Date of Award

Spring 2011

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Abstract

Approximately 1% of the general population suffers from epilepsy. 30% of these patients cannot control their seizures with currently available antiepileptic drugs. One of the devastating features of epilepsy is the uncertainty of when a seizure will occur. The discovery of new approaches aimed at predicting and treating impending epileptic seizures is therefore particularly important. Using state-of-the-art chemical profiling by mass spectrometry, we explored seizure-specific changes in the metabolome (profile of all small molecule chemicals) of the brain extracellular fluid (ECF) in patients with drug­resistant mesial temporal lobe epilepsy (MTLE). We hypothesized that several unique brain chemistry alterations precede and are associated with spontaneous seizures in patients with medication-refractory focal epilepsy. We found that concentrations of the molecules 5-aminovaleric acid, proline and 4-aminobutanal, which are involved in the metabolism of glutamate and GABA, were altered in the ECF prior to epileptic seizures. These metabolites can also be found in the blood, urine and saliva and therefore are potential target biomarkers for predicting "spontaneous seizures" in patients. An appreciation of the chemical pathways in which these metabolites are involved has the potential to shed some light on the neurochemical basis of epileptic seizures. With the identification of these target pathways, we hope to measure these metabolites in more accessible body fluids, replicate human findings in animal models of epilepsy, and determine if these metabolites can trigger or halt spontaneous seizures in these models. Such information would facilitate a better understanding of the origin and termination of seizures, and potentially provide a diagnostic (predictive) tool in the fight against epilepsy.

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