Ketogenic Diet and Epilepsy: The Role of Adenosine
The ketogenic diet (KD) debuted in the 1920s as a metabolic treatment for epilepsy, based on the historical observation that fasting could prevent seizures. Similar to fasting, the high-fat, low-carbohydrate KD restricts glucose and favors oxidation of fatty acids, which in turn generates ketones for energy. Despite nearly a century of clinical use, proof of efficacy was only recently established, and little is known about how the KD works. The lure of a continually growing armamentarium of pharmacological options and the inherent challenges in implementing a dietary treatment versus a drug have combined to relegate the KD to a therapy of last resort. Indeed, better knowledge of how the KD exerts broad-spectrum clinical activity would be required to develop enhanced metabolism-based treatments, and perhaps even a “diet in a pill.” Recent evidence strongly implicates adenosine as a mediator of KD action, as it is well known that adenosine is a fundamental link between metabolism and neuronal membrane excitability. Through a greater mechanistic understanding of how the KD―and adenosine in particular―works to dampen aberrant excitation in the brain, novel insights and molecular targets are bound to emerge. However, given the complexity of metabolic pathways in both normal and disease states, it will be important to determine specific cause-and-effect relationships. At present, given growing interest in metabolic dysfunction as a major pathophysiological substrate for a multiplicity of disease states, as well as urgent concerns regarding unbridled healthcare costs worldwide, we predict that research in the area of “translational metabolism” will gain further momentum. Here we highlight current research on mechanism(s) of KD action, with a focus on adenosine, and promote the concept that the KD is both an accessible and affordable therapy by describing an international case study of recent KD training and initial outcomes in the Republic of Georgia.
KeywordsKetogenic Diet Anticonvulsant Effect Refractory Status Epilepticus Adenosine Kinase Electrographic Seizure
The authors would like to acknowledge the National Institutes of Health, National Science Foundation, Trinity College, the Alberta Children’s Hospital Research Institute, and the Charlie Foundation to Cure Pediatric Epilepsy for support.
- Boison D (2011) Adenosine: a novel regulator of DNA methylation in epilepsy. Presented as part of “The “Methylation Hypothesis:” Does Epigenetic Chromalin Modification Play a Role in Epileptogenesis?”, organized by I. Blumcke, American Epilepsy Society 65th annual meeting, 2011, IW.8. Baltimore, MDGoogle Scholar
- Henderson JF (1979) Regulation of adenosine metabolism. In: Baer HP, Drummond GI (eds) Physiological and regulatory function of adenosine and adenine nucletides. Raven, New York, pp 315–322Google Scholar
- Kossoff EH, Zupec-Kania BA, Amark PE, Ballaban-Gil KR, Christina-Bergqvist AG, Blackford R, Buchhalter JR, Caraballo RH, Helen Cross J, Dahlin MG, Donner EJ, Klepper J, Jehle RS, Kim HD, Christiana Liu YM, Nation J, Nordli DR Jr, Pfeifer HH, Rho JM, Stafstrom CE, Thiele EA, Turner Z, Wirrell EC, Wheless JW, Veggiotti P, Vining EP, Charlie Foundation, Practice Committee of the Child Neurology Society, Practice Committee of the Child Neurology Society, International Ketogenic Diet Study Group (2009b) Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. Epilepsia 50(2):304–317PubMedCrossRefGoogle Scholar
- Kossoff EH, Caraballo RH, du Toit T, Kim HD, Mackay MT, Nathan JK, Philip SG (2011) Dietary therapies: a worldwide phenomenon. Epilepsy Res [Epub Aug 17]Google Scholar
- Masino SA, Rho JM (2012) Mechanisms of ketogenic diet action. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Jasper’s basic mechanisms of the epilepsies, 4th edn. Oxford University Press, New York, pp 1001–1022Google Scholar
- Masino SA, Kawamura M Jr, Ruskin DN, Geiger JD, Boison D (2011b) Purines and neuronal excitability: links to the ketogenic diet. Epilepsy Res [Epub Aug 29]Google Scholar
- Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, Williamson PD, Treiman DM, McNamara JO, McCutchen CB et al (1985) Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 313(3):145–151PubMedCrossRefGoogle Scholar
- Nabbout R, Mazzuca M, Hubert P, Peudennier S, Allaire C, Flurin V, Aberastury M, Silva W, Dulac O (2010) Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia 51(10):2033–2037PubMedCrossRefGoogle Scholar
- Rho JM, Stafstrom CE (2011) The ketogenic diet: what has science taught us? Epilepsy Res [Epub Aug 29]Google Scholar
- World Health Organization (WHO) (2004) Special issue on diet, nutrition and prevention of chronic diseases. Public Health Nutr 7(1A):Suppl 1001Google Scholar