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of Child Neurology

Application of a Ketogenic Diet in Children With Autistic Behavior: Pilot Study

Athanasios Evangeliou, Ioannis Vlachonikolis, Helen Mihailidou, Martha Spilioti, Astrinia Skarpalezou, Nikolaos Makaronas,
Ahilleas Prokopiou, Panagiotis Christodoulou, Georgia Liapi-Adamidou, Emmanouel Helidonis, Stylianos Sbyrakis and Jan
Smeitink
J Child Neurol 2003 18: 113
DOI: 10.1177/08830738030180020501

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Original Article

Application of a Ketogenic Diet in Children With

Autistic Behavior: Pilot Study
Athanasios Evangeliou, MD; Ioannis Vlachonikolis, MD; Helen Mihailidou, MD; Martha Spilioti, MD;
Astrinia Skarpalezou, MD; Nikolaos Makaronas, MD; Ahilleas Prokopiou, MD; Panagiotis Christodoulou, MD;
Georgia Liapi-Adamidou, MD; Emmanouel Helidonis, MD; Stylianos Sbyrakis, MD; Jan Smeitink, MD

ABSTRACT

A pilot prospective follow-up study of the role of the ketogenic diet was carried out on 30 children, aged between 4 and
10 years, with autistic behavior. The diet was applied for 6 months, with continuous administration for 4 weeks, inter-
rupted by 2-week diet-free intervals. Seven patients could not tolerate the diet, whereas five other patients adhered to the
diet for 1 to 2 months and then discontinued it. Of the remaining group who adhered to the diet, 18 of 30 children (60%),
improvement was recorded in several parameters and in accordance with the Childhood Autism Rating Scale. Significant
improvement (> 12 units of the Childhood Autism Rating Scale) was recorded in two patients (pre-Scale: 35.00 ± 1.41[mean
± SD]), average improvement (> 8–12 units) in eight patients (pre-Scale: 41.88 ± 3.14[mean ± SD]), and minor improve-
ment (2–8 units) in eight patients (pre-Scale: 45.25 ± 2.76 [mean ± SD]). Although these data are very preliminary, there is
some evidence that the ketogenic diet may be used in autistic behavior as an additional or alternative therapy. (J Child
Neurol 2003;18:113–118).

Wilder first introduced the ketogenic diet as a therapeutic hood epilepsy was rekindled. Further progress in the basic
method for epileptic seizures in 1921. The implementation sciences has established a clear understanding of the ways
of the ketogenic diet was based on clinical observation that in which ketone bodies affect the central nervous system,
fasting had beneficial effects in the control of epileptic and, as a result, the ketogenic diet is being used as one of
seizures.1 With the widespread use of modern antiepilepsy a number of therapeutic means for epilepsy in all major
drugs, the ketogenic diet was not applied until the end of epilepsy centers.2– 4
the 1970s, when interest in its use for the treatment of child- There have also been reports of application of a keto-
genic diet for patients with Rett syndrome. Ketogenic diets
were used for these patients primarily for the control of
seizures, but it has been found that, in addition, the Ketogenic
diet is beneficial for mental behavior and hyperactivity.5,6
Received Aug 15, 2002. Received revised Dec 17, 2002. Accepted for publi- Apart from epilepsy, ketogenic diets have been used
cation Dec 18, 2002. in cancer patients, in whom this diet seems to have a
From the Department of Paediatrics (Drs Evangeliou, Mihailidou, and retarding effect on tumor progress by affecting glucose
Sbyrakis), Medical School, University of Crete, Crete, Greece; Department
of Neurology (Dr Spilioti), Medical School, University of Crete, Crete, metabolism at the tumor site,7,8 and has also been applied
Greece; Biostatistic Laboratory (Dr Vlachonikolis), University of Crete, in the treatment of patients with pyruvate dehydrogenase
Heraklion, Crete, Greece; Institute of Child Health (Dr Skarpalezou), deficiency.9
Children’s Hospital Agia Sofia, Athens, Greece; Center of Mental Health (Dr
Makaronas), Heraklion, Crete, Greece; Center of Mental Health (Dr On Crete, an island of Greece, with a relatively secluded
Prokopiou), Chania, Crete, Greece; Department of Ear, Nose and Throat and isolated population, there is a significant number of
(Dr Helidonis), Medical School, University of Crete, Crete, Greece; Second patients with autistic behavior.10 Furthermore, as part of
Department of Pediatrics (Dr Liapi-Adamidou), University of Athens, Athens,
Greece; Department of Pediatrics (Dr Smeitink), University Hospital metabolic testing, we recorded high levels of blood ketone
Nijmegen, Nijmegen, The Netherlands. bodies following glucose loading tests in some of the patients
Address correspondence to Dr Athanasios Evangeliou, Department of we studied. It is possible that these patients harbor a dis-
Paediatrics, University Hospital of Heraklion, POB 1352, Heraklion 71110, turbance somewhere in mitochondrial energy production,
Crete, Greece. Tel: +30 81392326; fax: +30 81392827; e-mail:
evangeli@med.uoc.gr. leading to an excess of reduced nicotinamide adenine

