Seizure occurrence is linked to multiday cycles in diverse physiological signals

Abstract

Objective
The factors that influence seizure timing are poorly understood, and seizure unpredictability remains a major cause of disability. Work in chronobiology has shown that cyclical physiological phenomena are ubiquitous, with daily and multiday cycles evident in immune, endocrine, metabolic, neurological, and cardiovascular function. Additionally, work with chronic brain recordings has identified that seizure risk is linked to daily and multiday cycles in brain activity. Here, we provide the first characterization of the relationships between the cyclical modulation of a diverse set of physiological signals, brain activity, and seizure timing.

Methods
In this cohort study, fourteen subjects underwent chronic ambulatory monitoring with a multimodal wrist worn sensor (recording heart rate, accelerometry, electrodermal activity, temperature) and an implanted responsive neurostimulation system (recording interictal epileptiform abnormalities (IEA) and electrographic seizures). Wavelet and filter-Hilbert spectral analyses characterized circadian and multiday cycles in brain and wearable recordings. Circular statistics assessed electrographic seizure timing and cycles in physiology.

Results
Ten subjects met inclusion criteria. The mean recording duration was 232 days. Seven subjects had reliable EEG seizure detections (mean 76 seizures). Multiday cycles were present in all wearable device signals across all subjects. Seizure timing was phase locked to multiday cycles in five (temperature), four (heart rate, phasic electrodermal activity), and three (accelerometry, heart rate variability, tonic electrodermal activity) subjects. Notably, after regression of behavioral covariates from heart rate, six of seven subjects had seizure phase locking to the residual heart rate signal.

Significance
Seizure timing is associated with daily and multiday cycles in multiple physiological processes. Chronic multimodal wearable device recordings can situate rare paroxysmal events, like seizures, within a broader chronobiology context of the individual. Wearable devices may advance the understanding of factors that influence seizure risk and enable personalized time-varying approaches to epilepsy care.

Authors

Nicholas M. Gregg, Tal Pal Attia, Mona Nasseri, Boney Joseph, Philippa Karoly, Jie Cui, Rachel E. Stirling, Pedro F. Viana, Thomas J. Richner, Ewan S. Nurse, Andreas Schulze-Bonhage, Mark J. Cook, Gregory A. Worrell, Mark P. Richardson, Dean R. Freestone, and Benjamin H. Brinkmann.