OVERVIEW: WHAT IS THE KETOGENIC DIET?
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that is carefully calculated by a dietitian and menus created for a parent to follow.1 A ketogenic diet ratio of 4:1 describes the ratio of grams of fat to both carbohydrate and protein combined, and provides 90% of calories from fat (Fig. 53–1). A 3:1 ratio is used primarily for infants and adolescents in whom either higher protein or more carbohydrates are needed for either growth or tolerability.
Foods are carefully weighed and measured based on either dietitian-created meal plans or family-oriented computerized exchange program. In most cases, calories are restricted to 75% of daily requirements, although both increases and decreases from this may be made based on the individual child’s daily metabolic demands to achieve an ideal body mass index.1 Fluids are also restricted to 85% of the daily allowance. Neither calorie nor fluid restriction has ever been demonstrated to be effective in children and many dietitians will target either 100% or the baseline prediet intake of each child.
The diet can be provided as solids, liquids (formula), or as a combination of both. Solid foods eaten not only include 36% heavy whipping cream, mayonnaise, oil, butter, cheese, hot dogs, and other high-fat foods but also protein sources typically totaling 1 g/kg body weight per day. The majority of the small amounts of remaining calories include carbohydrates such as fruits and vegetables, which help alleviate constipation. Many families have been very creative in recipe and meal choices (Fig. 53–2).
The diet can also be easily implemented as a formula, either using a single powdered source such as Nutricia KetoCal®, (Fig. 53–3) available in either a 4:1 or now 3:1 preparation, or “modular” components comprised of Ross Carbohydrate-Free® and Polycose® with Novartis Microlipid®.2 This liquid method of diet administration is used predominantly in infants and gastrostomy-tube fed children and compliance is assured. A formula-only diet has been demonstrated to be very effective, with approximately double the likelihood of a >90% seizure reduction compared to all children on the diet, possibly due to improved compliance.2,3
INDICATIONS FOR ITS USE
The ketogenic diet has been used for nearly 90 years in patients with a wide variety of seizure types and epilepsies. Despite this impressive record, there is a paucity of literature regarding its effectiveness for specific clinical circumstances. Earlier publications were retrospective, and therefore subject to ascertainment bias. Later work studied patients with specific seizure types but not epilepsy syndromes. No studies to date have been both prospective and controlled. For these reasons, systematic reviews of the ketogenic diet that are based upon formal medical evidence cannot support efficacy.4,5 Still, interest in the diet continues to grow worldwide.6 While most of these studies do not meet the stringent criteria, one would insist for formal drug approval; they can be used to suggest clinical circumstances where the ketogenic diet might be particularly helpful (Fig. 53–4).
The ketogenic diet is first-line therapy for the treatment of seizures in association with glucose-transporter protein deficiency (GLUT1-DS) and pyruvate dehydrogenase deficiency (PDH).7,8,9 In both cases, the diet effectively treats seizures while providing essential fuel for brain metabolic activity. Ketone bodies enter the mitochondria and are used in aerobic metabolism, effectively bypassing the limited supply of brain glucose in GLUT1-DS and the enzymatic block that prohibits incorporation of pyruvate into the tricarboxylic acid (TCA) cycle in PDH. The utilization of ketone bodies is thermodynamically very efficient. In this manner, the diet is not only an anticonvulsant treatment, but it is also treats the other nonepileptic manifestations of these diseases that are due to energy deficiency.
The ketogenic diet has been used historically as an alternative treatment, usually after the failure of valproate, for childhood myoclonic epilepsies including severe myoclonic epilepsy of infancy (Dravet syndrome) and myoclonic-astatic epilepsy (Doose syndrome).10,11 Given the effectiveness of the diet in the treatment of myoclonic epilepsies, it could possibly be considered as first-line treatment for patients with these conditions, but no comparative studies exist. The ketogenic diet can be beneficial in infants with West syndrome who are refractory to corticosteroids and other medications.12,13,14
A prompt response of absence seizures in patients with GLUT1-DS is common. Based upon Keith’s data and our own experience, the ketogenic diet may also be useful in the treatment of children with other refractory absence epilepsies, with or without myoclonus.15 Other forms of dietary treatment may also be useful in absence epilepsies. In one study, a modified Atkins diet was used to treat children with intractable epilepsy. Four out of five children with absence had a greater than 50% seizure reduction and three went at least 1 month without seizures.16
It is very difficult to precisely determine the efficacy of the diet in the treatment of epilepsies manifesting with predominantly focal seizures. Livingston stated that the diet was not effective for partial seizures. Keith did not classify his patients in a manner that allows one to determine the effectiveness in partial seizures.15 A recent study of children with a dramatic, seizure-free response to the diet within 2 weeks found that none of these children had solely partial seizures.17 In kindled animals, a model of focal epilepsy, the diet was shown to have at least transient anticonvulsant properties.18 To the degree that one can extrapolate from animals to humans, this study bolsters the use of the ketogenic diet in children with refractory partial epilepsy.
Nevertheless, while the diet may be considered in this group, there is no compelling clinical data to favor its use. Therefore, children with refractory focal seizures should be evaluated to determine if they are candidates for focal resective surgery. If they are, then surgery need not be delayed to institute a trial of the ketogenic diet. On the other hand, if drugs have failed and the patient is deemed to be a poor surgical candidate, then the diet should be considered. Based upon our own experience and limited published information infants with migrating partial seizures may not respond favorably to the ketogenic diet.19
It would seem inappropriate to treat children with otherwise benign seizure disorders, such as febrile seizures, benign Rolandic epilepsy, benign occipital epilepsy including Panayiotopoulos syndrome, and benign familial neonatal convulsions with the ketogenic diet.
Preliminary experience showing some beneficial effects of the ketogenic diet have also been reported in the following disorders: seizures in children with tuberous sclerosis complex,20,21 Rett syndrome,22 glycogenosis type V,23 and subacute sclerosing panencephalitis.24
The ketogenic diet could have lethal consequences in certain clinical circumstances where cerebral energy metabolism is deranged. An example of this is pyruvate carboxylase (PC) deficiency. Patients with PC deficiency may present early in life with refractory myoclonic seizures. PC is the first step in gluconeogenesis but also controls production of oxaloacetate, the rate-limiting substrate in the Krebs cycle. Patients with PC cannot utilize ketone bodies efficiently so the loss of carbohydrate can have devastating consequences.25 Patients with fatty acid oxidation problems would also be adversely affected by the ketogenic diet, but such patients do not, as a rule, present with seizures. Patients with organic acidurias may worsen with ketogenic diet treatment. Although patients with mitochondrial disorders are not traditionally started on the ketogenic diet, recent evidence suggests safety and efficacy.26
INITIATION OF THE KETOGENIC DIET
Perhaps no other aspect of the clinical management of the ketogenic diet has created as much controversy for physicians and anxiety for parents as the initiation protocol. For many decades, the ketogenic diet was started only as an inpatient, with a mandatory fasting period until high levels of urinary ketosis were achieved, followed by gradually increasing calories over 3 days.1 Over the past few years, both retrospective and prospective studies have analyzed specific aspects of the “Hopkins protocol” (Table 53–1).
Day prior to admission (Sunday)
Day 1 (Monday)
Day 2 (Tuesday)
Day 3 (Wednesday)
Day 4 (Thursday)