SUDEP and Antiepileptic Drugs

In the search to understand the mystery of SUDEP, physicians, scientists and people living with epilepsy have wondered not only about seizures as a cause of death, but also about the way we treat seizures. Could epilepsy treatments have an effect on the risk of SUDEP? Given that the overwhelming majority of people with epilepsy are treated with antiepileptic drugs (AEDs), there has been significant interest in how the use of AEDs may increase or decrease the risk of SUDEP.

Recently, two publications have shed some more light on the relationship between the drugs used for seizures and SUDEP.

Incidence of SUDEP Lower Among People Taking Add-On Medications vs. Placebo

In the November 2011 issue of The Lancet Neurology, Dr. Philippe Ryvlin and his colleagues reported on their meta-analysis of 112 randomized placebo-controlled studies that examined the efficacy of specific drugs to reduce seizures[1]. In these studies, adults with epilepsy were randomly assigned to be treated with an add-on AED (given in addition to their current AED) or a placebo (in addition to their current AED). A placebo is a harmless substance, such as a sugar pill, that is given to subjects in research studies to compare the effect of the placebo with the drug being studied.

In their paper, Dr. Ryvlin and his colleagues compared the occurrence of SUDEP among people who received an add-on AED and those who received a placebo. They found that the incidence of SUDEP was markedly reduced in people treated with the add-on AED. Among all 112 studies, there were 18 deaths due to definite or probable SUDEP. Although the number of deaths is not large, they are able to compute the rates of death in each group. The rate of SUDEP for adults receiving an add-on AED at the appropriate dose was 0.9 per 1000 people per year, while the rate of SUDEP for adults receiving an add-on placebo was 6.9 per 1000 people per year. The authors of the study concluded that the most probable explanation for the lower SUDEP rate among the people that received the AED was a reduction in seizure frequency. This conclusion is strongly supported by other medical literature that identifies frequent seizures as the most important risk factor for SUDEP.

The International League Against Epilepsy Subcommission on Mortality, under the lead of Dr. Dale Hesdorffer, undertook an analysis of four studies, from the USA, Scotland, England and Sweden, that examined risk factors for SUDEP. The combined analysis, first published in 2011[2], confirmed that SUDEP was associated with younger age of onset and longer duration of epilepsy, frequency of generalized tonic–clonic seizures and antiepileptic drug use. In follow up to this report, the authors dug deeper into the data to examine whether the association between SUDEP and AED use is related to the drugs themselves, or to the fact that people who have more frequent seizures often use more AEDs.

In the February 2012 issue of the journal Epilepsia, the results of their further analysis were published[3]. This time, they examined whether it is frequency of generalized tonic-clonic seizures, or the combination of medications, that contribute to an increased risk of SUDEP. The authors found that, when the number of seizures was controlled for, there was no increased risk of SUDEP associated with taking AEDs or with the number of AEDs a person was taking. Furthermore, no individual AED was associated with an increased risk of SUDEP.

Improving Seizure Control is Best Way to Reduce Risk of SUDEP

The reason these articles are so important is that they highlight the fact that improving seizure control is the best way to reduce SUDEP risk. While some have suggested that polytherapy, or using multiple drugs to control seizures, is associated with an increased risk of SUDEP, we now understand that the likely reason for this association is that people with more difficult to control seizures take more AEDs. In fact, it is probably the fact that their seizures are hard to control that increases their risk of SUDEP, not the number of drugs they are taking.

  1. Ryvlin, P et al. Risk of sudden unexpected death in epileptic patients with uncontrolled seizures given adjunctive antiepileptic treatment: a meta-analysis of placebo-controlled randomised trials. Lancet Neurology, 2011; 10:961.
  2. Hesdorffer, DC et al. Combined analysis of risk factors for SUDEP. Epilepsia, 2011; 52:1150.
  3. Hesdorffer, DC et al. Do antiepileptic drugs or generalized tonic–clonic seizure frequency increase SUDEP risk? A combined analysis. Epilepsia, 2012; 53:249.

Dr. Elizabeth Donner is a Pediatric Neurologist and Associate Professor at the Hospital for Sick Children, Toronto. She conducts SUDEP research, is implementing a pediatric SUDEP registry and is a Director/Co-founder of SUDEP Aware.