Optimal clinical management of children receiving the ketogenic diet: recommendations of the international ketogenic diet study group

Epilepsia, **(*):1–14, 2008
doi: 10.1111/j.1528-1167.2008.01765.x
Optimal clinical management of children receiving the
ketogenic diet: Recommendations of the International
Ketogenic Diet Study Group
∗Eric H. Kossoff, Beth A. Zupec-Kania, Per E. Amark, §Karen R. Ballaban-Gil,
A. G. Christina Bergqvist, #Robyn Blackford, ∗∗Jeffrey R. Buchhalter,
††Roberto H. Caraballo, ‡‡J. Helen Cross, Maria G. Dahlin, §§Elizabeth J. Donner,
¶¶Joerg Klepper, §Rana S. Jehle, ##Heung Dong Kim, §§Y. M. Christiana Liu,
∗∗∗Judy Nation, #Douglas R. Nordli, Jr., †††Heidi H. Pfeifer, ‡‡‡Jong M. Rho,
§§§Carl E. Stafstrom, †††Elizabeth A. Thiele, ∗Zahava Turner, ¶¶¶Elaine C. Wirrell,
###James W. Wheless, ∗∗∗∗Pierangelo Veggiotti, ∗Eileen P. G. Vining and The Charlie
Foundation, and the Practice Committee of the Child Neurology Society
∗The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA; Children’s Hospital of Wisconsin, Milwaukee,
Wisconsin, U.S.A.;
Karolinska Hospital, Stockholm, Sweden; §Montefiore Medical Center, Bronx, New York, USA;
Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A.; #Children’s Memorial Hospital, Chicago,
Illinois, U.S.A.; ∗∗Phoenix Children’s Hospital, Phoenix, Arizona, U.S.A.; ††Hospital de Pediatr´ıa Prof. Dr. Juan P.
Garrahan, Buenos Aires, Argentina; ‡‡Institute of Child Health and Great Ormond Street Hospital for Children
NHS Trust, London, United Kingdom; §§Hospital for Sick Children, Toronto, Canada; ¶¶Children’s Hospital,
Aschaffenburg, Germany; ##Severance Children’s Hospital, Seoul, South Korea; ∗∗∗Royal Children’s Hospital,
Melbourne, Australia; †††Massachusetts General Hospital, Boston, Massachusetts, U.S.A.; ‡‡‡Barrow Neurologic
Institute, Phoenix, Arizona, U.S.A.; §§§University of Wisconsin – Madison, Madison, Wisconsin, U.S.A.; ¶¶¶Mayo
Clinic, Rochester, Minnesota, U.S.A.; ###Le Bonheur Children’s Medical Center, Memphis, Tennessee, U.S.A.; and
∗∗∗∗University of Pavia, Pavia, Italy
ment regarding the clinical management of the KD.
The ketogenic diet (KD) is an established, effec-
Subsequently endorsed by the Practice Commit-
tive nonpharmacologic treatment for intractable
tee of the Child Neurology Society, this resultant
childhood epilepsy. The KD is provided differently
manuscript addresses issues such as patient selec-
throughout the world, with occasionally signifi-
tion, pre-KD counseling and evaluation, specific di-
cant variations in its administration. There exists a
etary therapy selection, implementation, supple-
need for more standardized protocols and manage-
mentation, follow-up management, adverse event
ment recommendations for clinical and research
monitoring, and eventual KD discontinuation. This
use. In December 2006, The Charlie Foundation
paper highlights recommendations based on best
commissioned a panel comprised of 26 pediatric
evidence, including areas of agreement and contro-
epileptologists and dietitians from nine countries
versy, unanswered questions, and future research.
with particular expertise using the KD. This group
WORDS: Children,
was created in order to create a consensus state-
Epilepsy, Ketogenic.
The ketogenic diet (KD) is a nonpharmacologic treat- (Stafstrom & Rho, 2004; Kossoff & McGrogan, 2005; ment used worldwide for children with intractable epilepsy Freeman et al., 2007). It has been used to treat epilepsy inchildren since 1921 with little variation until recent years Accepted June 20, 2008; Online Early publication xxxxxx xxxx.
(Freeman et al., 2007). The original protocol using a high Address correspondence to Eric Kossoff, Suite 2158 - 200 North Wolfe Street, The Johns Hopkins Hospital, Baltimore, MD, U.S.A. E-mail: fat, low carbohydrate diet was created at the Mayo Clinic in Rochester, MN (Wilder, 1921), and popularized by the Johns Hopkins Hospital in Baltimore, MD (Freeman et al., C 2008 International League Against Epilepsy 1998). The KD was traditionally started in the hospital after E. H. Kossoff et al.
a 48-h fast followed by a gradual introduction of calories As comments and changes were received by all consen- in the form of a KD over a 3-day period. Children were sus members regarding details of the recommendations, it then seen periodically in clinic for medical and nutritional became clear that there were certain topics that were more controversial than others. To convey these areas where con- Over the past decade, however, there has been world- sensus was not obtained, a short survey of 15 questions was wide investigation into which children should be started on then emailed to all 26 participants to obtain a group consen- the KD, as well as the ideal protocol for its implementation sus. Results from this survey were then incorporated into and subsequent follow-up management. Unlike anticonvul- the body of the manuscript, providing percentage responses sant therapy, there are many ways in which to provide the for topics. Following this, all participants later reviewed the KD and each may be valid. With its inherent variability, full manuscript again prior to submission. This consensus there exists a need for standardized KD protocols both in statement has been since endorsed by the Child Neurology order to guide neurologists and dietitians beginning to of- Society who also reviewed the full manuscript.
fer the KD in their individual centers as well as to guidemulticenter research studies. At this time, there are no in- CONSENSUS RECOMMENDATIONS
ternational KD recommendations, with published attemptsmade on a national level in Germany only to date (Klepper Patient selection
Most individuals who develop epilepsy will respond to Recognizing that there is currently insufficient class I ev- pharmacologic treatment, however, approximately 20%– idence for the majority of the clinical management issues 30% will develop medically refractory epilepsy (Sillanp¨a¨a regarding the KD to create a practice parameter (Hender- & Schmidt, 2006). For this population, “alternative” or son et al., 2006), The Charlie Foundation commissioned nonpharmacologic treatments such as dietary therapy can an international committee of neurologists and dietitians be highly efficacious and should be seriously considered.
with expertise in the KD in December 2006 at the Amer- In the past, the use of the KD was limited by the scarcity ican Epilepsy Society meeting in San Diego, CA, U.S.A.
