Abstracts

Rationale: Over one third of patients with epilepsy receive insufficient benefit from oral anti-epileptic drug (AED) therapy, and continue to experience seizures whilst on medication. Additionally patients often experience significant side effects, both acute and chronic, in part through the systemic effects of AED use. Methods to deliver AEDs directly to the seizure focus in the brain allow higher, potentially more effective doses to the seizure focus while potentially avoiding systemic side effects. We describe implantation of a pump infusion system to allow continuous delivery of AED (Valproic acid) directly into the lateral ventricle in proximity to the presumed seizure focus in subjects with mesial temporal onset of seizure activity. We describe the methods employed to implant the pump and delivery system, and the results and side effects experienced to date.  Methods: Three adult female patients (age 25-38 years), with severe long standing focal epilepsy refractory to more than 3 AEDs for many years, experiencing at least 10 complex partial seizures monthly, and who had undergone extensive clinical and radiological assessment including with video-EEG, MRI and MEG, and had electro clinical and/or imaging features consistent with mesial temporal onset, were implanted with a subcutaneous abdominal pump (Flowonix Medical Inc., Mt. Olive, NJ, USA ), delivering a programmed dose of valproic acid to the lateral ventricle via an intracranial catheter as a continuous infusion. An additional intraventricular catheter connected to an Ommaya reservoir was used to establish CSF drug levels and kinetics. Peripheral blood samples were taken for systemic AED levels also. Doses were increased step-wise to a predetermined level, and then were increased according to a protocol against suitable clinical parameters. Results: The procedure and implantation were well tolerated by all subjects. A single pump was replaced after 5 months without incident. All subjects experienced a marked reduction in seizure frequency and severity (50-90%), despite earlier unsuccessful use of oral preparations of valproic acid. Side effects included nausea and appetite loss, but were not dose-limiting. CSF valproic acid levels were 45 micrograms per ml (range 20 – 70 micrograms per ml), with corresponding serum levels of 4 micrograms per ml. Conclusions: Chronic intraventricular administration of valproic acid is safe and effective. The procedure is safe and well tolerated. High CSF levels are achieved with low serum levels, and are shown to be effective despite unsuccessful early use of oral preparations. Side effects were minimal. Alternative AEDs may be administered by this method, including those without suitable oral preparations. This method introduces new options to the treatment of refractory epilepsy. Funding: Study sponsored by Cerebral Therapeutics, Colorado.