Ketogenic Diet and Epilepsy: What We Know So Far

Isabella D'Andrea Meira, Tayla Taynan Romão, Henrique Jannuzzelli Pires do Prado, Lia Theophilo Krüger, Maria Elisa Paiva Pires, Priscila Oliveira da Conceição, Isabella D'Andrea Meira, Tayla Taynan Romão, Henrique Jannuzzelli Pires do Prado, Lia Theophilo Krüger, Maria Elisa Paiva Pires, Priscila Oliveira da Conceição

Abstract

The Ketogenic Diet (KD) is a modality of treatment used since the 1920s as a treatment for intractable epilepsy. It has been proposed as a dietary treatment that would produce similar benefits to fasting, which is already recorded in the Hippocratic collection. The KD has a high fat content (90%) and low protein and carbohydrate. Evidence shows that KD and its variants are a good alternative for non-surgical pharmacoresistant patients with epilepsy of any age, taking into account that the type of diet should be designed individually and that less-restrictive and more-palatable diets are usually better options for adults and adolescents. This review discusses the KD, including the possible mechanisms of action, applicability, side effects, and evidence for its efficacy, and for the more-palatable diets such as the Modified Atkins Diet (MAD) and the Low Glycemic Index Diet (LGID) in children and adults.

Keywords: diet therapy; ketogenic diet; low glycemic index; modified Atkins diet; refractory epilepsy.

