Sleep, night and SUDEP
[Part 2: Questions; Buchanan G, Li R, Petrucci A & Purnell B]
It has been appreciated for quite some time that SUDEP occurs frequently during the night (Lamberts et al., 2012; Ali et al., 2017). While this is a recurrent scenario in the case vignettes presented in this resource, it is perhaps best exemplified by the Mortality in Epilepsy Monitoring Units study (MORTEMUS) in which 16 SUDEP cases that occurred during epilepsy monitoring were evaluated. Fourteen of these cases occurred during the night. Seven of the 10 cases for which sleep/wake state could be determined occurred during sleep (Ryvlin et al., 2013). There are a variety of factors that may contribute to the nighttime predilection of SUDEP, including circumstances associated with being alone, circumstances associated with being in bed, sleep related factors, and time-of-day or circadian related factors.
Circumstances associated with being alone. When SUDEP happens at night, the person is often found deceased after having been alone and unobserved through the night. It has been suggested that reduced supervision and monitoring during the night, and thus, delayed or absent resuscitative efforts, contribute to the day-night distribution of SUDEP. Early reports indicate that SUDEP occurs less frequently when patients with epilepsy live together. Thus if someone had a seizure, another person was there to attend to them and administer a potentially lifesaving intervention thereby reducing SUDEP risk (Nashef et al., 1995). This hypothesis is corroborated by the findings that more rapid intervention reduces the seizure duration and results in a less drastic reduction of oxygen concentration in the blood (Seyal et al., 2013). In the MORTEMUS study, when resuscitation was attempted, SUDEP was averted (Ryvlin et al., 2013). Increasing nocturnal supervision by the use of monitoring devices, regular checks or having someone else sleep in the same room as the patient is currently the best way of reducing nocturnal SUDEP risk (Ryvlin et al., 2006; Langan et al., 2005; Geertsema et al., 2018; van der Lende et al., 2016).
Circumstances associated with being in bed. Not that surprisingly since people spend the night in bed, patients who die of SUDEP are frequently found in bed, face down. A recent meta-analysis reveals that upwards of 80% of SUDEP victims are found face down, often with their nose and mouth in a pillow or blanket (Ali et al., 2017). This could indicate that the airway was blocked following a seizure leading to a failure to exchange the air in the lungs and a fatal inability to oppose falling levels of oxygen and rising levels of carbon dioxide (CO2) in the blood. The rise in CO2 is initially good, as it increases respiratory drive under normal circumstances (Richerson, 2004), and can cause arousal from sleep (Berthon-Jones & Sullivan, 1984; Buchanan & Richerson, 2010; Smith et al., 2018). However, if the airway continues to be obstructed the abnormalities in blood gases will continue until they reach potentially fatal levels. Similar mechanisms have been proposed for the sudden infant death syndrome (SIDS), another sudden death entity that has similarities to SUDEP (Kinney et al., 2009). In SIDS, the “Back to Sleep” campaign wherein babies are placed on their backs to sleep, resulted in a significant reduction in incidence (Hunt and Brouillette, 1987). A similar concept has been proposed for SUDEP (Tao et al., 2015), but it is unclear if this would be helpful given that the body position will likely change if a seizure occurs. Interestingly, one study found that non-fatal seizures are associated with the patient not lying face down (Shmuely et al., 2016).
Seizures during sleep. Seizures can have profound effects on cardiovascular and respiratory function. At present, SUDEP is thought to occur due to seizure induced disruption of breathing and/or cardiac function (Devinsky et al., 2016). Sleep also affects cardiovascular and respiratory function (Snyder et al., 1964; Shea, 1996). Thus, it follows that the combined effects of sleep and seizures on cardiovascular and respiratory function could be particularly detrimental. Indeed, in at least one animal model, seizures induced during sleep have more profound effects on breathing and on suppression of brain electrical activity. Seizures induced during sleep, especially rapid eye movement (REM) sleep, in this model are more likely to be fatal (Hajek and Buchanan, 2016). Even non-fatal seizures induced during non-REM (NREM) sleep suppress breathing to a greater degree than seizures induced during wakefulness. Seizures induced during NREM sleep are also associated with prolonged suppression of EEG activity following the seizure in this model (Hajek & Buchanan, 2016) and in patients in an epilepsy monitoring unit (Peng et al., 2017). EEG suppression may correlate with reduced arousability following the seizure in mice (Petrucci et al., 2018) and duration of respiratory dysfunction in humans (Kuo et al., 2016). The duration of such post-ictal generalized EEG suppression (PGES) has been correlated with an increased risk of SUDEP in at least one study (Lhatoo et al., 2010), but not others (Surges et al., 2011; Kang et al., 2017). Notably, many neurotransmitter systems that have been implicated in SUDEP are modulated in a sleep state-dependent manner and are involved in sleep-wake regulation (Brown et al., 2012; Mitchell and Weinshenker, 2010; Basheer et al., 2004). These include serotonin (Buchanan et al., 2014; Richerson & Buchanan, 2011), norepinephrine (Zhang et al., 2017; Zhao et al., 2017), and adenosine (Shen et al., 2010; Lazarus et al., 2017).