113

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114 Journal of Child Neurology / Volume 18, Number 2, February 2003

Table 1. Classification of Autism Scale

1. Disorder in human relationship (No appreciation by the individual of the interest that other people show for him/her)
2. Mimicking (the extent to which the patient mimics)
3. Improper emotions (eg, the unsuitable timing of emotions such as laughing and crying)
4. Bizarre use of bodily movements and persistence to stereotypy
5. Peculiar relations with objects (eg, correct use of objects)
6. Resistance to changes in the environment
7. Idiosyncratic optic reactions (eg, avoidance of eye contact)
8. Idiosyncratic acoustic reactions (avoidance of or exaggerated reaction to noise)
9. Putting objects in mouth, licking, smelling, and rubbing
10. Stress reactions (eg, intensity of repression)
11. Verbal communication (eg, lack of speech, echolalia, replacement of personal pronouns)
12. Nonverbal communication (eg, use of or response to gestures)
13. Extreme levels of activity (eg, apathy or hyperactivity)
14. Mental function (lack of homogeneity of cognitive characteristics)
15. General impressions (eg, general ranking)
Ranking of symptoms: 1 = normal for age; 2 = mild disorder; 3 = moderate disorder; 4 = serious disorder.

dinucleotide (NADH) or a lack of nicotinamide adenine metric data collection, hearing examination with audiogram and audi-
dinucleotide (NAD). This is particularly true in the post- tory evoked potentials, ophthalmologic examination with funduscopy,
absorptive period, when more NAD is required to adequately and optical acuity testing. Following these, a detailed laboratory inves-
oxidize glycolytic substrate (eg, if the citric acid cycle is tigation was performed, including the following: complete blood
hampered, ketone body synthesis increases after meals owing count, biochemical tests (electrolytes, blood glucose, transami-
to channeling of acetyl coenyzme A toward ketogenesis).11,12 nases, cholesterol, triglycerides, thyroid hormones), electro-
Thus, for the children of our study, we hypothesize that cardiogram, and alert-phase electroencephalogram (EEG). Finally,
the application of a ketogenic diet should produce an more specific examinations were performed, such as determination
improved mitochondrial function by sparing NAD, which of amino acid carnitine, serum purine and pyrimidine, urine amino
will be consumed in the oxidation of glycolytic substrates. On acids, organic acids, and glucose challenge.14 Specifically, following
the basis of these observations and also from other research 8 hours of fasting, blood was drawn for the determination of lactic
on disturbed glucose metabolism in autism, we proceeded acid, pyruvate, and β-hydroxybutyric acid, which was followed by
to administer a ketogenic diet to children with autistic the administration of a dose of a 10% glucose solution (2 g/kg of body
behavior.13,14 weight; maximum dose 50 g). Following the glucose loading, blood
was drawn at 60 minutes for the assessment of the same
MATERIALS AND METHOD parameters.
Following this detailed investigation, the parents’ consent was
Thirty children with autistic behavior (16 boys and 14 girls, between obtained to have the children placed on a ketogenic diet. The rec-
4 and 10 years of age; median age 7 years) participated in a 1-year ommended diet was the John Radcliffe diet, which distributes daily
prospective study of the role of a ketogenic diet in autistic behav- energy intake as follows: 30% of energy as medium-chain triglyceride
