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Ketogenic Diet



About one third of patients with epilepsy are pharmacoresistent. For a subgroup of this population, the ketogenic diet can be highly efficacious and should be considered early. This review discusses the different types of ketogenic diet, proposed mechanism of actions and its evidence for use in children and adults with both generalized and focal epilepsies where surgery is not feasible. In addition we discuss a practical approach to diet initiation, maintenance and monitoring for side effects. We also summarize the emerging evidence for the use of ketogenic diet in a broad range of neurological disorders.
In historic times before medications were popular, dietary
alterations were prescribed for a variety of illnesses including
epilepsy. Ancient Greek physicians treated epilepsy, by changing
their patients' diet. An early treatise in the Hippocratic Corpus,
“On the Sacred Disease”, from 400 BC argued against the
existing view that epilepsy was supernatural in origin, and
proposed that dietary therapy had a rational basis
The first modern study of fasting as a treatment for epilepsy
was in France in 1911. Twenty patients were treated with a low-
calorie vegetarian diet, combined with periods of fasting and
purging. While two benefited greatly, most failed to maintain
. Around this time, Bernarr Macfadden, an
American exponent of physical culture, popularized the use of
fasting to restore health. His student, Hugh Conklin, an
osteopathic physician from Michigan, began to treat his epilepsy
patients with fasting. Later analysis of Conklin's case records
showed 20% of his patients achieved seizure-freedom and 50%
had some improvement.
Conklin's fasting therapy was later
adopted by many neurologists, including Dr. Geyelin at the
Presbyterian Hospital in New York
While fasting may be an option in short term control of
seizures, it is clearly not a long term treatment. In 1921, Dr.
Wilder at Mayo Clinic first proposed the ketogenic diet (KD),
which was designed to mimic fasting state but to provide
adequate protein and calories for growth, and as such, to be a
long term option for control of epilepsy
. The ketogenic diet
became more widely used at that time as there were only a few
anticonvulsant medications available including bromides (1857)
and phenobarbital (1912). However as more anticonvulsants
came on the market, the ketogenic diet was used only in limited
ABSTRACT: About one third of patients with epilepsy are pharmacoresistent. For a subgroup of this
population, the ketogenic diet can be highly efficacious and should be considered early. This review
discusses the different types of ketogenic diet, proposed mechanism of actions and its evidence for use
in children and adults with both generalized and focal epilepsies where surgery is not feasible. In
addition we discuss a practical approach to diet initiation, maintenance and monitoring for side effects.
We also summarize the emerging evidence for the use of ketogenic diet in a broad range of neurological
RÉSUMÉ: Diète cétogène. Environ le tiers des patients atteints d'épilepsie sont pharmacorésistants. Pour un sous-
groupe de ces patients, la diète cétogène peut être très efficace et devrait être considérée tôt au cours du traitement.
Dans cette revue, nous discutons de différents types de diète cétogène, des mécanismes d'action proposés et des
données appuyant son utilisation chez les enfants et les adultes présentant tant une épilepsie généralisée qu'une
épilepsie focale, chez qui la chirurgie n'est pas une option. De plus, nous discutons d'une approche pratique à
l'implantation de la diète, à son maintien et à la surveillance des effets secondaires. Nous présentons également un
sommaire des observations centes concernant l'utilisation d'une diète cétogène dans une panoplie de troubles
Can J Neurol Sci. 2013; 40: 158-167
Ketogenic Diet
Radhika Dhamija, Susan Eckert, Elaine Wirrell
From the Division of Child and Adolescent Neurology, Mayo Clinic Children’s Center,
Rochester, MN, USA.
Correspondence to: Elaine Wirrell, Division of Child and Adolescent Neurology, Mayo
Building, 16th floor, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
settings. In an attempt to make the diet more palatable, the
medium chain triglyceride (MCT) KD was introduced and used
in various childhood epilepsy syndromes
. However in the last
two decades, advocacy groups, such as the Charlie Foundation
and Matthew’s Friends have facilitated a reemergence of interest
and research in this diet which is now used throughout the world
to treat patients with intractable epilepsy
. A large single center
study on a cohort of children with intractable epilepsy showed
marked improvement in > 60% of the patients
. Similar results
(> 50% patients with > 50% reduction in seizures at six months)
were found in a large multicentre study on children between age
one to eight years with more than ten seizures per week at
. The first randomized, prospective, controlled trial
utilizing the KD in children was published in 2008 and
examined 145 children (2 -16 years) who had at least daily
seizures and had failed to respond to at least two antiepileptic
drugs. After three months, seizures was significantly lower in the
diet group than in controls (75% decrease, p<0.0001)
Table 1 summarizes important studies done using the various
forms of the KD and their efficacy in decreasing seizure
Volume 40, No. 2 March 2013 159
In a study surveying the use of this diet world wide, it was
found that the overall physician and patient acceptance of the
diet is high and cultural and religious issues are not limiting.
International collaborative groups are forming rapidly to
study this diet
. A multicenter expert guideline that outlines the
ideal manner in which to provide the ketogenic diet has also been
Different types of ketogenic diet
There are four different ketogenic diets available: the
traditional ‘classic’ ketogenic diet (KD), the medium-chain
triglyceride (MCT) ketogenic diet, the modified Atkins diet
(MAD) and the low glycemic index treatment (LGIT). The
composition of the diets and their pros and cons are discussed in
Table 2.
The traditional “classic” ketogenic diet contains a fixed ratio
by weight of fat to combined protein and carbohydrate. This is
achieved by excluding high-carbohydrate foods while increasing
the consumption of foods high in fat. In young children and
infants, the traditional diet is frequently started in a hospital
Most dietary fat is made of molecules called long-chain
triglycerides. However, medium-chain triglycerides (MCTs) of
octanoic and decanoic acids produce more ketones per unit of
. A variant of the classic diet known as the MCT
ketogenic diet uses MCT oil to provide around half the calories.
