Overexpression of drug efflux pumps at the blood brain barrier (BBB) has been suggested to be one important factor contributing to drug resistance in epilepsy. This would imply that resected brain tissue of drug-resistant patients is drug-sensitive in absence of the BBB. Here we studied the effects of carbamazepine (CBZ) at therapeutically relevant concentration on epileptiform activity electrophysiologically recorded in acute hippocampal slices of patients with mesial temporal lobe epilepsy (MTLE; 28 patients, 49 slices) or extra-hippocampal tumours (tumour; 6 patients, 11 slices). Epileptiform activity was induced by hilar stimulation (0.067 Hz) during elevation of extracellular potassium concentration ([K(+)](o)) and remained self-sustained in presence of 10-12 mM [K(+)](o). Quantitative analysis of data revealed that epileptiform activity in tissue of tumour-patients was predominantly suppressed by CBZ, indicating that the 'epilepsy model' used is CBZ-sensitive. In contrast, epileptiform activity in tissue of drug-resistant MTLE patients was resistant to CBZ in 82% of patients, partially suppressed in 11% and completely suppressed in 7%. The effects of CBZ in tissue of MTLE patients did not depend on the type of activity, hippocampal pathology, excitability of the tissue, or equilibration time of the drug. Considering that CBZ has direct access to all compartments of the slice, our results suggest that CBZ-resistance mechanisms are located within the parenchyma of the dentate gyrus and contribute to drug resistance in the majority of MTLE patients. BBB-located drug-resistance mechanisms per se may play a minor role in this region, because CBZ-sensitivity was only observed in 7% of CBZ-resistant patients.
Drug resistant patients undergoing epilepsy surgery have a good chance to become sensitive to anticonvulsant medication, suggesting that the resected brain tissue is responsible for drug resistance. Here, we address the question whether P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRPs) expressed in the resected tissue contribute to drug resistance in vitro. Effects of anti-epileptic drugs [carbamazepine (CBZ), sodium valproate, phenytoin] and two unspecific inhibitors of Pgp and MRPs [verapamil (VPM) and probenecid (PBN)] on seizure-like events (SLEs) induced in slices from 35 hippocampal and 35 temporal cortex specimens of altogether 51 patients (161 slices) were studied. Although in slice preparations the blood brain barrier is not functional, we found that SLEs predominantly persisted in the presence of anticonvulsant drugs (90%) and also in the presence of VPM and PBN (86%). Following subsequent co-administration of anti-epileptic drugs and drug transport inhibitors, SLEs continued in 63% of 143 slices. Drug sensitivity in slices was recognized either as transition to recurrent epileptiform transients (30%) or as suppression (7%), particularly by perfusion with CBZ in PBN containing solutions (43, 9%). Summarizing responses to co-administration from more than one slice per patient revealed that suppression of seizure-like activity in all slices was only observed in 7% of patients. Patients whose tissue was completely or partially sensitive (65%) presented with higher seizure frequencies than those with resistant tissue (35%). However, corresponding subgroups of patients do not differ with respect to expression rates of drug transporters. Our results imply that parenchymal MRPs and Pgp are not responsible for drug resistance in resected tissue.
ZusammenfassungEinleitung: Die pharmakoresistente mesiale Temporallappenepilepsie (mTLE) geht häufig mit einer Ammonshornsklerose (AHS) einher. Die AHS ist durch Verlust an Nervenzellen und strukturelle Veränderungen der Astrozyten (Gliose) charakterisiert. Wir vermuteten, dass diese Astrozyten ihre Fähigkeit verloren haben, Kaliumionen mittels bariumsensitiver K + -Kanäle aufzunehmen und umzuverteilen. Deshalb untersuchten wir die Wirkung von Barium auf evozierte Anstiege der extrazellulären Kaliumkonzentration (K + ) o im Hippokampusgewebe von Epilepsiepatienten, epileptischen Ratten und nichtepileptischen Kontrollratten. Methodik: Die Veränderungen evozierter K + -Signale durch Barium wurden mit Hilfe zweikanaliger K + -selektiver Referenz Mikroelektroden in der CA1-Region akuter Hirnschnitte aus Hippokampusresektaten mit und ohne AHS und aus dem Hippokampus von Ratten (mit chronischer Epilepsie [PilokarpinModell], mit Kindling-Epilepsie und ohne Epilepsie) gemessen. Die Auslösung der Signale erfolgte durch repetitive elektrische Reizung des Alveus oder durch K + -Iontophorese. Ergebnisse: Barium verursachte eine Vergröûerung iontophoretisch evozierter K + -Signale in der CA1 von Kontrolltieren und von Hippokampusresektaten ohne AHS. Barium vergröûerte auch die durch antidrome Reizung ausgelösten K + -Signale in der nichtsklerotischen CA1 von Epilepsiepatienten, Ratten mit Kindling-Epilepsie und Kontrollratten. Im Gegensatz dazu war in der CA1 von Resektaten mit AHS und im Gewebe chronisch epileptischer Ratten der Bariumeffekt nicht nachweisbar bzw. stark verringert. Schluss-
Introduction The instantaneous center of rotation (iCOR) of a motion segment has been shown to correlate with its total range of motion (ROM). Importantly, a correlation of the correct placement of cervical total disc replacement (cTDR) to preserve a physiological iCOR has been previously identified. However, changes of these parameters and the corresponding clinical relevance have hardly been analyzed. This study assesses the radiological and clinical correlation of iCOR and ROM following cTDR. Materials/methods A retrospective multi-center observational study was conducted and radiological as well as clinical parameters were evaluated preoperatively and 1 year after cTDR with an unconstrained device. Radiographic parameters including flexion/extension X-rays (flex/ex), ROM, iCOR and the implant position in anterior–posterior direction (IP ap), as well as corresponding clinical parameters [(Neck Disability Index (NDI) and the visual analogue scale (VAS)] were assessed. Results 57 index segments of 53 patients treated with cTDR were analyzed. Pre- and post-operative ROM showed no significant changes (8.0° vs. 10.9°; p > 0.05). Significant correlations between iCOR and IP (Pearson’s R: 0.6; p < 0.01) as well as between ROM and IP ap (Pearson’s R: − 0.3; p = 0.04) were identified. NDI and VAS improved significantly (p < 0.01). A significant correlation between NDI and IP ap after 12 months (Pearson’s R: − 0.39; p < 0.01) was found. Conclusion Implantation of the tested prosthesis maintains the ROM and results in a physiological iCOR. The exact position of the device correlates with the clinical outcome and emphasize the importance of implant design and precise implant positioning.
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