In animal studies, clear diurnal (ie, 24-hour) seizure patterns in various epilepsy models have been observed. For example, studies in rodents with limbic epilepsy have shown that more spontaneous seizures occurred and seizure latency was shorter under light than during darkness. Quigg and colleagues¹ used continuous electroencephalogram (EEG) recordings to confirm the clock timing of seizures in epileptic rats. The animals were first entrained to a 12-hour/12-hour light-dark cycle then exposed to constant darkness to unmask their free-running circadian rhythmicity. During light-dark exposure, spontaneous limbic seizures occurred nearly twice as often during the light period. Seizures continued to occur in the same pattern during constant darkness after correcting for the core body temperature (CBT) rhythm. These findings show that spontaneous limbic seizures in rats occur in a true endogenously mediated circadian pattern.¹

More than a century ago, Gowers² classified human seizure occurrence into 3 categories: diurnal, nocturnal, and diffuse. Later studies have confirmed and extended his findings. Examples of such are the hypermotor seizures of some frontal lobe epilepsies that occur preferentially during sleep (nocturnal frontal lobe epilepsy), and the myoclonic seizures in juvenile myoclonic epilepsy (JME) that occur most often shortly after awakening in the morning.^3,4

Only a few studies provide detailed information about temporal distribution (clock timing) of seizures over the 24-hour day. One case report based on a seizure diary maintained for 5 years by a subject with 2 epileptic foci showed that temporal and parietal seizures occurred independently from each other in nonrandom daily patterns.⁵ For temporal seizures, a peak incidence was found at 1210 hours, and for parietal seizures the peak was at 0250 hours.

Three retrospective studies used continuous EEG monitoring to confirm the clock timing of seizures.^6–8 Quigg and colleagues⁸ studied the clock timing of seizures in 64 patients with mesial temporal lobe epilepsy (MTLE), 26 with extra–temporal lobe epilepsy (XTLE), and 8 with lesional temporal lobe epilepsy (LTLE). The investigators found that seizures in LTLE and XTLE occur randomly, but seizures in the patients with MTLE had a distinct nonrandom pattern with a peak incidence at approximately 1500 hours. Quigg and colleagues further found that patients with MTLE had a similar circadian cycle of seizures to that observed in a rat model of limbic epilepsy. Pavlova and colleagues⁷ found that nonrandom timing to seizures varied in the patients with TLE and XTLE in 26 patients with epilepsy. The peak incidence was between 1500 and 1900 hours in the patients with TLE, and between 1900 and 2300 hours in those with XTLE.

Hofstra and colleagues⁶ recently evaluated the temporal distribution of 808 clinical seizures in 100 adults and 76 children with partial epilepsies seen in the authors’ tertiary epilepsy center. This study found nonrandom daytime peaks in all types of seizures, with significantly more seizures than expected occurring from 1100 to 1700 hours and fewer seizures from 2300 to 0500 hours. The investigators found clear daytime peak incidences in seizures, especially for extratemporal seizures in children and temporal lobe seizures in adults. Lowest incidences and numbers of seizures, especially complex partial seizures, were seen in the adults between 2300 and 0500 hours, and the children with either tonic, TLE, or XTLE seizures also had significantly fewer seizures in this time period.

Karafin and colleagues⁹ analyzed the circadian timing of seizures in 60 patients with MTLE for 2 to 16 days who had a mean of 11 seizures per patient. Patients showed a bimodal pattern of seizure occurrence, with peak seizure frequencies occurring between 0600 and 0800 hours and between 1500 and 1700 hours. Loddenkemper and colleagues¹⁰ evaluated the diurnal incidence of seizures in 332 consecutive children with lesional focal epilepsy who had inpatient video-EEG monitoring at their institution over a 3-year period. Data were analyzed in relation to clock time, wakefulness/sleep, and seizure localization. Seizures in patients with frontal lesions occurred mostly during sleep (72%). Seizures in mesial temporal (64%), neocortical temporal (71%), and occipital (66%) lesional epilepsy occurred mostly during wakefulness. Temporal lobe seizures occurred more frequently during wakefulness (66%) compared with extratemporal seizures (32%) (odds ratio, 2.7). Temporal lobe seizures peaked between 0900 and 1200 hours as well as from 1500 to 1800 hours, whereas extratemporal seizures peaked between 0600 and 0900 hours. Sleep, not clock time, provides a more robust stimulus for seizure onset, especially for frontal lobe seizures. Temporal lobe seizures are more frequent during wakefulness than are extratemporal seizures.

