Epilepsy after the first drug fails: substitution or add-on?

When and how a combination of antiepileptic drugs (AEDs) should be used in patients unresponsive to monotherapy is not known. We followed up prospecti vely 248 patients in whom treatment with the first AED was unsuccessful. Wh en treatment failed due to intolerable adverse events, a second (substitute d) drug was prescribed. When failure was due to lack of efficacy, either AE D substitution or combination (add-on) was undertaken. Patients were consid ered to be seizure-free if they had no seizures for at least 1 year. Among patients with inadequate seizure control on the first well tolerated AED, t hose who received substituted monotherapy (n = 35) and those who received a dd-on treatment (n = 42) had similar seizure-free rates (substitution vs. a dd-on: 17% vs. 26%) and incidence of intolerable side effects (substitution vs. add-on: 26% vs. 12%). Based on the drugs' perceived primary mode of ac tion, more patients became seizure-free when the combination involved a sod ium channel blocker and a drug with multiple mechanisms of action (36%) com pared to other combinations (7%, P = 0.05). None of the 1 1 patients who re ceived add-on treatment after a second drug had also failed became seizure- free, compared to 26% in those who received add-on as soon as the first tol erated AED proved to be ineffective (n = 42, P = 0.05). These preliminary o bservations have generated verifiable hypotheses regarding the early manage ment of epilepsy. A randomized study comparing substitution and combination after the failure of the first AED is underway. (C) 2000 BEA Trading Ltd.