ior. The children were admitted to the Pediatric Clinic of the Uni- oil, 30% as fresh cream, 11% as saturated fat, 19% as carbohydrates,
versity Hospital of Heraklion, Crete, during the period from May 1999 and 10% as protein. Patients also received vitamin and mineral sup-
to May 2000. All patients were concurrently treated with haloperi- plements according to the recommended daily allowances for age.16,17
dol. The children of this study were treated with haloperidol at least In this diet, 30% of total energy is derived from medium-chain triglyc-
6 months before the initiation of a ketogenic diet without having any erides. The John Radcliffe diet is a variation of the medium-chain
changes in the Childhood Autism Rating Scale. During and 6 months triglyceride diet and is easy to manage practically. The classic keto-
before and after the diet, no behavioral treatments were given. The genic diet is very restrictive and requires a large amount of dietetic
haloperidol treatment was continued after the diet was completed, involvement in terms of calculations, monitoring, patient support,
but no increased dosage was needed for the children who, during and motivation from the family to adhere to the diet; consequently
the diet, diminished or stopped the medication. it is difficult to adapt the diet for children with mental retardation.
Before admission to the hospital, all subjects were referred to The diet was executed for 6 months with continuous administration
a child psychiatrist for a general psychiatric evaluation according for 4 weeks at a time, interrupted by 2-week intervals that were diet
to the Childhood Autism Rating Scale as this was adapted by Schopler free. Laboratory examinations, including a complete blood count and
et al in 1980.15 According to this scale, scores between 30 and 36 indi- the assessment of serum electrolytes, carnitine, and β-hydroxybu-
cate mild to moderate cases, whereas scores of 37 and over indicate tyric acid, were performed at the end of each 4-week diet phase and
severe cases (Table 1). Although the child psychiatrist was aware at the end of each 2-week interval diet-free phase. Family urine
of the current study, he evaluated and followed up all of the enrolled ketones were estimated every afternoon using ketone urine strips
autistic children, who were among others with autistic behavior, with- (Ketostix, Firma Bayer). The readings were kept and referred to the
out knowledge of which of the children were included in the study. dietitian with the diet records (including fluid intake). If the child
At the time of admission, all of the children had to undergo a was not toilet trained, the strips were used on his/her wet diaper at
detailed clinical pediatric and psychiatric examination, somato- the same time every day.

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 Ketogenic Diet in Children With Autism / Evangeliou et al 115

Table 2. Patients With Pathologic Increased β-Hydroxybutyrate

After GLT Values in mmol/L
β-Hydroxybutyrate β-Hydroxybutyrate
Patient Before GLT After GLT
1 1.45 1.82
2 1.05 1.49
3 1.23 1.65
4 1.45 1.88
5 1.30 1.45
6 1.15 1.34
GLT = glucose loading test.

Following the completion of the diet, children were followed

up for 6 months and were submitted to a monthly psychiatric
examination. As an assessment criterion, we set an optimistic tar-
get of 50% diet tolerance, that is, continuation of the diet beyond
4 weeks. In every psychiatric examination, the children were eval-
uated according to the Childhood Autism Rating Scale. The dif-
ference between the baseline and follow-up Childhood Autism
Rating Scale was assessed by the t-test for paired comparisons.18

