Exploring the Causes and Possible Prevention of Sudden Death in Epilepsy
Respiratory arrest and sudden asystole fingered as key suspects
- Rosemary Frei, MSc
The face of young, handsome and athletic Christopher Donalty smiles up from the desk of Carl L. Faingold, PhD. Christopher died at the age of 21 from a phenomenon known as sudden unexplained death in epilepsy – or SUDEP – in 2002. His picture reminds Dr. Faingold, a professor and chairman of pharmacology at Southern Illinois University School of Medicine, Springfield, why he and his team are taking the road less travelled and researching SUDEP.
"I show Chris Donalty's picture to my students whenever they lose some of their enthusiasm," said Dr. Faingold, who received a Christopher Donalty Memorial Award from a Chicago-based group called CURE – Citizens United for Research in Epilepsy -- to study SUDEP in mice. "This is why we're doing it -- to try and prevent the terrible waste of lives, and the sadness and grieving that SUDEP leaves behind."
Dr. Faingold and his graduate students hypothesized that fluoxetine (Prozac, Eli Lilly) may improve the function of those parts of the brain that are known to control respiration in a serotonin-dependent fashion. Indeed, they showed that low doses of fluoxetine significantly reduced the proportion of specially-bred mice that went into respiratory arrest during seizures. In contrast, they found that an agent known as cyproheptadine (Periactin) -- which blocks the action of serotonin rather than enhancing it -- increased the proportion of mice with respiratory arrest.
The mice were from the strain DBA/2, which frequently have seizures followed by respiratory arrest and death when exposed to a very loud sound for 30-60 seconds. Dr. Faingold is the first and so far the only researcher to use them to study potential drug therapies to prevent SUDEP.
"I'd now like to see this studied in patients; if for example Chris Donalty had been treated with Prozac, he might be alive today," commented Dr. Faingold, who presented the results of the study in poster form at the 85th Annual Meeting of the American Epilepsy Society (AES; abstract # 2.048).
Dr. Faingold points to a seminal study that may lend support to his theory. Australian researchers examined 50 SUDEP cases from among 4,357 coronial autopsies in Victoria between December 1997 and August 1999 (
Seizure 2003;12:456-464). As part of their examination of the risk factors for SUDEP, the investigators noted that three of the controls – people with epilepsy who died of causes other than SUDEP -- had been taking fluoxetine, while none of those who died of SUDEP were using that drug. Overall, anti-anxiolytic drug use was significantly less common in the SUDEP group than in controls (P<0.05).
The Hunt for Causes
Clinical studies on SUDEP are difficult and unpleasant because they essentially involve watching and waiting for people to die. Further compounding this problem is the fact that most epilepsy advocacy groups focus on combating stigma and discrimination among people with epilepsy who are functioning relatively well. CURE emphasizes the significant morbidity and mortality associated with epilepsy, and provides approximately eight grants a year for innovative studies in epilepsy, including on SUDEP. But money to study SUDEP is still scarce – so scarce that James Wheless, MD, had to dip into his own pocket to pay for his most recent SUDEP study.
Dr. Wheless is director of the Texas Comprehensive Epilepsy Program, University of Texas – Houston. He and a colleague reviewed the records of all 17 children and adolescents who were patients of the program who died of autopsy-confirmed possible, probable or definite SUDEP from August 1992 to April 2004. They presented these results in poster form at the recent AES meeting (Abstract #2.249).
The study confirmed that all of the children suffered from generalized, tonic-clonic seizures, a widely recognized risk factor for SUDEP. Furthermore, among the 13 cases in which the circumstances of death were known, all 13 were found in bed at night. The position in bed of five of the SUDEP victims was also documented, and all were lying on their backs.
"The problem we run into is many families and even physicians become complacent if we eliminate the day-time seizures," said Dr. Wheless. "I think it's important for the physicians and families to be aware that we can't be complacent at that point – these night-time seizures can be deadly. We need to strive for better control of the seizures."
Is Sympathetic Shock to the Heart and Lungs the Culprit?
But why do these and some other circumstances, such as in chronic, refractory partial seizures, cause a disproportionate number of SUDEP cases in both young people and adults? The answer may lie in the effect on the heart and respiratory system of the surge of sympathetic activity that occurs during seizures.
Lawrence J. Hirsch, MD, associate clinical professor of neurology, Comprehensive Epilepsy Center, Columbia University, New York, was a co-investigator in a study showing 99% of seizures are associated with an increase in heart rate, and one in 10 epilepsy patients has potentially serious electrocardiogram (EKG) abnormalities during seizures (
Epilep Res 2002;52:117-127). The investigators found a higher risk of ictal EKG abnormalities in people with generalized seizures, and a trend to higher risk when seizures arose during sleep or from the left hemisphere, or when the ictal heart rate was elevated. Moreover, a later investigation indicated these types of ictal EKG changes and elevated heart rate are associated with subsequent SUDEP (
Epilepsia 2004;45:338-345).
The strongest evidence to date of the link between seizures and abnormal heart activity comes from a study by an English team published in December (
Lancet 2004;364:2212-2219). John Duncan, DM, professor of neurology, University College London, and four colleagues took long-term EKG recordings of 19 people with refractory epilepsy over 24 months, for a total of 220,000 person-hours.
All 19 patients were found to have sinus tachycardia during some seizures, and seven experienced bradycardia. Four of these seven patients had periods of either severe bradycardia or complete asystole, including three people with potentially fatal heart stoppage. Furthermore, all four patients had a period of tachycardia immediately before the severe bradycardia or asystole. One of the four patients had 450 seizures recorded, but only during two did he experience tachycardia followed by a sudden period of asystole. All four subsequently received pacemakers.
"The point I take from this is that it's an occasional, potentially very serious, event," explained Professor Duncan. "As an analogy, imagine someone's running across a busy highway. Most of the time they get away with it, but then once they're hit by a truck. That's the way I look at SUDEP – one time in a thousand the heart stops."
Dr. Duncan and his colleagues are beginning a study in which they will conduct long-term EKG recording in 200 patients with various kinds of epilepsy. Since respiratory causes are also implicated in many cases of SUDEP -- for example, other investigators found 12 of 15 cases of SUDEP involved respiratory difficulties (
J Neurol Neurosurg Psychiatry 2000;68[2]:211-213) -- in the future he also would like to perform long-term monitoring of respiration patterns in epilepsy patients.
"This is really new and important information," enthused Dr. Hirsch, who co-authored a commentary on Professor Duncan's study (
Lancet 2004;364:2157-2158). "It's the first study that suggests some cases of SUDEP could be prevented, by giving at-risk patients pacemakers."
[Reprinted with permission from CNS New York]
