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Management of Epilepsy with Ketogenic Diet



Intractable epilepsy has been defined as epilepsy that failed to respond to 3 or more anti-epileptic drugs (AED). About 30% of children with epilepsy experience uncontrolled seizures or side effects due to AED. The ketogenic diet (KD) was found to be effective in treatment of intractable seizures. The KD consists of a high fat, low carbohydrate and adequate protein. The KD need to be tailored individually for every patient. Different protocols and variable dosing of KD have been used. The KD is prescribed by physician and dietician, thereafter side effects such as acidosis, hypoglycemia, vomiting, gastro-esophageal reflux, constipation, hyper-lipidemia, renal stone, growth failure, bone density, micro-nutrient and vitamin deficiency need to be monitored.
Cite: Jain S. Management of Epilepsy with Ketogenic Diet. Indian Journal of Psychosocial Sciences. 2017
Apr; 7(1):15-20
Management of Epilepsy with Ketogenic Diet
Shobhit Jain
Department of Psychiatry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, INDIA
Intractable epilepsy has been defined as epilepsy that failed to respond to 3 or more anti-epileptic drugs
(AED). About 30% of children with epilepsy experience uncontrolled seizures or side effects due to AED
The ketogenic diet (KD) was found to be effective in treatment of intractable seizures. The KD consists of
a high fat, low carbohydrate and adequate protein. The KD need to be tailored individually for every
patient. Different protocols and variable dosing of KD have been used. The KD is prescribed by physician
and dietician, thereafter side effects such as acidosis, hypoglycemia, vomiting, gastro-esophageal reflux,
constipation, hyper-lipidemia, renal stone, growth failure, bone density, micro-nutrient and vitamin
deficiency need to be monitored.
History of Ketogenic Diet in Epilepsy
Fasting has been recognized since Hippocratic era (460BC-370BC) as treatment for epilepsy. In early 20th
Century, French and American physicians like Guelpa, Marie, Conklin, and Geyelin started research on
fasting and starvation as treatment for epilepsy (1). It was shown that the fasting is more effective more
in treating children than adolescents and its efficacy decreases with increasing age. Thereafter, Lennox
and Cobb (1922) explained dehydration, acidosis, and ketosis as possible mechanism by which fasting
helps in treating epilepsy.
Dr. Wilder proposed that the diet which produces ketosis could also be used in treatment of epilepsy.
He termed such diet as “Ketogenic Diet”, which were rich in fat and deficient in carbohydrate. He found
benefit of KD over starvation in providing similar efficacy, but can be used for prolonged maintenance.
Later, in 1938 diphenylhydantoin was discovered and thereafter research focus shifted to development
of other AED, which were found convenient to administer.
Due to intractable seizures which remained uncontrolled despite of several trial of AEDs, KD regained its
popularity. In 1972, Dr. Robert C. Atkins promoted “Atkins Diet” which consisted of high fat and low
carbohydrate and produces ketosis. Thereafter, “Modified Atkins Diet” was developed in 2003 at John
Hopkins. These diets were more palatable and tolerable than previous ones.
Subsequently, low glycemic index treatment diet was proposed in 2005, which hypothesis that stable
blood glucose at a lower level would result in modulation of insulin release and other metabolic effects,
thus improving seizure.