RESULTS

At the beginning of the study, the pediatric psychiatric eval- Figure 1. Thirty children participated in the study. From the 23 chil-
dren who tolerated the diet, 18 ( 60%) improved according to the Child-
uation according to the Childhood Autism Rating Scale hood Autism Rating Scale (CARS). β-OHb = β-hydroxybutyrate; GLT
yielded 2 patients with scores of 34 and 36, or mild to mod- = glucose loading test.
erate autistic condition, whereas the remaining patients
(28 cases) had scores between 37 and 54, that is, more
severe cases. sented with improvements in their social behavior and inter-
The laboratory and clinical investigations of three chil- actions, speech, cooperation, stereotypy, and, principally,
dren indicated increased levels of 3-hydroxy-isovaleric acid; hyperactivity, which contributed significantly to their
however, no evidence of biotinidase or multiple carboxylase improvement in learning.
deficiency was established in any of these cases, and none Specifically, of the 18 patients who tolerated a ketogenic
of these patients was under valproate treatment. Patho- diet for the entire recommended duration, 2 boys experi-
logic levels of β-hydroxybutyrate were recorded following enced the most significant improvement, with a reduction
glucose loading in six children (Table 2). This is indicative of more than 12 units on the Childhood Autism Rating Scale.
of a disorder of oxidative phosphorylation with consequent This improvement was so significant that the children could
increase in the concentration of reducing equivalents in attend a school for non–mentally handicapped children.
both mitochondria and cytoplasm and in the functional Eight patients (six boys and two girls) experienced average
impairment of the citric acid cycle, owing to the excess of improvement (8–12 units on the Childhood Autism Rating
NADH and the lack of NAD. Therefore, an increase in the Scale) and eight (four boys and four girls) displayed minor
ketone body (3-hydroxybutyrate) might be expected in the improvement (2–8 units on the Childhood Autism Rating
plasma of affected individuals, especially in the postab- Scale) (Figure 1). Interestingly patients who did not toler-
sorptive period, when more NAD is required to adequately ate or had their diet interrupted early belonged to the cat-
oxidize glycolytic substrates.11,12 In these particular cir- egory of severe cases with Childhood Autism Rating Scale
cumstances, the ketogenic diet would assist an improved scores above 50.
mitochondrial function by reducing the flow of glycolytic It is also noted that the two patients displaying the
substrates in the Krebs cycle.11,12 There were no abnormal greatest improvement were the patients with mild autis-
findings in the remaining 21 children. tic behavior (16 and 13 units on the Childhood Autism
Twenty-three patients (76.6%) tolerated the diet beyond Rating Scale, respectively). In contrast, the 16 patients
4 weeks, whereas the remaining seven patients (23.3%) with severe autistic behavior who completed the diet dis-
could not. Thus, the diet tolerance was 76.6%, significantly played moderate or minor improvement (average 7.1 units)
higher than the set target of 50% (Z = 3.759; P <.001). Of these (Table 3). These latter patients, although belonging to the
23 patients, 5 discontinued application after 4 to 10 weeks severe autism group, had lower initial Childhood Autism
owing to lack of improvement. The remaining 18 patients Rating Scale scores compared with those who did not tol-
(60%), who concluded the diet for a 6-month period, pre- erate or interrupted their diet (43.6 and 52.7 average units,

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116 Journal of Child Neurology / Volume 18, Number 2, February 2003

Table 3. Patients With Improvement After a Ketogenic Diet

Significant improvement (CARS: > 12 units) 2: Pre-CARS: 35.00 ± 1.41 (mean ± SD)
Average improvement (CARS: > 8–12 units) 8: Pre-CARS: 41.88 ± 3.14(mean ± SD)
Minor improvement (CARS: 2–8 units) 8: Pre-CARS: 45.25 ± 2.76(mean ± SD)
CARS = Childhood Autism Rating Scale.

