Mortality in children with epilepsy is significantly higher than the general population [1]; although, most deaths in children with epilepsy are not related to seizures or epilepsy [2]. The higher risk is explained by several factors: respiratory illness with underlying neurological condition that presents with seizures, systemic comorbidities, indirect factors as well as deaths presumably or demonstrably due to seizures. Sudden unexpected death in epilepsy (SUDEP), which belongs to the last group, has gained prominence as a cause of death in epilepsy in recent years.

DEFINITION

SUDEP is defined as a “sudden unexpected witnessed or unwitnessed, non-traumatic, non-drowning death in a patient with epilepsy with or without evidence of a seizure and excluding documented status epilepticus in which post-mortem examination does not reveal a toxicological or anatomical cause of death [3].’’ This definition requires a postmortem examination to diagnose SUDEP, which is not available in the majority of instances. Hence, criteria have been described for definite, probable and possible SUDEP [4] (Box I).

BURDEN

The incidence rates of SUDEP in children have been reported to be 0.36-0.43 per 1000 person-years [5-7]. Although SUDEP rates have been reported to be lower in children compared to adults, the American Academy of Neurology (AAN) practice guidelines on SUDEP established the incidence rate of SUDEP in children with epilepsy to be 0.22/1000 patient–years (95% CI 0.16-0.31) after a systematic review of 12 class I studies [8]. Due to imprecision in incidence data results, random-effect meta-analysis was further performed. SUDEP was found to affect 1 in 4,500 children with epilepsy in one year, making the risk of SUDEP rare.

Risk Predictors

There are very few studies assessing risk factors in childhood SUDEP and most of the data is derived from larger studies in adults.

•   The presence and frequency of generalized tonic-clonic seizures (GTCS) is an important risk predictor for SUDEP [8].

•   The relative risk of SUDEP is 7.7 times higher in patients with onset of epilepsy between 0-15 years compared to onset after the age of 45 years [9].

•   All-cause mortality, including SUDEP, is also higher in children with developmental delay [10].

•   Children with uncontrolled seizures have a higher risk [11].

•   SUDEP has also been shown to increase with the duration and severity of seizures, with 15-fold risk with more than 50 GTCS per year, nocturnal seizures and the occurrence of GTCS [12], as well as prolonged tonic state leading to post-ictal immobility [13].

•   Postictal generalized EEG suppression beyond 50 seconds also may have a predictive role in SUDEP and is associated with sleep, shorter duration of clonic phase, symmetric tonic extension posturing and terminal burst-suppression after a seizure [14].

•   Symptomatic epilepsy has a higher risk of SUDEP compared to idiopathic generalized epilepsy.  Patients with Dravet syndrome are also at a higher risk of death [15].

SUDEP shares certain features with the syndrome of sudden infant death (SIDS), suggesting possible common mechanisms. SIDS is sudden and unexpected death that occurs in infants below the age of one year. Both SIDS and SUDEP are diagnoses of exclusion, and autopsy findings are usually not revelatory. Deficiency in arousal response to rise in carbon dioxide in both syndromes may contribute to death, suggesting that these two entities may lie on a continuum [16].

PATHOPHYSIOLOGY

The pathophysiology of SUDEP is not well elucidated and is believed to arise from an interaction between predisposing factors and triggers. Predisposing factors include effects of long-standing seizure disorder such as altered autonomic function, etiology of epilepsy (e.g. symptomatic, familial), factors related to drug therapy such as abrupt withdrawal or polypharmacy etc. A triggering seizure leads to preterminal events including cardiac, respiratory, autonomic and cerebral dysfunction. The various mechanisms (Fig. 1) include the following:

Cardiac dysfunction: Sudden cardiac arrest is a proposed mechanism with certain ion channel abnormalities being implicated in both epilepsy and cardiac arrhythmia. The most widely implicated is the sodium channel abnor-mality, which may also explain the higher rates of SUDEP in Dravet syndrome [17]. Another link is the association between long QT syndrome and familial epilepsies, both of which are channelopathies.

Fig. 1 Various pathophysiological mechanisms leading to sudden unexpected death in epilepsy (SUDEP).

Respiratory dysfunction: Severe peri-ictal hypoxia occurs in one-fourth of patients with SUDEP [17]. Autopsy changes of pulmonary edema have also been observed in SUDEP cases, but this is likely an effect than a cause of SUDEP.

