Neurotherapeutics

, Volume 6, Issue 2, pp 406–414 | Cite as

Ketogenic diets: Evidence for short- and long-term efficacy

Theme 5: Hormonal and Dietary Therapy

Summary

The use of dietary treatments for epilepsy (ketogenic, modified Atkins, and low glycemic index diets) has been in continuous use since 1921. These treatments have been well studied in the short term, with approximately half of children having at least a 50% reduction in seizures after 6 months. Approximately one third will attain >90% reduction in their seizures. Animal studies confirm these findings, with broad evidence demonstrating acute anticonvulsant effects of the diet. Furthermore, the diet appears to maintain its efficacy in humans when provided continuously for several years. Interestingly, benefits may be seen long term even when the diet is discontinued after only a few months of use, suggesting neuroprotective effects. This potential antiepileptogenic activity has been recently demonstrated in some animal studies as well. This review discusses the animal and human evidence for both short- and long-term benefits of dietary therapies.

Key Words

Ketogenic diet clinical efficacy short-term long-term ketone bodies fatty acids 

References

  1. 1.
    Henderson CB, Filloux FM, Aider SC, Lyon JL, Caplin DA. Efficacy of the ketogenic diet as a treatment option for epilepsy: meta-analysis. J Child Neurol 2006;21: 193–198.PubMedGoogle Scholar
  2. 2.
    Wilder RM. The effects of ketonemia on the course of epilepsy. Mayo Clin Bull 1921;2: 307–308.Google Scholar
  3. 3.
    Freeman JM, Kossoff EH, Hartman AL. The ketogenic diet: one decade later. Pediatrics 2007;119: 535–543.CrossRefPubMedGoogle Scholar
  4. 4.
    Kossoff EH, Dorward JL. The modified Atkins diet. Epilepsia 2008;49 Suppl 8: 37–41.CrossRefPubMedGoogle Scholar
  5. 5.
    Pfeifer HH, Lyczkowski DA, Thiele EA. Low glycemic index treatment: implementation and new insights into efficacy. Epilepsia 2008: 49 Suppl 8: 42–45.CrossRefPubMedGoogle Scholar
  6. 6.
    Keith HM. Factors influencing experimentally produced convulsions. Arch Neural Psychiatry 1933;29: 148–154.Google Scholar
  7. 7.
    Höld KM, Sirisoma NS, Ikeda T, Narahashi T, Casida JE. α-Thujone (the active component of absinthe): γ-aminobutyric acid type A receptor modulation and metabolic detoxification. Proc Natl Acad Sci U S A 2000;97: 3826–3831.CrossRefPubMedGoogle Scholar
  8. 8.
    Likhodii SS, Serbanescu I, Cortez MA, Murphy P, Snead OC 3rd, Bumham WM. Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet. Ann Neural 2003;54: 219–226.CrossRefGoogle Scholar
  9. 9.
    Rho JM, White HS, Anderson G, Donevan S. Acetoacetate, acetone, and dibenzylamine (a contaminant in L-(+)-β-hydroxybutyrate) exhibit direct anticonvulsant actions in vivo. Epilepsia 2002;43: 358–361.CrossRefPubMedGoogle Scholar
  10. 10.
    Thio LL, Wong M, Yamada KA. Ketone bodies do not directly alter excitatory or inhibitory hippocampal synaptic transmission. Neurology 2000;54: 325–331.PubMedGoogle Scholar
  11. 11.
    Millichap JG, Jones JD, Rudis BP. Mechanisms of anticonvulsant action of ketogenic diet. Am J Dis Child 1964;107: 593–604.PubMedGoogle Scholar
  12. 12.
    Uhlemann ER, Neims AH. Anticonvulsant properties of the ketogenic diet in mice. J Pharmacol Exp Ther 1972;180: 231–238.PubMedGoogle Scholar
  13. 13.
    Appleton DB, DeVivo DC. An animal model of the ketogenic diet. Epilepsia 1974;15: 211–227.CrossRefPubMedGoogle Scholar
  14. 14.
    Mahoney AW, Hendricks DG, Bernhard N, Sisson DV. Fasting and ketogenic diet effects on audiogenic seizures susceptibility of magnesium deficient rats. Pharmacol Biochem Behav 1983;18: 683–687.CrossRefPubMedGoogle Scholar
