Abstracts

Rationale: Although it is assumed that antiepileptic drugs (AEDs) exhibit a positive dose-response (DR) relationship, where increasing effect on seizure frequency is seen with increasing dosage, there is little data to support this assumption, particularly in refractory epilepsy. We previously studied a population of highly refractory developmentally disabled epilepsy patients, finding that only the combination of lamotrigine (LTG) and valproate (VPA) showed superior efficacy (Poolos et al., Neurology 2012). We studied this same patient population to determine how the efficacy of LTG and VPA, as well as carbamazepine (CBZ) and phenytoin (PHT) depended on the dosages given, and whether positive DR relationships existed.Methods: We retrospectively analyzed medical records from 1980 to 2011, consisting of monthly seizure frequency and AED dosages, for 148 developmentally disabled adults with refractory epilepsy housed in two Washington State institutions. We quantified the ratio of average seizure frequency observed during treatment with each AED regimen (divided into quartiles of dose range) to the seizure frequency observed in the aggregate average of all other AED regimens to which the patient had been exposed. This seizure frequency ratio (SFR) gave a within-patient measure of response to each AED regimen that normalized for variation in baseline seizure frequency.Results: CBZ, VPA, and PHT used in monotherapy failed to show improved SFR in any dosage quartile, consistent with our prior findings that none of these drugs showed superior efficacy. CBZ showed a negative trend in its DR relationship, with an average 27% improvement in SFR in the lowest dosage quartile, and 0.4% worsening in the highest quartile. VPA similarly showed a negative DR, with 7% improvement in SFR in the lowest quartile and 7% worsening in the highest. PHT did show a positive DR relationship (36% worsening in lowest quartile; 29% improvement in highest), but as with CBZ and VPA, without significantly improved SFR in any quartile. LTG monotherapy showed statistically significant improvements in SFR in the lowest (51%) and the highest quartiles (49%), with insignificant effects in the middle quartiles, yielding a U-shaped DR relationship. When LTG was co-administered with VPA, significantly improved SFR was seen in the lowest and second LTG dose quartiles (26% and 49%, respectively), and a positive DR relationship was observed across all dose quartiles (70% and 84% improvement in SFR in the third and highest quartiles).Conclusions: We observed negative DR relationships for CBZ and VPA in refractory epilepsy, where increasing AED dosage yielded less response. We observed a positive DR with PHT administration, but insignificant efficacy. LTG yielded significant efficacy at the highest and lowest dosage quartiles, while only the combination LTG/VPA yielded both significant efficacy and a positive DR relationship. These results suggest some AEDs may not exhibit positive dose-response relationships in refractory epilepsy patients, and that dosage escalation of LTG in combination with a fixed dose of VPA may be an effective strategy in refractory epilepsy.