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Epilepsy doctors are being encouraged to discuss a topic with patients and families that is very difficult, emotional and important. The topic is sudden unexpected death in epilepsy (SUDEP).
SUDEP can be defined as:
24 year-old male who had a history of uncontrolled seizures since infancy. Seizure types included generalized tonic-clonic seizures (= grand mal seizures) and tonic seizures (brief stiffening seizures). The patient had intellectual disabilities. He was able to work stocking shelves at a local grocery store. He enjoyed bowling and watching movies. He was very social- he loved going to stimulating events such as parties or to the state fair. He smiled and laughed easily. Other than epilepsy and intellectual limitations, he was healthy. One day, he became ill and vomited up his seizure medications. He went to sleep early that night. Tragically, he was found dead in bed the next morning. There was evidence of a seizure—he had bitten his tongue and was incontinent of urine. An autopsy was performed. A medical cause for the death was not identified. The death certificate indicated cause of death: sudden unexpected death in epilepsy.
INCIDENCE AND RISK FACTORS FOR SUDEP
Fortunately, SUDEP is an uncommon occurrence. However, it is a tragedy that does occur, and families are far too often unprepared. Families who have lost a loved one have expressed great disappointment in having never been told about this well documented phenomena. Families consistently indicate that if they had been educated about SUDEP, they would have been better prepared for the tragedy. Health care providers need to discuss this important issue with patients and families. Although death is not easy to talk about, it clearly is an important conversation to have.
It should be noted that patients with epilepsy do have a greater risk of early death compared to the general population. The increased risk is usually not directly related to the seizures, but rather to the underlying cause of the epilepsy. For example, patients with brain tumors and epilepsy usually die from the tumor, not from the epilepsy. Although the incidence is not high, some patients can die more directly from their seizures- for example due to drowning, crashing a motor vehicle or very prolonged and intense seizure activity (= status epilepticus).
It should be stressed that patients who do not have an underlying disorder that will shorten their life (such as a tumor or stroke, for example) can be expected to live a full life span. As noted above, accidental injuries are more common in certain patients with epilepsy- thus appropriate precautions should be taken to keep a patient safe—for living a long and full life.
The rate of sudden death in the general population < 45 years of age is estimated at 0.05-0.1/1000 person-years of follow-up (Nashef, 2008) . In comparison, patients with epilepsy whose seizures are not controlled have been found to have SUDEP rates of 1-6/1000 patient years of follow-up. If you compare these numbers, you can see that patients with poorly controlled seizures have several times the risk of sudden death, compared to the general population. The more severe the seizures, the higher the incidence of SUDEP. For example, studies have demonstrated that patients who continue having seizures despite several seizure medication trials and who even fail epilepsy surgery are at relatively higher risk of SUDEP (4.5-6/1000 patient years of follow-up). Interestingly, epilepsy surgery, if it controls the seizures, appears to be effective at reducing the risk of SUDEP. Patients who have had epilepsy surgery have been followed long-term (Stavern, Epilepsy Res, 2005). Those who are seizure free after the surgery have the same incidence of sudden death as the general population.
Several studies have looked at clinical variables that are associated with a higher risk for SUDEP (Nashef, 2008/Walczak, Neurology, 2001). A summary of important clinical characteristics associated with SUDEP:
WHAT CAUSES SUDEP?
Patients who have died of SUDEP typically are found in bed. In one study evaluating 135 SUDEP patients, two thirds of patients died while in bed (Langan, JNNP, 2000). The patient had typically gone to sleep the night before, with no issues to forewarn of the impending tragedy. How exactly the death occurs is currently an area of active research. Patients may be found with evidence of having an intense seizure- for example, tongue bite or urine incontinence may be noted. Although most SUDEP cases are not witnessed, when SUDEP is seen, seizure activity has often been described to occur at the time of the death. It is known that intense seizure activity can disrupt respiratory function and cause cardiac arrhythmias. Most experts suspect that intense seizure activity triggers cardiac or respiratory arrest—which then results in the death of the patient. Causes other than seizure activity have been postulated. For example, cardiac arrhythmias due the affects of seizure medications or due to brain pathology have been suggested.
