Abstracts

Resective surgery is a validated approach for the treatment of pharmacoresistant temporal lobe epilepsy (TLE), but it is an invasive approach accompanied by substantial risks. We have investigated local delivery of therapeutic agents as a less invasive and potentially safer approach to the treatment of intractable localization-related epilepsy. We use convection-enhanced delivery (CED), which provides for a controlled infusion to a restricted brain area and avoids the tissue damage produced by bolus infusion. In the present study we studied botulinum toxins A and B (BTX-A and BTX-B) with the CED approach. These toxins are highly potent, irreversible inhibitors of neurotransmitter release. We hypothesized that inhibition of the release of neurotransmitters involved in seizure generation, including glutamate, would confer an antiepileptic action against amygdala kindled seizures, a model of TLE. Rats were implanted with a combination guide cannula-stimulation electrode into the right basolateral amygdala. Daily stimulations continued until each rat was fully kindled (stage 5 seizures for at least five consecutive days). Then, the rats received CED infusions of BTX-A (1-10 ng) or BTX-B (3.2-10 ng) into the stimulation site over 20 min. Carbamazepine (0.1 mg) was studied for comparison. Each dose was delivered in a volume of 5 [mu]L at a rate of 0.25 [mu]L/min. Depth EEG (afterdischarge threshold and duration) and behavioral (seizure stage and duration) measures of amygdala-kindled seizures were recorded up to 64 d after the infusion. Infusion of vehicle had no effect on the EEG or behavioral measures. In contrast, infusions of BTX-A resulted in a dose- and time-dependent protection against kindled seizures as reflected by significant increases in the afterdischarge threshold with accompanying decreases in the afterdischarge duration. These effects reached a maximum at 21 d post infusion and then gradually returned to baseline levels over the subsequent 40 days. Infusions of BTX-A had little effect on seizure stage and seizure duration. Similarly, infusions of BTX-B resulted in a significant protection against kindled seizures, with an elevation in the afterdischarge threshold lasting for 7 d; other measures of seizures (i.e. afterdischarge duration, seizure stage, and seizure duration) were affected for as long as 50 d post-infusion. Infusions of both toxins were well tolerated and were not associated with any immediate or long-term behavioral sequelae. In contrast to the long-lasting effects produced by the toxins, CED infusion of carbamazepine protected against seizures for only a few hours post-infusion. CED infusion of BTX-A and BTX-B produces long-lasting protection against seizures in the rat kindling model indicating that CED delivery of these toxins could be of utility in the treatment of TLE. (Supported by ERS/NINDS/NIH.)