Authors :
Presenting Author: Veronica Singh, BS – SUNY Upstate Medical University
Kyle Wagner, BS – SUNY Upstate Medical University
Pranitha Anoor, BS – SUNY Upstate Medical University
Justin Ryan, PhD – SUNY Upstate
David Auerbach, PhD – SUNY Upstate
Rationale:
SUDEP is the leading cause of death in people with epilepsy, yet the mechanisms of SUDEP are not well understood. It is likely a multi-system cascade of cardiac arrythmias, post-ictal generalized EEG suppression (PGES), respiratory failure, and autonomic disturbances. The MORTEMUS study showed that following a generalized tonic-clonic seizure (GTCS), there is a multisystem cascade of cardio-respiratory dysfunction that culminated in SUDEP. Long QT Syndrome Type-2 (LQT2) is a potassium channelopathy caused by loss-of-function KCNH2 gene variants, which is expressed in the heart and brain. KCNH2 variants were detected in DNA analysis from SUDEP cases. We developed a knock-in Kcnh2 mutant rabbit model of LQT2, which reproduces the neuro-cardiac pathologies seen in people with LQT2. These include cardiac QTc prolongation, arrhythmias, seizures, and sudden death (sudden cardiac death & SUDEP). Using our novel model of LQT2, we evaluated the temporal concordance of peri-ictal cerebral-cardiac-respiratory-autonomic changes surrounding non-lethal and lethal drug-induced convulsive seizures.Methods:
We acquired video, EEG, ECG, plethysmography, and capnography recordings from conscious restrained LQT2-mutant and WT rabbits during baseline physiological conditions. We administered 10 incremental doses (1 to 10mg/kg) of pentylenetetrazol (PTZ) every 10 mins in juvenile (1-3 months) and adult ( >6 months) rabbits. We assessed the temporal evolution of peri-ictal EEG, ECG, respiration, and heart rate variability (HRV, autonomic) metrics.
Results:
When assessing the pre- to post-ictal multi-system changes surrounding non-lethal and lethal seizures, both juvenile and adult mutant and WT rabbits demonstrate seizure-induced QTc, JTec, and JTpc shortening (cardiac repolarization metrics) and an increase in time-domain HRV metrics; the cardiac changes are significantly larger in juvenile mutant vs WT rabbits. During the post-ictal period, there are periods of apnea and increased respiratory rate. For the lethal seizures, there is a rapid onset of post-ictal terminal apnea. PGES is more pronounced following lethal vs non-lethal seizures. ECG abnormalities surrounding non-lethal seizures include triggered beats, bundle branch block, ST segment changes, and sinus arrythmias. ECG abnormalities surrounding lethal seizures include 2:1 and 3:1 atrio-ventricular block, polymorphic ventricular tachycardia and ventricular fibrillation. Juvenile mutant vs WT rabbits have reduced freedom from motor seizures (p< 0.05), and adult mutant vs WT rabbits have reduced post-ictal refractoriness from subsequent seizures and reduced threshold for sudden death (p< 0.01).