As less overall fat is needed in this diet, a greater proportion of
carbohydrate and protein can be consumed, allowing a slightly
greater variety of food choices. This diet was first tested in 1971
by Dr. Huttenlocher on twelve children and adolescents with
intractable seizures. A therapeutically significant anticonvulsant
effect was seen in 50% of the children with a mean age of eight
years with slightly higher incidence of gastrointestinal side
. In another study on children with refractory epilepsy >
50 % of patients had > 75 % reduction in seizure frequency using
MCT diet
Modified Atkins diet allows for carbohydrate intake of 10-
20g/day and strongly encourages fat intake. There is no calorie
restriction or meticulous weighing of food involved and hence
meals are easier to prepare. It can be started in home setting. This
diet appears to be well-tolerated and efficacious in most
. Long-term experience with this diet has also been
reported in 87 children with intractable epilepsy, of which 54
continued for more than six months. After a mean of 19.9
months, 30 of 54 (55%) children with diet durations of more than
six months achieved >50% improvement; 19 (35%) were
*AED’s: Antiepileptic drugs
Traditional ketogenic diet
umber of patients
esponse Rate
Kinsman et al 1992
58 children (>= 2 AED’s and multiple seizure types)
67% had >50 % reduction at 6 months
Vining et al 1998
51 children (>10 seizures/week)
50% had >50% reduction at 6 months
DiMario et al 2001
24 children (multiple seizure types)
54% had >50% reduction at 6 months
Kang 2005
199 children (>=4 seizures/month and >=3 AED’s)
58% had >50% reduction at 6 months
Neal et al 2009
73 children (daily seizures and >= 2 AED’s)
25 % had >50% reduction at 6 months
ressler 2010
0 children (>= 2 AED’s))
0% had >50% reduction at 6 months
hamongkol 2012
4 children and 4 adults (failed >=2 AED’s)
8% had >50% reduction at 3 months
Medium chain
triglyceride oil diet
Huttenlocher 1971
12 children (>=2 AED’s)
>50% had >50% reduction at 6 months
Mak et al 1999
13 children (>=2 AED’s and multiple seizure types)
>70% had >50% reduction at 6 months
Neal et al 2009
72 (daily seizures and >= 2 AED’s)
20 % had >50% reduction at 6 months
Low glycemic index diet
Pfeifer et al 2005
20 patients (>= 3 AED’s)
50% had >90% reduction at 6 months
Muzykewicz 2009
76 children (>=3 AED’s)
54% had >50% reduction at 6 months
Coppolla 2011
15 patients ( 4 seizures/months and (>=3 AED’s)
40% had a 75-90% reduction at 12 months
Modified atkins diet
Kossoff et al 2006
20 children (>3 seizures/week and failed >= 2AED’s)
65% had >50% reduction at 6 months;
35% had >90% reduction
Kossoff et al 2008
30 adults (>1 seizures/week and failed >=2 AED’s)
33 % had >50% reduction at 6 months
Weber et al 2009
20 children (>1seizures/week and failed >=2 AED’s)
40% had >50% reduction at 3 months
Chen et al 2012
87 children (>=2 AED’s)
55% had >50% reduction at 6 months; 38%
had >50% seizure reduction at 12 months
Kim et al 2012
20 children (>=2 AED’s)
45% had >50% reduction
Table 1: Efficacy of different types of ketogenic diets in patients with intractable epilepsy
seizure-free. At 12 months, 33 of 87 (38%) had >50% seizure
reduction; 16 (18%) were seizure-free
The low glycemic index treatment is a low-carbohydrate diet
(carbohydrate intake is usually limited to 40-60g/day). Only
foods with low glycemic index (< 50) are used. In a study on 20
patients who had failed at least three anticonvulsant medications
previously, 50% had greater than 90% reduction in the seizures
In another retrospective chart review study, 40 % of the enrolled
patients with generalized or focal seizures, refractory to at least
three consecutive anticonvulsant drugs, with at least four
seizures per month, had a 75-90% seizure reduction
In the authors experience, occasional children may show a
robust reduction in seizures with a traditional ketogenic diet after
responding suboptimally to a low glycemic or modified Atkins
diet. But overall, the different types of ketogenic diets appear to
have similar efficacy.
Does ketosis matter?
There is evidence in the literature that continued large ketosis
(> 160 mg/dl) is not always needed for seizure control, though
higher ketosis can lead to improved seizure control in some
patients. In a prospective study, 20 children, aged 3–18 years
were treated for six months with modified Atkins diet.
Carbohydrates were initially limited to 10 g per day and fats
were encouraged. At six months, 80% remained on the diet, 65%
experienced a >50% reduction, and 35% a greater than 90%
reduction in seizures. All children on the modified Atkins diet
achieved moderate ketosis (> 80–160 mg/dl) within four days
(mean 1.9 days) of diet initiation. Only 29% maintained large
ketosis long term. Large ketosis was not predictive of better
outcome beyond one month. At six months, three of the five
patients with zero to trace ketosis were >90% improved, and a
fourth patient was 50– 90% improved
While using the traditional KD, the typical ratio used to
obtain moderate to high urinary ketones is usually 3-4:1, with
few children requiring a lower ratio. Ratio is based on the degree
of ketosis and seizure control and is different for every child. In
a study by Seo et al, the antiepileptic efficacy and diet
tolerability of a 3:1 and 4:1 ratio were compared. Initial
antiepileptic efficacy was higher for the 4:1 than the 3:1 diet (p
< 0.05), however dietary tolerability was better for the 3:1 than
the 4:1 diet. For seizure-free patients who started on the 4:1 diet,
antiepileptic efficacy was maintained after changing to the 3:1
. Thus it appears reasonable to decrease the ratio in those
with significant gastrointestinal intolerance without fear of
losing efficacy.
It is often not possible to achieve moderate ketosis in the low
glycemic index diet but this diet has been shown to have similar
efficacy as discussed above
. Thus the degree of ketosis may be
less important than previously thought.
