Abstracts

Rationale: The objective of these studies was to determine whether an anticonvulsive and/or anti-kindling property is present in CSF of rats exposed to acute or subacute/chronic VNS. VNS has proven to be an effective treatment for epilepsy. It has an acute abortive effect, as well as subacute/chronic anti-convulsant effects. Such a time course is consistent with CNS biochemical changes. VNS in rats causes up-regulation of fos gene product expression in the brain. Following cessation of a VNS train there is a gradual decline in anticonvulsant effects. Perhaps the best evidence that CNS biochemical changes are occurring during VNS is the observation that the biochemistry of human CSF is altered. Methods: An acute VNS study was conducted with 28 male rats randomly divided into two groups. Both groups received a 15 uL intraventricular injection of CSF obtained from donor rats which either received VNS for 30 min under ketamine anesthesia or a sham. Flurothyl seizure thresholds were measured following the injection, and once daily over the next three days. A subacute/chronic study was then conducted with 23 rats randomly divided into two groups. Both groups received a 15uL intraventricular injection of CSF obtained from donor rats that either received two weeks of VNS or a sham. Flurothyl seizure thresholds were measured using the same method as described for the acute study. All results were analyzed using repeated measures mixed-model statistics. Results: There were no significant differences in the seizure threshold LS means or daily means for any of the four days between the two groups in either study (p>0.1). In the acute study, the LS mean seizure thresholds were VNS: 112s; Sham:110s for the myoclonic seizures and VNS:221s; Sham: 222s for the tonic seizures. In the subacute/chronic study the LS mean seizure thresholds were VNS:104s; Sham: 113s for the myoclonic seizures and VNS: 203s; Sham: 213s for the tonic seizures. A significant decrease in seizure latency time was observed over the four days of inducing seizures in both groups, in both studies (p<0.0001), referred to as kindling. There was no statistically significant difference in kindling between the groups in either study over the four days (p>0.1); however, in a post-hoc analysis, a possible anti-kindling effect was suggested between days 1 and 2 for the tonic seizures in the acute VNS study (p=.01). Plots of daily mean seizure thresholds for both myoclonic (Fig. 1) and tonic (Fig. 2) seizures in the acute VNS study are shown. Conclusions: These results do not support the hypothesis that there is an anticonvulsive and/or anti-kindling substance present in the CSF following either acute or subacute/chronic VNS. No anti-kindling effect was indicated over the four day study duration; however, a post-hoc analysis suggested a possible transient anti-kindling effect between days 1 and 2 for the tonic seizures in the acute VNS study. Future studies are planned which will support or refute these conclusions.