Parviz Bahrami MD

Epileptologist, Associate professor of neurology, Khatam Hospital

Dr B.Jalalian,Dr N.Zangiabadi,Dr M.Rezvani

The role of combination therapy as a treatment strategy for epilepsy is undergoing reevaluation. A growing appreciation that all seizure cannot be controlled by monotherapy and introduction of over 14 new antiepileptic drugs (AEDs) for the adjunctive treatment in refractory epilepsy in the past twenty years has triggered a renewed interest in combination.

Principle of polytherapy in epilepsy;

 Rational polytherapy in epilepsy involves combining Antiepileptic drugs that, 1) have different mechanism of action, 2) Do not have complex pharmacokinetic interaction, 3) do not have similar adverse effect profile, 4) can be combined in minimum doses to produce maximum effect

Practice Recommendations.

START WIYH MONOTHERAPY, Choose AED appropriate for seizure type and epilepsy syndrome, emphasize on safety and tolerability. More than 50% of patients respond to the first appropriately chosen drug in moderate doses. Dose escalation should always be steady and gradual to avoid poor tolerance.

If the first drug produces idiosyncratic adverse effect or side effects at low doses, substitute with a suitable alternative drug.

Combination therapy: When and How;

1) If first drug reduces seizures, dose should be escalated to the maximum tolerated dose. If seizure freedom is elusive despite full doses of the first AED, a second drug may be added. The second drug should have a different mechanism of action and should not have an overlapping side effect profile. Drug with similar mechanism of action should preferably not be combined.

2) Combination therapy should also be tried after two monotherapy regimes fail, as chances of seizure control on third monotherapy are slim.

3) Before considering AED changes or combination for lack of effective seizure control, the diagnosis of epilepsy, seizure type and syndrome should be reviewed and compliance of the patient with AEDs should also be confirmed

4) If seizure freedom is achieved on the combination therapy, does of the first drug may be reduced gradually, if necessary, to avoid drug overload.

5) If seizure control is good on the combination, but seizure freedom is still elusive a third drug with a different mechanism of action may be tried in small doses. However adding of fourth or a fifth drug is unlikely to be successful.

6) Three drug regimen are generally avoided if possible. Indeed the vast majority of patients reaching seizure freedom do so with two AEDs, and virtually no one achieves seizure freedom with four AEDs. If patient is on four or more AEDs, a concerted attempt should be made to reduce the regimen to two or three AEDs.

7) Treatment for each patient is individualized based on seizure type, syndrome, age, gender, comorbid conditions and comedication.

8) When two monotherapy fail or a combination of two AEDs fails to achieve seizure freedom, the patient qualifies to have drug resistant epilepsy. Such patients should be evaluated for alternative therapeutic strategies such as epilepsy surgery.

Combination therapy: when Not

Women who are likely to become pregnant should be maintained on monotherapy in moderate does as far as possible. Suboptimal control of seizures other than tonic clonic seizures during this period may be an acceptable trade off, to reduce the risk of teratogenicity from poly therapy or high drug load. Risk of teratogenicity is highest soon after conception and in the first trimester, hence AED therapy has to be rationalized before conception. High dose valproate either alone or in combination therapy is best avoided throughout pregnancy.