JOURNAL OF NEUROCHEMISTRY

| 2012 | 121 | 2835

doi: 10.1111/j.1471-4159.2012.07670.x

*Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Abstract
Seizures that are resistant to standard medications remain a
major clinical problem. One underutilized option for patients
with medication-resistant seizures is the high-fat, low-carbohydrate ketogenic diet. The diet received its name based on
the observation that patients consuming this diet produce
ketone bodies (e.g., acetoacetate, b-hydroxybutyrate, and
acetone). Although the exact mechanisms of the diet are unknown, ketone bodies have been hypothesized to contribute
to the anticonvulsant and antiepileptic effects. In this review,

anticonvulsant properties of ketone bodies and the ketogenic

diet are discussed (including GABAergic and glutamatergic
effects). Because of the importance of ketone body metabolism in the early stages of life, the effects of ketone bodies on
developing neurons in vitro also are discussed. Understanding
how ketone bodies exert their effects will help optimize their
use in treating epilepsy and other neurological disorders.
Keywords: b-hydroxybutyrate, acetoacetate, acetone, epilepsy, ketogenic diet, seizure.
J. Neurochem. (2012) 121, 2835.

Epilepsy is a devastating and widespread disease that affects

around 1% of the US population and at least 50 million
people worldwide (Hauser and Kurland 1975; Hirtz et al.
2007; Kobau et al. 2008). While an array of antiepileptic
drugs has been developed, they remain unable to control
seizures in approximately 30% of patients with epilepsy
(Kwan and Brodie 2000). Some of these patients are
candidates for surgical resection of abnormal tissue (e.g.,
mesial temporal sclerosis) but options are limited for those
without such lesions. To help these patients with nonsurgical
intractable epilepsy, a high-fat, low-carbohydrate diet known
as a ketogenic diet was developed in the 1920s to mimic the
beneficial effects of fasting on seizure control (Hartman and
Vining 2007). Many clinical studies have confirmed its
beneficial effects, with a randomized study showing a 75%
decrease in seizures in children on a ketogenic diet for
3 months (Neal et al. 2008). However, while many possibilities have been investigated, the mechanisms through
which a ketogenic diet confers its anticonvulsant effects
remain unknown. Unraveling these mechanisms will allow
refinement of its clinical use as well as identification of new
targets for future therapy development.
A ketogenic diet receives its name due to the high ketone
levels found in the blood and urine of patients consuming the
diet, which traditionally consists of either long- or mediumchain fatty acids (Hartman and Vining 2007). In the setting
of elevated fatty acids and low dietary carbohydrate content
while on a ketogenic diet, the liver produces ketone bodies

by shunting excess acetyl-CoA to ketogenesis (Fig. 1). The

two primary ketone bodies produced are acetoacetate and
b-hydroxybutyrate. Acetone, the other major ketone elevated
in patients on a ketogenic diet, is a metabolite of acetoacetate. During infancy, the brain is much more efficient at
extracting and utilizing ketone bodies from the blood due to
the higher levels of ketone metabolizing enzymes and
monocarboxylic acid transporters produced during this
period (Sokoloff 1973; Bilger and Nehlig 1992). Notably,
however, the adult brain increases its levels of monocarboxylic acid transporters and ketone metabolizing enzymes
rapidly during periods of stress such as ischemia, trauma, or
low glucose (Prins 2008). In addition, there is evidence that
astrocytes can produce ketone bodies under conditions of
glucose deprivation (Blazquez et al. 1999). Thus, given the
brains ability to adapt to ketone utilization, the elevated
levels of ketone bodies in patients on a ketogenic diet, and
the robust anticonvulsant effects observed in these patients,
ketone bodies are an attractive candidate to investigate in
studies of a ketogenic diets anticonvulsant mechanism.

28

Received August 23, 2011; revised manuscript received January 16,

2012; accepted January 16, 2012.
Address correspondence and reprint requests to Adam L. Hartman,
600N. Wolfe St., Meyer 2-147, Baltimore, MD 21287, USA.
E-mail: [email protected]
Abbreviations used: ATP, adenosine tri-phosphate; GABA, c-aminobutyric acid; VGLUTs, vesicular glutamate transporters.

