Is there a circadian variation of epileptiform abnormalities in idiopathic generalized epilepsy?

Abstract

Epileptiform abnormalities often occur at specific times of day or night, possibly attributable to state of consciousness (sleep vs. wake) and/or influences from the endogenous circadian pacemaker. In this pilot study we tested for the existence of circadian variation of interictal epileptiform discharges (IEDs), independent of changes in state, environment, or behavior. Five patients with generalized epilepsy underwent a protocol whereby their sleep/wake schedule was evenly distributed across the circadian cycle while undergoing full-montage electroencephalography and hourly plasma melatonin measurements. Light was <8 lux to prevent circadian entrainment. All patients completed the protocol, testifying to its feasibility. All patients had normal circadian rhythmicity of plasma melatonin relative to their habitual sleep times. In the three patients with sufficient IEDs to assess variability, most IEDs occurred during non-rapid eye movement (NREM) sleep (ratio NREM:wake=14:1, P<0.001). In both patients who had NREM at all circadian phases, there was apparent circadian variation in IEDs but with different phases relative to peak melatonin.

Fig. 1. The laboratory protocol

The graph below provides visual description of our Forced Desynchrony protocol. Each horizontal line represents a 24 hour period of the laboratory stay. The white boxes represent wakefulness, and the shaded areas represent sleep opportunities. The protocol was performed in dim light (<8 lux) so that the internal circadian pacemaker continued at its inherent rate of ~ 24 hours. In that way, the protocol allows for wakefulness and sleep to be seen at all times of the circadian cycle.

Fig. 2. Melatonin profile from the ~48 hour FD protocol

The hourly plasma levels of melatonin of each of the five patient are displayed as single lines as per legend. As seen, the profile is similar in all 5 patients with a sharp increase, followed by a plateau and a sharp decrease at the end of the ‘biological night’. There is a mild to moderate brief ‘dip’ in plasma melatonin close to the midpoint of melatonin secretion in some of the patients, likely caused by postural changes (see text). The profile is aligned according to circadian phase (presented on the x-axis). The top label presents the averaged corresponding clock times.

Fig. 3. Circadian distribution of epileptiform discharges per patient and sleep/wakefulness

Top three panels: Variation of IED across circadian phase, separately for NREM and wakefulness in three individual patients. 0 degrees represents the circadian phase of the fitted melatonin peak, which occurs around the middle of each subject’s habitual sleep time. Data are double plotted (data on the left are repeated on the right) to aid visual assessment of any underlying circadian rhythmicity. The rate of IED per minute of each state (NREM, wakefulness) is averaged for each circadian bin and presented as a separate line. Underlying circadian rhythmicity is apparent particularly in NREM sleep for patients 1 and 3, as discussed in the text. As seen, the number of IED per minute in NREM is much higher than in wakefulness in all circadian bins in patients 1 and 2, and in 5 of 6 bins in patient 3. The top label presents the corresponding clock times. Bottom panel: Double plot of the distribution of wakefulness, NREM sleep and REM sleep in each circadian phase bin aligned according to phase of the melatonin rhythm (0 degrees represents the circadian phase of the fitted melatonin peak). In each circadian phase bin, the opportunity for sleep is 50% of the time (dashed line). The amount of sleep averaged 35% overall (equivalent to 70% of the sleep opportunity), and NREM was present at all circadian phases. The proportion of REM sleep follows an expected circadian pattern being largest at 60 degrees (for most people corresponding to the latter part of the habitual sleep period and early morning).