Seizures induce obstructive apnea in DBA/2J audiogenic seizure‐prone mice: Lifesaving impact of tracheal implants

Irizarry, Rachel; Sukato, Daniel C.; Kollmar, Richard; Schild, Samuel; Silverman, Joshua B.; Sundaram, Krishnamurthi; Stephenson, Stacy; Stewart, Mark

doi:10.1111/epi.16431

Cited by 19 publications

(27 citation statements)

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“…Data obtained from mouse models of SUDEP support this notion. Death is due to respiratory arrest for the stimulated seizures of Lmx1b f/f/p and DBA/1&2 mice ( Faingold et al, 2010 ; Buchanan et al, 2014 ; Irizarry et al, 2020 ), and the spontaneous seizure-induced deaths in Cacna1a S 218L mice and Scn1a R 1407X , a mouse model of Dravet Syndrome ( Kim et al, 2018 ; Jansen et al, 2019 ; Loonen et al, 2019 ). Breathing dysfunction is also reported for seizures induced under urethane anesthesia using Kcna1 KO , RyR2 R 176Q , Cacna1a S 218L mice, and Sprague-Dawley rats ( Aiba and Noebels, 2015 ; Aiba et al, 2016 ; Loonen et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…Such models include the DBA/1&2, Cacna1a S 218L , Scn1a R 1407X , RyR2 R 176Q , Scn1a KO, and Kcna1 KO mouse models as well as inducible kainic acid and maximal electroshock seizure models. These approaches have fueled various hypotheses concerning the mechanisms of SUDEP, including brainstem spreading depolarization ( Aiba and Noebels, 2015 ; Aiba et al, 2016 ; Jansen et al, 2019 ; Loonen et al, 2019 ), autonomic dysregulation and cardiac arrhythmias ( Glasscock et al, 2010 ; Auerbach et al, 2013 ; Kalume et al, 2013 ), and respiratory arrest due to central ( Faingold et al, 2010 ; Buchanan et al, 2014 ; Kim et al, 2018 ; Kruse et al, 2019 ), or obstructive apnea ( Nakase et al, 2016 ; Villiere et al, 2017 ; Irizarry et al, 2020 ). Of these models, only the Dravet Syndrome models (i.e., Scn1a R 1407X and Scn1a KO ) directly represent a patient population that is susceptible to SUDEP ( Escayg and Goldin, 2010 ; Kim et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy

et al. 2021

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Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death amongst patients whose seizures are not adequately controlled by current therapies. Patients with SCN8A encephalopathy have an elevated risk for SUDEP. While transgenic mouse models have provided insight into the molecular mechanisms of SCN8A encephalopathy etiology, our understanding of seizure-induced death has been hampered by the inability to reliably trigger both seizures and seizure-induced death in these mice. Here, we demonstrate that mice harboring an Scn8a allele with the patient-derived mutation N1768D (D/+) are susceptible to audiogenic seizures and seizure-induced death. In adult D/+ mice, audiogenic seizures are non-fatal and have nearly identical behavioral, electrographical, and cardiorespiratory characteristics as spontaneous seizures. In contrast, at postnatal days 20–21, D/+ mice exhibit the same seizure behavior, but have a significantly higher incidence of seizure-induced death following an audiogenic seizure. Seizure-induced death was prevented by either stimulating breathing via mechanical ventilation or by acute activation of adrenergic receptors. Conversely, in adult D/+ mice inhibition of adrenergic receptors converted normally non-fatal audiogenic seizures into fatal seizures. Taken together, our studies show that in our novel audiogenic seizure-induced death model adrenergic receptor activation is necessary and sufficient for recovery of breathing and prevention of seizure-induced death.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy

et al. 2021

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“…The absence of “stress” during amygdala-evoked apnea and the minimal oxygen desaturation is consistent with spontaneous ictal central apnea events having resemblance to the diving response. Mouse deaths from audiogenic seizures have been suspected to involve central apnea or respiratory arrest due to brainstem disruption, particularly brainstem circuits involving serotonergic neurons ( 27 , 29 , 32 , 59 – 64 ), but we showed deaths to include obstructive apnea leading to respiratory arrest ( 65 ).…”

