b i o m e d i c a l j o u r n a l 4 5 ( 2 0 2 2 ) 1 9 e2 6

Available online at www.sciencedirect.com

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Biomedical Journal
journal homepage: www.elsevier.com/locate/bj

Review Article: Special Edition

Updates on the ketogenic diet therapy for

pediatric epilepsy

Ara Ko a, Hye Eun Kwon b, Heung Dong Kim c,*

a
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST),
Daejeon, Korea
b
Department of Pediatrics, International St. Mary's Hospital, College of Medicine, Catholic Kwandong University,
Incheon, Korea
c
Division of Pediatric Neurology, Department of Pediatrics, Severance Children's Hospital, Yonsei University College
of Medicine, Seoul, Republic of Korea

article info abstract

Article history: The ketogenic diet (KD) is a high-fat, low-carbohydrate diet, in which fat, instead of
Received 21 July 2021 glucose, acts as a major energy source through the production of ketone bodies. The KD
Accepted 7 November 2021 was formally introduced in 1921 to mimic the biochemical changes associated with fasting
Available online 19 November 2021 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 epi-
Keywords: lepsy patients for its anti-seizure efficacy, safety, and tolerability. The KD is also receiving
Ketogenic diet growing attention as a potential treatment option for other neurological disorders. This
Epilepsy article will review on the recent updates on the KD, focusing on its mechanisms of action,
Pediatric its alternatives, expansion on its use in terms of age groups and different regions in the
world, and future issues.

Collection [1]. The first documented modern use of fasting for

History of the ketogenic diet epilepsy appeared in 1911, when fasting successfully
improved the seizures of 20 children and adults with epilepsy
The ketogenic diet (KD) is a high-fat, low-carbohydrate diet, [2]. Subsequently, it was discovered that the benefits of
in which fat, instead of glucose, acts as a major energy source fasting could be replicated by inducing ketosis through a
through the production of ketone bodies. Before advent of high-fat diet, which led to implementation of a KD in epi-
the KD, fasting was recognized for centuries as a potential lepsy patients, with the distinct advantage that this treat-
therapeutic modality for epilepsy; indeed, it was described as ment could be maintained for a prolonged period of time [3].
the only anti-epileptic treatment in the Hippocratic KDs were widely applied throughout the 1920s and 1930s, but

* Corresponding author. Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro,
Seodaemun-gu, Seoul 03722, Republic of Korea.
E-mail address: [email protected] (H.D. Kim).
Peer review under responsibility of Chang Gung University.
https://doi.org/10.1016/j.bj.2021.11.003
2319-4170/© 2021 Chang Gung University. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
20 b i o m e d i c a l j o u r n a l 4 5 ( 2 0 2 2 ) 1 9 e2 6

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 PPARg expression, which
in turn diminishes IL-1b 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-1b, interleukin 1b; KD, ketogenic diet, MCT, medium-chain triglyceride; MT2, metallothionein 2; NRF2, nuclear
factor E2-related factor 2; PGD2, prostaglandin D2; PPARg, peroxisome proliferator activated receptor gamma; PUFAs,
polyunsaturated fatty acids; ROS, reactive oxygen species; UCP, uncoupling protein.

