Abstracts

We have reported that the interictal basal glutamate levels are abnormally elevated within the epileptogenic hippocampus in patients with medication-resistant TLE (Cavus et al. Annals Neurology,2005). Since patients with TLE often have decreased hippocampal volume and cellular loss, which has been related to seizure frequency, we investigated how these clinical markers are related to the hippocampal extracellular neurotransmitter levels measured with in vivo microdialysis., Patients undergoing intracranial EEG monitoring for surgical evaluation participated in magnetic resonance (MR) imaging and microdialysis research protocols approved by the Yale University School of Medicine IRB. 13 TLE patients (6 female) had quantitative hippocampal volume measurements followed by hippocampal microdialysis study. 12 patients had in vivo microdialysis study, followed by hippocampal resection and immunostaining for cell counts. The absolute basal interictal levels of glutamate, glutamine and GABA were measured interictally, using zero-flow microdialysis method and HPLC on post-surgical days 3-6. Data obtained from the epileptogenic hippocampi was log-transformed and analyzed using multiple regression and mixed statistical models., Increased extracellular glutamate levels, but not glutamine or GABA levels were significantly related to both the absolute and the normalized hippocampal volume (p [lt] 0.002 for both tests, multiple regression model), with 83% of the variability in the hippocampal volume being related to the glutamate levels (p [lt] 0.0001, n = 13). Although, as reported previously seizure frequency (p=0.002) but not disease duration correlated with the hippocampal volume, when controlled for these clinical parameters, only glutamate levels predicted significantly both the absolute (p=0.02) and normalized hippocampal volume (p=0.03). Increased glutamate levels were significantly related to decreased cell count in the granular layer, (p=0.004 mixed model) but not in CA regions. In contrast, higher glutamine levels were related to increased glial and GFAP (p=0.004) count in the CA regions, (p=0.02) but not in the granular layer (p[gt]0.05)., Elevated extracellular basal glutamate levels in the epileptogenic hippocampus are highly significant predictors of the hippocampal volume measured by MRI, even when controlled for seizure frequency and duration. These abnormally elevated glutamate levels are related to granular cell loss but not to neuronal loss in the CA regions. The glial proliferation in CA regions may be in part to compensate for their suppressed glutamine synthase activity. These results have implications for other neurodegenerative disorders with hippocampal atrophy and glutamate dysregulation., (Supported by Epilepsy Project-Epilepsy Foundation, BIRWCH 1K12DA14038-01, NIH P01-NS-39092.)