An Overview of the Ketogenic Diet for Pediatric EpilepsyFrom Nutritional Services, Children's Hospital of Wisconsin, Milwaukee, Wisconsin. Address correspondence to: Beth A. Zupec-Kania, RD, Children's Hospital of Wisconsin, Nutritional Services MS#802, 9000 W. Wisconsin Ave, Milwaukee, WI 53122; e-mail: bkania{at}chw.org.
Epilepsy is the most common serious neurological condition in the world, with an estimated prevalence of 1% of the population. The highest incidence occurs in childhood and in the elderly, with lower levels in early adulthood. Traditional epilepsy management includes pharmacological treatment, epilepsy surgery, and vagal nerve stimulation. Despite these therapies, 25% of children continue to have uncontrolled seizures. The ketogenic diet (KD), which has been in use since 1921, is a treatment option for many of these children. A meta-analysis of 19 studies with a combined sample of 1084 pediatric patients was completed in 1998 by Blue Cross Blue Shield. Estimates of the overall efficacy of the KD in controlling seizures were reported as follows: 16% became seizure free, 32% had a >90% reduction in seizures, and 56% had a >50% reduction. The KD is high in fat, moderate in protein, and low in carbohydrates. This combination of energy results in a sustained ketosis that somehow serves to abate seizures through an unknown mechanism. Strict adherence to the diet is required for it to be effective. Newer, more liberal versions of the KDs have been recently introduced and are being studied in children and adults. Administration of all of these metabolically adjusted diets must be medically managed as there can be adverse effects. The focus of this review is on the pediatric application of the KD.
Key Words: diet therapy • ketosis • ketones • seizures • epilepsy Fasting as a method to control seizures has been recognized for centuries, perhaps since biblical times. Deliberate fasting has been shown to control seizures.1 The impracticality of prolonged starvation became the drive to formulate the ketogenic diet (KD). The diet was designed to simulate the ketosis of starvation by supplying fat as the major source of calories, while restricting protein and carbohydrate. During metabolism of a regular diet, glucose is derived from carbohydrate and is the main fuel source for the body and brain. Conversely, in the absence of significant carbohydrate and the abundance of dietary fat, mitochondrial β-oxidation of fatty acids in the liver generates large quantities of the ketone bodies acetoacetate and β-hydroxybutryate (BHB), which the brain can readily use as energy metabolites. Excess production of ketone bodies results in a state of ketosis. The exact mechanisms of seizure inhibition remains unknown; however, animal research has demonstrated the neuroprotective effects of the diet, which no other antiepileptic therapy has been known to provide.2,3 Ketogenic diets are categorized as either long-chain fatty acid based (classic) or medium-chain fatty acid based. Common to both diets is the low glycemic effect that they produce because carbohydrate is restricted and the high fat content slows the absorption of carbohydrate. Serum glucose levels of children on KDs are typically between 55 and 75 mg/dL. These diets are provided with controlled calories to prevent excessive weight gain but with sufficient calories to support growth. The classic diet is calculated using a ratio of the weight of fat to the sum of protein and carbohydrate. In a 4:1 ratio, there are 4 g of fat for every 1 g of protein and carbohydrate combined. Protein is provided to meet dietary reference intake, which is approximately 1 g per kilogram of body weight. Carbohydrate completes the remaining allowance of the ratio. A 3:1 ratio is generally used for older children who have greater body mass and therefore higher protein needs. To achieve these ratios, foods rich in carbohydrate are eliminated from the diet, including sugar, pasta, bread, and grains; however, low-carbohydrate vegetables and fruit are allowed. The main sources of fat are heavy cream, vegetable oils, and butter. In addition to meals, KD snacks are recommended for active children. A typical day includes 3 meals plus 1-2 snacks (as shown in Table 1).
An example of a 1000-cal diet with a 4:1 ratio provides the following: 100 g fat, 18 g protein, and 7 g carbohydrate. These values are divided evenly among the number of daily meals and thus all meals are interchangeable. A mathematical algorithm is used to account for the fat, protein, and carbohydrate content of each food and to calculate the amounts of food in grams that are needed to achieve goal values per meal. Each meal plan becomes a recipe to guide the caregiver on how to prepare and then weigh each food item on a metric scale. The calculation of a single meal can be tedious, and the possibility for errors is significant. Computer applications for calculating KDs, such as KetoCalculator, are available and can save time and minimize errors.4 A sample calculation of a single meal is shown in Table 2.
