Researchers from University of Washington, Seattle, WA analyzed the treatment records from 148 developmentally disabled adults with refractory epilepsy cared for in 2 state-run institutions. Records charted monthly convulsive seizure occurrence and AED regimen over 30 years. Patients had a predominance of focal over generalized EEG abnormalities. The effects of 8 commonly used AEDs alone and in combination on seizure frequency were studied in within-patient comparisons. In decreasing order of frequency, the drugs compared were lamotrigine, valproate, carbamazepine, phenytoin, topiramate, levetiracetam, gabapentin, and zonisamide; phenobarbital and oxcarbazine were used at only one institution and were excluded from calculations. Individual AED combinations were first compared to an aggregate measure of all other combinations to which a patient had been exposed. This allowed greater statistical power to assess efficacy of individual combinations.
Out of the most frequently used AED combinations, only lamotrigine (LTG) and valproate (VPA) combination had superior efficacy; seizure frequency was reduced by 50% or more in comparison to other regimens. The LTG/VPA combination was superior to VPA or LTG monotherapy, and CBZ/VPA, VPA/GBP, or CBZ/VPA/PHT combinations. While 2 concurrent AEDs provided improved efficacy over monotherapy, use of 3 AEDs at a time provided no further benefit over two AEDs combined. AEDs should be used no more than 2 at a time for optimal response. 
COMMENT. The superior efficacy of LTG/VPA combination compared to other AED combinations is reported previously [2, 3] (Refs cited by authors). Synergism between the 2 drugs may explain the improved seizure control by a valproate-induced reduction in hepatic clearance of lamotrigine. However, the present study found no VPA effect on LTG serum concentrations, and the mechanism of synergism is unexplained.