Mechanism of Action
The exact mechanism of action of ketogenic diet is still not fully clear. However, preclinical studies have
suggested following possible mechanism as alterations in mitochondrial function, effect of ketone
bodies and fatty acids, and glucose stabilization. Ketone bodies easily cross the blood brain barrier, and
are only source of energy to brain during starvation. Substitution of glucose by ketones in brain results
in decreased glycolysis and increased krebs cycle for energy production. Ketone bodies causes γ-
aminobutyric acid (GABA) synthesis, neuronal membrane hyperpolarization, decrease release of
glutamate, increase norepinephrine and adenosine, neuroprotective and antioxidant activity, decrease
insulin-like growth factor 1 (IGF-1) and the mammalian target of rapamycin (mTOR), and increase
sirtuins and adenosine monophosphate-activated protein kinase (AMPK) in brain. The GABA is
synthesized during krebs’s cycle when glutamate is converted into GABA by enzyme glutamate
decarboxylase. Studies have shown that beta-hydroxybutyrate (ketone body) inhibits GABA-
transaminase expression thus increases GABA in brain. Ketone bodies regulates activity of these enzyme
thus increases the level of GABA in the brain. Increased level of GABA results in stimulation of chloride
receptors and ATP sensitive potassium channel leading to hyperpolarisation of neuronal membrane and
inhibition of sodium and calcium channels leading to decreased excitability. Studies have shown ketone
bodies (acetoacetate more than betahydroxybutyrate) affect VGLUT channels on presynaptic glutamate
vesicles (via chloride channels), thus leading decreased release of excitatory glutamate
neurotransmitters. Ketone bodies also cause alteration in level of biogenic amines such as increase in
nor-epinephrine and adenosine, and decrease in dopamine and serotonin. Increased adenosine causes
activation of adenosine A1 receptors resulting in decreased brain excitability. Ketone bodies have
neuroprotective role by causing mitochondrial biogenesis. It also have antioxidant role by increasing
uncoupling protein in mitochondrial electron transport chain thus reducing reactive oxygen species and
increasing level of mitochondrial reduced glutathione level thus protecting mitochondrial level from
oxidative stress. Increase in sirtuins causes increase in mitochondrial number and size, and also cause
decrease in insulin like growth factor-1. Increase in AMPK is directly related to ATP production. Ketone
bodies by inhibiting mTOR pathway have anticonvulsant action. Since ketone bodies metabolizing
enzyme (namely, monocarboxylic acid transporter) is found more abundant in infants and children,
which later decreases with increasing age and adults. Therefore the KD is more effective during infants
and childhood than in adulthood (2).
The Classical Ketogenic Diet
Most of classical ketogenic diet consist of higher fat than carbohydrate and protein, in such a ratio that
the ratio of quantity of fat and the sum of quantity of carbohydrate and protein is in range of 3:1 to 4:1.
Therefore, 90% of the total calories delivered in KD is by fat and the remaining 10% is by carbohydrate
and protein. The total calories is restricted to 80 to 90% of daily recommendation for the age and the
fluid restriction is 90% of previous dietary intake. The KD is preferably started after admitting patient in
hospital. Whereas, out-patient setting is not a contraindication, in-door setting has several advantages
as it provides better opportunity to thoroughly examine and evaluate the case for diagnosis and
contraindications of KD, provide education session for parents about KD preparation and administration,
monitoring of side effects, and also some centers initiate 4:1 preparation of classical KD after brief
fasting to provide accelerated ketosis. However, gradual initiation of KD is better tolerated, lesser side
effects, similar level of maintenance ketosis, and similar level of seizure control compared with fasting
KD initiation. Therefore, gradual initiation of KD should be preferred over fasting KD initiation. During
gradual initiation, initially 2:1 combination of KD is started which is later increased to 3:1 and 4:1 based
on tolerability (2). Most of patients respond well to one year treatment with KD, averaging about 80%
response rate. Among responders, more than 50% response is noticed in initial 3 months, and among
those with less than 50% response in initial 3 months, not much improvement is noticed thereafter. The
average time for treatment with KD is 2years after which it may be discontinued (2). As a clinical
practice, usually KD is used as a reserved therapy for intractable seizures. The International Ketogenic
Diet Study Group, the therapy should be offered after failure of two AED trial. However, KD remains
treatment of choice for GLUT1 deficiency syndrome and pyruvate dehydrogenase deficiency syndrome.
Whereas, for Dravet Syndrome (myoclonic epilepsy of infancy) and Doose Syndrome (myoclonic-atonic
epilepsy), Infantile Spasm/West Syndrome, Lennox Gestaut Syndrome, KD have been found more
effective and hence can be considered earlier. The adverse effects reported for KD are unpalatability,
taste change, nausea, vomiting, abdominal pain, constipation, diarrhea, infection, dehydration, hunger,
lack of energy, mood changes. Pancreatitis though rare but serious and found in association with
triglyceridemia among patients on KD. Other long term complications are growth retardation in children,
electrolyte, vitamins, and mineral deficiency, hyperlipidemia, nephrolithiasis (3).
The KD is contraindicated in patients with disorder of disorders of fatty acid transport and oxidation.
