by Liu Lin Thio, MD, PhD
Dr. Thio is an Assistant Professor of Neurology at Washington University School of Medicine and an epileptologist in the Pediatric Epilepsy Center at St. Louis Children’s Hospital.
The ketogenic diet is only one of several methods available for treating epilepsy. Other treatment options include antiepileptic drugs, epilepsy surgery, and the vagal nerve stimulator. If your child’s epilepsy is treated, most neurologists will try using an antiepileptic drug first. Generally, the ketogenic diet will not be the first choice, though exceptions exist.
The ketogenic diet is a high fat, low carbohydrate, and low protein diet designed to increase the body’s dependence on fat rather than glucose for energy. It mimics the fasting state, and can treat disorders of the brain. The two disorders most commonly treated with the ketogenic diet are epilepsy and certain inborn errors of metabolism involving glucose utilization. This paper will briefly review the history, physiology, efficacy, mechanism of action, indications, contraindications, deficiencies, adverse effects, and some of the practical aspects of initiating and maintaining the ketogenic diet as related to epilepsy.
The ketogenic diet has its origin in the observation that fasting reduces seizures. This observation is old since Hippocrates used fasting to treat seizures, and the Bible mentions fasting as a treatment for seizures. In 1921, Wilder proposed a high fat, low carbohydrate diet as a means of mimicking fasting, which is not practical for extended periods. After phenobarbital and phenytoin became available, interest in the diet declined. However, interest has increased recently because 20-30% of epileptic children have seizures that are resistant to antiepileptic drugs. The introduction of several new antiepileptic drugs during the 1990’s has not changed the proportion of epileptic children with difficult to control seizures.
The basis of the ketogenic diet is the brain’s ability to utilize ketones as an energy source. Ketones include b-hydroxybutyrate, acetoacetate, and acetone, which are products of fat breakdown. Under normal conditions, the brain derives most of its energy from glucose. Under fasting conditions, hormonal changes cause fat cells to release fats, which are then broken down in the liver. The liver packages the energy contained in fat into ketones. The liver releases ketones into the blood, which then transports them to the brain.
While on the ketogenic diet, your child will be in ketosis and will have elevated levels of ketones in his/her blood. Ketone levels can be measured in the blood, but blood levels generally are not measured daily. Instead, they are monitored using a urine dipstick since they also spillover into urine when present at high levels in the blood. Normally, urine has no ketones.
Treatment of seizures. Many studies report that the ketogenic diet effectively treats a variety of seizures in children and adults. The seizure types that can be helped by the diet include absence, myoclonic, generalized tonic, generalized clonic, generalized tonic-clonic, simple partial, complex partial, and partial seizures with secondary generalization. It may be most effective against myoclonic, astatic or drop seizures, and atypical absence seizures. It can be effective in children with multiple seizure types including Lennox Gastaut syndrome. About 1/3 of children have a >90% reduction in seizures with 5% becoming seizure free at 6-12 months. Another 1/3 have a 50-90% reduction in seizure frequency at 6-12 months with the remainder having no significant improvement. Other potential benefits of the diet include a reduction in the number of antiepileptic drugs, increased alertness, and improved behavior even if seizure control is not improved.
Treatment of inborn errors of metabolism. The ketogenic diet is the treatment of choice for some inborn errors of metabolism and is a treatment option for others. It is the treatment of choice for children with glucose transporter protein syndrome since they cannot get glucose to their brains. Children with diseases characterized by an inability to metabolize pyruvate such as pyruvate dehydrogenase complex deficiency are candidates for the diet. It may also be helpful in infantile phosphofructokinase deficiency.
Mechanism of action
The mechanism by which the ketogenic diet stops seizures is unknown.
The ketogenic diet has two primary indications. Some children with epilepsy that standard antiepileptic drugs cannot control are candidates for the ketogenic diet. Although the diet can treat several seizure types effectively, it is not a first line treatment because it is difficult to implement and maintain, and the long-term effects are not well studied. Children with certain inborn errors of metabolism such as the glucose transporter syndrome and pyruvate dehydrogenase deficiency are also candidates. While the diet offers potential benefits, a pediatric neurologist should carefully evaluate each child before recommending a trial on the ketogenic diet.
Medical contraindications to the ketogenic diet include metabolic disorders with a defect in fat metabolism, ketone metabolism, or mitochondrial disorders. These include β-oxidation defects, primary and secondary carnitine deficiency, carnitine cycle defects, electron transport chain defects, ketogenic defects, ketolytic defects, pyrvuate carboxylate deficiency, and pyruvate dehydrogenase phosphatase deficiency. Though the diet can exacerbate ketotic hypoglycemia, this condition is not an absolute contraindication.
Some antiepileptic drugs can potentially exacerbate some of the adverse effects of the ketogenic diet, and these drugs require careful use when combined with the diet. These antiepileptic drugs include acetazolamide, topiramate, and zonisamide, which all can cause acidosis and kidney stones. Another antiepileptic drug requiring careful monitoring in children on the diet is valproate.
Finally, some children and adolescents are not candidates for the diet because they can get their own food and cannot understand the restrictions of the diet. These children and adolescents will not maintain the diet without constant supervision, which usually is not practical.
The ketogenic diet is deficient in some micronutrients and may be deficient in carnitine. It is deficient in vitamin B, vitamin C, vitamin D, calcium, magnesium, and iron. Children on the diet receive supplements of these vitamins and minerals. Carnitine supplementation may be helpful for some children but generally is not required.