Autonomic dysfunction: Various autonomic abnor-malities have been described in patients with refractory epilepsy and include lower parasympathetic and higher sympathetic tone, increased vasomotor tone and impaired heart rate variability [18]. Changes in ictal heart rate also suggest autonomic dysfunction, with tachycardia occur-ring in up to 60% of seizures and bradycardia in 6% of focal seizures [17,19]. As per the Mortality in epilepsy monitoring units study (MORTEMUS), an initiative that assessed cases of SUDEP and near-SUDEP in patients admitted for video-EEG monitoring, post-ictal centrally mediated cardiac and respiratory depression associated with post-ictal generalized EEG suppression was a strong mechanism leading to SUDEP [20]. The switch from parasympathetic to sympathetic state, combined with sympathetic over-drive that accompanies the state of drug withdrawal that accompany seizures may be a possible precipitant.

Channelopathies: Channelopathies are disorders characterised by dysfunction of ion channels. Traditio-nally channelopathies have been considered genetic defects eg., long QT syndrome and Dravet syndrome. In inherited channelopathies, the same ion channel abnormalities are expressed in the heart as well as the brain. Hence, these epilepsies are associated with an arrythmia-prone cardiac condition.

Recently, there is an emerging concept of acquired channelopathy i.e., channel dysfunction in patients with chronic epilepsy. Animal studies have shown that epilepsy alters the expression of sodium, potassium, calcium and cationic channels in the heart. In these acquired cardiac channelopathies, epilepsy increases the pro-arrhythmic state increasing predisposition to sudden death [21].

Cerebral dysfunction: SUDEP occurs more often in sleep and almost all cases are nocturnal and associated with the prone position. Various neurotransmitter abnormalities have been reported in association with SUDEP including low serotonin state [22] and excessive opioid [23] and adenosine activity. Brainstem serotonin modulates respiratory drive and has also been implicated in sudden infant death syndrome [24]. It may contribute to SUDEP by a similar mechanism.

INTERVENTIONS FOR PREVENTION

As uncontrolled epilepsy is a known risk factor, effective epilepsy treatment to reduce frequency and duration of seizures as well as GTCS should be targeted. Nocturnal supervision was found to be protective in one case-control study [25] and may be combined with seizure detection devices, but clinching evidence in SUDEP prevention is lacking. It is of potential benefit in children with uncontrolled or nocturnal seizures. In India, nocturnal supervision of children is generally culturally acceptable as co-sleeping of children with their parents is common. A blanket ‘back to sleep’ advice to avoid prone positioning may be recommended, with the caveat that it is the post-ictal turning prone which is usually responsible. Hence parents should be counseled to turn the child to a lateral position and avoid prone position after the seizure. The use of lattice or safety pillows may reduce the contribution of prone position to post-ictal cardiorespiratory distress.

In terms of preventive drug therapy, it has been observed in mouse models of SUDEP that selective serotonin reuptake inhibitors (SSRI) such as fluoxetine may decrease apnea risk [26]. Serotonergic neurons in the brainstem are believed to be responsive to rise in CO2 and fall in pH levels in the blood and thereby stimulate respiration and arousal. In a retrospective study on adults with focal seizures [27], it was noted that patients on SSRIs (for co-morbid mental health problems) had a reduced likelihood of post-ictal oxygen desaturation as compared to patients who were not on SSRIs. Recently, two randomized controlled trials have been completed to evaluate the role of fluoxetine to prevent post-seizure apneas and desaturation; however, the results have not been published yet. Massive release of endogenous opioids and adenosine is induced by seizures and helps in seizure termination [28]. However, this surge can also lead to post-ictal apnea. Naloxone is currently under a randomized trial for this purpose. Adenosine antagonists may also be beneficial for this purpose.

These therapies; however, are still in the emerging phase and currently being tried in adults. More evidence is needed before the data can be extrapolated to children.