respectively). The overall average improvement (based only a small percentage of parents reported marked changes
on all 30 patients) in terms of the Childhood Autism Rat- in their child’s behavior after the diet application.
ing Scale, was 4.77 (standard error = 0.89); the result is higly The application of a ketogenic diet for children with
significant (t = 5.347; df = 29; P < .001). autistic behavior constitutes an attempt to find an addi-
Regarding the six children with a pathologic increase tional or alternative treatment for children who show min-
of β-hydroxybutyrate after glucose challenge, one was the imal or no improvement with the conventional methods of
one with the most significant improvement in the study. This treatment.
child underwent muscle biopsy for identification of possi- In this study, the application of a ketogenic diet was
ble mitochondrial disorder, which was negative. In another highly successful for the two patients with mild autistic
two patients, average improvement was observed, whereas behavior, whereas minor or moderate improvement was
one child showed minor improvement. The last two patients established in patients with severe autistic behavior. We
of this group were part of the five patients who discontin- note that higher improvement was seen in children with
ued the ketogenic diet owing to lack of improvement. lower initial Childhood Autism Rating Scale scores, although
Regarding the three children with increased levels of 3- they belonged to the severe autism group.
hydroxy-isovaleric acid, two of them with Childhood Autism The patients in this study received the John Radcliffe
Rating Scale scores over 40 were among the patients who ketogenic diet. This particular diet is considered the most
did not tolerate the diet at all, and one was among the chil- acceptable by children and most easy to use at home while
dren without improvement who interrupted the diet after simultaneously achieving very satisfactory levels of ketosis.
1 month. The John Radcliffe diet is a variation of the medium-chain
The values of β-hydroxybutyrate in serum were main- triglyceride diet and is easy to manage practically. The clas-
tained at 1.8 to 2.2 mmol/L during the ketogenic diet phase sic ketogenic diet is very restrictive and requires a large
and 0.8 to 1.5 mmol/L during the diet-free phase. From all amount of dietetic involvement in terms of calculations,
ketones, β-hydroxybutyrate is largely metabolized in the monitoring, patient support, and motivation from the fam-
body, is easy to assess in the blood, and is excreted in the ily to adhere to the diet; consequently, it is difficult to adapt
urine, giving also the positive ketone urine strips test. So β- for children with mental retardation.24 Nevertheless, the
hydroxybutyrate readings in serum reflect the ketosis lev- John Radcliffe diet is still a restrictive and arduous diet
els we reached. Low readings of β-hydroxybutyrate (< 1.7 when adhered to with absolute precision. The detailed and
mmol/L) indicate that we have not reached the ketosis lev- continuous education of parents, as well as their multifac-
els we require to achieve therapeutic results. None of the eted support, was necessary for them to cope with the
adverse effects reported in patients following a ketogenic extremely high demands placed on them by their child’s nutri-
diet were observed during the study period. tion. The percentage (76.6%) of children who tolerated and
Also, no pathologic EEGs were recorded in our patients, adhered to the dietetic guidelines is very satisfactory,
before, during, and 6 months after the diet was discontin- indeed very optimistic, keeping in mind the above-men-
ued. Following termination of the study, all of the children tioned difficulties. The parents invested in this diet for their
had regular follow-up care at a special outpatient child psy- child’s improvement, and their positive attitude acted as
chiatry clinic for 6 months. Monthly follow-up with the a strong motivation for the adherence to the diet. More-
Childhood Autism Rating Scale was repeated at the end of over, the administration of the diet (4-week intervals fol-
the diet and every month after discontinuation of the diet lowed by 2 weeks without the diet) resulted in no
and for 6 months. No significant changes in the Childhood complications, usually described in children on a ketogenic
Autism Rating Scale were recorded. diet. In addition, no other changes were observed in the
Childhood Autism Rating Scale during the diet-free period.
DISCUSSION Two of the 30 patients in this study presented with high
improvement, whereas 6 presented with average improve-
Observations that certain foods may have an effect on the ment, indicating that 26.66% of the patients benefited sig-
behavior in some patients with autism have been made on nificantly from the diet. The overall reduction of the total
many occasions. These observations led to the develop- Childhood Autism Rating Scale, about 5 units, was also a
ment of a variety of dietetic protocols, with the gluten- and significant improvement. The diet proved to be effective
casein-free diets being the most promising.19,20 Many other in diminishing various generalized behaviors as it allowed
dietary interventions have been used, such as the use of vit- the patients to concentrate better and increase their
amin B6 and secretin.21–23 However, in all of these trials, learning abilities.