References

    1. Armeno M., Caraballo R., Vaccarezza M., Alberti M. J., Ríos V., Galicchio S., et al. (2014). [National consensus on the ketogenic diet]. Rev. Neurol. 59 213–223.
    1. Atkins R. C. (2002). Dr. Atkins’ New Diet Revolution. M. Evans. Available at: [accessed December 21 2018].
    1. Auvin S., Nabbout R. (2011). Le Régime Cétogène Chez L’enfant. Montrouge: John Libbey Eurotext; Available at:
    1. Barborka C. J. (1928). Ketogenic diet treatment of epilepsy in adults. J. Am. Med. Assoc. 91 73–78. 10.1001/jama.1928.02700020007003
    1. Bergqvist A. G. C., Schall J. I., Gallagher P. R., Cnaan A., Stallings V. A. (2005). Fasting versus gradual initiation of the ketogenic diet: a prospective, randomized clinical trial of efficacy. Epilepsia 46 1810–1819. 10.1111/j.1528-1167.2005.00282.x
    1. Bough K. (2008). Energy metabolism as part of the anticonvulsant mechanism of the ketogenic diet. Epilepsia 49(Suppl. 8), 91–93. 10.1111/j.1528-1167.2008.01846.x
    1. Bough K. J., Rho J. M. (2007). Anticonvulsant mechanisms of the ketogenic diet. Epilepsia 48 43–58. 10.1111/j.1528-1167.2007.00915.x
    1. Bough K. J., Wetherington J., Hassel B., Pare J. F., Gawryluk J. W., Greene J. G., et al. (2006). Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann. Neurol. 60 223–235. 10.1002/ana.20899
    1. Carrette E., Vonck K., de Herdt V., Dewaele I., Raedt R., Goossens L., et al. (2008). A pilot trial with modified Atkins’ diet in adult patients with refractory epilepsy. Clin. Neurol. Neurosurg. 110 797–803. 10.1016/j.clineuro.2008.05.003
    1. Cervenka M. C., Terao N. N., Bosarge J. L., Henry B. J., Klees A. A., Morrison P. F., et al. (2012). E-mail management of the Modified Atkins Diet for adults with epilepsy is feasible and effective. Epilepsia 53 728–732. 10.1111/j.1528-1167.2012.03406.x
    1. Clanton R. M., Wu G., Akabani G., Aramayo R. (2017). Control of seizures by ketogenic diet-induced modulation of metabolic pathways. Amino Acids 49 1–20. 10.1007/s00726-016-2336-7
    1. Coppola G., D’Aniello A., Messana T., Di Pasquale F., della Corte R., Pascotto A., et al. (2011). Low glycemic index diet in children and young adults with refractory epilepsy: first Italian experience. Seizure 20 526–528. 10.1016/j.seizure.2011.03.008
    1. Devivo D. C., Leckie M. P., Ferrendelli J. S., McDougal D. B. (1978). Chronic ketosis and cerebral metabolism. Ann. Neurol. 3 331–337. 10.1002/ana.410030410
    1. Dupuis N., Curatolo N., Benoist J. F., Auvin S. (2015). Ketogenic diet exhibits anti-inflammatory properties. Epilepsia 56 e95–e98. 10.1111/epi.13038
    1. El-Rashidy O. F., Nassar M. F., Abdel-Hamid I. A., Shatla R. H., Abdel-Hamid M. H., Gabr S. S., et al. (2013). Modified Atkins diet vs classic ketogenic formula in intractable epilepsy. Acta Neurol. Scand. 128 402–408. 10.1111/ane.12137
    1. Garriga-Canut M., Schoenike B., Qazi R., Bergendahl K., Daley T. J., Pfender R. M., et al. (2006). reduces epilepsy progression by NRSF-CtBP–dependent metabolic regulation of chromatin structure2-Deoxy-D-glucose. Nat. Neurosci. 9 1382–1387. 10.1038/nn1791
    1. Gasior M., Hartman A. L., Rogawski M. A. (2008). The anticonvulsant activity of acetone does not depend upon its metabolites. Epilepsia 49 936–937. 10.1111/j.1528-1167.2007.01518_3.x
    1. Greene A. E., Todorova M. T., Seyfried T. N. (2003). Perspectives on the metabolic management of epilepsy through dietary reduction of glucose and elevation of ketone bodies. J. Neurochem. 86 529–537. 10.1046/j.1471-4159.2003.01862.x
    1. Huttenlocher P. R. (1976). Ketonemia and seizures: metabolic and anticonvulsant effects of two ketogenic diets in childhood epilepsy. Pediatr. Res. 10 536–540. 10.1203/00006450-197605000-00006
    1. Juge N., Gray J. A., Omote H., Miyaji T., Inoue T., Hara C., et al. (2010). Metabolic control of vesicular glutamate transport and release. Neuron 68 99–112. 10.1016/j.neuron.2010.09.002
    1. Kang H.-C., Lee H. S., You S. J., Kang D. C., Ko T.-S., Kim H. D. (2007). Use of a modified atkins diet in intractable childhood epilepsy. Epilepsia 48 182–186. 10.1111/j.1528-1167.2006.00910.x
    1. Kim D. W., Kang H. C., Park J. C., Kim H. D. (2004). Benefits of the nonfasting ketogenic diet compared with the initial fasting ketogenic diet. Pediatrics 114 1627–1630. 10.1542/peds.2004-1001
    1. Kim D. Y., Simeone K. A., Simeone T. A., Pandya J. D., Wilke J. C., Ahn Y., et al. (2015). Ketone bodies mediate antiseizure effects through mitochondrial permeability transition. Ann. Neurol. 78 77–87. 10.1002/ana.24424
    1. Kim S. H., Kang H.-C., Lee E. J., Lee J. S., Kim H. D. (2017). Low glycemic index treatment in patients with drug-resistant epilepsy. Brain Dev. 39 687–692. 10.1016/j.braindev.2017.03.027
