DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE

The ketogenic diet improves recently worsened focal epilepsy

1
NATHALIE VILLENEUVE | FLORENCE PINTON MD 2 | NADIA BAHI-BUISSON MD PHD 3 |
MD

OLIVIER DULAC MD 3 | CATHERINE CHIRON MD PHD 3 | RIMA NABBOUT MD PHD 3

1 Henri-Gastaut Hospital, Marseille, France. 2 Kremlin BicÞtre Hospital, Department of Neuropediatrics, Kremlin-BicÞtre, France. 3 Necker-Enfants Malades Hospital,
Department of Neuropediatrics, Centre de rfrence pilepsies rares; Inserm, U663; Paris Descartes University, Paris, France.

Correspondence to Dr Rima Nabbout at Department of Neuropediatrics, Centre de rfrence pilepsies rares, APHP, Necker-Enfants Malades Hospital, 149 rue de
Svres, 75015, Paris, France. E-mail: rimanabbout@yahoo.com, rima.nabbout@nck.aphp.fr

PUBLICATION DATA
Accepted for publication on 15th October
2008.
Published online 3rd February 2009.
AIM We observed a dramatic response to the ketogenic diet in several patients
with highly refractory epilepsy whose seizure frequency had recently worsened.
This study aimed to identify whether this characteristic was a useful indication
for the ketogenic diet.
METHOD From the 70 patients who received the ketogenic diet during a 3-year
period at our institution, we retrospectively selected patients with focal epilepsy.
There were 22 children, 13 females and nine males, aged from 5 months to 18
years 6 months (mean 6y 9mo, SD 5y 11mo). Fifteen had symptomatic and
seven had cryptogenic focal epilepsy. Seizure frequency 1 week before initiating
the ketogenic diet was compared with that at 1 month and at the last visit on the
diet.
RESULTS Eleven patients were responders (defined as reduction of seizures by
more than 50%) at 1 month. Responders were higher (p=0.046) in the group with
a recent worsening of seizures than in those with stable seizure frequency.
Seven patients were still seizure-free at 6 months on the diet. Tolerability was
excellent in 10 patients. Five patients stopped the diet because of early side
effects.
INTERPRETATION The ketogenic diet may be a valuable therapeutic option for
children with pharmacoresistant focal epilepsy, particularly those with a recent
deterioration of seizure control and neurological status. Because of its rapid
effect, the ketogenic diet may be a useful support to intravenous emergency
drugs in such a situation.

The ketogenic diet has, for nearly a century, been repeat-
edly advocated in the treatment of childhood drug-resis-
tant epilepsy.1,2 Many investigators have confirmed the
benefits that this treatment can offer to young patients with
epilepsy,3–6 including infants.7,8
However, the best indications for using the diet have not
been clearly defined since it was shown to be helpful in
treating a large range of different seizure types and epilepsy
syndromes. Special interest has been given to various con-
ditions associated with epilepsy including myoclonic astatic
epilepsy,5,9 infantile spasms,7 Dravet syndrome,10 atypical
absences,11 acquired epileptic aphasia,12 tuberous sclero-
sis,13 and Rett syndrome.14,15 One study found slightly
better results in generalized as opposed to focal epilepsy
although this was not significant.16 Lack of complex focal
seizures was reported as a predictive factor for early, com-
plete, and sustained response.3 However, studies that
addressed the effects of the ketogenic diet according to the
type of seizures or epilepsy failed to identify any significant
difference.17,18 Animal studies have concentrated more on
models for generalized convulsions19,20 than on focal sei-
zures,21 although in both instances ketosis proved to be
efficient. These models failed to generate any hypothesis
regarding possible mechanisms of antiepileptic and anti-
convulsive properties, despite the increase in neurogenesis
after kainic-acid-induced seizures in mice.22 Therefore, the
choice of the best candidate for a ketogenic diet remains to
be determined.

