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

Abstract

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.

Applications of Positron Emission Tomography (PET) in Neurology

“…49 Hammers et al investigated 18 patients with refractory temporal lobe epilepsy and normal MRI using 11 C-FMZ PET. Sixteen patients showed abnormalities in temporal lobe 11 C-FMZ binding, in seven of whom the findings were concordant with clinical and EEG data 50 ( fig 3). Three patients subsequently underwent anterior temporal lobe resection with significant clinical improvement.…”

[11C]Flumazenil PET in Temporal Lobe Epilepsy: Do We Need an Arterial Input Function or Kinetic Modeling?

“…For assessment of medial temporal changes, statistical parametric maps were re-thresholded at P = 0.01 uncorrected, assessed using a medial temporal lobe mask, and significant changes assessed at a threshold of Z > 2.5 and characterized in terms of Z score, extent (k), and coordinates, as described and used previously (Hammers et al, 2001(Hammers et al, , 2002Koepp et al, 1997aKoepp et al, , 1997bKoepp et al, , 2000. This combination of thresholds has a theoretical foundation in the correction for approximately four independent comparisons at the smoothing level of the final SPM (7Z = 2.5 corresponds to a P of 0.0124, that is B0.05/4, a traditional Bonferroni correction for multiple comparisons) and has been empirically validated by approximately yielding the expected false-positive rates in our previous studies.…”

Temporal lobe epilepsy: Differential pattern of damage in temporopolar cortex and white matter

“…Data from other studies suggest in fact that textural changes may be observed within the sclerotic hippocampus in TLE [Yu et al, 2001[Yu et al, , 2002 and demyelinating processes [Gasperini et al, 1996;Mathias et al, 1999]. Alternatively, in light of the histopathological findings described earlier [Hammers et al, 2001[Hammers et al, , 2002, it is possible that the ''simplified'' TPWM texture as defined by entropy may point to alterations in the course of corticogenesis and is reflective of heterotopia, a developmental malformation leading to abnormal neuronal collection and positioning.…”

“…Partial volume effect-corrected PET with carbon-11-labeled-flumazenil (FMZ-PET), a marker for the functional integrity of the GABAergic inhibitory neurotransmitter system, is uniquely suited to the study of microdysgenesis in the WM due to its highly specific binding to neurons and the resulting high contrast-tonoise ratio. This elegant technique has shown that in the WM, 11 C-flumazenil binding is strongly related to the number of heterotopic neurons measured semiquantitatively ex vivo in resected specimens of patients who underwent anterior temporal lobe resection [Hammers et al, 2001[Hammers et al, , 2002. Therefore, it is conceivable that our models of blurring mirror increased neuronal heterotopia in this compartment.…”