Douglas A. Eagles

Summary: Ketogenic diets (KDs) are designed to create the metabolic conditions of fasting, which was among the earliest therapies discovered for epilepsy. The major measures used to evaluate dietary effectiveness have been the levels of urinary ketone bodies and the successful reduction of seizure activity. Modifications of the “classical” animal fat KD have been used in an attempt to boost ketonuria or ketonemia, increase palatability and compliance, and reduce side effects. Studies of KDs in experimental animals have been largely confined to rodents (mice and rats) for reasons of cost and convenience, and both have been found to be protected against experimentally induced seizures following consumption of KDs. Most of these studies have been designed to test hypotheses about the mechanism(s) by which reductions in carbohydrate or increases in fat result in elevated seizure threshold, decreased seizure duration, and decreased seizure severity. So far, underlying mechanisms have proven elusive. Rodent studies have led to a degree of general agreement that ketone levels per se do not correlate well with seizure protection, that reduction of glucose levels is fundamentally important, and that calorie restriction is additive to high fat diets in providing seizure protection.

Ketogenic diets are used in the treatment of epilepsy in children refractory to drug therapy. This study identifies changes in liver morphology in rats fed four different diets: a normal rodent chow diet, a calorie-restricted high-fat (ketogenic) diet and each diet supplemented with clofibric acid. Hepatocytes of rats fed the ketogenic diet show many lipid droplets and these are reduced to control levels when clofibrate is present in the diet. Mitochondria are enlarged in the livers of rats fed the ketogenic diet and further enlarged if clofibrate is present. Alterations in the appearance or numbers of other organelles are also found.

Summary: Purpose:The purpose of this study was to measure quantitatively the effectiveness of the ketogenic diet (KD) in comparison to two clinically important anticonvulsant drugs (AEDs), valproic acid (VPA) and phenytoin (PHT), and to evaluate possible associated neurotoxicity.Methods:Rats were maintained on either a calorie‐restricted, KD or calorie‐restricted, rodent‐chow diet for 3–5 weeks, after which neurobehavioral and seizure testing was completed. AEDs (either VPA or PHT) were injected acutely at the time to peak effect before neurotoxic and seizure assessment. Seizures were induced by timed infusion of pentylenetetrazole (PTZ) and maximal electroshock (MES).Results:VPA protected from both MES‐ and PTZ‐induced seizures, whereas the KD only elevated PTZ seizure threshold; PHT only attenuated MES‐induced seizures. The KD was as effective as a high dose of VPA (i.e., 300 mg/kg) and combined treatment (i.e., KD + VPA) showed an additive increase in PTZ seizure threshold. No observed neurobehavioral deficits were associated with either diet treatment; however, drug‐related side effects were noted with high doses of either VPA or PHT.Conclusions:These data suggest that the KD ranks among VPA and PHT as an effective treatment for seizures, without observed drug‐associated neurobehavioral contraindications. In combination with AEDs, our results indicate that the KD plus VPA work synergistically to increase seizure threshold, whereas the KD plus PHT may be complementary, elevating seizure threshold (KD) and reducing seizure severity (PHT). These findings may provide insights into future directions for rational polytherapy; however, it is important to be aware that the KD has been shown to elevate VPA‐induced hepatotoxicity.