Abstracts

Rationale: Some anti-epileptic drugs (AED) may aggravate some epilepsies. This is mainly the case of generalized epileptic syndromes with GABAergic AED. The aim of this work is to test the hypothesis that this bad adaptation of the initial AED to the epileptic syndrome could aggravate epilepsy and have some deleterious long term effects particularly on the therapeutic results of the next well adapted AED. This should be particularly true during infancy, on a maturing brain. Methods: We used an inbred mouse model of childhood absence epilepsy, BS/Orl, manifesting spontaneous and recurrent spike-wave discharges. Four groups of BS/Orl mice were constituted. The first treatment started for every group at the age of 5 weeks during brain maturation. The two first weeks, the first group was treated with valproate (VPA); the second group with vigabatrin (VGB) that is known to aggravate absence epilepsy in childhood; the third group received ethosuximide (ESM) that is known as the best treatment in human for this epileptic syndrome and a fourth control group received saline solution (PHY). During the 42 next days, every group except the control group, received VPA that is one of the reference treatment for this syndrome in France. Overall, the mice were tested at 5 different periods of time, and 3 times of one hour each period: before any treatment, after the first-line treatment and 3 times during the second-line treatment. Results: During the two first weeks of treatment the four groups were significantly different. As expected, the comparison treatments vs PHY has given a significant result (p<0.006) with VGB worsening seizures whereas VPA and ESM reducing seizures with a much greater effect for ESM. During the next 6 weeks (until the mice turn adults) when every group received VPA, the groups treated initially with ESM (ESM-VPA) or VPA (VPA-VPA) tended to do the same; in the aggravated group VGB stopping VGB and introducing VPA (VGB-VPA group) failed to reverse the tendency of an aggravation of the seizure level and the mice never did as well as in the other groups (p<0.008). Conclusions: As observed in this mouse model, the first treatment in this syndrome seems to influence not only the short term but also the long term prognosis and the drug sensitivity of this epilepsy. This may be linked to a direct deleterious effect of the inadequate first line drug, but also of the seizures by itself on a developing brain.