ARTICLES
This article addresses the Core Competency of Patient Care
Sudden Unexpected Death in Epilepsy: Some Approaches to Prevent It Archana Verma, M.D., D.M., and Alok Kumar, M.D.
Mortality because of epilepsy is a major concern worldwide. People with epilepsy have a two to three times increased risk of death in comparison with the general population. Sudden unexplained death in epilepsy is a mysterious, rare condition, in which typically young or middle-aged people with epilepsy die without a clearly defined cause. Several different mechanisms probably exist, and most research has focused on seizure-related respiratory depression, cardiac arrhythmia, cerebral depression, and autonomic dysfunction. In recent years, some significant risk factors have been recognized and strategies have been suggested that may be useful in prevention of sudden unexpected death in epilepsy (SUDEP). The present review provides some of the updates on new advances in prevention of SUDEP. J Neuropsychiatry Clin Neurosci 2015; 27:e28–e31; doi: 10.1176/appi.neuropsych.13120366
Epilepsy is one of the most common neurological disorders and affects approximately 50 million people worldwide. Sudden unexpected death in epilepsy (SUDEP) represents a significant category of mortality in the population with epilepsy. The mechanism of sudden death in epilepsy is unknown. There has been an increase in the awareness of SUDEP in the last several years, leading to a greater appreciation of its role in epilepsy-related mortality.1–3 The objective of the present communication is to highlight some of the new advances in prevention of SUDEP. DEFINITIONS SUDEP has been defined as the sudden, unexpected, witnessed or unwitnessed, nontraumatic, and nondrowning death in patients with epilepsy, with or without evidence for a seizure, with exclusion of documented status epilepticus, and when postmortem examination does not reveal a structural or toxicological cause for death. The Nashef4 definition focuses on strictly defined cases with negative post mortem, while the Annegers5 definition additionally gives guidance on classifying the many cases where information is incomplete, with definite, probable, and possible categories. Cases fulfilling the above definition fall into the ‘‘definite SUDEP’’ category; sudden deaths occurring in benign circumstances with no known competing cause for death but without autopsy are classified as ‘‘probable SUDEP.’’ Cases where SUDEP cannot be excluded, either because of limited information regarding death circumstances or because there is a plausible competing explanation for death, are classified as ‘‘possible SUDEP.’’ e28
neuro.psychiatryonline.org
INCIDENCE OF SUDEP In the overall epilepsy population, mortality rates are approximately 2.5-fold higher than in the general population.6,7 The most common epilepsy-related cause of death is thought to be SUDEP. Population based study from USA showed that although SUDEP is a rare cause of death in the epilepsy population but exceeds the expected rate of sudden death in the general population by nearly 24 times. The incidence of SUDEP in this study was 0.35 per 1,000 person-years.8 Incidence rates may vary widely according to study cohort and design, ranging from 0.09 to 0.35 per 1,000 personyears in unselected cohorts to 0.9 to 2.3 per 1,000 person-years in general epilepsy populations.1,9 In refractory epilepsy mortality rates are still higher than in the general population and incidence of SUDEP may be as high as 1.1 to 5.9 per 1,000 person-years.1,9 In epilepsy surgery, candidates or in patients who continue to have seizures after surgery incidence rate varies from 6·3 to 9·3 per 1,000 person-years.10–13 Sillanpaa et al. in their study that followed 245 children with epilepsy for 40 years and reported 24% mortality of which 30% were classified as SUDEP. The risk of SUDEP in this population was 7% over the follow-up period of 40 years.14 RISK FACTORS FOR SUDEP Certain risk factors have been shown to be associated with SUDEP in case-control studies. These studies have different methodologies and are not directly comparable. The Task Force on Epidemiology of the International League Against Epilepsy (ILAE) recently pooled data from four J Neuropsychiatry Clin Neurosci 27:1, Winter 2015
VERMA AND KUMAR
