Chronoepileptology: Mapping the Rhythms of Seizure Risk

Abstract

Seizure occurrence in epilepsy is governed by biological rhythms, challenging the traditional view of seizures as random events. Circadian and multidien cycles shape seizure risk, with patient-specific chronotypes and stable temporal patterns observed across epilepsy types. The Molecular Oscillations and Rhythmicity of Epilepsy hypothesis posits that molecular oscillations—particularly those involving core clock genes and region-specific protein expression—create dynamic windows of increased seizure susceptibility. In epilepsy, these rhythms are altered, amplifying seizure risk through metabolic and genetic reorganization. Seizure timing is also modulated by hormonal cycles in women with catamenial epilepsy. Estrogen promotes seizures, while progesterone and its metabolite allopregnanolone are protective. Three distinct catamenial patterns guide diagnosis and treatment, though evidence for hormonal therapies remains limited. Personalized approaches, including adjunctive medications and cycle-specific dosing, may reduce seizure burden. Importantly, sudden unexpected death in epilepsy predominantly occurs at night, implicating sleep, circadian timing, and environmental factors. Nocturnal vulnerability is conserved across species, suggesting a biological mechanism potentially involving serotonin, which regulates respiration, cardiac function, and arousal. Finally, chronotherapeutic approaches offer a promising avenue for epilepsy management by aligning treatment with seizure timing. Time-adjusted dosing of antiseizure medications has shown improved outcomes in patients with predictable seizure patterns. Future strategies may include closed-loop systems and biomarker-guided interventions to shift seizure susceptibility rhythms. Together, these findings underscore the importance of temporal biology in epilepsy. Understanding when seizures occur provides insight into why they occur, paving the way for personalized, rhythm-informed care that enhances prediction, prevention, and treatment.

Circadian and Multidien Rhythms Shape Seizure Risk

The apparent randomness of seizure occurrence has long challenged our understanding of epilepsy. However, emerging evidence reveals that seizures follow predictable temporal patterns operating across multiple timescales, fundamentally reshaping our conceptualization of epilepsy from a disorder of unpredictable events to one governed by biological rhythms.^1–3 This chronobiological perspective offers profound implications for seizure prediction, therapeutic timing, and our mechanistic understanding of epilepsy. ^{1 4–9}

Pervasive Temporal Patterns in Seizure Occurrence

Recent analyses of long-term electroencephalographic recordings demonstrate that most patients exhibit circadian seizure cycles, with distinct chronotypes emerging based on preferred timing.^10–12 These patterns manifest as morning, afternoon, evening, early night, or late-night preferences, often specific to individual patients but usually stable over years. The circadian influence on seizure timing varies by epilepsy type and seizure focus: temporal lobe seizures frequently show bimodal patterns with afternoon and evening peaks, while frontal lobe seizures predominantly occur nocturnally.^13–15

Beyond circadian rhythms, multidien (multiday) cycles represent an equally important yet underappreciated dimension of seizure timing. Again, most patients display multidien seizure cycles with periodicities ranging from a few days to months. These longer rhythms show remarkable stability within individuals over months to years, yet vary considerably between patients. ¹² Crucially, seizures tend to occur preferentially during the rising phase of these multidien cycles, providing a mechanistic framework for understanding seizure clustering and the long-range temporal dependencies observed in epilepsy.^12,15

The strength of multidien modulation equals that of circadian rhythms in many patients, with phase-locking values comparable between the two timescales. This finding underscores that seizure risk prediction requires integration of information across multiple temporal domains, not simply circadian considerations alone. ¹³

Molecular Mechanisms: The Molecular Oscillations and Rhythmicity of Epilepsy Hypothesis

What biological mechanisms could account for these robust temporal patterns in seizure risk? The Molecular Oscillations and Rhythmicity of Epilepsy (MORE) hypothesis provides a mechanistic framework. ⁴ At its core lies the recognition that circadian molecular oscillations are ubiquitous throughout the body, with approximately 43% of protein-coding genes showing circadian rhythmicity across twelve mouse organs. ¹⁶

These molecular oscillations arise from transcriptional–translational feedback loops involving core clock genes (CLOCK, BMAL1, PER, CRY) that generate approximately 24 h cycles in gene and protein expression. ¹⁷ Importantly, the brain displays region-specific patterns of molecular rhythmicity. In the forebrain, two-thirds of synaptic proteins oscillate in a circadian manner.^18,19 In the hippocampus alone, numerous genes and proteins oscillate in a circadian fashion in control mice, with different brain regions exhibiting distinct sets of rhythmic transcripts. ²⁰