    1. Kossoff E. H. (2004). More fat and fewer seizures: dietary therapies for epilepsy. Lancet Neurol. 3 415–420. 10.1016/S1474-4422(04)00807-5
    1. Kossoff E. H., Bosarge J. L., Miranda M. J., Wiemer-Kruel A., Kang H. C., Kim H. D. (2010). Will seizure control improve by switching from the modified Atkins diet to the traditional ketogenic diet? Epilepsia 51 2496–2499. 10.1111/j.1528-1167.2010.02774.x
    1. Kossoff E. H., Cervenka M. C., Henry B. J., Haney C. A., Turner Z. (2013). A decade of the modified Atkins diet (2003–2013): results, insights, and future directions. Epilepsy Behav. 29 437–442. 10.1016/j.yebeh.2013.09.032
    1. Kossoff E. H., Dorward J. L. (2008). The modified atkins diet. Epilepsia. 49 37–41. 10.1111/j.1528-1167.2008.01831.x
    1. Kossoff E. H., McGrogan J. R., Bluml R. M., Pillas D. J., Rubenstein J. E., Vining E. P. (2006). A modified atkins diet is effective for the treatment of intractable pediatric epilepsy. Epilepsia 47 421–424. 10.1111/j.1528-1167.2006.00438.x
    1. Kossoff E. H., Rowley H., Sinha S. R., Vining E. P. G. (2008). A prospective study of the modified atkins diet for intractable epilepsy in adults. Epilepsia 49 316–319. 10.1111/j.1528-1167.2007.01256.x
    1. Kossoff E. H., Turner Z., Bluml R. M., Pyzik P. L., Vining E. P. G. (2007). A randomized, crossover comparison of daily carbohydrate limits using the modified Atkins diet. Epilepsy Behav. 10 432–436. 10.1016/j.yebeh.2007.01.012
    1. Kossoff E. H., Zupec-Kania B. A., Amark P. E., Ballaban-Gil K. R., Christina Bergqvist A. G., Blackford R., et al. (2009). Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. Epilepsia 50 304–317. 10.1111/j.1528-1167.2008.01765.x
    1. Kossoff E. H., Zupec-Kania B. A., Ephane Auvin S., Ballaban-Gil K. R., Bergqvist A. G. C., Blackford R., et al. (2018). Optimal clinical management of children receiving dietary therapies for epilepsy: updated recommendations of the International Ketogenic Diet Study Group. Child Neurol. Soc. Epilepsia Open 3 175–192. 10.1002/epi4.12225
    1. Kverneland M., Selmer K. K., Nakken K. O., Iversen P. O., Taubøll E. (2015). A prospective study of the modified Atkins diet for adults with idiopathic generalized epilepsy. Epilepsy Behav. 53 197–201. 10.1016/j.yebeh.2015.10.021
    1. Kwan P., Arzimanoglou A., Berg A. T., Brodie M. J., Allen Hauser W., Mathern G., et al. (2009). Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51 1069–1077. 10.1111/j.1528-1167.2009.02397.x
    1. Li D.-P., Chen S.-R., Pan H.-L. (2010). Adenosine inhibits paraventricular pre-sympathetic neurons through ATP-dependent potassium channels. J. Neurochem. 113 530–542. 10.1111/j.1471-4159.2010.06618.x
    1. Likhodii S. S., Serbanescu I., Cortez M. A., Murphy P., Snead O. C., Burnham W. M. (2003). Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet. Ann. Neurol. 54 219–226. 10.1002/ana.10634
    1. Lima P. A., Sampaio L. P., Damasceno N. R. (2014). Neurobiochemical mechanisms of a ketogenic diet in refractory epilepsy. Clinics 69 699–705. 10.6061/clinics/2014(10)09
    1. Liu H., Yang Y., Wang Y., Tang H., Zhang F., Zhang Y., et al. (2018). Ketogenic diet for treatment of intractable epilepsy in adults: a meta-analysis of observational studies. Epilepsia Open 3 9–17. 10.1002/epi4.12098
    1. Lutas A., Yellen G. (2013). The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci. 36 32–40. 10.1016/j.tins.2012.11.005
    1. Ma W., Berg J., Yellen G. (2007). Ketogenic diet metabolites reduce firing in central neurons by opening KATP channels. J. Neurosci. 27 3618–3625. 10.1523/JNEUROSCI.0132-07.2007
    1. Martin K., Jackson C. F., Levy R. G., Cooper P. N. (2016). Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst. Rev. 2:CD001903. 10.1002/14651858.CD001903.pub3
    1. Miranda M. J., Mortensen M., Povlsen J. H., Nielsen H., Beniczky S. (2011). Danish study of a Modified Atkins diet for medically intractable epilepsy in children: can we achieve the same results as with the classical ketogenic diet? Seizure 20 151–155. 10.1016/j.seizure.2010.11.010
    1. Miranda M. J., Turner Z., Magrath G. (2012). Alternative diets to the classical ketogenic diet—Can we be more liberal? Epilepsy Res. 100 278–285. 10.1016/j.eplepsyres.2012.06.007
    1. Mironov S., Richter D. (2000). Intracellular signalling pathways modulate KATP channels in inspiratory brainstem neurones and their hypoxic activation: involvement of metabotropic receptors, G-proteins and cytoskeleton. Brain Res. 853 60–67. 10.1016/S0006-8993(99)02234-9
    1. Muzykewicz D. A., Lyczkowski D. A., Memon N., Conant K. D., Pfeifer H. H., Thiele E. A. (2009). Efficacy, safety, and tolerability of the low glycemic index treatment in pediatric epilepsy. Epilepsia 50 1118–1126. 10.1111/j.1528-1167.2008.01959.x
