The safety and tolerability of ketogenic diet (KGD) and valproate (VPA) cotherapy in the treatment of intractable seizures were evaluated retrospectively at the Massachusetts General Hospital, Boston. The ages of a total of 71 patients were 7 months to 20 years (mean, 7 years). All had received the KGD, and 24 were treated concomitantly with VPA. Two patients (2.8%) developed pancreatitis after 4 months on the KGD alone. Adverse events affecting patients equally in the KGD/VPA and non-VPA groups included symptomatic acidosis (39.4%), nausea and vomiting (23.9%), hypertriglyceridemia (21.1%), infections (eg otitis media, URI) in 21%, lethargy (18.3%), and behavioral abnormalities and irritability (15.5%). Renal calculi affected 6.4% of the KGD alone group. Elevations in liver function tests occurred in 2 patients taking VPA cotherapy. Carnitine supplements were given to 19 patients on the diet, and no patient reported symptoms of carnitine deficiency. Treatment was continued at 1 year in 32 patients, 11 taking the combined KGD and VPA therapy. Reductions in seizure frequency at 1 year were 47% with >90% reduction, 25% with 50-90% reduction, and 29% with <50% reduction. Seizure control was not significantly different in the KGD and VPA cotherapy groups and was unrelated to the KGD fat to carbohydrate ratio. The majority received a ratio of 4:1 at initiation of the diet, 17 had ratios of 3.5-3.9:1, and 12, ratios of 3-3.4:1, fat to carbohydrate + protein. Anticonvulsant regimens were adjusted or eliminated during the trial of the KGD. The authors consider KGD and VPA cotherapy to be safe and effective in the management of refractory pediatric epilepsy. 
COMMENT. The authors' experience shows that concerns regarding possible adverse effects of cotherapy with the KGD and VPA in refractory epilepsy should not exclude a trial of the simultaneous use of these agents, with careful monitoring. Since seizure control was apparently not related to degree of ketosis in the above study, the introduction of the diet using the original Mayo Clinic regimen (with lower fat: carbohydrate ratios) rather than the Hopkins method of initiation (with a 4:1 ratio) should lower the incidence of adverse events and heighten the tolerability. (Ped Neur Briefs Feb 2005;19:12-13). [2, 3]
In a trial of the KGD in 20 patients with Dravet syndrome (severe myoclonic epilepsy in infants), 10 (77%) of the 13 children who remained on the diet at 1 year had achieved a >75% reduction in seizures, and quality of life was improved.