ª The Authors. Journal compilation ª Mac Keith Press 2008

276 DOI: 10.1111/j.1469-8749.2008.03216.x
 We recently observed a dramatic response to the keto-
genc diet in several patients with highly refractory focal
epilepsy, in the setting of recent worsening, mainly in the
form of nearly continuous seizures or status epilepticus. In
order to ascertain whether this characteristic could be of
interest as an indication for the ketogenic diet, we selected
from our ketogenic-diet database a subgroup that was both
exhaustive and as homogeneous as possible regarding the
type of epilepsy. It consisted of children with focal
epilepsy.
METHOD
Ketogenic diet procedure
On initiating the ketogenic diet, we administered the
4:1 ratio of lipid to non-lipid advised by Freeman and
Vining, with the minimum of 1g ⁄ kg proteins, a mean
65ml ⁄ kg ⁄ day liquid, and vitamin supplementations.23
The ketogenic diet was started over a 3-day period,
after 24 hours fasting, during a 5-day admission to hos-
pital. The last day was dedicated to the validation of
parental education. Tube feeding was used for patients
with status epilepticus or very frequent seizures affecting
consciousness. Since this study was done before the
availability of a commercial ketogenic diet (KetoCal,
SHS International Ltd, Fulda, Germany), all patients
had the classic diet used for meals administered by tube
feeding. Clinical and biological follow-up comprised
monitoring of glucose blood levels and ketosis every 4
to 6 hours. Whenever glucose levels fell under 3mmol ⁄ l,
intensive clinical monitoring was performed in order to
detect signs of hypoglycaemia. In patients with very
high seizure frequency, including those with status
epilepticus, a low glucose level (<2.5mmol ⁄ l) was an
indication for glucose administration.
Selection and evaluation of patients
During a 3-year period at our centre, Hôpital Saint
Vincent de Paul, we administered the ketogenic diet to 70
children with drug-resistant epilepsy (treatment failure
after at least three antiepileptic drugs had been given alone
or in combination). In order to identify a frequent and
homogeneous study group, we excluded patients with gen-
eralized epilepsy syndromes, including infantile spasms,
Lennox)Gastaut syndrome, epileptic encephalopathy with
continuous spike waves in slow sleep, myoclonic)astatic
epilepsy, pharmacoresistant absence epilepsy, and other
symptomatic generalized epilepsies. We therefore selected
for this retrospective study the 22 children diagnosed with
symptomatic or cryptogenic focal epilepsy on the basis of
history, clinical examination, and imaging, and who had at
least one focal seizure recorded on an electroencephalo-
gram (EEG).
Ketogenic Diet Improves Recently Worsened Focal Epilepsy Nathalie Villeneuve et al. 277
We distinguished patients who had experienced recent
seizure worsening from those with a stable epileptic condi-
tion. Recent worsening was defined as a more than 100%
increase in seizure frequency during the previous month.
This resulted in very high frequency seizures or status epi-
lepticus, requiring intravenous antiepileptic drugs. At this
point, when the patients had received intravenous drugs
including benzodiazepines, it was no longer possible to dis-
tinguish high-frequency seizures from status epilepticus
because the level of consciousness was altered in both
instances. For this reason, we decided not to make any dis-
tinction and, for the purpose of the study, to label the
whole group as ‘status epilepticus’. The cognitive or motor
impact of such seizure worsening was evaluated on clinical
grounds.
Patients were evaluated during the week before they
started the ketogenic diet, 1 month after introduction of
the diet and at the last visit on the diet. The modification
of seizure frequency after introduction of the ketogenic
diet fell into the following categories: freedom from
seizures; reduction of seizures by more than 50% (both
categories being defined as ‘responders’); and seizure
reduction of 50% or less (defined as ‘non-responders’). For
responders, the ketogenic diet was maintained after 1
month if well tolerated.
Participants
The study group comprised nine males and 13 females
aged from 5 months to 18 years 6 months (mean 6y 9mo,
SD 5y 11mo). Fifteen participants presented with symp-
tomatic epilepsy (focal cortical dysplasia in five patients,
Rasmussen encephalitis in four, sequelae of grey mater
encephalitis in two, and one instance each of polymicro-
gyria, microcephaly with diffuse cortical atrophy, hypo-
melanosis of Ito syndrome, and Sturge)Weber syndrome).
The seven others had cryptogenic epilepsy (including one
with autosomal dominant nocturnal frontal lobe epilepsy).
The age at onset of epilepsy ranged from 1 day to 12 years
(median 2y 7mo). The characteristics of the epilepsy are
given in Table I. On the basis of clinical and EEG reports,
all patients had simple focal seizures, with complex focal
seizures reported in 14, and secondary generalized seizures
in four patients. All patients had daily seizures except one
who suffered from clusters of seizures for 2 to 3 days every
other week.
Ten patients (including seven with symptomatic
epilepsy) had experienced recent seizure worsening with or
without secondary generalization, based on clinical and
EEG assessment. In eight of them, seizure worsening was
associated with negative functional impact consisting of
unilateral (six patients) or bilateral (one patient) motor
and ⁄ or cognitive deterioration (three patients). Patients
 Table I: Patients' clinical data