Although seizures induced during REM sleep in the aforementioned animal model are fatal (Hajek & Buchanan, 2016), seizures are generally more likely to occur during NREM sleep than during REM sleep in patients with epilepsy (Ng & Pavlova, 2013) and in many, but not all, animal models of epilepsy (Shouse et al., 2004; Sedigh-Sarvestani et al., 2014b), suggesting an underlying seizure gating mechanism to prevent seizures, and consequently SUDEP. One candidate mechanism for this may involve serotonin. Serotonin modulates both sleep (Monti, 2011) and seizures (Bagdy et al., 2007), and serotonin neurons are essential in CO2-induced arousal (Smith et al., 2018; Buchanan & Richerson, 2010), which may play a critical role in arousal after a seizure. These serotonin neurons project to the hippocampus (Commons, 2016), a key node in the pathogenesis of epilepsy (Huberfeld et al., 2015), and participate in regulation of electrocerebral rhythms during REM sleep (Pignatelli et al., 2012) including those that have been found to have anticonvulsant effect in animal seizure models (Miller et al., 1994).
Seizures during the night. While the fact that SUDEP happens during the night, could speak to effects of sleep, or to being unattended, this could also suggest independent time-of-day, or circadian, influences. Seizures are subject to both sleep-state dependent (Ng & Pavlova, 2013; Sedigh-Sarvestani et al., 2014a) and circadian dependent regulation (Durazzo et al., 2008; Quigg et al., 1998; Loddenkemper et al., 2011). Cardiovascular (Piccione et al., 2005) and respiratory (Buchanan, 2013) function are also regulated in a circadian fashion. Thus, cardiorespiratory changes which occur during the night could increase SUDEP risk independent of sleep state. In the same aforementioned animal model, time-of-day altered the outcomes of seizures both in terms of breathing and EEG suppression (Purnell et al., 2017). In another animal model frequently employed in the study of SUDEP, mortality is heavily influenced by time of day (Moore et al., 2014). Many of the neurotransmitter systems relevant to SUDEP are regulated in a circadian fashion (Poncet et al., 1993; Linsell et al., 1985; Chagoya de Sanchez, 1995). Furthermore, physiological parameters such as Q-T interval and the respiratory response to CO2, which have been implicated in SUDEP etiology, are different during the night (Molnar et al., 1996; Buchanan, 2013; Spengler et al., 2000; Peever & Stephenson, 1997; Bulow, 1963).
We need to better understand how all these factors interact to result in SUDEP. Animal models have been and will continue to be helpful in parsing out the mechanisms of SUDEP. The key to reliably predicting and preventing the occurrence of SUDEP lies in our ability to understand and model SUDEP mechanisms.
Gordon F. Buchanan [1,2], Rui Li [1], Alexandra N. Petrucci [1,2], Benton S. Purnell [1,2]
[1] Department of Neurology & [2] Neuroscience Program
University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA
July 2018
How to cite:
Buchanan G, Li R, Petrucci A & Purnell B. Sleep, night and 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.
References
My daughter Kristen was diagnosed with epilepsy when she was nearly 15 years old. For ten years her epilepsy had been fairly well controlled with medication... That changed when she became pregnant...
Peter had his first epileptic seizure at the age of 14... At no stage were we told that the likelihood of an early death was increased with epilepsy...
Ali A, Wu S, Issa NP, Rose S, Towle VL, Warnke P, Tao JX. Association of sleep with sudden unexpected death in epilepsy. Epilepsy Behav 2017;76:1-6.
Bagdy G, Kecskemeti V, Riba P, Jakus R. Serotonin and epilepsy. J Neurochem 2007;100(4):857-73.
Basheer R, Strecker RE, Thakkar MM, McCarley RW. Adenosine and sleep-wake regulation. Prog Neurobiol 2004;73:379-396.
Berthon-Jones M, Sullivan CE. Ventilation and arousal responses to hypercapnia in normal sleeping humans. J Appl Physiol 1984;57:59-67.
Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of sleep and wakefulness. Physiol Rev 2012;92:1087-1187.
Buchanan GF. Timing, sleep and respiration in health and disease. Prog Mol Biol Transl Sci 12013;19:191-219.
Buchanan GF, Murray NM, Hajek MA, Richerson GB. Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality. Journal Physiol 2014;592(Pt 19):4395-410.
