A path from bench to bedside in sudden death in epilepsy (SUDEP) – an opinion from Mark Stewart

Written by Mark Stewart, State University of New York Downstate Medical Center, NY, USA

Background

Sudden death in epilepsy (SUDEP) has received considerable attention in the last decade, resulting in refinements in the definition (“… a non-traumatic, non-drowning death that occurs in benign circumstances in an individual with epilepsy …”  See e.g. [1,2]), more detailed calculations of incidence (from approximately one to nine deaths per 1000 patient years) [2–4], and the identification of key cardiopulmonary events that contribute to an overall pattern ending with death [3].

A wide range of animal models has been used to explore cardiac and/or respiratory derangements due to or associated with seizure activity that may contribute to an individual’s death (for wide-ranging review: [5]). For example, research employing transgenic mouse models has suggested critical contributions from genetic mutations impacting serotonergic neurotransmission and function in brainstem respiratory centers [2,6–8].

What is known and what is unknown about the circumstances of each human death, however, has been used to raise questions about the appropriateness of particular animal models for the study of SUDEP. As examples, because of data indicating that the majority of deaths occur at night (suggesting a circadian variance in some parameter) and when the individual was in bed (suggesting that, as with some infants, the airway might become obstructed by bedding) (reviewed in [2]), data from animal models not specifically incorporating these details have been dismissed as incomplete. Identification of clear linkages between the animal model and human pathophysiology has not occurred.

Our rat model and data relevant to SUDEP

Our approach to the SUDEP mechanism has been different.  Having used urethane as an anesthetic for work on hippocampal theta rhythm, one of the best studied EEG signals reflecting synchrony in the limbic system [9], we found that seizure activity could be induced under urethane, but remarkably, there were not motor convulsions [10, 11]. This preparation has permitted an extraordinary range of recordings during seizure activity. With a starting view that a seizure that causes death must do so by spreading to autonomic brain regions to ultimately impact cardiovascular or respiratory function, we began by looking for such spread in recordings from autonomic peripheral nerves.

Each seizure was able to increase parasympathetic activity by about 10-fold and sympathetic tone by nearly as much [12]. Although both divisions of the autonomic nervous system showed significant increases in activity, the resulting change in heart rate and rhythm, which could be either brady- or tachy-arrhythmia, depended upon the relative levels in each division and the baseline conditions.

With regard to bradyarrhythmia, extremes would significantly impact cardiac output and the resulting decrease in brain blood flow would terminate any ongoing seizure activity [13,14]. If the seizure was the stimulus for increased vagal tone and bradyarrhythmia, terminating the seizure would end the stimulus and permit a return to baseline conditions. This result suggests that a seizure-induced overdrive of the vagal output to the heart could not be lethal because it would always be self-terminating.

We looked, therefore, at conditions that might favor ventricular fibrillation, a condition that when initiated would be lethal, whether a precipitating seizure continued or not. Briefly, we found that entry into ventricular tachycardia and ventricular fibrillation could occur spontaneously under narrow conditions of moderate – but not severe – hypoxia, sympathetic overdrive and minimal vagal activity [15, 16]. Even small amounts of vagal activity were protective. Most interesting was the finding that repeated seizure activity in rats led to eccentric cardiac hypertrophy (essentially a cardiac dilatation) that actually lowered the already small risk for ventricular fibrillation [17].  Protection by the vagus and the very specific conditions necessary for destabilizing the ventricular conduction pathways suggested that this mechanism was not the most likely.

Most recently, we have explored respiratory consequences of seizure activity with an eye toward the ways in which seizure activity can impact otherwise normal physiology. We found during seizure activity that episodes of central apnea (defined as periods of no airflow and no evidence of respiratory effort) and obstructive apnea (defined as periods of no airflow with evidence of inspiratory effort) can both be observed [18,19], but only the periods of obstructive apnea were associated with severe systemic consequences and death. The basis for the airway obstruction was seizure-induced laryngospasm [18]. This was sufficient to completely prevent airflow and precipitated rapid desaturation, ischemic cardiac rhythm and functional changes, respiratory arrest, cardiac arrest and finally death. Central apneic episodes were associated with small changes in oxygen saturation and were found to result from seizure-triggered activation of the diving reflex (a ‘normal’ response that results from co-activation of both divisions of the autonomic nervous system) [19].

Translation to the bedside

As detailed as our studies have been, how could it be possible to translate results from rats, which are anesthetized and induced to have seizures with a chemical convulsant, to epilepsy patients? The answer came as we were responding to reviews for a manuscript where the reviewer was undoubtedly trying to get us to acknowledge that translating our findings would be impossible. The detailed publication of results from the MORTality in Epilepsy Monitoring Unit Study (MORTEMUS) [3] presented a sequence of events between seizure and death that included the onset of “terminal apnea” followed by cardiac arrest. A supplement to the paper showed raw data from the key cases that led to this overall sequence.

