Abstracts

Rationale: The interictal extracellular glutamate levels in the epileptogenic hippocampus of patients with intractable epilepsy are abnormally elevated (Cavus et al, 2005) and this increase is related to hippocampal atrophy (Cavus et al, 2008). Here, we report on the basal glutamate, glutamine and GABA levels in a series of 84 patients chronically implanted with microdialysis and depth electrodes, in the hipocampal and cortical non-epileptic, epileptogenic, and seizure propagation sites, as well as in the cortical non-localizable and developmental lesion sites. Methods: Patients (n=84) with refractory epilepsy undergoing intracranial EEG evaluation from1998 to 2008 had microdialysis probes coupled to depth electrodes implanted in suspected seizure onset sites. Basal interictal samples were collected using the zero-flow or very low flow methods, within 2-4 days of the implantation, 4-6 hrs away from any seizure activity. Samples were analyzed for glutamate, glutamine and GABA using HPLC. The hippocampal or cortical probes were classified into non-epileptic, epileptogenic, seizure propagation, non-localizable, and developmental lesion sites according the EEG data and consensus agreement of expert epileptologists. Data was log-transformed for normalization and modeled to account for within-subject variation. Student’s t test (significance set at 0.05) was used for statistical comparison between sites. Data are reported as mean ± SEM with Bonferroni-adjusted P-values. Results: Glutamate in the non-epileptogenic cortex and hippocampus were similar, at low 2.6 μM. In the cortex, glutamate was significantly elevated in the epileptogenic as well as propagated, non-localizable and developmental lesion sites (all p < 0.0001, see Table 1). Similarly, glutamate was also elevated in the epileptogenic (p<0.005) as well as propagated sites (p<0.0005). In contrast, glutamine concentrations were similar among all sampled sites. GABA was significantly elevated in the cortical (p<0.0005) and hippocampal (p<0.01) propagated sites, with marginal increase in the epileptogenic hippocampus (p=0.054). There were no significant differences in glutamate, glutamine, or GABA between the hippocampus and cortex. Combination of the hippocampal and cortical probes revealed significant elevation of glutamate in the propagated sites (p=0.0001) and of GABA in the epileptogenic sites (p<0.002). Conclusions: The basal extracellular levels of glutamate and GABA in the human cortex and hippocampus are kept at similar low levels. These levels are abnormally elevated not only in the epileptogenic cortex and hippocampus, but also in the propagated sites, as well as in the non-localizable cortex and the developmental lesions. Glutamine does not vary significantly between sites. There are no significant differences for any of these metabolites between the hippocampus and cortex. The neurochemical abnormalities in medication-refractory epilepsy extend beyond the site of seizure onset, which may contribute to the poor response to antiepileptic drugs, and may have implications for treatment.