Molecular signaling pathways underlying sudden unexpected death in epilepsy

Dominique F. Leitner, James D. Mills, Geoffrey Pires, Arline Faustin, Eleanor Drummond, Evgeny Kanshin, Shruti Nayak, Manor Askenazi, Chloe Verducci, Bei Jun Chen, Michael Janitz, Jasper J. Anink, Johannes C. Baayen, Sander Idema, Erwin A. van Vliet, Sasha Devore, Daniel Friedman, Beate Diehl, Catherine Scott, Roland Thijs, Thomas Wisniewski, Beatrix Ueberheide, Maria Thom, Eleonora Aronica, Orrin Devinsky. Proteomics and Transcriptomics of the Hippocampus and Cortex in SUDEP and High-Risk SUDEP Patients. Neurology May 2021, 96 (21) e2639-e2652; DOI: 10.1212/WNL.0000000000011999

Objective To identify the molecular signaling pathways underlying sudden unexpected death in epilepsy (SUDEP) and high-risk SUDEP compared to control patients with epilepsy. 

Methods For proteomics analyses, we evaluated the hippocampus and frontal cortex from microdissected postmortem brain tissue of 12 patients with SUDEP and 14 with non-SUDEP epilepsy. For transcriptomics analyses, we evaluated hippocampus and temporal cortex surgical brain tissue from patients with mesial temporal lobe epilepsy: 6 low-risk and 8 high-risk SUDEP as determined by a short (<50 seconds) or prolonged (≥50 seconds) postictal generalized EEG suppression (PGES) that may indicate severely depressed brain activity impairing respiration, arousal, and protective reflexes. 

Results In autopsy hippocampus and cortex, we observed no proteomic differences between patients with SUDEP and those with non-SUDEP epilepsy, contrasting with our previously reported robust differences between epilepsy and controls without epilepsy. Transcriptomics in hippocampus and cortex from patients with surgical epilepsy segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 long noncoding RNAs, 3 pending) in hippocampus. 

Conclusion The SUDEP proteome and high-risk SUDEP transcriptome were similar to those in other patients with epilepsy in hippocampus and cortex, consistent with diverse epilepsy syndromes and comorbid conditions associated with SUDEP. Studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions, may identify molecular mechanisms of SUDEP.