Adding vs substituting AEDs

The drug of choice for the particular type of seizure or epilepsy is started at the lowest effective dose. If seizures continue, the daily dose is increased by small increments to an effective dose that does not cause the patient significant side effects. Except in an emergency, there is no need for rapid titration. Most AEDs work within several days to a week of starting treatment. Rapid titration is not only unnecessary, but may even be harmful. It increases the risk of cutaneous hypersensitivity reactions, for example, with carbamazepine, lamotrigine, and phenytoin, and adds to the risk of avoidable central nervous system toxicity, particularly during early primidone therapy. It was found in recent years that the average effective dose achieves seizure control in about 70–80% of those who respond at all doses, including above-average doses. As a consequence, in those who are not controlled by a well-tolerated average dose, a dose increment may be useful, but only for about 20–30%.

If seizure control cannot be achieved with the maximum tolerated dose or if toxic symptoms or high plasma concentrations indicate that an increased risk of toxicity may develop before seizures are controlled, a second AED is added, again guarding against toxicity. Interactions between the drugs can interfere with their rates of metabolic degradation. When a patient does not respond sufficiently, gradual withdrawal from the initial, failed AED and a switch to monotherapy with the recently added AED is an option. If the patient responds well, a combination of both drugs is usually maintained unless side effects require downtitration to lower the total drug load.

When single-drug therapy is not able to control seizures, adding a second drug and substitution monotherapy are common options. When the initially prescribed AED fails to produce seizure freedom, transfer to monotherapy with an alternative agent (substitution) will lead to seizure control in as many as 15–30% of cases. Based on the available evidence, there are no conclusive data favoring either substitution monotherapy or add-on treatment. Except for patients with severe idiosyncratic reactions, where substitution is clearly preferable, a pragmatic choice is to evaluate the combination first and to slowly taper and finally discontinue the first drug. This may prevent the substitution of a partially efficacious drug with a nonefficacious drug. Reduction of the first drug prevents unnecessary drug exposure in the case of adverse effects.

The choice of the second drug should be based on which first drug failed. The use of newer-generation AEDs that are not involved in drug interactions may provide a better outcome for add-on treatment, which is more vulnerable to adverse drug interactions than substitution monotherapy. The main advantages of substitution monotherapy compared with combination therapy include simplicity, allowing clear attribution of the observed clinical effect; no unnecessary drug load (overtreatment) as in combination therapy; no detrimental drug interactions; and no adverse effects of specific combinations, for example, increased teratogenicity with a combination of valproate and lamotrigine. Furthermore, transfer to monotherapy has been shown to be useful when combination therapy has failed to provide sufficient seizure control. A safe and well-communicated schedule for transitioning from one monotherapy to the next is as essential as the choice of optimal agent for the success of either combination or substitution therapy.

Adapted from Elger CE, Schmidt D. Modern management of epilepsy. Epilepsy Behav 2008;12:501-39.

Simplifying AEDs

(Adapted from Richardson SP et al. Improvement in seizure control and quality of life in medically refractory epilepsy patients converted from polypharmacy to monotherapy. Epilepsy Behav 2004;5:343-7.)

The treatment of refractory seizures is often believed to require polypharmacy, as monotherapy is "good, [but] it is still not good enough" [1 and 2]. Rational polypharmacy in epilepsy is based on combining antiepileptic drugs (AEDs) based on their mechanisms of action as well as pharmacokinetic and pharmacodynamic interactions (i.e., valproic acid and lamotrigine) [3]. About 20–30% of patients with epilepsy have refractory seizures and many of these patients are on multiple medications at the same time in an attempt to achieve full seizure control [4]. The risks of uncontrolled epilepsy are increased mortality, cognitive and behavioral dysfunction, and social disadvantage [5]. While there is clearly justification for aggressive attempts at seizure control (e.g., polypharmacy), the concern with this approach to refractory seizures is that treatment of epilepsy can easily turn into "overtreatment" [6]. Polypharmacy may increase the side effects of medications through drug–drug interactions and, paradoxically, may increase seizure frequency [7].

The paradigm in refractory seizures has oscillated between monotherapy and "rational polypharmacy," neither of which has been shown to be superior in a randomized clinical trial in patients with refractory epilepsy. While the efficacy of monotherapy versus polypharmacy is unclear, a recent trial has shown the two approaches to be no different with respect to neurotoxicity in patients with newly diagnosed epilepsy [8].

There is some evidence that patients on multiple AEDs may benefit from reduction of polypharmacy. In a study in Japan of outpatients with chronic epilepsy, seizures were not aggravated by polypharmacy reduction, and quality of life (QOL) actually improved [9]. But this study did not specifically compare polypharmacy with monotherapy. Another prospective trial showed that when two-drug therapy was reduced to single-drug therapy in patients with intractable complex partial seizures, the majority of patients had no increase in seizure frequency and 36% actually had improvement in seizure control [10]. The authors did not include information on QOL except to note a smaller number of side effects with single-drug therapy.

While there is some information that the reduction of polypharmacy to monotherapy is beneficial to patients with refractory refractory seizures, there is still a lack of information supporting this approach.

In a retrospective chart review, Richardson et al identified 35 patients with refractory seizures who had been converted from polypharmacy to monotherapy and maintained on monotherapy for at least 12 months. None of the 35 patients had worsening of their seizure frequency after the conversion to monotherapy. Fourteen of the 35 patients (40%) became seizure-free. Nine of 35 patients (26%) had a 50% reduction in seizure frequency. Five of 35 patients (14%) had a 75% reduction in seizure frequency. Twenty-eight (80%) of 35 patients participated in a quality-of-life questionnaire. Quality of life was rated as better on monotherapy as compared with polypharmacy in a number of domains: memory loss, concern over medication long-term effects, difficulty in taking the medications, trouble with leisure time activities, and overall state of health. This improvement reached statistical significance. The authors conclude that conversion to monotherapy in patients with refractory seizures may be successful in achieving a reduction in seizure frequency and an improvement in quality-of-life parameters but cautioned that a prospective, randomized trial would be necessary to validate these findings.