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Ketone bodies in epilepsy | 29

Fig. 1 A high-fat, low-carbohydrate ketogenic diet causes a shift in

the metabolic activity of hepatocytes. Under these conditions, the
Krebs cycle cannot utilize the high levels of acetyl-CoA generated
from fat. Remaining acetyl-CoA is converted to the ketone body
acetoacetate. The two additional ketone bodies, acetone and
b-hydroxybutyrate, are derived from acetoacetate by spontaneous

degradation and enzymatic conversion with b-hydroxybutyrate

dehydrogenase, respectively. The three ketone bodies are then released from the hepatocyte, cross the bloodbrain barrier, and may
exert their effects in the brain. CAT, carnitine-acylcarnitine translocase; ACA, acetoacetate; BHB, b-hydroxybutyrate; BBB, bloodbrain
barrier.

Ketone bodies: anticonvulsant properties

In trying to understand a ketogenic diets therapeutic
mechanism, many laboratories have investigated whether
ketone bodies at pharmacological doses have intrinsic
anticonvulsant properties. The anticonvulsant properties of
acetoacetate were first reported by Keith (1935) where its
administration in rabbits protected against thujone-induced
seizures. In agreement with this early report, Rho and
colleagues found that intraperitoneally administered acetoacetate and acetone, but not b-hydroxybutyrate, protected
against seizures in the Frings audiogenic seizure-susceptible
juvenile mouse (Rho et al. 2002). More recently, acute
acetone administration by intraperitoneal injection in rats
decreased their seizure susceptibility in a broad range of
seizure tests including the maximal electroshock test, the
subcutaneous pentylenetetrazol test, the amygdala kindling
test, and the AY-9944 test (Likhodii et al. 2003). Acutely
administered acetone, but not its metabolites, protected
juvenile mice from seizures induced by pentylenetetrazol
and 4-aminopyridine (Gasior et al. 2007). However, in this
study, the doses of acetone necessary to cause significant
protection from seizures caused motor impairment in the
mice, limiting its clinical pharmacological implementation.
Collectively, the evidence is strong that acutely administered
acetone and acetoacetate have intrinsic anticonvulsant properties in many standardized animal models of epilepsy.
However, clinical translatability remains unclear. We are
unaware of reports examining the anticonvulsant effects of
chronic exogenously administered ketone bodies in models
similar to those discussed previously.
While acetone has emerged as a broad-spectrum anticonvulsant in animal models, a ketogenic diet in the same tests
has not consistently conferred a similar level of protection

(specifically, against pentylenetetrazol-induced seizures in

mice) suggesting that acetone and the ketogenic diet may
have different anticonvulsant mechanisms (Uhlemann and
Neims 1972; Samala et al. 2008). Additionally, plasma
levels of acetone in rats fed a ketogenic diet were 10-fold
lower than the levels found to be therapeutic (> 2 mM), even
in the presence of an inhibitor of acetone metabolism (Nylen
et al. 2006). In contrast, using proton magnetic resonance
spectroscopy in epilepsy patients fully controlled by a
ketogenic diet, brain acetone levels were approximately
0.7 mM (Seymour et al. 1999). These data suggest that
humans and rats may produce acetone at different levels in
response to a ketogenic diet, possibly explaining the different
anticonvulsant profiles observed in animal seizure models
using acetone versus a ketogenic diet (Rho et al. 2002). To
better understand the observed inconsistency (and the
possibility that acetones volatility may lead to inaccurate
estimates of actual brain exposure), studies comparing levels
of acetone in the brain during a ketogenic diet versus those
found with exogenously administered acetone are needed. At
this time, acetones role in the anticonvulsant mechanisms of
the ketogenic diet remains unclarified.
Ketone bodies: possible mechanisms of action
The in vivo studies discussed previously suggest that ketone
bodies have anticonvulsant properties. A number of theories
have emerged to explain the decreased seizure threshold in
these models. Glutamate and c-aminobutyric acid (GABA),
respectively, are the major excitatory and inhibitory neurotransmitters in the brain. How ketone bodies affect levels of
these neurotransmitters and their receptors, their receptor
activity, and their handling has been debated. New theories
also are emerging surrounding the effects of ketone bodies on

