Circadian rhythm sleep disorders

Abstract

There have been remarkable advances in our understanding of the molecular, cellular, and physiologic mechanisms underlying the regulation of circadian rhythms, and of the impact of circadian dysfunction on health and disease. This information has transformed our understanding of the effect of circadian rhythm sleep disorders (CRSD) on health, performance, and safety. CRSDs are caused by alterations of the central circadian timekeeping system, or a misalignment of the endogenous circadian rhythm and the external environment. This article reviews circadian biology and discusses the pathophysiology, clinical features, diagnosis, and treatment of the most commonly encountered CRSDs in clinical practice.

Figure 1. Schematic representation of the phase response curves to light and melatonin

Circadian time point 0 is the timing of the nadir of the circadian core temperature rhythm. Light exposure prior to the temperature nadir results in a delay of circadian rhythms, whereas light exposure after the temperature nadir causes phase advances. Note that there is a dead zone in the middle of the day where bright light exposure has no effect on the timing of circadian rhythms. In contrast, melatonin administered in the beginning of the night advances the circadian rhythm, while melatonin in the morning delays the circadian rhythm. The figure is derived from data presented by Lewy et al and Khalsa et al. The figure is reprinted with permission (from Zee PC and Manthena P. The brain's master circadian clock: implications and opportunities for therapy of sleep disorders; Sleep Medicine Review 2007 Feb;11(1):59-70).

Figure 2. Clinical approach to the diagnosis of circadian rhythm sleep disorders (CRSD)

A history of sleep and wake disturbance due to alteration of circadian timing and function is the mainstay of the clinical diagnosis. It is important to consider other sleep disorders and mood disorders in the differential diagnosis of most CRSDs. The pattern of sleep and wake disturbance differs among the various types of CRSDs as illustrated in this figure.

Figure 3. Actogram of a patient with DSPD

Panel A shows an actogram derived from actigraphy data obtained over 9 days in a patient with severe DSPD. The yellow lines depict light exposure. The high amplitude dense bars are representative of wakefulness and no to low activity time is representative of sleep. Note that average sleep onset is 5-6 am and wake time from noon to 1 pm. Note the stable delay of the sleep–wake rhythm in relation to the conventional sleep time and wake-up time. Panel B shows the 24-hour plasma melatonin level rhythm of this patient. The dim light melatonin onset (DLMO) was defined as an absolute threshold at 10 pg/mL. The DLMO of this patient is delayed at 1:23am (which is approximately 5 hours later than would be expected in non-delayed persons).

Figure 4. Actogram of a patient with ASPD

Panel A shows an actogram derived from actigraphy data obtained over 9 days in a patient with severe ASPD. The yellow lines depict light exposure. The high amplitude dense bars are representative of wakefulness and no to low activity time is representative of sleep. Note that average sleep onset is 8:00 to 9:00 pm, and wake time from 4:00 to 5:00 am. Note the stable advance of the sleep–wake rhythm in relation to the conventional sleep time and wake-up time. Panel B shows the 24-hour plasma melatonin level rhythm of this patient. The dim light melatonin onset (DLMO) was defined as an absolute threshold at 10 pg/mL. The DLMO of this patient is advanced at 7.30 pm (which is approximately 2-3 hours earlier than would be expected in non-advanced persons).

Figure 5. Actogram of a patient with non-24 hour sleep wake disorder (N24HSWD)

Panel A shows an actogram derived from actigraphy data obtained over 14 days in a sighted patient with N24HSWD. The high amplitude dense bars are representative of wakefulness and no to low activity time is representative of sleep. Note the daily drift to later times of the sleep-wake pattern with a period that is slightly longer than 24 hours.

Figure 6. Treatment Options for the Management of Shift Work Disorder (SWD)

This example illustrates the timing of light exposure and the use of pharmacologic agents, either alone or in combination for the management of SWD. The habitual pre-shift sleep time of this 42 year old male is 11pm-7am. The new work shift requires that he work from 10pm to 6am for 4-5 days per week. Circadian alignment can be achieved by manipulating light and dark exposure. In order to delay his circadian rhythm, bright light exposure (continuous or intermittent) should start early in the shift and stop about 1-2 hours before the shift, and wear sunglasses to avoid advancing circadian rhythms in the morning. If needed, melatonin taken before bedtime may help improve sleep quality. To address the issue of excessive sleepiness, scheduled 1-2 hour nap prior to the shift work, if possible a short 30 minute nap in the middle of the shift, and/or caffeine can help decrease sleepiness at work. If sleepiness persists, modafinil 200 mg and armodafinil 150 mg have been shown to improve alertness during work and is approved by the FDA for the treatment of excessive sleepiness in patients with SWD.

Figure 7. Strategies to accelerate circadian adaption to jet lag

Panel A illustrates an example of a treatment strategy for jet lag associated with an eastward flight over six time zones (from Chicago to London). Adjustment requires an equal number of hours of phase advance. Upon arrival, the traveler should avoid bright light in the early morning hours (before 9 am) for the first 2 days so that light does not fall before nadir of the minimum of the core temperature (which will induce a phase delay), and exposure to bright light after 9 am in the morning to induce phase advances. In addition, melatonin 1-5 mg taken at 1800 local time on the departure day and at local bedtime (2200–2300) on arrival for 4 days has shown to be effective. Panel B illustrates the treatment strategy for jet lag associated with a westward flight over five time zones (from Chicago to Hawaii). The subject should be exposed as much as light as possible in the late afternoon and early evening to at the destination, which will result in the required phase delay.