Two published studies have evaluated the timing of seizures in patients undergoing intracranial EEG monitoring (a gold standard for confirming the location of seizures). Daruzzo and colleagues¹¹ found that seizures from the parietal, occipital, mesial temporal, and neocortical temporal lobes were nonuniformly distributed when they analyzed the timing of 669 seizures of 131 adult patients with different focal epilepsies. Occipital seizures were seen most frequently between 1600 and 1900 hours, whereas parietal and frontal lobe seizures peaked between 0400 and 0700 hours. Two peaks were found in the occurrence of seizures from the mesial temporal lobe (1600–1900 hours and 0700–1000 hours). Seizures from the neocortical temporal lobe also had a peak incidence between 1600 and 1900 hours. Hofstra and colleagues¹² analyzed the temporal distribution of 450 spontaneous seizures in 33 patients with epilepsy who underwent long-term intracranial EEG and video monitoring. The investigators found that seizures showed an uneven distribution over the day, depending on lobe of origin: temporal lobe seizures occurred preferentially between the hours of 1100 and 1700 hours, frontal seizures between 2300 and 0500 hours, and parietal seizures between 1700 and 2300 hours.¹²

A significant limitation of all the aforementioned studies is that they analyzed the time of day, not circadian rhythmicity. To further study the interaction between circadian rhythmicity and seizure occurrence, Hofstra and colleagues¹³ performed a prospective pilot study in the authors’ tertiary epilepsy center, analyzing 124 seizures of 21 patients admitted for long-term video-EEG monitoring. The investigators found that temporal lobe seizures occurred most often between 1100 and 1700 hours and frontal seizures primarily between 2300 and 0500 hours. The investigators also measured dim light melatonin onset (DLMO) in each patient and correlated it with the clock timing of their seizures, and found that temporal seizures occurred most frequently in the 6 hours before DLMO and frontal seizures in the 6 to 12 hours after the DLMO. These results suggest that temporal and frontal seizures not only occur in diurnal patterns, but also are truly time-locked to the circadian phase. More research with larger sample sizes is needed to confirm these results.

The preferential timing of interictal epileptic discharges (IEDs) during seizure-free periods has been studied extensively in humans. In several studies, it has been found that the number of IEDs increases significantly during sleep, in parallel with ultradian 100-minute cycles of rapid eye movement (REM)/non–rapid eye movement (NREM).¹⁴ During NREM sleep (especially NREM 1 and 2), focal and generalized IEDs are common. Although attenuated, focal IEDs persist in REM sleep, but generalized IEDs are rare in REM sleep. However, none of the aforementioned studies evaluated the pure influence of circadian rhythmicity, and their results may be masked by the sleep-wake cycle. These studies give an insight into the influence of sleep on IEDs, but not the contribution of the endogenous 24-hour circadian rhythm.

To date, only one study has focused on circadian rhythmicity in IEDs using a forced desynchrony protocol. Pavlova and colleagues¹⁵ measured hourly plasma melatonin levels in 5 patients with generalized epilepsy undergoing continuous video-EEG monitoring according to a protocol whereby their sleep/wake schedule was evenly distributed across the circadian cycle. Patients were studied in dim light (<8 lux) to prevent circadian entrainment. The investigators found that all 5 subjects had normal circadian rhythmicity of plasma melatonin relative to their habitual sleep times. In the 3 patients with sufficient IEDs to assess circadian variability, IEDs most often occurred during NREM sleep (NREM/wake ratio = 14:1). Two patients had NREM sleep in all circadian phases and apparent circadian variation in IEDs, but with different phases relative to peak melatonin.