Therefore, developmental delay, cardiomyopathy, hypotonia, exercise intolerance, myoglobinuria, and
easy fatigability are few features that should raise high suspicion of fatty acid metabolism disorder, and
patients with such feature should undergo screening test for inborn error of metabolism before
initiation of KD therapy. The use of KD with valproate may cause liver failure. The studies on efficacy of
KD have been summarized in table 1.
Vining et al. 1998
51 children with
average 230
Continued treatment for a year: 47%
Efficacy in terms of seizure control after 1 year treatment:
>90% response 43%; 50-90% response 39%; <50% response 17%
Adverse effects: lethargy, severe dehydration, acidosis, mood changes,
increased infections, constipation, and vomiting.
Reason for discontinuation: intolerance, difficulty of maintaining the
restrictive diet, and inadequate seizure control.
Freeman et al. 1998
150 children with
average 410
Efficacy in terms of seizure control after 1 year treatment:
100% response - 7%; >90% response - 27%; 50-90% response - 50%
More than 50% improvement in initial 3 months responded well,
whereas less than 50% response in initial 3 months did not had much
improvement later.
Freitas et al. 2007
70 children with
refractory epilepsy
Continued treatment for a year: 55%
Efficacy in terms of seizure control after 1 year treatment:
>75% response - 70%; 75-25% response - 25%; <25% response 2.5%
Reason for discontinuation: unpalatability, nausea, and vomiting
More effective for generalized epilepsy than for partial epilepsy
Neil et al. 2008 (7)
Efficacy in terms of seizure control after 3 months of treatment:
KD Group (n = 54) had 75% reduction in seizure frequency compared
Controlled Trial on
103 children with
refractory epilepsy
to Control (AED) Group (n = 49).
> 90% response 7%; 50-90% response 38%
Adverse effect: Constipation, vomiting, lack of energy, hunger,
diarrhea, abdominal pain, and taste problems among 25% KD Group.
Table 1: Summary of studies on efficacy of Ketogenic Diet.
The Medium Chain Triglyceride (MCT) Diet
Since unpalatability was one of the major reason for discontinuation of use, MCT diet limited this
adverse effect to some extent with a greater proportion of carbohydrate and protein content than KD.
The MCT diet are more rapidly metabolized compared to long chain triglycerides in classical KD,
therefore has several advantages over classical KD. It produces more ketosis per kilocalorie of energy
and requires lesser amount of fat intake than classical KD. It also has lesser total cholesterol to high
density lipoprotein ratio compared to classical KD. Although, it has adverse effects as diarrhea, vomiting,
bloating, and abdominal pain. Therefore to reduce these adverse effects, the modified MCT diet have
been developed. Instead of providing 60% total energy with MCT diet, the modified MCT diet provides
30% of energy with MCT and 30% energy with long chain triglycerides. However, contraindications for
MCT diet are almost similar to KD.
The Modified Atkins Diet (MAD)
The MAD in composed of fat, protein , and carbohydrate is a ratio such that 60-65% calories is delivered
by fat, 30% by protein, and the remaining 10% by carbohydrate. For children, the net carbohydrate are
initially limited to 10 g/day which is later on increased to 20 g/day, whereas in adults the initial
carbohydrate dose is started at 15 g/day which is later on increased to 20-30 g/day. Goal of MAD is to
increase the ketosis without causing weight loss, therefore only carbohydrate consumption is restricted
but fat and protein consumption is encouraged. There is no fasting required, calories are not restricted,
weighing of food is not required, lesser education to family members and patient required and can be
safely started at home.
Sharma et al. 2013
Efficacy in terms of seizure control after 3 months of treatment:
MAD Group (n= 50) had significant reduction in seizure frequency
controlled trial
comparing MAD
and AED on 102
children and
adolescents with
refractory epilepsy.
compared to Control (AED) Group (n = 52).
The MAD was well tolerated and did not required discontinuation,
though constipation was most common side effect.
Table 2: Summary of study on efficacy of Modified Atkins Diet.
The Low Glycemic Index Treatment (LGIT)
The low glycemic index (GI) food has lesser tendency to elevate postprandial blood sugar level. The food
with GI less than 50 is preferred, with total carbohydrate 40-60 g/day initially, however, fat and protein
is encouraged. The LGIT produces lower level of ketosis than the classical KD. The key findings of studies
on efficacy is summarized in table 3.
Muzykewicz et al.