  15. 15.
    Nakazawa M, Kodama S, Matsuo T. Effects of ketogenic diet on electroconvulsive threshold and brain contents of adenosine nucleotides. Brain Dev 1983;5: 375–380.PubMedGoogle Scholar
  16. 16.
    Otani K, Yamatodani A, Wada H, Mimaki T, Yabuuchi H. Effect of ketogenic diet on convulsive threshold and brain monoamine levels in young mice [In Japanese]. No To Hattasu 1984;16: 196–204.Google Scholar
  17. 17.
    Bough KJ, Eagles DA. A ketogenic diet increases the resistance to pentylenetetrazole-induced seizures in the rat. Epilepsia 1999;40: 138–143.CrossRefPubMedGoogle Scholar
  18. 18.
    Bough KJ, Matthews PJ, Eagles DA. A ketogenic diet has different effects upon seizures induced by maximal electroshock and by pentylenetetrazole infusion. Epilepsy Res 2000;38: 105–114.CrossRefPubMedGoogle Scholar
  19. 19.
    Rho JM, Kim DW, Robbins CA, Anderson GD, Schwartzkroin PA. Age-dependent differences in flurothyl seizure sensitivity in mice treated with a ketogenic diet. Epilepsy Res 1999;37: 233–240.CrossRefPubMedGoogle Scholar
  20. 20.
    Muller-Schwarze AB, Tandon P, Liu Z, Yang Y, Holmes GL, Stafstrom CE. Ketogenic diet reduces spontaneous seizures and mossy fiber sprouting in the kainic acid model. Neuroreport 1999; 10: 1517–1522.CrossRefPubMedGoogle Scholar
  21. 21.
    Noh HS, Kim YS, Lee HP, et al. The protective effect of a ketogenic diet on kainic acid-induced hippocampal cell death in the male ICR mice. Epilepsy Res 2003;53: 119–128.CrossRefPubMedGoogle Scholar
  22. 22.
    Hartman AL, Lyle M, Rogawski MA, Gasior M. Efficacy of the ketogenic diet in the 6-Hz seizure test. Epilepsia 2008;49: 334–339.CrossRefPubMedGoogle Scholar
  23. 23.
    Samala R, Willis S, Borges K. Anticonvulsant profile of a balanced ketogenic diet in acute mouse seizure models. Epilepsy Res 2008; 81: 119–127.CrossRefPubMedGoogle Scholar
  24. 24.
    Stafstrom CE. Animal models of the ketogenic diet: what have we learned, what can we learn? Epilepsy Res 1999;37: 241–259.CrossRefPubMedGoogle Scholar
  25. 25.
    Stafstrom CE. Dietary approaches to epilepsy treatment: old and new options on the menu. Epilepsy Curr 2004;4: 215–222.CrossRefPubMedGoogle Scholar
  26. 26.
    Thavendiranathan P, Mendonca A, Dell C, et al. The MCT ketogenic diet: effects on animal seizure models. Exp Neurol 2000; 161: 696–703.CrossRefPubMedGoogle Scholar
  27. 27.
    Freeman JM, Vining EPG. Seizures decrease rapidly after fasting: preliminary studies of the ketogenic diet. Arch Pediatr Adolesc Med 1999;153: 946–949.PubMedGoogle Scholar
  28. 28.
    Kossoff EH, Laux LC, Blackford R, et al. When do seizures improve with the ketogenic diet? Epilepsia 2008;49: 329–333.CrossRefPubMedGoogle Scholar
  29. 29.
    Freeman JM, Vining EPG, Kossoff EH, Pyzik PL, Ye X, Goodman SN. A blinded, crossover study of the ketogenic diet. Epilepsia 2009;50: 322–325.CrossRefPubMedGoogle Scholar
  30. 30.
    Pfeifer HH, Thiele EA. Low-glycemic-index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy. Neurology 2005;65: 1810–1812.CrossRefPubMedGoogle Scholar
  31. 31.
    Freeman JM, Vining EPG, Pillas DJ, Pyzik PL, Casey JC, Kelly MT. The efficacy of the ketogenic diet—1998: a prospective evaluation of intervention in 150 children. Pediatrics 1998;102: 1358–1363.CrossRefPubMedGoogle Scholar
  32. 32.
    Neal EG, Chaffe H, Schwartz RH, et al. The ketogenic diet in the treatment of epilepsy in children: a randomised, controlled trial. Lancet Neurol 2008;7: 500–506.CrossRefPubMedGoogle Scholar
  33. 33.
