Overview of section: current research on causes of SUDEP
[Part 2: Questions; Teran FA, Massey C & Richerson GB]
Sudden unexpected death in epilepsy (SUDEP) has continued to garner much attention in the scientific and clinical fields. Research in the past decade has expanded our understanding of the pathophysiology involved (Massey et al., 2014). In this section of SUDEP: continuing the global conversation, leaders in the field discuss cutting edge research on SUDEP. The unpredictable and often unwitnessed occurrence of SUDEP presents a challenge to investigators and physicians in research studies. Fortunately, clues from witnessed cases, epilepsy monitoring units and data from animal models have provided hints of pathological mechanisms underlying SUDEP. In order to better care for patients with epilepsy and decrease the number of SUDEP cases, physicians and patients need to be familiar with the science behind SUDEP and help guide research that is currently being performed. Articles in this section discuss current research into pathophysiological mechanisms that underlie SUDEP, possible molecular mechanisms that play a role in its cause, and potential approaches to prevent these deaths.
Most SUDEP cases are preceded by a generalized tonic-clonic seizure (GTCS) (Nashef et al., 1998; Ryvlin et al., 2013). However, the mechanisms that lead from seizures to death remain unknown. Among several proposed mechanisms underlying SUDEP, cardiac and respiratory abnormalities have received the most attention in recent years. In particular, recent advances in SUDEP research have indicated that respiratory and arousal deficits may play a role (Massey et al., 2014; Sowers et al., 2013). Analyzing data from monitored human patients has refined our understanding of the final events occurring prior to death. The MORTEMUS study reported that in patients who died of SUDEP while being surveilled in epilepsy monitoring units, cardiac and respiratory dysfunction both preceded death (Ryvlin et al., 2013). Although it was not clear which of the two was the primary cause, terminal apnea always preceded terminal asystole. This was a significant finding in the field that steered research to focus more on seizure-induced changes in respiratory physiology than had previously been the case. For example, recent studies showed that ictal central apnea, or the cessation of breathing during a seizure, is frequently observed in focal epilepsy (Bateman et al., 2008; Lacuey et al., 2018). Similarly, patients with Dravet Syndrome (DS), a severe childhood-onset epilepsy with a high incidence of SUDEP, commonly have ictal and postictal respiratory dysfunction (Kim et al., 2018). This is also seen in a mouse model of DS, in which spontaneous seizures cause death due to respiratory arrest (Kim et al., 2018). Collectively, the existing clinical and experimental evidence makes it reasonable to conclude that changes in respiratory physiology induced by seizures are relevant to SUDEP and that low blood oxygen saturation levels caused by prolonged apnea may comprise a potential biomarker for SUDEP. Although this view has been proposed for some time, this is a major shift from the previous majority, which held that cardiovascular dysfunction was the primary cause of most cases of SUDEP.
Only by fully understanding the underlying causes of SUDEP can effective screening or preventive strategies be developed. Therefore, scientific research into cardiorespiratory and arousal abnormalities during and after seizures is vital to the long term goal of decreasing SUDEP. Articles in this section will detail what is currently known about cardiorespiratory dysfunction and arousal deficits in patients following seizures. They will discuss pertinent animal models that have given the field greater insight into the mechanisms that are involved with these abnormalities. This section will also highlight gene mutations that have been linked to an increased risk of sudden death in both humans and animal models.
Scientific research has included a variety of approaches to understanding the causes of SUDEP, such as the following: 1) Detailed study of individual patients who died of SUDEP, including monitoring that was done at the time of death and genetic testing, 2) Study of patients with epilepsy to examine changes in cardiac and respiratory function after nonfatal seizures, and 3) Examination of the cause of death in animal models of SUDEP. Articles in this section describe data from each of these approaches.
Neurons in the brain send signals to each other via electrical impulses, and neurotransmitters play a critical role in this process. Research has shown there is disruption of neurotransmitter signaling, including serotonin and adenosine, in some sudden death pathologies. For example, multiple defects in the serotonergic system have been identified in sudden infant death syndrome (SIDS) cases. SIDS shares many similarities with SUDEP: SIDS cases are predominantly male and are usually found in the prone position, and it appears to involve failed physiological defense mechanisms that may be related to breathing and sleep. Abnormal adenosine and serotonin signaling have been implicated in the cardiorespiratory and arousal defects that have been observed after seizures in SUDEP and near-SUDEP cases (Boison, 2006; Richerson, 2004; Richerson and Buchanan, 2011). Recent data from people with epilepsy suggest that peripheral serum serotonin levels may play a role in seizure characteristics and recovery (Murugesan et al., 2018). Moreover, accumulating evidence from animal models of SUDEP point to serotonin dysfunction as a potential molecular mechanism due to its major role in the control of breathing (Kinney et al., 2009; Richerson and Buchanan, 2011; Sowers et al., 2013). Notably, recent data suggest that some SIDS cases may be in fact due to unrecognized seizures that led to SUDEP (Kinney et al., 2013; Rodriguez et al., 2012). In support of this, a group recently identified pathophysiological variants in the SCN1A gene, which is implicated in febrile seizures and Dravet Syndrome, in two infants who died of SIDS (Brownstein et al., 2018). The many similarities between the two syndromes reinforce the evidence that serotonin dysfunction may play a role in SUDEP pathophysiology, and suggest that some cases of SIDS may in fact be SUDEP. Articles in this section will discuss data implicating both adenosine and serotonin in cardiorespiratory and/or arousal dysfunction, including research from mouse models. Research into the molecular mechanisms that are likely to cause abnormalities after seizures will be critical in the future, and will allow the field to develop better interventions.
