Initial development of an implantable drug delivery device for the treatment of epilepsy

Epilepsy is a chronic neurological condition, characterized by recurrent seizures. Treatment with conventional anti-epileptic drugs (AED) results in only 33% of patients having no seizure recurrence after a prolonged period. Some evidence suggests that the lack of effectiveness of AED penetration into the brain parenchyma could be one of the mechanisms for resistance to treatment. Furthermore, AED side effects often prevent large increases in their dose. It was for these reasons that a new alternative approach to therapy, intracranial implantation of polymer-based drug delivery systems aimed at improving the bioavailability of AED, was investigated in this PhD research project. Genetic Absent Epilepsy Rats from Strasbourg (GAERS) is a strain of rat that has 100% of the animals with recurrent generalised non-convulsive seizures. This animal model has become the gold standard to study the mechanisms underlying absence epilepsy. After validating an automated spike and wave discharges (SWDs) detection algorithm applied to GAERS’ electroencephalograms (EEG) and demonstrating some effects of enrofloxacin on the GAERS’ epileptic activity, in vitro characterisation and in vivo testing of the antiepileptic efficacy of Poly(D,L-lactide-co-glycolide) (PLGA) polymers loaded with anticonvulsants, either phenytoin or lacosamide, were performed. PLGA is a biodegradable copolymer that it is very well tolerated by the brain and can be used as a passive release substrate. In prospective randomized masked experiments, GAERS underwent surgery for implantation of skull electrodes, skull electrodes and blank polymers, or skull electrodes and AED loaded polymers. The polymers were implanted bilaterally and subdurally on the surface of the cortex. Electroencephalogram recordings were started at day 7 post-surgery and continued for eight weeks. The number of SWDs and mean duration of one SWD were compared week-by-week between the groups. Although temporary changes were seen, phenytoin loade