Non-24-hour sleep–wake disorder

It has been estimated that non-24 occurs in more than half of all people who are totally blind. as the photosensitive ganglion cells in the retina are also removed. Without light to the retina, the suprachiasmatic nucleus (SCN), located in the hypothalamus, is not cued each day to synchronize the circadian rhythm to the 24-hour social day, resulting in non-24 for many totally blind individuals. ==Symptoms==

People with this disorder might find it difficult to follow a regular clock scheme, as their biological clock can shift so much that they are sleepy during the day and experience insomnia during night. • Joint pain • Loss of muscle coordination (ataxia) • Menstrual irregularities • Muscle pain • Suicidal thoughts • Weight gain • Hallucinations ==Causes==

The possible causes of non-24-hour sleep-wake disorder are 2-fold: (1), extrinsic: isolation from daily light cycles (such as working in an environment completely devoid of natural lighting); and (2), intrinsic: where some condition, such as blindness or malfunctioning biochemical response to light in the subject, prevent normal levels of light-activated melatonin release. Melatonin is responsible for sleep regulation, and its release is controlled by the amount of light entering the eyes. Sighted Sighted people with non-24 appear to be more rare than blind people with the disorder, and the etiology of their circadian disorder is less well understood. At least one case of a sighted person developing non-24 was preceded by head injury; another patient diagnosed with the disorder was later found to have a "large pituitary adenoma that involved the optic chiasma". Several other cases have been preceded by chronotherapy, a prescribed treatment for delayed sleep phase disorder. There have been several experimental studies of sighted people with the disorder. McArthur et al. reported treating a sighted patient who "appeared to be subsensitive to bright light". In other words, the brain (or the retina) does not react normally to light (people with the disorder may or may not, however, be unusually subjectively sensitive to light; one study found that they were more sensitive than the control group That is appreciably longer than the 24.02-hour average shown by the control subjects in that study, which was near the average innate cycle for healthy adults of all ages: the 24.18 hours found by Charles Czeisler. The literature usually refers to a "one- to two-hour" delay per 24-hour day (i.e. a 25- to 26-hour cycle). Uchiyama et al. had earlier determined that sighted non-24 patients' minimum core body temperature occurs much earlier in the sleep episode than the normal two hours before awakening. They suggest that the long interval between the temperature trough and awakening makes illumination upon awakening virtually ineffective, as per the phase response curve (PRC) for light. In their clinical review in 2007, Okawa and Uchiyama reported that people with non-24 have a mean habitual sleep duration of nine to ten hours and that their circadian periods average 24.8 hours. ==Circadian rhythm==

All living animals have an internal clock, the circadian rhythm, which is close to 24 hours' duration. For humans, the average duration is 24 hours and 20 minutes, and individually some people have more or less than 24 hours. Everyday exposure to the morning light resets the circadian rhythm to 24 hours, so that there is no drifting. However, people with non-24 have a circadian rhythm significantly longer (or, rarely, shorter) than 24 hours. the disorder is also known as: non-24-hour sleep–wake syndrome or disorder, circadian rhythm sleep disorder—free-running type or nonentrained type, non-24-hour circadian rhythm disorder. or just N24 for short in everyday speech. The disorder is an invisible disability that can be "extremely debilitating in that it is incompatible with most social and professional obligations". ==Mechanisms==

The internal circadian clock, located in the hypothalamus of the brain, generates a signal that normally is slightly longer (occasionally shorter) than 24 hours, on average 24 hours and 11 minutes. The most easily observed of these is the propensity for sleep and wake; thus, people with non-24 experience symptoms of insomnia and daytime sleepiness (similar to "jet lag") when their endogenous circadian rhythms drift out of synchrony with the social/solar 24-hour day, but they conform to a conventional schedule. Eventually, their circadian rhythms will drift back into normal alignment, when symptoms temporarily resolve. Thus the overall pattern involves periodic symptoms on a weekly or monthly basis, depending on the length of the internal circadian cycle. For example, an individual with a circadian period of 24.5 hours would drift 30 minutes later each day and would be maximally misaligned every 48 days. If patients set their own schedule for sleep and wake, aligned to their endogenous non-24 period (as is the case for most sighted patients with this disorder), symptoms of insomnia and wake-time sleepiness are much reduced. However, such a schedule is incompatible with most occupations and social relationships. The AASM suggests that non-24 might be different disorders in sighted and blind people, with different internal and external contributing factors—as these can affect treatment response, different treatments could be needed. Future studies should therefore try to identify and assess these factors. ==Diagnosis==

This disorder can have symptomatic periods, where "the time of high sleep propensity gradually shifts, such that patients experience daytime hypersomnolence and nighttime insomnia". ==Medical classification==

International Classification of Sleep Disorders (ICSD) Since 2005, the disorder has been recognized by name in the U.S. National Center for Health Statistics and the U.S. Centers for Medicare and Medicaid Services in their adaptation and extension of the WHO's International Statistical Classification of Diseases and Related Health Problems (ICD): • ICD-9-CM: Circadian rhythm sleep disorder, free-running type; code 327.34 became effective in October 2005. Prior to the introduction of this code, the nonspecific code 307.45, Circadian rhythm sleep disorder of non-organic origin, was available, and as of 2014 remains the code recommended by the DSM-5. • ICD-10-CM: Circadian rhythm sleep disorder, free running type; code G47.24 was due to take effect October 1, 2014. Since 2013, the disorder has been recognized by the American Psychiatric Association: • DSM-5, 2013: Circadian rhythm sleep–wake disorders, Non-24-hour sleep–wake type; ICD-9-CM code 307.45 is recommended (no acknowledgement of 327.34 is made), and ICD-10-CM code G47.24 is recommended when it goes into effect. ==Treatment==