their use dramatically decreased with the introduction of

new anti-epileptic drugs (AEDs) [1]. Proposed mechanisms of the ketogenic diet
The modern era of KDs for epilepsy began in 1994 with the
appearance of a story on television of a boy named Charlie Despite a steady increase over the past decade in our knowl-
whose drug-resistant seizures were controlled by a KD. This edge of the underlying mechanisms of the KD, it is still not
gained nationwide attention in the United States. Subsequent completely understood how the diet is clinically effective in
clinical trials confirmed the efficacy of KDs for seizure control, seizure disorders [7]. Multiple mechanisms likely participate
especially in childhood drug-resistant epilepsy [4]. in interconnected ways to produce anti-seizure effects, as well
Current practices of KDs for epilepsy are well outlined in as neuroprotective effects. These mechanisms probably act
guidelines published by the International Ketogenic Diet jointly and in parallel with one another. Several main pro-
Study Group in 2009 and 2018. These guidelines provide posed mechanisms of action of KDs are discussed in the
practical information regarding patient selection, pre-KD following paragraphs (Fig. 1).
counseling, diet selection and implementation, dietary sup-
plementation, follow-up evaluation, adverse effects, and (1) Alteration of neurotransmitters and regulation of ion
discontinuation of the diet [5,6]. KDs have been established as channels
one of four main treatments for drug-resistant epilepsy,
together with newer AEDs, epilepsy surgery, and neuro- KDs may produce anti-seizure effects via altering neuro-
modulation. In contrast to surgical treatments, use of a KD is transmitter levels [8]. Increases in gamma-aminobutyric acid
reversible, inexpensive, and easily accessible. (GABA), adenosine, and norepinephrine levels and decreases
in glutamate levels have been observed during KDs [9]. In
 b i o m e d i c a l j o u r n a l 4 5 ( 2 0 2 2 ) 1 9 e2 6 21