of centers experienced in its use as well as lack of confi- The charge of this consensus group was to provide practi- dence in the diet’s efficacy (Freeman et al., 2007). How- cal recommendations to guide management of the KD.
ever, over the past decade the role of the KD in the treat-ment of intractable epilepsy has become evident from theincreased number of publications available as well as the increased number of epilepsy centers that offer the KD (Kossoff & McGrogan, 2005; Henderson et al., 2006; Free- Experts in the clinical use of the KD were identified by Jim Abrahams, founder of The Charlie Foundation, Beth The KD can effectively treat epilepsy in individuals from Zupec-Kania, RD, CD, Dietitian for The Charlie Founda- infancy through adulthood. For years it was thought that tion, and Eric Kossoff, MD, Medical Director of the Johns infants have difficulty maintaining ketosis while meeting Hopkins Ketogenic Diet Center. Identified clinicians had at their growth requirements, and they therefore were not rou- least one authored, peer-reviewed publication regarding the tinely treated with the diet (Nordli et al., 2001). Adoles- KD or were a member of a center that had published about cents and adults have typically not been considered can- the KD. Attempts were made to avoid more than three clin- didates for KD treatment, although data for its benefit in icians from any individual center. Twenty-six clinicians, of these populations does exist (Barborka, 1930; Sirven et al., which seven (27%) were dietitians, were identified. Eleven 1999; Mady et al., 2003; Kossoff et al., 2008a). When sur- (42%) participants were from outside the U.S.A. Dr. Kos- veyed, 10 (38%) of the consensus group offered dietary soff and the other 24 experts (other than Ms. Zupec-Kania) therapy to adults. Regardless of age, seizure type, or eti- did not receive direct funds from The Charlie Foundation ology, the KD appears to provide a third of the patients nor was this consensus statement subsidized in any way.
with >90% reduction in their seizure frequency (Hender- Participants were asked to write a section topic either individually or in pairs based on both their individual ex- Traditionally, the KD has been reserved as a “last pertise and an outline of clinical issues created by the two treatment option” after establishment of medical in- primary authors (E.K. and B.Z.K.). Instructions were given tractability, typically defined as the failure of three or to keep each section brief (2–3 paragraphs) and focus pri- more anticonvulsant medications. Given its efficacy, the marily on peer-reviewed publications when available. In poor chance of improvement with further anticonvul- the absence of published literature, the participants were sant trials, and the availability of more easily imple- asked to base recommendations on their professional or mented alternatives such as the modified Atkins diet center’s experience. Sections were collected (by E.K.), in- (Kossoff et al., 2006) and Low Glycemic Index Treat- corporated into a full document, and then emailed to the ment (LGIT) (Pfeifer & Thiele, 2005), we propose that dietary therapy be considered earlier as an option for Epilepsia, **(*):1–14, 2008
doi: 10.1111/j.1528-1167.2008.01765.x
Consensus Statement for the Ketogenic Diet
Table 1. Epilepsy syndromes and conditions
Table 2. Contraindications to the use of the KD
in which the KD has been reported
as particularly beneficial
Probable benefit (at least two publications) Carnitine palmitoyltransferase (CPT) I or II deficiency Glucose transporter protein 1 (GLUT-1) deficiency Myoclonic-astatic epilepsy (Doose syndrome) Medium-chain acyl dehydrogenase deficiency (MCAD) Long-chain acyl dehydrogenase deficiency (LCAD) Short-chain acyl dehydrogenase deficiency (SCAD) Severe myoclonic epilepsy of infancy (Dravet syndrome) Medium-chain 3-hydroxyacyl-CoA deficiency.
Children receiving only formula (infants or enterally fed patients) Suggestion of benefit (one case report or series) Surgical focus identified by neuroimaging and video EEG monitoring Subacute sclerosing panencephalitis (SSPE) Preliminary experience also showing some beneficial treatment of difficult-to-manage epilepsy. When surveyed, effects of the KD have been reported in symptomatic 81% of the group believed that the KD should be epilepsies due to Lafora body disease (Cardinali et al., offered to a child after two anticonvulsants are used 2006), Rett syndrome (Haas et al., 1986; Liebhaber et al., 2003; Giampietro et al., 2006), Landau-Kleffner syndrome There are several specific conditions in which the group (Bergqvist et al., 1999), and subacute sclerosing panen- considered the KD could be used potentially even earlier cephalitis (Bautista, 2003). Single reports describe the use (Table 1). The diet is the treatment of choice for two dis- of the diet in metabolic disorders such as phosphofructok- tinct disorders of brain energy metabolism: GLUT1 de- inase deficiency (Swoboda et al., 1997), glycogenosis type ficiency syndrome (Klepper & Leiendecker, 2007) and V (Busch et al., 2005), and mitochondrial respiratory chain pyruvate dehydrogenase deficiency (PDHD) (Wexler et al., complex disorders (Kang et al., 2007a).
1997). In GLUT1 deficiency syndrome, glucose trans- The KD is contraindicated in several specific disorders port across the blood-brain barrier is impaired resulting (Table 2). The metabolic adaptation to the KD involves a in seizures, developmental delay, and a complex move- shift from use of carbohydrates to lipids as the primary ment disorder (Klepper & Leiendecker, 2007). Twenty- energy source. As such, a patient with a disorder of fat four members of the consensus (92%) believed the KD metabolism might develop a severe deterioration in the set- should be considered as a first-line therapy for GLUT1 ting of fasting or a KD. Therefore, before initiating the KD, deficiency syndrome. In PDHD, a severe mitochondrial a child must be screened for disorders of fatty acid trans- disease with lactic acidosis and severe impairment, pyru- vate cannot be metabolized into acetyl-CoA (Wexler et al., Long-chain fatty acids are transported across the mito- 1997). In both disorders, the KD provides ketones that by- chondrial membrane by carnitine, facilitated by carnitine pass the metabolic defect and serve as an alternative fuel to palmitoyltransferase (CPT) I and II and carnitine translo- case (Tein, 2002). Once in the mitochondrion, fatty acids The KD has also been described as particularly useful are β-oxidized to two carbon units of acetyl-CoA that can for certain epilepsy and genetic syndromes as well. My- then enter the tricarboxylic acid cycle and be utilized for oclonic epilepsies, including severe myoclonic epilepsy energy production or ketone body formation. An inborn of infancy (Dravet Syndrome) and myoclonic-astatic metabolic error at any point along this pathway can lead to epilepsy, as described by Doose (Oguni et al., 2002; a devastating catabolic crisis (i.e., coma, death) in a patient Laux et al., 2004; Caraballo et al., 2005, 2006; Kilaru & fasted or placed on a KD. Deficiency of pyruvate carboxy- Bergqvist, 2007; Korff et al., 2007) appear to respond well lase, a mitochondrial enzyme that catalyzes the conversion to the KD. The KD can be beneficial in infants with West of pyruvate to oxaloacetate, will impair tricarboxylic acid syndrome who are refractory to corticosteroids and other cycle function and energy production in patients on the medications (Nordli et al., 2001; Kossoff et al., 2002b; Eun KD. Finally, the KD is contraindicated in porphyria, a dis- et al., 2006). There is evidence from three epilepsy centers order of heme biosynthesis in which there is deficient por- for the benefits of the KD in tuberous sclerosis (Kossoff phobilinogen deaminase; the lack of carbohydrates in the et al., 2005; Coppola et al., 2006a; Kossoff et al., 2007c; KD can exacerbate acute intermittent porphyria. Contrary to prior anecdotal evidence, the KD has been reported in a Epilepsia, **(*):1–14, 2008
