Abstracts

RATIONALE: Several findings suggest widespread mitochondrial dysfunction in the epileptic human temporal lobe. Postictal clearance of elevated glutamate is prolonged by 200-300%, suggesting that glial glutamate transporter mechanisms are defective in the gliotic, epileptogenic hippocampus. The failure of glutamate uptake may be related to failure of glial glutamine synthesis and energy metabolism. METHODS: We studied 12 patients scheduled for hippocampectomy for uncontrolled MTLE. A 20% solution of 2-13-glucose was infused at a rate of 4 g/hr for 3.5 hours prior to resection. Blood glucose isotopic fractions were measured every 30 minutes. Blood and quickly frozen brain samples were extracted then analyzed by high-resolution 13C/1H magnetic resonance spectroscopy at 11.75 Tesla. Adjacent slices were used for cell counts. RESULTS: Standard histology showed 8 patients with hippocampal sclerosis (HS), 3 minimal neuronal loss(MNL)(1 insular oligodendroglioma), and 1 hippocampal oligodendroglioma. Glial and neuronal counts segregated by pathology, except for 1 with CA1 sclerosis. Glial counts were higher and neurons fewer in HS. Glutamine/creatine molar ratios were higher in HS than MNL and correlated with glial counts. Glutamate/creatine ratios were the same in HS and MNL and correlated with N-acetylaspartate. The rates of glutamine synthesis normalized to the rate of the tricarboxylic acid cycle (Vgs/Vtca) were lower in HS (median 0.05, 95%CI <0.01-0.10) than MNL (0.41, range 0.29-0.57). The normalized rates of the neuron-glia (glutamate-glutamine) cycle (Vcycle/Vtca) were lower in HS (median 0.03, 95%CI 0.01-0.06) than MNL (0.13, range 0.07-0.21). CONCLUSIONS: The low rate of glutamine synthesis in HS suggests impaired glial metabolism. The inverse relationships between Vgs/Vtca and glial counts and glutamine also suggest glial metabolic defects. The low rates of glutamate-glutamine cycling that result from a failure of glial glutamate detoxification could account for slow glutamate clearance from synapses and continuing low-grade hyperexcitability. Support: Yale University and NIH-NINDS grant NS39092.