By Betsan Williams and Professor Alan Richens,
Epilepsy Research Foundation, U.K
As far back at 1904, Spratling described epilepsy as "a disease which destroys life suddenly and without warning, through a single, brief attack…." 1. He noted that 4% of the deaths that had occurred over a number of years in a large population of institutionalized patients with epilepsy appeared to have been sudden and unexpected and, according to results of post-mortem examinations, without demonstrable cause. Since then, epidemiological surveys have indicated that mortality among people with epilepsy is two- to threefold higher than that observed in the general population2.
This increased death rate is made up of a number of components including status epilepticus, asphyxia [oxygen deficiency], aspiration of gastric contents, drowning or other accidents that are seizure-related, and underlying disease3. However, a proportion of otherwise healthy patients with epilepsy die suddenly and unexpectedly in the apparent absence of an anatomical or toxicological cause. This phenomenon has become known as Sudden Unexpected Death in Epilepsy (SUDEP). Between 7.5% and 17% of deaths in people with epilepsy are reported to fall into this category4.
Although SUDEP has been reported since the turn of the century, the incidence and pathophysiology of this phenomenon are not well understood. The incidence of SUDEP, possible mechanisms involved, potential risk factors and current research strategies are reviewed here.
INCIDENCE OF SUDEP
It is not easy to judge the precise incidence of SUDEP. Data range from approximately 1 in 100 to 1 in 1,000 depending on the epilepsy population studied5. The highest rate is reported in a survey of candidates for epilepsy surgery7, while SUDEP rates in the general epilepsy population are considerably lower. One study found no cases in 3712 patient years16 and another reported only 2 such deaths among patients in remission in over 5000 patient years17.
Thus, it appears that cohorts with uncontrolled epilepsy carry a much higher risk of SUDEP than controlled patients, who have an extremely low risk.
MECHANISM OF SUDEP
Little is known about the mechanisms that cause sudden death in epilepsy. While centrally induced cardiac arrhythmia [irregular heartbeat] has long been suspected as the most likely culprit, centrally induced pulmonary [lung] failure is also a prime candidate.
Recently, ictal [seizure] cardiorespiratory variables were recorded in patients with epilepsy undergoing EEG video recording18. Tachycardias [abnormally rapid heart rate], also reported previously19, occurred very often. This is considered a sympathetically mediated consequence of seizure discharge. Ictal apnoea [temporary stoppage of breath during a seizure] was often seen and the occurrence of bradycardia [slow heart beat] in association with apnoea suggests the involvement of cardiorespiratory reflexes. Since SUDEP is more common in young patients, it is interesting to note that the magnitude of cardiorespiratory reflexes diminishes with age20. In a sheep seizure model of epileptic sudden death, marked hypoventilation [reduced air entering lungs] is seen in the sudden death group, but not in the surviving animals 21.
It remains speculative as to whether patients shown to have cardiorespiratory changes consistently during seizures are more at risk of sudden death18. It is likely that the pathologic process underlying sudden death in epilepsy is multifactorial.
RISK FACTORS FOR SUDEP
In the absence of a clear understanding of mechanism, an analysis of risk factors can only be tentative22. Studies have identified individuals with generalized seizures, symptomatic epilepsy, severe or frequent seizures and additional mental handicap or neurological deficit as being most at risk. The majority of SUDEP cases are reported to occur in patients with chronic epilepsy. Those aged 15-35 years appear to have the highest risk, and most studies report a higher incidence in males. Post-mortem antiepileptic drug levels suggest that withdrawal or non-compliance [with medication] may also be a cause23. The majority of SUDEP cases are unwitnessed. This raises the possibility that a witnessed seizure is less likely to be fatal and has implications for prevention13.
While the prognosis is excellent for most patients with epilepsy and the life expectancy of patients with well-controlled seizures differs little from that of the general population,24,16,25 the fact that epilepsy, particularly generalised uncontrolled seizures, carries a small but definite risk to life should not be ignored. Patients with intractable epilepsy should be allowed to consider the small but definite risk of sudden death when contemplating treatment options, whether medical or surgical18.
It is important that potential risk factors are identified so that patients and physicians may take preventative steps to decrease the risk of SUDEP.