E. H. Kossoff et al.
single case series as safe and efficacious in mitochondrial view all current medications to determine carbohydrate diseases, mostly those with Complex I disease (Kang et al., content and options of switching to lower carbohydrate Clinical suspicion about an inborn error of metabolism Before starting the diet, it is crucial to also discuss includes developmental delay, cardiomyopathy, hypotonia, psychosocial issues inherent in the KD. The physician exercise intolerance, myoglobinuria, and easy fatigability should ensure that the parent or caregiver understands (Sankar & Sotero de Menezes, 1999). The presence of one their involvement in administering the KD to their child, of those clinical features suggests that the child should be specifically the importance of strict adherence to the diet, tested to rule out an inborn error of metabolism prior to KD avoidance of carbohydrates, need for multivitamin and mineral supplementation, and awareness of potential ad- Although not a true contraindication, there is recent ev- verse effects. One should also identify any behavioral or idence that children with very focal epilepsy may do less personality traits in the child that will significantly chal- well with the KD than resective surgery (Stainman et al., lenge successful administration of the diet and determine 2007). In this situation, the KD may offer a period of any food allergies and intolerances and cultural/religious both reduced seizures and anticonvulsants, but only rarely a preferences that will need to be considered in meal prolonged seizure-free response. The consensus group had mixed opinion on whether to offer the KD for a child with a Several laboratory studies are suggested before starting clear surgically resectable lesion, with 15 (58%) providing the KD (Table 3). If there is a personal or strong family the KD in this situation as long as the family was ade- history of kidney stones, a renal ultrasound and nephrol- ogy consultation should be obtained. As part of the diag- There are several uncontrolled trials and animal studies nostic workup of a progressive epileptic encephalopathy, describing the potential benefits of the KD for neurologic cerebrospinal fluid evaluation (for glucose, protein, lac- conditions other than epilepsy and the metabolic condi- tate, folate metabolites, amino acids, and potentially neu- tions described previously. These include amyotrophic lat- rotransmitters) as well as a full serum and urine metabolic eral sclerosis (ALS), Parkinson’s disease, Alzheimer’s dis- evaluation should be performed if no clear etiology for the ease, migraine, autism, narcolepsy, brain tumors, and trau- child’s epilepsy has been identified. An electroencephalo- matic brain injury (Freeman et al., 2007). At this time, there gram (EEG) and magnetic resonance imaging (MRI) will is insufficient evidence to recommend the use of the KD for assist in identifying those patients who are possible sur- these conditions other than on an investigational basis.
gical candidates; therefore, these investigations should bestrongly considered.
A key component of the KD is the information the fam- The KD should be strongly considered in a child who ily receives prior to the initiation of the diet. Many fami- has failed two to three anticonvulsant therapies, regard- lies will have preconceived notions about what the KD is, less of age or gender, and particularly in those with symp- how it will be initiated, and expectations of its efficacy, tomatic generalized epilepsies. It can be considered the especially since families have different experiences while treatment of choice for two distinct disorders of brain initiating the diet even within the same facility. Helpful re- metabolism, GLUT-1 deficiency syndrome and PDHD. In sources for families include The Ketogenic Diet: A Treat- the particular epilepsy syndromes of Dravet syndrome, in- ment for Epilepsy in Children and Others (Freeman et al., fantile spasms, myoclonic-astatic epilepsy, tuberous scle- 2006) and publications and videos from support groups rosis complex, the KD could be offered earlier. The KD is such as The Charlie Foundation and Matthew’s Friends.
