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People with epilepsy have greatly increased probability of premature mortality due to sudden unexpected death in epilepsy (SUDEP). Identifying which patients are most at risk of SUDEP is hindered by a complex genetic etiology, incomplete understanding of the underlying pathophysiology and lack of prognostic biomarkers. Here we evaluated heterozygous  Scn2a  gene deletion ( Scn2a  +/− ) as a protective genetic modifier in the  Kcna1  knockout mouse ( Kcna1  –/– ) model of SUDEP, while searching for biomarkers of SUDEP risk embedded in electroencephalography (EEG) and electrocardiography (ECG) recordings. The human epilepsy gene  Kcna1  encodes voltage-gated Kv1.1 potassium channels that act to dampen neuronal excitability whereas  Scn2a  encodes voltage-gated Nav1.2 sodium channels important for action potential initiation and conduction. SUDEP-prone  Kcna1  –/–  mice with partial genetic ablation of Nav1.2 channels (i.e.  Scn2a  +/– ;  Kcna1  –/– ) exhibited a two-fold increase in survival. Classical analysis of EEG and ECG recordings separately showed significantly decreased seizure durations in  Scn2a  +/– ;  Kcna1  –/–  mice compared with  Kcna1  –/–  mice, without substantial modification of cardiac abnormalities. Novel analysis of the EEG and ECG together revealed a significant reduction in EEG–ECG association in  Kcna1  –/–  mice compared with wild types, which was partially restored in  Scn2a  +/– ;  Kcna1  –/–  mice. The degree of EEG–ECG association was also proportional to the survival rate of mice across genotypes. These results show that  Scn2a  gene deletion acts as protective genetic modifier of SUDEP and suggest measures of brain–heart association as potential indices of SUDEP susceptibility.

Scn2a deletion improves survival and brain–heart dynamics in the Kcna1 -null mouse model of sudden unexpected death in epilepsy (SUDEP)