Indications and Evidence
The ketogenic diet is most often considered in cases of
refractory epilepsy and epileptic encephalopathies where surgery
is not feasible. All types of seizures have been reported to
respond to the ketogenic diet, although in the authors experience,
while patients with focal epilepsy may improve, they do not
achieve complete seizure freedom on KD
. The efficacy of the
diet is not specific to any syndrome, although it is most
commonly used in the epileptic encephalopathies of childhood.
arents know exactly how much of each
food to give;
Very consistent, therefore little variation in
Easy to adjust as dietician knows exactly
what child is getting;
Requires less record keeping by parents
ifficult to adjust amount consumed based on child’s appetite;
Child must eat everything on their plate;
Protein limited to recommended dietary allowance,
which is often less than child is used to;
Involves weighing and measuring;
more time-consuming to prepare the meals
Provides more protein;
Greater protein serving size allows more
volume in which to mix the fats and
ncreased variety of food;
Involves weighing and measuring food;
time-consuming to prepare the meals;
Gastrointestinal side effects
Greater flexibility to adjust meal to
ariations in appetite;
Provides more protein;
Greater protein serving size allows more
volume in which to mix the fats;
Less weighing, measuring, faster meal prep;
No firm guidelines regarding fat amounts;
equires experimentation to determine adequate fats to ensure
desired ketosis;
Often more variability in ketone production;
Requires more record keeping to allow adjustments in diet
index diet
Greater flexibility to adjust meal to
variations in appetite;
Provides more protein;
Greater protein serving size allows more
volume in which to mix the fats;
Less weighing, measuring, faster meal prep;
Requires knowledge of the foods that have low glycemic index;
Requires more record keeping to allow adjustments in diet
Table 2: Composition and pros/cons of the different ketogenic diets
Volume 40, No. 2 March 2013 161
Evidence for the use of this diet exists both in adults and
children, though predominantly in uncontrolled cohort studies.
The first randomized, prospective, controlled trial utilizing
the KD in children was published in 2008 and examined 145
children (2 -16 years) who had at least daily seizures and had
failed to respond to at least two antiepileptic drugs. Children
were randomized to either receive KD or no change in treatment.
After three months, seizures was significantly lower in the diet
group than in controls (75% decrease, p<0.0001). Twenty eight
children (38%) in the diet group had greater than 50% seizure
reduction compared with only four (6%) controls (p<0.0001),
and five children (7%) in the diet group had greater than 90%
seizure reduction compared with no controls (p=0.0582). There
was no significant difference in the efficacy of the treatment
between symptomatic generalized or symptomatic focal
Evidence in Specific syndromes (Table 3)
Infantile Spasms
A study from a single institution evaluating the efficacy of
ketogenic diet in infantile spasms showed that there was 50%
spasm improvement in nearly two thirds of children at six
months and 77% after one to two years. Thirty seven percent
became spasm-free for at least a six month period within
a median 2.4 months of starting the KD. In addition, 62%
reported improvement in neurodevelopment, 35% had
electroencephalogram (EEG) improvement, and 29% were able
to reduce concurrent anticonvulsants. Thus it is recommended
that KD should be considered strongly after failure of
corticosteroids, adrenocorticotrophic hormone (ACTH) and
vigabatrin as a treatment for infantile spasms
. Another group
compared short term use (eight months) vs long term traditional
use (two years) of KD in infantile spasms. It was found that the
use of the diet for only eight months in children who become
spasm-free appears to be justified, with similar outcomes,
recurrence rate, and less growth disturbance than a longer-term,
traditional use
. In the authors opinion, the KD is not an ideal
first line therapy for infantile spasms as it usually takes longer to
be effective compared to other first line therapies. Given the
concern for adverse developmental impact of ongoing
hypsarrhythmia, if used first line, the diet should be trialed for a
maximum period of two weeks, and therapy switched at that
time if there are ongoing spasms or persisting hypsarrhythmia.
Dravet syndrome
Ketogenic diet has been shown to be effective in children
with Dravet syndrome. In two modest sized cohorts of children
with Dravet syndrome placed on KD, nearly two thirds had a
>75% decrease in seizures. In addition to efficacy on seizure
frequency, KD was beneficial on behavior disturbances
including hyperactivity
. Thus, the diet should be considered
early in the course of this syndrome.
Myoclonic-atonic epilepsy
Myoclonic-atonic epilepsy is an idiopathic generalized
epilepsy syndrome affecting preschool-aged children. In a small
study of 11 children with myoclonic-atonic epilepsy on a KD,
Carabello found that over half showed a > 50% reduction in
seizures, and seizure-freedom was seen in 18%
. In ten patients
treated with KD after an average of five antiepileptic medication
trials, five achieved seizure freedom
. In a large retrospective
study evaluating treatment and long term prognosis of 81
Response Rate
Infantile Spasms
Hong et al 2010
104 infants (64% of children had 50% spasm
improvement at 6 months)
Dravet syndrome
Caraballo et al 2011
Nabbout, 2011
24 children (62.5% had a 75-99% decrease in
seizures at 2 years after diet initiation)
15 children (66% had a decrease of seizure
frequency >/=75% at 1 month)
Myoclonic-astatic epilepsy
Caraballo et al 2006
Kilaru et al 2007
11 children (> 50% had a > 50% reduction in
seizures at 18 months.)
10 children (50% had seizure freedom at 6 months)
Lennox-Gastaut syndrome
Lemmon et al 2012
71 children (51% had > 50% seizure
reduction at 6 months)
Febrile infection-related
epilepsy syndrome (FIRES)
Nabbout et al 2010
9 children ( > 70% had >50% seizure
reduction at 5 days)
Metabolic disorders:
Respiratory complex
defect, Pyruvate
Glucose transporter-
1 deficiency
Non ketotic
Kang et al 2007
Caraballo et al 2011
Cusmai et al 2012
14 children ( 50% had seizure freedom)
KD considered first line based on mechanism
3 children (significant reduction of seizures)
Table 3: Evidence in specific electroclinical syndromes
children with myoclonic-atonic epilepsy, Oguni reported that the
most effective treatment for myoclonic-atonic epilepsy was the
ketogenic diet
. In conclusion, the diet should be considered
early in the course of myoclonic-atonic epilepsy and not as a last
Lennox-Gastaut syndrome
Similarly favorable outcomes have been seen in children with
Lennox-Gastaut syndrome
. In a retrospective study from a
single institution, of 71 children (range 18 months-18years), with
Lennox-Gastaut syndrome who were initiated on the ketogenic
diet, 51% achieved more than 50% seizure reduction, 23% more
than 90% seizure reduction, and 1% achieved seizure freedom
after six months
. In another retrospective, collaborative,
multicenter study from Argentina involving 216 patients with
various seizure syndromes started on the KD, 56.5% of the
patients had a >75% reduction in seizure frequency. The best
results were found in patients with epilepsy with myoclonic
atonic epilepsy, Lennox-Gastaut syndrome, and West
Febrile infection-related epilepsy syndrome (FIRES)
FIRES is a poorly understood and devastating condition
triggered by fever of unknown cause. Status epilepticus may last
more than one month, and this condition frequently evolves into
pharmacoresistent epilepsy associated with severe cognitive
impairment. Nabbout reported on nine patients over a 12 year
period with FIRES who were treated with KD. In seven, KD was
efficacious within a mean of 4.8 days following the onset of the
diet. In one responder, early disruption of the diet was followed
by relapse of intractable SE. In conclusion, KD may be an
alternative therapy for refractory SE in FIRES and should be
considered early in pharmacoresistent cases
Focal etiologies
There are reports of ketogenic diet being of benefit in
refractory epilepsy due to focal lesions like hypothalamic
hamartoma, cortical dysplasia and tuberous sclerosis
. In a
retrospective chart review over five years, twelve children with
tuberous sclerosis were identified from a single institution. All
children had daily seizures at the time of diet initiation. Eleven
children (92%) had >50% reduction in their seizures at six
months on the KD and eight (67%) had a >90% response. Five
children achieved seizure freedom for five months. The children
remained on the KD for a mean of two years. Eight (67%)
children were able to reduce their antiepileptics while on the KD.