published case-control studies to increase the power to determine risk factors for SUDEP.3 One US and three European studies were utilized to yield a final sample of 289 cases of definite or probable SUDEP and 958 living controls.15–18 DEMOGRAPHIC VARIABLES The risk of SUDEP was 1.4 times higher in male patients than in female patients, 1.7 times higher in those with onset of epilepsy before the age of 16 years.3 In contrast, the Norwegian study reported on comparison with 42 patients of SUDEP with 37 non-SUDEP patients, no significant differences were found for sex, age at death, or duration of epilepsy. Age at onset of epilepsy was significantly lower in the SUDEP group than in the non-SUDEP group (p=0.04).19 EPILEPSY FACTORS It was observed by ILAE task force that increasing number of generalized tonic clonic seizures (GTCS) per year was associated with a statistically significant increased risk for SUDEP compared with people without GTCS [odds ratio (OR) 2.94 for 1–2 GTCS, OR 8.28 for 3–12 GTCS, OR 9.06 for 13–50 GTCS, and OR 14.51 for .50 GTCS].3 Increased frequency of GTCS and polytherapy both emerged as strong risk factors, more so when these factors are combined. Compared with those without GTCS on no antiepileptic drug (AED) therapy or monotherapy, the risk for SUDEP was statistically significantly increased, 4.92-fold for those with 1–2 GTCS or unknown number on no therapy or monotherapy, 10.40-fold for those with 1–2 GTCS or unknown GTCS and polytherapy, 13.90-fold for those with $ 3 GTC and no therapy or monotherapy, and 25.20-fold for those with $3 GTCS and polytherapy. These results suggest that GTCS frequency and polytherapy contributed to SUDEP risk.3 Seizure type is a strong predictive factor of SUDEP. Of all seizure types, 90% of SUDEP patients report a history of primary or secondary GTCS.1 Norway study reported statistically significant more primarily generalized seizures in the SUDEP group (p=0.03).19 In addition to the previously described risk factors, various epilepsy syndromes can predict the likelihood of SUDEP. Patients with absence epilepsy and benign epilepsy have a negligible risk for SUDEP,20 whereas Dravet syndrome patients have a greatly increased risk.21 Idiopathic/cryptogenic etiology and idiopathic generalized epilepsy (IGE) were associated with a lower risk for SUDEP.3 Duration of epilepsy was significantly longer among SUDEP cases than among the nondeceased controls in the largest casecontrol study,15 and long duration was also identified as a risk factor in the prospective US case-control study.17 Duration of epilepsy for more than 15 years was associated with a 1.95-fold increased risk of SUDEP.3 AED It is important to know whether the drugs are associated with risk of SUDEP or whether judicious treatment lowers J Neuropsychiatry Clin Neurosci 27:1, Winter 2015
this risk. Nevertheless, important risk factors relating to AED treatment including nonadherence to treatment, abrupt withdrawal, polytherapy, and choice of AED are important because they are amenable to manipulation in routine management. The Stockholm study, which only includes SUDEP cases with treated epilepsy, identified that polytherapy and frequent medication changes as independent risk factor for SUDEP.4 Taking three AEDs was associated with a relative risk for SUDEP of 8 (2.3–28) compared with monotherapy even after adjustment for seizure frequency.15 Polytherapy was also found to be an independent risk factor in the US study.17 AEDs in some circumstances might increase the risk of SUDEP. Some epilepsy drugs have potential effects on cardiac conduction through their membrane stabilizing effects and their effects on autonomic function. Attention has mostly focused on the sodium-channel blocking drugs such as carbamazepine and lamotrigine. Timmings22 found carbamazepine used at a significantly higher rate among the 14 SUDEP patients than among the general epilepsy patients attending the clinics. In this analysis, a carbamazepine plasma level was reported above 40 mmol/L at the last visit and was associated with an increased risk, even when adjusted for seizure frequency. Carbamazepine has been associated with lengthening of the ECG QT interval or reduction of heart rate variability23,24 combined with a mild proarrhythmic effect of epileptic seizure discharges, might lead to fatal arrhythmia. These associations were, however, not confirmed in the ILAE Task Force pooled analysis, which included these two case-control studies.3 They found high antemortem blood levels of carbamazepine, phenytoin, and valproic acid as possible SUDEP risk factors; only valproic acid levels .100 mg/L were associated with an increased SUDEP risk, but this was not statistically significant. Lamotrigine has been shown, in vitro, to inhibit the cardiac rapid delayed rectifier potassium ion current (IKr), which is of interest as drugs that block IKr may cause a prolonged QT interval and be associated with the fatal arrhythmia, torsades de pointes. The recent ILAE risk factor analysis found a 2.3 times increased risk for SUDEP among those with epilepsy onset before age 16 years on lamotrigine therapy. Further to this, lamotrigine therapy was associated with significantly increased risk for SUDEP among individuals with idiopathic generalized epilepsy.3 Ryvlin et al.25 found SUDEP risk increased in patients with poor compliance and nocturnal, generalized tonic-clonic seizures. Maintaining stable therapeutic drug levels is crucial to avoid SUDEP. Kloster R et al. found supposedly subtherapeutic concentrations of one or more antiepileptic drugs in 57% of SUDEP patients; 77% had concentrations in the recommended range of one or more antiepileptic drugs.19 Other studies reported similar findings.26–28 Walczak et al.17 found no difference in compliance drugs between cases and controls. The recent ILAE task force has found that number of AEDs was no longer associated with SUDEP after adjustment neuro.psychiatryonline.org
