When and how a combination of antiepileptic drugs (AEDs) should be used in patients unresponsive to monotherapy is not known. We followed up prospectively 248 patients in whom treatment with the first AED was unsuccessful. When treatment failed due to intolerable adverse events, a second (substituted) drug was prescribed. When failure was due to lack of efficacy, either AED substitution or combination (add-on) was undertaken. Patients were considered 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, those who received substituted monotherapy (n= 35) and those who received add-on treatment (n= 42) had similar seizure-free rates (substitution vs. add-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 action, more patients became seizure-free when the combination involved a sodium channel blocker and a drug with multiple mechanisms of action (36%) compared to other combinations (7 %, P= 0.05). None of the 11 patients who received 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 tolerated AED proved to be ineffective (n= 42, P= 0.05). These preliminary observations have generated verifiable hypotheses regarding the early management of epilepsy. A randomized study comparing substitution and combination after the failure of the first AED is underway.
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