Postictal Death Is Associated with Tonic Phase Apnea in a Mouse Model of Sudden Unexpected Death in Epilepsy

Wenker, Ian C.; Teran, Frida A.; Wengert, Eric R.; Wagley, Pravin K.; Panchal, Payal S.; Blizzard, Elizabeth A.; Saraf, Priyanka; Wagnon, Jacy L.; Goodkin, Howard P.; Meisler, Miriam H.; Richerson, George B.

doi:10.1002/ana.26053

Cited by 27 publications

(53 citation statements)

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“…In the study known as MORTEMUS, in which several patients who died from convulsive seizures had cardiorespiratory recordings, it was observed that bradycardia preceded death (Ryvlin et al, 2013). Bradycardia during and after fatal seizures has also been observed in animal models of epilepsy, including in anesthetized cats (Wasterlain, 1974), and a number of mouse models of epilepsy (Kalume et al, 2013;Aiba and Noebels, 2015;Aiba et al, 2016;Nakase et al, 2016;Kim et al, 2018;Loonen et al, 2019), including mice with Scn8a mutations used in the present study (Frasier et al, 2016;Wengert et al, 2021;Wenker et al, 2021).…”

Section: Introductionmentioning

confidence: 58%

“…The central nervous system exercises significant control of cardiac function via both branches of the ANS: the sympathetic and parasympathetic. Ictal bradycardia has been observed in a number of animal models of epilepsy (Wasterlain, 1974;Doba et al, 1975;Goodman et al, 1990Goodman et al, , 1999Kalume et al, 2013;Aiba and Noebels, 2015;Aiba et al, 2016;Kim et al, 2018;Dhaibar et al, 2019;Loonen et al, 2019;Wengert et al, 2021;Wenker et al, 2021). The use of muscarinic antagonists has demonstrated that this bradycardia is due to activation of the parasympathetic nervous system in anesthetized cats (Doba et al, 1975) and in kindled rats (Goodman et al, 1990(Goodman et al, , 1999.…”

Section: Introductionmentioning

confidence: 99%

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Peri-Ictal Autonomic Control of Cardiac Function and Seizure-Induced Death

et al. 2022

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Sudden unexpected death in epilepsy (SUDEP) accounts for the deaths of 8–17% of patients with epilepsy. Although the mechanisms of SUDEP are unknown, one proposed mechanism is abnormal control of the heart by the autonomic nervous system (ANS). Our objective was to determine whether the broad changes in ictal heart rate experienced by mouse models of SUDEP are (1) due to the ANS and (2) contribute to seizure-induced death. Seizures were induced by electrical stimulation of the hippocampus of a mouse carrying the human SCN8A encephalopathy mutation p.Asn1768Asp (N1768D; “D/+ mice”). Using standard autonomic pharmacology, the relative roles of the parasympathetic and sympathetic nervous systems on heart rate changes associated with seizures were determined. All induced seizures had pronounced ictal bradycardia and postictal tachycardia. Seizure susceptibility or severity were unchanged by the pharmacological agents. Administration of Atropine, a muscarinic antagonist, eliminated ictal bradycardia, while carbachol, a muscarinic agonist, had no effect on ictal bradycardia, but reduced postictal tachycardia. Sotalol, an adrenergic β-receptor antagonist, had no effect on ictal bradycardia, but did suppress postictal tachycardia. Isoproterenol, a β-receptor agonist, had no effect on either ictal bradycardia or postictal tachycardia. Administration of the α1-receptor antagonist prazosin increases the incidence of seizure-induced death in D/+ mice. Although postictal heart rate was lower for these fatal seizures in the presence of prazosin, rates were not as low as that recorded for carbachol treated mice, which all survived. Both ictal bradycardia and postictal tachycardia are manifestations of the ANS. Bradycardia is mediated by a maximal activation of the parasympathetic arm of the ANS, and tachycardia is mediated by parasympathetic inactivation and sympathetic activation. While the changes in heart rate during seizures are profound, suppression of postictal heart rate did not increase seizure mortality.

