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SUDEP basic mechanisms: on course to understand, predict, and prevent - Part I: Respiratory dysfunction

[Part 2: Questions; Goldman AM. Part II. Cardiac and autonomic dysfunction]



Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with epilepsy (Tomson et al., 2008) and the risk is not uniformly distributed. While most SUDEP occurs in early adulthood (Thurman et al., 2014), there is now evidence that some epilepsy types maybe put patients at an increased risk (Sillanpaa & Shinnar, 2013) from early age. The epidemiological studies indicate that symptomatic epilepsies and ongoing convulsive seizures pose the most significant risk for premature mortality (Hesdorffer et al., 2011). Yet, even patients with apparent well controlled epilepsy remain at risk (Nashef et al., 1998). Therefore, the future of personalized risk prediction rests in understanding of the underlying SUDEP biology. The clinical and laboratory based research have shown that seizures are frequently associated with cardiac, autonomic or respiratory dysfunction (Massey et al., 2014; Ryvlin et al., 2013). Naturally, most research has been focused in these areas in an effort to understand the underlying biology, define opportunities for preemptive screening, effective intervention, and SUDEP prevention.


Respiratory dysfunction in SUDEP physiology

Seizure-related ictal oxygen desaturation has been observed in epilepsy patients (Bateman et al., 2008) and in SUDEP (Bateman et al., 2010). Animal models have provided important clue with regards to the possible role of serotonin (5-hydroxytryptamine or 5-HT) in respiration, arousal, and ictally-induced apnoea (Massey et al., 2014). Mice deficient in 5-HT2c receptor were noted to develop epileptic seizures and to be susceptible to premature death (Tecott et al., 1995). While the genetically engineered Lmx1bf/f/p mice, almost completely devoid of all 5-HT neurons, suffer from severe apnoea, hypoventilation, diminished hypercapnic response, compromised arousal from sleep, and premature mortality (Hodges et al., 2009). Additionally, this mouse model exhibits lower threshold for maximal electroshock or pilocarpine-induced seizures, as well as an increased seizure-related mortality driven by terminal respiratory failure (Buchanan et al., 2014). Chemical inhibition of 5-HT synthesis in otherwise healthy mice also lowers threshold for seizures induced by maximal electroshock (Buchanan et al., 2014). Another model animal, the DBA/1 and DBA/2 mice do not exhibit spontaneous epilepsy, yet they are prone to audiogenic seizures, ictally-induced respiratory arrest and sudden death (Uteshev et al., 2010). Moreover, the DBA/2 animals have definite alterations in the expression levels of several 5-HT receptors (Uteshev et al., 2010). While there is the translational evidence implicating the 5-HT2c receptor in SUDEP, the role of the remaining 5-HT ligand gated ion channels in epilepsy-related mortality is largely unexplored. Recent genetic analysis of a pediatric SUDEP case suggested a contributory role of the inherited variants in the serotonoergic receptor genes HTR3C and HTR3D (Klassen et al., 2013). Large meta-analysis of patients affected by obstructive sleep apnea (OSA) found that -1438G/A polymorphism in the HT2A receptor gene was a positive risk factor for OSA in males (Wu et al., 2013).


The discoveries of the 5-HT link to SUDEP led to preliminary pharmacological explorations on potentially beneficial effect of the widely-available serotonin reuptake inhibitors (SSRIs) on SUDEP risk (Tupal & Faingold, 2006; Faingold et al., 2011). The experimental studies in the DBA/1 model have shown that exogenous administration of SSRI ameliorated ictally-induced respiratory arrest and death (Faingold et al., 2011). The animal research was subsequently validated in a clinical study in which patients chronically exposed to the SSRIs where were less prone to ictal oxygen desaturation during partial seizures (Bateman et al., 2010). Curiously, there was no definite protective effect of the SSRIs on ventilation in generalized seizures (Bateman et al., 2010). In going back to the DBA model, Faingold et al. found that the effect of SSRIs may be influenced by several factors, such a differential expression of 5-HT receptors, animal age and sex, as well as by differences in the effective dose and potency of individual SSRI preparations (Faingold et al., 2011; Faingold & Randall, 2013; Faingold et al., 2014). We will need carefully designed clinical studies to corroborate this experimental finding with respect to prevention or acute intervention in seizure-induced respiratory compromise. Aside from 5-HT pathways, the PHOX2B gene has emerged as a candidate molecule in respiratory compromise in SUDEP due to the previously described link to the central hypoventilation syndrome (Weese-Mayer et al., 2003) and sudden infant death syndrome (SIDS) (Liebrechts-Akkerman et al., 2014). However, the initial screen of 68 Australian SUDEP cases indicates that detrimental mutations on this gene may not be a common SUDEP risk factor (Bagnall et al., 2014). 


The clinical studies in adults and children indicate that respiratory dysfunction is frequently accompanied by cardiac or autonomic disturbances (Ryvlin et al., 2013; Singh et al., 2013). Serious periictal and interictal arrhythmias have been reported in 10-35% of epilepsy patients (Singh et al., 2013; Bagnall et al., 2014) and ictally-induced cardio-respiratory compromise has emerged as another principal candidate pathogenic SUDEP mechanism in pediatric and adult studies (Ryvlin et al., 2013; Singh et al.; 2013).  This is discussed in SUDEP basic mechanisms: on course to understand, predict and prevent. Part II: Cardiac and autonomic dysfunction.