A medium-chain triglyceride (MCT) diet contains 70% calories from fat, using MCT oil as the main source (50%) and 20% from polyunsaturated sources. (MCT oil is extracted from coconut oil by a process called fractionation.) This results in a ratio of fat to nonfat of approximately 1:1, allowing more carbohydrate and protein and significantly less fat than the classic KD. The main complaints from users of this version of the diet have been GI side effects, including diarrhea and abdominal pain. Another disadvantage includes the high cost of MCT oil and the difficulty in receiving reimbursement from insurance companies for its use.5 A study of 6 children receiving the MCT diet who were transitioned to coconut oil (which contains 45% MCTs) was recently presented. This small study revealed that coconut oil was equally effective in maintaining ketosis, was well tolerated by all 6 children, provided the same seizure-control benefits, and was more economical than MCT oil.6 Dietitians with extensive experience in managing these diet therapies have resorted to combining features of both diets. For example, adding MCT oil to the classic KD is a strategy that is used in an attempt to improve seizure control by improving ketosis. Another example is reducing the diet to a ratio of 3:1 or 2:1 to provide a larger quantity and variety of protein-rich and carbohydrate-rich foods. These adjustments are often employed when seizure control has been successful but the individual is struggling to adhere to the diet. Through trial and error, we have also learned to begin the diet with lower ratios, such as 2:1 or 1:1, for adolescents and teenagers for whom we believe compliance will be best achieved (similar to the newer versions of the diet described later). Within these liberal ratios, we also use a much greater quantity of protein than carbohydrate, going by the theory that protein consumed in excess of needs will be converted to glucose (gluconeogenesis) more slowly than carbohydrate conversion to glucose (glycolysis). This may contribute to more stable glucose levels and stronger ketosis and may benefit seizure control; however, this theory has not been tested. We also incorporate MCT oil or coconut oil into these liberal ratios when attempting to achieve better seizure control.
Two newer, more liberal versions of the KD have been recently reported to have seizure-control benefits. The low-glycemic-index treatment focuses on limiting specific types of carbohydrate. Foods that have an individual glycemic index of 50 or greater are eliminated.7 In addition, 60% of calories are provided from fat, and protein is provided at approximately 1 g/kg of body weight. This diet requires measuring or estimating foods in household measure and is offered when the classic KD is expected to be too difficult to manage, especially for adolescents. The second version is the modified Atkins diet, which limits carbohydrate and provides 65% of calories from fat.8 Both versions result in an approximate ratio of 1:1 (fat to nonfat). Early reports of both diets show encouraging results; however, there is no efficacy data of long-term use of either of these diets. Medical monitoring of patients following these diets is the same as for the stricter versions.
Indications The KD has been used with infants as young as 3 months and adults as old as 58 years. Practitioners agree that compliance is highest in children up to 5 years. Older children are more likely to resist the strictness of the diet. Children with enteral feeding tubes are not affected by the compliance factor and, from this standpoint, make good candidates. The diet appears to have a broad spectrum of efficacy among different epilepsy syndromes. No seizure or epilepsy type has been shown to be uniquely resistant to the KD, and several types have been reported to respond well to the diet, including Doose syndrome, tuberous sclerosis complex, Rett syndrome, Dravet syndrome, myoclonic astatic epilepsy, and infantile spasms.10-15 The KD is the treatment of choice for 2 metabolic disorders: glucose 1 deficiency syndrome and pyruvate dehydrogense deficiency.16,17 In both conditions, glucose metabolism is impaired, and the KD provides ketones as an alternative fuel source. There have been many anecdotal reports of beneficial effects of the diet on behavior and cognition; however, there is limited research on this topic. A preliminary report from researchers at Johns Hopkins of 34 children who received developmental testing prior to and after 1 year on KD therapy found significant improvements in the children's attention and social functioning.18 In a recent study, epileptiform activity was measured using electroencephalogram monitoring prior to the initiation of the KD and after 3 months on the diet. A significant correlation was found between the reduction in the interictal discharges and clinical seizures and improvement in attention and concentration in these children.19
Contraindications
Adverse Effects Abnormal lipid levels are a concern for most caregivers and providers with this therapy. A prospective study of 141 children following the KD revealed elevations in low-density lipoproteins and reductions in the high-density lipoprotein lipids but concluded that further studies were necessary to determine if these effects promoted athersclerosis.25 Diet adjustments for improving lipid profiles are addressed later in this article. Adverse effects related to nutrition include growth retardation, hypoproteinemia, and micronutrient deficiencies. Additional serious adverse effects have been reported in a few patients and include hemolytic anemia, Fanconi renal tubular acidosis, elevations in liver function tests, pancreatitis, increased bruising, prolonged QT intervals, and coma.21,26,27 It is worthwhile to note that these effects occurred in combination with antiepileptic medications and may have been an exacerbated effect of the medication in combination with the diet.
