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Abstract
Several aspects of human physiology and behavior are dominated by 24-h circadian rhythms with key impacts on health and well-being. These include mainly the sleep–wake cycle, vigilance and performance patterns, and some hormone secretions. The rhythms are generated spontaneously by an internal “pacemaker,” the suprachiasmatic nuclei within the anterior hypothalamus. This master clock has, for most humans, an intrinsic rhythm slightly longer than 24 h. Daily retinal light exposure is necessary for the synchronization of the circadian rhythms with the external 24-h solar environment. This daily synchronization process generally poses no problems for sighted individuals except in the context of jetlag or working night shifts being conditions of circadian desynchrony. However, many blind subjects with no light perception had periodical circadian desynchrony, in the absence of light information to the master clock leading to poor circadian rhythm synchronization. Affected patients experience cyclical or periodic episodes of poor sleep and daytime dysfunction, severely interfering with social, academic, and professional life. The diagnosis of Non-24 Sleep–Wake Rhythm Disorder, also named free-running disorder, non-entrained disorder, or hypernycthemeral syndrome, remains challenging from a clinical point of view due to the cyclical symptoms and should be confirmed by measurements of circadian biomarkers such as urinary melatonin to demonstrate a circadian period outside the normal range. Management includes behavioral modification and melatonin. Tasimelteon, a novel melatonin receptor 1 and 2 agonist, has demonstrated its effectiveness and safety with an evening dose of 20 mg and is currently the only treatment approved by the FDA and the European Medicines Agency.
Highlights
KEY MESSAGESNon-24-h sleep–wake rhythm disorder is an orphan disease in the general population but common in the totally blind
Most biological processes display an endogenous, entrainable oscillation with a period of about 24 h, a rhythm driven by a circadian clock named “circadian rhythm” [1, 2]
A non-24 SWRD is defined by ICSD-3 criteria according to 4 criteria [27]: 1/History of insomnia, excessive daytime sleepiness, or both, which alternate with asymptomatic episodes, due to misalignment between the 24-h light-dark cycle and the nonentrained endogenous circadian rhythm of sleep–wake propensity; 2/Symptoms persist over the course of at least 3 months, 3/Daily sleep logs and actigraphy for at least 14 days, preferably longer for blind persons, demonstrate a pattern of sleep and wake times that typically delay each day, with a circadian period that is usually longer than 24 h, and 4/the disorder is not better explained by another current sleep disorder, medical or neurological disorder, mental disorder, and medication use of substance use disorder
Summary
Non-24-h sleep–wake rhythm disorder is an orphan disease in the general population but common in the totally blind. Lack of light information to the suprachiasmatic nucleus, the central biological clock leads to the patient’s biological rhythms following their innate period, which is often longer than 24 h. This circadian drift leads to cyclical sleep disturbances and daytime sleepiness which pose a major handicap. Accurate diagnosis and treatment with both behavioral therapy and medication targeting circadian rhythms, such as melatonin and melatonin agonists, improves symptoms
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