Development of a surrogate marker for P-glycoprotein expression in drug-resistant epilepsy using the (R)-[11C]-Verapamil PET/MR with cyclosporine

Abstract

Background and Purpose: The development of resistance to antiepileptic drugs is explained well by the transporter hypothesis, which suggests that drug resistance is caused by inadequate penetration of drugs into the brain barrier as a result of increased levels of efflux transporter such as p-glycoprotein. To evaluate the brain expression of p-glycoprotein (Pgp) in patients with drug-resistant epilepsy (DRE), including neocortical epilepsy, we developed a non-invasive quantitative analysis including asymmetry indices (AIs) based on (R)-[11C]-verapamil PET/MRI with cyclosporine (CS)

a Pgp inhibitor. Materials and Methods: Nine patients with DRE, five patients with drug-sensitive epilepsy (DSE), and eight healthy subjects underwent dynamic (R)-[11C]-verapamil PET/MRI with an intravenous infusion of CS. AIs [(right region – left region)/(right region + left region) ×200%] of the standard uptake values in each of the paired lobes were calculated. Results: All DRE patients, except for patients with parietal lobe epilepsy, had significantly different asymmetry from the healthy subjects, whereas all DSE patients had asymmetry similar to healthy subjects. In the temporal lobe, the AIs of patients with left temporal lobe DRE were more positive than those of healthy subjects (healthy subjects: 4.0413 ± 1.7452

patients: 7.2184 ± 1.8237

p = 0.048), and those of patients with right temporal DRE were more negative (patients: -1.6496 ± 3.4136

p = 0.044). In addition, specific regions which had significant asymmetry were different between lateral and medial temporal lobe epilepsy groups. In the frontal lobe, the AI of patient with right frontal lobe DRE was more negative than healthy subjects. Conclusions: We confirmed that Statistical Parametric Mapping analysis using AIs of (R)-[11C]-verapamil PET/MRI with CS could be used as a surrogate marker for DRE, and this approach might be helpful for localizing or lateralizing the epileptic zone. ClinicalTrials.gov number: NCT02144792