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Seizure Cycles in Focal Epilepsy

Educational Objective
To establish the prevalence, strength, and temporal patterns of seizure cycles over timescales of hours to years.
1 Credit CME
Key Points

Question  What are the prevalence, strength, and patterns of seizure cycles in focal epilepsy?

Findings  In this cohort study of 222 patients who received an implantable continuous electroencephalographic recording device, the prevalence was 12% of weak circannual seizure cycles, 60% of moderate multidien seizure cycles, and 89% of moderate circadian seizure cycles. Prevalent cycles were further classified into 5 multidien (7, 15, 20, and 30 days and irregular) and 5 circadian (morning, mid-afternoon, evening, early night, and late night) seizure chronotypes.

Meaning  The findings establish the high prevalence of circadian and multidien seizure cycles and reveal the existence of distinct seizure chronotypes in focal epilepsy.


Importance  Focal epilepsy is characterized by the cyclical recurrence of seizures, but, to our knowledge, the prevalence and patterns of seizure cycles are unknown.

Objective  To establish the prevalence, strength, and temporal patterns of seizure cycles over timescales of hours to years.

Design, Setting, and Participants  This retrospective cohort study analyzed data from continuous intracranial electroencephalography (cEEG) and seizure diaries collected between January 19, 2004, and May 18, 2018, with durations up to 10 years. A total of 222 adults with medically refractory focal epilepsy were selected from 256 total participants in a clinical trial of an implanted responsive neurostimulation device. Selection was based on availability of cEEG and/or self-reports of disabling seizures.

Exposures  Antiseizure medications and responsive neurostimulation, based on clinical indications.

Main Outcomes and Measures  Measures involved (1) self-reported daily seizure counts, (2) cEEG-based hourly counts of electrographic seizures, and (3) detections of interictal epileptiform activity (IEA), which fluctuates in daily (circadian) and multiday (multidien) cycles. Outcomes involved descriptive characteristics of cycles of IEA and seizures: (1) prevalence, defined as the percentage of patients with a given type of seizure cycle; (2) strength, defined as the degree of consistency with which seizures occur at certain phases of an underlying cycle, measured as the phase-locking value (PLV); and (3) seizure chronotypes, defined as patterns in seizure timing evident at the group level.

Results  Of the 222 participants, 112 (50%) were male, and the median age was 35 years (range, 18-66 years). The prevalence of circannual (approximately 1 year) seizure cycles was 12% (24 of 194), the prevalence of multidien (approximately weekly to approximately monthly) seizure cycles was 60% (112 of 186), and the prevalence of circadian (approximately 24 hours) seizure cycles was 89% (76 of 85). Strengths of circadian (mean [SD] PLV, 0.34 [0.18]) and multidien (mean [SD] PLV, 0.34 [0.17]) seizure cycles were comparable, whereas circannual seizure cycles were weaker (mean [SD] PLV, 0.17 [0.10]). Across individuals, circadian seizure cycles showed 5 peaks: morning, mid-afternoon, evening, early night, and late night. Multidien cycles of IEA showed peak periodicities centered around 7, 15, 20, and 30 days. Independent of multidien period length, self-reported and electrographic seizures consistently occurred during the days-long rising phase of multidien cycles of IEA.

Conclusions and Relevance  Findings in this large cohort establish the high prevalence of plural seizure cycles and help explain the natural variability in seizure timing. The results have the potential to inform the scheduling of diagnostic studies, the delivery of time-varying therapies, and the design of clinical trials in epilepsy.

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: December 11, 2020.

Published Online: February 8, 2021. doi:10.1001/jamaneurol.2020.5370

Corresponding Author: Maxime O. Baud, MD, PhD, Sleep-Wake-Epilepsy Center, NeuroTec, Center for Experimental Neurology, Department of Neurology, Inselspital Bern, University Hospital, University of Bern, Bern, Switzerland (maxime.baud.neuro@gmail.com); Vikram R. Rao, MD, PhD, Department of Neurology, University of California San Francisco Epilepsy Center, 400 Parnassus Ave, 8th Floor, San Francisco, CA 94143 (vikram.rao@ucsf.edu).

Author Contributions: Drs Rao and Baud had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Rao and Baud are co–senior authors and contributed equally to this work.

Concept and design: Leguia, Andrzejak, Tcheng, Rao, Baud.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Leguia, Andrzejak, Tcheng, Rao, Baud.

Critical revision of the manuscript for important intellectual content: Andrzejak, Rummel, Fan, Mirro, Tcheng, Rao, Baud.

Statistical analysis: Leguia, Andrzejak, Rummel, Fan, Tcheng, Baud.

Obtained funding: Baud.

Administrative, technical, or material support: Mirro, Rao, Baud.

Supervision: Andrzejak, Rao, Baud.

Conflict of Interest Disclosures: Ms Mirro and Dr Tcheng are employees of NeuroPace Inc and report having equity ownership and receiving stock options. Dr Rao reported receiving grants and personal fees from NeuroPace Inc during the conduct of the study. Dr Baud reported receiving grants from Swiss National Foundation for Science, Wyss Center for Bio and Neuroengineering, and Velux Stiftung; personal fees from Wyss Center for Bio and Neuroengineering as a part-time employee during the conduct of the study; and having a patent for a brain monitoring device pending under PCT 62665486. No other disclosures were reported.

Funding/Support: Dr Leguia is supported through a grant for a postdoctoral fellowship from the Wyss Center for Bio and Neuroengineering. Dr Rao is supported by the Ernest Gallo Foundation Distinguished Professorship in Neurology at the University of California, San Francisco. Dr Baud is supported by an Ambizione grant (PZ00P3_179929) from the Swiss National Science Foundation and by a grant from the Velux Stiftung (1232).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The contents do not represent the views of the US Department of Veterans Affairs or the US government.

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