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Safety and tolerability of the ketogenic diet used for the treatment of refractory childhood epilepsy: a systematic review of published prospective studies

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Abstract

Background

To review the available evidence from prospective studies on the safety and tolerability of the ketogenic diet (KD) for the treatment of refractory childhood epilepsy.

Methods

A comprehensive bibliographic search was performed with the aim of retrieving prospective studies that monitored adverse effects (AEs) in children after receiving the classic or medium-chain triglyceride KD therapy for refractory epilepsy.

Results

A total of 45 studies were retrieved, including 7 randomized controlled trials. More than 40 categories of AEs were reported. The most common AEs included gastrointestinal disturbances (40.6%), hyperlipidemia (12.8%), hyperuricemia (4.4%), lethargy (4.1%), infectious diseases (3.8%) and hypoproteinemia (3.8%). Severe AEs, such as respiratory failure and pancreatitis, occurred in no more than 0.5% of children. Specifically, patients receiving KD therapy should be monitored for osteopenia, urological stones, right ventricular diastolic dysfunction, and growth disturbance. The total retention rates of the diet for 1 year and 2 years were 45.7% and 29.2%, respectively. Nearly half of the patients discontinued the diet because of lack of efficacy. AEs were not the main reason for the KD discontinuation. None of the 24 deaths reported after initiation of the diet was attributed to the KD.

Conclusions

KD is a relatively safe dietary therapy. However, because the KD can cause various AEs, it should be implemented under careful medical supervision. Continuous follow-up is needed to address the long-term impact of the diet on the overall health of children.

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References

  1. Sillanpää M, Schmidt D. Natural history of treated childhoodonset epilepsy: prospective, long-term population-based study. Brain 2006;129:617–624.

    Article  PubMed  Google Scholar 

  2. Winesett SP, Bessone SK, Kossoff EH. The ketogenic diet in pharmacoresistant childhood epilepsy. Expert Rev Neurother 2015;15:621–628.

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. 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 

  5. Ketogenic Diet Study Group of the Subspecialty Group of Neurology, the Society of Pediatrics, Chinese Medical Association. Prospective multicenter study on long-term ketogenic diet therapy for intractable childhood epilepsy. Zhonghua Er Ke Za Zhi 2013;51:276–282. [In Chinese]

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Kwiterovich PO Jr, Vining EP, Pyzik P, Skolasky R Jr, Freeman JM. Effect of a high-fat ketogenic diet on plasma levels of lipids, lipoproteins, and apolipoproteins in children. JAMA 2003;290:912–920.

    Article  CAS  PubMed  Google Scholar 

  8. Williams S, Basualdo-Hammond C, Curtis R, Schuller R. Growth retardation in children with epilepsy on the ketogenic diet: a retrospective chart review. J Am Diet Assoc 2002;102:405–407.

    Article  PubMed  Google Scholar 

  9. Peterson SJ, Tangney CC, Pimentel-Zablah EM, Hjelmgren B, Booth G, Berry-Kravis E. Changes in growth and seizure reduction in children on the ketogenic diet as a treatment for intractable epilepsy. J Am Diet Assoc 2005;105:718–725.

    Article  PubMed  Google Scholar 

  10. Kielb S, Koo HP, Bloom DA, Faerber GJ. Nephrolithiasis associated with the ketogenic diet. J Urol 2000;164:464–466.

    Article  CAS  PubMed  Google Scholar 

  11. Bergqvist AG, Schall JI, Gallagher PR, Cnaan A, Stallings VA. Fasting versus gradual initiation of the ketogenic diet: a prospective, randomized clinical trial of efficacy. Epilepsia 2005;46:1810–1819.

    Article  CAS  PubMed  Google Scholar 

  12. Seo JH, Lee YM, Lee JS, Kang HC, Kim HD. Efficacy and tolerability of the ketogenic diet according to lipid:nonlipid ratios-comparison of 3:1 with 4:1 diet. Epilepsia 2007;48:801–805.

