Diaphragmatic pacing for the prevention of sudden unexpected death in epilepsy

Abstract

Abstract Sudden unexpected death in epilepsy is the leading cause of epilepsy related death. Currently, there are no reliable methods for preventing sudden unexpected death in epilepsy. The precise pathophysiology of sudden unexpected death in epilepsy is unclear; however, convergent lines of evidence suggest that seizure-induced respiratory arrest plays a central role. It is generally agreed that sudden unexpected death in epilepsy could be averted if the patient could be rapidly ventilated following the seizure. The diaphragm is a muscle in the chest which contracts to draw air into the lungs. Diaphragmatic pacing is a surgical intervention which facilitates normal ventilation in situations, such as spinal cord injury and sleep apnoea, in which endogenous respiration would be inadequate or non-existent. In diaphragmatic pacing, electrodes are implanted directly onto diaphragm or adjacent to the phrenic nerves which innervate the diaphragm. These electrodes are then rhythmically stimulated, thereby eliciting contractions of the diaphragm which emulate endogenous breathing. The goal of this study was to test the hypothesis that seizure-induced respiratory arrest and death can be prevented with diaphragmatic pacing. Our approach was to induce respiratory arrest using maximal electroshock seizures in adult, male, C57BL6 mice outfitted with EEG and diaphragmatic electrodes (n = 8 mice). In the experimental group, the diaphragm was stimulated to exogenously induce breathing. In the control group, no stimulation was applied. Breathing and cortical electrographic activity were monitored using whole body plethysmography and EEG, respectively. A majority of the animals that did not receive the diaphragmatic pacing intervention died of seizure-induced respiratory arrest. Conversely, none of the animals that received the diaphragmatic pacing intervention died. Diaphragmatic pacing improved postictal respiratory outcomes (two-way ANOVA, P < 0.001) and reduced the likelyhood of seizure-induced death (Fisher’s exact test, P = 0.026). Unexpectedly, diaphragmatic pacing did not instantly restore breathing during the postictal period, potentially indicating peripheral airway occlusion by laryngospasm. All diaphragmatically paced animals breathed at some point during the pacing stimulation. Two animals took their first breath prior to the onset of pacing and some animals had significant apnoeas after the pacing stimulation. Sudden unexpected death in epilepsy results in more years of potential life lost than any other neurological condition with the exception of stroke. By demonstrating that seizure-induced respiratory arrest can be prevented by transient diaphragmatic pacing in animal models we hope to inform the development of closed-loop systems capable of detecting and preventing sudden unexpected death in epilepsy.