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REVIEW Sudden unexpected death in epilepsy (SUDEP): risk factors and case control studies
Seizure 2000; 9: 179–183
doi: 10.1053/seiz.2000.0388, available online at http://www.idealibrary.com on
REVIEW
Sudden unexpected death in epilepsy (SUDEP): risk factors and case control studies Y. LANGAN Epilepsy Research Group, Institute of Neurology, Queen Square, London, WC1N 3BG, UK Correspondence to: Y. Langan, Department of Neurology, Middlesbrough General Hospital, Ayresome Green Lane, Middlesbrough, TS5 5AZ, UK
Sudden unexpected death is an important category of mortality in the population with epilepsy. Possible risk factors have been identified from an epidemiological study of this phenomenon, but the exact mechanisms remain unclear. Some of these factors include: male sex; age 20–40 years; generalized seizures; poor seizure control; poor compliance with medication. Case-control studies now being undertaken are the next step in the elucidation of these factors. The results of one study to date reinforce the view that, in the majority of cases, sudden unexpected death in epilepsy (SUDEP) is a seizure-related event. This suggests that improvement in seizure control and the avoidance of polytherapy may be important in risk reduction. An ongoing exploratory case-control study in the UK has identified 154 cases of SUDEP, each of which will have four controls, matched for age and geographical location, in order to examine the influence of various parameters on the risk of sudden death. c 2000 BEA Trading Ltd
Key words: epilepsy; sudden death; risk factors; case-control study; prevention.
INTRODUCTION Individuals with epilepsy have a mortality rate 2– 3 times that of the general population1–3 , attributable to both the underlying disease and epilepsy itself. Epilepsy-related deaths are either seizure or treatment related. The most common category of seizure-related death is sudden unexpected death in epilepsy (SUDEP). The exact mechanisms underlying SUDEP are unclear so risk factors have, to date, been identified from descriptive epidemiological studies. These factors are described here.
Age and sex The fact that the age group 20–40 years seems most susceptible is borne out by various studies. In a study of SUDEP in an outpatient cohort conducted by Nashef et al.4 the mean age of death was 28.6 years. The average age of death in the outpatient group ex1059–1311/00/030179 + 05
$35.00/0
amined by Timmings was 35 years5 with similar result being found by Leestma et al.6, 7 in their work. The majority of studies have reported more deaths in males5, 7, 8 , although this is not always the case4, 9 .
Epilepsy syndrome The Rochester study reported more sudden deaths among those with localization-related symptomatic epilepsy10 ; in most, but not all studies, the majority of SUDEP victims have had localization-related epilepsy. In post-mortem series a pathological substrate for the epilepsy is found in 34–70% of cases6, 7, 11 . In the interview study conducted by Nashef12 , 9 of 26 individuals who died had a history of idiopathic localizationrelated epilepsy, and in the study by Timmings13 , which examined mortality in a cohort attending an epilepsy clinic, the majority of deaths occurred in individuals with idiopathic generalized epilepsy. Derby et al.14 found that those with cryptogenic epilepsy c 2000 BEA Trading Ltd
180
were more at risk of SUDEP than those with symptomatic localization-related epilepsy. The recent casecontrol study by Nilsson et al.15 found an increased risk of SUDEP among men with idiopathic generalized epilepsy compared with localization-related symptomatic epilepsy.
Seizure type and frequency The majority of victims of SUDEP have a history of generalized tonic–clonic seizures (GTCS)4, 5, 7, 9, 16 . Such deaths have, however, been reported in association with other seizure types17 . Incidence data suggest that the risk of sudden-death is related to seizure control, higher sudden death rates being found in cohorts with intractable epilepsy4, 16–18 . On the other hand, population-based studies such as the Medical Research Council (MRC) study of drug withdrawal and the NGPSE, where a large number of patients had well-controlled epilepsy or were in remission, identified few sudden deaths2, 19 .