Parental Counseling

Counseling of caregivers and sensitization towards SUDEP is imperative. Caretakers should be educated regarding the importance of adherence to treatment, nocturnal supervision, especially to avoid prone position after seizures, as well as basic life support training imparted to willing caregivers. However, whether all patients with epilepsy should be counseled about the risk of SUDEP or only high-risk patients remains a matter of debate, and scientific data till date does not permit the establishment of evidence-based guidelines for the same. However, disclosure of SUDEP risk to all epilepsy patients has been endorsed by multiple neurological societies, including a joint task force of the American Epilepsy Society and the Epilepsy Foundation and the American Academy of Neurology (AAN) [29], and in India by the joint consensus document on parental counseling by Association of Child Neurology (AOCN) and Indian Epilepsy Society (IES) [30]. In a study on parental views regarding the counseling of SUDEP risk, parents generally expressed a preference for receiving routine SUDEP counseling at the time of the diagnosis of epilepsy [31]. In another study from Malaysia (32% of participants were of Indian origin), 70.9% of parents felt that receiving SUDEP information was positive [32]. Most parents did not report any impact on their own functioning. However, increasing numbers over time reported an impact on the child’s functioning. In a study from UK, 74% of pediatric neurologists conveyed SUDEP information to a select group of patients only. In contrast, 94% of parents of children with epilepsy expected the physician to provide SUDEP information [33].

In India, many neurologists and pediatricians feel that imparting the knowledge of SUDEP may increase parental anxiety and stress levels, which may be unwarranted as the complication is so rare. However, it is also known that many parents are afraid their child would die when they witness the child having a seizure for the first time. The information that the risk of death is very low may be reassuring. Also, the knowledge of this condition may improve drug compliance, as seen in studies from outside India. In an Indian study of SUDEP counseling of adults with epilepsy and their caregivers, it was shown to increase drug adherence without any increase in anxiety or stress levels in either the patients or their caregivers [34]. More experience is needed in this field to understand parental perceptions and reactions.

CONCLUSION

SUDEP is an under-recognized but important threat in patients with epilepsy. It is important to assess SUDEP risk in all epilepsy patients, particularly in those with generalized tonic-clonic convulsions, nocturnal seizures, as well as co-morbid developmental delay. Appropriate antiepileptic drug therapy with stress on compliance, early surgical referral for surgically remediable epilepsies, avoiding post-seizure prone positioning, and caretaker counseling and support will go a long way in the prevention of this condition.

Contributors: DG performed the literature review and wrote the first draft which was critically revised by SS. Both authors approved the final version of the submitted manuscript.

Funding: None; Competing interest: None stated.

REFERENCES

1. Appleton R. Mortality in paediatric epilepsy. Arch Dis Child. 2003;1091-4.

2. Gaitatzis A, Johnson AL, Chadwick DW, Shorvon SD, Sander JW. Life expectancy in people with newly diagnosed epilepsy. Brain. 2004;127:2427-32.

3. Nashef L. Sudden unexpected death in epilepsy: Terminology and definitions. Epilepsia. 1997;38:S6-8.

4. Nashef L, E. So P. Ryvlin T. Tomson. Unifying the definitions of sudden unexpected death in epilepsy. Epilepsia. 2012;53:227-33.

5. Sillanpää M, Shinnar S. Long-term mortality in childhood-onset epilepsy. N Engl J Med. 2010;363:2522-9.

6. Weber P, Bubl R, Blauenstein U, Tillmann BU, Lütschg J. Sudden unexplained death in children with epilepsy: A cohort study with an eighteen-year follow-up. Acta Paediatr. 2005;94:564-7.

7. Sillanpää M, Shinnar S. SUDEP and other causes of mortality in childhood-onset epilepsy. Epilepsy Behav. 2013;28:249-55.

8. Harden C, Tomson T, Gloss D, Buchhalter J, Cross JH, Donner E, et al. Practice Guideline Summary: Sudden Unexpected Death in Epilepsy Incidence Rates and Risk Factors. Report of the Guideline Development, Dissemi-nation, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2017;88:1674-80.

9. Berg AT, Nickels K, Wirrell EC, Geerts AT, Callenbach PM, Arts WF, et al. Mortality risks in new-onset childhood epilepsy. Pediatrics. 2013;132:124-31.

10. Shinnar S, Pellock JM. Update on the epidemiology and prognosis of pediatric epilepsy. J Child Neurol. 2002; 17: S4-S17.

11. Nickels KC, Grossardt BR, Wirrell EC. Epilepsy-related mortality is low in children: A 30-year population-based study in Olmsted County, MN. Epilepsia. 2012;53:2164-71.

12. Hesdorffer DC, Tomson T, Benn E, Sander JW, Nilsson L, Langan Y, et al. Combined analysis of risk factors for SUDEP. Epilepsia. 2011;52:1150-9.

13. Tao JX, Yung I, Lee A, Rose S, Jacobsen J, Ebersole JS. Tonic phase of a generalized convulsive seizure is an independent predictor of postictal generalized EEG suppression. Epilepsia. 2013;54:858-65.

