Updates on the ketogenic diet therapy for pediatric epilepsy

Abstract

The ketogenic diet (KD) is a high-fat, low-carbohydrate diet, in which fat, instead of glucose, acts as a major energy source through the production of ketone bodies. The KD was formally introduced in 1921 to mimic the biochemical changes associated with fasting and gained recognition as a potent treatment for pediatric epilepsy in the mid-1990s. Recent clinical and scientific knowledge supports the use of the KD in drug-resistant epilepsy patients for its anti-seizure efficacy, safety, and tolerability. The KD is also receiving growing attention as a potential treatment option for other neurological disorders. This article will review on the recent updates on the KD, focusing on its mechanisms of action, its alternatives, expansion on its use in terms of age groups and different regions in the world, and future issues.

Keywords: Epilepsy; Ketogenic diet; Pediatric.

Fig. 1

Proposed mechanisms of action of the KD. KD alters neurotransmitter levels: GABA, norepinephrine, and adenosine levels are increased, while glutamate level is decreased. Increased decanoic acid levels in MCT KD directly inhibits AMPA receptors. KD induces changes in regulation in ion channels: ATP-sensitive potassium channels are activated and voltage-gated calcium channels are inhibited. Increase in polyunsaturated fatty acids also results in increased excitation of voltage-gated potassium channels. KD enhances mitochondrial function and biogenesis, inducing increased ATP production and decreased ROS production. KD enhances expression of uncoupling proteins and increased glutathione biosynthesis via NRF2 pathway activation, both of which lead to decreased ROS production as well. KD inhibits mitochondria permeability transition, and thus inhibits apoptotic and necrotic cell death. Decreased glycolysis during KD decreases cellular excitability. KD activates hydroxy-carboxylic acid receptor 2, which in turn stimulates the synthesis of prostaglandin D2, inducing a neuroprotective phenotype in monocytes and/or macrophages. KD also suppresses NLRP3 inflammasome activation. KD increased PPARγ expression, which in turn diminishes IL-1β levels. KD increases histone acetylation by inhibiting histone deacetylases, leading to increased transcription of genes encoding for oxidative stress resistant factors (FOXO3 and MT2). KD induces gut microbiome alteration, which in turn leads to increased GABA/glutamate ratio. AMPA, alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid; ATP, adenosine triphosphate; FOXO3, forkhead box O3; GABA, gamma-aminobutyric acid; HCA₂, hydroxy-carboxylic acid receptor 2; IL-1β, interleukin 1β; KD, ketogenic diet, MCT, medium-chain triglyceride; MT2, metallothionein 2; NRF2, nuclear factor E2-related factor 2; PGD2, prostaglandin D2; PPARγ, peroxisome proliferator activated receptor gamma; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; UCP, uncoupling protein.

Fig. 2

Applications of the KD in the past and present. With accumulation of experience with the KD, indications for the KD and application methods have expanded (bigger box) from the narrow application of the classic KD in the past (smaller box).