2009 (9)
76 children with
refractory epilepsy
Efficacy in terms of seizure control after 1 year treatment: >50%
response - 66%
Only 3 patients reported transient lethargy as side effect.
Most common reason for discontinuation was restrictiveness.
Coppolla et al. 2011
15 children and
young adults with
refractory epilepsy
Efficacy in terms of seizure control after 1 year of treatment:
75-90% response - 40%; 50% response - 13%; <50% response 47%
No adverse effect reported.
Table 3: Summary of studies on efficacy of Low Glycemic Index Treatment.
Though, the classical KD is proven treatment for intractable epilepsy, the newer diet have been
developed in order to reduce the side effects and making it more palatable for prolonged maintenance
use. Despite having fewer side effects and better tolerability, the studies have found these newer diets
to be comparably effective as the classical KD (Table 4). Based on understanding about mechanism of
ketogenic diet, the recent researches are focusing to develop newer dietary alternatives eg. pyruvate,
triheptanoin, alpha-ketoglutarate, succinate, oxaloacetate supplementation. The development of future
diet for epilepsy may reduce side effects of classical KD and increase palatability, tolerability, and
Neal et al. 2009 (11)
controlled trial
comparing MCT and
classical KD.
No difference among efficacy of the MCT diet (n = 49) and the KD (n =
Martin et al. 2016
Cochrane review of
7 Randomised
Controlled Trial
among children and
adolescents with
Efficacy of classical KD: 85% seizure reduction and 55% seizure free.
Efficacy of MAD: 60% seizure reduction and 10% seizure free.
Gastrointestinal symptoms (diarrhoea, constipation and vomiting) were
among most commonly reported side effects, and also one of the most
common reason for discontinuation. Whereas, cardiovascular adverse
effects were among most common long term side effects.
Classical KD had greater side effects.
Klein et al. 2014
Review of studies
on KD and MAD
among adults with
refractory epilepsy.
Efficacy of classical KD: >50% response 32% and >90% response 9%.
Efficacy of MAD: >50% response 29% and >90% response 5%.
Side effects of both diets are benign and similar. The most common
being weight loss and most serious being reversible hyperlipidemia.
Refusal to participate because of diet restrictiveness and complexity is
more for KD than MAD. Also, discontinuation rate is more among KD
(51%) than MAD (42%).
Ye et al. 2015 (14)
comparing efficacy
of KD (n = 168),
MAD (n = 87), MCT
+ KD (n = 15) among
270 adults with
The KD (52%) had significantly higher efficacy than MAD (34%).
The overall compliance rate of KD(38%) was significantly lower than
MAD (56%).
Due to better compliance rate MAD may be initial treatment of choice
for adults, which may be switched to classical KD if greater seizure
control is desired.
intractable epilepsy.
Table 4: Comparing of efficacy of Ketogenic Diet with newer variants.
1. Sampaio LP de B. Ketogenic diet for epilepsy treatment. Arq Neuropsiquiatr. 2016;74(10):842848.
2. Lima PA de, Sampaio LP de B, Damasceno NRT. Neurobiochemical mechanisms of a ketogenic diet
in refractory epilepsy. Clinics. 2014;69(10):699705.
3. Vaccarezza MM, Silva WH. Dietary therapy is not the best option for refractory nonsurgical
epilepsy. Epilepsia. 2015;56(9):13301334.
4. Vining EPG, Freeman JM, Ballaban-Gil K, Camfield CS, Camfield PR, Holmes GL, et al. A Multicenter
Study of the Efficacy of the Ketogenic Diet. Arch Neurol. 1998 Nov 1;55(11):14337.
5. Freeman JM, Vining EP, Pillas DJ, Pyzik PL, Casey JC, others. The efficacy of the ketogenic diet
1998: a prospective evaluation of intervention in 150 children. Pediatrics. 1998;102(6):13581363.
6. Freitas A, Paz JA da, Casella EB, Marques-Dias MJ. Ketogenic diet for the treatment of refractory
epilepsy: a 10 year experience in children. Arq Neuropsiquiatr. 2007 Jun;65(2B):3814.
7. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, et al. The ketogenic diet
for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol.
8. Sharma S, Sankhyan N, Gulati S, Agarwala A. Use of the modified Atkins diet for treatment of
refractory childhood epilepsy: a randomized controlled trial. Epilepsia. 2013;54(3):481486.