Similar to other antiepileptic drugs, the ketogenic diet has a variety of side effects that range from minor to severe. Common ones include nausea, vomiting, constipation, and loss of appetite. Less common ones include poor growth, kidney stones, and abnormal heart rhythms. It may impair white blood cell and platelet function. White blood cells help our bodies to fight infections, and platelets help our blood to clot. In rare cases, it can cause death.
Ratio of the ketogenic diet
Just as your child may take different doses of an antiepileptic medication, your child can take different strengths of the diet. The ratio, which refers to the grams of fat to the grams of protein plus carbohydrate, gives the strength of the diet. Thus, a 3:1 ketogenic diet means that the diet contains 3 grams of fat for every gram of protein plus carbohydrate. Since each gram of fat provides 9 calories and each gram of protein and carbohydrate provides 4 calories, 87% of the total calories in a 3:1 ketogenic diet come from fat. In comparison, fat provides 25-40% of the total calories in the typical diet consumed by American children while protein provides 10-20% and carbohydrates provide 40-60%. The ketogenic diet ratio usually ranges from 3:1 to 4.5:1. For the diet to be successful, you and your child must adhere to this ratio strictly, since any deviation may lead to your child coming out of ketosis. If your child is not consistently in ketosis, the diet will likely fail to control the seizures. Thus, the fat, protein, and carbohydrate content of everything your child eats, including medications, must be taken into account. In short, the diet will not work if you child cheats on the diet.
Before using the ketogenic diet to treat your child’s epilepsy, he/she must undergo a thorough evaluation by a pediatric neurologist or epileptologist familiar with the diet. The evaluation must consider medical factors such as your child’s epilepsy type, the etiology of his/her epilepsy, his/her age, his/her developmental level, and any other medical conditions your child may have. All of these factors will help determine whether your child can adhere to the diet without cheating. Obviously, children too young to or incapable of feeding themselves cannot cheat. In addition, the evaluation must consider psychosocial factors such as your determination to see the diet succeed, the willingness of your child’s daycare or school to abide by the diet, and your child’s interactions with his/her siblings. Finally, you must be willing to commit at least two months to the diet assuming no medical reasons for discontinuing the diet arise sooner.
Initiation of the ketogenic diet
If your child is a good candidate for the ketogenic diet after a thorough evaluation, his or her pediatric neurologist or epileptologist will refer you to a pediatric epilepsy center with an epileptologist and dietician experienced in implementing and managing the diet. Most centers will start the diet during a hospital admission to allow for monitoring of your child’s blood glucose, degree of hydration, and other metabolic parameters. Usually, the first step is a fast that begins after dinner the night prior to admission. The admitting physician will likely obtain blood and urine samples from your child for some baseline laboratory studies. Your child may also have an electroencephalogram (EEG) and electrocardiogram (EKG). Initiating the diet outside a hospital has resulted in some deaths.
The remainder of the protocol for initiating the diet depends on the institution, though many follow the protocol used at The Johns Hopkins Medical Institutions. Generally, the fast will continue for 1-2 days, which often is long enough to produce ketosis. During the fast, your child’s epileptologist and nurses will monitor his/her condition closely. They will also monitor his/her blood sugars with the same device used by diabetic children and his/her urinary ketones using a urine dipstick. According to the Johns Hopkins protocol, the diet starts with dinner on the second day of admission. However, your child will receive only one third of the calculated meal. The same will be true for breakfast and lunch the following or third day of admission. Starting with dinner on the third day of admission, your child will receive two thirds of each calculated meal. Beginning with dinner on the fourth day of admission, your child will receive full meals.
During the admission, the dietician will teach you about the diet. You will learn how to design menus that will give your child the number of calories he/she needs in accordance with the prescribed ratio. You will also learn how to measure the ketones in your child’s urine.
Ketogenic diet calculations
The ketogenic diet requires careful calculation of the fat, protein, and carbohydrate content of all meals. Nutritional tables and computer software are available to make these calculations. Free ketogenic diet software can be downloaded from the Packard’s Children’s Hospital, Stanford University Medical Center, Ketogenic Diet website–http://www.stanford.edu/group/ketodiet/.
Intercurrent illnesses and the use of over-the-counter and prescription medications
Your child likely will continue to have colds or other illness while on the ketogenic diet just as he/she did before starting the diet. Your child may take over-the-counter and prescription medications, but their carbohydrate content must be included in the calculations for preparing meals on those days. Almost all chewable tablets and syrups contain sugar. The carbohydrate content of many commonly used medications can be found at the Packard’s Children’s Hospital, Stanford University Medical Center, Ketogenic Diet website–http://www.stanford.edu/group/ketodiet/. If your child’s intercurrent illness triggers more seizures, a benzodiazepine, such as chlorazepate, can be given.
Discontinuing the ketogenic diet
Your child’s pediatric neurologist or epileptologist may discontinue the ketogenic diet after your child has been seizure free for two years or more. Alternatively, your child’s physician may discontinue the diet because it failed or caused an undesirable side effect. Generally, your child will be weaned off the diet by gradually reducing the ratio over several weeks or months just as he/she would be weaned off any other antiepileptic drug.
The ketogenic diet is an effective treatment option for refractory epilepsy in children and is the treatment of choice for some inborn errors of metabolism. However, your child should only be started on the diet at a center having a team of neurologists/epileptologists, dieticians, and nurses experienced with the diet. An experienced team is required because the diet can have serious consequences that can be avoided with a thorough evaluation before starting the diet and carefully implementing and maintaining the diet.
- Thio LL, Sitzwohl A, Trevathan E. (2002) The ketogenic diet. In: American Academy of Pediatrics Pediatric Nutrition Handbook 5th Ed (Kleinman RE, ed) (in press).
- © 2002 by K. Liu Lin Thio.