Impaired Interictal CO2 Chemoreception and Seizure-Induced Death Due to Central Apnea in Mice with Mutations of SCN1A and SCN8A: Link to SUDEP
Abstract number :
3.168
Submission category :
3. Neurophysiology / 3F. Animal Studies
Year :
2021
Submission ID :
1825782
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:50 AM
Authors :
Eduardo Bravo, PhD - University of iowa; Brian Dlouhy, MD - Neurosurgeon, neurosurgery, University of iowa; George Richerson, MD, PhD - Neurology chairman, Neurology, University of Iowa; Frida Teran, student - MSTP student, Neurology, University of iowa
Rationale: Scn1aR104X/+ (DS) and Scn8aN1768D/+ mice are both epilepsy models that recapitulate the cascade of events in SUDEP patients. They develop breathing abnormalities after seizures with subsequent fatal apnea, bradycardia, terminal asystole, and death. There is increasing evidence from DS mouse models and Scn8aN1768D/+ mice that the primary mechanism of death is often seizure-induced respiratory arrest. In adult patients with other types of epilepsy, seizure spread into the amygdala coincides with the onset of central apnea with concomitant O2 desaturation. Central apnea can also be elicited in epilepsy patients upon stimulation of the amygdala or hippocampus using depth electrodes. Based on these findings, we hypothesized that the amygdala is a critical node in the anatomical pathway by which seizures in the forebrain influence the brainstem respiratory network. In this work, we show that both mice share mechanisms of ventilatory dysregulation that increase the incidence of SUDEP and the amygdala plays a critical role.
Methods: Baseline breathing, the hypercapnic ventilatory response (HCVR), and the hypoxic ventilatory response (HVR) were assessed using whole-body plethysmography in mice. Mice were instrumented with a headmount with EEG, ECG, and EMG electrodes. After 5 days of recovery, DS mice were connected to a preamplifier and placed in a plethysmography chamber to noninvasively measure breathing and monitor EEG, ECG, and EMG. Seizures were induced in DS mice using a heat lamp to slowly raise body temperature at a rate of 0.5°C every 2 minutes until a seizure occurred with full hindlimb extension and ventilatory arrest, or until 42.5°C was reached.
Results: The baseline (interictal) slope of the HCVR and HVR were significantly lower in D/+ mice (n=8) compared to WT littermates (n=6) by 47% (p = 0.0096) and 31% (p = 0.002), respectively. DS mice did not have any difference in baseline breathing, the HCVR, or HVR compared to WT.
Deaths due to spontaneous and induced seizures were recorded in both mouse models. In each case, central apnea occurred first, followed by cardiac activity persisting for several minutes until terminal asystole. Ventilatory effort accompanied by obstructive apnea has not been observed in either of these mouse models during spontaneous or induced seizures.
In some cases, seizure spread into the amygdala occurred at the same time as ventilatory arrest in both epileptic mouse models.
Conclusions: Our results suggest that interictal and postictal ventilatory abnormalities play a major role in SUDEP in patients with epileptic encephalopathy and may be a biomarker for those at highest risk. The amygdala is a critical component of the neural pathway required for seizures in the forebrain to disrupt brainstem function to cause ventilatory arrest and SUDEP.
Funding: Please list any funding that was received in support of this abstract.: NIH NINDS (U01 NS090414, U01 NS090407, F31 NS110333.
Neurophysiology