non-24-hour sleep–wake disorder non-24-hour sleep–wake disorder non-24-hour sleep–wake disorder (non-24 or n24swd) is one of several chronic circadian rhythm sleep disorders (crsds). it is defined as a "chronic steady pattern comprising daily delays in sleep onset and wake times in an individual living in a society". symptoms result when the non-entrained (free-running) endogenous circadian rhythm drifts out of alignment with the light–dark cycle in nature. although this sleep disorder is more common in blind people, affecting up to 70% of the totally blind, it can also affect sighted people. non-24 may also be comorbid with bipolar disorder, depression, and traumatic brain injury. the american academy of sleep medicine (aasm) has provided crsd guidelines since 2007 with the latest update released in 2015. non-24-hour sleep–wake disorderother nameshypernychthemeral syndrome, free-running disorderspecialtyneurology symptomsprogressively shifting nighttimecomplicationsnone if sleeping according to biological clock, sleep deprivation otherwisedurationlifetimecausesblindness for the blind, unknown cause for the sighteddiagnostic methodsleep diary, actigraphytreatmentmedicationmedicationtasimelteon, melatoninfrequency50–70% of total blind people, less prevalent in sighted sighted in people with non-24, the body essentially insists that the length of a day (and night) is appreciably longer (or, very rarely, shorter) than 24 hours and refuses to adjust to the external light–dark cycle. this makes it impossible to sleep at normal times and also causes daily shifts in other aspects of the circadian rhythm such as peak time of alertness, body temperature minimum, metabolism and hormone secretion. non-24-hour sleep–wake disorder causes a person's sleep–wake cycle to move around the clock every day, to a degree dependent on the length of the cycle, eventually returning to "normal" for one or two days before "going off" again. this is known as free-running sleep. people with the disorder may have an especially hard time adjusting to changes in "regular" sleep–wake cycles, such as vacations, stress, evening activities, time changes like daylight saving time, travel to different time zones, illness, medications (especially stimulants or sedatives), changes in daylight hours in different seasons, and growth spurts, which are typically known to cause fatigue. they also show lower sleep propensity after total sleep deprivation than do normal sleepers. non-24 can begin at any age, not uncommonly in childhood. it is sometimes preceded by delayed sleep phase disorder. most people with this disorder find that it severely impairs their ability to function in school, in employment, and in their social lives. typically, they are "partially or totally unable to function in scheduled activities on a daily basis, and most cannot work at conventional jobs". attempts to keep conventional hours by people with the disorder generally result in insomnia (which is not a normal feature of the disorder itself) and excessive sleepiness, to the point of falling into microsleeps, as well as myriad effects associated with acute and chronic sleep deprivation. sighted people with non-24 who force themselves to live to a normal workday "are not often successful and may develop physical and psychological complaints during waking hours, i.e. sleepiness, fatigue, headache, decreased appetite, or depressed mood. patients often have difficulty maintaining ordinary social lives, and some of them lose their jobs or fail to attend school." blind it has been estimated that non-24 occurs in more than half of all people who are totally blind. the disorder can occur at any age, from birth onwards. it generally follows shortly after loss or removal of a person's eyes, 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. non-24 is rare among visually impaired patients who retain at least some light perception. researchers have found that even minimal light exposure at night can affect the body clock. 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. another common diagnostic feature is the cyclical nature of non-24: people will experience certain periods, whether they be weeks or months, of sleeping during the day (symptomatic periods) that alternate with periods of sleeping during normal nighttime hours (asymptomatic periods). symptoms reported by patients forced into a 24-hour schedule are similar to those of sleep deprivation and can include: apraxia including ideational apraxia, ideomotor apraxia, kinetic apraxia, limb apraxia, verbal apraxia cognitive dysfunction difficulties concentrating confusion depressed mood diarrhea extreme nausea extreme fatigue hair loss headaches impaired balance photosensitivity 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". thus the problem appears to be neurological. specifically, it is thought to involve abnormal functioning of the suprachiasmatic nucleus (scn) in the hypothalamus. several other cases have been preceded by chronotherapy, a prescribed treatment for delayed sleep phase disorder. "studies in animals suggest that a hypernyctohemeral syndrome could occur as a physiologic aftereffect of lengthening the sleep–wake cycle with chronotherapy". according to the american academy of sleep medicine (aasm), "patients with free-running (frd) rhythms are thought to reflect a failure of entrainment". 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). in 2002 uchiyama et al. examined five sighted non-24 patients who showed, during the study, a sleep–wake cycle averaging 25.12 hours. 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. blind as stated above, the majority of patients with non-24 are totally blind. the failure of entrainment is explained by the loss of photic input to the circadian clock. non-24 is rare among visually impaired patients who retain at least some light perception; even minimal light exposure can synchronize the body clock. a few cases have been described in which patients are subjectively blind, but are normally entrained and have an intact response to the suppressing effects of light on melatonin secretion, indicating preserved neural pathways between the retina and hypothalamus. 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. this makes it difficult to reset to 24 hours daily, just like it is difficult for people with a rhythm close to 24 hours to try to reset to 25 hours daily. the majority of people with non-24 are totally blind, and the failure of entrainment is explained by an absence of light (photic) input to reset the circadian clock. their brains may have normal circadian clocks that do not receive input from the eyes about environmental light levels, as the clocks require a functioning retina, optic nerve, and visual processing center. this makes the sleep pattern variable from one day to the next, with different wake-up time and bedtime every day. people with a circadian rhythm that is quite near to 24 hours may be able to sleep on a conventional, socially acceptable schedule, that is, at night. others, with a "daily" cycle upwards of 25 hours or more, may need to adopt a sleep pattern that is congruent with their free-running circadian clock: by daily shifts in their sleep times, which often results in satisfactory sleep but with negative social and occupational consequences. the disorder also occurs in sighted people for reasons that are not well understood. their circadian rhythms are not normal, often running to more than 25 hours. their visual systems may function normally but their brains are incapable of making the large adjustment to a 24-hour schedule. though often referred to as non-24, for example by the fda, the disorder is also known as: non-24-hour sleep–wake syndrome or disorder, free-running disorder (frd), hypernychthemeral syndrome, hypernychthemeral sleep-wake cycle disturbance, 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. this slight deviation is, in almost everyone, corrected by exposure to environmental time cues, especially the light–dark cycle, which reset the clock and synchronize (entrain) it to the 24-hour day. morning light exposure resets the clock earlier, and evening exposure resets it later, thereby bracketing the rhythm to an average 24-hour period. if people who do not have non-24-hour sleep-wake disorder are deprived of external time cues (living in a cave or artificial time-isolated environment with no light), their circadian rhythms will "free-run" with a cycle of a little more (occasionally less) than 24 hours, expressing the intrinsic period of each individual's circadian clock. the circadian rhythms of individuals with non-24 can resemble those of experimental subjects living in a time-isolated environment even though they are living in normal society. the circadian clock modulates many physiological rhythms. 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