Buchanan GF, Richerson GB. Central serotonin neurons are required for arousal to CO2. Proc Natl Acad Sci USA 2010;107:16354-16359.
Bulow K. Respiration and wakefulness in man. Acta Physiol Scand Suppl 1963;59:1-110.
Chagoya de Sanchez V. Circadian variations of adenosine and of its metabolism. Could adenosine be a molecular oscillator for circadian rhythms? Can J Physiol Pharmacol 1995;73:339-355.
Commons KG. Ascending serotonin neuron diversity under two umbrellas. Brain Struct Funct 2016;221:3347-3360.
Devinsky O, Hesdorffer DC, Thurman DJ, Lhatoo S, Richerson G. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol 2016;15:1075-1088.
Durazzo TS, Spencer SS, Duckrow RB, Novotny EJ, Spencer DD, Zaveri HP. Temporal distributions of seizure occurrence from various epileptogenic regions. Neurology 2008;70:1265-1271.
Geertsema EE, Thijs RD, Gutter T, Vledder B, Arends JB, Leijten FS, Visser GH, Kalitzin SN. Automated video-based detection of nocturnal convulsive seizures in a residential care setting. Epilepsia 2018 Jun;59 Suppl 1:53-60.
Hajek MA, Buchanan GF. Influence of vigilance state on physiologic consequences of seizures and seizure-induced death in mice. J Neurophysiol 2016;115:2286-2293.
Huberfeld G, Blauwblomme T, Miles R. Hippocampus and epilepsy: Findings from human tissues. Rev Neurol (Paris) 2015;171:236-251.
Hunt CE, Brouillette RT. Sudden infant death syndrome: 1987 perspective. J Pediatr 1987;110:669-678.
Kang JY, Rabiei AH, Myint L, Nei M. Equivocal significance of post-ictal generalized EEG suppression as a marker of SUDEP risk. Seizure 2017;48:28-32.
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.
Kuo J, Zhao W, Li CS, Kennedy JD, Seyal M. Postictal immobility and generalized EEG suppression are associated with the severity of respiratory dysfunction. Epilepsia 2016;57:412-417.
Lamberts RJ, Thijs RD, Laffan A, Langan Y, Sander JW. Sudden unexpected death in epilepsy: people with nocturnal seizures may be at highest risk. Epilepsia 2012;53(2):253-57.
Langan Y, Nashef L, Sander JW. Case-control study of SUDEP. Neurology 2005;64(7):1131-33.
Lazarus M, Chen JF, Huang ZL, Urade Y, Fredholm BB. Adenosine and Sleep. Handb Exp Pharmacol 2017 Jun 24.
Lhatoo SD, Faulkner HJ, Dembny K, Trippick K, Johnson C, Bird JM. An electroclinical case-control study of sudden unexpected death in epilepsy. Ann Neurol 2010;68(6):787-96.
Linsell CR, Lightman SL, Mullen PE, Brown MJ, Causon RC. Circadian rhythms of epinephrine and norepinephrine in man. J Clin Endocrinol Metab 1985;60:1210-1215.
Loddenkemper T, Lockley SW, Kaleyias J, Kothare SV. Chronobiology of epilepsy: diagnostic and therapeutic implications of chrono-epileptology. J Clin Neurophysiol 2011;28:146-153.
Miller JW, Turner GM, Gray BC. Anticonvulsant effects of the experimental induction of hippocampal theta activity. Epilepsy Res 1994;18:195-204.
Mitchell HA, Weinshenker D. Good night and good luck: norepinephrine in sleep pharmacology. Biochem Pharmacol 2010;79:801-809.
Molnar J, Zhang F, Weiss J, Ehlert FA, Rosenthal JE. Diurnal pattern of QTc interval: how long is prolonged? Possible relation to circadian triggers of cardiovascular events. J Am Coll Cardiol 1996;27:76-83.
Monti JM. Serotonin control of sleep-wake behavior. Sleep Med Rev 2011 Aug;15(4):269-81.
Moore BM, Jerry JC, Tatalovic M, Kaufman ES, Kline DD, Kunze DL. The Kv1.1 null mouse, a model of sudden unexpected death in epilepsy (SUDEP). Epilepsia 2014;55:1808-1816.
Nashef L, Fish DR, Garner S, Sander JW, Shorvon SD. Sudden death in epilepsy: a study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 1995;36:1187-1194.
Ng M, Pavlova M. Why are seizures rare in rapid eye movement sleep? Review of the frequency of seizures in different sleep stages. Epilepsy Res Treat 2013:932790.
Peever JH, Stephenson R. Day-night differences in the respiratory response to hypercapnia in awake adult rats. Respir Physiol 1997;109:241-248.