Antiepileptic drugs (AEDs) and compliance At present there is no evidence that any particular anticonvulsant can influence the risk of SUDEP although there are anecdotal reports of bradyarrhythmia and sinus arrest being associated with carbamazepine20–22 . Some authors suggest that the proportion of SUDEP victims taking carbamazepine is significantly higher than the proportion taking this AED in the rest of the population with epilepsy23 . There are reports in the literature of two cases where patients in both cases were taking oxcarbazepine and vigabatrin, and in one case additional lamotrigine, developed SIADH (syndrome of inappropriate antiduretic hormone secretion) and died suddenly. The authors recommend electrolyte analysis in victims of SUDEP particularly when on carbamazepine and oxcarbazepine24 . Tennis et al.25 found that those on polytherapy were over represented among cases compared with controls, with a 1.7-fold increase in risk for each AED added. The conventional wisdom thus far has been that AED number is a surrogate marker for epilepsy severity. Changes in AED therapy may also increase the risk of SUDEP for an individual with epilepsy, perhaps by influencing reflex function. Lip and Brodie8 found that 5 of 12 cases had had a recent change in AED therapy, mostly involving a dose reduction or drug withdrawal. Poor compliance with medication appears to be associated with an increased risk of SUDEP as in the study by Lip and Brodie8 where poor compliance was reported in 25% of cases. Many cases of SUDEP are associated with subther-
Y. Langan
apeutic anticonvulsant levels at post-mortem26 . Some have taken this to indicate non-compliance with medication which is a feature of a number of cases of SUDEP7, 27 ; however, the relationship of these levels to ante-mortem levels is uncertain28 . Investigators have found that ante-mortem serum levels of carbamazepine were not significantly different from wholeblood concentrations taken up to 72 hours after death. Ante-mortem phenytoin levels in whole blood were only 65% of the serum concentration and were only 35% of serum concentrations when measured at postmortem29 .
Witnessed seizures Terrence et al.30 found 9 of 37 patients’ died as a result of a single seizure or a few seizures in the presence of witnesses. Lip and Brodie8 found that 3 of the 12 deaths they identified were witnessed, with only one having a convulsive seizure prior to death. Leestma7 reported that in 38%, or 23 out of 60 cases, collapse was witnessed and a seizure was seen in 14 of these. Hirsch and Martin31 report 42% of cases being witnessed and, in a study of SUDEP in the Republic of Ireland32 , 1 of 15 cases of death was witnessed as having been preceded by a generalized seizure. Nashef12 . in the interview study, found that 2 of 26 deaths were witnessed. Most authors report a substantial proportion of patients being found dead in bed32 . It has been suggested that obstructive apnoea may be a possible mechanism although the circumstances surrounding many cases would not support this view. It is important to note that, in a study of SUDEP in a residential school for children with epilepsy who were closely supervised at night, there was a lower incidence during term time and no cases were witnessed. Therefore, it may be that attention to the recovery of the individual following a seizure, and positioning or stimulation if necessary, may be important in the prevention of SUDEP16 .
Other factors Other factors which may alter the risk of SUDEP in those with epilepsy include neurological deficit and learning difficulty, which may be markers for epilepsy severity18 . The same may be true of the fact that there has been an observed increased use of psychotropic drugs in the SUDEP population compared with that in the population with epilepsy as a whole25 . It should be noted that there is also an increased incidence of sudden unexpected death in the psychiatric population. Such deaths were noted prior to the advent of phenothiazine therapy but since their introduction
Sudden unexpected death in epilepsy (SUDEP): risk factors and case control studies
these drugs have been repeatedly associated with such deaths, although the nature of any relationship remains unclear33, 34 . The Afro-American population may be more at risk of sudden death, although this observation may be a reflection of the increased prevalence of epilepsy in this population7 . An excessive alcohol intake has also been found in some cases of SUDEP7, 31 .