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for GTCS frequency and that neither were specific AEDs alone or in polytherapy.29 CIRCUMSTANCES OF DEATH A consistent feature is that most of these deaths are unwitnessed occur in bed presumably during sleep. Langans et al. in their 15 cases of witnessed SUDEP found that 12 of the 15 cases experienced respiratory difficulty. Where witnessed most cases occurred in association with a seizure and respiratory compromise. Positioning or stimulation of respiration may be important in the prevention of these deaths.30 A case-controlled study on SUDEP from Norway, found 17 cases (40% of all) in the prone position and only one (2%) in the supine position, whereas six (14%) were found in other positions.19 The prone position may cause obstruction of the nose and mouth due to pressure against the bed clothing. Changing the sleeping position from prone to supine has brought about a marked reduction in the incidence of the sudden infant death syndrome. Nashef et al.,31 in their study of SUDEP among pupils in a residential school for patients with learning disabilities, observed that all the 14 deaths occurred while the pupils were not under supervision of the school, again suggesting that supervision and intervention may reduce the risks. PREVENTIVE MEASURES The development of better preventive measures will depend on understanding of the pathophysiology of SUDEP, risk factors, and identification of high risk population. Several predisposing and initiating factors may coexist and contribute to SUDEP; however, the exact causal mechanisms are poorly understood. Frequency of GTCS is an important known risk factor, a seizure type that triggers the majority of witnessed SUDEP. Therefore, one likely way to prevent SUDEP is to reduce the frequency of GTCS with optimal medical management and patient education. Another hypothetical strategy to prevent SUDEP is to reduce the risk of GTCS-induced postictal respiratory distress. This might be achieved by using lattice pillow, providing nocturnal supervision, reinforcing interictal serotoninergic tone, and lowering opiate or adenosine-induced postictal brainstem depression.32 Supervision at night for patients at high risk includes attendance and use of alarms (balancing the benefits of independent living and the penalties of intrusive monitoring). Supervision after a tonic-clonic seizure includes continuous attendance until full consciousness is restored and call emergency services for high-risk seizures. Trigger factors for seizures should be identified and avoided. Adherence with medication is important and avoiding sudden changes in the taking of medication. Improvement of seizure control and possibly the avoidance of polytherapy may be few effective measures to reduce the risk of SUDEP. e30
neuro.psychiatryonline.org
If these approaches are unsuccessful, other measures that could be considered are epilepsy surgery, vagus nerve stimulation, and dietary management (e.g., ketogenic diet and omega23 supplementation). A lower prevalence of SUDEP in pet-owners with epilepsy living in single individual households than in non-pet-owners living in single individual households would emphasize that pets play a beneficial role as supervisors of epilepsy patients.33 There are some monitoring devices that claim to detect seizure-like movement in bed or changes in breathing, heart rate, or blood oxygen levels, to trigger an alarm. Some people find these useful but many find them intrusive. Based on data from a mice model, treatment with antidepressants of the selective serotonin-reuptake inhibitor type could reduce the risk of SUDEP by prevention of postictal respiratory arrest.34 Improvement in the quality of life and participation in physical activity and sports in people with epilepsy around the world will decrease the risk of cardiovascular abnormalities and SUDEP for those who are at high risk for these outcomes.35 Further research must, therefore, be undertaken to fully understand the mechanisms underlying SUDEP. Although sudden death remains a rare occurrence, it is important to increase awareness within the medical and lay communities. AUTHOR AND ARTICLE INFORMATION From the Department of Neurology (AV) and the Dept. of Forensic Medicine and Toxicology(AK), UP Rural Institute of Medical Sciences and Research, Saifai, Etawah, India. Send correspondence to Dr. Verma; e-mail: archanashiva2010@rediffmail. com Received Dec. 10, 2013; revised Feb. 11, 2014; accepted Feb. 24, 2014.
