Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Ketogenic diet for epilepsy: an overview of systematic review and meta-analysis

Abstract

Ketogenic diet therapy (KDT) is an established nonpharmacologic treatment in various types of epilepsy. We aim to evaluate the quality of the systematic reviews and meta-analyses (SRMAs) of KDT for epilepsy and summarize the evidence on their effects. We conducted an overview on MEDLINE, EMBASE, Cochrane Database of Systematic Review, and Web of Science from database inception to 3 September 2020. Two investigators independently performed study selection to include SRMAs, extracted data and assessed the quality of SRMAs with the AMSTAR-2 and PRISMA statement. Twenty-four SRMAs were selected which encompassed a total of 255 original studies. Four reviews assessed the effects of KDT on infant patients; thirteen reviews reported on children and adolescent patients; eight reviews focused on adults or all patients; four assessed cognitive and behavior outcomes; three assessed quality of life; two assessed growth and development outcomes; seventeen reported on adverse effects; seven reported on retention; ten reported on attrition and reasons; and four reported on death outcomes. Overall, positive effects of KDT for epilepsy on seizure frequency reduction, as well as cognition and behavior were observed. In contrast, the effects of KDT on quality of life, growth and development were more controversial. The present overview indicates that KDT is safe. The most prevalent adverse events were GI, weight loss, and metabolic disorders, while the most common reasons for discontinuance were the lack of observed efficacy and dietary intolerance.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1
Fig. 2: Methodological quality assessment of the included reviews on the AMSTAR 2 scale.

References

  1. Rezaei S, Abdurahman AA, Saghazadeh A, Badv RS, Mahmoudi M. Short-term and long-term efficacy of classical ketogenic diet and modified Atkins diet in children and adolescents with epilepsy: a systematic review and meta-analysis. Nutr Neurosci. 2019;22:317–34.

    Article  CAS  PubMed  Google Scholar 

  2. Sourbron J, Klinkenberg S, Kuijk SMJV, Lagae L, Majoie M. Ketogenic diet for the treatment of pediatric epilepsy: review and meta-analysis. Childs Nerv Syst. 2020;36:1099–109.

    Article  PubMed  Google Scholar 

  3. Martin-Mcgill KJ, Bresnahan R, Levy RG, Cooper PN. Ketogenic diets for drug-resistant epilepsy. Cochrane Database Syst Rev. 2020;6:CD001903.

    PubMed  Google Scholar 

  4. Lyons L, Schoeler NE, Langan D, Cross JH. Use of ketogenic diet therapy in infants with epilepsy: a systematic review and meta-analysis. Epilepsia 2020;61:1261–81.

    Article  PubMed  Google Scholar 

  5. Sourbron J, Klinkenberg S, Kessels A, Schelhaas HJ, Lagae L, Majoie M. Vagus Nerve Stimulation in children: A focus on intellectual disability. Eur J Paediatr Neurol. 2017;21:427–40.

    Article  PubMed  Google Scholar 

  6. Martin K, Jackson C, Levy RG, Cooper PN. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst Rev. 2016;2:CD001903.

    PubMed  Google Scholar 

  7. Rho JM. How does the ketogenic diet induce anti-seizure effects? Neurosci Lett. 2017;637:4–10.

    Article  CAS  PubMed  Google Scholar 

  8. Simeone TA, Simeone KA, Stafstrom CE, Rho JM. Do ketone bodies mediate the anti-seizure effects of the ketogenic diet? Neuropharmacology. 2018;133:233–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang YQ, Fang ZX, Zhang YW, Xie LL, Jiang L. Efficacy of the ketogenic diet in patients with Dravet syndrome: a meta-analysis. Seizure 2020;81:36–42.

    Article  PubMed  Google Scholar 

  10. Li HF, Zou Y, Ding G. Therapeutic Success of the Ketogenic Diet as a Treatment Option for Epilepsy: a Meta-analysis. Iran J Pediatr. 2013;23:613–20.

    PubMed  PubMed Central  Google Scholar 

  11. Levy RG, Cooper PN, Giri P, Pulman J. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst Rev. 2012;3:CD001903.

    Google Scholar 

  12. Rezaei S, Harsini S, Kavoosi M, Badv RS, Mahmoudi M. Efficacy of low glycemic index treatment in epileptic patients: a systematic review. Acta Neurol Belg. 2018;118:339–49.