CURRENT RESEARCH STRATEGIES FOR SUDEP
To increase awareness of SUDEP an international workshop took place in London [England] on 28 October 1997 under the auspices of [the SUDEP awareness organization named] "Epilepsy Bereaved?". One of the aims of this workshop was to highlight areas for further research. Discussions identified two areas deserving further study:
1. A case-controlled study focusing on risk factors amenable to manipulation, such as seizure control and seizure severity, antiepileptic drug changes, and the relation between level of supervision and response to seizures.
2. An investigation into the effect of abrupt medication withdrawal on seizure activity and changes in cardiac rhythm26.
Earlier this year, the U.K. Epilepsy Research Foundation awarded two Lord Hastings Fellowships specifically for research into these aspects of SUDEP. A total of £37,200 was made available in collaboration with the organization "Epilepsy Bereaved?" to fund this important area of research. Dr. Yvonne Langan and her colleagues from the Epilepsy Research Group at the Institute of Neurology in London were awarded a grant to fund a case control study to examine potential risk factors for SUDEP. Dr. Michael Hennessy and his research group at the Institute of Epileptology, Kings Neuro-sciences, also in London, will investigate the changes in heart rate variability and arrhythmia profile following abrupt antiepileptic drug withdrawal in patients with epilepsy.
It is hoped that these studies will contribute to the elucidation of the mechanism of SUDEP and lead to a greater understanding of the risk factors involved. This will enable patients and physicians to take preventative steps to minimize the risk of SUDEP.
"Controlled patients have an extremely low risk of SUDEP."
CONCLUSION
It is estimated that 400 people with epilepsy per year in the U.K. die a sudden unexpected death. This figure excludes other epilepsy-related deaths23. However, the exact numbers involved remain unknown due to variations in reporting the cause of death by coroners. If a profile is to be built of people who are at risk, SUDEP must be stated on the death certificate27. The international workshop recommended that a toxicological screen and an adequate necropsy [autopsy], including examination of the heart, be done routinely. If no cause is found, the death should then be certified as a "Witnessed or Unwitnessed Sudden Unexpected Death/Epilepsy"26.
A classification of SUDEP must also be agreed if future epidemiological studies are to be comparable. The workshop proposed the following definition,
"Sudden, unexpected, witnessed or unwitnessed, non-traumatic, and non-drowning death in patients with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus, where necropsy examination does not reveal a toxicological or anatomical cause for death."26.
Epilepsy is common, yet as one bereaved mother wrote, "Nobody knows how my son died because, although epilepsy is the most common neurological brain disorder in the world, it is also the most neglected."28. It is vital that this important area of research is not neglected.
REFERENCES
1. Spratling WP. Prognosis. In: Epilepsy and its treatment. Philadelphia: WB Saunders, 1904:304.
2. Hauser WA, Hesdorfer DC. Mortality. In: Epilepsy: frequency, causes and consequences. MD Epilepsy Foundation of USA, 1990:269-326.
3. Appleton RE. Sudden, unexpected death in epilepsy in children. Seizure 1997; 6:175-177.
4. Wannamaker BB. A perspective on death of persons with epilepsy. In: Lathers CM, Schaeder PL, eds. Epilepsy and sudden death. New York: Marcel Dekker, 1990:27-37.
5. Leestma JE, Annegers JF, Brodie MJ, Brown S, Schraedser, Siscovick D, Wannamaker BB, Tennis PS, Cierpial MA and Earl NL. Sudden unexplained death in epilepsy: observations from a large clinical development program. Epilepsia 1997; 38:47-55.
6. Annegers JF, Hauser WA, Shirts SB. Heart disease mortality and morbidity in patients with epilepsy. Epilepsia 1984; 25:609-704.
7. Dasheiff RM. Sudden unexpected death in epilepsy: a series from an epilepsy surgery program and speculation on the relationship to sudden cardiac death. Journal of Clinical Neurophysiology 1991; 8: 216-222.
8. Lip GY and Brodie MJ. Sudden death in epilepsy: an avoidable outcome? Journal Royal Society medicine 1992; 85:609-611.
9. Jick SS, Cole TB, Mesher A, Tennis P, Jick H. Sudden unexplained death in young persons with primary epilepsy. Pharmacoepidemiol Drug Safety 1992; 1:59-64.
