Over millennia, humans have tried to unveil the mechanisms behind epileptic seizure cyclicity.¹ Despite patients with epilepsy often experiencing seizures at consistent times of the day, week, month, or year, the reasons for seizure timing are still unclear.¹ The debate on the possible causes of seizure cyclicity has ancient origins, but newly available techniques have shed light on this interesting topic, with important implications for the management of epilepsy.¹

Perception of seizure cyclicity throughout History: From lunar phases to interictal epileptiform activity (IEA)

Cyclicity of seizures was already identified by the Babylonians, who argued that seizure timing might be influenced by the moon phases.¹ The potential correlation between seizure cyclicity and lunar phases was extensively investigated until the late eighteenth century, and even recent cross-sectional studies focused on the influences of the moon on seizure timing.^2-5 However, results from these studies demonstrated weak or no effect, revealing complex patterns of seizures that are unexplainable by the moon’s influence alone. ^2-5 The recent availability of self-management online tools, like diaries for seizure trackers, led to large datasets of self-reported seizures.¹ However, the results obtained with these approaches may be affected by self-selection and reporting bias.¹ Instead, chronic electroencephalography (cEEG) uses newly available instruments, such as intracranial devices, that allow the long-term recordings of seizures and IEA.¹ Today, IEA and seizure electrographic recording provide some of the strongest evidence for seizure cyclicity.¹

Seizure cyclicity manifests over multiple timescales

Seizure cycles can manifest over circadian (daily), multidien (multiple days), and circannual (about one year) timescales.¹ Circadian seizure timing shows a wide variability within individuals, while multidien timing tends to be stable among the general population of patients with epilepsy.¹ Some studies highlighted that IEA phases possibly correlate with multidien seizure cycles, but this correlation becomes weaker in circadian and circannual seizure cycles.^1,6 Circannual cycles have shown a weak correlation with seizure rates, and only play a role in a minority of subjects.¹

Zeitgebers, precipitants and endogenous cycles can affect seizure timing

A “zeitgeber” is an external factor that influences but does not cause biological rhythms.¹ Researchers have identified some putative zeitgebers for several timescales of seizure cyclicity. A common zeitgeber for circadian timescale is the day-night cycle.¹ However, evidence suggests that additional endogenous factors besides the day-night cycle may influence peak seizure times.¹ In multidien seizure cycles, a clear zeitgeber still needs to be confirmed.¹ In terms of the circannual timescale, the main zeitgeber seems to be the revolution of earth around the sun, which affects modulation of the photoperiod.¹ Seizure timing can also be impacted by precipitants, namely factors acknowledged to trigger seizures consistently.¹ Some of the main seizure precipitants identified so far are exogenous factors that influence metabolism and neuronal activity, stress, sleep deprivation, changes in body temperature and, in rare cases, sensory inputs.¹ Seizure cyclicity can also be modulated by endogenous cycles, like the sleep-wake cycle and hormonal cycles.^6,7 Furthermore, metabolism, inflammation, diet and mechanisms underlying neural plasticity also seem to play a role in determining seizure timing.^8-11

Understanding seizure timing might improve epilepsy management

Despite the large number of studies conducted to investigate the mechanisms regulating this cyclicity, many unknowns still remain.¹ Understanding the mechanisms underlying seizure cyclicity can have multiple benefits for the management of epilepsy. For instance, multidien cycles could be leveraged to optimise scheduled admissions to the epilepsy monitoring units, thus potentially improving diagnosis.¹ Moreover, it might allow forecasting seizures days in advance and help tailor seizure prevention strategies.¹ More studies are needed to unveil the mechanisms influencing seizure cycles, and cEEG has been proposed to be the golden standard investigation method.¹

References

1. Rao VR, et al. Epilepsia 2021;62 Suppl 1:S15-s31.
2. Baxendale S, et al. Epilepsy Behav 2008;13:549-50.
3. Benbadis SR, et al. Epilepsy Behav 2004;5:596-7.
4. Barber CF. J Psychiatr Ment Health Nurs 2010;17:274-9.
5. Polychronopoulos P, et al. Neurology 2006;66:1442-3.
6. Borbély AA. Hum Neurobiol 1982;1:195-204.
7. Jozsa R, et al. Biomed Pharmacother 2005;59 Suppl 1:S109-16.
8. Khan S, et al. Lancet Neurol 2018;17:1098-108.
9. Vezzani A, et al. Nat Rev Neurol 2019;15:459-72.
10. Olson CA, et al. Cell 2018;173:1728-41.e13.
11. Jessberger S, et al. Cold Spring Harb Perspect Biol 2015;7.