9. Muzykewicz DA, Lyczkowski DA, Memon N, Conant KD, Pfeifer HH, Thiele EA. Efficacy, safety, and
tolerability of the low glycemic index treatment in pediatric epilepsy. Epilepsia. 2009;50(5):1118
10. Coppola G, D’Aniello A, Messana T, Di Pasquale F, della Corte R, Pascotto A, et al. Low glycemic
index diet in children and young adults with refractory epilepsy: First Italian experience. Seizure.
2011 Sep;20(7):5268.
11. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, et al. A randomized trial
of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy.
Epilepsia. 2009;50(5):11091117.
12. Martin K, Jackson CF, Levy RG, Cooper PN. Ketogenic diet and other dietary treatments for
epilepsy. Cochrane Libr [Internet]. 2016 [cited 2017 Feb 11]; Available from:
13. Klein P, Tyrlikova I, Mathews GC. Dietary treatment in adults with refractory epilepsy A review.
Neurology. 2014;83(21):19781985.
14. Ye F, Li X-J, Jiang W-L, Sun H-B, Liu J. Efficacy of and patient compliance with a ketogenic diet in
adults with intractable epilepsy: a meta-analysis. J Clin Neurol. 2015;11(1):2631.
... Klasik ketojenik diyetin kademeli olarak başlatılmasının hastalarda tolerasyonu artırdığı gözlemlenmiştir. Aşamalı başlatma sırasında, başlangıçta 2:1 ketojenik diyet (KD) kombinasyonu başlatılır; bu daha sonra tolerasyona bağlı olarak 3:1 ve 4:1'e çıkarılmaktadır (19,20). ...
... gastrointestinal sistem üzerinde bazı olumsuz etkileri olduğu bilinmektedir. MCT diyetinde elzem yağ asitleri LCT'lerden sağlanabildiği için hastanın MCT toleransı göz önünde bulundurularak kademeli artış sonucunda MCT diyeti ile enerjinin %30'u MCT'den ve %30'u LCT'den sağlanmaktadır (19). ...
... MAD'nin amacı vücut ağırlığı kaybına neden olmadan ketozisi artırmasıdır. Bu nedenle, diyette sadece karbonhidrat alımı kısıtlanır, ancak yağ ve protein alımında herhangi bir kısıtlama yapılmamaktadır (19). Çocuklar için, karbonhidrat alımı başlangıçta 10 g/gün ile sınırlandırılır, daha sonra 20 g/gün'e çıkarılır; erişkinlerde ise karbonhidrat alımı 15 g/gün ile başlar, daha sonra 20-30 g/gün'e çıkarılır. ...
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Epilepsi her yaşta ortaya çıkabilen, tedavi süresi uzun olan ve izlem gerektiren bir hastalık olmakla beraber yaşam kalitesini büyük ölçüde etkilemektedir. İlk kez Hipokrat tarafından “beyin hastalığı” olarak ifade edilmiştir. Epilepsinin tedavisinde, ilaç tedavisi, cerrahi tedavi ve ketojenik tıbbi beslenme tedavisi kullanılabilmektedir. Açlık, Hipokrat döneminden itibaren epilepsinin tedavisi olarak kabul edilmiştir. Ketojenik tıbbi beslenme tedavisi, yüksek yağ ve düşük karbonhidrat içeriği ile açlığın metabolik durumunu taklit ederek yağların vücutta ilk enerji kaynağı olarak kullanılmasını sağlamaktadır. Keton cisimciklerini metabolize eden enzim, bebeklerde ve çocuklarda daha fazla bulunmaktadır ve artan yaş ile azalmaktadır. Bu nedenle bebeklerde ve küçük yaştaki çocuklarda daha etkin bir tıbbi beslenme tedavisidir. Ketojenik tıbbi beslenme tedavisine başlanmadan önce, bireyden ayrıntılı besin tüketim kaydının alınması, bebeklerde ve çocuklarda çeşitli parametreler göz önünde bulundurularak büyümenin değerlendirilmesi, obezite, malnütrisyon vb. durumların saptanması ve bu doğrultuda uygun günlük enerji gereksinimin hesaplanması önemlidir. Bu derlemede ketojenik tıbbi beslenme tedavisine güncel yaklaşımla birlikte ketojenik tıbbi beslenme tedavisi hesaplama örneklerine de yer verilmiştir.
