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 and 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]

SUDEP occurs in about 1 in 1,000 adults and 1 in 4,500 children with epilepsy a year.^[6] Rates of death as a result of prolonged seizures (status epilepticus) are not classified as SUDEP.^[7]

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^[8]
• Poly-therapy of epilepsy. It remains unclear whether this is an independent risk factor or a surrogate marker for severity of epilepsy.^[9]
• Being asleep during a seizure is likely to favour SUDEP occurrence.^[10]

Mechanism

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.^[11]

• 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.^[12][13]
• 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.^[9]
• 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.^[14] Some studies however indicate that some antiepileptic drugs such as lamotrigine and carbamazepine, may increase the risk of SUDEP in certain individuals.^[15] 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,^[11] or because a high drug dosage could be a surrogate marker for poor seizure control.^[16]
• 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.^[11]

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,^[11] 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.^[11]
• Successful epilepsy surgery may reduce the risk of SUDEP, but this depends on the outcome in terms of seizure control.^[11]
• 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.^[9]

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.^[17]
• The risk of sudden death in young adults with epilepsy is increased 24-fold compared to the general population.^[9]
• SUDEP is the number one cause of epilepsy related death in people with pharmaco-resistant epilepsy.^[9]
• Children with epilepsy have a cumulative risk of dying suddenly of 7% within 40 years.^[9]
• In children, SUDEP accounts for 34% of all sudden deaths.^[18]

References

External links

• Harden, C; Tomson, T; Gloss, D; Buchhalter, J; Cross, JH; Donner, E; French, JA; Gil-Nagel, A; Hesdorffer, DC; Smithson, WH; Spitz, MC; Walczak, TS; Sander, JW; Ryvlin, P (25 April 2017). "Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society.". Neurology. 88 (17): 1674–1680. PMID 28438841. 
• Defining SUDEP at epilepsy.com
• About SUDEP, at EpilepsyFoundation.org
• SUDEP Action, UK at SUDEP.org
• SUDEP Aware, Canada at SUDEPaware.org
• SUDEP Global Conversation at SUDEPglobalconversation.com