Sudden unexpected death in epilepsy

Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy.^[1] It is defined as the sudden and unexpected, non-traumatic and non-drowning death of a person with epilepsy, without a toxicological or anatomical cause of death detected during the post-mortem examination.^[2][3] While the mechanisms underlying SUDEP are still poorly understood, it is possibly the most common cause of death as a result of complications from epilepsy, accounting for between 7.5 to 17% of all epilepsy-related deaths^[2] and 50% of all deaths in refractory epilepsy.^[4][5] The causes of SUDEP seem to be multifactorial^[2] and include respiratory, cardiac and cerebral factors, as well as the severity of epilepsy and seizures.^[5] Proposed pathophysiological mechanisms include seizure-induced cardiac and respiratory arrests.^[4] Instances of death as a result of prolonged seizures (status epilepticus) are not classified as SUDEP.^[6]

Risk factors

Consistent risk factors include:

• Severity of seizures, increased refractoriness of epilepsy and presence of generalized tonic-clonic seizures:^[4] the most consistent risk factor is an increased frequency of tonic–clonic seizures.^[5]
• Poor compliance.^[4] Lack of therapeutic levels of anti-epileptic drugs, non-adherence to treatment regimens, and frequent changes in regimens are risk factors for sudden death.^[5]
• Young age, and early age of seizures onset.^[4]
• Male gender^[4]
• Poly-therapy of epilepsy. It remains unclear whether this is an independent risk factor or a surrogate marker for severity of epilepsy.^[7]
• Being asleep during a seizure is likely to favour SUDEP occurrence.^[8]

Causes

The mechanisms underlying SUDEP are not well understood but probably involve several pathophysiological mechanisms and circumstances. The most commonly involved are seizure-induced hypoventilation and cardiac arrhythmias but different mechanisms may be involved in different individuals, and more than one mechanism may be involved in any one individual.^[9]

• Cardiac factors: cardiac arrhythmias and other cardiac events are known to be involved in some cases of SUDEP.^[5] Such arrhythmias are defined as ictal arrhythmias and include the ictal asystole which is a rare occurrence mostly in people that have temporal lobe epilepsy.^[10][11]
• Respiratory factors: impaired respiration and seizure induced pulmonary dysfunction as well as central apnea as a result of brain-stem respiratory centers suppression are known to play a role in some cases of SUDEP.^[5]
• Cerebral and autonomic nervous system dysregulation: cardiac arrhythmia and respiratory failure as a result of seizure related changes to brain function and dysfunction of the autonomic nervous system have been described in cases of SUDEP. These include cases of post-ictal generalized EEG suppression described as cerebral shutdown, but its significance remains unclear.^[7]
• Genetic factors: mutations in several genes have been associated with an increased susceptibility to SUDEP. Over 33% of these are related to mutations which lead to increased susceptibility for arrhythmia. Genes involved include the hyperpolarization-activated cyclic nucleotide-gated channels genes (HCN1, HCN2, HCN3, and HCN4).^[2]
• Anti epileptic drugs: most evidence suggests that antiepileptic drugs are not associated with an increased risk for SUDEP, but rather reduce its incidence.^[12] Some studies however indicate that some antiepileptic drugs such as lamotrigine and carbamazepine, may increase the risk of SUDEP in certain individuals.^[13] It is unclear if this is because of the potential cardio-respiratory adverse effects such as lengthening of the QT interval and reduction of heart rate known to be associated with these drugs under certain circumstances,^[9] or because a high drug dosage could be a surrogate marker for poor seizure control.^[14]
• Vagal nerve stimulation: concerns have been raised that vagal nerve stimulation may induce bradycardia or cardiac arrest, and may exacerbate sleep apnoea common in people with epilepsy.^[9]

Management

The lack of generally recognized clinical recommendations available are a reflection of the dearth of data on the effectiveness of any particular clinical strategy,^[9] but on the basis of present evidence, the following may be relevant:

• Epileptic seizure control with the appropriate use of medication and lifestyle counseling is the focus of prevention.^[5]
• Reduction of stress, participation in physical exercises, and night supervision might minimize the risk of SUDEP.^[2]
• Knowledge of how to perform the appropriate first-aid responses to seizure by persons who live with epileptic people may prevent death.^[5]
• People associated with arrhythmias during seizures should be submitted to extensive cardiac investigation^[2] with a view to determining the indication for on-demand cardiac pacing.^[9]
• Successful epilepsy surgery may reduce the risk of SUDEP, but this depends on the outcome in terms of seizure control.^[9]
• The use of anti suffocation pillows have been advocated by some practitioners to improve respiration while sleeping, but their effectiveness remain unproven because experimental studies are lacking.^[5]
• Providing information to individuals and relatives about SUDEP is beneficial.^[7]

Epidemiology

• Approximately 50,000 people die each year in the USA from status epilepticus (prolonged seizures), SUDEP, and other seizure-related causes. SUDEP accounts for 8-17% of deaths in people with epilepsy.^[15]
• The risk of sudden death in young adults with epilepsy is increased 24-fold compared to the general population.^[7]
• SUDEP is the number one cause of epilepsy related death in people with pharmaco-resistant epilepsy.^[7]
• Children with epilepsy have a cumulative risk of dying suddenly of 7% within 40 years.^[7]
• In children, SUDEP accounts for 34% of all sudden deaths.^[16]