probably only of limited benefit in children who are candi- High glycemic carbohydrate foods can be reduced slightly dates for epilepsy surgery. Before starting the KD, inborn in advance of the KD to prepare the child for the dietary errors of metabolism that could lead to a severe metabolic crisis should be ruled out. These include disorders of fatty It is important for the ketogenic team to thoroughly dis- acid mitochondrial transport, β-oxidation, and other mito- cuss parental expectations in advance of KD initiation to ensure its success. Many families expect not only seizure Prediet evaluation and counseling
reduction, but also medication reduction and cognitive im- A clinic visit prior to initiation of the KD is neces- provement (Farasat et al., 2006). The team should keep sary and recommended. The goals of this visit are to iden- the expectations realistic for each individual child. The ex- tify the seizure type, rule out metabolic disorders that are pected length of time on the KD if successful is often a contraindications to the diet, and evaluate for complicat- concern that the family wishes to discuss prior to start- ing factors (presence of kidney stones, dyslipidemia, liver ing the KD and a minimum of 3 months (to allow for po- disease, failure to thrive, gastroesophageal reflux, poor tential improvement to occur) should be suggested. The oral intake, constipation, cardiomyopathy, and chronic family should know what challenges they may face both metabolic acidosis) (Table 3). The KD team should re- short- and long-term, such as possible nausea, vomiting, Epilepsia, **(*):1–14, 2008
doi: 10.1111/j.1528-1167.2008.01765.x
Consensus Statement for the Ketogenic Diet
Table 3. Recommendations for pre-KD evaluation
Discuss seizure reduction, medication, and cognitive expectationsIdentify potential psychosocial barriers to the use of KDReview anticonvulsants and other medications for carbohydrate contentRecommend family read parent-oriented KD information Baseline weight, height, and ideal weight for statureBody mass index (BMI) when appropriateNutrition intake history: 3-day food record, food preferences, allergies, aversions, and intolerancesEstablish diet formulation: infant, oral, enteral, or a combinationDecision on which diet to begin (MCT, classic, modified Atkins, or low glycemic index)Calculation of calories, fluid, and ketogenic ratio (or percentage of MCT oil)Establish nutritional supplementation products based on dietary reference intake Complete blood count with plateletsElectrolytes to include serum bicarbonate, total protein, calcium, zinc, selenium, magnesium, and phosphateSerum liver and kidney tests (including albumin, AST, ALT, blood urea nitrogen, creatinine)Fasting lipid profileSerum acylcarnitine profileUrinalysisUrine calcium and creatinineAnticonvulsant drug levels (if applicable)Urine organic acidsSerum amino acids Renal ultrasound and nephrology consultation (if a history of kidney stones)EEGMRICerebrospinal fluid (CSF) (if no clear etiology has been identified)EKG (echocardiogram) if history of heart disease behavioral outbursts, and various other medical complica- et al., 1989; Neal et al., 2008). In the classic KD, fat is tions, and how to address these issues if they arise. A social a LCT and obtained primarily from standard foods, protein worker on the team can be instrumental in helping the fam- is based on minimum requirements for growth, and carbo- ily transition to the KD by assessing family needs, gather- hydrates are restricted. MCT oils yield more ketones per ing resources, and contacting other families on the KD for kilocalorie of energy than their long chain counterparts; they are absorbed more efficiently and carried directly to It is also important for the family to know what to ex- the liver. This increased ketogenic potential means less to- pect during the hospital stay, such as whether tests (such as tal fat is needed in the MCT diet, thus allowing inclusion of EEG) or medical interventions (such as intravenous fluids) more carbohydrate and protein. Data from studies 20 years are likely. Parents are allowed to bring games and books apart now suggest no difference in efficacy between the to help keep the child comfortable during this time. Topics two diets if applied appropriately in a calculated fashion including meal preparation, managing sick days, traveling, (Schwartz et al., 1989; Neal et al., in press). There may celebrations, and nutritional supplements can be discussed be some differences in tolerability but this did not reach statistical significance in a recent randomized controlledtrial with direct comparison between the two (Neal et al., There are several important prerequisites to starting the The classic KD is calculated in a ratio of grams of fat KD to ensure both safety and to maximize the chances of to grams of protein plus carbohydrate. The most common ratio is 4 g of fat to 1 g of protein plus carbohydrate Specific diet selection and provision
(described as “4:1”). This means that 90% of the energy There has often been discussion as to whether there is comes from fat and 10% from protein and carbohydrate an optimal way to administer the KD. The classic (long combined. Sometimes it is necessary to provide the KD chain triglyceride or LCT) diet has been the more tradi- at a lower ratio to increase protein or carbohydrate intake.
tional KD treatment, for which most data are available, There is some evidence that a 4:1 ratio, when used at ini- but the medium chain triglyceride (MCT) diet may be tiation, may be more advantageous for the first 3 months preferable in some cases (Huttenlocher, 1976; Schwartz Epilepsia, **(*):1–14, 2008
E. H. Kossoff et al.
Calories are typically restricted to 80%–90% of the daily emulsion such as Microlipid (Nestle, Vevey, Switzerland) recommendations for age; however, this has never been to add the needed fat to achieve the goal KD ratio. In addi- shown in patients to be beneficial (Vaisleib et al., 2004).
tion, water must be added to Ross Carbohydrate Free for- Additionally, an underweight child should be started at mula for proper dilution. Both combinations are fortified calories based on current weight then increased gradu- with vitamins and minerals; however each should be com- ally over time. An overweight child should be allowed to pared to age-appropriate requirements and supplemented grow to appropriate length for weight rather than incurring to meet the Dietary Reference Intakes (DRI) established weight loss, although in some children attaining a more by the National Academy of Sciences. In addition, a for- ideal body weight may be nutritionally indicated. Simi- mula may also be created from pureed infant foods with the larly, fluid restriction to 90% is also based on historical use addition of a liquid fat source, diluted with water, and sup- of the diet rather than on scientific evidence. Many centers plemented with micronutrients. This formula may be nec- no longer fluid restrict children on the KD.
essary when allergies to both soy and milk protein formulas The traditional MCT diet comprises 60% energy from MCT. This level of MCT can cause gastrointestinal dis- In the past few years, two other dietary therapies have comfort in some children, with reports of abdominal been developed for the treatment of epilepsy: the modi- cramps, diarrhea, and vomiting. For this reason, a mod- fied Atkins diet and LGIT (Pfeifer & Thiele, 2005; Kossoff ified MCT diet was developed, using 30% energy from et al., 2006; Kang et al., 2007b; Kossoff et al., 2007b). Un- MCT, with an additional 30% energy from long chain fat.
like the classic KD, both of these dietary therapies are ini- In practice, a starting MCT level somewhere between the tiated without an inpatient hospital stay and they do not two (40%–50% energy) is likely to be the best balance be- require precise weighing of food ingredients and portions.
tween gastrointestinal tolerance and good ketosis. This can Both diets require less dietitian time for meal calculations, be increased or decreased as necessary during fine-tuning; but more parental independence. All but one member of the many children will tolerate 60% or higher energy from consensus group (96%) offers these diets to children.
MCT and need this amount for optimum ketone levels and The modified Atkins diet is similar to the classic KD in seizure control. MCT oil has also been used to augment the its composition and is approximately a 1:1 ketogenic ratio traditional KD to stimulate ketones and for its beneficial (Kossoff et al., 2006). The initial daily carbohydrate con- laxative property. MCT can be given in the diet as oil, as sumption on the modified Atkins diet is approximately 10 coconut oil, or as an emulsion (Liquigen, SHS, Liverpool, g (comparable to the strict initiation phase of the Atkins U.K.). MCT should be included in all meals when used.
diet used for weight loss), with a planned increase to 15– Less quantity of MCT with each meal, with more meals 20 g/day after 1–3 months (Kossoff et al., 2007b). How- ever, there are no limitations on protein, fluids, and calo- The KD may be delivered as an all-liquid, formula-based diet (Kossoff et al., 2004a; Hosain et al., 2005). Tolera- The LGIT was developed following the observation that bility and adverse effects of the KD in infants is similar children on the classic KD have stable blood glucose lev- to that in older children. The KD may also be easily ad- els and the hypothesis that this may relate at least in part ministered to enterally fed children. As expected, enter- to the mechanism of the KD (Pfeifer & Thiele, 2005).