Case-control studies Case-control studies are the next step in identifying factors which influence the risk of sudden death for an individual with epilepsy. Initial attempts at case-control study involved highly selected case series and a paucity of suitable controls. The results of the case-control study undertaken by Nilsson et al.15 in Sweden have recently been published. The study population comprised those between 15 and 70 years living in Stockholm who had at least one admission for the assessment of epilepsy between 1980 and 1989. Cases studied were those who had died, epilepsy having been written on the death certificate and whose medical record and autopsy report were compatible with SUDEP, and were only included if they had been taking one of the AEDs carbamazepine, phenytoin or sodium valproate continuously for the previous year. The study, therefore, does not address recent or untreated cases. Fifty-seven cases, 34 men and 23 women were identified of whom 91% had undergone post-mortem examination. The relative risk of SUDEP increased with increasing number of seizures per year. The estimated recovery rate (RR) was 10.16 (2.94–35.18) in those with more than 50 seizures per year compared with those who had two seizures per year and RR was 23.2 (3.16–170.28) when those having any seizure were compared with those who were seizure free. The risk of SUDEP increased with increasing numbers of concomitant AEDs. There was a risk factor of 9.89 for three AEDs compared with monotherapy and was independent of seizure control. Other major risk factors were frequent changes of AED dosage compared with unchanged dosage, RR 6.08 (1.99– 18.56). There was an 18-fold increase in RR associated with epilepsy in childhood compared with onset at over 45 years of age. The association between SUDEP risk and early onset of epilepsy and SUDEP risk and seizure frequency was weaker for women than men, whereas the association between dosage change and increased risk was stronger in female patients. Dementia has been reported as a possible risk factor for SUDEP, RR 6 (1.5–23.99). It may have been previously unreported because of the younger age group included in previous studies. This work did not confirm any association between alcohol intake and risk
181
of SUDEP in this patient group. This case-control study reinforces the theory that SUDEP is a seizure-related event and that improvement of seizure control and the avoidance of polytherapy may be important in the prevention of SUDEP, but intractable seizures and polytherapy with trials of new treatment go together in clinical practice. While polytherapy may be at times unavoidable, abrupt drug changes certainly are and should be avoided. Further information on the drug changes in the study, and of the rate of SUDEP in subjects after AED withdrawal, would be of great interest as the physician recommending medication needs to balance the risk of instability consequent to medication against the prospect of improved control. Gradual changes are strongly recommended. The population-based study of SUDEP incidence conducted by Ficker et al.9 has already been alluded to. Of the nine cases identified most had a history of GTCS and absent or subtherapeutic AED levels were a characteristic of these cases. Although the authors planned to undertake statistical analysis with a view to risk-factor identification, it proved impossible given the small number of cases identified.
An ongoing case-control study In an ongoing exploratory case-control study we seek to examine the influence of various parameters on the risk of sudden death. There are 154 cases, between the ages of 16 and 50 years, which have been identified by: •
coroners in England and Wales, in fact we are uniquely placed in the UK as 90% of SUDEP cases are referred to the coroner;
•
neurologists via the British Neurological Surveillance Unit;
•
the charity ‘Epilepsy Bereaved?’ with whose assistance approximately 50 bereaved families have been interviewed.
Cases all have a history of active epilepsy and fulfil the following definition. They are sudden, unexpected, witnessed or unwitnessed, non-traumatic and non-drowning death in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus where post-mortem examination does not reveal a cause for death. Background information has been obtained from general practitioners, hospital consultants and, where appropriate, coroners. Where necessary GPs were traced through the Office for National Statistics.
182
Y. Langan
BNSU and interview Coroner and interview BNSU Interview Coroner 0
20
40
60
80
100
Fig. 1: Sources of referral.
150 Bed
100
Home 50
Elsewhere
0 Fig. 2: Location when found.
Witnessed Bitten tongue Incontinence Position Secretions Timing None
Fig. 3: Evidence for recent seizure.