In analyzing our data, we found that during inspiratory attempts against an occluded airway, EMG signals from the effort mixed with the ECG recordings. The MORTEMUS paper interpreted these signals as evidence of actual breathing, and we could show with certainty that these events also reflected effort during airway occlusion and, further, that the amplitude of these signals correlated with the effort [20].

Going forward faster

The challenge for identifying the mechanism of a clinical condition that occurs rarely and under circumstances where physiological data are rarely available is daunting. The availability of a small animal model that can be extensively manipulated and monitored opens a number of doors for accelerating advances in SUDEP research. This or equivalent models can be studied to define the critical window of opportunity for resuscitation, specific resuscitation interventions and approaches that can lead to prevention.

The views expressed in this article are those of the author and do not necessarily reflect those of Neurology Central or Future Science Group.

References

  1. Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in epilepsy. Epilepsia 53(2), 227–233 (2012).
  2. Devinsky O, Hesdorffer DC, Thurman DJ, Lhatoo S, Richerson G. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 15(10), 1075–1088 (2016).
  3. Ryvlin P, Nashef L, Lhatoo SD et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 12(10), 966–977 (2013).
  4. Tomson T, Walczak T, Sillanpaa M, Sander JW. Sudden unexpected death in epilepsy: a review of incidence and risk factors. Epilepsia 46(Suppl. 11), 54–61 (2005).
  5. Lathers CM, Schraeder PL, Leestma JE, Wannamaker BB, Verrier RL, Schachter SC. Sudden unexpected death in epilepsy: mechanisms and new methods for analyzing risks. CRC Press, Taylor & Francis Group, FL, USA (2015).
  6. 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. 189(2), 315–323 (2013).
  7. 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. 37C, 198–203 (2014).
  8. Tupal S, Faingold CL. Evidence supporting a role of serotonin in modulation of sudden death induced by seizures in DBA/2 mice. Epilepsia 47(1), 21–26 (2006).
  9. Stewart M, Fox SE. Do septal neurons pace the hippocampal theta rhythm? Trends Neurosci. 13(5), 163–168 (1990).
  10. Saito T, Sakamoto K, Koizumi K, Stewart M. Repeatable focal seizure suppression: a rat preparation to study consequences of seizure activity based on urethane anesthesia and reversible carotid artery occlusion. J. Neurosci. Methods 155(2), 241–250 (2006).
  11. Stewart M. The urethane/kainate seizure model as a tool to explore physiology and death associated with seizures. In: Sudden death in epilepsy: forensic and clinical issues. Lathers CM, Schraeder PL, Bungo MW, Leetsma JE (Eds).Taylor & Francis Group, FL, USA 627–644 (2011).
  12. Sakamoto K, Saito T, Orman R et al. Autonomic consequences of kainic acid-induced limbic cortical seizures in rats: peripheral autonomic nerve activity, acute cardiovascular changes, and death. Epilepsia 49(6), 982–996 (2008).
  13. Hotta H, Lazar J, Orman R et al. Vagus nerve stimulation-induced bradyarrhythmias in rats. Auton. Neurosci .151(2), 98–105 (2009).
  14. Hotta H, Watanabe N, Orman R, Stewart M. Efferent and afferent vagal actions on cortical blood flow and kainic acid-induced seizure activity in urethane anesthetized rats. Auton. Neurosci. 156(1,2), 144–148 (2010).
  15. Naggar I, Stewart M. A rat model for exploring the contributions of ventricular arrhythmias to sudden death in epilepsy. In: Sudden Unexpected Death in Epilepsy: Mechanisms and New Methods for Analyzing Risks. Lathers CM, Schraeder PL, Leestma JE, Wannamaker BB, Verrier RL, Schachter SC (Eds).Taylor & Francis, London, UK 241–250 (2015).
  16. Naggar I, Uchida S, Kamran H, Lazar J, Stewart M. Autonomic boundary conditions for ventricular fibrillation and their implications for a novel defibrillation technique. J. Physiol. Sci. 62(6), 479–492 (2012).
  17. Naggar I, Lazar J, Kamran H, Orman R, Stewart M. Relation of autonomic and cardiac abnormalities to ventricular fibrillation in a rat model of epilepsy. Epilepsy Res. 108(1), 44–56 (2014).
  18. Nakase K, Kollmar R, Lazar J et al. Laryngospasm, central and obstructive apnea during seizures: Defining pathophysiology for sudden death in a rat model. Epilepsy Res. 128 126–139 (2016).
  19. Villiere SM, Nakase K, Kollmar R, Silverman J, Sundaram K, Stewart M. Seizure-associated central apnea in a rat model: Evidence for resetting the respiratory rhythm and activation of the diving reflex. Neurobiol. Dis. 101, 8–15 (2017).
  20. Stewart M, Kollmar R, Nakase K et al. Practical biomarkers for obstructive apnea in potential sudden death in epilepsy (SUDEP) cases.Presented at: American Epilepsy Society Annual Meeting TX, USA, 2–6 December 2016.