Medical nutrition therapy (MNT) is described by the American Dietetic Association as an essential component of healthcare that affects the outcome of an individual's health and/or chronic medical condition. It can increase productivity and satisfaction levels through decreased doctor visits and hospitalizations and reduced prescription drug use. The KD should be viewed as an MNT, and one that necessitates a team approach. Of foremost importance in establishing a KD program is the commitment of an epileptologist or neurologist as a medical director. This individual should have pediatric experience and an active involvement in this labor-intensive regimen. A registered nurse is essential in providing medical management of the KD. The nurse should also have a background in pediatric epilepsy care. The team may also include a medical or psychiatric social worker to aid the family in the challenges of this therapy. A registered pharmacist is an important asset to the team in providing current information regarding the carbohydrate content of medications and nutrition supplements. A registered dietitian with pediatric experience is vital to the success of a KD program. The dietitian provides nutrition management and technical manipulation of the diet to optimize seizure control. The dietitian's frequent communication between caregivers and the KD team necessitates his/her role as coordinator of the KD program. Because of the multiple demands of this program, it is advantageous to have a second dietitian (within the facility) with training on the KD protocols to provide continuous care in the absence of the primary dietitian. Table 3 identifies the educational goals that should be taught to caregivers by the dietitian for the safe management of this therapy.
The KD is generally used for a period of up to 3 years. Seizure control
benefits are typically seen within 1-3 months of the diet's initiation. The
international study group reports that the diet should be trialed for at least
for 3
Of the children who respond positively to the KD, some experience a complete cessation of seizures with the onset of ketosis. Most children, however, experience gradual improvements. After 1 or 2 years, the diet is gradually tapered by lowering its fat content and increasing the carbohydrate and protein portion of the diet (by lowering the ratio) until ketosis is eliminated. The exact period of time depends on the individual patient. Most families will make this determination by weighing the improvement in seizure control and quality of life with the time invested in managing the diet.
The planning and preparation of a KD program begins with hospital administration. The process should include a protocol for inpatient and outpatient care, caregiver education materials, and a computer program for calculating and managing the diet. In 1999, it was estimated that the KD required 16 hours of dietitian time over a period of 5 months for each patient initiated on the diet.28 A comparison of medical costs for the management of a patient with epilepsy on the KD indicated that children who were successfully maintained on the KD had lower medical costs during the course of the diet than prior to the diet.29 To assist in the assessment of a candidate for KD therapy, an intake form should be completed by the caregiver. Pertinent dietary information, including food preferences, intolerances, and allergies, should be collected along with a diet diary. Current medications, supplements, weight, height, bowel habits, as well as seizure type and frequency should also be obtained. This information will assist in the design of an individual's diet and assist the dietitian in counseling the caregiver regarding expectations. A pharmacist or nurse should review the current medications of the patient and provide recommendations for alternatives to minimize the carbohydrate contribution from this source. A social worker can help the family to obtain healthcare services that may assist with the special needs of the diet, including the appropriate food procurement and purchase of a scale and the required vitamin and mineral supplements. A psychiatric social worker is beneficial in counseling the family regarding the restraints that the diet may place on family life.
Prior to initiating the KD, the candidate should be evaluated by an epileptologist or neurologist. Laboratory studies should be obtained to determine baseline nutrition status. In addition, antiepileptic drug levels (when appropriate) and biochemical studies to rule out disorders in fatty acid oxidation should be obtained (Table 4).
