Fasting versus gradual initiation of the ketogenic diet: a prospective, randomized clinical trial of efficacy.

PURPOSE The ketogenic diet (KD) is a 90% fat diet that is an effective treatment for intractable epilepsy. Rapid initiation of the KD requires hospital admission because of the complexity of the protocol and frequent mild and moderate adverse events. The purpose of the study was to compare the efficacy of a gradual KD initiation with the standard KD initiation preceded by a 24- to 48-h fast. METHODS Children ages 1 to 14 years with intractable epilepsy were randomized to a fasting initiation (FAST-KD) or gradual initiation (GRAD-KD). Baseline seizure activity was recorded daily for 28 days before admission and continued for the 3-month duration of the study. Effectiveness was measured in two ways: (a) the proportion of subjects with >50% reduction in target seizure type from baseline to 3-month evaluation, and (b) percentage reduction in the frequency of the target seizure type from baseline to 3-month evaluation. Blood glucose was assessed q4 to 6h, and weights, electrolytes, hydration status, vomiting, acid balance, need for interventions (citric acid and sodium citrates (Bicitra) and IV fluids) were assessed daily. Fisher's exact tests were used to examine the association between protocol and occurrence of adverse events, and longitudinal mixed-effects models were used to look for trends in tolerability data over time. RESULTS Forty-eight subjects, 24 in each arm, were randomized. In the FAST-KD protocol, 58% of the children had >50% reduction in the target seizure type at 3 months, and 21% were seizure free. In the GRAD-KD protocol, 67% had a >50% reduction at 3 months, and 21% were seizure free. The two protocols were equivalent in efficacy (p = 0.033). At 3 months, the FAST-KD median percentage seizure reduction rate was 78% (ranging from 100% reduction to 73% increase in seizures per week) and was 94% (ranging from 100% reduction to 161% increase in seizures per week) for the GRAD-KD protocol. By using a logarithmic transformed percentage reduction rate and an equivalence limit difference of 20%, the efficacy of the two protocols was equivalent (p = 0.0002). Children in the GRAD protocol lost significantly less weight (p = 0.006), and had fewer and less-severe episodes of hypoglycemia (p < 0.001), fewer treatments for acidosis (citric acid and sodium citrates) (p < 0.04) and dehydration (IV fluids) (p < 0.04), but no difference in vomiting was noted. CONCLUSIONS These data suggest that in children with intractable epilepsy, a gradual initiation results in fewer adverse events and is tolerated better overall while maintaining the efficacy of the KD.