10. Timmings PL. Sudden unexpected death in epilepsy: a local audit. Seizure 1993; 2:287-290.
11. Klenerman P, Sander JW, Shorvon SD. Mortality in patients with epilepsy: a study of patients in long term residential care. Journal of Neurology, Neurosurgery and Psychiatry 1993; 56:149-152.
12. Tennis P, Cole TB, Annegers JF, Leestma JE, McNutt M, Rajput A. A cohort study of the incidence of sudden unexplained death in people with seizure disorder in Saskatchewan, Canada. Epilepsia 1995; 36:29-36.
13. Nashef L, Fish DR, , Sander JWAS and Shorvon SD. Incidence of sudden unexpected death in an adult outpatient cohort with epilepsy at a tertiary referral centre. Journal of Neurology, Neurosurgery and Psychiatry 1995; 58:462-464.
14. Nashef L, Fish DR, Garner S, Sander JWAS and Shorvon SD. Sudden death in epilepsy: a study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 1995; 36:1187-1194.
15. Derby LE, Tennis P, Jick H. Sudden unexplained death among subjects with refractory epilepsy. Epilepsia 1996; 37:931-935.
16. Cockerell OC, Johnson AL, Sander JWAS, Hart YM, Goodridge DMG, Shorvon SD. Mortality from epilepsy: results from a prospective population-based study. Lancet 1994; 344:918-921.
17. Medical Research Council antiepileptic drug withdrawal study group: prognostic index for recurrence of seizures after remission of epilepsy. British Medical Journal 1993; 306:1374-1378.
18. Nashef L, Walker F, Allen P, Sander JWAS, Shorvon SD, Fish DR. Apnoea and bradycardia during epileptic seizures: relation to sudden death in epilepsy. Journal of Neurology, Neurosurgery and Psychiatry 1996; 60: 297-300.
19. Blumhardt LD, Smith PEM and Owen L. Electrocardiographic accompaniments of temporal lobe epileptic seizures. Lancet 1986; 1:1051-1056.
20. Wieling W. Non-invasive continuous recording of heart rate and blood pressure in the evaluation of neurovascular control. In: Bannister R, Mathias CJ, eds. Autonomic failure. 3rd ed. 1992:291-311.
21. Johnston SC, Horn JK, Valente J, Simon RP. The role of hypoventilation in a sheep model of epileptic sudden death. Annals of Neurology 1995; 37: 531-537.
22. Shorvon S. Sudden unexpected death in epilepsy - risk factors. Epilepsy and sudden death (Abstracts). Royal College of Physicians, London, 28 October 1996.
23. Nashef L and Sander JWAS. Sudden unexpected deaths in epilepsy - where are we now? Seizure 1996; 5:235-238.
24. Hauser WA, Annegers JF, Elveback LR. Mortality in patients with epilepsy. Epilepsia 1980; 2:399-412.
25. Olafsson E, Hauser WA, Gudmundsson G. Long term mortality in people with epilepsy. Epilepsia 1997 (in press).
26. Nashef L and Brown S. Epilepsy and sudden death. Lancet 1996; 348:1324-1325.
27. Coyle HP, Baker-Brian N, Brown SW. Coroners' autopsy reporting of sudden unexplained death in epilepsy (SUDEP) in the UK. Seizure 1994; 3:247-254.
28. Hanna J. Bereaved relatives - a personal view. Epilepsy and sudden death. Royal College of Physicians, London, 28 October 1996.
LIVING WITH SUDEP
from an address given by Ann Farrell to the Women and Epilepsy Conference at the University of Toronto, 22 March 1997.
Eighteen months ago, around supper time, I found my daughter Judy lying dead on the chesterfield in her Hamilton apartment. When I first looked at her, it seemed she was just sleeping. However, I knew she had come home from her night shift with the Hamilton police some nine hours earlier, so it was unlikely she was still resting. It only took me a few moments, then, to realize the awful truth. At the time, she was 32 years old. She had been diagnosed with epilepsy at the age of 12.
One of the first people we called shortly after Judy's death was Dr. Mac Burnham, a long-time friend. Mac was shocked, of course. Then he told me he thought it was likely Judy had died from SUDEP (Sudden Unexplained Death in Epilepsy Patients). "SUDEP," I asked him, "What's that?" I had never heard of it.
