Which treatment strategy in patients with epilepsy with focal seizures uncontrolled by the first anti-seizure medication?

There is no definite proven or accepted strategy in the management of patients with focal epilepsy uncontrolled by the first anti-seizure medication (ASM). Clinical studies failed to find a significant difference in efficacy or tolerability between alternative monotherapy and/or adjunctive therapy in these patients. A second ASM is often added, the efficacy of the combination is assessed, and the dose of the first drug can be gradually reduced and withdrawn. If seizures recur, the effective combination therapy can be reinstated. In this review, we discussed experimental and clinical data about the efficacy and tolerability of the most frequently used combinations of ASMs. Animal studies suggested that the most favorable combinations are those between ASMs with different or multiple mechanisms of action, whereas combining drugs with similar pharmacodynamic properties is often associated with additive or infra-additive efficacy and additive or synergistic toxicity. Clinical studies have shown that levetiracetam (LEV) can be favorably combined with the sodium channel blockers (SCBs) lacosamide (LCM) and lamotrigine (LTG). Lamotrigine is particularly effective when associated with valproate (VPA) and possibly with LEV and topiramate (TPM). Carbamazepine (CBZ) has negative pharmacokinetic interactions with several ASMs and should not be combined with other SCBs; it could be effectively and safely combined with gabapentin (GBP) and LEV. Valproic acid has enzyme inhibiting properties and can be cautiously used with SCBs; its combination with TPM or zonisamide (ZNS) may be associated with higher toxicity.