ally (including gastrostomy and jejunostomy) fed children The LGIT allows liberalization of total daily carbohydrate demonstrate very high compliance rates, exceeding those intake to approximately 40–60 g/day, but regulates the in most solid food KD series, and efficacy is also high type of carbohydrate, favoring those that produce relatively (Kossoff et al., 2004a; Hosain et al., 2005). Prescription small changes in blood glucose (those with low glycemic of a formula-based KD is generally simpler for dietitians to calculate, requires less education of families and care- Small, uncontrolled reports suggest that both modified givers, and due to the ease of delivery of an all-liquid KD, diets show efficacy rates similar to the classic KD. These ketosis is easily maintained as errors are less common.
diets may also be of value for adolescents and adults not To prepare a formula-based KD, three commercial prod- typically offered the traditional KD. In fact, 11 (42%) of ucts are currently available. KetoCal (for North America: the consensus group believed these diets should be used Nutricia, Rockville, MD, U.S.A. and for Europe: SHS) is primarily when treating adolescents. Larger, randomized a milk protein-based, powdered formula to which water studies are needed to better understand the efficacy and is added. This provides either a 3:1 or 4:1 KD; however, tolerability of these diets, how they compare to the clas- fat and protein modulars may be added to customize the sic KD, and potential use in adults.
diet for each child. Ross Carbohydrate Free Soy FormulaBase With Iron (Abbott Nutrition, Columbus, OH, U.S.A.), which provides protein, some fat, and vitamins and miner- There is no evidence of increased efficacy of MCT ver- als, may also be combined with a carbohydrate polymer sus LCT, therefore which KD is chosen should be based such as Polycose powder (Abbott Nutrition), and a lipid on the dietary needs and habits of the individual child, Epilepsia, **(*):1–14, 2008
doi: 10.1111/j.1528-1167.2008.01765.x
Consensus Statement for the Ketogenic Diet
although it may be influenced by the experience of the (58%) members believed fasting was not necessary but did team involved. An all-liquid, formula-based KD is recom- have benefit, eight (31%) did not believe fasting should be mended for use in infants who have not yet transitioned to used, and three (11%) stated that fasting should be univer- solid foods and for individuals fed enterally. There is pre- liminary evidence for the use of both the less restrictive The main reasons for inpatient initiation include safety modified Atkins diet and LGITs, but the optimal patient (management of acute medical side effects) and education populations for these diets have not yet been identified.
of care providers. Twenty-three members (88%) routinely These latter two therapies may be advantageous for ado- admit children for initiation of the KD. However, it is pos- sible to start the KD as an outpatient, based on two retro-spective studies encompassing 8 and 37 patients, respec- Diet initiation
tively, in which no fasting period was used (Wirrell et al., The KD initiation practices have their origin in the 2002; Vaisleib et al., 2004). Although there were no serious historical use of periodic fasting to treat seizures. Fast- side effects related to unmasking an underlying metabolic ing is therefore part of the KD initiation in many centers disorder with an outpatient approach, the size of these worldwide. Because of concerns that fasting may result samples is too small to expect discovery of relatively rare in hypoglycemia, acidosis, nausea, vomiting, dehydration, anorexia, lethargy, and a small risk for increase in seizures, The potential advantages of an outpatient, gradual KD most centers begin the KD in the hospital so that the patient initiation include less stress for the child, no absence can be closely observed, and medical interventions can be from the home for the care providers, and significantly re- instituted if necessary. Hospitalization also provides the duced costs associated with hospitalization. However, to opportunity for intensive teaching of the caregivers on how provide the KD initiation as an outpatient, all children to calculate, weigh, design meals, and manage the KD at must be screened completely prior to starting the KD with metabolic testing, the child must be in close proximity to The traditional method of initiating the KD involves a medical care, and the KD team must be able to provide all period of fasting, with no carbohydrate-containing fluids the family education in an outpatient setting. Although as provided, and serum glucose monitored periodically (Free- stated previously, most centers still routinely admit for KD man et al., 2006). The duration of fasting varies from 12 h initiation, 19 (73%) members believed that an outpatient to “when urine ketones are large,” which can be longer than initiation could be used in very select situations.
48 h. Children should not be fasted longer than 72 h. The meals are then typically advanced daily in one-third caloric At this time, there is evidence that the traditional KD intervals until full calorie meals are tolerated, while keep- protocol can be altered successfully to ease its implemen- ing the KD ratio constant. Another approach begins with tation. Fasting may be appropriate when a quicker time to full calories, but the KD ratio increases daily from 1:1, 2:1, response is desired, but is not necessary for long-term effi- 3:1, to 4:1 to allow the patient to acclimate to the increasing cacy, and may have more immediate side effects. In select concentration of fat (Bergqvist et al., 2005).
situations, the KD can also be started as an outpatient.
In most clinical trials of KD efficacy, a fasting initia- tion protocol was used. However, there is now retrospec- Medications and the KD
tive (Kim et al., 2004) and prospective data indicating that The KD is traditionally used in patients who have failed fasting is not necessary for achievement of ketosis, and that to respond to anticonvulsant medications. Specifically, it is gradual initiation protocols offer the same seizure control customary to add the KD to an existing regimen of drugs.
at 3 months with significant lower frequency and sever- Hence, with the exception of patients whose drugs are ity of initiation related side effects (Bergqvist et al., 2005).
eventually discontinued due to an excellent response to the In addition, weight loss, hypoglycemia, and acidosis were KD, little is known about both the efficacy and tolerability less common when children were not fasted in this study of the KD without the confound of concomitant medica- (Bergqvist et al., 2005). Vomiting did not differ in the tions. Surprisingly, despite decades of combined use of an- two protocols, but intravenous fluids for dehydration were ticonvulsants and the KD, it remains unclear whether there more commonly needed in the fasting group. Continued are negative or positive pharmacodynamic interactions, and use of fasting protocols is therefore based on the centers’ only scant information regarding the impact of the KD on individual practice rather than a need for seizure control.
the pharmacokinetics of anticonvulsants.
