Abstracts

Rationale: A clinical feasibility study was undertaken at a single centre to evaluate the safety and efficacy of long-term intra-ventricular drug delivery of the anti-seizure medication valproic acid, using a long term implantable infusion system, into the CSF in order to treat drug resistant focal seizures. Methods: Subjects had 29-234 partial onset seizures/month and were considered to have a seizure focus involving the mesial temporal lobe.  Five adult subjects were implanted with the system All subjects had previously used oral preparations of valproic acid unsuccessfully. Post-surgery, pharmacokinetic studies of VPA were performed.  Valproic Acid doses were increased stepwise in a predetermined protocol.   Results: The procedure and implantation were well tolerated by all subjects. Four subjects responded with > 50% seizure reduction at maximum doses of 160 mg/day. Two subjects experienced extended periods of complete seizure freedom. All five subjects report significant QOL improvement. No clinical dose limiting side effects were encountered, and there was no evidence of local periventricular toxicity in 3 subjects who were evaluated with imaging (T2 MRI).  Side effects included nausea and appetite [ED1] loss but were not dose-limiting.  Mean CSF valproic acid levels were 45 micrograms per ml (range 20 – 120 micrograms per ml), with corresponding serum levels of 4- 14 micrograms per ml.  Devices have been permanently implanted for up to 2.5 years in total. Conclusions: The study demonstrated that chronic intraventricular administration of valproic acid is safe and effective in subjects with medically refractory epilepsy over many months. The procedure for implanting the infusion system is safe and well tolerated. High CSF levels are achieved with corresponding low serum levels and this therapy is shown to be effective despite unsuccessful earlier use of oral valproate preparations. Drug side effects were minimal.   Funding: This study was supported by Cerebral Therapeutics, Colorado