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30 | M. A. McNally and A. L. Hartman

neuronal membrane potential, neuronal excitability, and

reactive oxygen species. Presented here is an overview of
the current data evaluating these evolving hypotheses.
GABA
GABA signaling has remained a key target of investigation
since rodent models of epilepsy induced by GABA antagonists have a strong response to a ketogenic diet (Uhlemann
and Neims 1972; Bough et al. 2002). The role of GABA
signaling in the anticonvulsant mechanisms of ketone bodies
and/or the ketogenic diet is highly debated. Supporting a role
for GABA signaling, GABA levels in rat synaptosomes
exposed to acetoacetate or b-hydroxybutyrate are increased
(Erecinska et al. 1996). More recently, clinical studies of
patients on a ketogenic diet show increased GABA levels in
the cerebrospinal fluid, as well as with magnetic resonance
spectroscopy (Wang et al. 2003; Dahlin et al. 2005). GABA
is synthesized from the Krebs cycle intermediate a-ketoglutarate, which, via glutamate, is converted to GABA by
glutamate decarboxylase. Aspartate is a known inhibitor of
glutamate decarboxylase. Therefore, a decrease in aspartate
could theoretically promote the synthesis of GABA. Exploring this further, a 1-h exposure to acetoacetate or
b-hydroxybutyrate was found to decrease aspartate levels
in cultured astrocytes (Yudkoff et al. 1997). A similar
decrease in aspartate levels was detected in the forebrain and
cerebellum of mice fed a ketogenic diet (Yudkoff et al.
2001). The body of data from Yudkoffs group suggest a
model wherein the ketotic brain has increased conversion of
glutamate to glutamine in astrocytes; glutamine is then taken
up into neurons, where it is then converted eventually to
GABA (preferentially over aspartate), thus increasing neuronal inhibition (Yudkoff et al. 2008). One unanswered question
about the importance of GABA is why a ketogenic diet did not
protect murine models of epilepsy induced by the GABA
antagonist pentylenetatrazol in the same way it did rats
(Uhlemann and Neims 1972). Furthermore, a number of
studies have shown no changes in GABA levels from whole
brain samples of rodents fed a ketogenic diet, seemingly
inconsistent with an increase in GABA synthesis (Appleton
and DeVivo 1974; Al-Mudallal et al. 1996; Yudkoff et al.
2001, 2005; Melo et al. 2006). Additional studies are required
to investigate whether there are local or regional changes in
GABA levels, GABA shunt flow, or GABA responsiveness
within the brain in the presence of ketone bodies.
VGLUTs
Ketone bodies may alter the behavior of vesicular glutamate
transporters (VGLUTs) that are responsible for filling presynaptic vesicles with glutamate in a Cl)-dependent manner.
Using proteoliposomes as an in vitro model, Juge and
colleagues demonstrated that Cl) is an allosteric activator of
VGLUTs that is competitively inhibited by ketone bodies,
acetoacetate more strongly than b-hydroxybutyrate (Juge

et al. 2010). Strengthening their in vitro findings, they

showed that acetoacetate reversibly inhibited glutamate
release from both cultured rat neurons and mouse CA1
pyramidal neurons in hippocampal slices. Finally, acetoacetate was able to suppress in vivo glutamate release and
seizures in rat brains exposed to 4-aminopyridine. However,
the amount of acetoacetate that the authors used (10 mM) is
likely supratherapeutic, given that hippocampal extracellular
levels of b-hydroxybutyrate are 4050 lM in mice fed a
ketogenic diet for 23 weeks (Samala et al. 2011). As these
two compounds have a stoichiometric relationship (Owen
et al. 1967), it is expected that levels of acetoacetate would
be significantly < 10 mM in these mice. In addition, children
on a ketogenic diet have been found to have cerebrospinal
fluid levels of acetoacetate at 0.3 mM, much lower than the
concentrations utilized in the Juge et al. study (Nordli and de
Vivo 1997). Therefore, the clinical relevance of higher levels
used by Juge et al. needs to be further clarified.
Other neurotransmitters, transporters, and receptors
Controversy remains over how ketone bodies affect neurotransmitter responsiveness. Available data suggest that a
ketogenic diet does not alter levels of the neuronal glutamate
transporter EAAC1 in neocortex, hippocampus, or cerebellum,
measured by Western blot, electron microscopy and glutamate
uptake in hippocampal proteoliposomes (Bough et al. 2007).
In vitro patch clamp studies of post-synaptic GABAA receptors
on rat hippocampal neurons suggest that there is no change in
receptor activity in the presence of extracellular 2 mM
b-hydroxybutyrate or 1 mM acetoacetate (Thio et al. 2000).
In these studies, the ketone body containing solutions, which
also contained glucose, were pre-incubated with the neurons
for only 1 min. Examining the behavior of the receptors
following longer-term incubation with ketone bodies in the
absence of glucose would be of interest as these conditions
model more closely the clinical scenario in patients on a
ketogenic diet. More recent work using Xenopus oocytes
expressing human GABAA receptors shows that a 5-min
incubation with 10 mM b-hydroxybutyrate or 50 mM acetone
significantly increases GABAA receptor activity (Yang et al.
2007). While intriguing, Yang and colleagues did not find
similar changes at lower concentrations of the ketone bodies
that would be seen clinically. Good in vivo data to clarify what
role, if any, that altered GABA receptor responsiveness plays
in the anticonvulsant activity of ketone bodies, are lacking.
Other neurotransmitter systems not typically considered in
epilepsy also appear to be necessary for the ketogenic diets
anticonvulsant effects. Data for an effect of norepinephrine
includes the lack of a ketogenic diets protective effects
against the convulsant fluorothyl in dopamine b-hydroxylase
knockout mice that cannot synthesize norepinephrine (Szot
et al. 2001). Evidence of the need for adenosine neurotransmission was shown when mice with adenosine A1 receptor
mutations were not protected against recurrent seizures after

