Sudden unexpected death in epilepsy

Sudden Unexpected Death in Epilepsy (SUDEP) refers to the sudden, unexpected death of a person with epilepsy that is not the result of trauma, drowning, or an identified medical condition. In most cases, no structural or toxicological cause of death is found at autopsy. SUDEP can occur with or without evidence of a preceding seizure, and is often unwitnessed, especially during sleep.

The exact mechanisms underlying SUDEP remain unclear but are believed to be multifactorial. Potential contributors include seizure-related disruptions in breathing, heart rhythm, or brain function, often in combination.

SUDEP is estimated to affect approximately 1 in 1,000 adults and 1 in 4,500 children with epilepsy each year. It accounts for 7% to 17% of epilepsy-related deaths overall, and up to 50% in those with refractory epilepsy. Deaths caused by status epilepticus or accidents such as drowning are classified separately.

To improve consistency in clinical reporting and research, a unified classification system for SUDEP has been proposed. It defines SUDEP as a sudden, unexpected, nontraumatic, and nondrowning death in a person with epilepsy, occurring in benign circumstances, with or without evidence of a seizure, and without a known structural or toxicological cause identified on postmortem examination. Deaths due to documented status epilepticus are excluded.

The classification includes the following categories:

1. Definite SUDEP: meets the core definition and is confirmed by autopsy showing no alternative cause of death.
2. Definite SUDEP Plus: meets all criteria for definite SUDEP but occurs in the context of a potentially contributory comorbidity (e.g., cardiac or respiratory disease) that cannot be definitively established as the cause of death.
3. Probably SUDEP: meets the criteria for definite SUDEP but without autopsy confirmation.
4. Possible SUDEP: insufficient information is available regarding the death, with no autopsy confirmation.
5. Unlikely SUDEP: an alternate cause of death has been determined, ruling out the possibility of SUDEP being the cause.

In witnessed cases, an interval of one hour between collapse and death is often used as a practical threshold for classification. This framework is intended to improve surveillance, enable standardized reporting, and support research into risk factors and prevention.

Several clinical and demographic factors have been associated with an increased risk of SUDEP, although the precise mechanisms remain unclear. The most consistently identified risk factor is the presence of generalized tonic–clonic seizures (GTCS), especially when they are frequent, uncontrolled, or occur during sleep or when unobserved. Individuals with poorly controlled epilepsy — particularly those with drug-resistant epilepsy — are at significantly higher risk. Nocturnal seizures are associated with a higher risk of SUDEP, as they are more likely to be unwitnessed and may delay resuscitation efforts. Living alone or sleeping unsupervised has also been linked to elevated risk. Other possible risk factors include male gender, early onset of epilepsy, a longer duration of disease, irregular use of antiseizure medications, and the presence of cognitive impairment or structural brain abnormalities, although these associations vary across studies. Individuals with a history of substance abuse or alcohol dependence are found to have a twofold higher risk of SUDEP.

Genetic factors are believed to contribute to SUDEP risk, although the full extent of this contribution remains poorly understood. While specific gene mutations have been identified in individuals who died of SUDEP, it is likely that risk is determined by the interaction of multiple genetic variants affecting ion channel function and neuronal excitability. There is substantial overlap in the genes implicated in SUDEP and those associated with other sudden death syndromes, including sudden infant death syndrome (SIDS), sudden unexplained death in childhood (SUDC), and sudden unexpected death (SUD). Many of the genes are involved in long QT syndrome.

Mutations in the KCNQ1 gene, which encodes the voltage-gated potassium channel K_V7.1 have been implicated in cardiac arrhythmias, such as long QT syndrome 1 (LQT1), and epilepsy. Similarly, mutations in KCNH2 (linked to LQT2), SCN5A (LQT3), KCNJ2 (LQT7), and CACNA1C (LQT8) have been reported in cases of sudden death and may contribute to both cardiac and epileptic phenotypes. Other ion channel genes implicated in both epilepsy and SUDEP include SCN1A, SCN1B, SCN2A, and SCN8A, which encode subunits of voltage-gated sodium channels, as well as KCNA1, which encodes a voltage-gated potassium channel.

While the exact mechanisms of SUDEP are not fully understood, most evidence supports a cascade of physiological disturbances, often triggered by a generalized tonic–clonic seizure (GTCS) and culminating in respiratory and cardiac failure. In many cases, death results from failure of the brainstem to reestablish breathing and cardiac rhythm after a seizure. Contributing factors include central respiratory depression, cardiac arrhythmias, autonomic dysregulation, and — in some individuals — genetic susceptibility.

In monitored SUDEP cases, a typical sequence often follows a generalized tonic–clonic seizure: an initial increase in breathing and heart rate (tachypnea and tachycardia) is followed by central apnea, progressive bradycardia, and eventual asystole. In observed cases, respiratory arrest precedes cardiac arrest, consistent with a model of primary neurogenic respiratory failure. This cascade typically progresses over 3 to 15 minutes following seizure termination, often during sleep or unwitnessed nocturnal seizures. Although external factors such as prone positioning may contribute, the predominant mechanism appears to be centrally mediated collapse in the postictal state—a process sometimes termed early postictal neurovegetative breakdown.

