Correspondence Department of Neurology, University of Pennsylvania, 3 West Gates, 3400 Spruce Street, Philadelphia, PA 19104, USA

Email frenchj@mail.med.upenn.edu

Original article

Luciano AL and Shorvon SD (2007) Results of treatment changes in patients with apparently drug-resistant chronic epilepsy. Ann Neurol [doi: 10.1002/ana.21064]   Article

Synopsis

Background

It is often thought that patients with epilepsy are unlikely to ever respond to drug treatment if they have not done so within a few years of treatment initiation. In the past 15 years, however, several new antiepileptic drugs (AEDs) have become available; the effect of these treatments on chronic epilepsy has not yet been established.

Objective

To determine the effect of adding a new AED to the treatment regimen of patients with uncontrolled chronic epilepsy refractory to previous drug treatment.

Design and intervention

This retrospective study included patients aged 16 years or older with active epilepsy (defined as at least one seizure a month) and at least a 5-year history of epilepsy who were seen over a 2-year period at a single institution and received at least one new drug during the study period. The treatment regimen generally consisted of the newly introduced drug plus one or two 'anchor' drugs. The choice of initial drug was made by the consultant neurologist; the decision was based on the seizure classification, clinical context, and previous history of drug response. If the first drug failed, the patient was switched to a second; a planned sequence of changes was followed until a successful response was obtained. For drug introductions, dose increments were made every 2 weeks until the maintenance dose was reached; for reductions or withdrawals, decrements were made every 2–4 weeks. For a patient to be classed as free from seizures, they had to have a minimum follow-up period without seizures of 12 months.

Outcome measures

Freedom from seizures was the primary outcome measure; the secondary outcome was a 50–99% reduction in seizures.

Results

The study included 155 patients (72 male, 83 female) with a mean duration of epilepsy of 21.5 years (range 6–54 years). The cause of epilepsy was symptomatic in 82 patients, cryptogenic in 52 and idiopathic in 21. Monthly seizure frequency was 1–5 in 81 patients, 6–10 in 24 patients, and >10 in 50 patients. Patients had taken between 1 and 15 different previous AEDs (mean 5.8). A total of 265 new drug introductions were made (125 by addition, 140 by substitution). Mean follow-up was 18.3 months (range 6–60 months). Seizure freedom resulted from 16% of drug introductions, and a 50–99% reduction in seizures resulted from a further 21% of introductions. In all, 43 patients (28%) achieved complete remission, and 56 patients (36%) obtained a 50–99% reduction in seizures. More patients with idiopathic epilepsy achieved remission than did those with either cryptogenic or symptomatic epilepsy (27%,18% and 9%, respectively; P = 0.017).

Conclusion

Improved epilepsy control can be achieved by changing the drug regimen, even in patients who have not responded to several previous AED treatments.

Commentary

There is no consensus definition of refractory epilepsy. The most-quoted definition states that patients are refractory, or 'treatment-resistant', when they have had epilepsy for more than 2 years and have not responded to two or more AEDs. Indeed, a study of patients with newly diagnosed epilepsy found that those who showed a poor response (in terms of lack of efficacy rather than poor tolerance) to even a single drug had only an 11% chance of long-term seizure freedom.¹ This and other studies have painted a bleak picture of effectiveness of AEDs in the more difficult to treat patient, a particular concern in light of the recent approval of nine new drugs, which were expected to have a substantial impact. As a result, many patients are counseled that their likelihood of remission with serial drug trials is poor.

The current article provides a much more hopeful outlook. Even patients who had unsuccessfully been treated with a substantial number of AEDs had the potential to become seizure-free on a subsequent drug trial, and could remain so for at least a year. One previous study evaluated outcome in refractory patients, specifically those who were rejected as candidates for epilepsy surgery. The study reported a 21% long-term remission rate.² These findings should be of extreme interest and importance to treating physicians, as they indicate that no patient should lose hope. Likewise, the treating physician should continue to actively seek an effective medication. Practicing clinicians will find it most useful that the authors have provided a table in which they have described the starting dose, titration schedule and target dose for the medications that were added to obtain the reported benefit.

The patients evaluated in this study were having frequent seizures, had a long epilepsy duration, and had shown no response to up to 15 previous AEDs. Nevertheless, seizure freedom was not out of their reach. Less-refractory patients might be expected to fare even better.

An interesting aspect of the study was that the outcome was provided in reference to likelihood of seizure freedom per drug trial, not per patient, and even when the same patient moved through several trials in the hands of a single doctor, the outcome (15% seizure-free per trial) did not substantially change. This implies that the more AEDs that a patient tries, the greater the likelihood of benefit.

The study has several potential weaknesses. For example, the data were collected retrospectively, and patients who were referred from other centers, where they might not have received best treatment, were not excluded. In addition, the study did not follow patients long-term. We are told that patients who responded were seizure-free for 'at least a year'. It is unclear whether patients who become seizure-free will remain so indefinitely. This question will need to be addressed in studies of longer duration.

Several recent studies have indicated that patients might move in and out of a refractory state as their disease progresses.^{3, 4} It is possible that some of the patients who became seizure-free would have done so through the natural course of epilepsy, irrespective of a change in AEDs. In clinical practice, however, seizure freedom is rarely seen in refractory patients without treatment change. Appropriate aggressive AED treatment of uncontrolled seizures, therefore, seems to be warranted.

Acknowledgments

The synopsis was written by Jim Casey, Editorial Assistant, Nature Clinical Practice.

References

1. Kwan P and Brodie MJ (2000) Early identification of refractory epilepsy. N Engl J Med 342: 314–319 | Article | PubMed | ISI | ChemPort |
2. Selwa LM et al. (2003) Long-term outcome of nonsurgical candidates with medically refractory localization-related epilepsy. Epilepsia 44: 1568–1572 | Article | PubMed |
3. Sillanpaa M and Schmidt D (2006) Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study. Brain 129: 617–624 | Article | PubMed |
4. Berg AT et al. (2006) How long does it take for epilepsy to become intractable? A prospective investigation. Ann Neurol 60: 73–79 | Article | PubMed |

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Subject areas under which this article appears: Epilepsy