    Article  PubMed  Google Scholar 

  13. Operto FF, Matricardi S, Pastorino GMG, Verrotti A, Coppola G. The Ketogenic Diet for the Treatment of Mood Disorders in Comorbidity With Epilepsy in Children and Adolescents. Front Pharmacol. 2020;11:578396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Huttenlocher PR, Wilbourn AJ, Signore JM. Medium-chain triglycerides as a therapy for intractable childhood epilepsy. Neurology 1971;21:1097–103.

    Article  CAS  PubMed  Google Scholar 

  15. Atkins RC. Dr. Atkins’ diet revolution. Med Lett Drugs Ther. 1973;15:41–2.

    Google Scholar 

  16. Smith V, Devane D, Begley CM, Clarke M. Methodology in conducting a systematic review of systematic reviews of healthcare interventions. BMC Med Res Methodol. 2011;11:15.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62:1006–12.

    Article  PubMed  Google Scholar 

  18. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017;358:j4008.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ye F, Li XJ, Jiang WL, Sun HB, Liu J. Efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy: a meta-analysis. J Clin Neurol. 2015;11:26–31.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Araya-Quintanilla F, Celis-Rosati A, Rodriguez-Leiva C, Silva-Navarro C, Silva-Pinto Y, Toro-Jeria B. Effectiveness of a ketogenic diet in children with refractory epilepsy: a systematic review. Rev De Neurologia. 2016;62:439–48.

    CAS  Google Scholar 

  21. Poelzer K, Mannion C, Ortiz MM, Bang R, Woods P. A Systematic Review of the Quality of Life for Families Supporting a Child Consuming the Ketogenic Diet for Seizure Reduction. Curr Dev Nutr. 2018;3:nzz079.

    PubMed  PubMed Central  Google Scholar 

  22. Keene DL. A Systematic Review of the Use of the Ketogenic Diet in Childhood Epilepsy. Pediatr Neurol. 2006;35:1–5.

    Article  PubMed  Google Scholar 

  23. Liu XY, Chen J, Zhu M, Zheng G, Guo H, Lu X, et al. Three and Six Months of Ketogenic Diet for Intractable Childhood Epilepsy: a Systematic Review and Meta-Analysis. Front Neurol. 2019;10:244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lefevre F, Aronson N. Ketogenic diet for the treatment of refractory epilepsy in children: a systematic review of efficacy. Pediatrics 2000;105:E46.

    Article  CAS  PubMed  Google Scholar 

  25. Henderson CB, Filloux FM, Alder SC, Lyon JL, Caplin DA. Efficacy of the ketogenic diet as a treatment option for epilepsy: meta-analysis. J Child Neurol. 2006;21:193–8.

    Article  PubMed  Google Scholar 

  26. Cai QY, Zhou ZJ, Luo R, Gan J, Li SP, Mu DZ, et al. Safety and tolerability of the ketogenic diet used for the treatment of refractory childhood epilepsy: a systematic review of published prospective studies. World J Pediatr. 2017;13:528–36.

    Article  PubMed  Google Scholar 

  27. Liu H, Yang Y, Wang Y, Tang H, Zhang F, Zhang Y, et al. Ketogenic diet for treatment of intractable epilepsy in adults: a meta‐analysis of observational studies. Epilepsia Open. 2018;3:9–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Christensen MG, Damsgaard J, Fink-Jensen A. Use of ketogenic diets in the treatment of central nervous system diseases: a systematic review. Nord J Psychiatry. 2021;75:1–8.

    Article  PubMed  Google Scholar 

  29. Mahmoud SH, Ho-Uang E, Buhler J. Systematic review of ketogenic diet use in adult patients with status epilepticus. Epilepsia Open. 2019;5:10–21.

    Article  PubMed  PubMed Central  Google Scholar 

  30. van Berkel AA, Ijff DM, Verkuyl JM. Cognitive benefits of the ketogenic diet in patients with epilepsy: a systematic overview. Epilepsy Behav. 2018;87:69–77.

    Article  PubMed  Google Scholar 

  31. Zhang JH, Mao XY, Wu Y. Efficacy of ketogenic diets in children with refractory epilepsy: a meta-analysis. Int J Clin Exp Med. 2018;11:11396–405.

    Google Scholar 

  32. Prezioso G, Carlone G, Zaccara G, Verrotti A. Efficacy of ketogenic diet for infantile spasms: a systematic review. Acta Neurol Scand. 2018;137:4–11.

    Article  CAS  PubMed  Google Scholar 

  33. Song JM, Hahn J, Kim SH, Chang MJ. Efficacy of Treatments for Infantile Spasms: a Systematic Review. Clin Neuropharmacol. 2017;40:63–84.