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Section: Introductionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Peri-Ictal Autonomic Control of Cardiac Function and Seizure-Induced Death

et al. 2022

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“…Comparing the sudden death and long‐lived groups, the authors did not find any significant differences in the arrhythmias produced or malignant rhythm alteration, while marked differences in ventilation were found. 57 , 58 , 59 However, although different studies evidenced that respiratory dysfunction could be the first alteration in SUDEP and precede cardiac involvement, 54 , 55 data are still conflicting, and further research is needed to clarify the physiopathology of SUDEP.…”

Section: Cardiac Changes In Sudepmentioning

confidence: 99%

The brain–heart interaction in epilepsy: implications for diagnosis, therapy, and SUDEP prevention

Costagliola

Orsini

Coll

et al. 2021

Ann Clin Transl Neurol

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The influence of the central nervous system and autonomic system on cardiac activity is being intensively studied, as it contributes to the high rate of cardiologic comorbidities observed in people with epilepsy. Indeed, neuroanatomic connections between the brain and the heart provide links that allow cardiac arrhythmias to occur in response to brain activation, have been shown to produce arrhythmia both experimentally and clinically. Moreover, seizures may induce a variety of transient cardiac effects, which include changes in heart rate, heart rate variability, arrhythmias, asystole, and other ECG abnormalities, and can trigger the development of Takotsubo syndrome. People with epilepsy are at a higher risk of death than the general population, and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Although the cause of SUDEP is still unknown, cardiac abnormalities during and between seizures could play a significant role in its pathogenesis, as highlighted by studies on animal models of SUDEP and registration of SUDEP events. Recently, genetic mutations in genes co-expressed in the heart and brain, which may result in epilepsy and cardiac comorbidity/increased risk for SUDEP, have been described. Recognition and a better understanding of brainheart interactions, together with new advances in sequencing techniques, may provide new insights into future novel therapies and help in the prevention of cardiac dysfunction and sudden death in epileptic individuals.

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“…Current work by Wenker et al 10 delivers an important insight into the mechanisms of ictally-driven apnea and pathophysiology of SUDEP through investigation of a Scn8a genetic model. The authors performed cardiorespiratory monitoring of convulsive seizures and seizure-induced death in established conditional knock-in mice expressing a gain-of-function recurrent pathogenic human variant p.Arg1872Trp in the forebrain.…”

Section: Commentarymentioning

confidence: 99%

“…However, they did not find difference in the PGES magnitude between the fatal and non-fatal tonic seizures. 10 Nevertheless, PGES duration was not evaluated and the relevance of this EEG marker for SUDEP risk in this model remains uncertain.…”

Section: Commentarymentioning

confidence: 99%

When Apnea Turns Terminal: When, How, Why?

Goldman¹

2021

Epilepsy Curr

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Objective: Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of epilepsy that is believed to be due to cardiorespiratory failure immediately after generalized convulsive seizures. Methods: We performed cardiorespiratory monitoring of seizure-induced death in mice carrying either a p.Arg1872Trp or p.Asn1768Asp mutation in a single Scn8a allele-mutations identified from patients who died from SUDEP-and of seizure-induced death in pentylenetetrazole-treated wild-type mice. Results: The primary cause of seizure-induced death for all mice was apnea, as (1) apnea began during a seizure and continued for tens of minutes until terminal asystole, and (2) death was prevented by mechanical ventilation. Fatal seizures always included a tonic phase that was coincident with apnea. This tonic phase apnea was not sufficient to produce death, as it also occurred during many nonfatal seizures; however, all seizures that were fatal had tonic phase apnea. We also made the novel observation that continuous tonic diaphragm contraction occurred during tonic phase apnea, which likely contributes to apnea by preventing exhalation, and this was only fatal when breathing did not resume after the tonic phase ended. Finally, recorded seizures from a patient with developmental epileptic encephalopathy with a previously undocumented SCN8A likely pathogenic variant (p.Leu257Val) revealed similarities to those of the mice, namely, an extended tonic phase that was accompanied by apnea. Interpretation: We conclude that apnea coincident with the tonic phase of a seizure, and subsequent failure to resume breathing, are the determining events that cause seizure-induced death in Scn8a mutant mice.

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Postictal Death Is Associated with Tonic Phase Apnea in a Mouse Model of Sudden Unexpected Death in Epilepsy

Cited by 27 publications

References 46 publications

Peri-Ictal Autonomic Control of Cardiac Function and Seizure-Induced Death

Peri-Ictal Autonomic Control of Cardiac Function and Seizure-Induced Death

The brain–heart interaction in epilepsy: implications for diagnosis, therapy, and SUDEP prevention

When Apnea Turns Terminal: When, How, Why?

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