There were no reported complications
Status epilepticus (SE)
Ketogenic diet has been successfully used in the treatment of
refractory status epilepticus (convulsive and non convulsive)
both in adults and children. It has been shown to decrease
ventilation time and number of antiepileptic drugs. It has been
suggested, based on limited data, that KD can be tried after
failure to control ongoing seizures with standard measures for
Mitochondrial disease
A retrospective analysis evaluated outcomes in 14 children
with intractable epilepsy and respiratory chain complex defects
who were treated with the classic KD. The epileptic diagnoses
were as follows: five patients with infantile spasms, four with the
Lennox-Gastaut syndrome, one with the Landau-Kleffner
syndrome, one with nonspecific generalized epilepsy, and three
with focal epilepsy. Seven patients became seizure-free after
commencing the KD, one had > 90% seizure reduction, and two
had seizure reductions between 50% and 90%. Thus KD was a
safe and effective therapy for seizures in children with
intractable epilepsy and respiratory chain complex defects.
However, the KD is contraindicated in carnitine deficiency,
pyruvate carboxylase deficiency, and defects in fatty acid
Other metabolic disorders
Ketogenic diet is considered first line in certain metabolic
disorders like glucose transporter-1 (GLUT-1) deficiency and
pyruvate dehydrogenase deficiency
. For the treatment of
GLUT-1 deficiency syndrome, the modified Atkins diet has been
shown to have similar effectiveness
. Cases of successful
treatment of early myoclonic encephalopathy due to non ketotic
hyperglycinemia using KD have also been described
Thus, based on the above evidence, we can conclude that
most types of seizures respond to the ketogenic diet and the
efficacy of the diet is not specific to any syndrome
Evidence in adults
Evidence for KD use is less robust in adults
and its use in
adults less frequent among practicing physicians. Only 38% of
the consensus group offered dietary therapy to adults
. New diet
options that are more palatable and flexible than the traditional
KD, such as the modified Atkins diet or low glycemic index diet
have made this an attractive option for adults with intractable
epilepsy. In a prospective open-label pilot study on KD treatment
in adults with refractory epilepsy (generalized and focal), 50% of
subjects had a >50% reduction in seizures and 33% had a >85%
seizure reduction. The diet was felt to be well tolerated and
adverse effects were mild: nausea, vomiting, diarrhea,
constipation, and weight loss
. A prospective, open-label study
performed on 30 adults (>18 years-of-age, with at least weekly
seizures, prior use of at least two anticonvulsants) using a
modified Atkins diet showed that 47% had a >50% seizure
reduction after one and three months on the diet; 33% after six
. The medium chain triglyceride ketogenic diet and low
glycemic index treatments have not been studied systematically
in adults.
In conclusion, data in adult population must be interpreted
with caution as it is limited by small number of subjects.
However, in the authors opinion, it is a reasonable option in
medically intractable epilepsy in adults. In clinical practice
compliance with the traditional KD seems to be a significant
barrier in adults. The modified Atkins or low glycemic index
diets are probably the best options for adults as they have better
compliance, are better tolerated due to fewer gastrointestinal side
effects and probable lower risk of dyslipidemia.
Volume 40, No. 2 March 2013 163
To summarize, all the studies are heterogenous and difficult
to compare but overall, regardless of age, seizure type, or
etiology, the KD appears to provide a third of the patients with
>90% reduction in their seizure frequency and half of the
patients greater than 50% reduction in seizure frequency
. In
comparison vagal nerve stimulation has been studied in a
randomized controlled fashion in children with intractable
epilepsy and has been found to reduce seizure frequency by >
50% in >25% of the patients
. Addition of a third anticonvulsant
has been found to be of benefit in < 5% of the patients
. Thus
KD can be highly efficacious and should be considered early.
Mechanism of action
The exact mechanism of action of the diet is still unknown
though there are a number of theories and ongoing research.
Likely the KD works through multiple mechanisms. It is
unlikely that these numerous hypotheses can be unified into a
final common pathway; nevertheless, it is important to consider
each of these putative mechanisms and discuss the evidence.