REFERENCES 1. Tomson T, Walczak T, Sillanpaa M, et al: Sudden unexpected death in epilepsy: a review of incidence and risk factors. Epilepsia 2005; 46(Suppl 11):54–61 2. Shorvon S, Tomson T: Sudden unexpected death in epilepsy. Lancet 2011; 378:2028–2038 3. Hesdorffer DC, Tomson T, Benn E, et al; ILAE Commission on Epidemiology; Subcommission on Mortality: combined analysis of risk factors for SUDEP. Epilepsia 2011; 52:1150–1159 4. Nashef L: Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia 1997; 38(Suppl):S6–S8 5. Annegers JF: United States perspective on definitions and classifications. Epilepsia 1997; 38(Suppl):S9–S12 6. Cockerell OC, Johnson AL, Sander JW, et al: Mortality from epilepsy: results from a prospective population-based study. Lancet 1994; 344:918–921 7. Hauser WA, Annegers JF, Elveback LR: Mortality in patients with epilepsy. Epilepsia 1980; 21:399–412 8. Ficker DM, So EL, Shen WK, et al: Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology 1998; 51:1270–1274 9. Tomson T, Nashef L, Ryvlin P: Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 2008; 7:1021–1031 10. Dasheiff RM: Sudden unexpected death in epilepsy: a series from an epilepsy surgery program and speculation on the relationship to sudden cardiac death. J Clin Neurophysiol 1991; 8:216–222 J Neuropsychiatry Clin Neurosci 27:1, Winter 2015
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11. Nilsson L, Ahlbom A, Farahmand BY, et al: Mortality in a populationbased cohort of epilepsy surgery patients. Epilepsia 2003; 44:575–581 12. Sperling MR, Harris A, Nei M, et al: Mortality after epilepsy surgery. Epilepsia 2005; 46(Suppl 11):49–53 13. Hennessy MJ, Langan Y, Elwes RD, et al: A study of mortality after temporal lobe epilepsy surgery. Neurology 1999; 53:1276–1283 14. Sillanpää M, Shinnar S: Long-term mortality in childhood-onset epilepsy. N Engl J Med 2010; 363:2522–2529 15. Nilsson L, Farahmand BY, Persson PG, et al: Risk factors for sudden unexpected death in epilepsy: a case-control study. Lancet 1999; 353: 888–893 16. Langan Y, Nashef L, Sander JW: Case-control study of SUDEP. Neurology 2005; 64:1131–1133 17. Walczak TS, Leppik IE, D’Amelio MJ, et al: Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology 2001; 56:519–525 18. Hitiris N, Suratman S, Kelly K, et al: Sudden unexpected death in epilepsy: a search for risk factors. Epilepsy Behav 2007; 10:138–141 19. Kloster R, Engelskjøn T: Sudden unexpected death in epilepsy (SUDEP): a clinical perspective and a search for risk factors. J Neurol Neurosurg Psychiatry 1999; 67:439–444 20. So EL, Bainbridge J, Buchhalter JR, et al: Report of the American Epilepsy Society and the Epilepsy Foundation joint task force on sudden unexplained death in epilepsy. Epilepsia 2009; 50:917–922 21. Ragsdale DS: How do