    Kossoff EH, McGrogan JR, Bluml RM, Pillas DJ, Rubenstein JE, Vining EP. A modified Atkins diet is effective for the treatment of intractable pediatric epilepsy. Epilepsia 2006;47: 421–424.CrossRefPubMedGoogle Scholar
  34. 34.
    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 2008 Sept 23 [Epub ahead of print].Google Scholar
  35. 35.
    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.CrossRefPubMedGoogle Scholar
  36. 36.
    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: 425–430.CrossRefPubMedGoogle Scholar
  37. 37.
    Raol YS, Budreck EC, Brooks-Kayal AR. Epilepsy after early-life seizures can be independent of hippocampal injury. Ann Neurol 2003;53: 503–511.CrossRefPubMedGoogle Scholar
  38. 38.
    Baram TZ, Eghbal-Ahmadi M, Bender RA. Is neuronal death required for seizure-induced epileptogenesis in the immature brain? Prog Brain Res 2002; 135: 365–375.CrossRefPubMedGoogle Scholar
  39. 39.
    Hori A, Tandon P, Holmes GL, Stafstrom CE. Ketogenic diet: effects on expression of kindled seizures and behavior in adult rats. Epilepsia 1997;38: 750–758.CrossRefPubMedGoogle Scholar
  40. 40.
    Zhao Q, Stafstrom CE, Fu DD, Hu Y, Holmes GL. Detrimental effects of the ketogenic diet on cognitive function in rats. Pediatr Res 2004;55: 498–506.CrossRefPubMedGoogle Scholar
  41. 41.
    Cunnane SC, Likhodii SS. Claims to identify detrimental effects of the ketogenic diet on cognitive function in rats. Pediatr Res 2004; 56: 663–664.CrossRefPubMedGoogle Scholar
  42. 42.
    Bough KJ, Fetner JD, Eagles DA. A ketogenic diet exacerbates kainate-induced seizures in the rat. Soc Neurosci Abstr 1998;24: 1208.Google Scholar
  43. 43.
    Ko TS, Soo AC, Kim DW, Kim KJ. Ketogenic diet: effects on hippocampal c-fos expression and neuronal death after kainic acid-induced seizures in immature rats. Epilepsia 1999;40 Suppl 7: 79 (abstract).Google Scholar
  44. 44.
    Brigande JV, Wieraszko A, Albert MD, Balkema GW, Seyfried TN. Biochemical correlates of epilepsy in the El mouse: analysis of glial fibrillary acidic protein and gangliosides. J Neurochem 1992;58: 752–760.CrossRefPubMedGoogle Scholar
  45. 45.
    Todorova MT, Burwell TJ, Seyfried TN. Environmental risk factors for multifactorial epilepsy in EL mice. Epilepsia 1999;40: 1697–1707.CrossRefPubMedGoogle Scholar
  46. 46.
    Todorova MT, Tandon P, Madore RA, Stafstrom CE, Seyfried TN. The ketogenic diet inhibits epileptogenesis in EL mice: a genetic model for idiopathic epilepsy. Epilepsia 2000;41: 933–940.CrossRefPubMedGoogle Scholar
  47. 47.
    Maganti R, Allen C, Wilke J, Milligan H, Rho JM, Fenoglio KA. Ketogenic diet treatment improves circadian rhythmicity and abolishes seizure periodicity in epileptic Kcnal-nall mice. Epilepsia 2009 (in press).Google Scholar
  48. 48.
    Wenzel HJ, Vacher H, Clark E, et al. Structural consequences of Kcnal gene deletion and transfer in the mouse hippocampus. Epilepsia 2007;48: 2023–2046.CrossRefPubMedGoogle Scholar
  49. 49.
    Zuberi SM, Eunson LH, Spauschus A, et al. A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. Brain 1999;122: 817–825.CrossRefPubMedGoogle Scholar
  50. 50.
    Freeman J, Veggiotti P, Lanzi G, Tagliabue A, Perucca E; Institute of Neurology IRCCS C. Mondino Foundation. The ketogenic diet: from molecular mechanisms to clinical effects. Epilepsy Res 2006; 68: 145–180.CrossRefPubMedGoogle Scholar
  51. 51.
    Fraser DD, Whiting S, Andrew RD, Macdonald EA, Musa-Veloso K, Cunnane SC. Elevated polyunsaturated fatty acids in blood serum obtained from children on the ketogenic diet. Neurology 2003;60: 1026–1029.PubMedGoogle Scholar
  52. 52.
    Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. D-β-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc Natl Acad Sci U S A 2000;97: 5440–5444.CrossRefPubMedGoogle Scholar
