Hypometabolism precedes limbic atrophy and spontaneous recurrent seizures in a rat model of TLE

Purpose: Temporal hypometabolism on fluorodeoxyglucose positron emission tomography (FDG-PET) is a common finding in patients with drug-resistant temporal lobe epilepsy (TLE). The pathophysiology underlying the hypometabolism, including whether it reflects a primary epileptogenic process, or whether it occurs later as result of limbic atrophy or as a result of chronic seizures, remains unknown. This study aimed to investigate the ontologic relationship among limbic atrophy, histological changes, and hypometabolism in rats. Methods: Serial in vivo imaging with FDG-PET and volumetric magnetic resonance imaging (MRI) was acquired before and during the process of limbic epileptogenesis resulting from kainic acidinduced status epilepticus in the rat. The imaging data were correlated with histologic measures of cell loss, and markers of astrogliosis (glial fibrillary acid protein [GFAP]), synaptogenesis (synaptophysin), glucose transporter 1 (Glut1) and energy metabolism (cytochrome oxidase C), on brains of the animals following the final imaging point. Key Findings: Hippocampal hypometabolism on FDG-PET was found to be present 24 h following status epilepticus, tending to lessen by 1 week and then become more marked again following the onset of spontaneous seizures. Atrophy of limbic structures was evident from 7 days post-SE, becoming progressively more marked on serial MRI over subsequent weeks. No relationship was observed between the severity of MRI-detected atrophy or CA1 pyramidal cell loss and the degree of the hypometabolism on FDG-PET. However, an inverse relationship was observed between hypometabolism and increased expression of the Glut1 and synaptophysin in the hippocampus. Significance: These findings demonstrate that hypometabolism occurs early in the processes of limbic epileptogenesis and is not merely a consequence of pyramidal cell loss or the progressive atrophy of limbic brain structures that follow. The hypometabolism may reflect cellular mechanisms occurring early during epileptogenesis in addition to any effects of the subsequent recurrent spontaneous seizures.