Application of the ketogenic diet in pediatrics: a range of possibilities

Authors

DOI:

https://doi.org/10.15574/SP.2023.129.41

Keywords:

children, ketogenic diet, refractory seizure, metabolic disorders, indications, principles of appointment

Abstract

Purpose - to describe the possibilities of using a ketogenic diet (KD) in the pediatric population for therapeutic purposes in refractory seizure syndrome and congenital metabolic disorders.

The historical aspects of the development of special medical nutrition to achieve stable ketosis in children for the treatment of seizures of various genesis are briefly highlighted; the development of the evidence base for the effectiveness of the KD in children is presented. A review of current data on the multifactorial mechanisms of neuroprotective effects of KD is carried out. In particular, individual ways of modulating fundamental biochemical pathways, presynaptic and postsynaptic changes in vesicular transport and release of excitotoxic and inhibitory substrates at synapses are considered. Four types of diets are described according to the distribution of proteins, fats, and carbohydrates: the classic, modified Atkins diet, medium-chain triglyceride diet, and low glycemic index diet. The indications and contraindications for the appointment of medical ketogenic dietary therapy are considered. The most appropriate age periods of childhood for the type of KD are outlined to achieve maximum effectiveness. The authors describe in detail the main objectives of the stages of preparation of the child and family for the start of dietary treatment, the principles of initiation of KD, laboratory and instrumental monitoring and discontinuation of ketogenic dietary therapy. Particular attention is paid to the issue of counseling a child before starting a KD, the main steps in calculating the proportion of macronutrients and the principles of daily nutrition. The possibilities of prescribing medical ketogenic dietary therapy outside of refractory seizures, in particular, in glucose transaminase 1 deficiency syndrome, pyruvate dehydrogenase deficiency, mitochondrial disorders, heart failure, and brain injury, are analyzed. Available special products for medical purposes (clinical nutrition) for the organization of medical ketogenic therapy in pediatric patients, especially in the first years of life, are presented.

No conflict of interests was declared by the authors.

References

Acharya P, Acharya C, Thongprayoon C, Hansrivijit P, Kanduri SR, Kovvuru K et al. (2021). Incidence and Characteristics of Kidney Stones in Patients on Ketogenic Diet: A Systematic Review and Meta-Analysis. Diseases. 9 (2): 39. https://doi.org/10.3390/diseases9020039; PMid:34070285 PMCid:PMC8161846

Auvin S. (2021). New developments for dietary treatment of epilepsy after a century of history for the ketogenic diet. Brain Commun. 3 (4): fcab234. https://doi.org/10.1093/braincomms/fcab234; PMid:34704031 PMCid:PMC8536870

Branco AF, Ferreira A, Simões RF, Magalhães-Novais S, Zehowski C, Cope E et al. (2016). Ketogenic diets: from cancer to mitochondrial diseases and beyond. Eur J Clin Invest. 46 (3): 285-298. https://doi.org/10.1111/eci.12591; PMid:26782788

Cervenka M, Pascual JM, Rho JM, Thiele E, Yellen G, Whittemore V, Hartman AL. (2021). Metabolism-based therapies for epilepsy: new directions for future cures. Ann Clin Transl Neurol. 8 (8): 1730-1737. https://doi.org/10.1002/acn3.51423; PMid:34247456 PMCid:PMC8351378

Chida R, Shimura M, Nishimata S, Kashiwagi Y, Kawashima H. (2018). Efficacy of ketogenic diet for pyruvate dehydrogenase complex deficiency. Pediatr Int. 60: 1041-1042. https://doi.org/10.1111/ped.13700; PMid:30407699

Clanton RM, Wu G, Akabani G, Aramayo R. (2017). Control of seizures by ketogenic diet-induced modulation of metabolic pathways. Amino Acids. 49: 1-20. https://doi.org/10.1007/s00726-016-2336-7; PMid:27683025

Dąbek A, Wojtala M, Pirola L, Balcerczyk A. (2020). Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States. Nutrients. 12 (3): 788. https://doi.org/10.3390/nu12030788; PMid:32192146 PMCid:PMC7146425