mutant Nav1.1 sodium channels cause epilepsy? Brain Res Brain Res Rev 2008; 58:149–159 22. Timmings PL: Sudden unexpected death in epilepsy: is carbamazepine implicated? Seizure 1998; 7:289–291 23. Persson H, Ericson M, Tomson T: Carbamazepine affects autonomic cardiac control in patients with newly diagnosed epilepsy. Epilepsy Res 2003; 57:69–75 24. Surges R, Taggart P, Sander JW, et al: Too long or too short? New insights into abnormal cardiac repolarization in people with chronic epilepsy and its potential role in sudden unexpected death. Epilepsia 2010; 51:738–744
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25. Ryvlin P, Tomson T: Mortemus (Mortality in epilepsy monitoring unit study): preliminary findings. Epilepsia 2009; 50(Suppl 4):60 26. Lund A, Gormsen H: The role of antiepileptics in sudden death in epilepsy. Acta Neurol Scand 1985; 72:444–446 27. Tomson T, Sköld AC, Holmgen P, et al: Postmortem changes in blood concentrations of phenytoin and carbamazepine: an experimental study. Ther Drug Monit 1998; 20:309–312 28. Schnabel R, May Th, Rambeck B: Post-mortem determination of anticonvulsant concentrations and lung oedema in the sudden, unexpected death of epileptics. Seizure 1997; 6:327–328 29. Hesdorffer DC, Tomson T, Benn E, et al; ILAE Commission on Epidemiology (Subcommission on Mortality). Do antiepileptic drugs or generalized tonic-clonic seizure frequency increase SUDEP risk? A combined analysis. Epilepsia 2012; 53:249–252 30. Langan Y, Nashef L, Sander JWAS: Sudden unexpected death in epilepsy: a series of witnessed deaths. J Neurol Neurosurg Psychiatry 2000; 68:211–213 31. Nashef L, Fish DR, Garner S, et al: Sudden death in epilepsy: a study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 1995; 36:1187–1194 32. Ryvlin P, Nashef L, Tomson T: Prevention of sudden unexpected death in epilepsy: a realistic goal? Epilepsia 2013; 54(Suppl 2):23–28 33. Terra VC, Sakamoto AC, Machado HR, et al: Do pets reduce the likelihood of sudden unexplained death in epilepsy? Seizure 2012; 21:649–651 34. Faingold CL, Tupal S, Randall M: Prevention of seizure-induced sudden death in a chronic SUDEP model by semichronic administration of a selective serotonin reuptake inhibitor. Epilepsy Behav 2011; 22:186–190 35. Brook RD, Rajagopalan S, Pope CA 3rd, et al American Heart Association Council on Epidemiology and Prevention, Council on the Kidney in Cardiovascular Disease, and Council on Nutrition, Physical Activity and Metabolism: Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circulation 2010; 121:2331–2378
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This article addresses the Core Competency of Patient Care
Sudden Unexpected Death in Epilepsy: Some Approaches to Prevent It Archana Verma, M.D., D.M., and Alok Kumar, M.D.