About one-third of childhood epilepsy ultimately becomes drug resistant epilepsy. Only about one-third of drug resistant epilepsy is amenable for epilepsy surgery. Epilepsy surgery and vagal nerve stimulation is still beyond the reach of huge proportion of children with pharmacoresistant epilepsy. Ketogenic diet (KD) has been in use for almost a century now all over the world for drug resistant epilepsy, although in between there was a decline in its popularity with advent of newer antiepileptic drugs like valproate, phenytoin and carbamazepine. Again from 1990s there was resurgence of interest in KD for pharmacoresistant epilepsy and in the last two decades several randomized controlled trials and systemic reviews have proved its efficacy beyond any suspicion. Ketogenic diet is a high fat low carbohydrate and low protein diet, which has been found to reduce epileptogenesis in body most probably by production of ketone bodies. Modified Atkin’s Diet (MAD) first introduced in 2003 and Low Glycemic Index Treatment (LGIT) first introduced in 2005 are another two dietary therapies, which are less restrictive, more palatable with fewer adverse effects and comparable efficacy. MAD is also a high fat, low carbohydrate diet, in which high sugar foods are discouraged and protein and fluids are unrestricted. In LGIT, only carbohydrates with Glycemic Index <50 are allowed and carbohydrate intake is restricted to 40–60 g per day. Medium Chain Triglyceride KD (MCT KD) is another alternative, in which there are more food choices as compared to classic KD, with comparable efficacy.
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The ketogenic diet (KD), a high-fat, low-carbohydrate, and adequate-protein diet is an established, effective nonpharmacologic treatment option for intractable childhood epilepsy. The KD was developed in 1921 and even though it has been increasingly used worldwide in the past decade, many neurologists are not familiar with this therapeutic approach. In the past few years, alternative and more flexible KD variants have been developed to make the treatment easier and more palatable while reducing side effects and making it available to larger group of refractory epilepsy patients. This review summarizes the history of the KD and the principles and efficacy of the classic ketogenic diet, medium-chain triglyceride(s) (MCT) ketogenic diet, modified Atkins diet, and low glycemic index treatment. © 2016, Associacao Arquivos de Neuro-Psiquiatria. All rights reserved.
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Despite the successful use of a ketogenic diet in pediatric epilepsy, its application in adults has been limited. The aim of this meta-analysis was to summarize the findings of relevant published studies in order to identify the efficacy of and compliance with a ketogenic diet and its main subtypes (i.e., classic ketogenic diet and modified Atkins diet) in adults with intractable epilepsy, and to provide useful information for clinical practice. Electronic searches of PubMed, EMBASE, Google Scholar, and the ISI Web of Science were conducted to identify studies of the efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy; the included studies were reviewed. Meta-analyses were performed using STATA to determine combined efficacy rates and combined rates of compliance with the ketogenic diet and its main subtypes. In total, 12 studies qualified for inclusion, and data from 270 patients were evaluated.The results of the meta-analysis revealed combined efficacy rates of all types of ketogenic diet, a classical ketogenic diet, and a modified Atkins diet were 42%, 52%, and 34%, respectively; the corresponding combined compliance rates were 45%, 38%, and 56%. The results indicate that a ketogenic diet is a promising complementary therapy in adult intractable epilepsy, and that while a classical ketogenic diet may be more effective, adult patients are likely to be less compliant with it than with a modified Atkins diet.
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A ketogenic diet is an important therapy used in the control of drug-refractory seizures. Many studies have shown that children and adolescents following ketogenic diets exhibit an over 50% reduction in seizure frequency, which is considered to be clinically relevant. These benefits are based on a diet containing high fat (approximately 90% fat) for 24 months. This dietary model was proposed in the 1920s and has produced variable clinical responses. Previous studies have shown that the mechanisms underlying seizure control involve ketone bodies, which are produced by fatty acid oxidation. Although the pathways involved in the ketogenic diet are not entirely clear, the main effects of the production of ketone bodies appear to be neurotransmitter modulation and antioxidant effects on the brain. This review highlights the impacts of the ketogenic diet on the modulation of neurotransmitters, levels of biogenic monoamines and protective antioxidant mechanisms of neurons. In addition, future perspectives are proposed.