Falsaperla R, D'Angelo G, Praticò AD, Mauceri L, Barbagallo M, Pavone P et al. (2020). Ketogenic diet for infants with epilepsy: A literature review. Epilepsy & behavior. 112: 107361. https://doi.org/10.1016/j.yebeh.2020.107361; PMid:33181904

Gavrilovici C, Rho JM. (2021). Metabolic epilepsies amenable to ketogenic therapies: Indications, contraindications, and underlying mechanisms. J Inherit Metab Dis. 44 (1): 42-53. https://doi.org/10.1002/jimd.12283; PMid:32654164

Greco T, Glenn TC, Hovda DA, Prins ML. (2016). Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism. 36 (9): 1603-1613. https://doi.org/10.1177/0271678X15610584; PMid:26661201 PMCid:PMC5012517

Guo Y, Liu X, Li T, Zhao J, Yang Y, Yao Y et al. (2022). Alternate-day ketogenic diet feeding protects against heart failure through preservation of ketogenesis in the liver. Oxid Med Cell Longev. 2022: 4253651. https://doi.org/10.1155/2022/4253651; PMid:35707271 PMCid:PMC9192193

Huang L, Li H, Zhong J, Yang L, Chen G, Wang D et al. (2022). Efficacy and Safety of the Ketogenic Diet for Mitochondrial Disease with Epilepsy: A Prospective, Open-labeled, Controlled Study. Front Neurol. 13: 880944. https://doi.org/10.3389/fneur.2022.880944; PMid:35979062 PMCid:PMC9377015

Hwang CY, Choe W, Yoon KS, Ha J, Kim SS, Yeo EJ, Kang I. (2022). Molecular Mechanisms for Ketone Body Metabolism, Signaling Functions, and Therapeutic Potential in Cancer. Nutrients. 14 (22): 4932. https://doi.org/10.3390/nu14224932; PMid:36432618 PMCid:PMC9694619

Ismayilova N, Leung M-A, Kumar R, Smith M, Williams RE. (2018). Ketogenic diet therapy in infants less than two years of age for medically refractory epilepsy. Seizure. 57: 5-7. https://doi.org/10.1016/j.seizure.2018.02.014; PMid:29524777

Kim SH, Shaw A, Blackford R, Lowman W, Laux LC, Millichap JJ, Nordli DR. (2019). The ketogenic diet in children 3 years of age or younger: a 10-year single-center experience. Sci Rep. 9 (1): 8736. https://doi.org/10.1038/s41598-019-45147-6; PMid:31217425 PMCid:PMC6584655

Koppel SJ, Swerdlow RH. (2018). Neuroketotherapeutics: A modern review of a century-old therapy. Neurochem Int. 117: 114-125. https://doi.org/10.1016/j.neuint.2017.05.019; PMid:28579059 PMCid:PMC5711637

Kossoff E, Cervenka M. (2020). Ketogenic Dietary Therapy Controversies for Its Second Century. Epilepsy Currents. 20 (3): 125-129. https://doi.org/10.1177/1535759719890337; PMid:31786950 PMCid:PMC7281909

Kossoff EH, McGrogan JR, Bluml RM, Pillas DJ, Rubenstein JE, Vining EP. (2006). A modified Atkins diet is effective for the treatment of intractable pediatric epilepsy. Epilepsia. 47: 421-424. https://doi.org/10.1111/j.1528-1167.2006.00438.x; PMid:16499770

Kossoff EH, Zupec-Kania BA, Auvin S, Ballaban-Gil KR, Bergqvist C, Blackford AG et al. (2018). Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group. Epilepsia open. 3 (2): 175-192. https://doi.org/10.1002/epi4.12225; PMid:29881797 PMCid:PMC5983110

Lambert B, Neal E. (2020). A guide for the practical implementation of the Classical Ketogenic Diet for the dietary management of epilepsy and neurometabolic disease. Vitaflo International Ltd.: 23. URL: www.nestlehealthscience.com/Vitaflo/VIA.