Alica M Goldman

Assistant Professor, Department of Neurology

Baylor College of Medicine, Texas, USA

Dec 2014



How to cite:

Goldman AM. SUDEP basic mechanisms: on course to understand, predict, and prevent - Part I: Respiratory dysfunction. In: Hanna J, Panelli R, Jeffs T, Chapman D, editors. Continuing the global conversation [online]. SUDEP Action, SUDEP Aware & Epilepsy Australia; 2014 [retrieved day/month/year]. Available from:































Bagnall RD, Crompton DE, Cutmore C, Regan BM, Berkovic SF, Scheffer IE, et al. Genetic analysis of PHOX2B in sudden unexpected death in epilepsy cases. Neurology 2014;83(11):1018-21.

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(10):2211-14. 

Bateman LM, Li CS, Seyal M. Ictal hypoxemia in localization-related epilepsy: analysis of incidence, severity and risk factors. Brain 2008;131(Pt 12):3239-45.

Bateman LM, Spitz M, Seyal M. Ictal hypoventilation contributes to cardiac arrhythmia and SUDEP: report on two deaths in video-EEG-monitored patients. Epilepsia 2010;51(5):916-20.

Buchanan GF. Timing, sleep and respiration in health and disease. Prog Mol Biol Transl Sci 12013;19:191-219.

Faingold CL, Kommajosyula SP, Long X, Plath K, Randall M. Serotonin and sudden death: differential effects of serotonergic drugs on seizure-induced respiratory arrest in DBA/1 mice. Epilepsy Behav 2014;37:198-203.

Faingold CL, Randall M. Effects of age, sex, and sertraline administration on seizure-induced respiratory arrest in the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP). Epilepsy Behav 2013;28:78-82.

Faingold CL, Randall M, Mhaskar Y, Uteshev VV. Differences in serotonin receptor expression in the brainstem may explain the differential ability of a serotonin agonist to block seizure-induced sudden death in DBA/2 vs. DBA/1 mice. Brain Res 2011;1418:104-10.

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 Behav 2011;22:186-190.

Hesdorffer DC, Tomson T, Benn E, Sander JW, Nilsson L, Langan Y, et al. Combined analysis of risk factors for SUDEP. Epilepsia 2011;52(6):1150-59.

Hodges MR, Wehner M, Aungst J, Smith JC, Richerson GB. Transgenic mice lacking serotonin neurons have severe apnea and high mortality during development. J Neurosci 2009;29:10341-49.

Klassen TL, Bomben VC, Patel A, Drabek J, Chen TT, Gu W, et al. High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile. Epilepsia 2014;55(2):e6-12.

Liebrechts-Akkerman G, Liu F, Lao Grueso O, Ooms AHAG, van Duijn K, Vermeulen M, et al. PHOX2B polyalanine repeat length is associated with sudden infant death syndrome and unclassified sudden infant death in the Dutch population. Int J Legal Med 2014;128(4):621-29.

Massey CA, Sowers LP, Dlouhy BJ, Richerson GB. Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention. Nat Rev Neurol 2014;10(5):271-82.

Nashef L, Garner S, Sander JW, Fish DR, Shorvon SD. Circumstances of death in sudden death in epilepsy: interviews of bereaved relatives. J Neurol Neurosurg Psychiatry 1998;64(3):349-52.

Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, Boon P, Crespel A, Dworetzky BA, Høgenhaven H, Lerche H, Maillard L, Malter MP, Marchal C, Murthy JM, Nitsche M, Pataraia E, Rabben T, Rheims S, Sadzot B, Schulze-Bonhage A, Seyal M, So EL, Spitz M, Szucs A, Tan M, Tao JX, Tomson T. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol 2013;12(10):966-77.

Sillanpaa M, Shinnar S. SUDEP and other causes of mortality in childhood-onset epilepsy. Epilepsy Behav 2013;28:249-255.

Singh K, Katz ES, Zarowski M, Loddenkemper T, Llewellyn N, Manganaro S, et al. Cardiopulmonary complications during pediatric seizures: a prelude to understanding SUDEP. Epilepsia 2013;54(6):1083-91.

Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, et al. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 1995;374(6522):542-46.

Thurman DJ, Hesdorffer DC, French JA. Sudden unexpected death in epilepsy: assessing the public health burden. Epilepsia 2014;55:1479-85.

Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 2008;7(11):1021–31.

Tupal S, Faingold CL. Evidence supporting a role of serotonin in modulation of sudden death induced by seizures in DBA/2 mice. Epilepsia 2006;47(1):21-26.

Uteshev VV, Tupal S, Mhaskar Y, Faingold CL. Abnormal serotonin receptor expression in DBA/2 mice associated with susceptibility to sudden death due to respiratory arrest. Epilepsy Res 2010;88:183-88.

Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS, Silvestri JM, Curran ME, et al. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b. Am J Med Genet A.2003;123A:267–78.

Wu Y, Liu HB, Ding M, Liu JN, Zhu XF, Gu JH, et al. Association between the -1438G/A and T102C polymorphisms of 5-HT2A receptor gene and obstructive sleep apnea: a meta-analysis. Molec Biol Reports 2013;40(11):6223-31.

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continuing the global conversation

Sudden Unexpected Death in Epilepsy
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