For those of you who may also not know about SUDEP, a generally accepted explanation is that deaths of this nature typically occur in young adults, more often in males, and are more likely to occur when seizures are not well controlled. The individual simply stops breathing while asleep and the cause is uncertain.
For instance, it is recognized that epileptic seizures can commonly cause apnea (temporary stoppage of breath) and, although less often, cardiac arrhythmias (irregularity in heartbeat). Many coroners do not look for signs that epilepsy may have been a contributory cause of death. The family doctor's report on Judy's death, for example, said she died of natural causes. This about a devotee of Tai-Kwon-Do who was to all intents and purposes a healthy young woman, leading a full and active life.
SUDEP has never been easy to pinpoint or define, as a quote in the November 1996 issue of the British medical journal The Lancet indicates:
"The development of a working hypothesis on the nature of these deaths has been hampered by their usually being unwitnessed, and by the absence in (post mortems) of an adequate structural cause" [such as apnea].
So learning of SUDEP came as a profound shock to me. I had always been told that epilepsy is seldom life threatening, except in the case of accidents such as drowning or a road accident-- things that can largely be prevented. Even when a seizure led to someone going into status epilepticus, emergency measures taken in time were generally successful.
However, once I had recovered from the initial shock of Judy's death, my background as a journalist kicked in and I set about seeing what I could find out. It hasn't been easy.
First I visited Judy's family physician and her neurologist in Hamilton. "Yes," they said, both of them knew about SUDEP, but it was information they preferred not to pass on. Apparently, doctors not only keep quiet about SUDEP with their patients who have epilepsy, but also with their patients' families. Moreover, if these patients then die in circumstances that suggest SUDEP as the likely cause, the doctors continue to maintain silence about it. That is unless family members, like me, come asking questions!
According to these physicians, the decision is based on a desire not to cause undue alarm. The rationale is that, as little is known about SUDEP's cause and not much more about how to prevent it, they feel it is kinder and less alarming to all concerned to keep the information to themselves. My personal reaction to this attitude on the part of doctors is that it is patronizing, at the very least. Patients and their families are entitled to learn everything they can about epilepsy which, in many ways, continues to be a puzzling condition. It is then up to them to make their own decisions. It's like withholding information about the terminal nature of an illness, lest the patient can't handle it.
I don't say this just because I am determined to stand on my rights with doctors, but because there are good reasons why an individual with epilepsy needs this information. He or she needs to know about the crucial importance of doing everything possible to minimize the possibility of seizures and to prevent, as far as possible, anything worse from happening-- especially as it is recognized that SUDEP is more likely to occur when seizures are poorly controlled.
By way of illustrating how increased seizure patterns can have a more far-reaching effect than simple injury, in Clinics & Cases (a supplement of Medicine North America), editor-in-chief Dr. A. Guberman writes:
"The deleterious effects of uncontrolled seizures include psychosocial consequences, possible cognitive and memory deterioration, lowered seizure thresholds and also directly or indirectly, seizure-related injury or death."
"Learning of SUDEP came as a profound shock to me. I had always been told that epilepsy is not life-threatening."
Dr. Guberman's opinion was born out in Judy's case in the months before her death. During this period she complained of memory loss; in fact, her colleagues said the quality of her work did deteriorate and, because of their affection for her, two of them used to 'tidy up' her mistakes behind her back.
A decreasing level of work performance is one thing, but when it is followed by death, the situation cries out for preventative action.
The question then arises as to just how many people are believed to be dying as a result of SUDEP. In Canada, no firm statistics exist.
In England, Dr. Stephen Brown, a consultant neuropsychiatrist who works in affiliation with a number of internationally-based epilepsy groups, reports that in 1995 a shocking total of 771 deaths in England among the country's epilepsy population of 420,000 were caused by SUDEP. The figure was twice the annual average of between 200-300 SUDEP deaths. By comparison, in the same year England's crib deaths (which resemble SUDEP somewhat) numbered only 332. Incidentally, the amount of money spent on research into the causes of crib death in England far outstrips that spent on SUDEP research.
What is to be done about all this? The first thing that comes to mind, obviously, is education. SUDEP has to come out of the closet, public awareness needs to be significantly increased, and those with seizures need to know the danger implicit in failing to take more personal responsibility in the control of their seizures, over and above following the advice of their doctors regarding medication and so on.