Each case will have four controls matched for age and geographical location. The help of the MRC Epidemiology and Preventive Medicine Unit has been enlisted in this endeavour and practices in the appropriate areas identified from the MRC General Practice Research Framework. Randomly selected suitable controls are identified and relevant information extracted from the case notes. The factors under examination include epilepsy syndrome, seizure type and control, treatment history and compliance, other factors such as alcohol intake, ECG changes and supervision at night will also be included. Logistic regression analysis will be performed and a risk factor score determined. We aim to offer advice to those with epilepsy, their families and physicians on strategies to reduce the risk of SUDEP. The 154 cases identified comprise 97 men and 57 women with a mean age of 32 years. The sources of referral are illustrated in Fig. 1. The majority of indi-
viduals were found dead in bed and there was evidence to support a recent seizure in the majority (Figs 2 and 3) Twenty-one cases were witnessed, the majority occurring in association with a GTCS and, as we previously reported, witnesses often stated that victims appeared to have breathing difficulties prior to death35 . Thus far our work lends supporting evidence to the belief that SUDEP is a seizure-related event. The optimization of seizure control may play an important role in the prevention of these tragic deaths and the risk of SUDEP may need to be considered whenever decisions are made about alterations in therapy. Our work also suggests that a witnessed seizure is less likely to be fatal, and it may be that attention to recovery following a seizure and positioning or stimulation, if necessary, may be important in the prevention of SUDEP. We look forward with interest to the identification of risk factors.
REFERENCES 1. Zielinski, J. J. Epilepsy and mortality rate and cause of death. Epilepsia 1974; 15: 191–201. 2. Cockerell, O. C., Johnson, A. L., Sander, J. W., Hart, Y. M., Goodridge, D. M. and Shorvon, S. D. Mortality from epilepsy: results from a prospective population-based study [see comments]. Lancet 1994; 344: 918–921. 3. Nilsson, L., Tomson, T., Farahmand, B. Y., Diwan, V. and Persson, P. G. Cause-specific mortality in epilepsy: A cohort study of more than 9,000 patients once hospitalized for epilepsy. Epilepsia 1997; 38: 1062–1068.
Sudden unexpected death in epilepsy (SUDEP): risk factors and case control studies 4. Nashef, L., Fish, D. R., Sander, J. W. and Shorvon, S. D. 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. 5. Timmings, P. L. Sudden unexpected death in epilepsy: a local audit. Seizure 1993; 2: 287–290. 6. Leestma, J. E., Kalelkar, M. B., Teas, S. S. et al. Sudden unexpected death associated with seizures: Analysis of 66 cases. Epilepsia 1984; 25: 84–88. 7. Leestma, J. E., Walczak, T., Hughes, J. R., Kalelkar, M. B. and Teas, S. S. A prospective study on sudden unexpected death in epilepsy. Annals of Neurology 1989; 26: 195–203. 8. Lip, G. Y. and Brodie, M. J. Sudden death in epilepsy: an avoidable outcome? Journal of the Royal Society of Medicine 1992; 85: 609–611. 9. Ficker, D. M., So, E. L., Shen, W. K. et al. Populationbased study of the incidence of sudden unexplained death in epilepsy. Neurology 1998; 51: 1270–1274. 10. Annegers, J. F., Hauser, W. A. and Shirts, S. B. Heart disease mortality and morbidity in patients with epilepsy. Epilepsia 1984; 25: 699–704. 11. Thom, M. Neuropathologic findings in postmortem studies if sudden death in epilepsy. Epilepsia 1997; 38: S32–S34. 12. Nashef, L., Garner, S., Sander, J. W. A. S., Fish, D. R. and Shorvon, S. D. Circumstances of death in sudden death in epilepsy: interviews of bereaved relatives. Journal of Neurology, Neurosurgery and Psychiatry 1998; 64: 349–352. 13. Zaidi, A., Cotter, L. and Fitzpatrick, A. Sudden unexplained death [letter]. Lancet 1997; 349: 135. 14. Derby, L. E., Tennis, P. and Jick, H. Sudden unexplained death among subjects with refractory epilepsy. Epilepsia 1996; 37: 931–935. 15. Nilsson, L., Farahmand, B. Y., Persson, P., Thiblin, I. and Tomson, T. Risk factors for sudden unexpected death in epilepsy: a case control study. Lancet 1999; 353: 888–893. 16. Nashef, L., Fish, D. R., Garner, S., Sander, J. W. and Shorvon, S. D. Sudden death in epilepsy: a study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 1995; 36: 1187–1194. 17. Dasheiff, R. M. 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. 18. Klenerman, P., Sander, J. W. and Shorvon, S. D. Mortality in patients with epilepsy: a study of patients in long term residential care. Journal of Neurology, Neurosurgery and Psychiatry 1993; 56: 149–152. 19. Medical Research Council. Randomised study of antiepileptic drug withdrawal in patients in remission. Lancet 1991; 337: 1175–1180. 20. Boesen, F., Andersen, E. B., Kehn, E. et al. Cardiac conduction disturbances during carbamazepine therapy. Acta Neurologica
