Simultaneous cardiac and respiratory inhibition during seizure precedes death in the DBA/1 audiogenic mouse model of SUDEP

Abstract

This study was designed to evaluate cardiac and respiratory dysfunction in a mouse model of sudden unexpected death in epilepsy i.e., SUDEP. We simultaneously monitored respiration via plethysmography and the electrocardiogram via telemetry before, during, and after an audiogenic seizure. DBA/1 mice responded to an acoustic stimulus with one or two cycles of circling and jumping before entering a clonic/tonic seizure. This was followed by death unless the mice were resuscitated by mechanical ventilation using room air. During the initial clonic phase, respiration declined and cardiac rhythm is slowed. By the tonic phase, respiration had ceased, atrial P-waves were absent or dissociated from the QRS complex, and heart rate had decreased from 771±11 to 252±16 bpm. Heart rate further deteriorated terminating in asystole unless the mice were resuscitated at the end of the tonic phase which resulted in abrupt recovery of P-waves and a return to normal sinus rhythm, associated with gasping. Interestingly, P-waves were preserved in the mice treated with methylatropine during the pre-ictal period (to block parasympathetic stimulation) and heart rate remained unchanged through the end of the tonic phase (765±8 vs. 748±21 bpm), but as in control, methylatropine treated mice died from respiratory arrest. These results demonstrate that a clonic/tonic seizure in the DBA/1 mouse results in abrupt and simultaneous respiratory and cardiac depression. Although death clearly results from respiratory arrest, our results suggest that seizure activates two central nervous system pathways in this model—one inhibits respiratory drive, whereas the other inhibits cardiac function via vagal efferents. The abrupt and simultaneous recovery of both respiration and cardiac function with mechanical ventilation within an early post-ictal timeframe shows that the vagal discharge can be rapidly terminated. Understanding the central mechanism associated with the abrupt cardiorespiratory dysfunction and equally abrupt recovery may provide clues for therapeutic targets for SUDEP.

Recursive model identification for the analysis of cardiovascular autonomic modulation during epileptic seizures

“…Also, our model suggests that transient bradycardia following the seizure-induced tachycardia may be due to a massive vagal activation and a sympathetic withdrawal. This results are in accordance with recent animal experiments in the field suggesting that bradycardia preceding SUDEP is due to a significant vagal discharge [13].…”

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

“…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.…”

Cardiorespiratory findings in epilepsy: A recent review on outcomes and pathophysiology

“…Although cases of SUDEP point to cardiac causes, particularly undiagnosed cardiac channelopathies, the majority appear to be linked to the disruption of certain brain structures associated with autonomic control of the cardiorespiratory function due to epilepsy (Manolis et al., 2019). In a mice model study of SUDEP which was induced by audiogenic seizures, tonic‐clonic seizures had caused sudden and simultaneous respiratory and cardiac depression (Schilling et al., 2019). Although the endpoint death was resulted from respiratory arrest, the study showed that the seizure activity activated two central nervous system pathways in this model, where one of them inhibits the respiratory drive, while the other one inhibits cardiac function through vagal afferents (Schilling et al., 2019).…”