ARTICLE IN BRIEF
In a meta-analysis, investigators found that patients with drug-resistant seizures who received adjunctive AEDs on top of their baseline AED regimen were seven times less likely to die suddenly and unexpectedly.
The use of adjunct antiepileptic drugs (AEDs) at effective doses may significantly reduce the risk of sudden unexpected death in refractory epilepsy patients, according to a new meta-analysis of published studies.
The review by French researchers, published in the November edition of The Lancet Neurology, found that patients with drug-resistant seizures who received adjunctive AEDs on top of their baseline AED regimen were seven times less likely to die suddenly and unexpectedly.
Led by Philippe Ryvlin, MD, professor of neurology at the Hospices Civils, Hôpital Neurologique, in Lyon, the French team compared occurrence of definite or probable sudden unexplained death in epilepsy (SUDEP) among drug-resistant epilepsy patients given efficacious AED doses and those receiving placebo. Currently, no evidence-based intervention to prevent SUDEP exists for such patients, but the researchers found those taking any AEDs had more than half the risk of a SUDEP than their untreated counterparts, based on a review of 112 randomized studies published in Medline and the Cochrane Library.
Of 33 deaths, 20 were classified as SUDEP, 18 as definite or probable, and two as possible SUDEP. There were significantly fewer definite or probable SUDEP cases, overall SUDEP cases, and deaths from all causes in patients receiving adjunct AEDs, they found. The odds ratios for each category were 0.17 (p=0.0046), 0.17 (p=0.0046), and 0.37 (p=0.0131), respectively.
Rates of definite or probable SUDEP per 1000 person-years were 0.9 in patients who received a new AED versus 6.9 in those given a placebo.
“The more than seven-fold difference in SUDEP incidence observed between patients given placebo and those receiving AEDs at efficacious doses points to a significant finding with a magnitude that cannot be ignored,” Dr. Ryvlin told Neurology Today in an e-mail.
In addition, polytherapy did not appear to increase SUDEP risk in the pooled studies, he said. “This alone is useful clinical information, and the overall results highlight the importance of revising treatment in patients with refractory epilepsy by adding an extra AED when appropriate to enhance seizure control.”
A BALANCING ACT
“This is a very important paper because it provides evidence to back up what we know about SUDEP — that the probability of seizures declines with treatment,” said Orrin Devinsky, MD, professor of neurology, neurosurgery and psychiatry, and director of the New York University (NYU) Comprehensive Epilepsy Center at the NYU Langone Medical Center. “These patients had poorly controlled epilepsy, and treatment with additional AEDs, at least for a temporary time, reduced seizures and incidence of SUDEP.”
Nonetheless, determining the best drug regimen for patients remains problematic, he told Neurology Today in a telephone interview.
“We are dealing with a very complex scenario, and this a not a simple issue for neurologists. With short-term treatment, patient risk of SUDEP goes down, but the longer patients take the medications, their protection may decline. Other studies show that treatment with three antiepileptic drugs increases SUDEP risk. We need more information on the SUDEP risks with number of drugs and frequency and type of dose and drug changes.”
Frequent changes in AEDs can also pose risks, he said. “With taking two or more drugs, there are increased side effects, and typically, after four or six months of treatment many patients will often tell their doctor that they want to stop the new drug or take lower doses, and this may increase their risk of SUDEP.”
The ultimate decision is what to do for patients in the long term versus the short term, he noted. “We often increase drug or dosage changes in response to a short-term situation, but may need to refocus and try to make more effective long-term treatment decisions — but all of this needs more research.”
The current study should be interpreted two ways, he said. “The first is that SUDEP needs to be better recognized and the risk needs to be discussed more often with patients, especially those whose seizures are difficult to control, those with tonic-clonic seizures, and those who are non-adherent to their medication schedule.”
“Getting seizures under control is the key, but finding the right treatment regimen can be a balancing act. We still need to untangle all of these issues.”
Michael R. Sperling, MD, Baldwin Keyes Professor of Neurology and director of the Jefferson Comprehensive Epilepsy Center at Jefferson Medical College in Philadelphia, agreed that the study underscores the importance of seizure control to reduce the risk of SUDEP.
In a 2001 review of SUDEP studies, published in the American Epilepsy Society's journal, Epilepsy Currents, Dr. Sperling wrote that 7 percent to 17 percent of all deaths among epilepsy patients are due to SUDEP. And while pulmonary and respiratory issues appear to be linked to SUDEP in some studies, “the bulk of evidence” suggests that patients with uncontrolled seizures are at greatest risk while those with well-controlled epilepsy have very low risk, although even patients with rare seizures — as few as one per year — have an increased risk of sudden death.
Seizure control also reduces deaths from other causes and provides additional benefits, such as better social adaptation and reduced morbidity, he added.
“If seizures are well controlled, SUDEP should not be an issue, but if a patient relapses, it needs to be addressed as soon as possible.”
Reducing risk is even more important in younger people, he said. Patients from epilepsy clinics who enter studies tend to be healthy and relatively young and their deaths achieve greater attention.
“While all death is tragic, SUDEP seems especially heartbreaking because it tends to strike young, otherwise healthy individuals.”
There are also data pointing to seizure type as playing an important role in SUDEP, he said. Patients with tonic-clonic seizures have the highest risk, although deaths can occur in patients without tonic-clonic seizures, especially complex partial seizures and tonic seizures.
Dr. Sperling agreed that seizure control can be challenging. Side effects from AEDs are very common, but tend to be under-recognized and under-reported by patients, he told Neurology Today.
“Many people do not appreciate how difficult side effects can be for individuals taking antiepileptic drugs, and this can lead to some patients taking their medication erratically which can lead to recurrent seizures and increased SUDEP risk. Neurologists need to closely question patients about side effects and adherence to their regimen to avoid SUDEP risk.”
A study published earlier this year in the journal Neurological Sciences found that among Italian epileptologists, only 8.7 percent discussed SUDEP with all of their patients, while 19.5 percent discussed it with the majority of patients. But 61.8 percent said they discussed SUDEP with very few of their patients and 7.7 percent with none of their patients. The reasons for this are unclear, but respondents to the Italian survey admitted that they did not wish to worry patients or their families about sudden death risk.
MORE ON SUDEP
See these Neurology Today stories:
- Robinson R. News from the AAN Annual Meeting: Complex picture emerges from new knowledge of ion channel genes in epilepsy. June 26, 2011: http://bit.ly/vDfa48
- Talan J. Longitudinal study tracks mortality in children with epilepsy. Jan. 20, 2011: http://bit.ly/sf7AjI
- Friedman R. Sodium channel defects implicated in sudden death and epilepsy. Dec. 16, 2010: http://bit.ly/twGgJS