Circadian Rhythm Sleep-Wake Disorders

Abstract

The circadian system regulates a range of behavioural, physiological and cellular rhythms that allow organisms to anticipate changes in their physical environment, such as cycles of day and night. These predictive near-24-h oscillations persist in the absence of all environmental cues and are driven by the endogenous master pacemaker located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus in mammals (Stephan and Zucker 1972; Ralph et al. 1990; Edgar et al. 1993). Within individual SCN neurons, cyclic core clock genes and proteins establish a molecular basis of circadian control through transcriptional, translational and post-translational feedback loops (Reppert and Weaver 2002). This intracellular clock is not only found in the SCN, but in nearly all peripheral tissues of the mammalian body where it establishes tissue-specific gene expression to temporally coordinate physiology. Signals from the central SCN are relayed throughout the brain and body to synchronize these peripheral clocks to appropriate phases through neuronal, hormonal and physiological mechanisms (Buhr and Takahashi 2013). In this manner, the SCN regulates many diverse processes, including daily patterns of sleep, endocrine secretion, glucose homeostasis and core body temperature.

Appendix

1.1 Clinical Vignette A

Mr. X heard a radio programme in which circadian sleep disorders were described. He contacted the sleep clinic and, when seen, described a long-standing pattern of non-24-h sleep-wake cycles.

Mr. X was adopted at age 2 and he had difficulties as a child. At school he was regularly caned for being late. He did not complete school, although a subsequent assessment showed that he had an IQ higher than 125. Mr. X claimed to have had “hundreds of jobs”, most of which he has lost because of difficulties with timekeeping. The only job he kept for any length of time was in a photographic laboratory. As a technician he was allowed to come and go on his own schedule, provided a certain amount of work was done.

When seen initially he was living as a recluse, in a remote country cottage outside of Edinburgh. He made a number of statements suggesting a delusional disorder. For example, although he was unemployed, he believed that in the next few years, he would become a member of Margaret Thatcher’s cabinet. He spoke of occasions when he did not sleep at all for a few days and instead worked “by the white heat of the night”. Mr. X complained of difficulties making medical and dental appointments because of his rotating sleep pattern which caused him to go to bed and rise 1 h later every day. If an appointment was scheduled, he had to calculate whether he would be in a waking or sleeping phase during daytime hours.

Mr. X declined sleep a laboratory assessment. He was not heard of again until 3 years later when he had difficulties with the police. He had been writing and distributing malicious information about a senior civil servant. He telephoned the sleep clinic to request an intervention so that he would not have to appear in court the next day. He explained, “I will be sleeping in the middle of the day tomorrow”. At this point, Mr. X agreed to hospital admission so that his circadian rhythm disorder could be monitored. Monitoring confirmed that he did go to bed 1 h later every day. This caused great inconveniences to the nurses who had to serve breakfast at 3 am one day, 4 am the next day and 4 pm 2 weeks later! Monitoring other circadian rhythms showed that they were synchronized with his sleep-wake rhythms.

A trial of lithium (this was before the days of melatonin availability) was decided upon in the belief that it would make his circadian rhythm worse, i.e. extend his rhythm to a 26-h rhythm, with a plan to follow that in a single-blind manner with sodium valproate which has the opposite effect on circadian rhythm. Immediately on commencing the lithium after being on placebo (single blind), he settled into an exactly 24-h rhythm. An MRI brain scan was done which showed a pineal tumour.

This clinical vignette highlights the interaction between the circadian rhythm problem and a possible mood-related issue and the impact of two well-known mood-stabilizing agents on circadian rhythms.

1.2 Clinical Vignette B

A 16-year-old boy presented to the sleep clinic with what appeared to be phase delay syndrome. A dim light melatonin onset study was done which confirmed the diagnosis. A single-blind treatment with one packet of melatonin and one packet of placebo was provided with the instruction to take one tablet from packet A for a month and one tablet from packet B for a month. He was to take the tablets at 7 pm on a regular basis. After showing the clear benefit of the active melatonin treatment (when he returned at the 2-month mark), he was placed on over-the-counter melatonin which did not produce the same effect. He returned a month later with his mother, and they requested that we provide them with the “pharmaceutical grade” melatonin that we import from a company in the United Kingdom.

At the return visit, his mother walked in with a piece of paper which had a series of Es heavily ringed. The physician’s presumption was that this is a report card and that “E” is close to “F”—that is, the student has almost failed. The young man of 16 sat in the corner and smiled like a Cheshire cat. When asked what he was smiling about, his comment was “I am not stupid anymore, I am going to university”. The ‘Es were for “excellent” and his grade average had gone from 60 to 90% in a 3-month period. He entered university a year and a half later to a course that has only 24 slots and is the only course of its kind in the province.

This vividly illustrates the importance of detecting and treating circadian rhythm disorders as early as possible, particularly in adolescents who are in a very sensitive phase of their academic and social development.

1.3 Clinical Vignette C

A former professor at Harvard is travelling to Japan for a short trip. He uses the goggles that block out a narrow band of blue light during the day while he is in Japan. He takes a short nap each afternoon and sleeps during the night in Japan. Five days later he returns to Boston and has an immediate resumption of his normal circadian rhythm (unlike previous long trips to Australia or the Far East).

This vignette indicates the possibility of maintaining a set circadian period in the face of being in a different time zone. It is likely that the hour-long daytime naps were perceived as a “very short night” and the longer nocturnal sleeps in Japan were perceived as a “long nap”. For travellers making short trips abroad, this may be a very useful strategy.