gms | German Medical Science

62nd Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Polish Society of Neurosurgeons (PNCH)

German Society of Neurosurgery (DGNC)

7 - 11 May 2011, Hamburg

Multidrug transporter-inhibition in temporal lobe epilepsy – a study in resected tissue from pharmacoresistant, chronic epilepsy patients

Meeting Abstract

  • N. Sandow - Department of Neurosurgery, Charité - Universitätsmedizin Berlin; Institute of Neurophysiology, Charité - Universitätsmedizin Berlin
  • S. Gabriel - Institute of Neurophysiology, Charité - Universitätsmedizin Berlin
  • T.N. Lehmann - Department of Neurosurgery, Helios Kliniken Bad Saarow
  • P. Horn - Department of Neurosurgery, Charité - Universitätsmedizin Berlin
  • P. Vajkoczy - Department of Neurosurgery, Charité - Universitätsmedizin Berlin
  • U. Heinemann - Institute of Neurophysiology, Charité - Universitätsmedizin Berlin

Deutsche Gesellschaft für Neurochirurgie. Polnische Gesellschaft für Neurochirurgen. 62. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgen (PNCH). Hamburg, 07.-11.05.2011. Düsseldorf: German Medical Science GMS Publishing House; 2011. DocP 067

DOI: 10.3205/11dgnc288, URN: urn:nbn:de:0183-11dgnc2881

Published: April 28, 2011

© 2011 Sandow et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Outline

Text

Objective: 30% of epilepsies are pharmacoresistant. Temporal pole resection is often the only therapeutic option. Two concepts that may be responsible for pharmacoresistance in epilepsy are part of the current discussion: a) the target hypothesis favors changes in target conformation of antiepileptic drugs (AED) while b) the transporter hypothesis focuses on a decrease in AED-concentrations at their place of action by ATP-dependent drug efflux pumps located in the blood-brain-barrier (BBB) and / or the brain parenchyma. To determine the role of the temporal cortex in pharmacoresistant epilepsy, as well as the contribution of BBB or parenchymally expressed drug efflux pumps (Multidrug transporter 1 – MDTI) we performed this electrophysiological study on resected human temporal cortex specimens from patients suffering from pharmacoresistant temporal lobe epilepsy.

Methods: In a series of 49 patients, 166 slices of the temporal cortex were investigated for: 1) their potential to generate epileptiform activity after induction by elevation of extracellular K+ and 50μM bicuculline, 2) pharmacoresistance to common antiepileptic drugs such as phenytoin (PHT), carbamazepin (CBZ) and valproate (VPT) and 3) the efficacy of multidrug transporter-inhibitors (verapamil – VPM, probenecid – PBN) in restoring potency of AEDs.

Results: In 85% of experiments in 96% of patient probes, epileptiform activity was successfully induced by elevation of extracellular K+ and perfusion with 50μM bicuculline. In pathological tissue interictal spiking occurred significantly more often than seizure-like events (p≤0.001, chi-Quadrat). Only in 8.1% of experiments was the epileptiform activity sensitive to an antiepileptic drug (CBZ, PHT or VPA), showing that resected temporal cortex tissue is mostly pharmacoresistant. In 12.3% of cases AED-resistance was sensitive to a co-application of AED and MDTI (VPM and PBN), which puts the efficacy of multidrug transporter-inhibitors to restore the potency of AEDs in question.

Conclusions: This study demonstrated that 1) epileptiform activity can be induced in most of the temporal cortex specimens resected, 2) mechanisms located at the BBB may play a negligible role as epileptiform activity in a BBB-deprived model is pharmacoresistant and 3) multidrug transporter-inhibition is not sufficient to restore AED potency in this in vitro model.