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Scandinavica 1983; 68: 49–52. 21. Stone, S. and Lange, L. S. Syncope and sudden unexpected death attributed to carbamazepine in a 20-year-old epileptic. Journal of Neurology, Neurosurgery and Psychiatry 1986; 49: 1460–1461. 22. Tomson, T. and Kenneback, G. Arrhythmia, heart rate variability and antiepileptic drugs. Epilepsia 1997; 38: S48–S51. 23. Timmings, P. L. Sudden unexpected death in epilepsy: Is carbamazepine implicated? Seizure 1998; 7: 289–291. 24. Kloster, R., Borresen, H. C. and Hoff Olsen, P. Sudden death in two patients with epilepsy and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Seizure 1998; 7: 419–420. 25. Tennis, P., Cole, T. B., Annegers, J. F., Leestma, J. E., McNutt, M. and Rajput, A. Cohort study of incidence of sudden unexplained death in persons with seizure disorder treated with antiepileptic drugs in Saskatchewan, Canada. Epilepsia 1995; 36: 29–36. 26. George, J. R. and Davis, G. G. Comparison of anti-epileptic drug levels in different cases of sudden death. Journal of Forensic Science 1998; 43: 598–603. 27. Earnest, M. P., Thomas, G. E., Eden, R. A. and Hossack, K. F. The sudden unexplained death syndrome in epilepsy: demographic, clinical, and postmortem features. Epilepsia 1992; 33: 310–316. 28. Brown, S. W., Mawer, G. E., Lawler, W. et al. Sudden death and epilepsy [letter]. Lancet 1990; 335: 606–607. 29. Tomson, T., Skold, A., Holmgen, P., Nilsson, L. and Danielsson, B. Postmortem changes in blood concentrations of phenytoin and carbamazepine: An experimental study. Therapeutic Drug Monitoring 1998; 20: 309–312. 30. Terrence, C. F., Jr., Wisotzkey, H. M. and Perper, J. A. Unexpected, unexplained death in epileptic patients. Neurology 1975; 25: 594–598. 31. Hirsch, C. S. and Martin, D. L. Unexpected death in young epileptics. Neurology 1971; 21: 682–690. 32. Langan, Y., Nolan, N. and Hutchinson, M. The incidence of sudden unexpected death in epilepsy in South Dublin and Wicklow. Seizure 1998; 7: 335–358. 33. Jusic, N. and Lader, M. Post-mortem antipsychotic drug concentrations and unexplained deaths. British Journal of Psychiatry 1994; 165: 787–791. 34. Mehtonen, O. P., Aranko, K., Malkone, L. and Vapaatalo, H. A survey of sudden death associated with the use of antipsychotic or antidepressant drugs: 49 cases in Finland. Acta Psychiatrica Scandinavica 1991; 84: 58–64. 35. Langan, Y., Nashef, L. and Sander, J. W. A. S. Sudden unexpected death in epilepsy: a series of witnessed deaths. Journal of Neurology, Neurosurgery and Psychiatry 2000; 68: 211– 213.
doi: 10.1053/seiz.2000.0388, available online at http://www.idealibrary.com on
REVIEW
Sudden unexpected death in epilepsy (SUDEP): risk factors and case control studies Y. LANGAN Epilepsy Research Group, Institute of Neurology, Queen Square, London, WC1N 3BG, UK Correspondence to: Y. Langan, Department of Neurology, Middlesbrough General Hospital, Ayresome Green Lane, Middlesbrough, TS5 5AZ, UK
Sudden unexpected death is an important category of mortality in the population with epilepsy. Possible risk factors have been identified from an epidemiological study of this phenomenon, but the exact mechanisms remain unclear. Some of these factors include: male sex; age 20–40 years; generalized seizures; poor seizure control; poor compliance with medication. Case-control studies now being undertaken are the next step in the elucidation of these factors. The results of one study to date reinforce the view that, in the majority of cases, sudden unexpected death in epilepsy (SUDEP) is a seizure-related event. This suggests that improvement in seizure control and the avoidance of polytherapy may be important in risk reduction. An ongoing exploratory case-control study in the UK has identified 154 cases of SUDEP, each of which will have four controls, matched for age and geographical location, in order to examine the influence of various parameters on the risk of sudden death. c 2000 BEA Trading Ltd
Key words: epilepsy; sudden death; risk factors; case-control study; prevention.