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Ketone bodies in epilepsy | 31

ketogenic diet treatment (Masino et al. 2011). A ketogenic

diet also decreased the adenosine metabolizing enzyme,
adenosine kinase. Other neurotransmitters have not been
investigated as thoroughly.
KATP channels
Another way ketone bodies may be anticonvulsant is through
a direct effect on neuronal membrane potential. KATP
channels are of particular interest given their close relationship with cellular metabolism [activated when cellular
adenosine tri-phosphate (ATP) is low] and their hyperpolarizing effects. Additionally, they were found to play a key role
in CA3 hippocampal neuron hyperpolarization when the
neurons were cultured in low glucose media (Kawamura
et al. 2010). Exploring this idea further, in cultured mouse
hippocampal dentate gyrus neurons, both basal levels of
inward-rectifying KATP channel opening and the amount of
stimulus evoked KATP channel opening was increased in the
presence of b-hydroxybutyrate (Tanner et al. 2011). Adding
support to this in vitro work, live recordings of the
hippocampal dentate gyrus in rats fed a ketogenic diet show
decreased long-term potentiation, consistent with increased
neuronal inhibition (Koranda et al. 2011). Previously, Ma
and colleagues used GABAergic substantia nigra pars
reticulata neurons to study KATP channels given the hypothesis that very rapid firing of these neurons precede generalized seizure onset (Deransart et al. 2003; Ma et al. 2007).
When GABAergic substantia nigra pars reticulata neurons
were cultured in the presence of acetoacetate or b-hydroxybutyrate with glucose, firing rates (measured by loose-patch
cell-attached recordings) were decreased. Of note, this effect
was abolished in a variety of settings, including (a) when the
neurons were cultured from Kir6.2 knockout mice (no cell
surface KATP channels), and (b) when the experiments were
conducted in the presence of tolbutamide (an inhibitor of
KATP channel opening) or a GABAB receptor blocker. These
findings add further support to the hypothesis that the
anticonvulsant activities of ketone bodies are, in part, mediated
by their effects on KATP channels. The latter scenario suggests
that GABAB signaling might be important to mediate these
effects of ketone bodies. However, whether these results can
shed light on mechanisms of the ketogenic diet needs to be
considered carefully as rodent studies to date have shown that a
ketogenic diet elevates or maintains normal cellular ATP
levels, an otherwise negative regulator of KATP channels
(DeVivo et al. 1978; Bough et al. 2006; Nylen et al. 2009).
The notion has been advanced that a ketogenic diet enhances
KATP channel activity through ATP compartmentation by
decreasing glycolytic ATP levels, an hypothesis that awaits
further experimental evidence (Yellen 2008).
Krebs cycle and the electron transport chain
One theory of the ketogenic diets multifaceted effects is that
it may optimize Krebs cycle function, with a subsequent