    Article  PubMed  CAS  Google Scholar 

  34. Kim JA, Yoon JR, Lee EJ, Lee JS, Kim JT, Kim HD, et al. Efficacy of the classic ketogenic and the modified Atkins diets in refractory childhood epilepsy. Epilepsia. 2016;57:51–8.

    Article  PubMed  Google Scholar 

  35. Dressler A, Benninger F, Trimmel-Schwahofer P, Gröppel G, Porsche B, Abraham K, et al. Efficacy and tolerability of the ketogenic diet versus high-dose adrenocorticotropic hormone for infantile spasms: a single-center parallel-cohort randomized controlled trial. Epilepsia. 2019;60:441–51.

    Article  CAS  PubMed  Google Scholar 

  36. Kang HC, Lee YJ, Lee JS, Lee EJ, Eom S, You SJ, et al. Comparison of short- versus long-term ketogenic diet for intractable infantile spasms. Epilepsia. 2011;52:781–7.

    Article  PubMed  Google Scholar 

  37. Dominique MIJ, Postulart D, Lambrechts D, Majoie M, de Kinderen RJA, Hendriksen JGM, et al. Cognitive and behavioral impact of the ketogenic diet in children and adolescents with refractory epilepsy: a randomized controlled trial. Epilepsy Behav. 2016;60:153–7.

    Article  Google Scholar 

  38. Sharma S, Goel S, Jain P, Agarwala A, Aneja S. Evaluation of a simplified modified Atkins diet for use by parents with low levels of literacy in children with refractory epilepsy: a randomized controlled trial. Epilepsy Res. 2016;127:152–9.

    Article  PubMed  Google Scholar 

  39. Lambrechts D, de Kinderen RJA, Vles JSH, de Louw AJ, Aldenkamp AP, Majoie HJM. A randomized controlled trial of the ketogenic diet in refractory childhood epilepsy. Acta Neurol Scand. 2017;135:678.

    Article  CAS  PubMed  Google Scholar 

  40. Wijnen BFM, de Kinderen RJA, Lambrechts D, Postulart D, Aldenkamp AP, Majoie M, et al. Long-term clinical outcomes and economic evaluation of the ketogenic diet versus care as usual in children and adolescents with intractable epilepsy. Epilepsy Res. 2017;132:91–9.

    Article  PubMed  Google Scholar 

  41. Hallbook T, Ji S, Maudsley S, Martin B. The effects of the ketogenic diet on behavior and cognition. Epilepsy Res. 2012;100:304–9.

    Article  PubMed  CAS  Google Scholar 

  42. Yuen AWC, Sander JW. Rationale for using intermittent calorie restriction as a dietary treatment for drug resistant epilepsy. Epilepsy Behav. 2014;33:110–4.

    Article  PubMed  Google Scholar 

  43. Verrotti A, Iapadre G, Di Francesco L, Zagaroli L, Farello G. Diet in the Treatment of Epilepsy: What We Know So Far. Nutrients 2020;12:2645.

    Article  CAS  PubMed Central  Google Scholar 

  44. Dressler A, Stöcklin B, Reithofer E, Benninger F, Freilinger M, Hauser E, et al. Long-term outcome and tolerability of the ketogenic diet in drug-resistant childhood epilepsy—the Austrian experience. Seizure 2010;19:404–8.

    Article  PubMed  Google Scholar 

  45. Nagisa S, Tsuyoshi I. Electrical Control in Neurons by the Ketogenic Diet. Front Cell Neurosci. 2018;12:208.

    Google Scholar 

  46. Phillips MC, Murtagh DK, Gilbertson LJ, Asztely FJ, Lynch CD. Low-fat versus ketogenic diet in Parkinson’s disease: a pilot randomized controlled trial. Mov Disord. 2018;33:1306–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Stewart L, Moher D, Shekelle P. Why prospective registration of systematic reviews makes sense. Syst Rev. 2012;1.

Download references

Acknowledgements

This work was supported by Lanzhou Chengguan District Science and Technology Project (2020-1-2-3).

Author information

Authors and Affiliations

Authors

Contributions

Study concept and design: LG and LH. Literature search and data analysis: YR and LC. Paper preparation: YR and DLS. Paper modifification: YR and YFC. All authors approved the publication of this overview.

Corresponding authors

Correspondence to Long Ge or Lin Han.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ruan, Y., Chen, L., She, D. et al. Ketogenic diet for epilepsy: an overview of systematic review and meta-analysis. Eur J Clin Nutr 76, 1234–1244 (2022). https://doi.org/10.1038/s41430-021-01060-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41430-021-01060-8

Search

Quick links