astrocytes, glutamate is converted to glutamine, which is then Beta-hydroxybutyrate activates hydroxy-carboxylic acid re-
exported to neurons where glutamine is converted back to ceptor 2, which in turn stimulates the synthesis of prosta-
glutamate. This glutamate is then converted to either GABA or glandin D2, inducing a neuroprotective phenotype in
aspartate. Conversion of glutamate to aspartate requires monocytes and/or macrophages [25]. Beta-hydroxybutyrate
oxaloacetate, which is also an important component of the also suppresses mitochondrial translocation of dynamin-
tricarboxylic acid (TCA) cycle. During a KD, metabolism of related protein 1 to inhibit nucleotide-binding domain-like
ketone bodies leads to increased production of oxaloacetate, receptor protein 3 inflammasome activation, resulting in
but the oxaloacetate is diverted into the TCA cycle to provide neuroprotective effects [26,27].
cellular energy. This reduces the amount of oxaloacetate
available for conversion of glutamate to aspartate, thereby (4) Inhibition of histone deacetylases
increasing conversion of glutamate to GABA [10].
Glutamate release through vesicular glutamate trans- KDs may exhibit antioxidant activity through inhibition of
porters is regulated by chloride ions, which act as an allosteric histone deacetylases. Beta-hydroxybutyrate increases histone
activator [11]. The ketone bodies beta-hydroxybutyrate and acetylation by inhibiting class I histone deacetylases, leading
acetoacetate compete with chloride ions at the site of allo- to changes in the transcription of various genes, including
steric regulation and thus inhibit glutamate release, resulting those encoding two oxidative stresseresistant factors (fork-
in decreased presynaptic glutamate release [11]. KDs also head box O3 and metallothionein 2) [28,29].
decrease levels of adenosine kinase, a major adenosine-
metabolizing enzyme, and thus increase extracellular aden- (5) Alteration of gut microbiota
osine levels [12]. These diets also increase activation of
adenosine A1 receptors, resulting in increased inhibitory ef- Alteration of the gut microbiota is another proposed anti-
fects mediated by these receptors. KDs have also been shown seizure mechanism of KDs [30]. Dysbiosis of the gut micro-
to increase extracellular norepinephrine levels [13]. biota has been observed in patients with epilepsy, which can
KDs may further exhibit anti-seizure effects by inducing lead to reduced production of short-chain fatty acids and
changes in regulation of ion channels. These diets decrease neurotransmitters such as GABA and serotonin [31,32].
neuronal firing rates through activation of adenosine Reduction of anti-inflammatory short-chain fatty acids re-
triphosphate (ATP)-sensitive potassium channels and GABAB sults in alterations of the bloodebrain barrier [33]. KDs have
receptors [14]. Acetoacetate also inhibits voltage-dependent been shown to alter the gut microbiota, resulting in an
calcium channels, leading to reduced excitatory post- elevated GABA/glutamate ratio and thus anti-seizure effects
synaptic currents [15]. [34]. Moreover, KDs do not exhibit anti-seizure activity in
The medium chain-triglyceride (MCT) KD induces mice treated with antibiotics or reared in a germ-free envi-
increased plasma levels of decanoic acid and ketones [16]. The ronment [34].
decanoic acid directly and selectively inhibits alpha-amino-3-
hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) recep- (6) Decreased glycolysis and increased fatty acids
tor, acting as a non-competitive antagonist in a voltage- and
subunit-dependent manner [17,18]. Reduced glycolysis induced by KDs may lower cellular
excitability [35]. Polyunsaturated fatty acids (PUFAs) modulate
(2) Enhancement of mitochondrial function and oxidative voltage sensitivity of voltage-gated potassium channels and
stress reduction induce channel opening [36]. Increased PUFA intake with KDs
decrease excitation by opening voltage-gated potassium
Aberrant mitochondrial function and production of reac- channels, thereby improving seizures [36,37]. Increased fatty
tive oxygen species (ROS), both of which are known to acid levels during KDs also lead to increased expression of the
contribute to epileptogenesis, may be influenced by KDs [19]. transcription factor peroxisome proliferator activated recep-
These diets not only increase ATP production by mitochon- tor gamma (PPARg), which regulates genes involved in anti-
dria, but they also directly increase mitochondrial biogenesis inflammatory and antioxidant pathways, which in turn
[20,21]. KDs enhance expression of uncoupling proteins, caused diminished expression of interleukin-1b (IL-1b) cyto-
which in turn decrease the mitochondrial membrane poten- kine [38]. IL-1b is linked to hyperexcitability and seizure gen-
tial, leading to decreased ROS levels [22]. Activation of the eration, and decreased levels of IL-1b were associated
nuclear factor E2-related factor 2 pathway also occurs with reduction in seizures [38].
KDs, resulting in diverse changes, including increased
biosynthesis of glutathione, which has antioxidant activity
[23]. KDs also inhibit mitochondrial permeability transition, a
process linked to apoptotic and necrotic cell death [24]. This Modifications and alternatives to the classic
inhibition has anti-seizure effects, as well as presumed neu- ketogenic diet
roprotective effects [24].
Although its efficacy is proven, KD is not an easy and conve-
(3) Mediation of inflammatory and immune function nient method of treatment to both patients and caregivers.
Maintaining high-fat diet can be unpalatable and result in
Anti-inflammatory activity and improved immune func- various adverse effects. Preparing each meal with calculation
tion may contribute to the neuroprotective effects of KDs. and measurement of food composition and ingredients can be
22 b i o m e d i c a l j o u r n a l 4 5 ( 2 0 2 2 ) 1 9 e2 6

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).