effect on neuronal function. The logical starting point for this

theory is that acetyl CoA (one downstream product of
ketogenesis) is a primary substrate for the Krebs cycle
(Fig. 1). Downstream of the Krebs cycle, b-hydroxybutyrate
improved redox activity and decreased cell death in dopaminergic SH-SY5Y cells after exposure to the complex I
toxin rotenone (Imamura et al. 2006). b-Hydroxybutyrate
appears to require an intact complex II to confer its beneficial
effects in two different models of neurodegeneration,
including a complex II toxin (3-nitropropionic acid) model
and the SOD1-G93A mouse model of amyotrophic lateral
sclerosis (Lou Gehrigs disease) (Tieu et al. 2003; Zhao
et al. 2006). More recently, Kim do et al. (2010) showed in
hippocampal slices that a cocktail of b-hydroxybutyrate and
acetoacetate preserved synaptic activity after exposure to
rotenone or 3-nitropropionic acid, although there were some
regional disparities (i.e., different responses even within the
same slice) noted during ketone exposure to the latter.
The reason for differences between the two studies of 3nitropropionic acid is unclear.
A ketogenic diet also has been shown to induce transcription
of some electron transport chain subunit mRNAs (Bough et al.
2006). An increased number of electron transport chain
subunits might increase neuronal energy reserves and, in
fact, ketogenic diets increase brain ATP levels in some (but not
all) rodent studies (DeVivo et al. 1978; Bough et al. 2006;
Nylen et al. 2009; Kim do et al. 2010). A final hypothesis is
that increased ATP levels may stabilize neuronal membrane
potential by enhancing the function of Na+-K+-ATPases
(Bough and Rho 2007). Although teleologically satisfying,
the events outlined here have not been completely linked
experimentally in either normal or epilepsy animal models.
Nonetheless, individual experiments point to the potential
importance of the Krebs cycle and electron transport chain
function in the effects of ketone bodies.
Immature and developing neurons
Many studies have looked at the effects of ketone bodies on
immature neurons as a possible physiological model of the
ketogenic diet. In suckling rodents, circulating levels of
ketone bodies are high due to the high ketogenic ratio of
rodent milk (Nehlig 1999). During this time, the brain relies
most heavily on ketone bodies as a source of metabolic fuel
(Nehlig and Pereira de Vasconcelos 1993). Also during this
time, GABA is excitatory, an action found to be dependent
on the higher intracellular chloride levels in immature
neurons. As a neuron matures the Na+-K+-2Cl) co-transporter (NKCC1) is replaced with the K+-Cl) co-transporter
(KCC2) shifting GABA to an inhibitory neurotransmitter
(Aronica et al. 2011). Patch clamp work on neocortical
pyramidal neurons from mice demonstrated that b-hydroxybutyrate incubation at supra-physiologic levels decreased
both the resting membrane potential and the amount of
GABA-mediated excitation in a dose-dependent manner

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32 | M. A. McNally and A. L. Hartman

(Rheims et al. 2009). This group also showed that ketone

bodies at similarly high levels cause the same inhibition of
GABA-mediated excitation in murine hippocampal CA3
neurons (Holmgren et al. 2010), another important brain
region in epilepsy development. These data are supported by
recent in vivo work examining physiological levels of ketone
bodies in neonatal rats (Minlebaev and Khazipov 2011).
Minlebaev and Khazipov used 16-channel extracellular field
potential recordings from somatosensory barrel cortex in
postnatal day 59 awake rat pups to study epileptiform
activity induced by flurothyl when physiological ketosis was
inhibited. They found that blocking ketogenesis did not
affect a single flurothyl-evoked seizure, however consecutively evoked seizures were more severe in these animals. In
contrast to the preceding studies, a number of groups have
found that GABA-induced depolarization in neonatal rodent
cortical neurons is unaffected by the presence of ketone
bodies at both supraphysiologic and physiologic levels (Thio
et al. 2000; Kirmse et al. 2010; Tyzio et al. 2011). Possible
reasons for the discrepancies among the studies are outlined
in Tyzio et al. (2011);. Thus, while an effect of ketone bodies
on neonatal cortex excitability remains an intriguing possibility that could shed light on possible therapeutic mechanisms of a ketogenic diet, its existence remains controversial.
These data also should be interpreted with caution when
drawing parallels to a ketogenic diet as all these results were
found with solutions containing both ketone bodies and high
levels of glucose (510 mM). Basal glucose concentrations

