Date of Award

8-4-2010

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Idil Cavus, MD

Second Advisor

Robert Duckrow, MD

Third Advisor

Nihal de Lanerolle, PhD

Abstract

Antiepileptic drug (AED) resistance affects one third of patients with epilepsy and is associated with significant disability. Brain microdialysis studies on the epileptogenic hippocampus of patients with medication refractory epilepsy have identified elevations in extracellular glutamate, the primary brain excitatory neurotransmitter, both acutely during seizures and chronically during the interictal periods. Whether extracellular glutamate, along with the metabolites glutamine and the inhibitory neurotransmitter GABA (gamma-aminobutyric acid), are elevated in other cortical regions is unknown. In addition, the effect of the administration of AEDs on the extracellular levels of these neurochemicals in patients with medication-refractory epilepsy is also unknown. Microdialysis samples were obtained from probes coupled to the EEG depth electrodes and implanted in the cortex and hippocampus of 81 awake patients with medication-refractory epilepsy undergoing intracranial electroencephalographic (EEG) monitoring. Probes were classified according to location and seizure activity into cortical or hippocampal non-epileptic, epileptogenic, propagated, non-localized or lesion sites. Samples were collected during the interictal period, in all subjects on their full AED dose during the first couple of days of their hospitalization, and then again (in a subset of 38 patients) after their AEDs were tapered. The samples were analyzed with high performance liquid chromatography (HPLC) for glutamate, glutamine and GABA levels. Data were log-transformed and compared by ANOVA or multiple t-tests with a Bonferroni correction, where appropriate. In the cortex, glutamate was significantly higher in epileptogenic (mean ± SEM, 17.3 ± 5.1 µM), propagated (25.8 ± 4.0 µM), non-localized (43.9 ± 9.9 µM), and lesion (46.9 ± 9.0 µM) sites compared to non-epileptic cortex (2.6 ± 0.3 µM). In the hippocampus, glutamate was significantly higher in the epileptogenic (10.3 ± 1.9 µM) and propagated sites (33.0 ± 13.8 µM) than non-epileptic sites (2.8 ± 0.5 µM). Glutamine was not significantly different between sites in both the cortex and hippocampus. In the cortex, GABA was significantly elevated in propagated (1503 ± 273 nM) and lesion (827 ± 183 nM) sites compared to non-epileptic sites (265 ± 62 nM). In the hippocampus, GABA was elevated in the propagated (1079 ± 395 nM) compared to non-epileptic sites (391 ± 169 nM). There were no significant differences in glutamate, glutamine, or GABA between the hippocampus and cortex within non-epileptic, epileptogenic, or propagated sites, which enabled cortical and hippocampal probes to be combined. Glutamate was now found to be significantly elevated in propagated compared to non-epileptic sites (p = 0.0001). GABA was significantly elevated in epileptogenic compared to non-epileptic sites (p = 0.011) and in propagated compared to epileptogenic sites (p = 0.028). After AED taper, there were no significant changes in glutamate in any site, although it decreased non-significantly in non-localized sites (p = 0.090). Glutamine decreased significantly in lesion sites (p = 0.0095). GABA declined significantly in non-localized sites (p = 0.014). When all sites were examined together, there were overall significant decreases in glutamine (p = 0.0011) and GABA (p < 0.0001). In conclusion, elevations in glutamate and GABA extend beyond epileptogenic sites in patients with refractory epilepsy. Levels of glutamate, glutamine, and GABA were comparable between the hippocampus and cortex. AEDs may increase extracellular levels of glutamine and GABA but are inefficient in reducing glutamate to normal levels in these patients, which may relate to AED resistance.

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This is an Open Access Thesis.

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