RECENT ARTICLE SUPPORTS: BETTER SEIZURE CONTROL, LESS CHANCE FOR SUDEP
A recent article examined all SUDEP cases in a large number of randomised antiepileptic drug (AED) studies (Ryvlin, Lancet Neurol, 2011). What the authors did was a thorough review of the literature to find essentially all randomised AED studies that met their inclusion criteria. They found 112 studies that met their criteria. The authors then reviewed each of these studies to see if any patients in the study died of SUDEP. They identified 20 cases of SUDEP out of all these studies. Remember, patients can die during the course of a drug study. Sometimes, they may get in a car accident. Some may have a heart attack. Some patients may die of SUDEP. If a patient has died during a drug study, the reason for the death is reported.
The authors analyzed all the patients who died of SUDEP. They compared the SUDEP rate in those: 1) patients who were treated with the study AED to 2) those patients on placebo. As you may know, most AED drug trials are designed as follows: One group of patients has the study AED added to their current AEDs. The frequency of their seizures and side effects are studied. This study group is compared to a group of patients who have a placebo added to their current AEDs (basically, a sugar pill). By comparing the groups, you can tell if the AED is effective at improving seizure control and if side effects are a problem.
The results of the study were striking (Spencer, Epilepsy Currents, 2012). Treatment with the add on AED (study drug) reduced the incidence of SUDEP more than 7 times, compared to treatment with a placebo. This study provides arguably the best evidence to date the concept that improving seizure control may be helpful in reducing the incidence of SUDEP.
Early death rates are higher in patients with epilepsy compared to the general population. Most early deaths in patients with epilepsy are due to the underlying disorder, such as a brain tumor or stroke, and not due directly to the epilepsy. However, patients with epilepsy are at higher risk of death due to SUDEP. Although uncommon, SUDEP is a true tragedy, because it can strike patients who are young and otherwise in good health except for their seizures. There are many unanswered questions about SUDEP: 1) what is the cause of SUDEP?; 2) who is at greatest risk? 3) what is the best way to prevent SUDEP?
The current thinking on SUDEP is that patients and families should be educated about SUDEP. Also, the best possible seizure control should be pursued—poorly controlled intense seizures is probably the most important risk factor for SUDEP.
Although this article has reviewed the important topic of early death in patients with epilepsy, it should be stressed that most patients with epilepsy are expected to live long full lives, especially if seizures are well controlled and the patient is otherwise in good health!
Langan Y, Nashef L, Sander JW. Sudden unexpected death in epilepsy: a series of witnessed deaths. J Neurol Neurosurg Psychiatry 2000;68:211-213.
Sperling M. Sudden unexplained death in epilepsy. Epilepsy Currents 2001;1:21-23.
Nashef L, Tomson T. Sudden death in epilepsy. In: Engel J, Pedley T, editors. Epilepsy: A comprehensive textbook. Philadelphia: Lippincott Williams & Wilkins; 2008: 1991-1998.
Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjuctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled ranomised trials. Lancet Neurol 2011; 10:961-968.
Spencer D. SUDEP: Sudden unexpected death in epilepsy on placebo? Epilepsy Currents 2012;12:51-52.
Stavern K, Guldvog B. Long-term survival after epilepsy surgery compared with matched epilepsy controls and the general population. Epilepsy Research 2005;63:67-75.
Walczak TS, Leppik IE, D’Amelio M, et al. Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology 2001;56:519-525.
Dr. White has been practicing as a full-time epileptologist since 1999. His practice focuses on optimizing the diagnosis and treatment of patients with seizure disorders. Dr. White’s special interests include patient education, improving the side-effect profile of seizure medications, and epilepsy surgery.