Age at Age at
epilepsy start of Seizures ⁄ d
Patient Sex onset ketogenic diet Aetiology before diet Functional impact

1a Male 6mo 18y 6mo Ito syndrome Status epilepticus Cognitive deterioration,
hemiplegia
2a Female 6y 10y 6mo Rasmussen disease Very frequent seizures Cognitive deterioration,
hemiplegia
3a Female 1.5mo 2y 6mo Focal cortical dysplasia Very frequent seizures Hemiplegia
4a Female 8y 2mo 8y 4mo Grey-matter encephalitis Status epilepticus Cognitive deterioration,
bilateral hemiplegia
5 Male 6mo 1y Sturge–Weber syndrome Status epilepticus None
6a Female 8y 2mo 16y 8mo Rasmussen disease Very frequent seizures Hemiplegia
7a Female 8mo 3y 5mo Cryptogenic epilepsy Status epilepticus Hemiplegia
8 Female 8d 4y 3mo Cryptogenic epilepsy Very frequent seizures None
9a Female 7y 10y Cryptogenic epilepsy Status epilepticus Hemiplegia
10 Male 12y 16y Rasmussen disease Very frequent seizures None
11a Female 5y 7y 9mo Cryptogenic epilepsy 3 Cognitive deterioration
12a Female 4mo 1y Focal cortical dysplasia 10 None
13 Male 5mo 1y 1mo Focal cortical dysplasia 30 None
14 Male 1d 5mo Focal cortical dysplasia 20 None
15 Male 1y 3y 10mo Focal cortical dysplasia 25 None
16 Male 1d 10mo Polymicrogyria 10 None
17 Female 3y 12y 9mo Rasmussen disease 8 None
18a Female 3mo 4y 8mo Grey-matter encephalitis 5 None
19 Female 2mo 3y 6mo Microcephaly 1.3 None
20 Female 1y 6mo 3y 6mo Cryptogenic epilepsy 10 None
21 Male 10mo 2y 3mo Cryptogenic epilepsy 15 None
22 Male 5y 16y 3mo Autosomal dominant 10 None
nocturnal frontal lobe epilepsy

a
Responders.

were receiving a mean of 2.7 antiepileptic drugs (Table II). patient had pentobarbital for 48 hours with a suppression
After seizure worsening, nine of the 10 patients had burst pattern on EEG. Seizures recurred on withdrawing
received i.v. clonazepam and phenytoin, six i.v. pheno- pentobarbital.
barbital, and one pentobarbital without success. This last
Statistical analysis
We compared the population characteristics of responders
and non-responders (aetiology, age of onset of epilepsy,
Table II: Antiepileptic drugs used at the onset of the ketogenic diet
age when the ketogenic diet was started, time lag between
(number of patients)
onset of epilepsy and starting the diet, and recent worsen-
Vigabatrin 15 ing vs stable seizures frequency). In order to find out
Carbamazepine 12 whether this recent worsening was correlated to the
Phenytoin 11 response to the diet or whether there were other factors
Carbamazepine 10 underlying this positive correlation, we compared the age
Clobazam 8
at onset of epilepsy, the age when the ketogenic diet was
Phenobarbital 3
Topiramate 3
started, and the time lag from epilepsy onset to starting the
Valproate 3 diet, in the group of patients with recent worsening versus
Stiripentol 2 the group with stable epilepsy. The analysis was retrospec-
Lamotrigine 1 tive. We used the Mann)Whitney U test to compare
Oxcarbazepine 1
quantitative variables (age of epilepsy onset, time lag before
Pentobarbital 1
diet started) and Fisher’s Exact Test for qualitative vari-
Levetiracetam 1
ables (recent worsening vs stable epilepsy).

