Abstracts

RATIONALE: The basal glutamate, GABA, glucose and lactate levels in the epileptogenic and non-epileptogenic brain sites of patients with seizure disorder were compared using in vivo microdialysis in order to study the role of the major neurotransmitters and energy metabolytes in seizures.
METHODS: Patients with medically intractable seizure disorder undergoing presurgical evaluation to identify their seizure focus were implanted with microdialysis cathaters in the presumptive seizure focus and surrounding brain areas. The extracellular fluid (ECF) was sampled 5-60 hrs prior to any seizure activity. The basal glutamate, GABA, lactate and glucose levels were measured using the zero-flow microdialysis technique and HPLC. Data from the epileptogenic area (identified with intracranial EEG obtained during spontaneous seizures) and the non-epileptogenic (quiet or propagated) brain areas were compared.
RESULTS: 27 patients with intractable seizure disorder were studied. Total of 16 microdialysis catheters were localized to the epileptogenic brain areas (hippocampus 8, temporal lobe tumor 3, cingulate 3, motor cortex 2, frontoorbital cortex 1) and 24 catheters were in the non-epileptogenic sites (hippocampus 13, Heschel[ssquote]s gyrus 2, parietal cortex 2, amygdala 1, cingulate 4, frontoorbital cortex 1 and the insula 1). Basal ECF glutamate levels were markedly elevated in the epileptogenic brain sites vs. the non-epileptogenic brain sites (15 uM [plusminus] 3.8 vs. 2.9 uM [plusminus] 0.3, p=0.0003). Eleven patients had one probe within the epileptogenic area and another in an unaffected area allowing for within subject comparison. The basal glutamate level was consistently elevated within the epileptogenic sites in all 11 patients (11.8 uM [plusminus] 3.1 vs. 2.9 uM [plusminus] 0.6, p=0.008). The basal glutamate levels in the non-epileptogenic areas were within the range of previously reported normal ECF levels. However the ECF glutamate in the epileptogenic focus was at a neurotoxic range. Basal GABA, glucose and lactate levels were measured in the same 11 patients. Lactate levels were also significantly elevated within the epileptogenic sites (6.5 [plusminus] 0.6 mM vs. 5.1 [plusminus] 0.4 mM, n=11, p=0.02). No significant difference was detected for GABA (epileptogenic 174.5 [plusminus] 39.3 nM vs. non- 119.03 [plusminus] 20.7 nM, p=0.17) or glucose (2.03[plusminus] 0.5 mM vs. 1.8 [plusminus] 0.3 mM, p=0.5) levels.
CONCLUSIONS: The epileptogenic brain areas were characterized with markedly elevated interictal basal ECF glutamate level which was within the neurotoxic range. The higher ECF glutamate levels suggest an increased glutamate release and/or inadequate glutamate uptake within the epileptogenic focus. Glutamate uptake is coupled to glucose and lactate metabolism. Glucose, being readily supplied by the blood stream, was not depleted under basal conditions. The significant lactate increase may reflect an increased aerobic glycolysis in order to meet the energy demands of the elevated glutamate uptake. Out present finding of unchanged ECF GABA levels together with the previous reports of decreased total GABA are suggestive of decreased intracellular GABA levels in the epileptogenic areas.
[Supported by: NIH-PO1 NS39092-01 and BIRCWH 1K12DA14038-01 for I.Cavus]