Non-24-Hour Sleep–Wake Rhythm Disorder in the Totally Blind: Diagnosis and Management

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.

Perspectives in affective disorders: Clocks and sleep

“…Melatonin , the ideal “natural” soporific (Wirz‐Justice & Armstrong, ), has only been commercially developed for age‐related insomnia (in a patented slow release formulation, Circadin ® ); otherwise, it is available over the counter in many countries without regard to dosage, formulation, information as to appropriate timing, or control over purity or content. The evidence for melatonin as a treatment for circadian sleep–wake cycle disturbances in blind persons is strong (Quera Salva, Hartley, Leger, & Dauvilliers, ; Uchiyama & Lockley, ); also for other visually impaired individuals where light input is diminished, melatonin can provide the evening zeitgeber signal for sleep onset. Not surprisingly, patented melatonin agonists (Tasimelteon ® and Ramelteon ® ) have been more stringently studied and approved for treating sleep disorders in the blind than melatonin itself.…”

Understanding Quantitative Circadian Regulations Are Crucial Towards Advancing Chronotherapy

“…Precise synchronization of the circadian rhythmic systems to the 24-h a day necessitates regular adjustments driven by exposures to the various environmental time cues or zeitgebers [82,83]. Mammalian systems exhibit a typical “free-running period (FRP)” mode slightly different than 24-h [76,84,85,86]. The FRP expresses the SCN-based endogenous circadian rhythms without any corrective adjustments influenced by external cues.…”

Non‐24‐hour sleep‐wake disorder successfully treated with the combination of ramelteon and suvorexant in a case of autism spectrum disorder

“…Non‐24‐hour sleep‐wake disorder (N24SWD) is a relatively rare disorder that is often observed in the visually impaired and those who isolate indoors 1‐3 . In addition to lifestyle guidance and high‐intensity light therapy, the use of vitamin B12 and sleeping pills is recommended for treatment 1,2,4‐6 . However, with regard to hypnotics, benzodiazepine hypnotics have almost no effect on human biological rhythms themselves; thus, a therapeutic effect of a benzodiazepine hypnotic alone cannot be expected 7 .…”

“…However, the usefulness of ramelteon in N24SWD has not been shown so far. N24SWD is a disease that significantly impairs the patient's quality of life, 2 and it is expected that a treatment method will be established in the future. Here, we report a case of autism spectrum disorder (ASD) with N24SWD successfully treated with a combination of ramelteon and suvorexant.…”