278 Developmental Medicine & Child Neurology 2009, 51: 276–281

 This study was performed in accordance with French
ethical guidelines.
RESULTS (Table I AND Table III)
The age when the ketogenic diet was introduced ranged
from 5 months to 18 years 6 months (median 6y 6mo).
The time from onset of epilepsy to introduction of the diet
ranged from 2 months to 18 years (median 4y 4mo) and
the time from status epilepticus to ketogenic diet introduc-
tion ranged from 48 hours to 2 weeks.
Efficacy at 1 month (Table III)
Ten patients were responders at 1 month (numbers 1)4, 6,
7, 9, 11, 12, 18). Eight of them were seizure-free; two oth-
ers experienced more than 90% seizure reduction (12, 18).
The median time to seizure improvement was 3 days.
Eight out of the 10 responders had responded during the
first week on the diet.
The ketogenic diet was stopped during the first month
in seven patients: in two (10, 15) because of inefficacy after
10 days and 3 weeks respectively, and in the five others (3,
8, 9, 20, 21) because of adverse events (severe vomiting and
fatigue). Although they tolerated the ketogenic diet poorly,
these five patients were responders at 1 week, including
two who became seizure-free, with seizure control main-
tained at 1 month (3, 9). The three others relapsed one
week after stopping the diet.
There was no correlation between the response at 1 month
and the age at onset of epilepsy, the age at which the diet was
started, or the duration of the epilepsy before the ketogenic
diet was started (data not shown). Comparison of patients
with recently increased seizure frequency (group 1) with
those who exhibited no recent worsening (group 2) showed
that the number of responders was significantly higher for
the former (7 out of 10 vs 3 out of 12; p=0.046). Moreover, all
seizure-free responders belonged to group 1, but only one to
group 2. These two groups showed no difference in terms of
age when the diet was introduced or of time from epilepsy
onset to starting the ketogenic diet. In the group with recent
deterioration of seizure control, 7 out of 10 patients (1)4, 6,
7, 9) experienced a negative impact on motor or cognitive
function (isolated or associated; see Table I). All seven
patients dramatically improved 1 month after starting the
ketogenic diet. Response to the diet was not restricted to sei-
zure control but was associated with cognitive improvement
and with disappearance of the recent motor deficit.

Long-term efficacy (Table III)

The duration of the diet ranged from 5 days to 12 months
Table III: Results of the ketogenic diet (mean 5.3mo, median 4mo).
Ten patients were maintained on the diet for more than
Seizure Time to
1 month (1, 4, 7, 11)13, 16, 18, 19, 22; Table I). Eight of
reduction Time to seizure Diet
(%) at 1mo response relapse duration them were responders at 1 month, seven remained seizure-
Patient Sex of diet (d) (mo) (mo) free, and one had only occasional seizures. Response to the
diet was maintained for at least 6 months in seven of the 10
1a Male 100 3 6 6
responders and for at least 1 year in two patients. In two
2a Female 100 7 NA 1
3a Female 100 30 12 0.5
patients with cryptogenic epilepsy, the ketogenic diet was
4a Female 100 1 6 12 stopped after 6 and 11 months of seizure freedom (7, 11),
5 Male 0 2 0.5 1 but the epilepsy subsequently relapsed after 2 and 9
6a Female 100 1 0.3 1 months respectively. The reintroduction of the diet
7a Female 100 10 20 11
controlled seizures again for one of them.
8 Female 0 4 0.3 0.5
Three non-responders were maintained on the diet
9a Female 100 2 2 0.7
10 Male 0 NA NA 0.3 because of improved quality of life (16, 19, 22). One sei-
11a Female 100 1 8 6 zure-free responder stopped the diet for personal reasons
12a Female 99 1 6 12 and was lost to follow-up (2). Two responders stopped the
13 Male 0 15 NA 10 diet during the first month because of significant adverse
14 Male 0 3 0.5 1
events (3, 9) but continued to benefit in terms of seizure
15 Male 0 NA NA 0.7
16 Male 0 1 NA 6
control for 2 and 12 months respectively.
17 Female 0 NA NA 1
18a Female 92 1 2 4 Tolerability
19 Female 0 15 1 4 Tolerability was relatively good. No adverse events were
20 Female 0 5 0.23 0.7
reported in 10 patients. Five patients had to stop the diet
21 Male 0 4 0.46 0.7
because of early side effects. For four patients this
22 Male 0 NA NA 3
consisted of severe vomiting (two patients were tube-fed),
a
Responders. NA, not applicable. which was associated with severe asthenia in three of them.

