Circadian rhythm abnormalities

Abstract

Purpose: This article reviews the recent advances in understanding of the fundamental properties of circadian rhythms and discusses the clinical features, diagnosis, and treatment of circadian rhythm sleep disorders (CRSDs).

Recent findings: Recent evidence strongly points to the ubiquitous influence of circadian timing in nearly all physiologic functions. Thus, in addition to the prominent sleep and wake disturbances, circadian rhythm disorders are associated with cognitive impairment, mood disturbances, and increased risk of cardiometabolic disorders. The recent availability of biomarkers of circadian timing in clinical practice has improved our ability to identify and treat these CRSDs.

Summary: Circadian rhythms are endogenous rhythms with a periodicity of approximately 24 hours. These rhythms are synchronized to the physical environment by social and work schedules by various photic and nonphotic stimuli. CRSDs result from a misalignment between the timing of the circadian rhythm and the external environment (eg, jet lag and shift work) or a dysfunction of the circadian clock or its afferent and efferent pathways (eg, delayed sleep-phase, advanced sleep-phase, non-24-hour, and irregular sleep-wake rhythm disorders). The most common symptoms of these disorders are difficulties with sleep onset and/or sleep maintenance and excessive sleepiness that are associated with impaired social and occupational functioning. Effective treatment for most of the CRSDs requires a multimodal approach to accelerate circadian realignment with timed exposure to light, avoidance of bright light at inappropriate times, and adherence to scheduled sleep and wake times. In addition, pharmacologic agents are recommended for some of the CRSDs. For delayed sleep-phase, non-24-hour, and shift work disorders, timed low-dose melatonin can help advance or entrain circadian rhythms; and for shift work disorder, wake-enhancing agents such as caffeine, modafinil, and armodafinil are options for the management of excessive sleepiness.

Figure 7-1

Schematic illustration of the pathway responsible for entrainment of melatonin secretion by light. The circadian regulation of melatonin secretion is dependent on an indirect pathway that originates in photosensitive ganglion cells in the retina and reaches the suprachiasmatic nucleus, the circadian pacemaker, via the retinohypothalamic tract. The suprachiasmatic nucleus controls the sympathetic output to the pineal gland, which is responsible for melatonin secretion via an inhibitory projection to the paraventricular nucleus of the hypothalamus. This pathway is responsible for the peak of melatonin secretion during darkness. Reprinted with permission from Benarroch EE, Neurology.2 © 2008, American Academy of Neurology. www.neurology.org/content/71/8/594.extract.

Figure 7-2

Simplified representation of the transcription cycle.

Figure 7-3

Representative actogram of patient with delayed sleep-phase disorder. The blue arrows indicate sleep onset and the red arrows indicate the end of the major sleep period. The black horizontal arrows indicate naps. In high-amplitude actigraphy, dense bars are representative of wakefulness, and low, sparse bars are representative of sleep. Note that sleep onset is 2:00 AM to 4:00 AM and the end of the major sleep period varies from 8:00 AM all the way to 1:00 PM (on day 7). On day 5, when total sleep duration was from 2:00 AM to 7:00 AM, the patient takes two naps, resulting in less sleep homeostatic drive, and therefore sleep onset the next night is not until 5:00 AM.

Figure 7-4

Summary of treatment approaches for delayed sleep-phase disorder and advanced sleep-phase disorder. Bright light administered before the nadir of body core temperature is a potent stimulus for delaying circadian phase. The most commonly used treatment for advanced sleep-phase disorder is early-evening light therapy, usually between 7:00 PM and 9:00 PM. This approach has been shown to improve sleep duration and sleep maintenance, as well as daytime performance. The combination of light therapy and melatonin has been shown to have complementary benefits. Bright light in the morning for 1 to 2 hours shortly after the minimum of the core body temperature rhythm advances circadian rhythms and 0.5 mg to 5 mg of melatonin taken 5 to 6.5 hours before dim light melatonin onset (13 to 14 hours after natural wake-up time) results in advanced sleep and wake times in patients with delayed sleep-phase disorder. MLT = melatonin.

Figure 7-5

Actigraphy record of a sighted patient with non–24-hour sleep-wake disorder. Note the daily delay drift of the onset and offset of the sleep-wake rhythm with a circadian period that is longer than 24 hours.

Figure 7-6

Sleep-wake diary of a patient with shift work disorder. A, Patient’s sleep diary for 1 week before treatment. B, Patient’s sleep diary for 1 week after 1 month of treatment with a combination of intermittent naps when possible before the shift, bright light exposure (yellow) during the shift, and avoidance of light on the morning commute (sunglasses) together with maintaining a dark and quiet bedroom. In addition, 3 mg of melatonin (purple pill) was started to improve sleep as needed. Bright light exposure for 30 minutes to 1 hour (light bulb) was also initiated shortly after awakening during work days. During days off, she was instructed to maintain a compromised sleep and wake schedule so that she would have time with her husband and friends, but not completely revert to a daytime schedule.