Lima PA, Sampaio LP, Damasceno NR. (2014). Neurobiochemical mechanisms of a ketogenic diet in refractory epilepsy. Clinics. 69: 699-705. https://doi.org/10.6061/clinics/2014(10)09; PMid:25518023

Løkken N, Hansen KK, Storgaard JH, Ørngreen MC, Quinlivan R, Vissing J. (2020). Titrating a modified ketogenic diet for patients with McArdle disease: A pilot study. Journal of inherited metabolic disease. 43 (4): 778-786. https://doi.org/10.1002/jimd.12223; PMid:32060930

Mu Ch, Tompkins ThA, Rho JM, Scantlebury MH, Shearer J. (2022). Gut-based manipulations spur hippocampal mitochondrial bioenergetics in a model of pediatric epilepsy. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1868 (9): 166446. https://doi.org/10.1016/j.bbadis.2022.166446; PMid:35589071

Murugan M, Boison D. (2020). Ketogenic diet, neuroprotection, and antiepileptogenesis. Epilepsy Res. 167: 106444. https://doi.org/10.1016/j.eplepsyres.2020.106444; PMid:32854046 PMCid:PMC7655615

Nangia S, Caraballo RH, Kang HC, Nordli DR, Scheffer IE. (2012). Is the ketogenic diet effective in specific epilepsy syndromes? Epilepsy research. 100 (3): 252-257. https://doi.org/10.1016/j.eplepsyres.2012.01.015; PMid:22424762

Nordli DR Jr, Kuroda MM, Carroll J, Koenigsberger DY, Hirsch LJ, Bruner HJ, Seidel WT, De Vivo D. (2001). Experience with the ketogenic diet in infants. Pediatrics. 108 (1): 129-133. https://doi.org/10.1542/peds.108.1.129; PMid:11433065

Olson CA, Vuong HE, Yano JM, Liang QY, Nusbaum DJ, Hsiao EY. (2018). The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet. Cell. 173 (7): 1728-1741.e13. https://doi.org/10.1016/j.cell.2018.04.027; PMid:29804833 PMCid:PMC6003870

Parikh S, Goldstein A, Karaa A, Koenig MK, Anselm I, Brunel-Guitton C et al. (2017). Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genetics in medicine: official journal of the American College of Medical Genetics. 19 (12): 10.1038/gim.2017.107. https://doi.org/10.1038/gim.2017.107; PMid:28749475 PMCid:PMC7804217

Poff AM, Rho JM, D'Agostino DP. (2019). Ketone Administration for Seizure Disorders: History and Rationale for Ketone Esters and Metabolic Alternatives. Front. Neurosci. 13: 1041. https://doi.org/10.3389/fnins.2019.01041; PMid:31680801 PMCid:PMC6803688

Qu C, Keijer J, Adjobo-Hermans MJW, van de Wal M, Schirris T, van Karnebeek C et al. (2021). The ketogenic diet as a therapeutic intervention strategy in mitochondrial disease. Int J Biochem Cell Biol. 138: 106050. https://doi.org/10.1016/j.biocel.2021.106050; PMid:34298163

Rezaei S, Abdurahman AA, Saghazadeh A, Badv RS, Mahmoudi M. (2019). 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. Nutritional neuroscience. 22 (5): 317-334. https://doi.org/10.1080/1028415X.2017.1387721; PMid:29069983

Rho JM, Boison D. (2022). The metabolic basis of epilepsy. Nature reviews. Neurology. 18(6): 333-347. https://doi.org/10.1038/s41582-022-00651-8; PMid:35361967

Rogawski MA, Löscher W, Rho JM. (2016). Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harbor perspectives in medicine. 6 (5): a022780. https://doi.org/10.1101/cshperspect.a022780; PMid:26801895 PMCid:PMC4852797

Saris CGJ, Timmers S. (2022). Ketogenic diets and Ketone suplementation: A strategy for therapeutic intervention. Front Nutr. 9: 947567. https://doi.org/10.3389/fnut.2022.947567; PMid:36458166 PMCid:PMC9705794

Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L et al. (2017). ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 58 (4): 512-521. https://doi.org/10.1111/epi.13709; PMid:28276062 PMCid:PMC5386840

Simeone TA, Simeone KA, Rho JM. (2017). Ketone Bodies as Anti-Seizure Agents. Neurochem Res. 42 (7): 2011-2018. https://doi.org/10.1007/s11064-017-2253-5; PMid:28397070 PMCid:PMC5505793