Some older as well as recent evidence suggests that fast- At present, there are no data supporting any signifi- ing does lead to a quicker onset of seizure reduction, and cant pharmacodynamic interactions between anticonvul- therefore may be advantageous when a more immediate re- sant drugs and the KD. That is, no particular combination sponse is desired (Freeman & Vining, 1999; Kossoff et al., of anticonvulsants and the KD have been shown to yield 2008b). There was a difference of opinion between mem- either greater or less efficacy in terms of seizure protec- bers of the consensus group in regards to fasting. Fifteen tion at this time. The KD may have synergistic benefits Epilepsia, **(*):1–14, 2008
E. H. Kossoff et al.
when used in combination with a nonpharmacologic ther- 1976). Clinicians should be mindful that formulations of apy; namely vagus nerve stimulation (VNS) (Kossoff et al., many drugs, including nonanticonvulsants, contain carbo- 2007a). Serum levels of commonly used anticonvulsant hydrates or sugars as additives (Lebel et al., 2001), and agents, when corrected for changes in dose and weight (i.e., should seek alternatives whenever possible.
plasma concentration in relation to the dose per kilogram of body weight per day), do not appear to be altered by the At this time, there is little evidence of any consistent pos- itive interactions between the KD and anticonvulsants. The There is a historical perception that valproic acid should KD may work well in combination with VNS. Conversely, not be used together with the KD. This stems from the con- the KD is not negatively affected in regards to efficacy or cerns for idiosyncratic side effects of valproic acid (i.e., side effects by any particular anticonvulsant. Medications hepatotoxicity) and for the fact that this medication is a can often be reduced within the first few months if the KD short-chain fatty acid. Clinicians have generally feared that is successful, although caution is advised especially when enhanced fatty acid oxidation, a consequence of using the reducing phenobarbital and benzodiazepines.
high-fat KD, might increase the risk of hepatotoxicity. De- Diet supplementation
spite such fears, recent clinical evidence supports the safe Sufficient vitamins and minerals are normally found in use of valproic acid and the KD (Lyczkowski et al., 2005).
a well-balanced diet, however due to the limited quanti- But while idiosyncratic adverse reactions are not neces- ties of fruits, vegetables, enriched grains, and foods con- sarily heightened, it does appear that secondary carnitine taining calcium on the KD, supplementation is essential, deficiency, which can occur with either the KD or valproic especially for B vitamins (Table 4). There is little vitamin acid alone, can be worsened (Coppola et al., 2006b).
D and calcium in KD food and evidence for decreased Vi- The KD is also known to cause a transient but often clin- tamin D levels in children with epilepsy, and therefore both ically asymptomatic metabolic acidosis. Adding the KD vitamin D and calcium should be supplemented (Bergqvist to an existing regimen of carbonic anhydrase inhibitors et al., 2007). Additional supplementation (e.g., zinc, se- (topiramate and zonisamide) may in fact worsen preexist- lenium, magnesium, phosphorus) was suggested by some ing metabolic acidosis, but the greatest decreases in serum group members, but at this time there is insufficient evi- bicarbonate levels occur early after initiation of the diet dence to recommend their use above what is provided in a (Takeoka et al., 2002). It is recommended that bicarbonate levels should be monitored carefully, especially when re- Carbohydrate-free or minimal carbohydrate-containing ceiving these anticonvulsants, and that bicarbonate supple- multivitamin and mineral products should be used. Some ments be given when patients are clinically symptomatic vitamins and supplements that will be discussed may (vomiting, lethargy). There may be health benefits, specifi- have limited availability based on individual country. In cally to bone density, in the use of bicarbonate supplements the U.S., commonly used preparations include Centrum for children with acidosis, but this has not been proven. It (Wyeth, Madison, NJ, U.S.A.) and Bugs Bunny Sugar-free does not appear that carbonic anhydrase inhibitors, which (Bayer, Morristown, NJ, U.S.A.). Multibionta (Seven Seas, can increase the risk of kidney stones separately, have an Marfleet, U.K.) is a multivitamin supplement also available increased likelihood of stones when used in combination as a liquid formulation. A relatively new vitamin designed with the KD (Kossoff et al., 2002a). However, it is wise to for the KD and allergy population is called NanoVM observe children for stones more carefully when on car- (Solace Nutrition, Rockville, MD, U.S.A.). This product bonic anhydrase inhibitors and perhaps empirically startoral citrates such as Polycitra K (Cypress Pharmaceuticals,Madison, MS, U.S.A.) (Sampath et al., 2007). There is no Table 4. Supplementation recommended
evidence for routine renal ultrasound surveillance, how- for children receiving the KD
ever, or automatic discontinuation of these anticonvulsants Multivitamin with minerals (and trace minerals) Discontinuing medications is often a major goal of the KD and typically advised after several months of success.
However, there is evidence that anticonvulsants can be re- Oral citrates (Polycitra K)Laxatives: Miralax, mineral oil, glycerin suppository duced successfully even during the first month of the KD Additional selenium, magnesium, zinc, phosphorus, vitamin D (Kossoff et al., 2004b). Seizure exacerbations are more likely when phenobarbital or benzodiazepines are the an- ticonvulsants weaned, so caution is recommended when Salt (sodium to add to modular formulas if used for greater Finally, ingestion of carbohydrates can quickly reverse All supplements listed should be provided as carbohydrate- the ketosis achieved by the KD in some children and free preparations whenever possible.
may lead to resumption in seizure activity (Huttenlocher, Epilepsia, **(*):1–14, 2008
doi: 10.1111/j.1528-1167.2008.01765.x
Consensus Statement for the Ketogenic Diet
is virtually carbohydrate-free, is formulated to meet 100% be preventative for kidney stones, but its empiric use has of the micronutrient needs of children, and is available in not yet been established as beneficial.
two preparations for ages 1–3 and 4–8 years.
There is evidence for the preventative use of oral cit- Maintenance of children receiving the KD
rates (Polycitra K more so than Bicitra) in regards to reduc- The child on the KD should be seen regularly for follow- ing the risk of kidney stones. In a retrospective study, the up evaluation by both dietitian and neurologist familiar risk was reduced three-fold with their use; many children with the KD (Table 5). At discharge, the parents should be who presented with renal stones in this study had not been given specific contact phone numbers and e-mail addresses started on Polycitra K, despite occasionally borderline ele- for the KD team, especially the dietitian. The child should vations in their urine calcium to creatinine ratio (Sampath be seen initially at least every 3 months after hospital dis- et al., 2007). The empiric use of citrates in all children on charge with follow-up contact in the interim, especially if the KD may be sensible, but has not been tested prospec- expected urinary ketosis is not maintained. A child under tively in a controlled manner for kidney stone prevention.