Mortality because of epilepsy is a major concern worldwide. People with epilepsy have a two to three times increased risk of death in comparison with the general population. Sudden unexplained death in epilepsy is a mysterious, rare condition, in which typically young or middle-aged people with epilepsy die without a clearly defined cause. Several different mechanisms probably exist, and most research has focused on seizure-related respiratory depression, cardiac arrhythmia, cerebral depression, and autonomic dysfunction. In recent years, some significant risk factors have been recognized and strategies have been suggested that may be useful in prevention of sudden unexpected death in epilepsy (SUDEP). The present review provides some of the updates on new advances in prevention of SUDEP. J Neuropsychiatry Clin Neurosci 2015; 27:e28–e31; doi: 10.1176/appi.neuropsych.13120366
Epilepsy is one of the most common neurological disorders and affects approximately 50 million people worldwide. Sudden unexpected death in epilepsy (SUDEP) represents a significant category of mortality in the population with epilepsy. The mechanism of sudden death in epilepsy is unknown. There has been an increase in the awareness of SUDEP in the last several years, leading to a greater appreciation of its role in epilepsy-related mortality.1–3 The objective of the present communication is to highlight some of the new advances in prevention of SUDEP. DEFINITIONS SUDEP has been defined as the sudden, unexpected, witnessed or unwitnessed, nontraumatic, and nondrowning death in patients with epilepsy, with or without evidence for a seizure, with exclusion of documented status epilepticus, and when postmortem examination does not reveal a structural or toxicological cause for death. The Nashef4 definition focuses on strictly defined cases with negative post mortem, while the Annegers5 definition additionally gives guidance on classifying the many cases where information is incomplete, with definite, probable, and possible categories. Cases fulfilling the above definition fall into the ‘‘definite SUDEP’’ category; sudden deaths occurring in benign circumstances with no known competing cause for death but without autopsy are classified as ‘‘probable SUDEP.’’ Cases where SUDEP cannot be excluded, either because of limited information regarding death circumstances or because there is a plausible competing explanation for death, are classified as ‘‘possible SUDEP.’’ e28
neuro.psychiatryonline.org
INCIDENCE OF SUDEP In the overall epilepsy population, mortality rates are approximately 2.5-fold higher than in the general population.6,7 The most common epilepsy-related cause of death is thought to be SUDEP. Population based study from USA showed that although SUDEP is a rare cause of death in the epilepsy population but exceeds the expected rate of sudden death in the general population by nearly 24 times. The incidence of SUDEP in this study was 0.35 per 1,000 person-years.8 Incidence rates may vary widely according to study cohort and design, ranging from 0.09 to 0.35 per 1,000 personyears in unselected cohorts to 0.9 to 2.3 per 1,000 person-years in general epilepsy populations.1,9 In refractory epilepsy mortality rates are still higher than in the general population and incidence of SUDEP may be as high as 1.1 to 5.9 per 1,000 person-years.1,9 In epilepsy surgery, candidates or in patients who continue to have seizures after surgery incidence rate varies from 6·3 to 9·3 per 1,000 person-years.10–13 Sillanpaa et al. in their study that followed 245 children with epilepsy for 40 years and reported 24% mortality of which 30% were classified as SUDEP. The risk of SUDEP in this population was 7% over the follow-up period of 40 years.14 RISK FACTORS FOR SUDEP Certain risk factors have been shown to be associated with SUDEP in case-control studies. These studies have different methodologies and are not directly comparable. The Task Force on Epidemiology of the International League Against Epilepsy (ILAE) recently pooled data from four J Neuropsychiatry Clin Neurosci 27:1, Winter 2015
VERMA AND KUMAR
published case-control studies to increase the power to determine risk factors for SUDEP.3 One US and three European studies were utilized to yield a final sample of 289 cases of definite or probable SUDEP and 958 living controls.15–18 DEMOGRAPHIC VARIABLES The risk of SUDEP was 1.4 times higher in male patients than in female patients, 1.7 times higher in those with onset of epilepsy before the age of 16 years.3 In contrast, the Norwegian study reported on comparison with 42 patients of SUDEP with 37 non-SUDEP patients, no significant differences were found for sex, age at death, or duration of epilepsy. Age at onset of epilepsy was significantly lower in the SUDEP group than in the non-SUDEP group (p=0.04).19 EPILEPSY FACTORS It was observed by ILAE task force