Central respiratory dysfunction appears to play a primary role in many SUDEP cases. Transient apnea often occurs during generalized tonic–clonic seizures, but in most cases, breathing resumes spontaneously after the seizure. In SUDEP, this recovery fails, leading to sustained respiratory arrest. Observational studies consistently show that respiratory arrest precedes cardiac arrest, implicating central respiratory failure as the initiating event. This failure appears to result from seizure-related suppression of brainstem respiratory centers. Recent studies suggest that spread of seizure activity to paralimbic structures, such as the amygdala, can induce central apnea. Experimental stimulation of these regions has been shown to trigger apnea without conscious awareness.

Seizure-related cardiac abnormalities, including ictal arrhythmias, have been implicated in some cases of SUDEP. Ictal asystole — defined as seizure-related cessation of cardiac activity — is rare but well-documented, particularly in individuals with temporal lobe epilepsy. However, most seizure-related arrhythmias are transient and self-limiting.

While arrhythmias can occur during seizures, most evidence suggests that in SUDEP, cardiac arrest typically results from respiratory failure. In monitored cases, including those from the MORTEMUS study, bradycardia and asystole consistently followed the onset of postictal apnea; no cases showed cardiac arrest preceding respiratory arrest. This pattern supports a neurogenic origin for SUDEP, with respiratory failure triggering secondary cardiac arrest rather than a primary cardiac event.

Dysfunction of central and autonomic nervous system pathways may contribute to SUDEP by impairing the regulation of breathing, cardiac rhythm, and arousal. The brainstem plays a key integrative role in coordinating these functions, and seizure-related disruption of its regulatory circuits is believed to underlie many fatal cases.

OnOne proposed marker of cerebral dysfunction is postictal generalized EEG suppression (PGES), a transient period of low-amplitude activity on electroencephalography following a generalized seizure. PGES has been interpreted as evidence of widespread cortical shutdown and impaired arousal. Although PGES occurs in both fatal and nonfatal seizures, prolonged duration has been associated in some studies with postictal immobility and respiratory dysfunction. However, its predictive value remains uncertain, and it is not considered a consistent marker of SUDEP risk.

Seizure-related impairment of autonomic reflexes—particularly those involving baroreflex sensitivity, vagal tone, and chemoreceptor responses to elevated levels of carbon dioxide — may further hinder the restoration of homeostasis in the postictal period.

Prevention strategies for sudden unexpected death in epilepsy (SUDEP) primarily focus on reducing seizure frequency, particularly tonic-clonic seizures, which are the most consistently identified modifiable risk factor. Adherence to antiseizure medications, avoidance of known triggers, and timely optimization of treatment are central to risk reduction. Individuals with drug-resistant epilepsy may benefit from referral for surgical evaluation or adjunctive therapies, including neuromodulation.

Nocturnal supervision may also reduce SUDEP risk, particularly in individuals who experience seizures during sleep. Strategies such as sharing a bedroom, using listening devices, or considering alternative living arrangements may improve safety in selected cases. However, these approaches may not be feasible in all settings, particularly for adults living independently.

The prone position following a tonic-clonic seizure has been documented in a majority of SUDEP cases. This observation has drawn parallels to sudden infant death syndrome (SIDS), where public health campaigns encouraging supine sleep have been associated with reduced mortality. Similar recommendations have been proposed for epilepsy, though it remains unclear whether advising initial sleep position effectively reduces SUDEP risk.

Early intervention during postictal cardiorespiratory arrest may be lifesaving in some cases. In the MORTEMUS study, patients who received resuscitative efforts within three minutes of seizure-related cardiac arrest survived, whereas delayed intervention was associated with fatal outcomes. Although tools such as seizure detection devices and antisuffocation pillows have been proposed, their effectiveness likely depends on the presence of someone able to intervene promptly.

Counseling individuals with epilepsy and their caregivers about SUDEP risk and prevention is recommended in several clinical guidelines. The American Academy of Neurology and the National Institute for Health and Care Excellence advise that patients be informed of SUDEP risk as part of routine epilepsy care. Shared decision-making and individualized discussions may improve awareness and support the adoption of preventive strategies.

The risk of SUDEP is estimated to be approximately 20 times higher than in the general population. It is the most common cause of epilepsy-related mortality, especially among individuals with uncontrolled seizures. Overall risk is estimated at roughly 1 per 1,000 person, but the risk increases substantially in those with frequent tonic-clonic seizures.

In the United States, the annual incidence is approximately 1.16 cases per 1,000 adults with epilepsy. Comparisons with other causes of sudden death emphasize the elevated risk in epilepsy. For instance, the incidence of sudden cardiac death in individuals aged 1 to 35 years has been reported at 1.9 per 100,000 person-years, while sudden infant death syndrome (SIDS) occurs in approximately 1 in 2,000 infants in high-income countries.

SUDEP is estimated to account for between 8% and 17% of all deaths in people with epilepsy. Among young adults with epilepsy, the risk of sudden death is increased by a factor of 20 to 40 compared to the general population. Notably, SUDEP is the leading cause of epilepsy-related mortality in individuals with pharmacoresistant (drug-resistant) epilepsy.

In pediatric populations, the long-term risk is also significant. Children with epilepsy have a cumulative SUDEP risk of approximately 7% over a 40-year period. In cases of severe early-onset epilepsies, SUDEP can account for 30% to 50% of all deaths. The annual incidence in this subgroup ranges from 1 in 500 to 1 in 1,000 epilepsy patients.

• Epilepsy
• Seizure types
• Drug-resistant epilepsy
• Status epilepticus
• Sudden cardiac death
• Sudden infant death syndrome
• Postictal state
• Neuromodulation (medicine)

• 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. doi:10.1212/WNL.0000000000003685. PMID 28438841.