1 year of age may be seen back in 2–4 weeks and should Citrates may also reduce acidosis and theoretically bone have more frequent contact with the KD team. Other chil- mineral loss; however, there is evidence that folic acid ab- dren that may require extra attention include those with sorption is reduced in an alkaline environment induced by cerebral palsy, whose growth parameters are at or less than bicarbonate use, which may increase the risk for mega- the fifth percentile, and any child with continued difficulty loblastic anemia (Benn et al., 1971).
consuming the KD or with an illness shortly after KD ini- Gastrointestinal dysmotility can be a common side effect tiation. After 1 year on the KD, visits can be spaced out to of the KD; however, empiric supplementation to alleviate every 6 months with phone contact in the interim.
this has not been studied. Children are often started on H2- At this time, the majority (96%) of the consensus group blockers or proton pump inhibitors for gastroesophageal advocates routine urine ketosis evaluation by parents sev- reflux, but most commonly after this condition occurs.
eral times per week. There is limited data regarding the Constipation is even more common on the KD, and par- value of serum β-hydroxybutyrate (BOH), with one study ents should be aware of prevention techniques including suggesting that serum BOH may better correlate with the use of higher fiber vegetables, sufficient fluids, and if seizure control (Gilbert et al., 2000). Many members of necessary, the use of carbohydrate-free laxatives.
the consensus group believed that obtaining serum BOH at Carnitine supplementation has been a controversial is- routine KD clinic visits was valuable, but only four (15%) sue, with variability in its use between many centers world- suggested parents use home BOH meters. It is reasonable wide. Secondary hypocarnitinemia can cause serious sys- to obtain serum BOH in clinical situations where urine ke- temic complications such as hepatitis and cardiomyopathy, tosis does not correlate with expected seizure control (e.g., although the incidence is quite low (Berry-Kravis et al., absent urinary ketosis despite seizure freedom or large uri- 2001). Relatively common symptoms indicating hypocar- nary ketosis in the setting of worsening seizures).
nitinemia are generalized weakness, excessive fatigue, and In addition to a complete examination, including accu- decreased muscle strength, which are common in many pa- rate growth parameters such as weight and height, labora- tients with intractable epilepsy. Prolonged use of anticon- tory studies are recommended. Special attention is given vulsants such as valproic acid, poor nutritional status, and to serum albumin and total protein concentration to ensure long-term use of KD are the causes of secondary hypocar- the KD is providing enough protein and calories. Fasting nitinemia, especially in younger patients (Coppola et al., cholesterol and triglyceride levels typically rise and should 2006b). Laboratory measurement of serum carnitine is not be monitored. Decisions regarding withdrawal of anticon- easily feasible in some countries. Carnitine supplementa- vulsants depends on the child’s response to the diet (see tion may also be expensive if not covered by insurance previous section). The majority of centers do not obtain and adds an additional medication that is often dosed three routine renal or carotid ultrasounds, echocardiograms, or times a day. Seventy-seven percent of the consensus group bone mineral density evaluations. Nine (35%) consensus obtains baseline carnitine levels, and 81% check levels at members routinely check an EEG after several months on follow-up visits. The majority recommends that carnitine should only be supplemented orally if either levels are low While receiving the KD, there needs to be ongoing nutri- (65%) or children become symptomatic (27%).
tional support and management. Caloric intake and growthparameters should be reviewed at least every 3 months forthe first year on the KD to ensure appropriate weight gain for age and length. Infants under 1 year of age should be There is evidence for the use of low-carbohydrate multi- monitored more frequently to prevent growth disturbance vitamin and mineral supplements in the routine use of the (Vining et al., 2002). If a child is overly hungry or not eat- KD. There is no evidence for the empiric use of antacids, ing their meals, calories should be adjusted accordingly.
laxatives, or carnitine with the KD. Oral citrates appear to There is no evidence that excessive weight gain or loss Epilepsia, **(*):1–14, 2008
E. H. Kossoff et al.
Table 5. Recommendations for aspects of a follow-up KD clinic visita
Nutritional assessment (registered dietitian) Obtain height weight, ideal weight for stature, growth velocity, BMI when appropriateReview appropriateness of diet prescription (calories, protein, and fluid)Review vitamin and mineral supplementation based on dietary reference intake guidelinesAssess compliance to therapyAdjust therapy if necessary to improve compliance and optimize seizure control Efficacy of the diet (is the KD meeting parental expectations?)Anticonvulsant reduction (if applicable)Should the KD be continued? Complete blood count with plateletsElectrolytes to include serum bicarbonate, total protein, calcium, magnesium, and phosphateSerum liver and kidney profile (including albumin, AST, ALT, blood urea nitrogen, creatinine)Fasting lipid profileSerum acylcarnitine profileUrinalysisUrine calcium and creatinineAnticonvulsant drug levels (if applicable) Serum β-hydroxybutyrate (BOH) levelZinc and selenium levelsRenal ultrasoundBone mineral density (DEXA scan)EEG aVisits should be at least every 3 months for the first year of the KD.
adversely affects KD effectiveness for seizure control, on appropriate fluid volume as a daily goal. If appropriate fluid intake cannot be met, a urine specific gravity within The ketogenic ratio for the classic KD and percentage normal limits (<1.015) is a good measure of adequate MCT oil for the MCT diet may also be adjusted upwards in the case of decreased ketosis and loss of seizure con- At each clinic visit, but definitely according to the con- trol, and lowered in situations of diet intolerability, severe sensus group after a median of 2 years (range: 0.5–4 dyslipidemia, poor linear growth, or excessive ketosis re- years), a thorough reevaluation of the KD risks and benefits sulting in lethargy. A single study evaluating a planned de- should be considered. Parents should be allowed a primary crease from a 4:1 to 3:1 ratio after 3 months found no loss decision-making role in deciding how long to maintain the of seizure control by this change or significant improve- KD for their child unless there are clear medical concerns.
ment in seizure control by increasing the ratio (Seo et al., 2007). Ratios higher than 4.5:1 are generally not used for Ongoing clinic visits at least every 3 months for the first more than a few months, because of the increased risk of year with ready access to experienced advice are important adverse effects and poor compliance. Lowering the ratio to for successful management of children receiving the KD.
2:1 or 1:1 can be implemented for children who are expe- More frequent visits may be necessary for infants and other riencing extreme difficulties adhering to the stricter ratios, patients at high risk for nutritional deficiency. All children particularly older adolescents and teenagers. Liberalizing should be seen by an experienced pediatric neurologist and the diet in this manner is similar to implementing the low dietitian and have a nutritional assessment, laboratory eval- glycemic index or modified Atkins approaches (Pfeifer & uation, and discussion regarding KD and anticonvulsant Thiele, 2005; Kossoff et al., 2006).
