Abstracts

Summary: Resistance to drug treatment is an important hurdle in the therapy of epilepsy. Consequently, there is a pressing need to develop new and more effective treatment strategies. Whilst drug resistance is multifactorial, there are two broad likely mechanisms: (1) resistance to AEDs occurs from alteration in the postulated target(s) of these drugs - the “target hypothesis”; (2) resistance occurs because of reduced access of AEDs to their neuronal targets, as a result of increased efflux of AEDs away from these targets -the “transporter hypothesis”. This workshop will focus on the concept of the “transporter hypothesis”. These multidrug transporters, of which P-glycoprotein (P-gp) is the most-widely studied, are found in and contributes to the normal BBB, and as efflux transporters, actively transport substrates (including multiple AEDs) against concentration gradients from the brain to blood and cerebrospinal fluid. This hampers the build up of adequate tissue levels of these drugs in the brain, greatly limiting their therapeutic efficacy. This workshop will focus on the feasibility of non-invasive molecular imaging-methods to study multi-drug resistance in epilepsy. In-vivo imaging of multidrug transporter function will allow (1) direct evaluation of the effect of modulators on the cerebral uptake of various therapeutic drugs, (2) examination of the role of the blood-brain-barrier (BBB) in the pathophysiology of epilepsy and (3) exploration of the pharmacokinetics of test compounds within the CNS. Sanjay Sisodiya (UCL Institute of Neurology, London, UK) will outline the neuropathological foundation of transporter-mediated drugresistance. Oliver Langer (Medical University Vienna, Austria) will present recent tracer developments for imaging P-gp. Phillipe Ryvlin (Cermep Lyon, France) will assess the potential of existing PET tracers ([18F]-MPPF, [11C]-Flumazenil) for imaging P-gp function in epilepsy, and Matthias Koepp (UCL Institute of Neurology, London, UK) will report on early results of imaging P-gp function using 11C-verapamil in epilepsy in humans.