Abstracts

Rationale: Respiratory derangements, including irregular, tachypnic breathing and central or obstructive apnea can be consequences of seizure activity.  Periods of seizure-associated central apnea suggest that seizures spread to brainstem respiratory regions to disrupt breathing.  Recently, we showed that seizure-associated central apnea episodes are associated with (1) a reset of the respiratory rhythm, and (2) activation of brainstem regions serving the diving reflex to suppress respiratory behavior (Villiere et al., Neurobiol. Dis.  2017; 101:8-15).             Using a rat model, we demonstrated a sequence of events ending in death that begins with obstructive apnea caused by seizure-induced laryngospasm (Nakase et al., Epilepsy Res. 2016; 128:126-139) and we argued that this sequence is the core of the mechanism for sudden death in epilepsy (SUDEP).  We sought to determine if patterns of central apnea behavior (duration and/or frequency of occurrence) correlated with, and might therefore predict, the tendency for obstructive apnea to occur.   Methods: In a total sample of 12 rats, at least 1 episode of central apnea (≥ 3 seconds in duration) was detected in 6/12 rats and obstructive apnea was detected in 7/12 rats. Results: Obstructive apnea occurred in 1/7 rats without any prior episodes of central apnea.  The presence of at least 1 episode, ≥ 2 episodes, or ≥ 3 episodes of central apnea did not predict the animals that would experience obstructive apnea (Fisher exact test, p=1, 1, 1).  There were not statistically significant differences in central apneic episode duration (two-tailed t-test, p=0.5, t=0.6962, df=7) or number of recorded episodes (p=0.7, t=0.3445, df=7; crude frequency p=0.7, t=0.3864, df=7) in animals that eventually showed obstructive apnea compared with animals that never showed obstructive apnea. Apneic episodes that were early in a period of seizure activity, however, were, on average, significantly shorter than later episodes (average of first 3 episodes vs average of later episodes: two-tailed t-test, p=0.0202, t=2.362, df=96; shown in top figure as means ± SEM; F test to compare variances: p < 0.0001, F=17.05, DFn=59, DFd=37).  There was also a clear positive correlation of the average apneic episode duration with the number of apneic episodes recorded (R2=0.54; p=0.025) and their crude frequency of occurrence (events/min of recording; R2=0.58, p=0.017; bottom figure shows data plus linear regression).  Conclusions: Whereas the occurrence, frequency, or duration of central apneic episodes do not seem to be individual predictors of eventual obstructive apnea, the correlation of central apneic episode duration with (1) episode frequency and (2) whether events are early or late in a seizure suggests that central apneic episodes may reflect an attempt by brainstem networks to protect core physiology.  A deeper understanding of seizure spread into brainstem regions will be necessary to (1) conclude whether central apneic episodes are driven by seizure activity or a response to seizure activity and (2) may permit additional biomarkers (see e.g. Stewart et. al., Epilepsia 2017 in press doi:10.1111/epi.13765) to be established for identifying risk of severe systemic consequences of epileptic seizures. Funding: Philanthropic contributions supported all work.Villiere was supported by NIH RISE grant to CUNY Medgar Evers College