843 ISSN 1473-7175 2010 Expert Reviews Ltd www.expert-reviews.

com
Editorial
10.1586/ERN.10.35
The ketogenic diet: an appropriate
rst-line therapy?
Expert Rev. Neurother. 10(6), 843845 (2010)
...there is sufcient evidence today to warrant the use of the
ketogenic diet as a rst-line therapy in very select situations.
There are 28 anticonvulsants currently
being used worldwide for the treatment of
epilepsy, many of them introduced in the
past 15 years. Older anticonvulsants, such as
phenytoin, carbamazepine, pheno barbital
and valproate, are often used rst-line,
based on anecdotal experience. However,
according to the American Epilepsy Society
and the American Academy of Neurology,
only four of the newer medications have
sufcient evidence to warrant their use as
monotherapy (lamotrigine, oxcarbazepine,
gabapentin and topiramate) [1]. Despite
this, most child neuro logists will use an
anti convulsant rst if the clinical situation
warrants its use, for example, a child with
epilepsy and migraine may be treated with
topiramate rst, another with Lennox
Gastaut syndrome may start with run-
amide, and someone with benign rolan-
dic epilepsy could conceivably be treated
originally with levetiracetam.
The ketogenic diet (KD) is a high-fat,
low-carbohydrate, nonpharmacologic
treatment for epilepsy that has been in
continuous use since 1921 [2]. For the
past 89 years, the KD has been used
almost universally for intractable epi-
lepsy after multiple anti convulsants have
been tried unsuccessfully, but at what
point does this occur? According to the
2009 International Ketogenic Diet Group
Consensus Statement, the KD should be
strongly considered after no more than two
anticonvulsants have been tried, not the
ve to ten that, sadly, are often tried before
the child is referred to a KD center [3].
However, all treatments for epilepsy are
more effective in published clinical trials
when used earlier in the course of epilepsy.
What would it take to justify the use of
the KD rst?
The logical answer would be the pres-
ence of absolute or relative indications
for its use: situations in which the KD is
scientically proven to be highly effective
or, even more ideally, of greater efcacy
than anticonvulsants. These indications
for the KD exist and were the rst and
perhaps most important table in the 2009
Consensus Statement [3]. Two of these
conditions for which the KD can be the
only appropriate treatment, glucose trans-
porter 1 deciency and pyruvate dehy-
drogenase deciency, are predominantly
metabolic conditions notable for generally
infrequent seizures. Glucose transporter 1
deciency has recently been expanded in
its clinical phenotype, including absence
epilepsy, but still remains a somewhat rare
disease [4].
Certain epilepsy conditions, includ-
ing tuberous sclerosis complex, Rett
syndrome, severe myoclonic epilepsy of
infancy (Dravet syndrome) and mito-
chondrial disorders, also respond very
well to the KD, but no studies have shown
superiority over anticonvulsant medica-
tions [3]. The use of the KD earlier in
these conditions rather than after many
anticonvulsants have been used is prob-
ably warranted, but obviously not as a rst-
line treatment. Myoclonicastatic epilepsy
(Doose syndrome) is an epilepsy syndrome
in which young school-age children, most
commonly boys, present with the sudden
onset of myoclonic and atonic seizures
despite normal intelligence and a gener-
ally normal background EEG [5]. Several
retrospective studies of myoclonicastatic
epilepsy from centers in Japan, Argentina
and the USA have described 4050% sei-
zure-free response rates, which are supe-
rior to anti convulsants [57]. In fact, a 2007
Eric H Kossoff
Departments of Neurology
and Pediatrics, The John M
Freeman Pediatric Epilepsy
Center, Suite 2158,
200 North Wolfe Street,
The Johns Hopkins Hospital,
Baltimore, MD 21287, USA
Tel.: +1 410 955 4259
Fax: +1 410 614 2297
ekossoff@jhmi.edu
For reprint orders, please contact reprints@expert-reviews.com
Expert Rev. Neurother. 10(6), (2010) 844
Editorial Kossoff
study by the group at the Childrens Hospital of Philadelphia (PA,
USA) found that the KD was the thirteenth treatment typically
prescribed for myoclonicastatic epilepsy, but by far the most
effective, leading the authors to propose that the KD should be
considered earlier in treatment [5].
...the ketogenic diet center must be willing to
begin the ketogenic diet urgently (that day)...
Perhaps the most convincing evidence exists for infantile
spasms, a severe epilepsy syndrome affecting infants, typically
aged 48 months, with daily tonic seizures and often develop-
mental regression. Treatments are limited and fraught with nan-
cial implications and serious adverse effects; however, they are
effective, especially corticosteroids (adrenocorticotropin hormone
and oral high-dose prednisolone), demonstrating approximately
6070% spasm-free rates, and vigabatrin, with 4060% spasm-
free rates [8]. The KD has been reported as effective in reducing
spasms in large single-center retrospective studies from the USA
and Korea, with evidence suggesting earlier treatment is most
advantageous [9,10]. We reported our experience in using the KD
as a rst-line treatment for infantile spasms in 2008, typically
offered to infants who presented to medical care within 2 weeks
and without metabolic or nutritional concerns [11]. When used, we
counsel parents that the KD will be discontinued, and corticoste-
roids initiated, if not completely effective in eliminating spasms
within 2 weeks. To date, the KD has been successful in 11 out
of 19 infants (58%), often within 5 days. Interestingly, the most
common reasons families choose not to try the KD rst when
offered at our institution are a desire to continue breastfeeding
and a reluctance to have the infant admitted for the several-day
KD initiation.
Other than epilepsy syndromes, there are several clinical sce-
narios for a child with epilepsy that suggests a neurologist should
consider the KD early. Recent evidence from France suggests that
a worsening seizure frequency within the past month correlates
better with success than relative stability [12]. Many neurologists
have interpreted these results as predictive of the benecial role
of the KD in status epilepticus. Another reported condition is
that of a child with severe epilepsy who is formula-fed only [13,14].
Most of these children are infants but there are also many with
gastrostomy tubes for nutrition. There are three KD formulas
in existence, including Nutricias (MD, USA) KetoCal