Importance of ketones: The ketones may have direct
antiepileptic activity or may act to stabilize neuronal
membranes. The earliest demonstration of direct in vivo effects
of ketone bodies was made in the early 1930s when it was
determined that acetoacetate, when administered intra-
peritoneally in rabbits, prevented seizures induced by thujone, a
convulsant and an antagonist of GABA
. Mice
models for Dravet syndrome and genetic epilepsy with febrile
seizures plus have been studied using the KD. Higher levels of
β-hydroxybutyrate have been found in the mice with better
seizure control compared to the mice treated with standard diet
suggesting that ketones might have antiepileptic effects
. It has
been shown in rat models that higher ratios of ketogenic diet
(6:1), are more efficacious than traditional 4:1 ratio without more
neurotoxic effects
. However, as discussed previously, human
data suggests that the MAD and LGIT have efficacy similar to
traditional KD even with a lower degree of ketosis; suggesting
high ketosis may not be major mechanism in humans
Role of polyunsaturated acids (PUFAs): It is hypothesized
that specific polyunsaturated fatty acids regulate neuronal
membrane excitability by blocking voltage gated sodium or
calcium channels
. In a study comparing the blood levels of
arachidonate (PUFA) before and three to four weeks after
starting the KD in children, higher levels of arachidonate
correlated with improved seizure control. Thus, elevated PUFA
may represent a potential anticonvulsant mechanism of the
. However there are other clinical trials on humans which
have not supported this concept and the results show
. In a prospective randomized study on adults
with uncontrolled epilepsy who were randomized to either
mineral oil (placebo) n= 9 or EPA (eicosapentaenoic acid) and
DHA (docosahexaenoic acid) (ratio of 3:2) n=12; none on the n-
3 PUFA versus two on the placebo diet had at least a 50%
decrease in seizure frequency from baseline
. Another 12-week,
double-blind crossover trial, showed no significant benefits of
daily supplementation of EPA and DHA vs. placebo in patients
with intractable epilepsy
Anti-inflammatory and protection against excitotoxicity:
Several theories have suggested that the KD has anti-
inflammatory effects and protects against excitotoxicity-
mediated neuronal cell death
. It has been shown in
hippocampal cell lines to interfere with glutamate-mediated
toxicity, a major mechanism underlying neuronal injury
Alteration in neuro-metabolites and/or their receptors: The
KD can potentially alter the levels of neuro-metabolites and
influence seizure control
. In-vivo studies have shown that β -
hydroxybutyrate increases the brain synthesis of kynurenic acid,
an endogenous antagonist of glutamatergic and α7-nicotinic
receptors, thus potentially acting as an anticonvulsant
. In one
study, the addition of either acetoacetate or β-hydroxybutyrate
was associated with diminished consumption of glutamate via
transamination to aspartate and increased formation of labeled
. Recent positron emission tomography studies using
flumazenil have suggested that KD may control seizures by
directly or indirectly increasing the binding potential of the
benzodiazepine receptors
Positive energy balance: A study on rat brain reported that
the KD increased the total quantity of bioenergetic substrates
(such as adenosine triphosphate (ATP)) leading to stabilization
of the cell membrane. This can be potentially protective in states
of high energy demand like seizures
Antioxidant mechanisms: Ketone bodies have been shown to
reduce the amount of coenzyme Q semiquinone, thereby
decreasing free radical production. The KD also induces
glutathione peroxidase activity in the rat hippocampus.
Glutathione peroxidase is an enzyme found in erythrocytes that
prevents lipid peroxidation
In spite of large amounts of ongoing research, the exact
underlying cellular or metabolic mechanism of the ketogenic diet
remains elusive. More likely the above described hypotheses are
either parallel or synergistic in vivo
How to Initiate the Ketogenic diet
Patient selection
Before staring the KD, parental education about the nature of
the diet, side effects and benefits is very important. One must
ensure that the family is committed to a trial of the diet and have
resources available. Meeting a dietician prior to staring the diet
is essential. All prescription medications should be changed to
carbohydrate free or lowest carbohydrate content forms.
Information about over the counter products that have low or no
carbohydrates is also provided to families (http://www.charlie
html). Patients and families should understand that once started,
this diet has to be followed closely otherwise its beneficial effect
is lost
There are two specific metabolic conditions in which the KD
has unique efficacy, glucose transporter-1 deficiency and and
pyruvate dehydrogenase deficiency. In these disorders, the
ketogenic diet should be initiated at the time of diagnosis
Contraindications to the KD
Absolute contraindications include metabolic disorders
including pyruvate carboxylase deficiency, primary carnitine
deficiency, defects in fatty acid oxidation including carnitine
transporter defects and porphyria.
Relative contraindications include renal stones and
hyperlipidemia. Thus metabolic screening must be done before
diet initiation
Table 4 outlines the recommended initial and follow-up
laboratory studies for patients initiating and maintaining a
ketogenic diet.
Diet initiation
The diet may be initialed at home in older children when
closely supervised by a dietitian or ketogenic team to guide
them. In young children, or those at higher risk of hypoglycemia
or dietary intolerance, the diet is often initiated in the hospital
under more controlled settings. Children with gastrostomy tubes
can be easily initiated on the diet with good compliance
Fasting is not recommended at the time of initiation as was a
common practice in the past because it may increase the risk of
hypoglycemia and dietary intolerance. The non traditional KD
options, including the modified Atkins and low glycemic index
diets, can be started at home in most children. If the traditional
KD is being used, it is usually started on a 1:1 or 2:1 ratio of
grams of fat to grams of carbohydrate plus protein. That ratio is
advanced slowly to the target ratio. In most children, the target
ratio will be 3-4:1. Ratio is typically based on the degree of
ketosis and seizure control and is different for every child. As
discussed previously the degree of ketosis may be less important
and in the authors experience, it is recommended to decrease the
ratio in patients with significant gastrointestinal intolerance or
difficulty with variety of food selections without fear of losing
efficacy. Calorie restriction to promote ketosis is not
The diet requires that patients are maintained on calcium and
multivitamin supplementation (carbohydrate free formulation) as
the diet is inherently nutritionally incomplete.
Duration of KD
We recommend trying the diet for a minimum period of two
to three months, with achievement of at least moderate (> 80–
160 mg/dl) urinary ketosis to determine if the diet will be
effective. If the diet is effective, it is usually continued for one to
two years, and then gradually weaned. There is considerable
variation in practice for the duration of use of KD. In certain
syndromes that are likely to relapse after diet weaning, long term
use of ketogenic diet is done. Successful use of KD for as long
as 12 years in children has been published
. In such cases
gradual transition of the diet to modified Atkins diet or low
glycemic index treatment can be done. The side effects of the
long term use of the diet must be carefully weighed against the
risk of discontinuation of the diet in patients with intractable
Side Effects (Table 5)
The traditional KD has more problems with tolerability that
the modified versions. A common reason for discontinuation of
the diet is felt to be the “too restrictive nature” of the traditional
Acute side effects that can occur immediately upon starting
the diet include nausea and vomiting, hypoglycemia, excessive
ketosis and acidosis and lethargy
. The risk of hypoglycemia is
most frequent in the infants and young children who cannot
maintain adequate caloric intake and have frequent vomiting.