14. Lamberts RJ, Gaitatzis A, Sander JW, Elger CE, Surges R, Thijs RD. Postictal generalized EEG suppression: An inconsistent finding in people with multiple seizures. Neurology. 2013; 81:1252-6.

15. Skluzacek JV, Watts KP, Parsy O, Wical B, Camfield P. Dravet syndrome and parent associations: The IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia. 2011;52:95-101.

16. Buchanan GF. Impaired CO2-induced arousal in SIDS and SUDEP. Trend Neurosci. 2019:42:242-50.

17. Moseley BD, Wirrell EC, Nickels K, Johnson JN, Ackerman MJ, Britton J. Electrocardiographic and oximetric changes during partial complex and generalized seizures. Epilepsy Res. 2011;95:237-45.

18. Mukherjee S, Tripathi M, Chandra PS, Yadav R, Choudhary N, Sagar R, et al. Cardiovascular autonomic functions in well-controlled and intractable partial epilepsies. Epilepsy Res. 2009;85:261-9.

19. Zijlmans M, Flanagan D, Gotman J. Heart rate changes and ECG abnormalities during epileptic seizures: Prevalence and definition of an objective clinical sign. Epilepsia. 2002;43:847-54.

20. Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, et al. Incidence and mechanisms of cardio-respiratory arrests in epilepsy monitoring units (MORTEMUS): A retrospective study. Lancet Neurol.  2013;12:966-77.

21. Li MCH, O’Brien TJ,Todaro M, Powell KL. Acquired cardiac channelopathies in epilepsy: Evidence, mechanisms and clinical significance. Epilepsia. 2019:60: 1753-67.

22. Toczek MT, Carson RE, Lang L, Ma Y, Spanaki MV, Der MG, et al. PET imaging of 5HT1A receptor binding in patients with temporal lobe epilepsy. Neurology. 2003;60:749-56.

23. Tortella FC, Long JB, Holaday JW. Endogenous opiate systems: Physiological role in the self-limitation of seizures. Brain Res. 1985;332:174-8.

24. Paterson DS, Trachtenberg FL, Thompson EG, Belliveau RA, Beggs AH, Darnall R, et al. Multiple serotonergic abnormalities in sudden infant death syndrome. JAMA. 2006;296:254-32.

25. Langan Y, Nashef L, Sander JW. Case-control study of SUDEP. Neurology. 2005;64;1131-3.

26. 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 Beh. 2011;22:186-90.

27. Bateman LM, Li CS, Lin TC, Seyal M. Serotonin reuptake inhibitors are associated with reduced severity of ictal hypoxemia in medically refractory partial epilepsy. Epilepsia. 2010;51:2211-4.

28. Volpicelli JR, Alterman AI, Hayashida M, O’Brien CP. Naltrexone in the treatment of alcohol dependence. Arch Gen Psych. 1992;49:876-80.

29. Maguire MJ, Jackson CF, Marson AG, Nolan SJ. Treatments for the prevention of sudden unexpected death in epilepsy (SUDEP). Cochrane Database Syst Rev. 2016;7:CD011792.

30. Srivastava K, Sehgal R, Konanki R, Jain R, Sharma S, Mittal R. Association of Child Neurology-Indian Epilepsy Society Consensus Document on Parental Counseling of Children with Epilepsy. Indian J Pediatr. 2019;86:608-16.

31. Ramachandrannair R, Jack SM, Meaney BF, Ronen GM. SUDEP: What do parents want to know? Epilepsy Beh. 2013;29:560-4.

32. Fong CY, Lim WK, Kong AN, Lua PL, Ong LC. Provision of sudden unexpected death in epilepsy (SUDEP) information among Malaysian parents of children with epilepsy. Epilepsy Behav. 2017;75:6-12.

33. Gayatri NA, Morrall MC, Jain V, Kashyape P, Pysden K, Ferrie C. Parental beliefs regarding the provision and content of written sudden unexpected death in epilepsy (SUDEP) information. Epilepsia. 2010;51:777-82.

34. Radhakrishnan DM, Ramanujam B, Srivastava P, Dash D, Tripathi M. Effect of providing sudden unexpected death in epilepsy (SUDEP) information to persons with epilepsy (PWE) and their caregivers experience from a tertiary care hospital. Acta Neurol Scand.  2018;138:417-24.