Circadian rhythm sleep disorders in the blind and their treatment with melatonin
Introduction
In addition to visual impairment, ocular disease also impairs the transmission of light from the retina to the circadian clock, located in the suprachiasmatic nuclei (SCN) of the hypothalamus. In sighted people, light interacting with the opsin photopigments of the photoreceptor cells (rods and cones) and melanopsin in the photosensitive ganglion cells [1] transmits photic information primarily by means of the retinohypothalamic tract (RHT) to the SCN [2]. One of the roles of light and this “non-visual” pathway is the daily adjustment (resetting) of the circadian timing system so that the circadian clock and its output circadian rhythms remain synchronised (entrained) to the 24 h day created by the earth’s rotation [3], [4], [5]. Synchronisation serves to optimise the timing of the body’s physiology and behaviour with the environment: correct internal and external phase relationships are essential for optimal function [6], [7].
Section snippets
Photic and nonphotic entrainment
Ocular light is the major time cue (zeitgeber) responsible for synchronising the human circadian timing system. Although early work suggested that “nonphotic” time cues such as meals, caffeine, exercise, and sleep–wake cycle were important synchronisers of the human circadian clock [8], today light is considered the primary time cue [3]. In addition to studies in sighted subjects, strong evidence to support this view has come from detailed studies of totally blind people. The demonstration
Circadian rhythms in the blind
Disturbances of circadian rhythms in the blind have been extensively reported in the literature. Following several case reports [9], [14], [15], [16], Lewy and Newsome [17] defined different melatonin rhythms in their study cohort, some of whom were normally entrained (NE), some who were abnormally entrained (AE), some who had no distinct rhythm and some who had free-running rhythms (FR). Later we showed that these types of circadian rhythm patterns (NE, AE or FR) were related to an
Sleep disorders in the blind
Early studies reported a high incidence of sleep disorders in blind people [19], [20]. Whether this was related to specific visual diseases or loss of light perception had not been addressed. An epidemiological study of 388 blind subjects conducted by ourselves [21] showed a higher prevalence and more severe sleep disturbances in those with no light perception (NPL) than in those with some degree of light perception. However, there was no relationship between sleep disturbance (as assessed by
Treatment
The studies described above show a clear relationship between light perception, the type of circadian rhythm abnormality and sleep/wake disturbances.
Appropriately timed, exogenous melatonin has been shown to advance or, more controversially, delay the timing of the circadian clock [25], [26]. Melatonin’s phase shifting effect presumably occurs by means of receptors in the SCN (not MT1 [27], possibly MT2 [28]), although this has yet to be definitively proven. In recent years, this phase shifting
Clinical practice and the future
Recognition of disturbed circadian rhythms in the visually impaired by the clinician is important for the appropriate treatment and management of the sleep disorder. The use of traditional sleep medication (e.g., benzodiazepines, sedative hypnotics) has reportedly brought little benefit to blind people suffering from a circadian rhythm sleep disorder (Lockley, Hack, Skene and Arendt, unpublished data).
The use of melatonin has demonstrable benefits not only in correcting the underlying circadian
Acknowledgements
The authors wish to acknowledge the contribution of their colleagues at the University of Surrey (Drs. Lisa Hack and Steven W. Lockley) and at the Moorfields Eye Hospital (Dr. Homayoun Tabandeh and Prof Alan Bird). The financial support of South Thames Regional Health Authority, Servier R and D, The Wellcome Trust (Grant 048197/Z/96/Z) and Stockgrand Ltd. is gratefully acknowledged.
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