The ketogenic diet

INTRODUCTION

Antiepileptic drugs (AEDs) are the primary treatment for epileptic seizures, and are effective in controlling seizures in most patients. However, approximately one-third of patients will not become seizure-free with medications and require nonpharmacologic treatments [1]. Although epilepsy surgery is usually considered for these patients, there are many families and patients who are either unwilling to consider or are not candidates for epilepsy surgery, either because surgery would lead to intolerable motor, language, or memory deficits or for other reasons. In these patients, treatments such as vagus nerve stimulation (VNS) and diets are then considered.

This topic will review the ketogenic diet and alternative diets for the treatment of epilepsy. Some of the preliminary evidence for use of the ketogenic diet in other neurologic conditions will also be briefly reviewed. Other treatments for seizures and epilepsy in adults and children with epilepsy are reviewed separately. (See "Overview of the management of epilepsy in adults" and "Overview of the treatment of seizures and epileptic syndromes in children" and "Vagus nerve stimulation therapy for the treatment of epilepsy" and "Initial treatment of epilepsy in adults" and "Surgical treatment of epilepsy in adults".)

MECHANISMS OF ACTION

Published reports of the ketogenic diet as an effective treatment for epilepsy date to the early 1920s [2]. However, the mechanism(s) by which the ketogenic diet suppresses seizures remains unclear and is likely multifactorial [3].

The ketogenic diet utilizes a high fat, adequate-protein (1 gram/kg), low-carbohydrate diet that produces metabolic changes often associated with the starvation state. Often started with a brief fasting period, changes in plasma ketones, insulin, glucose, glucagon, and free fatty acids can occur within hours of starting the diet and can be quite profound [3].

Which of these metabolic changes are responsible for the improvement in seizure frequency is not known. The ketogenic diet was so called based upon the theory that ketone bodies (acetoacetate, acetone, and beta-hydroxybutyrate), created in the liver from long and medium-chain fatty acids, are directly anticonvulsant when crossing the blood-brain barrier. Urine and occasionally serum ketone levels are generally checked in patients on the ketogenic diet to ensure the diet is being managed correctly, in a manner analogous to following antiepileptic drug levels [4].

                  