Fasting is no longer considered necessary to begin the diet. Two randomized clinical trials of fasting versus gradual initiation of the diet showed that the patients had equivalent long-term seizure reduction at 3 months. Hypoglycemia and vomiting were less problematic for the groups that did not fast and therefore hospitalization was shorter.30,31 Even without a fasting period, the child is at risk for hypoglycemia, dehydration, acidosis, and antiepileptic drug toxicity. Therefore, initiation is usually provided in a hospital setting under the guidance of the KD team. The KD diet may be introduced with a gradual transition to the established ratio over a period of 3-4 days. After the initiation period, the child is followed in an outpatient clinic by the members of the KD team. Regularly scheduled appointments are necessary to monitor the child's seizures, growth, and nutrition status throughout the course of therapy. Laboratory studies are performed at these visits to monitor metabolic responses. Figure 1 outlines a clinical pathway for KD therapy.
During the course of therapy, the diet will need to be adjusted to support normal growth. Growth disturbances have been reported and are likely related to restricted energy and protein intake.32 An increase in energy expenditure may be experienced by children who have achieved improvements in seizure control and have become more active. A caloric increase should be considered in these cases. The diet may also require adjustments to make it more palatable. Some children enjoy consuming fat in the form of butter whereas others prefer less butter and cream with higher fat content (ie, 40% vs 36% cream). Some children are unable to consume the quantity of fat required in the 4:1 diet but will tolerate a 3:1 diet with lower fat, which also supplies more protein and carbohydrate. The initial goal is to ensure that 100% of the diet is being consumed. This may take several weeks, and the dietitian may need to offer creative meals to improve acceptance. Feeding the child at evenly spaced intervals throughout the day will assist with hunger management. Ketosis suppresses appetite, and most children adapt to the small volume of food without difficulty. Other children require strategies to assist them in adjusting, such as removing them from the eating area and engaging them in a different activity directly after the meal. The next goal is to find and maintain a state of ketosis that serves to abate seizures. After a few weeks of KD therapy, a defining pattern of ketosis will emerge. Ketosis is monitored at home with urine testing. Urine ketone levels are a crude estimate of serum ketone levels but can suffice for simple monitoring purposes. BHB can be measured quantitatively in blood serum and is less influenced by hydration status. According to one study, a BHB >4 mmol/L was associated with better seizure control than lower levels.33 Serum glucose monitoring is another method of monitoring this therapy, because serum glucose levels have been observed to occur in a narrow range of approximately 55-75 mg/dL (at least 2 hours postprandial) and strong ketosis is noted within this range. Patients who experience improved seizure control with low to moderate ketosis may achieve better seizure control with higher ketosis (although there are exceptions and the opposite may be true). One method to achieve higher ketosis is to increase the ratio of fat to nonfat calories of the diet. Another approach to achieving stronger ketosis is to adjust energy intake. If a patient is receiving too many calories, he or she may experience lower ketosis because of excessive energy intake and may gain weight too rapidly. In this case, reducing the calories of the diet may improve ketosis. Conversely, if a patient is receiving insufficient calories, he or she may experience lower ketosis (ie, the starvation effect) because of inadequate energy intake. In this case, increasing the calories of the diet may improve ketosis. Incorporation of MCT oil or coconut oil (which contains 45% MCT) into the classic diet is an effective strategy to enhance ketosis. The MCT also has a laxative effect, which is helpful because constipation is the main adverse effect of the KD. Adjusting or fine-tuning the diet should be discussed with the KD team. It is important to make only 1 change at a time, then to allow a period of time to ascertain the effect of each change. Possible causes of temporary breakthrough seizures may include the stressors that have triggered the child's seizures in the past, such as sleep deprivation, an illness, or becoming ill. Seizures may occur because of disruptions in the diet, such as a mistake made in the preparation or weighing of food, eating or drinking a non-KD food, or the introduction or change in a medication. Figure 2 outlines a flowchart to assist in fine-tuning and adjusting the diet during the course of therapy.
