| Summary: | Refractory epilepsy is a complex disorder, affecting approximately 40% of epilepsy patients.
To date, no medication has been found to be effective in the treatment of this disorder,
except for the ketogenic diet and w-3 supplementation, but the mechanism(s) by which these
two treatments inhibit seizures are not yet known. It is known that both these treatments
increase the concentrations of individual and total w-3 fatty acids in the plasma. DHA (an w-
3 fatty acid) is an important component of phospholipids in the cell membrane and influences
the membrane integrity and fluidity.
We explored the theory that there might be a defect in the biosynthesis of these w-3 fatty
acids, particularly docosahexaenoic acid (DHA), that could lead to an alteration in membrane
integrity and possibly affect the transport of AEDs (antiepileptic drugs) across the membrane
causing a refractory status in these patients. Carnitine facilitates the transport of w-3 fatty
acids across the inner mitochondria1 membrane, thus a defect in the carnitine transport or
biosynthesis, could lead to a decrease in the w-3 fatty acids in the plasma as well. This
investigation was a pilot study defining two aims: (a) are there any differences in the
concentrations and concentration ratios of the fatty acids in patients with drug-resistant
epilepsy versus patients with drug-responsive epilepsy and healthy individuals? (b) Are
there any differences in the acetylcarnitine concentrations in patients with drug-resistant
epilepsy versus patients with drug responsive epilepsy and healthy individuals?
We gathered urine and plasma samples from children in three groups, namely a control
group (healthy individuals), a group of drug-responsive epileptic children and a group of
refractory epileptic children. The urine samples were used for an organic acid analysis (for
screening purposes, to determine if there were metabolic disorders in any of the children that
would exclude them from this study) and an acylcarnitine analysis to determine if there were
any defects. The acylcarnitine analysis was performed by use of ESI MS-MS (electrospray
ionization tandem mass spectrometry). In the plasma we determined the concentrations and
concentration ratios of w-3 fatty acids by using the GGMS (gas chromatography mass
spectrometry).
The refractory epilepsy group did not reveal lower concentrations of w-3 fatty acids,
particularly DHA, in fact we found the concentrations to be higher than that of the control
group and more or less the same as that of the drug-responsive group. The same tendency
was evident for the long chain acylcarnitines (adipyl, suberyl, and octanoylcarnitine). Upon
merging the two epilepsy groups and dividing them into valproate and carbamazepine-treated
groups, we found that the DHA-concentration was higher in both the treated groups.
The valproate-group also showed increased levels of the long chain acylcarnitines. No
statistically significant differences were found between the valproate drug-responsive,
valproate refractory, carbamazepine drug-responsive and carbamazepine refractory groups.
The mechanisms by which valproate and carbamazepine inhibit seizures, have not yet been
established, but the possible mechanisms proposed for their inhibition differ vastly from each
other. Thus, these elevations in the DHA and long chain acylcarnitine concentrations could
possibly be attributed to the epileptogenic status of the patients, and not the AED-therarpy.
Combining our results with those of Henry (2004) we propose that DHA synthesis is not
affected in epileptic patients, but that the incorporation of DHA in the membranes is possibly
compromised. === Thesis (M.Sc. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2007.
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