Background: The ketogenic diet (KD), being high in fat and low in carbohydrates, has been suggested to reduce seizure frequency. It is currently used mainly for children who continue to have seizures despite treatment with antiepileptic drugs. Recently, there has been interest in less restrictive KDs including the modified Atkins diet (MAD) and the use of these diets has extended into adult practice. Objectives: To review the evidence for efficacy and tolerability from randomised controlled trials regarding the effects of KD and similar diets. Search methods: We searched the Cochrane Epilepsy Group's Specialized Register (30 March 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 30 March 2015), MEDLINE (Ovid, 30 March 2015), (30 March 2015) and the WHO International Clinical Trials Registry Platform (ICTRP, 30 March 2015). We imposed no language restrictions. We checked the reference lists of retrieved studies for additional reports of relevant studies. Selection criteria: Studies of KDs and similar diets for people with epilepsy. Data collection and analysis: Two review authors independently applied pre-defined criteria to extract data and assessed study quality. Main results: We identified seven randomised controlled trials that generated eight publications. All trials applied an intention-to-treat analysis with varied randomisation methods. The seven studies recruited 427 children and adolescents and no adults. We could not conduct a meta-analysis due to the heterogeneity of the studies. Reported rates of seizure freedom reached as high as 55% in a 4 : 1 KD group after three months and reported rates of seizure reduction reached as high as 85% in a 4 : 1 KD group after three months. One trial found no significant difference between the fasting-onset and gradual-onset KD for rates of seizure freedom and reported a greater rate of seizure reduction in the gradual-onset KD group. Studies assessing the efficacy of the MAD reported seizure freedom rates of up to 10% and seizure reduction rates of up to 60%. One study compared the MAD to a 4 : 1 KD, but did not report rates of seizure freedom or seizure reduction. Adverse effects were fairly consistent across different dietary interventions. The most commonly reported adverse effects were gastrointestinal syndromes. It was common that adverse effects were the reason for participants dropping out of trials. Other reasons for drop-out included lack of efficacy and non-acceptance of the diet. Although there was some evidence for greater antiepileptic efficacy for a 4 : 1 KD over lower ratios, the 4 : 1 KD was consistently associated with more adverse effects. No studies assessed the effect of dietary interventions on quality of life, or cognitive or behavioural functioning. Authors' conclusions: The randomised controlled trials discussed in this review show promising results for the use of KDs in epilepsy. However, the limited number of studies, small sample sizes and a sole paediatric population resulted in a poor overall quality of evidence. There were adverse effects within all of the studies and for all KD variations, such as short-term gastrointestinal-related disturbances, to longer-term cardiovascular complications. Attrition rates remained a problem with all KDs and across all studies, reasons for this being lack of observed efficacy and dietary tolerance. There was a lack of evidence to support the clinical use of KD in adults with epilepsy, therefore, further research would be of benefit. Other more palatable but related diets, such as the MAD ketogenic diet, may have a similar effect on seizure control as classical KD but this assumption requires more investigation. For people who have medically intractable epilepsy or people who are not suitable for surgical intervention, a KD remains a valid option; however, further research is required. © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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.
The ketogenic diet (KD) is currently a well-established treatment for patients with medically refractory, nonsurgical epilepsy. However, despite its efficacy, the KD is highly restrictive and constitutes a treatment with serious potential adverse effects, and often with difficulties in its implementation and compliance. Patients on the KD require strict follow-up and constant supervision by a medical team highly experienced in its management in order to prevent complications. Other alternative treatments for patients with refractory epilepsy include vagus nerve stimulation (VNS), new-generation antiepileptic drugs (AEDs), corpus callosotomy (CC), and responsive focal cortical stimulation (RNS). In this review, we explain not only the difficulties of the KD as a therapeutic option for refractory epilepsy but also the benefits of other therapeutic strategies, which, in many cases, have proven to have better efficacy than the KD itself. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.