that increasing number of generalized tonic clonic seizures (GTCS) per year was associated with a statistically significant increased risk for SUDEP compared with people without GTCS [odds ratio (OR) 2.94 for 1–2 GTCS, OR 8.28 for 3–12 GTCS, OR 9.06 for 13–50 GTCS, and OR 14.51 for .50 GTCS].3 Increased frequency of GTCS and polytherapy both emerged as strong risk factors, more so when these factors are combined. Compared with those without GTCS on no antiepileptic drug (AED) therapy or monotherapy, the risk for SUDEP was statistically significantly increased, 4.92-fold for those with 1–2 GTCS or unknown number on no therapy or monotherapy, 10.40-fold for those with 1–2 GTCS or unknown GTCS and polytherapy, 13.90-fold for those with $ 3 GTC and no therapy or monotherapy, and 25.20-fold for those with $3 GTCS and polytherapy. These results suggest that GTCS frequency and polytherapy contributed to SUDEP risk.3 Seizure type is a strong predictive factor of SUDEP. Of all seizure types, 90% of SUDEP patients report a history of primary or secondary GTCS.1 Norway study reported statistically significant more primarily generalized seizures in the SUDEP group (p=0.03).19 In addition to the previously described risk factors, various epilepsy syndromes can predict the likelihood of SUDEP. Patients with absence epilepsy and benign epilepsy have a negligible risk for SUDEP,20 whereas Dravet syndrome patients have a greatly increased risk.21 Idiopathic/cryptogenic etiology and idiopathic generalized epilepsy (IGE) were associated with a lower risk for SUDEP.3 Duration of epilepsy was significantly longer among SUDEP cases than among the nondeceased controls in the largest casecontrol study,15 and long duration was also identified as a risk factor in the prospective US case-control study.17 Duration of epilepsy for more than 15 years was associated with a 1.95-fold increased risk of SUDEP.3 AED It is important to know whether the drugs are associated with risk of SUDEP or whether judicious treatment lowers J Neuropsychiatry Clin Neurosci 27:1, Winter 2015
this risk. Nevertheless, important risk factors relating to AED treatment including nonadherence to treatment, abrupt withdrawal, polytherapy, and choice of AED are important because they are amenable to manipulation in routine management. The Stockholm study, which only includes SUDEP cases with treated epilepsy, identified that polytherapy and frequent medication changes as independent risk factor for SUDEP.4 Taking three AEDs was associated with a relative risk for SUDEP of 8 (2.3–28) compared with monotherapy even after adjustment for seizure frequency.15 Polytherapy was also found to be an independent risk factor in the US study.17 AEDs in some circumstances might increase the risk of SUDEP. Some epilepsy drugs have potential effects on cardiac conduction through their membrane stabilizing effects and their effects on autonomic function. Attention has mostly focused on the sodium-channel blocking drugs such as carbamazepine and lamotrigine. Timmings22 found carbamazepine used at a significantly higher rate among the 14 SUDEP patients than among the general epilepsy patients attending the clinics. In this analysis, a carbamazepine plasma level was reported above 40 mmol/L at the last visit and was associated with an increased risk, even when adjusted for seizure frequency. Carbamazepine has been associated with lengthening of the ECG QT interval or reduction of heart rate variability23,24 combined with a mild proarrhythmic effect of epileptic seizure discharges, might lead to fatal arrhythmia. These associations were, however, not confirmed in the ILAE Task Force pooled analysis, which included these two case-control studies.3 They found high antemortem blood levels of carbamazepine, phenytoin, and valproic acid as possible SUDEP risk factors; only valproic acid levels .100 mg/L were associated with an increased SUDEP risk, but this was not statistically significant. Lamotrigine has been shown, in vitro, to inhibit the cardiac rapid delayed rectifier potassium ion current (IKr), which is of interest as drugs that block IKr may cause a prolonged QT interval and be associated with the fatal arrhythmia, torsades de pointes. The recent ILAE risk factor analysis found a 2.3 times increased risk for SUDEP among those with epilepsy onset before age 16 years on lamotrigine therapy. Further to this, lamotrigine therapy was associated with significantly increased risk for SUDEP among individuals with idiopathic generalized epilepsy.3 Ryvlin et al.25 found SUDEP risk increased in patients with poor compliance and nocturnal, generalized tonic-clonic seizures. Maintaining stable therapeutic drug levels is crucial to avoid SUDEP. Kloster R et al. found supposedly subtherapeutic concentrations of one or more antiepileptic drugs in 57% of SUDEP patients; 77% had concentrations in the recommended range of one or more antiepileptic drugs.19 Other studies reported similar findings.26–28 Walczak et al.17 found no difference in compliance drugs between cases and controls. The recent ILAE task force has found that number of AEDs was no longer associated with SUDEP after adjustment neuro.psychiatryonline.org