The molecular architecture of neural networks thus undergoes continuous remodeling throughout the 24 h cycle. This dynamic landscape may create temporal windows when networks approach seizure threshold through coordinate changes in ion channel expression, neurotransmitter synthesis, metabolic enzyme activity, among many possible mechanisms. The MORE hypothesis proposes that these molecular oscillations provide the necessary conditions for seizure occurrence, though additional factors are required since seizures do not occur at every permissive phase. ⁴

Altered Molecular Dynamics in Epilepsy

In experimental epilepsy, the rules governing molecular rhythmicity are altered: 30% more genes show circadian rhythmicity, but only one-fourth oscillate in both conditions. Notably, core clock genes gain oscillation amplitude in epilepsy, potentially amplifying downstream rhythmic processes. ²⁰ Metabolism illustrates this concept. While control tissue shows enhanced oxidative phosphorylation from morning to afternoon with stable aerobic glycolysis, epileptic tissue demonstrates the opposite pattern: decreased oxidative metabolism and increased glycolysis over the same timeframe. Such metabolic reorganization may contribute to time-dependent changes in seizure susceptibility by altering the energetic state of neural networks.^20,21

The spatial specificity of molecular changes helps explain individual differences in seizure chronotypes. Since different brain regions display distinct sets of oscillating genes, the combination of affected circuits in each patient likely determines their unique seizure timing pattern. This regional specificity also accounts for the observation that seizure chronotypes vary with epilepsy syndrome and seizure focus.

Extending to Multidien Rhythms

While circadian mechanisms are increasingly well understood, the biological basis of multidien rhythms remains largely mysterious. These longer cycles cannot be explained by environmental factors alone, as they persist under controlled laboratory conditions and show patient-specific periodicities that do not align with weekly or monthly calendars.^12,22

The MORE hypothesis can be extended to encompass multidien rhythms by proposing that some molecular oscillators operate on longer timescales, perhaps through slower epigenetic modifications or hormonal cycles. These slower oscillations might modulate the amplitude or phase of circadian rhythms, creating beat frequencies that manifest as multidien patterns in seizure susceptibility. Importantly, a holistic approach may be necessary as heart rate also displays multidien rhythmicity in patients with epilepsy. ⁷

Clinical Implications and Future Directions

Recognition of seizure rhythmicity opens new therapeutic avenues. Chronotherapy—timing drug delivery to biological rhythms and at times of greatest seizure susceptibility—could optimize treatment efficacy while minimizing side effects. Seizure forecasting algorithms incorporating circadian and multidien information show improved predictive performance compared to those relying solely on electrographic features.^6,23

The chronobiology of epilepsy represents a rapidly evolving field with potential for clinical translation. Understanding when seizures occur provides insights into why they occur, revealing the temporal architecture underlying this complex neurological disorder. As we continue mapping the molecular and physiological rhythms that govern seizure risk, we move closer to a future where epilepsy management is precisely timed to each patient's unique chronobiological signature.

Hormonal Cycles and Catamenial Epilepsy

Scientific Premise

One of the oldest temporal seizure patterns documented in the medical literature is catamenial epilepsy, dating back to 1857. ²⁴ Catamenial epilepsy is characterized by seizure patterns that correlate with the menstrual cycle in reproductive-aged adolescents and women with epilepsy (WWE). ²⁵ Animal studies have demonstrated that estrogen is proconvulsant, while progesterone and its metabolite allopregnanolone are generally anticonvulsant.^26–31 Moreover, animal studies suggest that increased seizures immediately before menstrual flow may be due to the withdrawal of progesterone and allopregnanolone. ²⁹ Studies in humans are more sparse, but also support that seizure patterns can be influenced by estrogen and/or progesterone/allopregnanolone blood concentrations during the menstrual cycle.^32–34

Clinical Presentation

Three catamenial patterns have been identified, corresponding to the most commonly used criteria. ³⁵ The first day of menstrual flow is labeled as day 1. The perimenstrual C1 pattern is the most common and is defined as ≥2-fold average daily seizure frequency (ADSF) during days −3 through +3. The periovulatory C2 pattern is defined as ≥2-fold ADSF in days +10 through +15. The C3 pattern occurs during anovulatory cycles and is defined as ≥2-fold ADSF during days +10 of one cycle through day +3 of the next cycle.

