Sudden unexpected death in epilepsy
Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy. 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. 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 and 50% of all deaths in refractory epilepsy. The causes of SUDEP seem to be multifactorial and include respiratory, cardiac and cerebral factors, as well as the severity of epilepsy and seizures. Proposed pathophysiological mechanisms include seizure-induced cardiac and respiratory arrests. Instances of death as a result of prolonged seizures (status epilepticus) are not classified as SUDEP.
Consistent risk factors include:
- Severity of seizures, increased refractoriness of epilepsy and presence of generalized tonic-clonic seizures: the most consistent risk factor is an increased frequency of tonic–clonic seizures.
- Poor compliance. Lack of therapeutic levels of anti epileptic drugs, non adherence to treatment regimens, and frequent changes in regimens are risk factors for sudden death.
- Young age, and early age of seizures onset.
- Male gender
- Poly-therapy of epilepsy. If this is an independent risk factor or a surrogate marker for severity of epilepsy remains unclear.
- The use of lamotrigine in idiopathic generalized epilepsy cases.
- Being asleep during a seizure is likely to favour SUDEP occurrence.
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.
- Cardiac factors: cardiac arrhythmias and other cardiac events are known to be involved in some cases of SUDEP. 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.
- 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.
- 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.
- 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).
- Anti epileptic drugs: most evidence suggests that antiepileptic drugs are not associated with an increased risk for SUDEP, but rather reduce its incidence. Some studies however indicate that some antiepileptic drugs such as lamotrigine and carbamazepine, may increase the risk of SUDEP in certain individuals. 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, or because a high drug dosage could be a surrogate marker for poor seizure control.
- 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.
The lack of generally recognized clinical recommendations available are a reflection of the dearth of data on the effectiveness of any particular clinical strategy, 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.
- Reduction of stress, participation in physical exercises, and night supervision might minimize the risk of SUDEP.
- Knowledge of how to perform the appropriate first-aid responses to seizure by persons who live with epileptic people may prevent death.
- People associated with arrhythmias during seizures should be submitted to extensive cardiac investigation with a view to determining the indication for on-demand cardiac pacing.
- Successful epilepsy surgery may reduce the risk of SUDEP, but this depends on the outcome in terms of seizure control.
- 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.
- Providing information to individuals and relatives about SUDEP is beneficial.
- 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.
- The risk of sudden death in young adults with epilepsy is increased 24-fold compared to the general population.
- SUDEP is the number one cause of epilepsy related death in people with pharmaco-resistant epilepsy.
- Children with epilepsy have a cumulative risk of dying suddenly of 7% within 40 years.
- In children, SUDEP accounts for 34% of all sudden deaths.
The Center for SUDEP Research is a National Institute for Neurological Disorders and Stroke (NINDS) funded Center Without Walls for Collaborative Research in the Epilepsies. This milestone-driven collaboration is composed of researchers from 14 institutions across the United States and Europe and brings together extensive and diverse expertise to understand Sudden Unexpected Death in Epilepsy Patients (SUDEP).
The CSR's scientists and physicians investigate and elucidate these links with their expertise in molecular biology, genetics, histopathology, electrophysiology, brain imaging, data analysis, and more. The team will identify the molecular and structural brain abnormalities underlying SUDEP, utilize these discoveries to identify features that could predict and identify those at risk of SUDEP, and home in on those targets for the development of potential therapeutic interventions.
The rate of sudden unexpected death in people with epilepsy is as much as 24 times higher than the rate of unexpected death in the general population, with an estimated 2,750 cases of SUDEP in the U.S. alone every year. Recent research findings for the mechanisms underlying SUDEP have pointed to a complex pathologenetic processes involving changes to the brain in people with epilepsy that disrupt the autonomic nervous system, leading to abnormalities in brain function, heart rate, rhythm, and respiration.
Overall, this investment by NINDS over nearly five years promises to catalyze research on SUDEP and dramatically enhance our understanding of this poorly understand and devastating phenomenon.
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- eMedicine - Sudden Unexpected Death in Epilepsy : Article by Shahin Nouri
- "Epilepsy Facts". Citizens United for Research in Epilepsy. Retrieved 18 March 2014.
- 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.co.uk
- 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_evaluation_synthesis_resource.pdf, Bibliographic tool for extracting value from the large scientific literature on SUDEP