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Date of Award

10-1989

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

John M. Cleghorn

Abstract

After specific causes of chronic insomnia have been ruled out (e.g., noctural myoclonus, drug abuse), there remain in a substantial number of patients who have been inexplicably sleepless and fatigued for many years. We wished to learn whether the chronicity of insomnia in these patients was associated with phase-shifts in circadian rhythm, a disorder of internal timekeeping. We identified three types in a pilot study: 1) phase-delay, b) phase-advance, and c) an arrhythmic group.

Delayed sleep-phase insomnia (DSPI) has been well described. It is characterized by an intractably late sleep-onset and awakening time, a consistent sleep time-frame, and an essentially normal sleep EEG.

Advance sleep-phase insomnia (ASPI) is a much rarer phenomenon, with few reported cases. Sleepiness becomes overpowering in the late afternoon or early evening, followed by a very short sleep onset latency and exceedingly early awakening time. The EEG is essentially normal.

Amplitude disorders and arrythmia are even more rare under normal environmental conditions. They have been described but not carefully examined. We identified two patients in the pilot study who displayed a complete arrythmia of their core temperature cycle. Their sleep was marked by variable onset latencies, and severe difficulties with sleep maintenance. Sleep-time averaged less than two hours per night, and was associated with a substantial reduction in the slow-wave sleep.

Though these patterns sound easy to recognize, they are often obscured in patient reports. For example, social schedules requiring early rising for work in spite of phase-delay or explanations that patients develop to better account for their predicament may disguise true patterns. We tried to detect the more intractable features in patient histories and reported patterns of sleep and to predict which type of phase disturbance each might have.

The physiological aspects of the circadian phase disturbance was examined using the sleep-wake cycle (14 x 24 hours), core body temperature (5 x 24 hours), serum cortisol (1 x 24 hours) and serum melatonin (1 x 24 hours) as circadian parameters. Monitoring was carried-out on three patient groups identified in the Sleep Disorders Clinic as being : 1) phase-delayed, 2) phase advanced, or 3) arrythmic.

The phase-delay group showed a significant delay in the acrophase of core temperature rhythm, but not serum cortisol. The phase advance group showed a significant advance in the acrophase of both rhythm parameters. The arrhythmic group displayed a highly variable core temperature acrophase but intact 24 hour waveforms. Serum cortisol had no discernable rhythmic component in this group.

The circadian rhythm of serum melatonin showed a significant acrophase delay for all patient groups. This was an unexpected result, as the phase control of melatonin secretion is thought to originate from oscillators providing phase information to the other parameters meausred in this study.

Also important was the finding that there was no significant difference in the amplitude or period length for all three circadian rhythm parameters. Thus, "phase-disorders" seen in the present study possibly represent a defect in carcadian rhythm timing but not in the generation of rhythms themselves. However, in patient Group 3 the substantial increased point to point random variation in core temperature and the arrhythmic nature of the serum cortisol secretion could imply involvement of rhythm timing and/or generation.

Since these phase disorders were associated with a consistent and unidirectional phase change in the circadian pattern of melatonin secretion, it is hypothesized that the pathology in these patients may lie at the level of the suprachiasmatic nucleus. Hyposensitivity to light could interfere with melatonin "offset" signals, while allowing other pacemakers to move toward their endogenous cycling frequencies. Thus, phase delayed, or advanced, or a more drastic rhythm anomaly might ensue.

This study also indicates that it may be possible to identify each of the three types of rhythm disturbance on the basis of clinical features that can be obtained by interview. The most important aspects appear to be: 1) chronicity of symptoms, 2) consistency of symptoms, 3) pattern of symptoms, 4) psychiatric and medical histories, and 5) recnet drug histories. In addition, polysomnographic studies are required to exclude specific disorders such as nocturnal myoclonus.

Exogenous melatonin administration was carried out on this patient sample. A double-blind, placebo-controlled, 14-day trial showed a significant improvement of both total sleep time and day-time alertness with a 75mg oral does of melatonin as compared to placebo. This is the first study to demonstrate significant clinical soporiphic effects of exogenous melatonin in chronic insomniac patients.

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