Abnormalities of grey and white matter [11C]flumazenil binding in temporal lobe epilepsy with normal MRI

In 20% of potential surgical candidates with refractory epilepsy, current optimal MRI does not identify the cause. GABA is the principal inhibitory neurotransmitter in the brain, and GABA(A) receptors are expressed by most neurones. [(11)C]Flumazenil (FMZ) PET images the majority of GABA(A) receptor subtypes. We investigated abnormalities of FMZ binding in grey and white matter in 18 patients with refractory temporal lobe epilepsy (TLE) and normal quantitative MRI. Parametric images of FMZ volume of distribution (FMZ-V(d)) were calculated. Twenty-one healthy controls were scanned for comparison. Statistical parametric mapping (SPM99) was used to localize significant changes in FMZ-V(d) in individual patients and between groups, specifically including the entire white matter in all subjects through explicit masking. Sixteen of 18 patients showed single or multiple abnormalities of FMZ-V(d). Six had hippocampal decreases of FMZ-V(d). Eleven patients showed increased FMZ-V(d) in the temporal lobe white matter (TLWM). Outside the mesial temporal structures, seven showed multiple areas of increase or decrease and only one a single area of decrease. In seven of the 16 patients with abnormalities, findings were concordant with EEG and clinical data, enabling further presurgical evaluation. Group findings were: (i) decreased FMZ-V(d) in the ipsilateral (Z = 3.01) and contralateral (Z = 2.56) hippocampus; (ii) increased FMZ-V(d) in the ipsilateral (Z = 3.71) and contralateral TLWM (two clusters, Z = 3.11 and 2.79); and (iii) increased FMZ-V(d) in the ipsilateral frontal lobe white matter between the superior and medial frontal gyrus (Z = 3.80) with similar changes contralaterally (Z = 4.87). No changes were found in the thalamus and basal ganglia. Region-of-interest analyses indicated an average increase in FMZ binding of 16% in the TLWM ipsilateral to the epileptic focus. PET findings were corroborated by invasive EEG or pathology in five cases. FMZ-PET, analysed by SPM with explicit masking, was sensitive in patients with normal MRI, and hippocampal abnormalities were detected in a third of these patients. Furthermore, increases in FMZ binding in TLWM, indicating microdysgenesis, were detected in the majority of these patients and may represent the structural basis of their epilepsy.