impossible to some patients and caregivers. Therefore, alter- MAD and LGIT are suitable for adolescents and adults and can
natives to the classic KD have been developed and studied. be easily used in outpatient settings or in settings with limited
resources (e.g., lack of trained dietitians) [40].
(1) Medium-chain triglyceride diet, modified Atkins diet, The efficacy of the three KD alternativesdMCT diet, MAD,
and low glycemic index treatment and LGITdhas been compared to that of classic KD in various
studies, including randomized controlled trials. While the ef-
The term “ketogenic diet” refers to any diet that results in ficacy of each depends on the patient's age, specific epilepsy
the ketogenic stage of metabolism. Following the develop- syndrome, and etiology, these alternatives are not inferior to
ment of the classic KD, which consists of long-chain tri- the classic KD [43e47]. When KDs must be maintained for
glycerides, usually supplied as a 4:1 or 3:1 ratio of fats to several years because of seizure recurrence or clinical course
nonfats (proteins and carbohydrates), alternative diets have of the disease, it is reasonable to consider switching to MAD or
been proposed in attempts to increase compliance and LGIT from the classic KD when considering the risks of long-
palatability, while mimicking the metabolic effects of the term complications [48].
original diet. Currently, four main KDs are used in clinical
practice: the classic KD, the MCT diet, the modified Atkins diet (2) Triheptanoin
(MAD), and the low glycemic index treatment (LGIT).
As the name suggests, the main component of the MCT diet Triheptanoin is a synthetic MCT composed of three hep-
is MCT oils, which yield more ketones per kilocalorie than long- tanoate fatty acids [49]. It is a tasteless oil that dissolves
chain triglycerides [16,39]. This increased ketogenic potential easily in food and was first approved in the United States for
reduces the quantity of total fat that must be consumed, use in patients with long-chain fatty acid oxidation disorders
allowing for more carbohydrate and protein intake and [49,50]. Because of its anaplerotic ability to replenish TCA
potentially better food choices and less food refusal. MAD cycle intermediates, which are present in reduced amounts
typically consists of 1:1 to 1.5:1 ketogenic ratio, with no limi- in patients with epilepsy, triheptanoin has been studied for
tation on proteins, fluids, or calories, which makes meal plan- seizure control in these patients [50]. Triheptanoin is
ning and preparation easier and increases tolerability of the administered at mealtimes or with snacks, with a recom-
diet [40]. LGIT involves exchanging high glycemic index foods mended target daily dosage of up to 35% of the total pre-
with low glycemic index alternatives [41]. The glycemic index scribed daily caloric intake, which is divided into at least 4
reflects the tendency of a food to increase the blood glucose, doses [49]. The few studies evaluating triheptanoin usage in
compared to the increase induced by an equivalent amount of a patients with epilepsy have shown promising effects for
reference carbohydrate [42]. Refined carbohydrates are exam- seizure control, as well as good tolerability [51e53]. A clear
ples of high glycemic index foods, whereas meat, dairy, vege- advantage of triheptanoin is its simple preparation, in
tables, and unprocessed whole-grain foods are examples of low contrast to the difficult meal preparation with KDs, which
glycemic index foods [42]. While LGIT does not necessarily require calculations of food composition and special recipes.
produce ketosis, both decreased glucose metabolism and stable Further studies are warranted to assess the anti-seizure ef-
glucose levels contribute to the mechanism of KDs [41]. Both ficacy, safety, and tolerability of triheptanoin.
 b i o m e d i c a l j o u r n a l 4 5 ( 2 0 2 2 ) 1 9 e2 6 23

nutrition. Using the ketogenic parenteral nutrition can

Expansion of KD applications therefore prevent the delay on KD implementation, since its
efficacy on seizure reduction and safety are supported by
The indications for the KD are expanding, and broader patient several reports [63,67e70].
groups are being subject to the dietary therapy with accu-
mulation of experience with the KD (Fig. 2). (4) KD in specific genetic epileptic encephalopathy

(1) KD in infants/neonates In general, KDs improve seizure outcomes in 50% of pa-