Peng W, Danison JL, Seyal M. Postictal generalized EEG suppression and respiratory dysfunction following generalized tonic-clonic seizures in sleep and wakefulness. Epilepsia 2017;58:1409-1414.
Petrucci AN, Joyal KG, Buchanan GF. Effect of dorsal raphe serotonin neuron stimulation on post-ictal EEG suppression and arousal in mice. 2018 (in press)
Piccione G, Grasso F, Giudice E. Circadian rhythm in the cardiovascular system of domestic animals. Res Vet Sci 2005;79:155-160.
Pignatelli M, Beyeler A, Leinekugel X. Neural circuits underlying the generation of theta oscillations. J Physiol Paris 2012;106:81-92.
Poncet L, Denoroy L, Jouvet M. Daily variations in in vivo tryptophan hydroxylation and in the contents of serotonin and 5-hydroxyindoleacetic acid in discrete brain areas of the rat. J Neural Transm Gen Sect 1993;92:137-150.
Purnell BS, Hajek MA, Buchanan GF. Time-of-day influences on respiratory sequelae following maximal electroshock-induced seizures in mice. J Neurophysiol 2017;118:2592-2600.
Quigg M, Straume M, Menaker M, Bertram EH 3rd. Temporal distribution of partial seizures: comparison of an animal model with human partial epilepsy. Ann Neurol 1998;43:748-755.
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.
Ryvlin P, Montavont A, Kahane P. Sudden unexpected death in epilepsy: from mechanisms to prevention. Curr Opin Neurol 2006;19:194-199.
Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol 2013;12(10):966-77.
Sedigh-Sarvestani M, Blumenfeld H, Loddenkemper T, Bateman LM. Seizures and brain regulatory systems: consciousness, sleep, and autonomic systems. J Clin Neurophysiol 2014;32:188-193.
Sedigh-Sarvestani M, Thuku GI, Sunderam S, Parkar A, Weinstein SL, Schiff SJ, Gluckman BJ. Rapid eye movement sleep and hippocampal theta oscillations precede seizure onset in the tetanus toxin model of temporal lobe epilepsy. J Neurosci 2014;34:1105-1114.
Seyal M, Bateman LM, Li CS. Impact of periictal interventions on respiratory dysfunction, postictal EEG suppression, and postictal immobility. Epilepsia 2013;54(2):377-82.
Shea SA. Behavioural and arousal-related influences on breathing in humans. Exp Physiol 1996;81:1-26.
Shen HY, Li T, Boison D. A novel mouse model for sudden unexpected death in epilepsy (SUDEP): role of impaired adenosine clearance. Epilepsia 2010;51(3):465-68.
Shmuely S, Surges R, Sander JW, Thijs RD. Prone sleeping and SUDEP risk: The dynamics of body positions in nonfatal convulsive seizures. Epilepsy Behav 2016;62:176-179.
Shouse MN, Scordato JC, Farber PR. Sleep and arousal mechanisms in experimental epilepsy: epileptic components of NREM and antiepileptic components of REM sleep. Ment Retard Dev Disabil Res Rev 2004;10:117-121.
Smith HR, Leibold NK, Rappoport DA, Ginapp CM, Purnell BS, Bode NM, Alberico SL, Kim YC, Audero E, Gross CT, Buchanan GF. Dorsal raphe serotonin neurons mediate CO2-induced arousal from sleep. J Neurosci 2018;38:1915-1925.
Snyder F, Hobson J, Morrison D, Goldfrank F. Changes in respiration, heart rate, and systolic blood pressure in human sleep. J Appl Physiol 1964;19:417-422.
Spengler CM, Czeisler CA, Shea SA. An endogenous circadian rhythm of respiratory control in humans. J Physiol 2000;526 Pt 3:683-694.
Surges R, Strzelczyk A, Scott CA, Walker MC, Sander JW.Postictal generalized electroencephalographic suppression is associated with generalized seizures. Epilepsy Behav 2011;21:271-274.
Tao JX, Sandra R, Wu S, Ebersole JS. Should the "Back to Sleep" campaign be advocated for SUDEP prevention? Epilepsy Behav 2015;45:79-80.
Van der Lende M, Cox FM, Visser GH, Sander JW, Thijs RD. Value of video monitoring for nocturnal seizure detection in a residential setting. Epilepsia 2016;57:1748-1753.
Zhang H, Zhao H, Feng HJ. Atomoxetine, a norepinephrine reuptake inhibitor, reduces seizure-induced respiratory arrest. Epilepsy Behav 2017;73:6-9.
Zhao H, Cotten JF, Long X, Feng HJ. The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP. Epilepsy Res 2017;137:139-144.