Ketogenic Diet Improves Recently Worsened Focal Epilepsy Nathalie Villeneuve et al. 279
Severe vomiting did not resolve on decreasing the strength
of the diet (from 4:1 to 3:1 lipid to non-lipid ratio), nor on
fractioning the meals. The fifth patient experienced severe
anorexia.
Minor side effects were reported in seven other patients.
Four had non-symptomatic hypoglycaemia during the first
3 days of the ketogenic diet requiring oral glucose supple-
mentation. Three patients reported drowsiness that
resolved spontaneously in two of them and after adjust-
ment of the dose of antiepileptic drugs in one.
DISCUSSION
This study shows that children with pharmacoresistant
focal epilepsy who have experienced a recent severe wors-
ening of seizure frequency with negative functional impact
are likely to benefit from the ketogenic diet. This benefit
most often occurs within the first week of the diet. The
diet also permits cognitive and motor functions to return
to previous levels.
We could find no evidence from the literature that a
recent deterioration of seizure control in focal epilepsy is a
particularly good indication for the ketogenic diet.
Although one study reported a better response in general-
ized than focal epilepsies,16 others failed to identify any sig-
nificant difference in response according to the type of
epilepsy.17,18 We therefore decided to exclude this factor
and to concentrate on a single type of epilepsy, selecting
patients with focal epilepsy because they represent one
major group of pharmacoresistant epilepsy.
This study is retrospective with a relatively small sample
but the population of patients was fairly homogeneous,
including patients with Rasmussen syndrome who had
reached a stable condition before the recent worsening of
seizures and returned to their previous condition after
starting the ketogenic diet. We can therefore hypothesize
that the worsening was mainly related to the seizure
increase.
There are theoretical reasons to predict that recent sei-
zure worsening is a good indication that a child may bene-
fit from the ketogenic diet. Seizures increase cerebral
glucose consumption, as shown by ictal positron emission
tomography (PET).24,25 Increased seizure frequency accel-
erates this process, provided sufficient glucose supply is
offered to the brain. The ketogenic diet reduces the con-
sumption of glucose by the brain and provides ketone
bodies as an alternative fuel.26 The delivery rate of ketone
bodies to the brain is limited by the inability of the brain to
generate reserves of this fuel.27 Therefore, the sudden
increase of energy needs is likely to remain unmet, thus
preventing seizure recurrence. Indeed, Noh et al. identified
a protective effect of ketosis on the hippocampus in an
animal model.21 This might explain the better response in
280 Developmental Medicine & Child Neurology 2009, 51: 276–281
patients with status epilepticus and nearly continuous
seizure activity than in patients with stable sporadic
seizures.
The ketogenic diet in our series was particularly useful
for patients not responding to intravenous administration of
benzodiazepines, phenytoin, or barbiturates. We recently
applied the ketogenic diet to the management of status
epilepticus in children suffering from devastating epileptic
encephalopathy with dramatic efficacy in half the cases.28
Although our data are preliminary, they might suggest
that a recent increase in seizure frequency, developing into
very frequent seizures or status epilepticus resistant to
standard emergency drugs, should be treated with the
ketogenic diet, particularly when associated with neurolog-
ical regression because of seizure worsening. Our results
suggest the need for a prospective randomized trial in
order to validate the place of the ketogenic diet in thera-
peutic guidelines.
It takes several hours for drugs to prove inefficacy.
Although useless and dangerous escalation may then become
tempting,29,30 doses should be reduced to prevent adverse
effects. The issue is then the time lag to efficacy (ketosis) and
tolerability. Intravenous fluid, if necessary in this context,
could be free of glucose. A recently available liquid formula-
tion of the ketogenic diet (KetoCal) is easily delivered
through a gastric tube and offers a possible means for such
emergency therapy. Median time lag to seizure improvement
in our study was 3 days. Gradual initiation of the ketogenic
diet without fasting results in better tolerability and allows
ketosis to occur within 2 or 3 days,6 but glucose fasting gener-
ates ketosis within less than 15 hours27 and in one study the
response was quicker for fasted children (within 5d vs
14d).31The question will then arise of the appropriate dura-
tion of the diet in this indication.
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