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jul 2014. | This topic last updated: Jun 2, 2014.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.
References
Top
  1. Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia 2001; 42:1255.
  2. Wilder RM. The effect of ketonemia on the course of epilepsy. Mayo Clin Bulletin 1921; 2:307.
  3. Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia 2007; 48:43.
  4. Kossoff EH, Zupec-Kania BA, Amark PE, et al. Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. Epilepsia 2009; 50:304.
  5. Bough KJ, Wetherington J, Hassel B, et al. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol 2006; 60:223.
  6. Danial NN, Hartman AL, Stafstrom CE, Thio LL. How does the ketogenic diet work? Four potential mechanisms. J Child Neurol 2013; 28:1027.
  7. Henderson CB, Filloux FM, Alder SC, et al. Efficacy of the ketogenic diet as a treatment option for epilepsy: meta-analysis. J Child Neurol 2006; 21:193.
  8. Lefevre F, Aronson N. Ketogenic diet for the treatment of refractory epilepsy in children: A systematic review of efficacy. Pediatrics 2000; 105:E46.
  9. Levy RG, Cooper PN, Giri P. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst Rev 2012; 3:CD001903.
  10. Klein P, Janousek J, Barber A, Weissberger R. Ketogenic diet treatment in adults with refractory epilepsy. Epilepsy Behav 2010; 19:575.
  11. Payne NE, Cross JH, Sander JW, Sisodiya SM. The ketogenic and related diets in adolescents and adults--a review. Epilepsia 2011; 52:1941.
  12. Neal EG, Chaffe H, Schwartz RH, et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol 2008; 7:500.
  13. Kossoff EH, Hedderick EF, Turner Z, Freeman JM. A case-control evaluation of the ketogenic diet versus ACTH for new-onset infantile spasms. Epilepsia 2008; 49:1504.
  14. Kilaru S, Bergqvist AG. Current treatment of myoclonic astatic epilepsy: clinical experience at the Children's Hospital of Philadelphia. Epilepsia 2007; 48:1703.
  15. Caraballo RH, Cersósimo RO, Sakr D, et al. Ketogenic diet in patients with myoclonic-astatic epilepsy. Epileptic Disord 2006; 8:151.
  16. Oguni H, Tanaka T, Hayashi K, et al. Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood. Neuropediatrics 2002; 33:122.
  17. Mullen SA, Marini C, Suls A, et al. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch Neurol 2011; 68:1152.
  18. Haas RH, Rice MA, Trauner DA, Merritt TA. Therapeutic effects of a ketogenic diet in Rett syndrome. Am J Med Genet Suppl 1986; 1:225.
  19. Giampietro PF, Schowalter DB, Merchant S, et al. Widened clinical spectrum of the Q128P MECP2 mutation in Rett syndrome. Childs Nerv Syst 2006; 22:320.
  20. Liebhaber GM, Riemann E, Baumeister FA. Ketogenic diet in Rett syndrome. J Child Neurol 2003; 18:74.
  21. Kossoff EH, Thiele EA, Pfeifer HH, et al. Tuberous sclerosis complex and the ketogenic diet. Epilepsia 2005; 46:1684.
  22. Kossoff EH, Turner Z, Bergey GK. Home-guided use of the ketogenic diet in a patient for more than 20 years. Pediatr Neurol 2007; 36:424.
  23. Martinez CC, Pyzik PL, Kossoff EH. Discontinuing the ketogenic diet in seizure-free children: recurrence and risk factors. Epilepsia 2007; 48:187.
  24. Coppola G, Klepper J, Ammendola E, et al. The effects of the ketogenic diet in refractory partial seizures with reference to tuberous sclerosis. Eur J Paediatr Neurol 2006; 10:148.
  25. Caraballo RH, Cersósimo RO, Sakr D, et al. Ketogenic diet in patients with Dravet syndrome. Epilepsia 2005; 46:1539.
  26. Dressler A, Stöcklin B, Reithofer E, et al. Long-term outcome and tolerability of the ketogenic diet in drug-resistant childhood epilepsy--the Austrian experience. Seizure 2010; 19:404.
  27. Korff C, Laux L, Kelley K, et al. Dravet syndrome (severe myoclonic epilepsy in infancy): a retrospective study of 16 patients. J Child Neurol 2007; 22:185.
  28. Nabbout R, Copioli C, Chipaux M, et al. Ketogenic diet also benefits Dravet syndrome patients receiving stiripentol: a prospective pilot study. Epilepsia 2011; 52:e54.
  29. Thammongkol S, Vears DF, Bicknell-Royle J, et al. Efficacy of the ketogenic diet: which epilepsies respond? Epilepsia 2012; 53:e55.
  30. Klepper J, Leiendecker B. GLUT1 deficiency syndrome--2007 update. Dev Med Child Neurol 2007; 49:707.
  31. Leen WG, Klepper J, Verbeek MM, et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain 2010; 133:655.