References

1. Ryvlin, P; Nashef, L; Tomson, T (May 2013). "Prevention of sudden unexpected death in epilepsy: a realistic goal?". Epilepsia. 54 Suppl 2: 23–8. doi:10.1111/epi.12180. PMID 23646967.
2. Terra, VC; Cysneiros, R; Cavalheiro, EA; Scorza, FA (Mar 2013). "Sudden unexpected death in epilepsy: from the lab to the clinic setting.". Epilepsy & behavior : E&B 26 (3): 415–20. doi:10.1016/j.yebeh.2012.12.018. PMID 23402930.
3. Nashef, L; So, EL; Ryvlin, P; Tomson, T (Feb 2012). "Unifying the definitions of sudden unexpected death in epilepsy.". Epilepsia 53 (2): 227–33. doi:10.1111/j.1528-1167.2011.03358.x. PMID 22191982.
4. Tolstykh, GP; Cavazos, JE (Mar 2013). "Potential mechanisms of sudden unexpected death in epilepsy.". Epilepsy & behavior : E&B 26 (3): 410–4. doi:10.1016/j.yebeh.2012.09.017. PMID 23305781.
5. Devinsky, Orrin (10 November 2011). "Sudden, Unexpected Death in Epilepsy". New England Journal of Medicine 365 (19): 1801–1811. doi:10.1056/NEJMra1010481.
6. Tomson T, Nashef L, Ryvlin P (November 2008). "Sudden unexpected death in epilepsy: current knowledge and future directions". Lancet Neurology 7 (11): 1021–31. doi:10.1016/S1474-4422(08)70202-3. PMID 18805738.
7. Surges, R; Sander, JW (Apr 2012). "Sudden unexpected death in epilepsy: mechanisms, prevalence, and prevention.". Current opinion in neurology 25 (2): 201–7. doi:10.1097/WCO.0b013e3283506714. PMID 22274774.
8. Nobili, L; Proserpio, P; Rubboli, G; Montano, N; Didato, G; Tassinari, CA (Aug 2011). "Sudden unexpected death in epilepsy (SUDEP) and sleep.". Sleep medicine reviews 15 (4): 237–46. doi:10.1016/j.smrv.2010.07.006. PMID 20951616.
9. Shorvon, S; Tomson, T (Dec 10, 2011). "Sudden unexpected death in epilepsy.". Lancet 378 (9808): 2028–38. doi:10.1016/S0140-6736(11)60176-1. PMID 21737136.
10. So, N. K.; Sperling, M. R. (31 July 2007). "Ictal asystole and SUDEP". Neurology 69 (5): 423–424. doi:10.1212/01.wnl.0000268698.04032.bc.
11. Schuele, SU; Bermeo, AC; Alexopoulos, AV; Locatelli, ER; Burgess, RC; Dinner, DS; Foldvary-Schaefer, N (Jul 31, 2007). "Video-electrographic and clinical features in patients with ictal asystole.". Neurology 69 (5): 434–41. doi:10.1212/01.wnl.0000266595.77885.7f. PMID 17664402.
12. Ryvlin, P; Cucherat, M; Rheims, S (Nov 2011). "Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomised trials.". Lancet neurology 10 (11): 961–8. doi:10.1016/S1474-4422(11)70193-4. PMID 21937278.
13. Hesdorffer, DC; Tomson, T (Feb 2013). "Sudden unexpected death in epilepsy. Potential role of antiepileptic drugs.". CNS Drugs 27 (2): 113–9. doi:10.1007/s40263-012-0006-1. PMID 23109241.
14. Surges, R; Thijs, RD; Tan, HL; Sander, JW (Sep 2009). "Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms.". Nature reviews. Neurology 5 (9): 492–504. doi:10.1038/nrneurol.2009.118. PMID 19668244.
15. eMedicine - Sudden Unexpected Death in Epilepsy : Article by Shahin Nouri
16. "Epilepsy Facts". Citizens United for Research in Epilepsy. Retrieved 18 March 2014.

External links

• SUDEP eBrochures for download, eNewsletter signup, support at SUDEP Aware
• SUDEP awareness campaign
• Partners Against Mortality in Epilepsy 3-day conference (22-24 June 2012)
• Online book "SUDEP: continuing the global conversation"
• SUDEP described at patient.info
• Citizens United for Research in Epilepsy: epilepsy facts
• Defining SUDEP at epilepsy.com
• Unmasking Silent Killer in Epilepsy, New York Times, 26 July 2010.
• About SUDEP, at EpilepsyFoundation.org
• www.SUDEP.org SUDEP support at Epilepsy Bereaved UK
• SUDEP_literature_synthesis_tool, Bibliographic tool for extracting value from the large scientific literature on SUDEP
• sudep-registry.org/, NASR (North American SUDEP Registry)