurol, 2023, 22(12): 1113-1124.
9. Devi N, Madaan P, Kandoth N, et al. Efficacy and safety of dietary therapies for childhood drug-resistant epilepsy: a systematic review and network meta-analysis. JAMA Pediatr, 2023, 177(3): 258-266.
10. Paoli A, Tinsley GM, Mattson MP, et al. Common and divergent molecular mechanisms of fasting and ketogenic diets. Trends Endocrinol Metab, 2024, 35(2): 125-141.
11. Ozcan E, Yu KB, Dinh L, et al. Dietary fiber content in clinical ketogenic diets modifies the gut microbiome and seizure resistance in mice. Nat Commun, 2025, 16(1): 987.
12. Rho JM, Boison D. The metabolic basis of epilepsy. Nat Rev Neurol, 2022, 18(6): 333-347.
13. Gao K, Lin Z, Wen S, et al. Potassium channels and epilepsy. Acta Neurol Scand, 2022, 146(6): 699-707.
14. Ma W, Berg J, Yellen G. Ketogenic diet metabolites reduce firing in central neurons by opening K(ATP) channels. J Neurosci, 2007, 27(14): 3618-3625.
15. Lin G, Lu P, Zeng T, et al. GAPDH-mediated posttranscriptional regulations of sodium channel Scn1a and Scn3a genes under seizure and ketogenic diet conditions. Neuropharmacology, 2017, 113(Pt A): 480-489.
16. Dutton SBB, Sawyer NT, Kalume F, et al. Protective effect of the ketogenic diet in Scn1a mutant mice. Epilepsia, 2011, 52(11): 2050-2056.
17. Song T, Deng J, Chen C, et al. Long-term effectiveness and tolerability of ketogenic diet therapy in patients with genetic developmental and epileptic encephalopathy onset within the first 6 months of life. Epilepsia Open, 2024, 9(2): 643-652.
18. 中國醫師協會神經內科醫師分會兒童神經專業委員會, 中華醫學會兒科學分會神經學組. 生酮飲食治療兒童癲癇性腦病循證指南. 中華實用兒科臨床雜志, 2019, 34(12): 881-888.
19. Tian X, Chen J, Zhang J, et al. The efficacy of ketogenic diet in 60 chinese patients with dravet syndrome. Front Neurol, 2019, 10: 625.
20. Lim Z, Wong K, Olson HE, et al. Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients. Epilepsia, 2017, 58(8): 1415-1422.
21. 蔣瓊, 朱會, 王齊艷, 等. COL4A1基因相關腦穿通畸形1例報告并文獻復習. 中國生育健康雜志, 2023, 34(4): 370-372,387.
22. Mori T, Imai K, Oboshi T, et al. Usefulness of ketogenic diet in a girl with migrating partial seizures in infancy. Brain and Development, 2016, 38(6): 601-604.
23. 陳巖, 包新華, 章清萍, 等. KCNT1基因變異導致的早發性癲癇腦病患兒遺傳學和臨床分析. 中華兒科雜志, 2018, 56(11): 824-828.

Journal of Epilepsy

Efficacy and safety of the ketogenic diet in genetic developmental and epileptic encephalopathy

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