in murine hippocampal extracellular fluid as determined by

in vivo microdialysis were approximately 2 mM, and only
1.3 mM when the mice were fed a ketogenic diet (Samala
et al. 2011).
Antioxidant effects
Ketone bodies also may have antioxidant effects. Reactive
oxygen species production resulting from glutamate exposure is inhibited by ketone bodies in primary cultures of rat
neocortical neurons (Maalouf et al. 2007). The mechanism
appears to involve NADH oxidation, rather than a glutathione-mediated antioxidant effect. Conversely, the ketogenic diet (rather than ketone bodies) may alter glutathione
metabolism via the transcription factor Nrf2 (Milder et al.
2010). Ketone bodies also protect against cell death after
neocortical slices are exposed to hydrogen peroxide (Kim
do et al. 2007). Additionally, ketone bodies prevent
hydrogen peroxide-induced impairment of hippocampal
long-term potentiation (Maalouf and Rho 2008). Therefore,
in addition to effects on neurotransmission, these data
suggest ketone bodies may be neuroprotective against
reactive oxygen species produced in neuropathological
states.

Conclusions
A growing amount of in vivo and in vitro data show that
ketone bodies can alter neuronal activity and protect against

Fig. 2 Possible anticonvulsant effects of

ketone bodies on the brain. (1) Increased
GABA synthesis through alteration of glutamate cycling in glutamate-glutamine cycle
or altered neuronal responsiveness to
GABA at GABAA receptors. (2) Decreased
glutamate release by competitive inhibition
of vesicular glutamate transporters. (3)
Other neurotransmitters, including norepinephrine and adenosine. (4) Increased
membrane potential hyperpolarization via
KATP channels possibly mediated by GABAB receptor signaling. (5) Decreased
reactive oxygen species production from
glutamate exposure. (6) Electron transport
chain subunit transcription. A1R, adenosine
receptor; Cl, chloride; GLN, glutamine;
GLU, glutamate; GABA, c-aminobutyric
acid; GABABR, c-aminobutyric acid beta
receptor; GABAAR, c-aminobutyric acid alpha receptor; VGLUT, vesicular glutamate
transporter; ROS, reactive oxygen species.

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Ketone bodies in epilepsy | 33

seizures. The mechanisms through which ketone bodies may

confer an anticonvulsant effect are still debated. The
potential mechanisms discussed in this review center around
neurotransmitters and the resting neuronal membrane
potential (Fig. 2). Moving forward, work will need to be
completed exploring how physiological levels of ketone
bodies affect these systems. The exact targets of ketone
bodies still are unknown and may be direct (i.e., binding to a
specific neuronal target, as demonstrated for acetoacetate in
VGLUT), or indirect (i.e., supplying carbon equivalents to
the Krebs cycle or an antioxidant effect). Given both the
success of AC-1202 (an oral ketogenic compound that
rapidly elevates b-hydroxybutyrate levels) in improving
cognitive outcomes in Alzheimer disease patients (Henderson et al. 2009) and the success of a ketogenic diet in treating
children with medically intractable epilepsy, there is significant interest in pursuing these types of compounds for
epilepsy therapies. However, the contribution of ketone
bodies to the anticonvulsant effects of the ketogenic diet
remains elusive. Because of study design issues and the
amount of overlap between values in different patient groups,
the relationship between seizure control and serum levels of
b-hydroxybutyrate remains unclear (Gilbert et al. 2000).
Many other studies have failed to show that the levels of
serum or urine ketosis correlate with seizure protection in
animal models (Bough et al. 2000; Likhodii et al. 2000) or
patients (Ross et al. 1985; Fraser et al. 2003). Breath acetone
levels correlate with plasma levels of all three ketone bodies
but not with seizure control (Musa-Veloso et al. 2006). Some
of these studies highlight the potential difference between
administration of ketone bodies versus a ketogenic diet
(understanding the former as a product of the latter). Together,
some of the data discussed here suggest the ketogenic diet may
have anticonvulsant effects via mechanisms other than
elevated ketone body levels, even though ketone bodies have
numerous potential beneficial effects. Therefore, based on
current data, ketone bodies may represent a unique, additional
therapeutic modality to optimize for patients with epilepsy and
possibly other neurological disorders. Further studies are
required to understand how using these compounds may help
these populations.

Acknowledgements
Supported by the Howard Hughes Medical Institute Medical
Research
Fellows
Program
(MAM),
K12NS001696,
K08NS070931, and a Clinician Scientist Award (Johns Hopkins
University School of Medicine) (ALH). The authors have no
conflicts of interest to disclose.

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