Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in intractable epilepsies, but physiological mechanisms that lead to SUDEP are unknown. Dravet Syndrome (DS) is an infantile-onset intractable epilepsy caused by heterozygous loss-of-function mutations in SCN1A, which encodes Brain Type-I voltage-gated sodium channel NaV 1.1. We studied the mechanism of premature death in Scn1a heterozygous knockout mice and conditional brain- and cardiac-specific knockouts. Because NaV 1.1 channels are expressed in mammalian heart as well as brain, we tested the hypothesis that cardiac dysfunction may cause SUDEP in DS.Methods: Continuous digital videos of mice in their home cages were collected at 30 fps using high resolution, infrared equipped, digital video cameras (Swann Communications, Santa Fe, CA) connected to a Dell PC workstation for data storage. Simultaneous video-electroencephalography-electrocardiography records were collected in conscious mice on a PowerLab 8/35 data acquisition unit using LabChart 7.3.3 software (AD Instruments, Colorado Spring, Co). All bio-electrical signals were acquired at 1 KHz sampling rate. The EEG signals were processed off-line with a 1-80 Hz bandpass filter and the ECG signals with a 3-Hz highpass filter. Results: Video monitoring demonstrated that SUDEP occurred immediately following generalized tonic-clonic seizures. A history of multiple seizures was a strong risk factor for SUDEP. Combined video-EEG-ECG revealed suppressed interictal resting heart-rate variability and episodes of ictal bradycardia associated with the tonic phases of generalized tonic-clonic seizures. Prolonged atropine-sensitive ictal bradycardia preceded SUDEP. Similar studies in conditional knockout mice demonstrated that brain, but not cardiac, knockout of Scn1a produced similar cardiac and SUDEP phenotypes as in DS mice. Atropine or N-methyl scopolamine treatment reduced the incidence of ictal bradycardia and SUDEP in DS mice. Conclusions: These findings suggest that SUDEP in DS mice is caused by apparent parasympathetic hyperactivity immediately following tonic-clonic seizures, which leads to lethal bradycardia and electrical dysfunction of the ventricle. These results have important implications for treatment of SUDEP in DS patients.