  32. Klepper J, Scheffer H, Leiendecker B, 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.
  33. Striano P, Weber YG, Toliat MR, et al. GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy. Neurology 2012; 78:557.
  34. Ito S, Oguni H, Ito Y, et al. Modified Atkins diet therapy for a case with glucose transporter type 1 deficiency syndrome. Brain Dev 2008; 30:226.
  35. Slaughter L, Vartzelis G, Arthur T. New GLUT-1 mutation in a child with treatment-resistant epilepsy. Epilepsy Res 2009; 84:254.
  36. Ramm-Pettersen A, Nakken KO, Skogseid IM, et al. Good outcome in patients with early dietary treatment of GLUT-1 deficiency syndrome: results from a retrospective Norwegian study. Dev Med Child Neurol 2013; 55:440.
  37. Wexler ID, Hemalatha SG, McConnell J, et al. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology 1997; 49:1655.
  38. Weber TA, Antognetti MR, Stacpoole PW. Caveats when considering ketogenic diets for the treatment of pyruvate dehydrogenase complex deficiency. J Pediatr 2001; 138:390.
  39. Hosain SA, La Vega-Talbott M, Solomon GE. Ketogenic diet in pediatric epilepsy patients with gastrostomy feeding. Pediatr Neurol 2005; 32:81.
  40. Kossoff EH, McGrogan JR, Freeman JM. Benefits of an all-liquid ketogenic diet. Epilepsia 2004; 45:1163.
  41. Bergqvist AG, Chee CM, Lutchka LM, Brooks-Kayal AR. Treatment of acquired epileptic aphasia with the ketogenic diet. J Child Neurol 1999; 14:696.
  42. Freeman JM, Vining EP. Seizures decrease rapidly after fasting: preliminary studies of the ketogenic diet. Arch Pediatr Adolesc Med 1999; 153:946.
  43. Lemmon ME, Terao NN, Ng YT, et al. Efficacy of the ketogenic diet in Lennox-Gastaut syndrome: a retrospective review of one institution's experience and summary of the literature. Dev Med Child Neurol 2012; 54:464.
  44. Freeman JM, Vining EP, Kossoff EH, et al. A blinded, crossover study of the efficacy of the ketogenic diet. Epilepsia 2009; 50:322.
  45. Freeman JM. The ketogenic diet: additional information from a crossover study. J Child Neurol 2009; 24:509.
  46. Groomes LB, Pyzik PL, Turner Z, et al. Do patients with absence epilepsy respond to ketogenic diets? J Child Neurol 2011; 26:160.
  47. Bautista RE. The use of the ketogenic diet in a patient with subacute sclerosing panencephalitis. Seizure 2003; 12:175.
  48. Kang HC, Lee YM, Kim HD, et al. Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects. Epilepsia 2007; 48:82.
  49. Wusthoff CJ, Kranick SM, Morley JF, Christina Bergqvist AG. The ketogenic diet in treatment of two adults with prolonged nonconvulsive status epilepticus. Epilepsia 2010; 51:1083.
  50. Bodenant M, Moreau C, Sejourné C, et al. [Interest of the ketogenic diet in a refractory status epilepticus in adults]. Rev Neurol (Paris) 2008; 164:194.
  51. Nam SH, Lee BL, Lee CG, et al. The role of ketogenic diet in the treatment of refractory status epilepticus. Epilepsia 2011; 52:e181.
  52. Nabbout R, Mazzuca M, Hubert P, et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia 2010; 51:2033.
  53. Kumada T, Miyajima T, Kimura N, et al. Modified Atkins diet for the treatment of nonconvulsive status epilepticus in children. J Child Neurol 2010; 25:485.
  54. Villeneuve N, Pinton F, Bahi-Buisson N, et al. The ketogenic diet improves recently worsened focal epilepsy. Dev Med Child Neurol 2009; 51:276.
  55. Morrison PF, Pyzik PL, Hamdy R, et al. The influence of concurrent anticonvulsants on the efficacy of the ketogenic diet. Epilepsia 2009; 50:1999.
  56. Kossoff EH, Pyzik PL, Rubenstein JE, et al. Combined ketogenic diet and vagus nerve stimulation: rational polytherapy? Epilepsia 2007; 48:77.
  57. Maydell BV, Wyllie E, Akhtar N, et al. Efficacy of the ketogenic diet in focal versus generalized seizures. Pediatr Neurol 2001; 25:208.
  58. Kang HC, Lee HS, You SJ, et al. Use of a modified Atkins diet in intractable childhood epilepsy. Epilepsia 2007; 48:182.
  59. Stainman RS, Turner Z, Rubenstein JE, Kossoff EH. Decreased relative efficacy of the ketogenic diet for children with surgically approachable epilepsy. Seizure 2007; 16:615.
  60. Jung da E, Kang HC, Kim HD. Long-term outcome of the ketogenic diet for intractable childhood epilepsy with focal malformation of cortical development. Pediatrics 2008; 122:e330.
  61. Feldstein TJ. Carbohydrate and alcohol content of 200 oral liquid medications for use in patients receiving ketogenic diets. Pediatrics 1996; 97:506.