Individuals with epilepsy may experience normal growth and development; however, some may be severely incapacitated by seizures. A nutrition assessment should include an evaluation of the individual's ability to consume food and fluids, growth pattern, activity level, and cognitive function. The KD can be modified in consistency for safe consumption such as pureed textures or into liquid formulations for infant or enteral feeding. Individuals with severe feeding difficulty should be evaluated by a feeding therapist prior to considering the KD. If a child is at risk for aspiration of food or liquids, an enteral feeding tube can be placed, which will allow safe administration of the diet. Vitamin and mineral supplementation is vital because of insufficient sources supplied from the diet. A micronutrient analysis of an optimally selected 4:1 KD revealed that only 5 of the 24 known essential micronutrients were met even when only nutrient-dense foods were included. The water-soluble vitamins were significantly lacking except for vitamin B12. Fiber, linolenic acid, and vitamin K were also deficient. All the minerals except for chromium were present in suboptimal amounts.34 Vitamin D, calcium, and phosphorus are of particular concern because of osteoporosis, fractures, and rickets reported in children receiving long-term antiepileptic drug therapies.35 Although it is not known whether the KD demands certain nutrients, supplementation is recommended to meet minimum needs. Dietary reference intakes established by the Food and Nutrition Board of the Institute of Medicine are used as references for daily intake of micronutrients for the oral diet and for liquid feedings such as infant and enteral formulas. Monitoring of compliance to diet, fluids, and vitamin and mineral supplementation are recommended to ensure nutrition sufficiency. Monitoring of growth and laboratory indices during the course of this therapy are recommended outcome measures to ensure good nutrition status and to prevent or correct the adverse effects of the diet. Fluid restriction along with the KD has been a practice at some centers with the belief that a mild state of dehydration enhances the effect of the diet; however, this theory has never been proven. The diuretic effect of carbohydrate-restricted diets is a known physiological response. In addition, the limited volume of high-moisture and high-fiber foods on the diet indicates a need to ensure adequate hydration. Fluid education to the caregiver is necessary to ensure his or her understanding of this practice. Predictive equations for estimating fluid requirements may be used to determine daily needs such as the Holida–Segar equation or dietary reference intake for total water.
Adjusting the KD to improve abnormal lipids has not been documented in the
literature. A natural decline in elevated lipids over time has been observed
in our experience. Strategies that can be trialed to reduce persistently high
lipids include reducing the animal sources of cholesterol and replacing
saturated fats with monosaturated and polyunsaturated fats. The inclusion of
an There is limited evidence in the literature regarding the use of carnitine in combination with the KD. Carnitine is a nonessential amino acid that is involved in the transfer of long-chain fatty acids into the mitochondria for β-oxidation. There is a poor correlation of plasma carnitine levels in relation to tissues stores. The symptoms of carnitine deficiency are difficult to discern from other causes, that is, lethargy, anorexia, poor growth, hepatic insufficiency, and elevated triglycerides. Secondary carnitine deficiencies have been reported to occur, with patients receiving certain antiepileptic therapies including valproates, phenobaritol, phenytoin, carbamazepine, felbamate, and the KD.36,37 A consensus statement from a panel of 9 pediatric neurologists suggested that carnitine supplementation is "strongly suggested" for certain patients, including those receiving the KD who have hypocarnitinemia.38
As healthcare providers, we are faced with decisions regarding allocation of our resources. The KD is an MNT in which dietitians have the opportunity to positively affect patient outcome and to provide cost-effective care. Despite the restrictiveness of this therapy, most families are eager to try this option and their compliance is exceptional. Careful planning and inclusion of the appropriate team members will help ensure a successful KD program. The Charlie Foundation is a nonprofit organization that exists to promote the safe use of the KD. This organization has provided dietitians and the public with a variety of educational tools, which are described on their Web site.39 A surge of interest in the KD has spurned new research and collaborative projects, which will hopefully increase resources for healthcare professionals and provide wider availability of the KD and better outcomes to the patients we serve.
Financial disclosure: none declared.
Nutrition in Clinical Practice, Vol. 23, No. 6,
589-596 (2008) This article has been cited by other articles:
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Newer Versions of the...
Interdisciplinary Team Approach...
months before deciding to discontinue
it.
-3 fat source from foods or a high-quality supplemental source may
assist in increasing high-density lipoproteins. Lowering the fat content of
the diet by lowering the ratio is also an option that may also be trialed. 
