How to choose antiepileptic drug treatment for refractory epilepsy?

EAN 2020

How to choose antiepileptic drug treatment for refractory epilepsy?

1920 1280 Anne Carter, MA (Cantab)

While most patients with epilepsy respond to one or two drugs, it is estimated that 30% develop drug resistance.1 At EAN 2020, Sylvain Rheims (Department of Functional Neurology and Epileptology, Hospices Civils de Lyon, Lyon, France) presented the who, when and how of drug treatment for refractory epilepsy.

What’s the problem with treating refractory epilepsy?

Prof. Rheims defined refractory epilepsy as failure of any two anti-epileptic drugs, with failure being occurrence of seizures despite treatment that is appropriate for the syndrome, well tolerated and at a reasonable dose. Despite development of several anti-epileptic drugs in recent years, the proportion of patients with drug-resistant epilepsy has remained fairly constant.2–4

However, this may not be the whole story. While the proportion of patients achieving 1-year seizure freedom seems similar in patients treated during the 1980s, 1990s and 2000s,5 pharmacoresistant patients may achieve some degree of seizure freedom, even if it is transient. As Prof. Rheims explained, “even if it’s transient, sometimes it’s important, because for some patients this transient remission can improve the overall situation in daily life.”

Is there an evidence-based choice for refractory epilepsy treatment?

One key question when treating refractory epilepsy is whether to use monotherapy (i.e. switch to an alternative anti-epileptic drug) or try combining drugs in polytherapy. “I do not have a clear answer, and especially I do not have an evidence-based clear answer,” Prof. Rheims shared, but many healthcare professionals propose polytherapy when faced with drug resistance.
Regarding efficacy, Prof. Rheims presented results from a meta-analysis of anti-epileptic drugs.6 He noted that while the Phase 3 trials of the drugs use similar primary endpoints (responder rate) and all demonstrated superiority over placebo, “we do not have significant difference between drugs.” Looking at other endpoints is also problematic – for example, few patients in Phase 3 trials achieve seizure freedom, so it is difficult to see significant differences between drugs.

Beyond trial results, another potential factor to consider when choosing anti-epileptic treatment is mechanism of action. When adding two drugs, Prof. Rheims explained that there are three options for the results: additivity (response is similar to the addition of the responses to each individual drug), supra-additivity (synergy) and infra-additivity (antagonism). Of course, synergy would be the aim. However, with the exception of the combination of sodium valproate and lamotrigine, this is not seen in the literature.

When combining therapies, it is also important to consider adverse events: “in patients with drug-resistant epilepsy the quality of life might be mostly related to the number of adverse events of anti-epileptic drug rather than seizure frequency.”

How to choose in clinical practice?

With no clear clinical evidence that can serve as a guideline, how do we choose the most suitable anti-epileptic treatment for refractory patients? Prof. Rheims concluded by posing this question. In answering, he advocated proposing treatment for patients with drug-resistant epilepsy based on the underlying syndrome, the safety profile of the drug and avoidance of aggravating drugs. Regarding patients, he stressed the importance of assessing risks at an individual patient level. Prof. Rheims summed up the presentation with “I think that we should continue to be very pragmatic”.

For more coverage from EAN 2020, click here.


1. Kalilani L et al. Epilepsia. 2018;59:2170–93
2. Chen Z et al. JAMA Neurol. 2018;75:279–86
3. Brodie MJ et al. Neurology. 2012;78:1548–54
4. Kwan P, Brodie MJ. N Engl J Med. 2000;342:314–9
5. Perucca E et al. Lancet Neurol. 2020; S1474-4422(20)30035-1
6. Rheims S et al. Epilepsia. 2011;52:219–33


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