, Solace
Nutritions (MD, USA) KetoVolve

and Ketonia in South

Korea. Not only have two studies suggested that formulas may
have superior efcacy compared with solid food KDs [13,14], but
they probably have a lower incidence of dyslipidemia, due to lower
cholesterol content [15].
It seems logical that the KD should be used sooner in all
of these epilepsy syndromes and situations. However, there are
several unfortunate practical aspects inherent to the KD that
makes it perhaps a less attractive rst-line option. In order to
start the KD rst, the KD center must be willing to begin the
KD urgently (that day) and quickly mobilize their KD neuro-
logist, dietitian, kitchen and educational team to teach families.
Insurance must approve the use of the KD, which can already
be problematic, even for children with intractable epilepsy, and
requires days of coordinating. When used, ketogenic formu-
las have to be ordered and shipped quickly to be immediately
available in the childs home.
As well as these logistical problems, there are more subjective
factors that may play a role in deciding whether to use the KD
rst. Parents have to allow the KD time to work, sometimes
days as in the case of infantile spasms, but occasionally longer.
The KD is absolutely a lifestyle change for families, even for
those children on formulas. Evidence for this came this year
in a study surveying parents of children who had discontinued
the KD years prior, many of whom had intractable epilepsy and
became seizure-free with the KD [16]. When asked, surprisingly
only 48% would have tried the KD before medications years
ago had they been given the choice back then by their treating
neurologist [16]. These results conrm our suspicion that for most
families medications are simpler and easier than dietary treat-
ments and, even if successful, the KD can be a hardship. Would
adolescents or adults agree to disrupt their daily life in a public
way with a dietary change, or would they decide to try a more
private, easier tablet twice daily? The failure to recruit patients
for a dietary study of chronic migraine in adolescents, enroll-
ing only eight patients over a 4-year period, suggests diets are
difcult decisions for teens [17]. Lastly, would pediatricians and
emergency department physicians refer children to KD centers
for dietary treatment or would they start a medication that day?
Child neurologists have to be strong advocates and have con-
dence in the efcacy of the KD to use it rst-line. In my personal
experience using the KD for new-onset infantile spasms, one
major factor in whether a family decides to implement the KD
is which particular child neurologist consults and then counsels
the parents.
These less restrictive diets could potentially be
more appealing to both a neurologist and family
considering diets versus medications.
Despite all of these problems in using the KD rst, there
may be several good solutions. The modied Atkins diet and
low glycemic index treatments are recent, alternative KDs
that have been demonstrated in clinical trials to be safe and
effective for children and adults with intractable epilepsy [18,19].
Advantages include an out-patient initiation, which requires an
hour of instruction typically, a lack of protein, calorie or uid
restriction, which appeals to older children and adolescents,
the presence of copious recipes and information on the internet
and in books, and perhaps a reduced need for dietitian support
and direct involvement [20]. These less restrictive diets could
potentially be more appealing to both a neuro logist and family
considering diets versus medications. Another potential solution
may be to increase education about the KD to dietitians and
child neurologists and, even more importantly, to the pediatri-
cians and emergency department physicians who are on the
front-line when epilepsy begins. Lastly, creating an easier
www.expert-reviews.com
845
Editorial The ketogenic diet: an appropriate rst-line therapy?
KD, especially for those receiving formula-only diets, would be
helpful. For infantile spasms specically, if an internet-located,
standardized and age-/weight-based, formula program was
widely available, more dietitians could quickly create and ship
the KD to families.
In my opinion, there is currently sufcient evidence to war-
rant the use of the KD as a rst-line therapy in very select situ-
ations. First, select epilepsies (e.g., infantile spasms and myo-
clonicastatic epilepsy) and conditions (e.g., infants and those
with gastrostomy tubes). Second, select families, including those
who are motivated, compliant and willing to give the KD time
to work. Lastly, select child neurologists and dietitians knowl-
edgeable in the KD who are condent in its efcacy and able to
implement it within 12 days. I think this concept of KD initial
monotherapy will continue to grow in interest, especially as a
result of the increasing use of the modied Atkins diet, simpli-
ed ketogenic formulas and worldwide awareness of the value of
dietary treatments.
Acknowledgements
The author gratefully acknowledges the content review by Gerry Harris.
Financial & competing interests disclosure
Eric H Kossoff is on the Scientic Advisory Board of Atkins Nutritionals,
Inc. He has research support for a clinical study from Nutricia, Inc., related
to their product KetoCal