INTRODUCTION Individuals with epilepsy have a mortality rate 2– 3 times that of the general population1–3 , attributable to both the underlying disease and epilepsy itself. Epilepsy-related deaths are either seizure or treatment related. The most common category of seizure-related death is sudden unexpected death in epilepsy (SUDEP). The exact mechanisms underlying SUDEP are unclear so risk factors have, to date, been identified from descriptive epidemiological studies. These factors are described here.
Age and sex The fact that the age group 20–40 years seems most susceptible is borne out by various studies. In a study of SUDEP in an outpatient cohort conducted by Nashef et al.4 the mean age of death was 28.6 years. The average age of death in the outpatient group ex1059–1311/00/030179 + 05
$35.00/0
amined by Timmings was 35 years5 with similar result being found by Leestma et al.6, 7 in their work. The majority of studies have reported more deaths in males5, 7, 8 , although this is not always the case4, 9 .
Epilepsy syndrome The Rochester study reported more sudden deaths among those with localization-related symptomatic epilepsy10 ; in most, but not all studies, the majority of SUDEP victims have had localization-related epilepsy. In post-mortem series a pathological substrate for the epilepsy is found in 34–70% of cases6, 7, 11 . In the interview study conducted by Nashef12 , 9 of 26 individuals who died had a history of idiopathic localizationrelated epilepsy, and in the study by Timmings13 , which examined mortality in a cohort attending an epilepsy clinic, the majority of deaths occurred in individuals with idiopathic generalized epilepsy. Derby et al.14 found that those with cryptogenic epilepsy c 2000 BEA Trading Ltd
180
were more at risk of SUDEP than those with symptomatic localization-related epilepsy. The recent casecontrol study by Nilsson et al.15 found an increased risk of SUDEP among men with idiopathic generalized epilepsy compared with localization-related symptomatic epilepsy.
Seizure type and frequency The majority of victims of SUDEP have a history of generalized tonic–clonic seizures (GTCS)4, 5, 7, 9, 16 . Such deaths have, however, been reported in association with other seizure types17 . Incidence data suggest that the risk of sudden-death is related to seizure control, higher sudden death rates being found in cohorts with intractable epilepsy4, 16–18 . On the other hand, population-based studies such as the Medical Research Council (MRC) study of drug withdrawal and the NGPSE, where a large number of patients had well-controlled epilepsy or were in remission, identified few sudden deaths2, 19 .
Antiepileptic drugs (AEDs) and compliance At present there is no evidence that any particular anticonvulsant can influence the risk of SUDEP although there are anecdotal reports of bradyarrhythmia and sinus arrest being associated with carbamazepine20–22 . Some authors suggest that the proportion of SUDEP victims taking carbamazepine is significantly higher than the proportion taking this AED in the rest of the population with epilepsy23 . There are reports in the literature of two cases where patients in both cases were taking oxcarbazepine and vigabatrin, and in one case additional lamotrigine, developed SIADH (syndrome of inappropriate antiduretic hormone secretion) and died suddenly. The authors recommend electrolyte analysis in victims of SUDEP particularly when on carbamazepine and oxcarbazepine24 . Tennis et al.25 found that those on polytherapy were over represented among cases compared with controls, with a 1.7-fold increase in risk for each AED added. The conventional wisdom thus far has been that AED number is a surrogate marker for epilepsy severity. Changes in AED therapy may also increase the risk of SUDEP for an individual with epilepsy, perhaps by influencing reflex function. Lip and Brodie8 found that 5 of 12 cases had had a recent change in AED therapy, mostly involving a dose reduction or drug withdrawal. Poor compliance with medication appears to be associated with an increased risk of SUDEP as in the study by Lip and Brodie8 where poor compliance was reported in 25% of cases. Many cases of SUDEP are associated with subther-
Y. Langan
apeutic anticonvulsant levels at post-mortem26 . Some have taken this to indicate non-compliance with medication which is a feature of a number of cases of SUDEP7, 27 ; however, the relationship of these levels to ante-mortem levels is uncertain28 . Investigators have found that ante-mortem serum levels of carbamazepine were not significantly different from wholeblood concentrations taken up to 72 hours after death. Ante-mortem phenytoin levels in whole blood were only 65% of the serum concentration and were only 35% of serum concentrations when measured at postmortem29 .