1. I.E. Leppik, Monotherapy and polypharmacy. Neurology 55 Suppl. 3 (2000), pp. S25–S29.

2. J.P. Leach, Antiepileptic drugs: safety in numbers. Seizure 9 (2000), pp. 170–178.

3. L.J. Stephen and M.J. Brodie, Seizure freedom with more than one antiepileptic drug. Seizure 11 (2002), pp. 349–351.

4. P. Kwan and M.J. Brodie, Refractory epilepsy: a progressive, intractable but preventable condition? Seizure 11 (2002), pp. 77–84.

5. P. Kwan and M. Brodie, Epilepsy after the first drug fails: substitution or add-on?. Seizure 9 (2000), pp. 464–468.

6. B. Bourgeois, Reducing overtreatment. Epilepsy Res. 52 (2002), pp. 53–60.

7. J.A. Ferrendelli, Pharmacology of antiepileptic drug polypharmacy. Epilepsia 40 Suppl. 5 (1999), pp. S81–S83.

8. C. Deckers, Y.A. Hekster, A. Keyser et al., Monotherapy versus polytherapy for epilepsy: a multicenter double-blind randomized study. Epilepsia 42 (2001), pp. 1387–1394.

9. M. Matsuura, Patient satisfaction with polypharmacy reduction in chronic epileptics. Psychiatry Clin. Neurosci. 54 (2000), pp. 249–253.

10. D. Schmidt, Reduction of two-drug therapy in intractable epilepsy. Epilepsia 24 (1983), pp. 368–376.

AES/AAN guidelines

Based on a comprehensive review of the literature, guidelines on the use of seven seizure medicines (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide) to treat refractory epilepsy were developed and published by the American Epilepsy Society (AES) and the American Academy of Neurology (AAN) (French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: Treatment of refractory epilepsy. Neurology 2004;62:1261-1273). The guideline recommendations are further separated for adjunctive therapy in adults, adjunctive therapy in children and monotherapy.

A summary of the recommendations for clinicians may be found at (pdf), and information sheets for your patients are available at (pdf).

Expert opinion

Faced with the growing list of antiepileptic drugs (AEDs), clinicians must decide what therapy, or combination of therapies, is best for a given individual. Although controlled clinical trials exist for each treatment option, giving rise to evidence-based guidelines, the answer to these questions for an individual patient may remain unclear. In 2000, Karceski et al conducted a survey of expert opinion to address questions concerning which treatment options might be best in a number of clinical situations. They surveyed a group of US epileptologists again in 2004, compared the results of the two surveys and published their findings in Epilepsy & Behavior (2005;7:1-64).

The investigators sent a questionnaire on the treatment of adolescent and adult epilepsy syndromes to a group of opinion leaders in the field of epilepsy. The questions were formatted to simulate real-world clinical situations in the treatment of symptomatic localization related epilepsy (SLRE) and idiopathic generalized epilepsy (IGE). The experts were asked to rate treatment options based on a modified RAND 9-point scale (with "9" most appropriate and "1" least appropriate). Statistical analysis of data was performed as defined by the expert consensus method. The results were used to develop user-friendly recommendations concerning overall treatment strategies and choice of specific medications.

Of the 48 experts to whom the survey was sent, 43 (90%) responded; 29 (67%) of the respondents had also participated in the first survey. For initial monotherapy for IGE (generalized tonic-clonic [GTC], absence, and myoclonic seizures), valproate was rated as treatment of choice. For IGE-GTC seizures, lamotrigine and topiramate were also identified as usually appropriate for initial monotherapy. For IGE-absence seizures, ethosuximide was also a treatment of choice, and lamotrigine was usually appropriate. For SLRE, the experts were again asked to rate treatment options based on seizure type: simple partial seizures (SPS), complex partial seizures (CPS), and secondarily generalized tonic-clonic seizures (SGTC). In SLRE-SPS and SLRE-SGTC, carbamazepine and oxcarbazepine were treatments of choice, with lamotrigine and levetiracetam also usually appropriate. In SLRE-CPS, carbamazepine, lamotrigine. and oxcarbazepine were treatments of choice, while levetiracetam was also usually appropriate. For women who are pregnant or trying to conceive, lamotrigine was treatment of choice for both syndrome types. In the elderly, whether medically stable or ill, the treatment of choice was lamotrigine, while levetiracetam was also usually appropriate (along with gabapentin for persons with comorbid medical illness). In persons with HIV and epilepsy, lamotrigine and levetiracetam were usually appropriate. In people with both epilepsy syndromes who have depression, lamotrigine was treatment of choice. In a person with seizures and renal disease, lamotrigine was usually appropriate for both syndromes, with valproate also usually appropriate for IGE. In patients with hepatic disease, levetiracetam and lamotrigine were usually appropriate for IGE; in SLRE, levetiracetam was treatment of choice, with gabapentin also usually appropriate.

Although the panel of experts reached consensus on many treatment options, there are limitations to these types of data. Despite this, the expert consensus method concisely summarizes expert opinion, and this opinion may be helpful in situations in which the medical literature is scant or lacking.

Adapted from Karceski S, Morrell MJ, Carpenter D. Treatment of epilepsy in adults: expert opinion, 2005. Epilepsy Behav 2005;7:1-64.

Reviewed By: 
Steven C. Schachter MD
Friday, May 9, 2008