Intolerance due to gastrointestinal side effects is most common
reason for the early discontinuation of the diet especially in
Chronic complications include constipation, renal stones due
to increased urine calcium/creatinine ratio, cardiomyopathy due
to combination of acidosis and selenium deficiency
, retarded
growth, weight loss, anorexia, progressive bone mineral content
, high cholesterol levels, low albumin and carnitine levels
(especially when used in combination with valproate)
, higher
chances of infection, specific vitamin and/or mineral
deficiencies (example selenium) if not properly supplemented
and rarely fatal pancreatitis in those with abnormal lipid
. Though there have been a few cases describing
prolonged QT interval on electrocardiogram (EKG) and sudden
death in KD
, a systematic study on 27 children (six months-
Screening laboratory work before KD initiation
acylcarnitine, lactate, fasting lipid profile
organic acids, calcium/creatine ratio, urinalysis
Laboratory work to be performed at follow up
Blood (every 3 months)
complete blood count, electrolytes including calcium, magnesium, phosphorus,
albumin, lipase, selenium, alkaline phosphatase, 25-hydroxyvitamin D, fasting
lipid profile, carnitine (if on valproate), beta-hydroxybutyrate levels.
Urine (every 3 months)
urinalysis, calcium/creatinine ratio
Echocardiogram (annually)
Table 4: Laboratory studies suggested at initiation and during therapy with the ketogenic diet
Volume 40, No. 2 March 2013 165
five years) did not find any statistically significant change in the
corrected QT interval over one year time period
Use of KD in other diseases
A mouse model of malignant glioma has been used to study
the effects of KD. Animals fed KD had elevated levels of β-
hydroxybutyrate (p = 0.0173) and an increased median survival
of approximately five days relative to animals maintained on a
standard diet. In 9 of 11 animals treated with KD plus radiation,
the tumor cells diminished below the level of detection
(p<0.0001). Thus, based on animal studies, KD significantly
enhanced the anti-tumor effect of radiation, suggesting that it
may be useful as an adjuvant to the current standard of care for
the treatment of human malignant gliomas
. A case series of two
pediatric patients with anaplastic astrocytoma showed that KD
treatment was associated with decreased tumor glucose
metabolism as assessed by positron emission tomography (PET).
These preliminary results suggest a potential for clinical
application which merits further research
The medium chain triglyceride diet has been shown to reduce
the velocity of cortical spreading depression in a rat model of
. The modified Atkins diet has been studied in patients
with chronic daily headache and may have promise
A pilot, prospective follow-up study of a six month trial of the
KD in 30 children, aged 4-10 years, with autistic behavior
showed that 18 (60%) had improvement in several parameters on
the childhood autism rating scale
. These data are very
preliminary and a significant limitation is lack of a control
group. Further studies are needed before this therapy should be
considered for autism.
Head trauma
It has been shown in animal models of traumatic brain injury
that treatment with KD reduces cortical contusion volumes that
correlate well with beta hydroxybutyrate levels in serum;
suggesting a neuroprotective effect of the diet. Human studies
are needed before this therapy is considered in traumatic brain
injury patients
In conclusion, there is emerging evidence that KD may be
useful in a broad range of neurological disorders. However,
further studies are needed prior to accepting this as standard
therapy; underlying mechanism remains to be clearly
Most individuals who develop epilepsy will respond to
pharmacologic treatment, however, approximately 20%–30%
are pharmacoresistent
. For this population, KD can be highly
efficacious and should be considered early, as further
antiepileptic drug trials have low rates of success. Based on the
evidence that is reviewed and authors experience, KD should be
offered to both children and adults with intractable epilepsy that
is not potentially treatable with surgical options.
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Seizures and epilepsy can result from various aetiologies, yet the underlying cause of several epileptic syndromes remains unclear. In that regard, autoimmune-mediated pathophysiological mechanisms have been gaining attention in the past years and were included as one of the six aetiologies of seizures in the most recent classification of the International League Against Epilepsy. The increasing number of anti-neuronal antibodies identified in patients with encephalitic disorders has contributed to the establishment of an immune-mediated pathophysiology in many cases of unclear aetiology of epileptic syndromes. Yet only a small number of patients with autoimmune encephalitis develop epilepsy in the proper sense where the brain transforms into a state where it will acquire the enduring propensity to produce seizures if it is not hindered by interventions. Hence, the term autoimmune epilepsy is often wrongfully used in the context of autoimmune encephalitis since most of the seizures are acute encephalitis-associated and will abate as soon as the encephalitis is in remission. Given the overlapping clinical presentation of immune-mediated seizures originating from different aetiologies, a clear distinction among the aetiological entities is crucial when it comes to discussing pathophysiological mechanisms, therapeutic options, and long-term prognosis of patients. Moreover, a rapid and accurate identification of patients with immune-mediated epilepsy syndromes is required to ensure an early targeted treatment and, thereby, improve clinical outcome. In this article, we review our current understanding of pathogenesis and critically discuss current and potential novel treatment options for seizures and epilepsy syndromes of underlying or suspected immune-mediated origin. We further outline the challenges in proper terminology.
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Background The data on the effect of dietary fiber on severe headaches or migraine are limited. Therefore, this study aimed to investigate the association between dietary fiber intake and the prevalence of severe headaches or migraine. Methods We conducted a cross-sectional study involving 12,710 participants, all data collected from NHANES 1999–2004. A multivariable logistic regression model was used to analyze the relationship between dietary fiber intake (as an independent variable) and severe headaches or migraine (as outcome variable). We also performed sensitivity analyses, including multiple sensitivity analyses. Results The overall incidence of severe headache or migraine in the study was 2527/12,710 (19.9%). After adjusting for correlation covariates, we found a significant inverse association between dietary fiber intake and severe headache or migraine, with lowest prevalence in the fifth quintile (OR: 0.74, 95% CI: 0.61–0.90). Our study also revealed that for every 10 g/day increase in dietary fiber intake, the prevalence of severe headache or migraine decreased by 11%. However, no such inverse association was found among Mexican Americans, other races, or those with a body mass index (BMI) of 25–30. E -value analysis suggested robustness to unmeasured confounding. Conclusion Increasing the intake of fiber-rich foods might protect from severe headache or migraine. More prospective studies should be conducted to confirm their association before dietary recommendations.
