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  • Review Article
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Cycles in epilepsy

Nature Reviews Neurology volume 17, pages 267–284 (2021)Cite this article

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Abstract

Epilepsy is among the most dynamic disorders in neurology. A canonical view holds that seizures, the characteristic sign of epilepsy, occur at random, but, for centuries, humans have looked for patterns of temporal organization in seizure occurrence. Observations that seizures are cyclical date back to antiquity, but recent technological advances have, for the first time, enabled cycles of seizure occurrence to be quantitatively characterized with direct brain recordings. Chronic recordings of brain activity in humans and in animals have yielded converging evidence for the existence of cycles of epileptic brain activity that operate over diverse timescales: daily (circadian), multi-day (multidien) and yearly (circannual). Here, we review this evidence, synthesizing data from historical observational studies, modern implanted devices, electronic seizure diaries and laboratory-based animal neurophysiology. We discuss advances in our understanding of the mechanistic underpinnings of these cycles and highlight the knowledge gaps that remain. The potential clinical applications of a knowledge of cycles in epilepsy, including seizure forecasting and chronotherapy, are discussed in the context of the emerging concept of seizure risk. In essence, this Review addresses the broad question of why seizures occur when they occur.

Key points

  • Cyclical phenomena have long been described in epilepsy, but tools to quantify them in humans have only recently become available.

  • Chronic recordings of brain activity in rodents, canines and humans have yielded converging evidence that robust cycles in epilepsy exist across species.

  • Cycles of epileptic brain activity exist over multiple timescales, including circadian, multidien and circannual.

  • Critical phases of these cycles help determine periods of highest seizure risk, opening the possibility of forecasting seizures over long horizons.

  • Unanswered questions involve the mechanistic basis of cycles in epilepsy and how to leverage these cycles for clinical applications such as chronotherapy.

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Fig. 1: Circadian seizure cycles.
Fig. 2: Multidien seizure cycles.
Fig. 3: Circannual seizure cycles.
Fig. 4: Deterministic and probabilistic seizure forecasting.
Fig. 5: Probabilistic seizure forecasting in two individuals.

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Acknowledgements

The research of M.O.B. is supported by the Swiss National Science Foundation in the form of an Ambizione grant, number PZ00P3_179929/1, and by the Velux Stiftung, grant #1232. V.R.R. is supported by the Ernest Gallo Foundation Distinguished Professorship in Neurology at the University of California, San Francisco.

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  1. These authors contributed equally: Philippa J. Karoly, Vikram R. Rao and Maxime O. Baud

Authors and Affiliations

  1. Graeme Clark Institute, The University of Melbourne, Melbourne, Victoria, Australia

    Philippa J. Karoly & Mark J. Cook

  2. Department of Neurology, University of California, San Francisco, CA, USA

    Vikram R. Rao

  3. Weill Institute for Neurosciences, University of California, San Francisco, CA, USA

    Vikram R. Rao

  4. Bioelectronics, Neurophysiology and Engineering Laboratory, Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Nicholas M. Gregg & Gregory A. Worrell

  5. Aix Marseille University, Inserm, Institut de Neurosciences des Systèmes, Marseille, France

    Christophe Bernard

  6. Sleep-Wake-Epilepsy Center, Department of Neurology, Inselspital Bern, University Hospital, University of Bern, Bern, Switzerland

    Maxime O. Baud

  7. Center for Experimental Neurology, Department of Neurology, Inselspital Bern, University Hospital, University of Bern, Bern, Switzerland

    Maxime O. Baud

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Contributions

P.J.K., V.R.R., N.M.G., C.B. and M.O.B. researched data for the article, made a substantial contribution to the discussion of content, wrote the article, and reviewed and edited the manuscript before submission. G.A.W. and M.J.C. researched data for the article, made a substantial contribution to discussion of content, and reviewed and edited the manuscript before submission.

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Correspondence to Philippa J. Karoly or Maxime O. Baud.

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Competing interests

V.R.R. has served as a consultant for NeuroPace, Inc., manufacturer of the RNS System, a device used in some of the studies referenced here, but NeuroPace, Inc. did not provide targeted funding for this work. M.O.B. reports personal fees from Wyss Center for Bio- and Neuro-engineering as a part-time employee and grants from Wyss Center for Bio- and Neuro-engineering outside the submitted work. M.O.B. has a pending patent under the Patent Cooperation Treaty (#62665486).

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Glossary

Circadian

Noting or pertaining to biological cycles of ~24 hours that are generated endogenously in the absence of entrainment by an external cue.

Multidien

A recently coined term noting or pertaining to biological cycles that are likely to be generated endogenously with a period of >2 days to several weeks.

Circannual

Noting or pertaining to biological cycles of around 1 year that are likely to be generated endogenously.

Chronic EEG

(cEEG). EEG of long duration (months to years) that requires an implanted device, in contrast to conventional EEG that involves the temporary application of electrodes to the scalp.

Seizure chronotype

One of several discrete temporal patterns based on the observed clustering of seizure occurrence, at particular times or with a particular periodicity, prevalent at the group level in individuals with epilepsy.

Epilepsy colonies

Group housing facilities where people with epilepsy could live and work away from mainstream society, founded in England and elsewhere in the late 1800s owing to the stigma surrounding epilepsy.

Ictogenesis

The mechanisms and dynamics by which the epileptic brain generates seizures.

Epileptogenesis

The processes that lead the brain to become epileptic.

Ultradian

Noting or pertaining to biological cycles with a period of less than 24 hours (that is, a frequency above once per day) that are generated endogenously.

High-frequency oscillations

High-frequency (>80 Hz) interictal waveforms that can be pathological and relate to epilepsy.

Vigilance states

Different states of alertness and responsiveness to the environment. Specifically defined as wakefulness, non-rapid eye movement sleep (NREM sleep, further subdivided into N1–3) and rapid eye movement (REM) sleep.

Zeitgeber

From German, “time giver”; rhythmically occurring external or environmental cue that entrains or synchronizes a biological rhythm.

Seizure risk

Stratification of a seizure likelihood into a number of lower and higher risk states.

Pre-ictal state

Retrospectively defined as the period preceding the onset of seizures, often seconds to minutes long, the real-time detection of which would allow warning of imminent seizures.

Pro-ictal state

Consolidated periods of time when seizures are more likely but not certain.

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Karoly, P.J., Rao, V.R., Gregg, N.M. et al. Cycles in epilepsy. Nat Rev Neurol 17, 267–284 (2021). https://doi.org/10.1038/s41582-021-00464-1

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