Smith KA, Hendricks BK, DiDomenico JD, Conway BN, Smith TL, Azadi A, Fonkem E. (2022). Ketogenic Metabolic Therapy for Glioma. Cureus. 14 (6): e26457. https://doi.org/10.7759/cureus.26457

Sofou K, Dahlin M, Hallböök T, Lindefeldt M, Viggedal G, Darin N. (2017). Ketogenic diet in pyruvate dehydrogenase complex deficiency: short‐ and long‐term outcomes. J Inherit Metab Dis. 40: 237-245. https://doi.org/10.1007/s10545-016-0011-5; PMid:28101805 PMCid:PMC5306430

Sourbron J, Thevissen K, Lagae L. (2021). The Ketogenic Diet Revisited: Beyond Ketones. Front Neurol. 12: 720073. https://doi.org/10.3389/fneur.2021.720073; PMid:34393987 PMCid:PMC8363000

Tozzi R, Cipriani F, Masi D, Basciani S, Watanabe M, Lubrano C et al. (2022). Ketone Bodies and SIRT1, Synergic Epigenetic Regulators for Metabolic Health: A Narrative Review. Nutrients. 14 (15): 3145. https://doi.org/10.3390/nu14153145; PMid:35956321 PMCid:PMC9370141

Tumienė B, Del Toro Riera M, Grikiniene J, Samaitiene-Aleknienė R, Praninskienė R, Monavari AA, Sykut-Cegielska J. (2022). Multidisciplinary Care of Patients with Inherited Metabolic Diseases and Epilepsy: Current Perspectives. eCollection 2022. J Multidiscip Healthc. 15: 553-566. https://doi.org/10.2147/JMDH.S251863; PMid:35387391 PMCid:PMC8977775

Van der Louw E, van den Hurk D, Neal E, Leiendecker B, Fitzsimmon G, Dority L et al. (2016). Ketogenic diet guidelines for infants with refractory epilepsy. EJPN. 20 (6): 798-809. https://doi.org/10.1016/j.ejpn.2016.07.009; PMid:27470655

Verrotti A, Iapadre G, Di Francesco L, Zagaroli L, Farello G. (2020). Diet in the Treatment of Epilepsy: What We Know So Far. Nutrients. 12 (9): 2645. https://doi.org/10.3390/nu12092645; PMid:32872661 PMCid:PMC7551815

Villaluz MM, Lomax LB, Jadhav T, Cross JH, Scheffer IE. (2018). The ketogenic diet is effective for refractory epilepsy associated with acquired structural epileptic encephalopathy. Dev Med Child Neurol. 60: 718-723. https://doi.org/10.1111/dmcn.13687; PMid:29451698

Wheless JW. (2008). History of the ketogenic diet. Epilepsia. 49 (8): 3-5. https://doi.org/10.1111/j.1528-1167.2008.01821.x; PMid:19049574

Yang H, Shan W, Zhu F, Wu J, Wang Q. (2019). Ketone Bodies in Neurological Diseases: Focus on Neuroprotection and Underlying Mechanisms. Front Neurol. 10: 585. https://doi.org/10.3389/fneur.2019.00585; PMid:31244753 PMCid:PMC6581710

Yurista SR, Nguyen CT, Rosenzweig A, de Boer RA, Westenbrink BD. (2021). Ketone bodies for the failing heart: Fuels that can fix the engine? Trends Endocrinol Metab. 32: 814-826. https://doi.org/10.1016/j.tem.2021.07.006; PMid:34456121

Zhu H, Bi D, Zhang Y, Kong C, Du J, Wu X, Wei Q, Qin H. (2022). Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations. Signal transduction & targeted therapy. 7 (1): 11. https://doi.org/10.1038/s41392-021-00831-w; PMid:35034957 PMCid:PMC8761750

Zweers H, van Wegberg AMJ, Janssen MCH, Wortmann SB. (2021). Ketogenic diet for mitochondrial disease: A systematic review on efficacy and safety. Orphanet J Rare Dis. 16: 295. https://doi.org/10.1186/s13023-021-01927-w; PMid:34217336 PMCid:PMC8254320

Published

2023-02-27