tients but offer no benefits in the remaining patients. Pre-
The first two years of life are critical for rapid brain growth dicting KD efficacy before implementation therefore remains
and psychosocial development related to synapse formation an important question for treating epileptologists. With recent
and myelination [54]. Patients at this age are most at risk of advances in gene discovery and genetics, specific causative
neurodevelopmental impairment. Additionally, the incidence genetic variants are identified in about 1/3 of the patients
of epilepsy is highest during this period. Until recently, KDs previously classified as developmental and epileptic enceph-
were not used in infants based on assumptions that this age alopathy of unknown etiology [71]. In this context, KDs were
group could not maintain a state of ketosis and the risk of found to be effective for seizure control in patients with
adverse events was too high. However, it has been shown that SCN1A, KCNQ2, STXBP1, and SCN2A mutations but less effec-
ketone bodies constitute a significant fuel source for brain tive in patients with CDKL5 mutations in a small pilot study of
development in utero and during infancy, and the clinical ef- patients with identified causative genetic variants responsible
ficacy and safety of KDs in this age group have now been for developmental and epileptic encephalopathy [72]. How-
documented [55e57]. In a case series of patients younger than ever, another study suggested beneficial effect of the KD in
3 months of age in a neonatal intensive care unit, a KD was patients with CDKL5 mutations although poor long-term effi-
well tolerated and improved seizures [58]. KDs can also be cacy was noted [73]. More studies with larger patient cohorts
safely and effectively initiated in infants who are simulta- are warranted to draw conclusions on efficacy of KD according
neously receiving human breast milk [59]. Moreover, an to epilepsies caused by specific genetic variants.
interesting case of an exclusively breastfed infant was reported
recently, whose seizures were controlled after achieving (5) KD in metabolic/mitochondrial disorders
ketosis through altering the composition of the mother's own
milk by placing the healthy mother on the KD [60]. Metabolic epilepsies arise in the context of inborn errors of
metabolism. Drug-resistant epilepsy is one of the character-
(2) KD for refractory status epilepticus istic clinical manifestations of certain neurologic disorders,
including inborn errors of metabolism or genetic diseases in
Status epilepticus is one of the major causes for pediatric infancy. Although disorders caused by inborn errors of
neurocritical care admissions, along with traumatic brain metabolism are rare, their collective prevalence is 1 in 1000,
injury and infection/inflammation such as meningitis and and most have no cure. Given that KDs are a fundamentally
encephalitis [61]. The incidence of refractory status epi- metabolism-based treatment that induce a broad range of
lepticus is unknown, and adult data suggest that about 1/3 of biochemical, hormonal, and physiologic effects, they may be
patients with convulsive status epilepticus progress to re- considered a treatment option for these patients [9].
fractory status epilepticus [62]. There is an increasing report The effects of KDs have been reported for metabolic dis-
on efficacy of the KD in refractory status epilepticus patients orders involving mitochondria. Clinical results have indicated
in pediatric intensive care units, and the existing reports that the KD may effectively treat children with drug-resistant
consistently favor early applications of the KD in refractory epilepsy associated with mitochondrial respiratory chain
status epilepticus based on their experience on seizure complex defects and mitochondrial encephalopathy with
reduction in majority of the patients [63e66]. Although more lactic acidosis and stroke-like episodes [74e76]. Since KDs
evidences are needed for ascertainment, there was a trend enhance mitochondrial function and biogenesis, they are now
that patients with febrile infection-related epilepsy syndrome indicated and confirmed to be effective for treating mito-
showed more response to the KD than refractory status epi- chondrial disorders, especially complex 1 deficiency syn-
lepticus patients unrelated to the febrile infection-related drome. Of note, before publication of these clinical reports,
epilepsy syndrome [66]. KDs were generally considered contraindicated in patients
with mitochondrial disorders. Thus, continued efforts to
(3) Ketogenic parenteral nutrition expand the indications for KDs are warranted.

Application of the KD in the intensive care settings is (6) KD for other neurological disorders
facilitated by use of the ketogenic parenteral nutrition
administration. Patients with refractory status epilepticus are As KDs can elicit a broad spectrum of systemic effects,
usually under heavy sedation from effects of anesthetics and there has been considerable interest in using the diets for
anti-epileptic medications, and commonly experience gastro- neurologic disorders other than epilepsy. Although the data
intestinal dysmotility causing poor absorption of orally fed are preliminary, KDs have been used for many disorders,
24 b i o m e d i c a l j o u r n a l 4 5 ( 2 0 2 2 ) 1 9 e2 6

including autism spectrum disorder (ASD), Alzheimer's dis-

ease, brain tumors, and traumatic brain injury [77,78]. Interest Conflicts of interest
in neurodegenerative disorders arose from studies of neuro-
protection and energy metabolism related to the mechanisms There is no competing interest among the authors.
of KDs [79].
In patients with ASD and concomitant seizures, the
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