Liberalization of fluid should be considered for patients at increased risk for dehydration, such as those with in- Adverse effects of the KD
creased activity, febrile illness, or exposure to warm tem- Although there have been numerous clinical trials of the peratures, as well as infants. Low carbohydrate diets have KD, adverse events have not been consistently reported a diuretic effect and in addition, unlike a normal diet, the in these studies. However, side effects of the diet do oc- contribution of fluid from the restricted volume of foods in cur, and neurologists and dietitians need to be observant the KD is minimal. It is helpful for families to be counseled (Ballaban-Gil et al., 1998; Wheless, 2001).
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Metabolic abnormalities are relatively minor side effects of the KD and include hyperuricemia (2%–26%), hypocal- Like all medical therapies, the KD has potential adverse cemia (2%), hypomagnesemia (5%), decreased amino acid effects. Overall, the risk of serious adverse events is low, levels and acidosis (2%–5%) (Schwartz et al., 1989; Ches- and the KD does not need to be discontinued for these ney et al., 1999; Kang et al., 2004). Gastrointestinal symp- reasons for most children. However, physicians need to be toms including vomiting, constipation, diarrhea, and ab- aware of these potential risks so they can properly counsel dominal pain occur in 12%–50% of children (Kang et al., parents and monitor children for the development of these 2004). Carnitine deficiency has also been demonstrated, as described previously (Berry-Kravis et al., 2001). Hyperc-holesterolemia has been reported in 14%–59% of children KD discontinuation
on the KD (Chesney et al., 1999; Kwiterovich et al., 2003; The timing and actual method of KD discontinuation are often individualized based on patient response to the diet.
Renal calculi occur in 3%–7% of children on the KD Most parents are counseled to continue the KD, even if ap- (Furth et al., 2000; Kossoff et al., 2002a; Sampath et al., parently ineffective, for at least 3 months (Freeman et al., 2007). Stone composition includes uric acid (50% of 2006). The consensus group agreed that the KD should be stones), calcium oxalate, calcium phosphate, and mixed used for at least a mean of 3.5 months (SD 2.2 months) be- calcium/uric acid stones. They typically do not require diet fore considering discontinuation. Recent data suggests that discontinuation and lithotripsy is only rarely necessary. As the KD works rapidly when effective, with 75% of chil- previously stated, Polycitra K appears to help prevent stone dren responding within 14 days (Kossoff et al., 2008b), so shorter KD durations may be adequate to assess effi- There is conflicting data on the effect of the KD cacy. Should seizures worsen for more than a few days af- on growth in children. One retrospective review of lin- ter starting the KD, similar to anticonvulsants, it could be ear growth found that 86% of children on the diet had discontinued immediately. If a family chooses to remain slowed growth, and this effect was independent of mean on the KD for longer than 6 months despite no apparent age, length of time on the diet, or protein and energy in- seizure control, the decision is ultimately their own and take per body weight (Williams et al., 2002). A prospective study of 237 children found that the while older children In children with >50% seizure response, the KD is of- grew “almost normally”; younger children grew poorly ten discontinued after approximately 2 years; however, in (Vining et al., 2002). There does not appear to be a differ- children in whom seizure control is nearly complete (e.g., ence between diets used despite the greater protein content >90% seizure reduction) and side effects are low, the diet of the MCT diet (Neal et al., in press).
has been reported as helpful for as long as 6–12 years Cardiac abnormalities have been reported, most anecdo- (Groesbeck et al., 2006). This 2-year period is tradition- tally, in children on the KD, including cardiomyopathy and ally based on a similar time period used for anticonvul- prolonged QT interval (Best et al., 2000; Bergqvist et al., sant drugs, which are often discontinued after that time in 2003; Kang et al., 2004). The mechanism of these compli- children who become seizure-free. Children with GLUT-1, cations is unknown; one case was associated with selenium PDHD, or tuberous sclerosis complex may require longer deficiency, but others were not. Pancreatitis has also been KD durations than other conditions. Nineteen (73%) mem- reported (Stewart et al., 2001; Kang et al., 2004).
bers routinely obtain an EEG prior to a planned KD dis- The long-term complications in children maintained on continuation. For those in whom the diet has led to seizure the KD for greater than 2 years have not been systemat- freedom, 80% of children will remain seizure-free after the ically reviewed; there is only one report in the literature diet has been discontinued (Martinez et al., 2007). How- looking at this small subgroup (Groesbeck et al., 2006). In ever, the risk of recurrence is higher in those with epilepti- this population, there was a higher risk of bone fractures, form EEGs, structural abnormalities on neuroimaging, and kidney stones, and decreased growth, but dyslipidemia was tuberous sclerosis complex (Martinez et al., 2007).
not identified (Groesbeck et al., 2006). It may be advan- Although the diet can be discontinued abruptly in an tageous in any child receiving the KD for long-term use, emergency, typically in an intensive care unit, it is more of- or anticonvulsants for that matter, to have periodic dual ten tapered slowly over 2–3 months by gradually lowering energy x-ray absorptiometry (DEXA) screening for bone the ketogenic ratio from 4:1 to 3:1 to 2:1, then ketogenic health. In particular, the long-term effects of this high-fat foods are continued, but calories and fluids are increased diet on the cardiovascular system remain to be determined.
ad libitum. Once urinary ketosis is lost, high carbohy- There were no particular adverse effects that the consen- drate foods can be reintroduced. This recommendation is sus felt strongly should lead to automatic diet discontinu- based on traditional practice patterns, and mimics the sev- ation. All members believed that the adverse effects of the eral week gradual wean of anticonvulsant drugs (Freeman KD need to be considered always in comparison to its ben- et al., 2006). During this time period, the group recom- mends continued nutritional supplementation. If seizures Epilepsia, **(*):1–14, 2008
E. H. Kossoff et al.
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doi: 10.1111/j.1528-1167.2008.01765.x

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Structural phase stability and electron-phonon coupling in lithium Department of Physics, Georgetown University, Washington, DC 20057-0995 Lawrence Livermore National Laboratory, Livermore, California 94550 Department of Physics, Georgetown University, Washington, DC 20057-0995 Department of Physics, University of Guelph, Guelph, Ontario, Canada N1G 2W1 Department of Physics, Georgetow

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