The ketogenic diet has been used as a therapeutic alternative to antiepileptic drugs for refractory epilepsy (1,2,3). The diet consists of an intake of three or four times as much fat as carbohydrates and protein combined (1,2,3,4).

Fasting has long since been believed to be a cure for epilepsy. Hippocrates used fasting as a specific treatment for patients with epilepsy in the 5th century BC and in the Bible Jesus suggests fasting after an epilepsy attack (New Testament: Saint Mark 9; 14–29).

In 1921, Wilder (5), formulated the ketogenic diet to induce the metabolic effects of fasting for the management of seizures. In spite of its effectiveness, the diet was replaced by the new antiepileptic drugs (AEDs). Phenobarbital (PB), the first AED, was introduced in 1912 and between 1935 and 1968, 16 additional AEDs became available. The ketogenic diet was reserved for use in selected patients and at selected treatment centers. A variant of the classical diet using medium-chain triglycerides was introduced in the 1970s (6), but, in the last decade, most of the centers adopted the classic diet in a 4:1 ratio of fat to combined proteins and carbohydrates. The group of Johns Hopkins Hospital and Health System in Baltimore was the most enthusiastic in advising the ketogenic diet; they were able to reach public recognition through a movie and a very practical little book entitled “The Epilepsy Diet Treatment” (1). Furthermore, the popularity of the Atkins diet as a weight-loss diet in the United States helped the development of many food products that are also “Keto-compatible,” increasing the tolerability of this diet (7).

No mechanism of action of the diet has been defined. Its efficacy has been ascribed to acidosis, cellular and extracellular dehydration, the direct action of acetoacetate or β-hydroxybutyrate, and changes in the source or utilization of energy within the brain (8).

Ketones are induced within the first 24 to 36 hours. Ketones are lower in cerebrospinal fluid than in plasma and do not accumulate in the brain. Although there is a metabolic acidosis resulting from accumulation of ketones and decreased bicarbonate, plasma pH normalizes because of a reduction of both bicarbonate and partial pressure of carbon dioxide. Recent neuroimaging data suggest that there is an increase in brain ketones and the phosphocreatine/organic phosphate ratio (9,10,11).

Alternative mechanisms for the action of the ketogenic diet are an increase in brain gamma-aminobutyric acid (an inhibitory central nervous system neurotransmitter) (12). Whether ketones themselves have GABAergic effects on the brain and serve as direct neuroinhibitors remains uncertain (13). The proposed enhancement of a gamma-aminobutyric acid shunt has also been suggested (14). The potential effects of changes in water and electrolytes have also been indicated as antiepileptic mediators (3). There are decreased Na⁺, K⁺, and Mg²⁺ stores, with an increased Ca⁺ turnover. It is unclear what the direct consequences of these ionic alterations are within the central nervous system. As of yet, a predictable and definite effect on brain tissue concentrations of these plasma ionic alterations (Na⁺, K⁺, and Cl⁻) has not been demonstrated.

Recent reports of series of patients after 1 year on the diet show an overall efficacy ranging from 15% to 50% in terms of patients becoming seizure-free or having a 50% to 90% reduction in seizures (2,3,4,15,16,17,18,19). Use of ketogenic diet was generally advised for children between 2 and 6 to 8 years of age. A retrospective review of 32 infants treated with ketogenic diet (14 of whom started treatment at ages ≤ 12 months) showed that 71% were able to maintain strong ketosis, 19.4% became seizure free, and an additional 35.5% had > 50% reduction in seizure frequency. The diet was most effective for infants with infantile spasms or myoclonic seizures and overall effectiveness in infants was similar to that reported for older children (20). The largest prospective study done between 1994 and 1996 enrolled 150 consecutive children aged 1 to 16 years having a minimum of two seizures per week, despite the appropriate use of at least two anticonvulsant medications. Children were followed for a minimum of 1 year or until diet discontinuation. At 12 months, 55% remained on the diet and 27% had a >90% decrease in seizure frequency. Comparing efficacy in different seizure types after 6 months of diet, 5 of 13 children with infantile spasms (IS), 13 of 28 with myoclonic seizures, 9 of 17 with atonic seizures/drops, 4 of 11 with clonic seizures, and 5 of 11 with partial seizures achieved ≥90% seizure control or became seizure-free (21). A recent retrospective study of ketogenic diet in 45 adolescents between the ages of 12 and 19 years showed that 20 of them were still on the diet at 12 months of diet duration with >90% efficacy in 6 patients and 50% to 90% efficacy in 7. The authors concluded that ketogenic diet is as well tolerated and efficacious for adolescents with epilepsy as for the general childhood population (22). A prospective study of ketogenic diet in 11 adults with intractable epilepsy was presented not long ago. At the 8 months follow-up, seven remained on the diet with a >90% seizure reduction in three, 50% to 89% reduction in three, and <50% reduction in seizure activity in one (23).

Adverse effects or complications of ketogenic diet occurring during the initial hospital stay included: hypoglycemia, dehydration, vomiting, diarrhea, and refusal to eat, which may lead parents to early drop out (1). Long-term complications appear after several weeks of treatment and comprise metabolic derangements such as hyperuricemia, hypocalcemia, hypoproteinemia, carnitine deficiency, metabolic acidosis, hyperlipemia, and hypercholesterolemia. Some of these complications are seen during the course of intercurrent infections. The risk of hyperlipemia and hypercholesterolemia is obviously the first thought and it is reported in 25% to 65% of the cases (24,25). When successful in controlling the seizures, the diet should not be stopped because of lipid abnormalities, as adjustment of the diet ratio will bring the lipids levels toward normal. Ballaban–Gil et al. (26) prospectively monitored 52 children with ketogenic diet, aged 8 months to 16.5 years, looking for complications: five of their patients had serious adverse effects and the authors pointed out that four were receiving, at the same time, valproic acid (VPA).