Determinants of brain metabolism changes in mesial temporal lobe epilepsy.

OBJECTIVE: To determine the main factors influencing metabolic changes in mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis (HS). METHODS: We prospectively studied 114 patients with MTLE (62 female; 60 left HS; 15- to 56-year-olds) with (18) F-fluorodeoxyglucose-positron emission tomography and correlated the results with the side of HS, structural atrophy, electroclinical features, gender, age at onset, epilepsy duration, and seizure frequency. Imaging processing was performed using statistical parametric mapping. RESULTS: Ipsilateral hypometabolism involved temporal (mesial structures, pole, and lateral cortex) and extratemporal areas including the insula, frontal lobe, perisylvian regions, and thalamus, more extensively in right HS (RHS). A relative increase of metabolism (hypermetabolism) was found in the nonepileptic temporal lobe and in posterior areas bilaterally. Voxel-based morphometry detected unilateral hippocampus atrophy and gray matter concentration decrease in both frontal lobes, more extensively in left HS (LHS). Regardless of the structural alterations, the topography of hypometabolism correlated strongly with the extent of epileptic networks (mesial, anterior-mesiolateral, widespread mesiolateral, and bitemporal according to the ictal spread), which were larger in RHS. Notably, widespread perisylvian and bitemporal hypometabolism was found only in RHS. Mirror hypermetabolism was grossly proportional to the hypometabolic areas, coinciding partly with the default mode network. Gender-related effect was significant mainly in the contralateral frontal lobe, in which metabolism was higher in female patients. Epilepsy duration correlated with the contralateral temporal metabolism, positively in LHS and negatively in RHS. Opposite results were found with age at onset. High seizure frequency correlated negatively with the contralateral metabolism in LHS. SIGNIFICANCE: Epileptic networks, as assessed by electroclinical correlations, appear to be the main determinant of hypometabolism in MTLE. Compensatory mechanisms reflected by a relative hypermetabolism in the nonepileptic temporal lobe and in extratemporal areas seem more efficient in LHS and in female patients, whereas long duration, late onset of epilepsy, and high seizure frequency may reduce these adaptive changes.

Strategies to Inhibit ABCB1- and ABCG2-Mediated Efflux Transport of Erlotinib at the Blood-Brain Barrier: A PET Study on Nonhuman Primates.

The tyrosine kinase inhibitor erlotinib poorly penetrates the blood-brain barrier (BBB) because of efflux transport by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), thereby limiting its utility in the treatment of non-small cell lung cancer metastases in the brain. Pharmacologic strategies to inhibit ABCB1/ABCG2-mediated efflux transport at the BBB have been successfully developed in rodents, but it remains unclear whether these can be translated to humans given the pronounced species differences in ABCG2/ABCB1 expression ratios at the BBB. We assessed the efficacy of two different ABCB1/ABCG2 inhibitors to enhance brain distribution of 11C-erlotinib in nonhuman primates as a model of the human BBB. METHODS: Papio anubis baboons underwent PET scans of the brain after intravenous injection of 11C-erlotinib under baseline conditions (n = 4) and during intravenous infusion of high-dose erlotinib (10 mg/kg/h, n = 4) or elacridar (12 mg/kg/h, n = 3). RESULTS: Under baseline conditions, 11C-erlotinib distribution to the brain (total volume of distribution [VT], 0.22 ± 0.015 mL/cm3) was markedly lower than its distribution to muscle tissue surrounding the skull (VT, 0.86 ± 0.10 mL/cm3). Elacridar infusion resulted in a 3.5 ± 0.9-fold increase in 11C-erlotinib distribution to the brain (VT, 0.81 ± 0.21 mL/cm3, P < 0.01), reaching levels comparable to those in muscle tissue, without changing 11C-erlotinib plasma pharmacokinetics. During high-dose erlotinib infusion, 11C-erlotinib brain distribution was also significantly (1.7 ± 0.2-fold) increased (VT, 0.38 ± 0.033 mL/cm3, P < 0.05), with a concomitant increase in 11C-erlotinib plasma exposure. CONCLUSION: We successfully implemented ABCB1/ABCG2 inhibition protocols in nonhuman primates resulting in pronounced increases in brain distribution of 11C-erlotinib. For patients with brain tumors, such inhibition protocols may ultimately be applied to create more effective treatments using drugs that undergo efflux transport at the BBB.