    Article  CAS  PubMed  Google Scholar 

  13. Neal EG, Chaffe HM, Edwards N, Lawson MS, Schwartz RH, Cross JH. Growth of children on classical and medium-chain triglyceride ketogenic diets. Pediatrics 2008;122:e334–e340.

    Article  PubMed  Google Scholar 

  14. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, et al. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia 2009;50:1109–1117.

    Article  PubMed  Google Scholar 

  15. 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;52:781–787.

    Article  PubMed  Google Scholar 

  16. Raju KN, Gulati S, Kabra M, Agarwala A, Sharma S, Pandey RM, et al. Efficacy of 4:1 (classic) versus 2.5:1 ketogenic ratio diets in refractory epilepsy in young children: a randomized open labeled study. Epilepsy Res 2011;96:96–100.

    Article  CAS  PubMed  Google Scholar 

  17. Christodoulides SS, Neal EG, Fitzsimmons G, Chaffe HM, Jeanes YM, Aitkenhead H, et al. The effect of the classical and medium chain triglyceride ketogenic diet on vitamin and mineral levels. J Hum Nutr Diet 2012;25:16–26.

    Article  CAS  PubMed  Google Scholar 

  18. Hu Y, Lu XG, Wen JL, Wang C, Chen L, Chen Y, et al. Randomized control study on two different protocols of ketogenic diet for refractory epilepsy in children. Chin Pediatr Emerg Med 2012;19:473–476. [In Chinese]

    CAS  Google Scholar 

  19. El-Rashidy OF, Nassar MF, Abdel-Hamid IA, Shatla RH, Abdel-Hamid MH, Gabr SS, et al. Modified Atkins diet vs classic ketogenic formula in intractable epilepsy. Acta Neurol Scand 2013;128:402–408.

    Article  CAS  PubMed  Google Scholar 

  20. Ballaban-Gil K, Callahan C, O’Dell C, Pappo M, Moshé S, Shinnar S. Complications of the ketogenic diet. Epilepsia 1998;39:744–748.

    Article  CAS  PubMed  Google Scholar 

  21. Vining EP, Freeman JM, Ballaban-Gil K, Camfield CS, Camfield PR, Holmes GL, et al. A multicenter study of the efficacy of the ketogenic diet. Arch Neurol 1998;55:1433–1437.

    Article  CAS  PubMed  Google Scholar 

  22. Furth SL, Casey JC, Pyzik PL, Neu AM, Docimo SG, Vining EP, et al. Risk factors for urolithiasis in children on the ketogenic diet. Pediatr Nephrol 2000;15:125–128.

    Article  CAS  PubMed  Google Scholar 

  23. Lightstone L, Shinnar S, Callahan CM, O’Dell C, Moshe SL, Ballaban-Gil KR. Reasons for failure of the ketogenic diet. J Neurosci Nurs 2001;6:292–295.

    Article  Google Scholar 

  24. Freeman JM, Vining EP, Pillas DJ, Pyzik PL, Casey JC, Kelly LM. The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children. Pediatrics 1998;102:1358–1363.

    Article  CAS  PubMed  Google Scholar 

  25. Hemingway C, Freeman JM, Pillas DJ, Pyzik PL. The ketogenic diet: a 3- to 6-year follow-up of 150 children enrolled prospectively. Pediatrics 2001;108:898–905.

    Article  CAS  PubMed  Google Scholar 

  26. Vining EP, Pyzik P, McGrogan J, Hladky H, Anand A, Kriegler S, et al. Growth of children on the ketogenic diet. Dev Med Child Neurol 2002;44:796–802.

    Article  PubMed  Google Scholar 

  27. Liu YM, Williams S, Basualdo-Hammond C, Stephens D, Curtis R. A prospective study: growth and nutritional status of children treated with the ketogenic diet. J Am Diet Assoc 2003;103:707–712.

    Article  PubMed  Google Scholar 

  28. Hosain SA, La Vega-Talbott M, Solomon GE. Ketogenic diet in pediatric epilepsy patients with gastrostomy feeding. Pediatr Neurol 2005;32:81–83.