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Over the past few years, the interest in the application of the ketogenic diet (KD) for obesity management is growing. Although many studies have been performed on the effects of KD, the metabolic and physiological impact of KD is still not fully understood. Therefore, this study aimed to evaluate the effect of calorie-restricted KD on the body weight and composition, oxidative stress, and advanced glycation end products (AGEs) assessed in an animal model with young Wistar rats. KD was followed for 4 weeks in maturity after an obesity-inducing high-fat diet during adolescence, resulting in a slowing down of the weight gain but higher adiposity compared to a standard diet. Increased adiposity resulted in an deterioration of liver parameters, suggesting negative changes in this organ. No adverse effects of KD were determined in haematological parameters in young rats. KD did not affect AGEs; however, a decrease in oxidative stress was observed. Based on the presented results, it can be concluded that KD applied for weight loss in obesity induced in adolescence may reduce oxidative stress without compromising the haematological status; however, caution may be required to control adiposity, glucose level and liver health. Thus, KD therapy should be carefully controlled, especially in young subjects.
Introduction: Ketogenic diet (KD) therapy has been used as a dietary intervention in drug-resistant epilepsy for several years. Research currently suggests that KD therapy may carry neuroprotective and cognition enhancing effects for individuals with non-epileptic conditions as well as for healthy individuals. Therefore, KD may have potential as a non-invasive, nutritional treatment approach for difficult to manage conditions such as neurodegenerative illnesses or mood disorders. The aim of this review is to summarize the available evidence on ketogenic interventions and the resulting cognitive outcomes. Materials and Methods: The paper was based on PRISMA 2020 guidelines. The search was conducted in June 2021 on the following databases: CENTRAL, PubMed, EMBASE, PsycInfo, Web of Science. The search yielded 2014 studies, of which 49 were included. Results: There were 22 animal studies assessing murine models and 27 studies on humans. The primary indications in these studies were epileptic conditions, neurodegenerative disorders, cognitive impairment, and healthy populations. Discussion: Administration of KD seems to confer cognitive-enhancing effects in areas such as working memory, reference memory and attention. Studies found that KD treatment in animals has the potential to alleviate age-related cognitive decline. Over 80% of the 27 human studies reported a favourable effect of intervention, and none reported a detrimental effect of KD. While these findings suggest that KD may improve the functioning of certain cognitive domains, definitive conclusions were limited by studies with small sample sizes, the absence of controls and randomization, and the lack of objective measures of cognition.
Mitochondrial biogenesis, turnover, and function are metabolically active cellular processes that play crucial roles in regulating organism health and longevity. Mitochondrial metabolism is modulated by dietary interventions such as caloric restriction (CR), the oldest strategy known to promote health span and lifespan effectively, or intermittent fasting, and a plethora of CR mimetics used to emulate its beneficial effects. This chapter will review the mitochondrial pathways induced by dietary restriction regimes, their stimulation by CR mimetics, and their contribution to enhancing resilience to age-associated diseases.
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Mitochondria are considered the 'powerhouses' of cells, generating the essential energy in the form of adenosine triphosphate that they need for their energy demands. Nevertheless, their function is easily adaptable as regards the energy demands and the availability of chemical substrates. This allows cells to buffer sudden changes and reassure cellular metabolism, growth or survival. currently, humans have different dietary habits, which provide several stimuli to the cell. According to the energy substrate availability due to the diet quality and diet temporality, mitochondrial physiology is greatly affected. The present review article aimed to collect all the available information that has been published to date concerning the impact of five different popular diets (high-fat diet, ketogenic diet, fasting, caloric restriction diet and the Mediterranean diet) on specific mitochondrial physiological aspects, such as function, biogenesis, mitophagy and mitochondrial fission/fusion.
This review discusses the effects and mechanisms of ketogenic diet on neurodegenerative diseases on the basis of available evidence. A ketogenic diet refers to a high-fat, medium-protein, and low-carbohydrate diet that leads to a metabolic shift to ketosis. This review systematically summarizes the scientific literature supporting this effective treatment approach for neurodegenerative diseases, including effects on mitochondrial function, oxidative stress, neuronal apoptosis, neuroinflammation, and the microbiota–gut–brain axis. It also highlights the clinical evidence for the effects of ketogenic diet in the treatment of Alzheimer's disease, Parkinson's disease, and motor neuron disease. Finally, it discusses the common adverse effects of ketogenic therapy. Although the complete mechanism of ketogenic diet in the treatment of neurodegenerative diseases remains to be elucidated, its clinical efficacy has attracted many new followers. The ketogenic diet is a good candidate for adjuvant therapy, but its specific applicability depends on the type and the degree of the disease.
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Background The ketogenic diet (KD) has anti-tumor and anti-diabetic effects in addition to its anti-epileptic role. It could also improve cardiac function and attenuate neurological insult. However, the effect of KD on blood perfusion or tissue recovery after ischemia remains largely unknown. Thus, we observed blood flow and ischemic tissue recovery following hind limb ischemia (HLI) in mice. Methods C57 mice were fed with either a KD or normal diet (ND) for 2 weeks, before inducing hind limb ischemia, blood perfusion of ischemic limb tissue was observed at 0, 7, and 21 days post operation. Results KD not only decreased blood perfusion of ischemic limb tissue but also delayed muscle recovery after ischemia, induced muscle atrophy of non-ischemic tissue compared to mice fed with ND. Furthermore, KD delayed wound healing at the surgical site and aggravated inflammation of the ischemic tissue. At the cellular level, KD altered the metabolic status of limb tissue by decreasing glucose and ketone body utilization while increasing fatty acid oxidation. Following ischemia, glycolysis, ketolysis, and fatty acid utilization in limb tissue were all further reduced by KD, while ketogenesis was mildly increased post KD in this mice model. Conclusion The KD may cause impaired tissue recovery after ischemia and possible muscle atrophy under a prolonged diet. Our results hint that patients with limb ischemia should avoid ketogenic diet.