  53. 53.
    García O, Massieu L. Strategies for neuroprotection against l-trans-2,4-pyrrolidine dicarboxylate-induced neuronal damage during energy impairment in vitro. J Neurosci Res 2001;64: 418–428.CrossRefPubMedGoogle Scholar
  54. 54.
    Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF Jr. Ketone bodies, potential therapeutic uses. IUBMB Life 2001;51: 241–247.CrossRefPubMedGoogle Scholar
  55. 55.
    Noh HS, Hah YS, Nilufar R, et al. Acetoacetate protects neuronal cells from oxidative glutamate toxicity. J Neurosci Res 2006;83: 702–709.CrossRefPubMedGoogle Scholar
  56. 56.
    Bazan NG. Omega-3 fatty acids, pro-inflammatory signaling and neuroprotection. Curr Opin Clin Nute Metab Care 2007;10: 136–141.CrossRefGoogle Scholar
  57. 57.
    Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev 2008 Sep 25 [Epub ahead of print].Google Scholar
  58. 58.
    Willis S, Samala R, Rosenberger TA, Borges K. Eicosapentaenoic and docosahexaenoic acids are not anticonvulsant or neuroprotective in acute mouse seizure models. Epilepsia 2009;50: 138–142.CrossRefPubMedGoogle Scholar
  59. 59.
    Kim do Y, Davis LM, Sullivan PG, et al. Ketone bodies are protective against oxidative stress in neocortical neurons. J Neurochem 2007;101: 1316–1326.CrossRefGoogle Scholar
  60. 60.
    Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM. Ketones inhibit mitochondrial production of reactive oxygen species following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience 2007;145: 256–264.CrossRefPubMedGoogle Scholar
  61. 61.
    Jarrett SG, Milder JB, Liang LP, Patel M. The ketogenic diet increases mitochondrial glutathione levels. J Neurochem 2008; 106: 1044–1051.CrossRefPubMedGoogle Scholar
  62. 62.
    Bough KJ, Wetherington J, Hassel B, et al. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol 2006;60: 223–235.CrossRefPubMedGoogle Scholar
  63. 63.
    DeVivo DC, Leckie MP, Ferrendelli JS, McDougal DB Jr. Chronic ketosis and cerebral metabolism. Ann Neurol 1978;3: 331–337.CrossRefPubMedGoogle Scholar
  64. 64.
    Sullivan PG, Rippy NA, Dorenbos K, Concepcion RC, Agarwal AK, Rho JM. The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann Neurol 2004;55: 576–580.CrossRefPubMedGoogle Scholar
  65. 65.
    Acharya MM, Hattiangady B, Shetty AK. Progress in neuroprotective strategies for preventing epilepsy. Prog Neurobiol 2008;84: 363–404.CrossRefPubMedGoogle Scholar
  66. 66.
    Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia 2007;48: 43–58.CrossRefPubMedGoogle Scholar
  67. 67.
    Pan JW, Bebin EM, Chu WJ, Hetherington HP. Ketosis and epilepsy: 31P spectroscopic imaging at 4.1 T. Epilepsia 1999;40: 703–707.CrossRefPubMedGoogle Scholar
  68. 68.
    Noh HS, Lee HP, Kim DW, et al. A cDNA microarray analysis of gene expression profiles in rat hippocampus following a ketogenic diet. Brain Res Mol Brain Res 2004;129: 80–87.PubMedGoogle Scholar
  69. 69.
    Greene AE, Todorova MT, McGowan R, Seyfried TN. Caloric restriction inhibits seizure susceptibility in epileptic EL mice by reducing blood glucose. Epilepsia 2001;42: 1371–1378.CrossRefPubMedGoogle Scholar
  70. 70.
    Garriga-Canut M, Schoenike B, Qazi R, et al. 2-Deoxy-d-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure. Nat Neurosci 2006;9: 1382–1387.CrossRefPubMedGoogle Scholar
  71. 71.
    Stafstrom CE, Ockuly JC, Murphree L, Valley MT, Roopra A, Sutula TP. Anticonvulsant and antiepileptic actions of 2-deoxy-d-glucose in epilepsy models. Ann Neurol 2009 (in press).Google Scholar
  72. 72.
