Comparison of the anticonvulsant efficacies and neurotoxic effects of valproic acid, phenytoin, and the ketogenic diet

Purpose: The purpose of this study was to measure quantitatively the effect iveness of the ketogenic diet (KD) in comparison to two clinically importan t 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 an d seizure testing was completed. AEDs (either VPA or PHT) were injected acu tely at the time to peak effect before neurotoxic and seizure assessment. S eizures were induced by timed infusion of pentylenetetrazole (PTZ) and maxi mal 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 se izures. 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 sei zure threshold. No observed neurobehavioral deficits were associated with e ither diet treatment; however, drug-related side effects were noted with hi gh doses of either VPA or PHT. Conclusions: These data suggest that the KD ranks among VPA and PHT as an e ffective treatment for seizures, without observed drug-associated neurobeha vioral contraindications. In combination with AEDs, our results indicate th at the KD plus VPA work synergistically to increase seizure threshold, wher eas the KD plus PHT may be complementary, elevating seizure threshold (KD) and reducing seizure severity (PHT). These findings may provide insights in to future directions for rational polytherapy however, it is important to b e aware that the KD has been shown to elevate VPA-induced hepatotoxicity.