    Article  PubMed  Google Scholar 

  29. Klepper J, Scheffer H, Leiendecker B, Gertsen E, Binder S, Leferink M, et al. Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively. Neuropediatrics 2005;36:302–308.

    Article  CAS  PubMed  Google Scholar 

  30. Caraballo RH, Cersósimo RO, Sakr D, Cresta A, Escobal N, Fejerman N. Ketogenic diet in patients with myoclonic-astatic epilepsy. Epileptic Disord 2006;8:151–155.

    PubMed  Google Scholar 

  31. Rizzutti S, Ramos AM, Muszkat M, Gabbai AA. Is hospitalization really necessary during the introduction of the ketogenic diet? J Child Neurol 2007;22:33–37.

    Article  PubMed  Google Scholar 

  32. Nizamuddin J, Turner Z, Rubenstein JE, Pyzik PL, Kossoff EH. Management and risk factors for dyslipidemia with the ketogenic diet. J Child Neurol 2008;23:758–761.

    Article  PubMed  Google Scholar 

  33. Bergqvist AG, Schall JI, Stallings VA, Zemel BS. Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic diet. Am J Clin Nutr 2008;88:1678–1684.

    Article  CAS  PubMed  Google Scholar 

  34. Nathan JK, Purandare AS, Parekh ZB, Manohar HV. Ketogenic diet in Indian children with uncontrolled epilepsy. Indian Pediatr 2009;46:669–673.

    CAS  PubMed  Google Scholar 

  35. Sharma S, Gulati S, Kalra V, Agarwala A, Kabra M. Seizure control and biochemical profile on the ketogenic diet in young children with refractory epilepsy-Indian experience. Seizure 2009;18:446–449.

    Article  PubMed  Google Scholar 

  36. Spulber G, Spulber S, Hagenäs L, Amark P, Dahlin M. Growth dependence on insulin-like growth factor-1 during the ketogenic diet. Epilepsia 2009;50:297–303.

    Article  PubMed  Google Scholar 

  37. Coppola G, Verrotti A, Ammendola E, Operto FF, Corte RD, Signoriello G, et al. Ketogenic diet for the treatment of catastrophic epileptic encephalopathies in childhood. Eur J Paediatr Neurol 2010;14:229–234.

    Article  PubMed  Google Scholar 

  38. Hong AM, Turner Z, Hamdy RF, Kossoff EH. Infantile spasms treated with the ketogenic diet: prospective single-center experience in 104 consecutive infants. Epilepsia 2010;51:1403–1407.

    Article  PubMed  Google Scholar 

  39. Nabbout R, Copioli C, Chipaux M, Chemaly N, Desguerre I, Dulac O, et al. Ketogenic diet also benefits Dravet syndrome patients receiving stiripentol: a prospective pilot study. Epilepsia 2011;52:e54–e57.

    Article  PubMed  Google Scholar 

  40. Tagliabue A, Bertoli S, Trentani C, Borrelli P, Veggiotti P. Effects of the ketogenic diet on nutritional status, resting energy expenditure, and substrate oxidation in patients with medically refractory epilepsy: a 6-month prospective observational study. Clin Nutr 2012;31:246–249.

    Article  CAS  PubMed  Google Scholar 

  41. Sharma S, Gulati S. The ketogenic diet and the QT interval. J Clin Neurosci 2012;19:181–182.

    Article  PubMed  Google Scholar 

  42. Deng YH, Zhou JH, Li BM, Liu XR, Liao WP. Long-term retention rate and side effects of ketogenic diet in Chinese patients with refraetory epilepsy. Parenter Enter Nutr 2012;19:355–358. [In Chinese]

    Google Scholar 

  43. Pires ME, Ilea A, Bourel E, Bellavoine V, Merdariu D, Berquin P, et al. Ketogenic diet for infantile spasms refractory to firstline treatments: an open prospective study. Epilepsy Res 2013;105:189–194.