We review adjunctive ketogenic diet (KD) and modified Atkins diet (MAD) treatment of refractory epilepsy in adults. Only a few studies have been published, all open-label. Because of the disparate, uncontrolled nature of the studies, we analyzed all studies individually, without a meta-analysis. Across all studies, 32% of KD-treated and 29% of MAD-treated patients achieved ≥50% seizure reduction, including 9% and 5%, respectively, of patients with >90% seizure frequency reduction. The effect persists long term, but, unlike in children, may not outlast treatment. The 3:1 and 4:1 [fat]:[carbohydrate + protein] ratio KD variants and MAD are similarly effective. The anticonvulsant effect occurs quickly with both diets, within days to weeks. Side effects of both diets are benign and similar. The most serious, hyperlipidemia, reverses with treatment discontinuation. The most common, weight loss, may be advantageous in patients with obesity. Potential barriers to large-scale use of both diets in adults include low rate of diet acceptance and high rates of diet discontinuation. The eligible screened/enrolled subject ratios ranged from 2.9 to 7.2. Fifty-one percent of KD-treated and 42% of MAD-treated patients stopped the diet before study completion. Refusal to participate was due to diet restrictiveness and complexity, which may be greater for KD than MAD. However, long-term adherence is low for both diets. Most patients eventually stop the diet because of culinary and social restrictions. For treatment of refractory status epilepticus, only 14 adult cases of KD treatment have been published, providing insufficient data to allow evaluation. In summary, KD and MAD treatment show modest efficacy, although in some patients the effect is remarkable. The diets are well-tolerated, but often discontinued because of their restrictiveness. In patients willing to try dietary treatment, the effect is seen quickly, giving patients the option whether to continue the treatment.
Purpose: The aim of this study was to evaluate the efficacy of the modified Atkins diet in a randomized controlled trial in children with refractory epilepsy. Methods: Children aged 2-14 years who had daily seizures despite the appropriate use of at least three anticonvulsant drugs were enrolled. Children were randomized to receive either the modified Atkins diet or no dietary intervention for a period of 3 months. The ongoing anticonvulsant medications were continued unchanged in both the groups. Seizure control at 3 months was the primary end point. Analysis was intention to treat. Adverse effects of the diet were assessed by parental reports ( Identifier: NCT00836836). Key findings: Among a total of 102 children, 50 were in the diet group and 52 in the control group. Four children discontinued the diet before the study end point, and three children in the control group were lost to follow-up. The mean seizure frequency at 3 months, expressed as a percentage of the baseline, was significantly less in the diet group: 59 ± 54 (95% confidence interval [CI] 44-74.5) versus 95.5 ± 48 (95% CI 82-109), p = 0.003. The proportion of children with >90% seizure reduction (30% vs. 7.7%, p = 0.005) and >50% seizure reduction was significantly higher in the diet group (52% vs. 11.5%, p < 0.001). Constipation was the most common adverse effect among children on the diet (23, 46%). Significance: The modified Atkins diet was found to be effective and well tolerated in children with drug-refractory epilepsy.
To report the efficacy, safety, and tolerability of the low glycemic index treatment (LGIT) in pediatric epilepsy. A retrospective chart review was performed on patients initiating the LGIT at the Massachusetts General Hospital between January 2002 and June 2008. Demographic and clinical information including seizure type, baseline seizure frequency, medications, blood chemistries, side effects, and anthropometrics were collected. Initiation of the LGIT was done in an outpatient setting. Patients were educated by a dietitian to restrict foods with high glycemic index and to limit total daily carbohydrates to 40-60 g. Change in seizure frequency was assessed at 1-, 3-, 6-, 9-, and 12-month follow-up intervals. Seventy-six children were included in the study. Eighty-nine percent had intractable epilepsy (>or=3 antiepileptic drugs). A greater than 50% reduction from baseline seizure frequency was observed in 42%, 50%, 54%, 64%, and 66% of the population with follow-up available at 1, 3, 6, 9, and 12 months, respectively. Increased efficacy was correlated with lower serum glucose levels at some time points, but not with beta-hydroxybutyrate (BOHB) changes or ketosis status at any time point. Only three patients reported side effects (transient lethargy). Blood urea nitrogen (BUN) was elevated in approximately one-third of follow-up laboratory studies. No significant changes were seen in body mass index (BMI) or BMI z-score at any follow-up interval. The most cited reason for treatment discontinuation was the restrictiveness of the diet, in 18 patients (24%). The LGIT was associated with reduced seizure frequency in a large fraction of patients, with limited side effects.