Abstracts

Rationale: Subdural pharmacotherapy is a novel strategy for the treatment of intractable focal neocortical epilepsy (Ludvig et al., 2009, Epilepsia 50:1528-1167). For this strategy, we developed a triple-function subdural strip able to (1) deliver drugs transmeningeally, (2) remove neocortical cerebrospinal fluid [CSF], and (3) record local EEG activity (US patent pending). The functions of the strip are regulated by a control unit comprising a dual minipump, a microprocessor, a signal conditioner, a radiofrequency (RF) transceiver and a battery. This is the first safety and efficacy report on the long-term use of this system in nonhuman primates. Methods: Adult bonnet macaques (Macaca radiata; n = 2) were implanted with the subdural strip and its control unit. The strip was placed over the right frontal cortex, and connected to the control unit secured to the cranium. An additional subdural EEG electrode was placed in the contralateral area. In monkey 1, intermittent saline delivery (40 microliter/delivery at 12-hour intervals) started immediately after implantation. In monkey 2, similar delivery alternated with neocortical CSF removal (20 microliter/removal at 6-hour intervals). After a 2-month observation period, the control unit was modified to deliver a seizure-inducing concentration of acetylcholine (Ach, 200 mM) through the strip and subsequently deliver 1 mM muscimol in the same way. The monkeys were behaving freely during this test. Before this test, and after this test for up to 4 months, the behavior of the monkeys and the EEG activity of their implanted frontal cortices were monitored daily. Results: Before and after the subdural drug delivery test, the monkeys displayed no abnormal behavior or neurological symptoms. Artifact-free EEG recording from the implantation site was maintained throughout the study (Fig. 1A). In the monkey subjected to intermittent saline delivery only, the minipump tubing was clogged 1.5 months after implantation. In the monkey subjected to alternating saline delivery and CSF removal the minipump tubing was not clogged, allowing drug delivery. Subdural Ach induced EEG seizures localized to the ipsilateral implantation site, with the contralateral cortical EEG unaffected (Fig. 1B). Behavioral monitoring revealed contralateral clonic movements only. Subsequent muscimol delivery into the Ach-induced acute seizure focus terminated the EEG seizure (Fig. 1C). Similar pharmacological data could be obtained in the monkey with the clogged apparatus only after manual cleansing of the tubing. Conclusions: This preliminary study suggests that (1) local CSF removal may be necessary to maintain the long-term functional integrity of subdural drug delivery strips, (2) muscimol-delivering subdural strips can be used to control focal neocortical seizures, and (3) the long-term use of subdural implants for combined fluid-delivery, fluid-removal and EEG recording does not seem to be harmful. Support: Epilepsy Research Foundation grant #140929 to N.L.