Objective: The ketogenic diet (KD) is a high-fat, adequate-protein, and low-carb diet. Ketone bodies increase in the blood due to low carbohydrate content and high-fat content in the diet. The most important feature of the ketogenic diet is that it causes the production of ketone bodies in the liver. Ketone bodies are an alternative fuel to glucose for the brain and form the structure necessary for the cell membrane and biosynthesis of triglycerides. The ketogenic diet provides evidence on seizure control with anticonvulsant effects. In this review, the positive/negative effects of KD on seizure control, place, importance, quality of life, cognition, and behavior in the treatment of resistant epilepsy were examined. Methods: Scientific information on the subject was obtained from the literature accessed through databases such as MEDLINE, Embase, Web of Science, Cochrane Central,, PubMed, Science Direct, and Google Scholar. Results: Although it has started to be used as a treatment method in many diseases today, the main area of effect of KD is drug-resistant epilepsy. In order for the ketogenic diet to be successful in these patients, it is necessary to choose the appropriate patient, medical treatment and diet plan, inform the patient sufficiently, and perform frequent monitoring in accordance with the follow-up criteria. It is argued that KD is one of the most effective treatments for epilepsy. Conclusion: The fact that KDs generally have a restricted diet pattern, the need for supplementation, biochemical findings and possible side effects raise the issue of diet sustainability. More clinical studies are needed to generalize.
Temporal lobe epilepsy (TLE) is a neurological disorder affecting millions of people worldwide and currently represents the most common form of focal epilepsy. Thus, the search for aetiological and pathophysiological parameters of TLE is ongoing. Preclinical work and post-mortem human studies suggest adult hippocampal neurogenesis as a potentially relevant factor in TLE pathogenesis. Although progress has been made in elucidating the molecular links between TLE and hippocampal neurogenesis, recent evidence suggests that additional peripheral mediators may be involved. The microbiota-gut-brain axis mediates bidirectional communication between the gut and the brain and could comprise a link between neurogenesis and TLE. In this review, we discuss emerging evidence highlighting a potential role for the gut microbiome in connecting TLE pathogenesis and hippocampal neurogenesis. We focus in particular on mechanisms associated with neuronal excitability, neuroinflammation and gut microbial metabolites. As the evidence does not yet support a direct link between gut microbiota-regulated hippocampal neurogenesis and TLE aetiology or pathophysiology, future studies are needed to establish whether current findings comprise circumstantial links or a potentially novel avenue for clinically relevant research.
This is the report on the first Italian experience with the low glycemic index diet (LGIT) in a group of children, adolescents and young adults with refractory epileptic encephalopathies. A retrospective chart review was performed on patients initiating the LGIT in an outpatient setting from 2005 to 2010. Demographic and clinical information including seizure type, baseline seizure frequency, medications, blood chemistry, side effects, and anthropometrics were collected. Patients were educated and followed by a dietician to restrict foods with high glycemic index and to limit total daily carbohydrates to 40-60 g. Change in seizure frequency was assessed at each 3 month follow-up intervals in the first year and then at each 6 month intervals. Fifteen consecutive patients (13 males and 2 females, aged between 11.3 years and 22 years), almost all affected by generalized cryptogenic or symptomatic refractory epilepsy, were enrolled in the study. After a mean follow-up period of 14.5 ± 6.5 months (median 12.0; range 1-60 months), 6 patients (40%) had a 75-90% seizure reduction, while seizures decreased by 50% in other 2 (13.3%) and were unchanged in 7 (46.7%). The diet was discontinued in 4 patients within the first 5 months. No adverse events occurred during the diet. In conclusion, this initial experience confirms that some refractory patients may improve on the LGIT, even as first dietary option.
Long-term outcomes of the ketogenic diet in the treatment of epilepsy have not previously been reported. A retrospective chart review of children treated with the ketogenic diet for more than 6 years at the Johns Hopkins Hospital was performed. The response was documented at clinic visits and by telephone contacts; laboratory studies were obtained approximately every 6 to 12 months. Satisfaction and tolerability were assessed by means of a brief parental telephone questionnaire. In all, 28 patients (15 males, 13 females), currently aged 7 to 23 years, were identified. The median baseline seizure frequency per week at diet onset was 630 (range 1–1400). Diet duration ranged from 6 to 12 years; 19 remain on the diet currently. After 6 years or more, 24 children experienced a more than 90% decrease in seizures, and 22 parents reported satisfaction with the diet's efficacy. Ten children were at less than the 10th centile for height at diet initiation; this number increased to 23 at the most recent follow-up (p=0.001). Kidney stones occurred in seven children and skeletal fractures in six. After 6 years or more the mean cholesterol level was 201mg/dl, high-density lipoprotein was 54mg/dl, low-density lipoprotein was 129mg/dl, and triglycerides were 97mg/dl. Efficacy and overall tolerability for children are maintained after prolonged use of the ketogenic diet. However, side effects, such as slowed growth, kidney stones, and fractures, should be monitored closely.
To determine the efficacy of the ketogenic diet in multiple centers. A prospective study of the change in frequency of seizures in 51 children with intractable seizures who were treated with the ketogenic diet. Patients were enrolled from the clinical practices of 7 sites. The diet was initiated in-hospital and the patients were followed up for at least 6 months. Fifty-one children, aged 1 to 8 years, with more than 10 seizures per week, whose electroencephalogram showed generalized epileptiform abnormalities or multifocal spikes, and who had failed results when taking at least 2 appropriate anti-epileptic drugs. The children were hospitalized, fasted, and a 4:1 ketogenic diet was initiated and maintained. Frequency of seizures was documented from parental calendars and efficacy was compared with prediet baseline after 3, 6, and 12 months. The children were categorized as free of seizures, greater than 90% reduction, 50% to 90% reduction, or lower than 50% reduction in frequency of seizures. Eighty-eight percent of all children initiating the diet remained on it at 3 months, 69% remained on it at 6 months, and 47% remained on it at 1 year. Three months after initiating the diet, frequency of seizures was decreased to greater than 50% in 54%. At 6 months, 28 (55%) of the 51 initiating the diet had at least a 50% decrease from baseline, and at 1 year, 40% of those starting the diet had a greater than 50% decrease in seizures. Five patients (10%) were free of seizures at 1 year. Age, sex, principal seizure type, and electroencephalogram were not statistically related to outcome. The ketogenic diet is effective in substantially decreasing difficult-to-control seizures and can successfully be administered in a wide variety of settings.