Multiday Cycles of Heart Rate Modulate Seizure Likelihood at Daily, Weekly and Monthly Timescales: An Observational Cohort Study

Background: Circadian and multiday rhythms are found across many biological systems, including cardiology, endocrinology, neurology and immunology. In people with epilepsy, epileptic brain activity and seizure occurrence have been found to follow circadian, weekly and monthly rhythms. Understanding the relationship between these cycles of brain excitability and other physiological systems can provide new insight into the causes of multiday cycles. The brain-heart link is highly relevant for epilepsy, with implications for seizure prediction, therapy (i.e. vagal nerve stimulation) and mortality (i.e. sudden unexpected death in epilepsy).  Methods: We report the results from a non-interventional, observational cohort study, Tracking Seizure Cycles. This study quantified multiday cycles of heart rate and seizures in human participants (N=26) using wearable smartwatches and mobile seizure diaries over at least two months (M=6.4, SD=4.0). Participants had an epilepsy diagnosis and uncontrolled or partially controlled seizures. Significant cycles in heart rate were detected using a continuous wavelet transform. Significant co-modulation between heart rate cycles and seizure occurrence were measured from the distributions of seizure likelihood with respect to underlying cycle phase (Omnibus test). Weekly trends were also investigated from a retrospective cohort of continuous video-EEG-ECG records of people (N=29) undergoing diagnostic epilepsy monitoring for at least eight days (M=9.7, SD=1.3).  Findings: Heart rate cycles were found in all participants, with circadian (100%), about-weekly (88%) and about-monthly (92%) rhythms being the most prevalent. Seizures were significantly locked onto at least one heart rate cycle in 76% of eligible participants. Seizures occurred preferentially during the rising phase of the heart rate cycles. Significant weekly trends were also verified in 52% of the video-EEG-ECG cohort.  Interpretation: The existence and prevalence of multiday heart rate cycles may have clinical implications for cardiology. Heart rate cycles showed striking similarities to multiday epileptic rhythms and were co-modulated with seizure likelihood. The relationship between heart rate and seizures is relevant for epilepsy therapy, including seizure forecasting. More broadly, understanding the link between multiday cycles in the heart and brain can shed new light on endogenous physiological rhythms in humans. Funding Statement: This research was funded by an NHMRC Investigator Grant 1178220. This research was supported by the Epilepsy Foundation of America's My Seizure Gauge grant. Declaration of Interests: Dr. Brinkmann reports grants from Epilepsy Foundation of America, My Seizure Gauge, during the conduct of the study; other from Cadence Neurosciences, outside the submitted work. Dr. Freestone reports grants from Epilepsy Foundation USA, personal fees and other from Seer Medical, during the conduct of the study; In addition, Dr. Freestone has a patent Methods and Systems of Seizure Forecasting issued. Dr. Nurse reports grants from Epilepsy Foundation of America, grants from MTPConnect, during the conduct of the study; personal fees from Seer Medical, outside the submitted work. Dr. Cook reports personal fees and other from Seer Medical Australia, personal fees and other from Epi Minder, outside the submitted work; In addition, Dr. Cook has a patent Methods and Systems of Seizure Forecasting issued. Dr. Karoly reports grants from National Health and Medical Research Council (NHMRC), during the conduct of the study; other from Seer Medical (Australia), outside the submitted work; In addition, Dr. Karoly has a patent Methods and Systems of Seizure Forecasting issued. The remaining authors have no competing interests to declare. Ethics Approval Statement: The study was approved by the St Vincent’s Hospital Human Research Ethics Committee (HREC 009.19) and first enrolment was in August 2019. All participants provided written informed consent.