Abstracts

Rationale: Lamotrigine (LTG) and valproic acid (VPA) are antiepileptic drugs (AEDs) with a mechanism of action that includes blocking voltage-gated sodium channels. The effect on the pharmacokinetics of LTG in combination with VPA are inhibition of the metabolism of LTG through UGT1A4 glucuronidation, leading to an increase in plasma LTG concentrations. This is of major significance, as it can result in severe LTG related adverse effects including Stevens-Johnson syndrome and fatality. These serious reactions can be mitigated by lowering the dose of LTG and with careful titration. It has also been reported that the skin rash triggered by LTG occurs at initiation of LTG treatment, with no increased risk of rash if VPA is added to the drug regimen of patients already taking LTG. Due to the vigilance required when initiating combination therapy with LTG and VPA, and the intent of the physician to choose a 2nd AED with a different mechanism of action, many physicians avoid this AED combination, although studies and experience show that combination use of VPA and LTG can have a profoundly positive synergistic effect in the treatment of refractory epilepsy. Studies to date have not provided enough evidence to guide this combination therapy. The purpose of this study is to review our experience with co-administration of VPA and LTG in the treatment of refractory epilepsy to determine if there is an epilepsy type that responds better to this combination therapy.Methods: This was a chart review of patients in our epilepsy clinic treated with combination therapy of VPA and LTG for at least 6 months. Data collected included age, gender, epilepsy type, baseline seizure frequency, and EEG features before and after the co-administration of VPA and LTG. The primary outcome measure was change in baseline seizure frequency and EEG.Results: Twenty-nine patients were included (17 male,12 female), mean age 26, range 12-59 years. Twenty-three patients (79%) had generalized epilepsy, 6 (21%) had focal epilepsy. Seven had EEG Lennox-Gastaut features, 2 had EEG features of ESES. Twenty-seven patients took additional AEDs besides VPA and LTG. Comparing seizure frequency and EEG changes before and after combination treatment of LTG and VPA, 13 (45%) improved (at least 50% reduction in baseline seizure frequency), 7 of these 13 patients (24% of all patients) became seizure free, 3/6 (50%) focal epilepsy patients improved but none became seizure free, 10/23 (43%) patients with generalized epilepsy improved, 3/7 (43%) with Lennox-Gastaut improved but none became seizure free. Both patients with ESES became seizure free.Conclusions: Co-administration of VPA and LTG should be considered to treat both generalized and focal refractory epilepsy. Refractory epilepsy with EEG features of Lennox-Gastaut or ESES might respond to the combination use of VPA and LTG. Larger clinical studies and studies examining pharmacogenetics, isoenzymes, or polymorphisms in the sodium ion channel are needed to elucidate the underlying mechanism of this known synergy to realize the potential of individualized treatment for refractory epilepsy.