  62. Vaisleib II, Buchhalter JR, Zupanc ML. Ketogenic diet: outpatient initiation, without fluid, or caloric restrictions. Pediatr Neurol 2004; 31:198.
  63. Bergqvist AG, Schall JI, Gallagher PR, et al. Fasting versus gradual initiation of the ketogenic diet: a prospective, randomized clinical trial of efficacy. Epilepsia 2005; 46:1810.
  64. Kossoff EH, Laux LC, Blackford R, et al. When do seizures usually improve with the ketogenic diet? Epilepsia 2008; 49:329.
  65. Seo JH, Lee YM, Lee JS, et al. Efficacy and tolerability of the ketogenic diet according to lipid:nonlipid ratios--comparison of 3:1 with 4:1 diet. Epilepsia 2007; 48:801.
  66. McNally MA, Pyzik PL, Rubenstein JE, et al. Empiric use of potassium citrate reduces kidney-stone incidence with the ketogenic diet. Pediatrics 2009; 124:e300.
  67. Kossoff EH, Pyzik PL, Furth SL, et al. Kidney stones, carbonic anhydrase inhibitors, and the ketogenic diet. Epilepsia 2002; 43:1168.
  68. Takeoka M, Riviello JJ Jr, Pfeifer H, Thiele EA. Concomitant treatment with topiramate and ketogenic diet in pediatric epilepsy. Epilepsia 2002; 43:1072.
  69. Lyczkowski DA, Pfeifer HH, Ghosh S, Thiele EA. Safety and tolerability of the ketogenic diet in pediatric epilepsy: effects of valproate combination therapy. Epilepsia 2005; 46:1533.
  70. Coppola G, Epifanio G, Auricchio G, et al. Plasma free carnitine in epilepsy children, adolescents and young adults treated with old and new antiepileptic drugs with or without ketogenic diet. Brain Dev 2006; 28:358.
  71. Kang HC, Chung DE, Kim DW, Kim HD. Early- and late-onset complications of the ketogenic diet for intractable epilepsy. Epilepsia 2004; 45:1116.
  72. Stewart WA, Gordon K, Camfield P. Acute pancreatitis causing death in a child on the ketogenic diet. J Child Neurol 2001; 16:682.
  73. Dahlin MG, Beck OM, Amark PE. Plasma levels of antiepileptic drugs in children on the ketogenic diet. Pediatr Neurol 2006; 35:6.
  74. Kossoff EH, Pyzik PL, McGrogan JR, Rubenstein JE. The impact of early versus late anticonvulsant reduction after ketogenic diet initiation. Epilepsy Behav 2004; 5:499.
  75. Neal EG, Chaffe H, Schwartz RH, et al. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia 2009; 50:1109.
  76. Kossoff EH, Krauss GL, McGrogan JR, Freeman JM. Efficacy of the Atkins diet as therapy for intractable epilepsy. Neurology 2003; 61:1789.
  77. Kossoff EH, Dorward JL. The modified Atkins diet. Epilepsia 2008; 49 Suppl 8:37.
  78. Kossoff EH, Dorward JL, Turner Z, Pyzik PL. Prospective study of the modified atkins diet in combination with a ketogenic liquid supplement during the initial month. J Child Neurol 2011; 26:147.
  79. Kossoff EH, Rowley H, Sinha SR, Vining EP. A prospective study of the modified Atkins diet for intractable epilepsy in adults. Epilepsia 2008; 49:316.
  80. Carrette E, Vonck K, de Herdt V, et al. A pilot trial with modified Atkins' diet in adult patients with refractory epilepsy. Clin Neurol Neurosurg 2008; 110:797.
  81. Kossoff EH, Dorward JL, Molinero MR, Holden KR. The modified Atkins diet: a potential treatment for developing countries. Epilepsia 2008; 49:1646.
  82. Cervenka MC, Terao NN, Bosarge JL, et al. E-mail management of the modified Atkins Diet for adults with epilepsy is feasible and effective. Epilepsia 2012; 53:728.
  83. Kossoff EH, McGrogan JR, Bluml RM, et al. A modified Atkins diet is effective for the treatment of intractable pediatric epilepsy. Epilepsia 2006; 47:421.
  84. Porta N, Vallée L, Boutry E, et al. Comparison of seizure reduction and serum fatty acid levels after receiving the ketogenic and modified Atkins diet. Seizure 2009; 18:359.
  85. Weber S, Mølgaard C, Uldall P. Modified Atkins diet to children and adolescents with medical intractable epilepsy. Seizure 2009; 18:237.
  86. Kossoff EH, Turner Z, Bluml RM, et al. A randomized, crossover comparison of daily carbohydrate limits using the modified Atkins diet. Epilepsy Behav 2007; 10:432.
  87. Chapman K, Cardenas JF. Hemimegalencephaly in a patient with a neurocutaneous syndrome. Semin Pediatr Neurol 2008; 15:190.
  88. Smith M, Politzer N, Macgarvie D, et al. Efficacy and tolerability of the modified Atkins diet in adults with pharmacoresistant epilepsy: a prospective observational study. Epilepsia 2011; 52:775.
  89. Chen W, Kossoff EH. Long-term follow-up of children treated with the modified Atkins diet. J Child Neurol 2012; 27:754.