    1. Neal E. G., Chaffe H., Schwartz R. H., Lawson M. S., Edwards N., Fitzsimmons G., et al. (2008). The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 7 500–506. 10.1016/S1474-4422(08)70092-9
    1. Olson C. A., Vuong H. E., Yano J. M., Liang Q. Y., Nusbaum D. J., Hsiao E. Y. (2018). The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell 173 1728–1741.e13. 10.1016/j.cell.2018.04.027
    1. Park E. G., Lee J., Lee J. (2018). Use of the modified atkins diet in intractable pediatric epilepsy. J. Epilepsy Res. 8 20–26. 10.14581/jer.18004
    1. Payne N. E., Cross J. H., Sander J. W., Sisodiya S. M. (2018). The ketogenic and related diets in adolescents and adults-A review. Epilepsia 52 1941–1948. 10.1111/j.1528-1167.2011.03287.x
    1. Pfeifer H. H., Lyczkowski D. A., Thiele E. A. (2008). Low glycemic index treatment: implementation and new insights into efficacy. Epilepsia 49 42–45. 10.1111/j.1528-1167.2008.01832.x
    1. Pfeifer H. H., Thiele E. A. (2005). Low-glycemic-index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy. Neurology 65 1810–1812. 10.1212/01.wnl.0000187071.24292.9e
    1. Picot M.-C., Baldy-Moulinier M., Daurs J.-P., Dujols P., Crespel A. (2008). The prevalence of epilepsy and pharmacoresistant epilepsy in adults: a population-based study in a Western European country. Epilepsia 49 1230–1238. 10.1111/j.1528-1167.2008.01579.x
    1. Rezaei S., Abdurahman A. A., Saghazadeh A., Badv R. S., Mahmoudi M. (2017). 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. 10.1080/1028415X.2017.1387721 [Epub ahead of print].
    1. Rezaei S., Harsini S., Kavoosi M., Badv R. S., Mahmoudi M. (2018). Efficacy of low glycemic index treatment in epileptic patients: a systematic review. Acta Neurol. Belg. 118 339–349. 10.1007/s13760-018-0881-4
    1. Rho J. M. (2017). How does the ketogenic diet induce anti-seizure effects? Neurosci. Lett. 637 4–10. 10.1016/j.neulet.2015.07.034
    1. Rho J. M., Anderson G. D., Donevan S. D., White H. S. (2002). Acetoacetate, acetone, and dibenzylamine (a contaminant in l-(+)-beta-hydroxybutyrate) exhibit direct anticonvulsant actions in vivo. Epilepsia 43 358–361. 10.1046/j.1528-1157.2002.47901.x
    1. Rubenstein J. E. (2008). Use of the ketogenic diet in neonates and infants. Epilepsia 49(Suppl. 8), 30–32. 10.1111/j.1528-1167.2008.01829.x
    1. Sharma S., Jain P. (2014). The modified atkins diet in refractory epilepsy. Epilepsy Res. Treat. 2014:404202. 10.1155/2014/404202
    1. Shimazu T., Hirschey M. D., Newman J., He W., Shirakawa K., Le Moan N., et al. (2013). Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339 211–214. 10.1126/science.1227166
    1. Szot P., Weinshenker D., Rho J. M., Storey T. W., Schwartzkroin P. A. (2001). Norepinephrine is required for the anticonvulsant effect of the ketogenic diet. Dev. Brain Res. 129 211–214. 10.1016/S0165-3806(01)00213-9
    1. Thio L. L., Rensing N., Maloney S., Wozniak D. F., Xiong C., Yamada K. A. (2010). A ketogenic diet does not impair rat behavior or long-term potentiation. Epilepsia 51 1619–1623. 10.1111/j.1528-1167.2009.02515.x
    1. Tonekaboni S. H., Mostaghimi P., Mirmiran P., Abbaskhanian A., Abdollah Gorji F., Ghofrani M., et al. (2010). Efficacy of the Atkins diet as therapy for intractable epilepsy in children. Arch. Iran. Med. 13 492–497.
    1. Wang Z. J., Bergqvist C., Hunter J. V., Jin D., Wang D.-J., Wehrli S., et al. (2003). In vivo measurement of brain metabolites using two-dimensional double-quantum MR spectroscopy? exploration of GABA levels in a ketogenic diet. Magn. Reson. Med. 49 615–619. 10.1002/mrm.10429
    1. Wheless J. W. (2008). History of the ketogenic diet. Epilepsia 49 3–5. 10.1111/j.1528-1167.2008.01821.x
    1. Wilder R. (1921). The effect of ketonemia on the course of epilepsy. Mayo Clin. Proc. 2 307–308.
    1. Youngson N. A., Morris M. J., Ballard J. W. O. (2017). The mechanisms mediating the antiepileptic effects of the ketogenic diet, and potential opportunities for improvement with metabolism-altering drugs. Seizure 52 15–19. 10.1016/j.seizure.2017.09.005
    1. Yudkoff M., Daikhin Y., Horyn O., Nissim I., Nissim I. (2008). Ketosis and brain handling of glutamate, glutamine, and GABA. Epilepsia 49 73–75. 10.1111/j.1528-1167.2008.01841.x
    1. Yuen A. W. C., Sander J. W. (2014). Rationale for using intermittent calorie restriction as a dietary treatment for drug resistant epilepsy. Epilepsy Behav. 33 110–114. 10.1016/j.yebeh.2014.02.026
    1. Zare M., Okhovat A. A., Esmaillzadeh A., Mehvari J., Najafi M. R., Saadatnia M. (2017). Modified Atkins diet in adult with refractory epilepsy: a controlled randomized clinical trial. Iran. J. Neurol. 16 72–77.

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