Abstracts

Rationale: The ketogenic diet (KD) is an effective treatment for medically refractory epilepsy, resulting in a 50% or greater reduction in seizure frequency in the majority of patients. Anecdotally, patients who respond fully to the KD are reported to remain seizure-free even after discontinuation of treatment. We hypothesized that the KD may provide such an enduring functional neuroprotective effect in chronically epileptic mice. Methods: Kcna1-null (KO) mice (lacking the delayed rectifier potassium channel α subunit protein, Kv1.1) were generated using heterozygous breeding pairs. Pups were weaned on postnatal day 18 (P18) and treated with a KD (6:1 ratio of fats to carbohydrates + protein) beginning between P18-P21. For longevity assessments, KO mice remained on the KD until spontaneous death. For video-EEG studies, mice were implanted at P21-P23 with two parasagittal electrodes attached to a wireless transmitter (Data Sciences Int'l, St. Paul, MN) implanted subcutaneously. Mice were allowed to recover for 48 hrs before undergoing continuous 72-hr video-EEG recording (RP1). Immediately following recording (P26-P28), mice were stepped down from the KD to a standard diet (SD) over 18 hours. KO mice remained on the SD for an additional 72 hrs before being subjected to a second 72-hr round of video-EEG recording (RP2). Results: KO mice exhibited frequent recurrent spontaneous seizures beginning at P21-P28, and died from seizure-related events by P49 ± 1.5 (N=35). KD treatment (beginning at P21-25) significantly (P=0.003) increased the life-span of KO mice >61.3 ± 3.6 (N=19) compared to KO mice fed a standard diet (SD). During RP1, KD-treated KO mice exhibited significantly fewer seizures than SD-treated controls (P<0.05). Further, KO mice that were initially treated with the KD-but later weaned to a full SD-exhibited a significantly lower (P<0.01) mean daily seizure frequency as compared to age-matched KO mice continuously fed only a SD during RP2. Conclusions: Our data indicate that not only does the KD reduce seizure frequency and enhance longevity in epileptic Kcna1-null mice, but also exerts an enduring anticonvulsant effect beyond the treatment period, consistent with a functional neuroprotective effect. These results are consistent with anecdotal reports of lasting seizure protection in epileptic patients who have been weaned off the KD. Supported by NIH grant NS 044846 and the Barrow Neurological Foundation.