    Lian XY, Khan FA, Stringer JL. Fructose-1,6-bisphosphate has anticonvulsant activity in models of acute seizures in adult rats. J Neurosci 2007;27: 12007–12011.CrossRefPubMedGoogle Scholar
  73. 73.
    Groesbeck DK, Bluml RM, Kossoff EH. Long-term use of the ketogenic diet in the treatment of epilepsy. Dev Med Child Neurol 2006;48: 978–981.CrossRefPubMedGoogle Scholar
  74. 74.
    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: 424–425.CrossRefPubMedGoogle Scholar
  75. 75.
    Vining EP, Freeman JM, Ballaban-Gil K, et al. A multicenter study of the efficacy of the ketogenic diet. Arch Neurol 1998;55: 1433–1437.CrossRefPubMedGoogle Scholar
  76. 76.
    Hassan AM, Keene DL, Whiting SE, Jacob PJ, Champagne JR, Humphreys P. Ketogenic diet in the treatment of refractory epilepsy in childhood. Pediatr Neurol 1999;21: 548–552.CrossRefPubMedGoogle Scholar
  77. 77.
    Kankirawatana P, Jirapinyo P, Kankirawatana S, Wongam R, Thamanasiri N. Ketogenic diet: an alternative treatment for refractory epilepsy in children. J Med Assoc Thai 2001;84: 1027–1032.PubMedGoogle Scholar
  78. 78.
    Nordli DR Jr, Kuroda MM, Carroll J, et al. Experience with the ketogenic diet in infants. Pediatrics 2001;108: 129–133.CrossRefPubMedGoogle Scholar
  79. 79.
    Kossoff EH, Pyzik PL, McGrogan JR, Vining EP, Freeman JM. Efficacy of the ketogenic diet for infantile spasms. Pediatrics 2002; 109: 780–783.CrossRefPubMedGoogle Scholar
  80. 80.
    Coppola G, Veggiotti P, Cusmai R, et al. The ketogenic diet in children, adolescents and young adults with refractory epilepsy: an Italian multicentric experience. Epilepsy Res 2002;48: 221–227.CrossRefPubMedGoogle Scholar
  81. 81.
    François LL, Manel V, Rousselle C, David M. Ketogenic regime as anti-epileptic treatment: its use in 29 epileptic children [In French]. Arch Pediatr 2003;10: 300–306.CrossRefPubMedGoogle Scholar
  82. 82.
    Mady MA, Kossoff EH, McGregor AL, Wheless JW, Pyzik PL, Freeman JM. The ketogenic diet: adolescents can do it, too. Epilepsia 2003;44: 847–851.CrossRefPubMedGoogle Scholar
  83. 83.
    Klepper J, Leiendecker B, Riemann E, Baumeister FA. The ketogenic diet in German-speaking countries: update 2003 [In German]. Klin Padiatr 2004;216: 277–285.CrossRefPubMedGoogle Scholar
  84. 84.
    Vaisleib II, Buchhalter JR, Zupanc ML. Ketogenic diet: outpatient initiation, without fluid, or caloric restrictions. Pediatr Neurol 2004;31: 198–202.CrossRefPubMedGoogle Scholar
  85. 85.
    Kang HC, Kim YJ, Kim DW, Kim HD. Efficacy and safety of the ketogenic diet for intractable childhood epilepsy: Korean multicentric experience. Epilepsia 2005;46: 272–279.CrossRefPubMedGoogle Scholar
  86. 86.
    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.CrossRefPubMedGoogle Scholar
  87. 87.
    Eun SH, Kang HC, Kim DW, Kim HD. Ketogenic diet for treatment of infantile spasms. Brain Dev 2006;28: 566–571.CrossRefPubMedGoogle Scholar
  88. 88.
    Kossoff EH, Pyzik PL, Rubenstein JE, et al. Combined ketogenic diet and vagus nerve stimulation: rational polytherapy? Epilepsia 2007;48: 77–81.CrossRefPubMedGoogle Scholar
  89. 89.
    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.CrossRefPubMedGoogle Scholar
  90. 90.
    Hamdy RF, Turner Z, Pyzik PL, Kossoff EH. Lack of influence of body mass index on the efficacy of the ketogenic diet. J Child Neurol 2007;22: 1167–1171.CrossRefPubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2009

Authors and Affiliations

  1. 1.John M. Freeman Pediatric Epilepsy Center, Departments of Neurology and PediatricsJohns Hopkins HospitalBaltimore
  2. 2.The Barrow Neurological Institute and St. Joseph’s Hospital and Medical CenterPhoenix

Personalised recommendations