e29
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for GTCS frequency and that neither were specific AEDs alone or in polytherapy.29 CIRCUMSTANCES OF DEATH A consistent feature is that most of these deaths are unwitnessed occur in bed presumably during sleep. Langans et al. in their 15 cases of witnessed SUDEP found that 12 of the 15 cases experienced respiratory difficulty. Where witnessed most cases occurred in association with a seizure and respiratory compromise. Positioning or stimulation of respiration may be important in the prevention of these deaths.30 A case-controlled study on SUDEP from Norway, found 17 cases (40% of all) in the prone position and only one (2%) in the supine position, whereas six (14%) were found in other positions.19 The prone position may cause obstruction of the nose and mouth due to pressure against the bed clothing. Changing the sleeping position from prone to supine has brought about a marked reduction in the incidence of the sudden infant death syndrome. Nashef et al.,31 in their study of SUDEP among pupils in a residential school for patients with learning disabilities, observed that all the 14 deaths occurred while the pupils were not under supervision of the school, again suggesting that supervision and intervention may reduce the risks. PREVENTIVE MEASURES The development of better preventive measures will depend on understanding of the pathophysiology of SUDEP, risk factors, and identification of high risk population. Several predisposing and initiating factors may coexist and contribute to SUDEP; however, the exact causal mechanisms are poorly understood. Frequency of GTCS is an important known risk factor, a seizure type that triggers the majority of witnessed SUDEP. Therefore, one likely way to prevent SUDEP is to reduce the frequency of GTCS with optimal medical management and patient education. Another hypothetical strategy to prevent SUDEP is to reduce the risk of GTCS-induced postictal respiratory distress. This might be achieved by using lattice pillow, providing nocturnal supervision, reinforcing interictal serotoninergic tone, and lowering opiate or adenosine-induced postictal brainstem depression.32 Supervision at night for patients at high risk includes attendance and use of alarms (balancing the benefits of independent living and the penalties of intrusive monitoring). Supervision after a tonic-clonic seizure includes continuous attendance until full consciousness is restored and call emergency services for high-risk seizures. Trigger factors for seizures should be identified and avoided. Adherence with medication is important and avoiding sudden changes in the taking of medication. Improvement of seizure control and possibly the avoidance of polytherapy may be few effective measures to reduce the risk of SUDEP. e30
neuro.psychiatryonline.org
If these approaches are unsuccessful, other measures that could be considered are epilepsy surgery, vagus nerve stimulation, and dietary management (e.g., ketogenic diet and omega23 supplementation). A lower prevalence of SUDEP in pet-owners with epilepsy living in single individual households than in non-pet-owners living in single individual households would emphasize that pets play a beneficial role as supervisors of epilepsy patients.33 There are some monitoring devices that claim to detect seizure-like movement in bed or changes in breathing, heart rate, or blood oxygen levels, to trigger an alarm. Some people find these useful but many find them intrusive. Based on data from a mice model, treatment with antidepressants of the selective serotonin-reuptake inhibitor type could reduce the risk of SUDEP by prevention of postictal respiratory arrest.34 Improvement in the quality of life and participation in physical activity and sports in people with epilepsy around the world will decrease the risk of cardiovascular abnormalities and SUDEP for those who are at high risk for these outcomes.35 Further research must, therefore, be undertaken to fully understand the mechanisms underlying SUDEP. Although sudden death remains a rare occurrence, it is important to increase awareness within the medical and lay communities. AUTHOR AND ARTICLE INFORMATION From the Department of Neurology (AV) and the Dept. of Forensic Medicine and Toxicology(AK), UP Rural Institute of Medical Sciences and Research, Saifai, Etawah, India. Send correspondence to Dr. Verma; e-mail: archanashiva2010@rediffmail. com Received Dec. 10, 2013; revised Feb. 11, 2014; accepted Feb. 24, 2014.
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