The reported prevalence of catamenial epilepsy varies from 10% to 70% of WWE, ²⁵ in part due to differing definitions and epilepsy populations studied. In the landmark paper by Herzog et al, 33% of the WWE with drug-resistant temporal lobe epilepsy met criteria for catamenial epilepsy. ³⁵ A more recent study enrolled WWE with drug resistant epilepsy (DRE) with focal and generalized-onset seizures, and approximately half met criteria for catamenial epilepsy. ³⁶

Treatment Strategies in Catamenial Epilepsy

There has only been one large, multicenter, double-randomized controlled trial for the treatment of catamenial epilepsy. The progesterone treatment trial ³⁷ randomized 294 adult women with drug-resistant focal epilepsy. The treatment arm consisted of adjunctive progesterone lozenges for 3 months, administered as 200 mg three times daily (TID) on days 14 to 25, 100 mg TID on days 26 to 27, and 50 mg TID on day 28, then off. The primary outcome results were negative, with no difference in responder rates between the progesterone and the placebo groups. However, a secondary analysis reported that for women with a C1 pattern ≥3 increase in ADSF during the perimenstrual phase, the exacerbation level was a predictor of response to progesterone. This subset of WWE also demonstrated an inverse correlation between percentage changes in ADSF and allopregnanolone concentrations. ³⁴

Other treatments have focused on suppression of ovulation and cycling of sex steroid hormones, including combined oral contraceptives (preferably on a continuous basis), progestin subdermal implants, gonadotropin-releasing hormone analogs, and depo-medroxyprogesterone acetate injections. Bidirectional drug–drug interactions need to be considered with these approaches. Published evidence for these approaches is scant.^38,39

Other strategies with small studies include (1) using acetazolamide, 250 to 500 mg/day beginning day −7 to −3 until day +1 of the next cycle, ⁴⁰ (2) increasing daily dosage of antiseizure medications (ASM) during the phase with seizure worsening, and (3) adjunctive clobazam, 20 to 30 mg/day for 10 days, beginning 2 days before the increased seizure phase. ⁴¹

Clinical Implications and Future Directions

Diagnosing catamenial epilepsy is challenging and requires seizure and menstrual diaries over multiple cycles, without concurrent hormone use. Progestin-eluting intrauterine device (IUDs) can obscure menstrual patterns, and C3 diagnosis requires confirmation of anovulation. Diagnosis is further complicated in WWE with infrequent seizures, irregular cycles, or during menarche and menopause. Clarifying diagnostic criteria enhances individualized care. Recognizing patterns can be validating for WWE. Clinicians should assess treatment adjustments or adjunctive hormone therapy to reduce seizure burden through personalized care.

Sleep, Circadian Timing, and Sudden Unexpected Death in Epilepsy Vulnerability

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Factors that have been implicated in its etiology include seizure-induced cardiorespiratory dysfunction, seizure-induced arousal deficits, and dysregulation of several neurotransmitter systems. One consistent feature of SUDEP is that it commonly occurs during the night. Several factors may contribute to this phenomenon, include (1) being alone, (2) prone position, (3) sleep–wake regulation, and (4) time of day and/or circadian rhythms. ⁴²

Patients are often alone at night. Early intervention after someone has a seizure can decrease the duration of seizures and postictal oxygen desaturation. Ending up prone after a seizure can be detrimental, leading to airway obstruction and elevations in carbon dioxide levels. The recognition that prone sleeping could be detrimental was the driving force behind the “Back to Sleep” campaign for sudden infant death syndrome (SIDS) in the 1980s and 1990s. This initiative led to a significant reduction in SIDS incidence, although it did not eliminate it entirely, suggesting other factors are still at play.