Section: Introduction: Physiological Background and Key Conceptsmentioning

confidence: 71%

“…The second was extensive work with invasive and non-invasive monitoring in rodents that showed how OA occurs during seizures, how OA serves as the link between a seizure and respiratory arrest (RA), and how non-invasive measures can be used to interpret human data. Demonstrations that ictal OA can be due to laryngospasm ( 34 ), that inspiratory effort can be detected with EMG ( 45 ) or inductance plethysmography ( 73 ), and even that a surrogate airway protects against death in a widely-studied mouse model of SUDEP ( 65 ) collectively argue that OA is part of a common mechanism for SUDEP. These data permit events associated with a seizure to be defined as causes or effects.…”

Section: Proposed Sudep Mechanism Accounts For Causes and Effectsmentioning

confidence: 99%

Causes and Effects Contributing to Sudden Death in Epilepsy and the Rationale for Prevention and Intervention

et al. 2020

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Sudden unexpected death in epilepsy (SUDEP) claims the lives of one in every thousand epileptic patients each year. Autonomic, cardiac, and respiratory pieces to a mechanistic puzzle have not yet been completely assembled. We propose a single sequence of causes and effects that unifies disparate and competitive concepts into a single algorithm centered on ictal obstructive apnea. Based on detailed animal studies that are sometimes impossible in humans, and striking parallels with a growing body of clinical examples, this framework (1) accounts for the autonomic, cardiac, and respiratory data to date by showing the causal relationships between specific elements, and (2) highlights specific kinds of data that can be used to precisely classify various patient outcomes. The framework also justifies a "near miss" designation to be applied to any cases with evidence of obstructive apnea even, and perhaps especially, in individuals that do not require resuscitation. Lastly, the rationale for preventative oxygen therapy is demonstrated. With better mechanistic understanding of SUDEP, we suggest changes for detection and classification to increase survival rates and improve risk stratification.

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“…Curated cases with detailed records from multiple epilepsy centers were used to demonstrate a sequence of events from the end of the seizure consisting of “terminal” apnea, bradycardia, and asystole. Other work in rats and mice showed that seizure-associated laryngospasm could cause obstructive apnea that may persist to the point of respiratory arrest ( 13 – 15 ). The linkage between preclinical and clinical data was formed by EMG evidence of inspiratory attempts and specific changes in cardiac rhythm ( 14 , 16 , 17 ) [see also Supplemental Data in Ryvlin et al ( 10 )].…”

Section: Introductionmentioning

confidence: 99%

Proposed Mechanism-Based Risk Stratification and Algorithm to Prevent Sudden Death in Epilepsy

et al. 2021

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Sudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of death in young adults with uncontrolled seizures. First aid guidance to prevent SUDEP, though, has not been previously published because the rarity of monitored cases has made the underlying mechanism difficult to define. This starkly contrasts with the first aid guidelines for sudden cardiac arrest that have been developed based on retrospective studies and expert consensus and the discussion of resuscitation challenges in various American Heart Association certificate courses. However, an increasing amount of evidence from documented SUDEP cases and near misses and from animal models points to a consistent sequence of events that starts with sudden airway occlusion and suggests a mechanistic basis for enhancing seizure first aid. In monitored cases, this sudden airway occlusion associated with seizure activity can be accurately inferred from inductance plethysmography or (depending on recording bandwidth) from electromyographic (EMG) bursts that are associated with inspiratory attempts appearing on the electroencephalogram (EEG) or the electrocardiogram (ECG). In an emergency setting or outside a hospital, seizure first aid can be improved by (1) keeping a lookout for sudden changes in airway status during a seizure, (2) distinguishing thoracic and abdominal movements during attempts to inspire from effective breathing, (3) applying a simple maneuver, the laryngospasm notch maneuver, that may help with airway management when aggressive airway management is unavailable, (4) providing oxygen early as a preventative step to reduce the risk of death, and (5) performing cardiopulmonary resuscitation before the limited post-ictal window of opportunity closes. We propose that these additions to first aid protocols can limit progression of any potential SUDEP case and prevent death. Risk stratification can be improved by recognition of airway occlusion, attendant hypoxia, and need for resuscitation.

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Seizures induce obstructive apnea in DBA/2J audiogenic seizure‐prone mice: Lifesaving impact of tracheal implants

Cited by 19 publications

References 19 publications

Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy

Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy

Causes and Effects Contributing to Sudden Death in Epilepsy and the Rationale for Prevention and Intervention

Proposed Mechanism-Based Risk Stratification and Algorithm to Prevent Sudden Death in Epilepsy

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