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 Ketogenic Diet in Children With Autism / Evangeliou et al 117

The children with the most significant improvement content of GABA, showed that the metabolism of ketone bod-
interrupted the pharmacologic treatment, and two of them ies to acetyl coenyzme A results in a decrease of the pool
were able to attend mainstream school. In those with minor of brain oxaloacetate, which is consumed in the citrate syn-
to moderate improvement, a reduction of haloperidol dosage thetase reaction. As less oxaloacetate is available for the
was feasible without aggravation of behavior. An interest- aspartate aminotransferase reaction, thereby lowering the
ing observation was that the beneficial effects of the keto- rate of glutamate transamination, more glutamate becomes
genic diet persisted during the diet-free intervals. Even after accessible to the glutamate decarboxylase pathway, thus
termination of the ketogenic diet, its beneficial actions were favoring the synthesis of GABA.29 Changes in behavior have
maintained for a relatively long duration. We cannot for- also been observed with individuals who have developed
mulate any reasonable hypothesis for this. The question of ketosis during diet for weight reduction.30 Similar observa-
how the diet works remains to be answered. A similar effect tions have been made in laboratory animals on a ketogenic
of the ketogenic diet has been observed in children treated diet.31
for the control of resistant epileptic incidents, who had Our experience provides significant evidence that a
behavioral problems.25 A logical explanation is difficult to ketogenic diet may have its own place in our reserve for
establish because the mechanisms of action of the ketogenic the treatment of autism, in particular for less severe cases.
diet are still not well comprehended. The hypothesis that There is no doubt that this subject needs further investi-
individuals with autistic behavior may have deficient glucose gation. Although the number of patients in this study was
oxidation and therefore use ketone bodies as an alternative small, more than one subgroup was included (increased lev-
energy fuel in the brain is interesting. This hypothesis could els of 3-hydroxyisovaleric acid, increased levels of β-
be supported by the fact that four of the patients studied hydroxybutyrate after glucose loading). This heterogeneity
showed abnormal increase of ketone bodies after a glu- diminishes the ability of this pilot study to generate more
cose loading test, an indication of mitochondrial deficiency. focused hypotheses. The problem is further compounded
No evidence was found, however, of pyruvate dehydroge- by including some children with severe autistic behavior,
nase deficiency, other enzyme deficiency (respiratory chain as measured by the Childhood Autism Rating Scale. Com-
deficiency), or disorder of glucose metabolism in these pliance versus poor response to the treatment seems to
children. What makes things more complicated is the fact make this group less suitable to be studied further. Further
that the ketogenic diet had beneficial effects in patients questions arise concerning the optimal duration and man-
who had normal biochemical parameters after the glucose ner of diet application. Despite these concerns, we believe
loading test. It should be kept in mind, however, that nor- that it is necessary to expand our treatment options for
mal loading with glucose does not necessarily mean normal autistic behaviors and that a ketogenic diet may hold some
glucose oxidation in the brain or absence of mitochondrial promise.
deficiencies. There is the possibility of normal excretion of
lactic acid and other toxic metabolites in cases of mutations
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Correction
Interleukin-1β, Tumor Necrosis Factor-α, and corrections in your copies. The corrected information
Nitrite Levels in Febrile Seizures appears below for clarity.

In Journal of Child Neurology Volume 17, Number 10, Author names on page 749:
October 2002 “Interleukin-1β, Tumor Necrosis Factor-α,
and Nitrite Levels in Febrile Seizures” page 749, one of the Şenay Haspolat, MD; Ercan Mihçi, MD; Mesut Coşkun, PhD;
author names was incorrectly printed as Özbenm. Unfor- Saadet Gümüslü, MD; Tomris Ozben, MD; Olcay Yeğin, MD
tunately, this error was carried through to the author names
index in Volume 17, Number 12, December 2002 on page 926. Author name entry on page 926:
The correct spelling of the name is Ozben; please note these Ozben T, 749

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