Sleep and time of day, or circadian rhythms, also have profound effects on many factors related to SUDEP, including seizures themselves, breathing, cardiac function, and sensitivity to stimulus-induced arousal. In the Mortality in Epilepsy Monitoring Units study, 14 of the 16 cases of SUDEP while in the epilepsy monitoring unit occurred at night, and most of these happened during sleep. ⁴³ At least two meta-analyses have determined that most SUDEP occurs at night, probably during sleep.^44,45 Seizure-related death in several animal models occurs more commonly during the night, both when animals are housed in a light–dark cycle^46–48 and in constant darkness which eliminates time cues. ⁴⁹ Interestingly, the predilection for seizure-related death to occur at night is observed in both diurnal humans and nocturnal rodents, suggesting that the underlying causative factor is a conserved mechanism across species. One such possibility is the oscillation in serotonin levels in the brain. ⁴² Serotonin is an attractive candidate given its involvement in all the relevant factors mentioned above, and due to its implicated role in SUDEP and SIDS.^50,51

Chronotherapeutics and Temporal Pharmacology in Epilepsy

Seizures often occur in circadian and 24 h patterns. Specific examples include the occurrence of generalized seizures in the morning after awakening or tonic seizures during the early morning hours, and out of sleep. ⁵² Chronoepileptological evaluation of seizure patterns in the setting of diurnal or nocturnal, circadian, and 24 h patterns may offer additional information for seizure and epilepsy diagnosis, prediction, treatment, and prevention, in particular based on chronobiological processes and internal clocks. ⁵³

A variety of factors relating to circadian excitatory and inhibitory undulation have been evaluated, including central clocks, clock genes, tissue and brain region, and cell-specific circadian factors, as well as external zeitgebers . ⁵⁴ The latter, from the German “time givers,” are external environmental cues that help synchronize an organism's internal circadian rhythms with the 24 h day–night cycle, and include light (the most powerful), temperature, feeding times, and social interactions. While the rhythmic pattern of occurrence of spontaneous seizures may be related to a relationship to the endogenous clock system affecting seizure thresholding, circadian rhythms may be affected by seizures and epilepsy as well, implying that both interact. ⁵⁵ The inclusion of circadian rhythms in seizure detection and prediction, including circadian factors such as seizure timing or monitoring of wearable features, may enhance the sensitivity of seizure detection and prediction algorithms.^56,57

Chronotherapy consists of administering therapeutic interventions at times of the greatest susceptibility, to improve seizure control in patients with seizures that occur in predictable or circadian patterns. Options for treatment entail differential dosing by giving the highest medication doses at times of greatest seizure susceptibility, deploying drug or treatment delivery systems with adjusted or closed-loop treatment schedules, and/or attempting to shift endogenous rhythms for better treatment, that is, through “zeitgebers.” ⁵⁸ Individualized treatment regimens may also reduce side effects. ⁵⁸

Early trials in epilepsy suggest that chronopharmacology may provide improved seizure control compared with conventional treatment in selected patients. A chronotherapeutic dosing schedule of phenytoin and carbamazepine, with the majority of medication administered in the evening, improved seizure control and reduced side effects in diurnally active patients who had not responded to standard dosing regimens. ⁵⁹ In 17 children with nocturnal or early-morning seizures, treatment with higher evening antiseizure medication doses led to seizure freedom in 64.7%. Additionally, 15 out of 17 patients experienced a ≥50% seizure reduction. ⁶⁰ Furthermore, higher evening differential dose of clobazam in patients with night-time and early morning seizures led to a 75% seizure reduction in 27 patients, as compared to 50% seizure reduction in controls. ⁶¹

Future evaluation of chronotherapy—potentially combined with biomarkers beyond seizure occurrence that reflect circadian seizure susceptibility—may enable larger-scale, and potentially even closed-loop implementation of personalized, and even closed-loop, treatment strategies aimed at preventing seizures before they occur. Interventions may also lead to shifting seizure patterns and susceptibility, and ultimately, alternative seizure cycling in some patients that may require careful monitoring. Further evaluations are needed to evaluate chronotherapeutic biomarkers, pathways, and potentially closed-loop interventions.

Conclusion

Epilepsy is increasingly understood as a disorder shaped by temporal biology, with seizure risk modulated by circadian, multidien, and hormonal rhythms. This chronobiological framework challenges traditional notions of seizure unpredictability, opening new avenues for personalized care. From the molecular oscillations proposed in the MORE hypothesis to the clinical manifestations of catamenial epilepsy and the nocturnal vulnerability of SUDEP, time emerges as a critical dimension in epilepsy pathophysiology. Chronotherapeutic strategies, which align treatment with individual seizure timing, offer promising improvements in seizure control and patient outcomes. As research continues to unravel the interplay between biological clocks and neural excitability, integrating temporal dynamics into epilepsy diagnosis, prediction, and treatment may transform clinical practice—ushering in an era of rhythm-informed precision medicine.