  90. Sharma S, Sankhyan N, Gulati S, Agarwala A. Use of the modified Atkins diet for treatment of refractory childhood epilepsy: a randomized controlled trial. Epilepsia 2013; 54:481.
  91. Kossoff EH, Henry BJ, Cervenka MC. Efficacy of dietary therapy for juvenile myoclonic epilepsy. Epilepsy Behav 2013; 26:162.
  92. Kossoff EH, Bosarge JL, Miranda MJ, et al. Will seizure control improve by switching from the modified Atkins diet to the traditional ketogenic diet? Epilepsia 2010; 51:2496.
  93. Pfeifer HH, Thiele EA. Low-glycemic-index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy. Neurology 2005; 65:1810.
  94. Muzykewicz DA, Lyczkowski DA, Memon N, et al. Efficacy, safety, and tolerability of the low glycemic index treatment in pediatric epilepsy. Epilepsia 2009; 50:1118.
  95. Marsh EB, Freeman JM, Kossoff EH, et al. The outcome of children with intractable seizures: a 3- to 6-year follow-up of 67 children who remained on the ketogenic diet less than one year. Epilepsia 2006; 47:425.
  96. Kwiterovich PO Jr, Vining EP, Pyzik P, et al. Effect of a high-fat ketogenic diet on plasma levels of lipids, lipoproteins, and apolipoproteins in children. JAMA 2003; 290:912.
  97. Nizamuddin J, Turner Z, Rubenstein JE, et al. Management and risk factors for dyslipidemia with the ketogenic diet. J Child Neurol 2008; 23:758.
  98. Hawkes CP, Levine MA. Ketotic hypercalcemia: a case series and description of a novel entity. J Clin Endocrinol Metab 2014; 99:1531.
  99. Vining EP, Pyzik P, McGrogan J, et al. Growth of children on the ketogenic diet. Dev Med Child Neurol 2002; 44:796.
  100. Groesbeck DK, Bluml RM, Kossoff EH. Long-term use of the ketogenic diet in the treatment of epilepsy. Dev Med Child Neurol 2006; 48:978.
  101. 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.
  102. Spulber G, Spulber S, Hagenäs L, et al. Growth dependence on insulin-like growth factor-1 during the ketogenic diet. Epilepsia 2009; 50:297.
  103. Neal EG, Chaffe HM, Edwards N, et al. Growth of children on classical and medium-chain triglyceride ketogenic diets. Pediatrics 2008; 122:e334.
  104. Berry-Kravis E, Booth G, Sanchez AC, Woodbury-Kolb J. Carnitine levels and the ketogenic diet. Epilepsia 2001; 42:1445.
  105. Bergqvist AG, Schall JI, Stallings VA. Vitamin D status in children with intractable epilepsy, and impact of the ketogenic diet. Epilepsia 2007; 48:66.
  106. 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.
  107. Bank IM, Shemie SD, Rosenblatt B, et al. Sudden cardiac death in association with the ketogenic diet. Pediatr Neurol 2008; 39:429.
  108. Bergqvist AG, Chee CM, Lutchka L, et al. Selenium deficiency associated with cardiomyopathy: a complication of the ketogenic diet. Epilepsia 2003; 44:618.
  109. Best TH, Franz DN, Gilbert DL, et al. Cardiac complications in pediatric patients on the ketogenic diet. Neurology 2000; 54:2328.
  110. Berry-Kravis E, Booth G, Taylor A, Valentino LA. Bruising and the ketogenic diet: evidence for diet-induced changes in platelet function. Ann Neurol 2001; 49:98.
  111. Patel A, Pyzik PL, Turner Z, et al. Long-term outcomes of children treated with the ketogenic diet in the past. Epilepsia 2010; 51:1277.
  112. Worden LT, Turner Z, Pyzik PL, et al. Is there an ideal way to discontinue the ketogenic diet? Epilepsy Res 2011; 95:232.
  113. Barañano KW, Hartman AL. The ketogenic diet: uses in epilepsy and other neurologic illnesses. Curr Treat Options Neurol 2008; 10:410.
  114. Busch V, Gempel K, Hack A, et al. Treatment of glycogenosis type V with ketogenic diet. Ann Neurol 2005; 58:341.
  115. Swoboda KJ, Specht L, Jones HR, et al. Infantile phosphofructokinase deficiency with arthrogryposis: clinical benefit of a ketogenic diet. J Pediatr 1997; 131:932.
  116. Van der Auwera I, Wera S, Van Leuven F, Henderson ST. A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer's disease. Nutr Metab (Lond) 2005; 2:28.
  117. Henderson ST, Vogel JL, Barr LJ, et al. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond) 2009; 6:31.
  118. Seyfried TN, Kiebish M, Mukherjee P, Marsh J. Targeting energy metabolism in brain cancer with calorically restricted ketogenic diets. Epilepsia 2008; 49 Suppl 8:114.
  119. Evangeliou A, Vlachonikolis I, Mihailidou H, et al. Application of a ketogenic diet in children with autistic behavior: pilot study. J Child Neurol 2003; 18:113.