Witnessed seizures Terrence et al.30 found 9 of 37 patients’ died as a result of a single seizure or a few seizures in the presence of witnesses. Lip and Brodie8 found that 3 of the 12 deaths they identified were witnessed, with only one having a convulsive seizure prior to death. Leestma7 reported that in 38%, or 23 out of 60 cases, collapse was witnessed and a seizure was seen in 14 of these. Hirsch and Martin31 report 42% of cases being witnessed and, in a study of SUDEP in the Republic of Ireland32 , 1 of 15 cases of death was witnessed as having been preceded by a generalized seizure. Nashef12 . in the interview study, found that 2 of 26 deaths were witnessed. Most authors report a substantial proportion of patients being found dead in bed32 . It has been suggested that obstructive apnoea may be a possible mechanism although the circumstances surrounding many cases would not support this view. It is important to note that, in a study of SUDEP in a residential school for children with epilepsy who were closely supervised at night, there was a lower incidence during term time and no cases were witnessed. Therefore, it may be that attention to the recovery of the individual following a seizure, and positioning or stimulation if necessary, may be important in the prevention of SUDEP16 .
Other factors Other factors which may alter the risk of SUDEP in those with epilepsy include neurological deficit and learning difficulty, which may be markers for epilepsy severity18 . The same may be true of the fact that there has been an observed increased use of psychotropic drugs in the SUDEP population compared with that in the population with epilepsy as a whole25 . It should be noted that there is also an increased incidence of sudden unexpected death in the psychiatric population. Such deaths were noted prior to the advent of phenothiazine therapy but since their introduction
Sudden unexpected death in epilepsy (SUDEP): risk factors and case control studies
these drugs have been repeatedly associated with such deaths, although the nature of any relationship remains unclear33, 34 . The Afro-American population may be more at risk of sudden death, although this observation may be a reflection of the increased prevalence of epilepsy in this population7 . An excessive alcohol intake has also been found in some cases of SUDEP7, 31 .
Case-control studies Case-control studies are the next step in identifying factors which influence the risk of sudden death for an individual with epilepsy. Initial attempts at case-control study involved highly selected case series and a paucity of suitable controls. The results of the case-control study undertaken by Nilsson et al.15 in Sweden have recently been published. The study population comprised those between 15 and 70 years living in Stockholm who had at least one admission for the assessment of epilepsy between 1980 and 1989. Cases studied were those who had died, epilepsy having been written on the death certificate and whose medical record and autopsy report were compatible with SUDEP, and were only included if they had been taking one of the AEDs carbamazepine, phenytoin or sodium valproate continuously for the previous year. The study, therefore, does not address recent or untreated cases. Fifty-seven cases, 34 men and 23 women were identified of whom 91% had undergone post-mortem examination. The relative risk of SUDEP increased with increasing number of seizures per year. The estimated recovery rate (RR) was 10.16 (2.94–35.18) in those with more than 50 seizures per year compared with those who had two seizures per year and RR was 23.2 (3.16–170.28) when those having any seizure were compared with those who were seizure free. The risk of SUDEP increased with increasing numbers of concomitant AEDs. There was a risk factor of 9.89 for three AEDs compared with monotherapy and was independent of seizure control. Other major risk factors were frequent changes of AED dosage compared with unchanged dosage, RR 6.08 (1.99– 18.56). There was an 18-fold increase in RR associated with epilepsy in childhood compared with onset at over 45 years of age. The association between SUDEP risk and early onset of epilepsy and SUDEP risk and seizure frequency was weaker for women than men, whereas the association between dosage change and increased risk was stronger in female patients. Dementia has been reported as a possible risk factor for SUDEP, RR 6 (1.5–23.99). It may have been previously unreported because of the younger age group included in previous studies. This work did not confirm any association between alcohol intake and risk