. The author has no other relevant afliations or

nancial involvement with any organization or entity with a nancial
interest in or nancial conict with the subject matter or materials discussed
in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
6 Oguni H, Tanaka T, Hayashi K et al.
Treatment and long-term prognosis of
myoclonic-astatic epilepsy of early childhood.
Neuropediatrics 33(3), 122132 (2002).
7 Caraballo RH, Cerssimo RO, Sakr D,
Cresta A, Escobal N, Fejerman N.
Ketogenic diet in patients with
myoclonic-astatic epilepsy. Epileptic Disord.
8(2), 151155 (2006).
8 Hancock EC, Osborne JP, Edwards SW.
Treatment of infantile spasms. Cochrane
Database Syst. Rev. 4, CD001770 (2008).
9 Kossoff EH, Pyzik PL, McGrogan JR,
Vining EPG, Freeman JM. Efcacy of the
ketogenic diet for infantile spasms.
Pediatrics 109(5), 780783 (2002).
10 Eun SH, Kang HC, Kim DW, Kim HD.
Ketogenic diet for treatment of infantile
spasms. Brain Dev. 28(9), 566571
(2006).
11 Kossoff EH, Hedderick EF, Turner Z,
Freeman JM. A casecontrol evaluation of
the ketogenic diet versus ACTH for
new-onset infantile spasms. Epilepsia 49(9),
15041509 (2008).
First study to date to use the KD as a
rst-line therapy. In this series of
13 infants, the KD led to spasm freedom
in eight infants and was well tolerated.
12 Villeneuve N, Pinton F, Bahi-Buisson N,
Dulac O, Chiron C, Nabbout R.
The ketogenic diet improves recently
worsened focal epilepsy. Dev. Med. Child
Neurol. 51(4), 276281 (2009).
13 Kossoff EH, McGrogan JR, Freeman JM.
Benets of an all-liquid ketogenic diet.
Epilepsia 45(9), 1163 (2004).
Case series describing the higher efcacy
of a formula-only KD compared with
solid food, which has led to an increased
use of this form of the KD worldwide.
References
Papers of special note have been highlighted as:
of interest
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antiepileptic drugs, I: treatment of new
onset epilepsy: report of the Therapeutics
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(2004).
2 Murphy P. Use of the ketogenic diet as a
treatment for epilepsy refractory to drug
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769775 (2005).
3 Kossoff EH, Zupec-Kania BA, Amark PE
et al. Optimal clinical management of
children receiving the ketogenic diet:
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ketogenic diet study group. Epilepsia 50(2),
304317 (2009).
Summarizes recent recommendations by
26 pediatric epileptologists and dietitians
familiar with ketogenic diets (KDs),
including indications for using the KD.
4 Roulet-Perez E, Ballhausen D, Bonaf L,
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(2007).
Provides strong evidence for using the KD
as a rst-line treatment for this particular
epilepsy syndrome.
14 Hosain SA, La Vega-Talbott M,
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feeding. Pediatr. Neurol. 32(2), 8183
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15 Nizamuddin J, Turner Z, Rubenstein JE,
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16 Patel A, Pyzik PL, Turner Z,
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(2010) (Epub ahead of print).
First study to attempt to analyze the
long-term effects of the KD after it has
been discontinued. Results suggest no
obvious adverse effects and hints of
possible benets on seizure control even
after it has been discontinued.
17 Kossoff EH, Huffman J, Turner Z,
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headache. Cephalalgia (2010) (In press).
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