The goal of research into the pathophysiology of SUDEP is to develop therapies that will decrease the number of people that die from SUDEP. Articles in this section will detail current preventive measures that are designed to decrease the occurrence of SUDEP, including compliance with AED treatment and use of surgical treatments to decrease seizure activity.
Articles in this section will also highlight current research into devices, monitors, and alarms that can be used at home to alert family members or caregivers if a patient has a seizure during the night or is experiencing apnea. This section will also discuss more unproven experimental techniques that could be used to decrease SUDEP in the future, such as brain stimulation.
Research into mechanisms of SUDEP is steadily increasing and ongoing research has the potential to make groundbreaking discoveries in coming years. With support from the epilepsy community, governments, scientific societies, advocacy groups and private organizations from around the world, leaders in the field are making great progress. The collaborative atmosphere in SUDEP research and medical care of epilepsy patients brings together scientists, physicians, and patients with epilepsy. This concerted effort to demystify the mechanisms of SUDEP gives great hope that the goal of preventing SUDEP can be achieved.
Frida Teran , Cory Massey  & George Richerson 
 Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
 Department of Neurology, Baylor College of Medicine, Houston, Texas, USA
How to cite:
Teran, FA, Massey C & Richerson GB. Overview of section: current research on causes of SUDEP. In: Hanna J, Panelli R, Jeffs T, editors. Continuing the global conversation [online]. SUDEP Action & SUDEP Aware; 2018 [retrieved day/month/year]. Available from: www.sudepglobalconversation.com.
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.
Boison D. Adenosine kinase, epilepsy and stroke: mechanisms and therapies. Trends Pharmacol Sci 2006;27:652-658.
Brownstein CA, Goldstein RD, Thompson CH, Haynes RL, Giles E, Sheidley B, Bainbridge M, Haas EA, Mena OJ, Lucas J, Schaber B, Holm IA, George AL Jr, Kinney HC, Poduri AH. SCN1A variants associated with sudden infant death syndrome. Epilepsia 2018;59(4):e56-e62.
Kim Y, Bravo E, Thirnbeck CK, Smith-Mellecker LA, Kim SH, Gehlbach BK, Laux LC, Zhou X, Nordli DR Jr, Richerson GB. Severe peri-ictal respiratory dysfunction is common in Dravet syndrome. Journal of Clinical Investigation. 2018; Mar 1;128(3):1141-1153.
Kinney HC, McDonald AG, Minter ME, Berry GT, Poduri A, Goldstein RD. Witnessed sleep-related seizure and sudden unexpected death in infancy: a case report. Forensic Sci Med Pathol 2013;9(3):418-21.
Kinney HC, Richerson GB, Dymecki SM, Darnall RA, Nattie EE. The brainstem and serotonin in the sudden infant death syndrome. Annu Rev Pathol 2009;4:517-50.
Lacuey N, Zonjy B, Hampson JP, Rani MRS, Zaremba A, Sainju RK, Gehlbach BK, Schuele S, Friedman D, Devinsky O, Nei M, Harper RM, Allen L, Diehl B, Millichap JJ, Bateman L, Granner MA, Dragon DN, Richerson GB, Lhatoo SD. The incidence and significance of periictal apnea in epileptic seizures. Epilepsia 2018;Mar;59(3):573-582.
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.
Murugesan A, Rani MRS, Hampson J, Zonjy B, Lacuey N, Faingold CL, Friedman D, Devinsky O, Sainju RK, Schuele S, Diehl B, Nei M, Harper RM, Bateman LM, Richerson G, Lhatoo SD. Serum serotonin levels in patients with epileptic seizures. Epilepsia 2018;Jun;59(6):e91-e97.
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.
Richerson GB. Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci 2004;5(6):449-61.
Richerson GB, Buchanan GF. The serotonin axis: shared mechanisms in seizures, depression, and SUDEP. Epilepsia 2011;52:28-38.
Rodriguez ML, McMillan K, Crandall LA, Minter ME, Grafe MR, Poduri A, Kinney HC. Hippocampal asymmetry and sudden unexpected death in infancy: a case report. Forensic Sci Med Pathol 2012;8(4):441-46.
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.
Sowers LP, Massey CA, Gehlbach BK, Granner MA, Richerson GB. Sudden unexpected death in epilepsy: fatal post-ictal respiratory and arousal mechanisms. Respir Physiol Neurobiol 2013;189:315-23.
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