Abstracts

Rationale: Of the 1.4 million cases of traumatic brain injury (TBI) reported each year in the U.S., approximately 25% will develop post-traumatic epilepsy. Current treatments with antiepileptic drugs are ineffective in preventing the development of epilepsy following the insult. In an effort to identify a useful antiepileptogenic treatment, we examined the effects of the ketogenic diet (KD) on a rat model of TBI. Recent studies have shown the KD to be neuroprotective, thus providing some hope that this treatment could limit TBI-induced damage and reduce the likelihood of subsequent epileptogenesis. Methods: Male Sprague-Dawley rats were subjected to moderate lateral fluid percussion injury (FPI; 2.14 atmospheres) at 11 weeks postnatal. Treatment Group 1 was fed a standard diet (SD), starting 3 weeks prior to FPI and for 6 weeks post-FPI. Group 2 received KD (F3666; Bio-Serv, Frenchtown, NJ) for the same period. Group 3 received SD pre-FPI, KD for 3 weeks immediately following FPI, and then SD for the last three weeks of the protocol. Group 4 received KD for 3 weeks immediately preceding FPI but was then switched to SD after FPI. Both standard and ketogenic diets were provided ad libitum. Beta-hydroxybutyrate (β-HB) measurements were made weekly (STAT-Site Analyzer; Stanbio, Boerne, TX). Flurothyl-induced seizure thresholds were determined (latency to first myoclonic jerk, to bilateral forelimb clonus, and to generalized tonic-clonic seizure) at 6 weeks post-FPI. Results: Rats fed KD showed an approximately 4-fold increase in blood β-HB level over rats given SD; elevated β-HB levels were observed during the time the animals were fed the KD, and returned quickly to control levels when animals were shifted to standard diet (Fig.1). A significantly higher seizure threshold (longer latency to all three seizure measures) was observed 6 weeks post-FPI in Group 2 compared to Group 1 (Fig. 2). None of the other KD groups were significantly different from Group 1 or from each other; however, Group 4 (the rats fed KD pre-injury) showed a tendency toward higher seizure threshold (tonic-clonic seizure latency similar to Group 2). To test the possibility that KD treatment affected generalization of seizure activity, we calculated the delay between myclonic jerk and generalized tonic-clonic seizure, and between bilateral forelimb clonus and tonic-clonic seizure. Although none of the KD treatment groups was significantly different from the SD control (Group 1), the pre-FPI group (Group 4) showed a tendency toward greater delay. Conclusions: In this preliminary study, KD treatment raised seizure threshold when present at the time of threshold testing (Group 2), consistent with its previously demonstrated antiepileptic efficacy. KD also raised seizure threshold when given before the FPI - perhaps consistent with a neuroprotective effect. If KD is needed prior to injury to achieve an antiepileptogenic effect, this treatment would have limited clinical usefulness since such a prophylactic treatment would be difficult to implement, even in at-risk populations. Supported by a grant from CURE.