Tasimelteon The Food and Drug Administration (FDA) approved in January 2014 the melatonin agonist tasimelteon for the treatment of non-24 for blind people. This is the first FDA-approved drug for any circadian rhythm sleep disorder, since melatonin is unregulated. In the largest treatment study with non-24 patients, it was demonstrated that tasimelteon safely and effectively treated totally blind patients: entrainment occurred in 20% (8 of 40) of patients receiving the drug compared with 3% (1 of 38) receiving placebo. In a separate meta-analysis, melatonin supplementation achieved a 67% (12 of 18) entrainment rate. Studies directly comparing tasimelteon and melatonin have yet to be performed. Study authors noted that the lower rates of entrainment with tasimelteon may have been due to short duration of treatment. This can be combined with dark therapy (or scototherapy), which involves filtering blue light (using software, screen filters or (amber-color) glasses) and preferring red-colored lights with a low amount of lux in the few hours before bedtime to avoid melatonin suppression. Both melatonin administration and light therapy work by shifting circadian rhythms according to a phase response curve (PRC), with the melatonin PRC being essentially the inverse of the light PRC. Furthermore, light can suppress melatonin secretion. In addition to natural fluctuations within the circadian rhythm, seasonal changes including temperature, hours of daylight, light intensity and diet are likely to affect the efficacy of melatonin and light therapies since these exogenous zeitgebers would compete for hormonal homeostasis. Further to this, there are unforeseen disruptions to contend with even when a stabilized cycle is achieved, such as travel, exercise, stress, alcohol, or even the use of light-emitting technology close to a subjective evening/night. ==Prevalence==

There are an estimated 140,000 people with non-24—both sighted and blind—in the European Union, a total prevalence of approximately 3 per 10,000, or 0.03%. It is unknown how many individuals with this disorder do not seek medical attention, so incidence may be higher. The European portal for rare diseases, Orphanet, lists non-24 as a rare disease by their definition: fewer than 1 affected person for every 2000 population. The US National Organization for Rare Disorders (NORD) lists non-24 as a rare disease by its definition. Blind While both sighted and blind people are diagnosed with non-24, the disorder is believed to affect up to 70% of totally blind individuals. 10% have no light perception at all. Of that group, it is estimated that approximately half to three-quarters, or 65,000 to 95,000 Americans, have non-24. ==History==

In the 1980s and 1990s, several trials of melatonin administration to totally blind individuals without light perception produced improvement in sleep patterns, but it was unclear at that time if the benefits were due to entrainment from light cues. The ability of melatonin administration to entrain free-running rhythms was first demonstrated by Redman, et al. in 1983 in rats who were maintained in a time-free environment. Then, using endogenous melatonin as a marker for circadian rhythms, several research groups showed that appropriately timed melatonin administration could entrain free-running rhythms in the totally blind: they found that 6 out of 7 patients treated with 10 mg melatonin at bedtime were normally entrained, and when the dose was gradually reduced to 0.5 mg in three of the subjects, entrainment persisted. Subsequently, it was observed that treatment initiated with the 0.5 mg dose could produce entrainment on some patients. Interestingly, one subject who failed to entrain at a higher dose was successfully entrained at a lower dose. A low dose produces melatonin blood levels that are similar to the concentrations naturally produced by nightly pineal secretion. In 2005, ramelteon (trade name Rozerem) was the first melatonin agonist to be approved in the United States (US), indicated for insomnia treatment in adults. Melatonin in the form of prolonged release (trade name Circadin) was approved in 2007 in Europe (EU) for use as a short-term treatment, in patients 55 years and older, for primary insomnia. Tasimelteon (trade name Hetlioz) received FDA approval in January 2014 for blind persons diagnosed with non-24. TIK-301 (Tikvah Therapeutics, Atlanta, USA) has been in phase II clinical trial in the United States since 2002 and the FDA granted it orphan drug designation in May 2004, for use as a treatment for circadian rhythm sleep disorder in blind individuals without light perception as well as individuals with tardive dyskinesia. The first report and description of a case of non-24, a man living on 26-hour days, who happened to be sighted, was "A man with too long a day" by Ann L. Eliott et al. in November 1970. The related and more common delayed sleep phase disorder was not described until 1981. The first detailed study of non-24 in a blind subject was by Miles Le and his colleagues in 1977. The researchers reported on a 28-year-old male who had a 24.9-hour rhythm in sleep, plasma cortisol, and other parameters. Even while adhering to a typical 24-hour schedule for bedtime, rise time, work, and meals, the man's body rhythms continued to shift. ==Research==

Not all totally blind individuals have free-running rhythms, and those that do often show relative coordination as their endogenous rhythms approximate normal timing. It has been suggested that there are non-photic time cues that are important for maintaining entrainment, but these cues are yet to be characterized. Very preliminary research on light sensitivity suggest that not only insensitivity but also circadian hypersensitivity to light might be at play for patients with a delayed sleep phase disorder. ==Society==

NASA explored the potential impact on circadian rhythm and possible development of a sleep–wake disorder by human astronauts who would go on a mission to Mars, by assessing mission personnel who worked remotely on the Phoenix Mars Lander project and were asked to follow a Mars day of 24.65 hours for 78 days. ==See also==