Abstracts

Rationale: The MORTality in Epilepsy Monitoring Unit Study (MORTEMUS) identified a consistent sequence of events in epilepsy patients beginning with a generalized tonic clonic seizure and ending in death [Ryvlin et al., Lancet Neurol. 12:966, 2013]. Ten cases were used to establish that the end of the seizure was followed within minutes by terminal apnea and ultimately cardiac arrest. Using a rat model that permits simultaneous autonomic, cardiovascular, and respiratory monitoring, we demonstrated that seizure-induced laryngospasm caused obstructive apnea, which stopped the seizure and persisted until respiratory arrest, followed by cardiac arrest [Nakase et al., under review]. Methods: The MORTEMUS study used artifacts in EEG recordings as evidence of respiration. A critical finding in our experiments was that attempts to breathe during obstruction generated artifacts in EEG and ECG recordings that resembled artifacts associated with actual breaths [Figure; also Nakase et al.]. Results: We propose that the electrical artifacts of attempts to inspire during airway obstruction can be used as a practical biomarker of obstructive apnea. In the figure, we show artifacts related to respiration on ECG and EEG recordings (panels A and B). Highpass filtered artifact size was highly correlated with peak inspiratory pressure (r2=0.85; n=14 animals). The size of the artifact itself cannot discriminate between effective breaths and attempts to breathe. The specific biomarker is the upward trend in artifact size as a marker for increasing effort during airway obstruction. Bradyarrhythmia is present in most patients [Ryvlin et al.] and animals [Nakase et al.; Hotta et al. Epilepsia 50: 923, 2009]. Our data show an abrupt change in RR interval variability (SDNN; panels C, D) and that the normal lengthening of the RR interval during inspiration could be reversed during the late occlusion period (panels C, E). This pattern represents a second biomarker for airway obstruction, even with short time samples. Abnormally short RR intervals associated with inspiration occurred in no animals at baseline, 4/16 animals during early occlusion, and 15/16 late. Conclusions: These biomarkers can be applied to past cases and used to monitor patients to improve outcomes. Legend: Demonstration of inspiration associated artifacts and changes in RR interval length during obstruction as biomarkers for obstructive apnea. A. Artifacts enhanced in EEG and ECG by highpass filtering. Arrows indicate last breath attempt. B. Correlations of ECG and EEG artifacts with peak inspiratory pressure (PIP). C. Plot of RR over time (black), PIP during obstruction (blue) and PIP peak markers (red). RR variance increases late in the occlusion. Relative minima in RR intervals are ONLY shorter than baseline during extreme inspiratory effort. Arrows point to the artifact or RR plot minimum for the breath just before a missed breath. Heavy black line at the bottom of the graph is the time shown in the inset. D. Standard deviation of the RR intervals (n=16 animals). E. Plots of RR intervals as function of the time relative to the PIP (n=16). Fitted curves for baseline and onset use right ordinate. Note the reverse relation of RR to inspiratory peak. Funding: Philanthropic contributions