In the 20 years Judy lived with seizures, family doctors and neurologists did caution her from time to time that an appropriate lifestyle was advisable if her seizures were to be minimized in number and severity. This entailed not skipping medication, avoiding alcohol, maintaining regular and adequate sleep patterns, and taking proper nutrition. However, the crucial nature of this advice was never stressed: no one indicated it was likely essential, rather than merely advisable, to observe this regimen. No one warned her that ignoring the rules might even prove fatal.
Now please do not think I fail to recognize doctors' difficulties in this respect. They spend their working lives advising patients how to maintain wellness, their good advice so often falling on deaf ears. Certainly that was the case with Judy who pursued every day as if it were her last. Despite the fact she was an adult at the time of her death, naturally I feel a certain amount of guilt. Her colleagues also wish they had known more about the implicit danger of her happy-go-lucky ways. But Judy was an adult.
Although I, her friends, and her siblings, all remonstrated with her from time to time, she was not the sort of person who responded to good advice-- and certainly not to nagging. So she went her merry way and in the final years of her life, her seizures did increase in number and severity. Her employers listed her as a disabled person and persuaded her to take out disability insurance shortly before her death.
"Not skipping medication, avoiding alcohol, maintaining regular sleep patterns and taking proper nutrition... are essential"
In hindsight, it appears that people with epilepsy-- like Judy-- whose medication allows them to lead more or less normal lives may tend to push their epilepsy onto the back burner. Some of the old stigma surrounding epilepsy still remains and, because of this, people whose seizures are fairly well controlled may be tempted to keep their condition to themselves or, possibly, even from themselves. After all, denial is a common problem among those with ongoing medical conditions. The bottom line, though, is that epilepsy calls for regular medical monitoring, proper medication, and a lifestyle that is beneficial for control of seizures.
A generation ago, not much was written about the importance of a factor such as lifestyle in relation to avoidance of killers such as heart disease, stroke and lung cancer. Now many people are aware of the dangers inherent in disobeying lifestyle rules, where these diseases are concerned.
Surely it is time for some serious education on the subject. Falls and drowning, for example, are widely recognized as situations which can potentially result in death among people with epilepsy and advice is given about observing safety precautions. Some of these tragedies, in fact, might actually be averted (or at least lessened in frequency) if individuals would only exercise personal responsibility, thereby maximizing control over their seizures and avoiding potential dangers whenever possible.
Up to this point, we have been talking about what those who have seizures can do for themselves. But what about the rest of us? What can we do? Not long ago a friend in England sent me a newspaper clipping from the Sunday Telegraph. It contained a story about SUDEP and how British families have banded together to fight it from a public forum.
In the beginning, several parents of young adults who had died of SUDEP got together, initially to form a bereavement support group. They call themselves "Epilepsy Bereaved?". What propelled them into action was the devastation they felt because the deaths of their children were so sudden--so unexpected--when, until the very moment of death, their sons and daughters had apparently been leading healthy lives.
The 130 members of Epilepsy Bereaved say they were outraged that doctors had not shared with them details about SUDEP. They took issue with coroners who often failed to look for or identify epilepsy as a possible cause of death. They set about educating themselves, getting some doctors on side, and lobbying for changes in the whole area surrounding SUDEP. They also approached government, and sought research money. Who knows: perhaps if coroners were more aware of SUDEP when performing autopsies, useful clues for researchers might emerge.
As it happens, I have two other adult children-- a son and a daughter-- who experience seizures. Although they are both well controlled, the fear remains at the back of one's mind. Work has indeed begun on learning more about SUDEP and how better to avoid it, if not actually prevent it. An education program is under way, but much more needs doing before public awareness can be adequately established and professional involvement fully engaged.
SUDEP SUPPORT
The newly formed SUDEP Awareness and Support Association, or SASA, is a network of people who are affected by Sudden Unexplained Death in Epilepsy. Started by Ann Farrell, a Toronto woman who lost her adult daughter to SUDEP (see above story), SASA is associated with the Epilepsy Association, Metro Toronto and Epilepsy Ontario, and works in conjunction with Bereaved Families of Ontario.
SASA offers information and support to people who have lost a loved one to SUDEP, and is working to raise awareness of SUDEP among people with epilepsy, doctors, coroners, and the general public. More research into this mysterious syndrome is necessary if SUDEP is to be prevented in the future.
