We selected 16 patients with pharmacoresistant temporal lobe epilepsy who had seizures despite treatment with at least two antiepileptic drugs, eight patients who had been seizure-free on antiepileptic drugs for at least a year after 3 or more years of active temporal lobe epilepsy, and 17 healthy controls. All participants had a baseline PET scan with the P-glycoprotein substrate (R)-[11C]verapamil. Pharmacoresistant patients and healthy controls then received a 30-min infusion of the P-glycoprotein-inhibitor tariquidar followed by another (R)-[11C]verapamil PET scan 60 min later. Seizure-free patients had a second scan on the same day, but without tariquidar infusion. Voxel-by-voxel, we calculated the (R)-[11C]verapamil plasma-to-brain transport rate constant, K1 (mL/min/cm3). Low baseline K1 and attenuated K1 increases after tariquidar correspond to high P-glycoprotein activity.
Between October, 2008, and November, 2011, we completed (R)-[11C]verapamil PET studies in 14 pharmacoresistant patients, eight seizure-free patients, and 13 healthy controls. Voxel-based analysis revealed that pharmacoresistant patients had lower baseline K1, corresponding to higher baseline P-glycoprotein activity, than seizure-free patients in ipsilateral amygdala (0¡¤031 vs 0¡¤036 mL/min/cm3; p=0¡¤014), bilateral parahippocampus (0¡¤032 vs 0¡¤037; p<0¡¤0001), fusiform gyrus (0¡¤036 vs 0¡¤041; p<0¡¤0001), inferior temporal gyrus (0¡¤035 vs 0¡¤041; p<0¡¤0001), and middle temporal gyrus (0¡¤038 vs 0¡¤044; p<0¡¤0001). Higher P-glycoprotein activity was associated with higher seizure frequency in whole-brain grey matter (p=0¡¤016) and the hippocampus (p=0¡¤029). In healthy controls, we noted a 56¡¤8 % increase of whole-brain K1 after 2 mg/kg tariquidar, and 57¡¤9 % for 3 mg/kg; in patients with pharmacoresistant temporal lobe epilepsy, whole-brain K1 increased by only 21¡¤9 % for 2 mg/kg and 42¡¤6 % after 3 mg/kg. This difference in tariquidar response was most pronounced in the sclerotic hippocampus (mean 24¡¤5 % increase in patients vs mean 65 % increase in healthy controls, p<0¡¤0001).
Our results support the hypothesis that there is an association between P-glycoprotein overactivity in some regions of the brain and pharmacoresistance in temporal lobe epilepsy. If this relation is confirmed, and P-glycoprotein can be identified as a contributor to pharmacoresistance, overcoming P-glycoprotein overactivity could be investigated as a potential treatment strategy.
EU-FP7 programme (EURIPIDES number 201380).