181
of SUDEP in this patient group. This case-control study reinforces the theory that SUDEP is a seizure-related event and that improvement of seizure control and the avoidance of polytherapy may be important in the prevention of SUDEP, but intractable seizures and polytherapy with trials of new treatment go together in clinical practice. While polytherapy may be at times unavoidable, abrupt drug changes certainly are and should be avoided. Further information on the drug changes in the study, and of the rate of SUDEP in subjects after AED withdrawal, would be of great interest as the physician recommending medication needs to balance the risk of instability consequent to medication against the prospect of improved control. Gradual changes are strongly recommended. The population-based study of SUDEP incidence conducted by Ficker et al.9 has already been alluded to. Of the nine cases identified most had a history of GTCS and absent or subtherapeutic AED levels were a characteristic of these cases. Although the authors planned to undertake statistical analysis with a view to risk-factor identification, it proved impossible given the small number of cases identified.
An ongoing case-control study In an ongoing exploratory case-control study we seek to examine the influence of various parameters on the risk of sudden death. There are 154 cases, between the ages of 16 and 50 years, which have been identified by: •
coroners in England and Wales, in fact we are uniquely placed in the UK as 90% of SUDEP cases are referred to the coroner;
•
neurologists via the British Neurological Surveillance Unit;
•
the charity ‘Epilepsy Bereaved?’ with whose assistance approximately 50 bereaved families have been interviewed.
Cases all have a history of active epilepsy and fulfil the following definition. They are sudden, unexpected, witnessed or unwitnessed, non-traumatic and non-drowning death in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus where post-mortem examination does not reveal a cause for death. Background information has been obtained from general practitioners, hospital consultants and, where appropriate, coroners. Where necessary GPs were traced through the Office for National Statistics.
182
Y. Langan
BNSU and interview Coroner and interview BNSU Interview Coroner 0
20
40
60
80
100
Fig. 1: Sources of referral.
150 Bed
100
Home 50
Elsewhere
0 Fig. 2: Location when found.
Witnessed Bitten tongue Incontinence Position Secretions Timing None
Fig. 3: Evidence for recent seizure.
Each case will have four controls matched for age and geographical location. The help of the MRC Epidemiology and Preventive Medicine Unit has been enlisted in this endeavour and practices in the appropriate areas identified from the MRC General Practice Research Framework. Randomly selected suitable controls are identified and relevant information extracted from the case notes. The factors under examination include epilepsy syndrome, seizure type and control, treatment history and compliance, other factors such as alcohol intake, ECG changes and supervision at night will also be included. Logistic regression analysis will be performed and a risk factor score determined. We aim to offer advice to those with epilepsy, their families and physicians on strategies to reduce the risk of SUDEP. The 154 cases identified comprise 97 men and 57 women with a mean age of 32 years. The sources of referral are illustrated in Fig. 1. The majority of indi-
viduals were found dead in bed and there was evidence to support a recent seizure in the majority (Figs 2 and 3) Twenty-one cases were witnessed, the majority occurring in association with a GTCS and, as we previously reported, witnesses often stated that victims appeared to have breathing difficulties prior to death35 . Thus far our work lends supporting evidence to the belief that SUDEP is a seizure-related event. The optimization of seizure control may play an important role in the prevention of these tragic deaths and the risk of SUDEP may need to be considered whenever decisions are made about alterations in therapy. Our work also suggests that a witnessed seizure is less likely to be fatal, and it may be that attention to recovery following a seizure and positioning or stimulation, if necessary, may be important in the prevention of SUDEP. We look forward with interest to the identification of risk factors.
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