    Article  CAS  PubMed  Google Scholar 

  44. Lu ZY, Yu LF, Gong XY, Wang XH, Hua HM, Zhang LM, et al. Compliance and safety of ketogenic diet therapy for children with intractable epilepsy. Chin J Pract Pediatr 2013;28:378–381. [In Chinese]

    CAS  Google Scholar 

  45. Li BM, Tong LL, Jia GJ, Wang JW, Lei GF, Yin P, et al. Influence of ketogenic diet on the clinical effects and electroencephalogram features in 31 children with pharmacoresistant epileptic encephalopathy. Zhonghua Er Ke Za Zhi 2013;51:362–366. [In Chinese]

    PubMed  Google Scholar 

  46. Caraballo RH, Fortini S, Fresler S, Armeno M, Ariela A, Cresta A, et al. Ketogenic diet in patients with Lennox-Gastaut syndrome. Seizure 2014;23:751–755.

    Article  PubMed  Google Scholar 

  47. Kayyali HR, Gustafson M, Myers T, Thompson L, Williams M, Abdelmoity A. Ketogenic diet efficacy in the treatment of intractable epileptic spasms. Pediatr Neurol 2014;50:224–227.

    Article  PubMed  Google Scholar 

  48. Groleau V, Schall JI, Stallings VA, Bergqvist CA. Long-term impact of the ketogenic diet on growth and resting energy expenditure in children with intractable epilepsy. Dev Med Child Neurol 2014;56:898–904.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Kapetanakis M, Liuba P, Odermarsky M, Lundgren J, Hallböök T. Effects of ketogenic diet on vascular function. Eur J Paediatr Neurol 2014;18:489–494.

    Article  CAS  PubMed  Google Scholar 

  50. Zhu DN, Xie MM, Wang JH, Wang J, Ma DY, Sun L, et al. Therapeutic effect of ketogenic diet for refractory epilepsy in children: a prospective observational study. Zhongguo Dang Dai Er Ke Za Zhi 2014;16:513–517. [In Chinese]

    PubMed  Google Scholar 

  51. Zhu DN, Xie MM, Wang J, Wang JH, Wang MM, Zhang GY, et al. Clinical observation of ketogenic diet adding for refractory epilepsy in 36 cases of children. Chin J Appl Clin Pediatr 2014;29:1483–1487. [In Chinese]

    Google Scholar 

  52. Doksöz Ö, Çeleğen K, Güzel O, Yılmaz Ü, Uysal U, İşgüder R, et al. The short-term effects of ketogenic diet on cardiac ventricular functions in epileptic children. Pediatr Neurol 2015;53:233–237.e1.

    Article  PubMed  Google Scholar 

  53. Lambrechts DA, de Kinderen RJ, Vles HS, de Louw AJ, Aldenkamp AP, Majoie MJ. The MCT-ketogenic diet as a treatment option in refractory childhood epilepsy: a prospective study with 2-year follow-up. Epilepsy Behav 2015;51:261–266.

    Article  PubMed  Google Scholar 

  54. Doksöz Ö, Güzel O, Yılmaz Ü, İşgüder R, Çeleğen K, Meşe T, et al. The short-term effect of ketogenic diet on carotid intimamedia thickness and elastic properties of the carotid artery and the aorta in epileptic children. J Child Neurol 2015;30:1646–1650.

    Article  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  56. Kim JT, Kang HC, Song JE, Lee MJ, Lee YJ, Lee EJ, et al. Catch-up growth after long-term implementation and weaning from ketogenic diet in pediatric epileptic patients. Clin Nutr 2013;32:98–103.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China

    Qian-Yun Cai, Rong Luo, De-Zhi Mu & Chao-Min Wan

  2. Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China

    Zhong-Jie Zhou

  3. Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, China

    Qian-Yun Cai, Rong Luo, Jing Gan, Shi-Ping Li, De-Zhi Mu & Chao-Min Wan

  4. Department of Pediatrics, West China Second University Hospital, Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, 610041, China

    Chao-Min Wan

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Cai, QY., Zhou, ZJ., Luo, R. 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 13, 528–536 (2017). https://doi.org/10.1007/s12519-017-0053-2

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  • DOI: https://doi.org/10.1007/s12519-017-0053-2

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