Investigation of stress hormones across multiday seizure cycles

It is well established that most people with epilepsy experience cyclical fluctuations in seizure susceptibility. These seizure patterns have been associated with multiday oscillations in cortical excitability and autonomic changes, although the mechanistic drivers of these cycles are not well understood. In this study, we measured stress hormone levels at seizure cycle peaks and troughs (high and low risk, respectively) to investigate stress hormones as a possible co-oscillator with multiday cycles of seizure susceptibility. Thirteen participants with focal epilepsy were recruited for this longitudinal cohort study. Participants reported seizures in an electronic diary for at least 6 months prior to study commencement. Four 3-day salivary sampling periods were scheduled using a cycle forecasting algorithm trained on each participant's historical seizure diary to prospectively identify high- and low-risk periods. Twenty-four saliva samples were collected per person across two predicted high-risk periods and two predicted low-risk periods ('allocated risk'). Saliva samples were analysed for cortisol and dehydroepiandrosterone sulphate (DHEAS) levels. Linear mixed models were fitted to predict stress hormones with fixed effects: multiday seizure cycle (retrospective peak or trough), time of day, allocated risk, perceived stress scale score and pre- and post-sample seizure occurrence. Participants recorded an average of 47 (SD = 62) seizures between their first and final saliva collection (duration: 11.8 ± 8.0 months). Three hundred and twelve saliva samples were collected in total. Cortisol levels were significantly higher in the epilepsy cohort compared to the expected general population. On a group level, cortisol was significantly associated with fixed effects time of day, pre-sample seizure occurrence and multiday seizure cycle, with cortisol levels heightened at multiday cycle peaks compared to troughs, particularly evident in the morning saliva samples. These results provide new insights into cortisol as a possible mechanistic driver or co-oscillator of multiday seizure cycles in people with epilepsy. The novel methodology presented in this work may be used to explore interactions between other biomolecules of interest and multiday seizure cycles.