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Non-24-hour sleep–wake disorder

non-24-hour sleep–wake disorder, non-24-hour sleep–wake disorders
Non-24-hour sleep–wake disorder non-24, 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 society"1 Symptoms result when the non-entrained free-running endogenous circadian rhythm drifts out of alignment with the light/dark cycle in nature

The sleep pattern can be quite variable 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, shifting their sleep times daily, thereby often obtaining satisfactory sleep but suffering social and occupational consequences

The majority of people with non-24 are totally blind, and the failure of entrainment is explained by an absence of photic input to the circadian clock1 These people's brains may have normal "body clocks", but the clocks do not receive input from the eyes about environmental light levels, as that requires a functioning retina, optic nerve and visual processing center

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,2 the disorder is also known by the following terms:

  • Non-24-hour sleep–wake syndrome1
  • Non-24-hour sleep–wake disorder
  • Non-24-hour sleep-wake rhythm disorder
  • Free running disorder FRD
  • Hypernychthemeral disorder
  • Circadian rhythm sleep disorder – free-running type
  • Circadian rhythm sleep disorder – nonentrained type
  • N24HSWD
  • Non-24-hour circadian rhythm disorder

The disorder in its extreme form is an invisible disability that can be "extremely debilitating in that it is incompatible with most social and professional obligations"3


  • 1 Mechanisms
  • 2 Characteristics
    • 21 Sighted
    • 22 Blind
  • 3 Symptoms
  • 4 Prevalence
    • 41 Sighted
    • 42 Blind
  • 5 Causes
    • 51 Sighted
    • 52 Blind
  • 6 Diagnosis
    • 61 Sighted
    • 62 Blind
  • 7 Treatment
    • 71 Sighted
    • 72 Blind
  • 8 History
    • 81 Sighted
    • 82 Blind
  • 9 Research directions
  • 10 Classifications
  • 11 See also
  • 12 References
  • 13 External links


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 minutes4 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 normal people 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 rhythms5 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 and they attempt to conform to a conventional schedule Eventually, their circadian rhythms will drift back into normal alignment, and symptoms temporarily resolve, but then their clocks drift out of alignment again Thus the overall pattern involves recurring 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 245 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



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 rhythms 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 sleepers6

Non-24 can begin at any age, not uncommonly in childhood It is sometimes preceded by delayed sleep phase disorder3

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"1 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,1 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 on a normal workday "are not often successful and may develop physical and psychological complaints during waking hours, ie 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"6


It has been estimated that non-24 occurs in more than half of all people who are totally blind78 The disorder can occur at any age, from birth onwards It generally follows shortly after loss or removal of a person’s eyes,9 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 individuals7 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 clock10


Symptoms reported by patients forced into a 24-hour schedule are similar to those of sleep deprivation and can include:


There are an estimated 140,000 people with N24 – both sighted and blind – in the European Union, a total prevalence of approximately 3 per 10,000, or 003%14 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 population15 The US National Organization for Rare Disorders NORD lists Non-24 as a rare disease by its definitioncitation needed


As of 2005, there had been fewer than 100 cases of sighted people with non-24 reported in the scientific literature16


While both sighted and blind people are diagnosed with non-24, the disorder is believed to affect more totally blind individuals than sighted It has been estimated by researchers that of the 13 million blind people in the US,17 10% have no light perception at all18 Of that group, it is estimated that approximately half to three-quarters, or 65,000 to 95,000 Americans, suffer from non-248



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 understood19 At least one case of a sighted person developing non-24 was preceded by head injury;20 another patient diagnosed with the disorder was later found to have a "large pituitary adenoma that involved the optic chiasma"1 Thus the problem appears to be neurological Specifically, it is thought to involve abnormal functioning of the suprachiasmatic nucleus SCN in the hypothalamus21 Several other cases have been preceded by chronotherapy, a prescribed treatment for delayed sleep phase disorder19 "Studies in animals suggest that a hypernyctohemeral syndrome could occur as a physiologic aftereffect of lengthening the sleep–wake cycle with chronotherapy"3 According to the American Academy of Sleep Medicine AASM: "Patients with free-running FRD rhythms are thought to reflect a failure of entrainment"22

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"23 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 group6 In 2002 Uchiyama et al examined five sighted non-24 patients who showed, during the study, a sleep–wake cycle averaging 2512 hours24 That is appreciably longer than the 2402-hour average shown by the control subjects in that study, which was near the average innate cycle for healthy adults of all ages: the 2418 hours found by Charles Czeisler4 The literature usually refers to a "one to two hour" delay per 24-hour day ie 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,25 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 248 hours6


As stated above, the majority of patients with Non-24 are totally blind, and 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 clock10 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 hypothalamus1826



The diagnosis is typically made based on a history of persistently delayed sleep onset that follows a non-24-hour pattern In their large series, Hayakawa reported the average day length was 249 ± 04 hours range 244–26516 There may be evidence of "relative coordination" with the sleep schedule becoming more normal as it coincides with the conventional timing for sleep Most reported cases have documented a non-24-hour sleep schedule with a sleep diary see below27 or actigraphy16 In addition to the sleep diary, the timing of melatonin secretion23 or core body temperature rhythm2829 has been measured in a few patients who were enrolled in research studies, confirming the endogenous generation of the non-24-hour circadian rhythm


The disorder can be considered very likely in a totally blind person with periodic insomnia and daytime sleepiness, although other causes for these common symptoms need to be ruled out In the research setting, the diagnosis can be confirmed, and the length of the free-running circadian cycle can be ascertained, by periodic assessment of circadian marker rhythms, such as the core body temperature rhythm,30 the timing of melatonin secretion,831 or by analyzing the pattern of the sleep–wake schedule using actigraphy32 Most recent research has used serial measurements of melatonin metabolites in urine or melatonin concentrations in saliva These assays are not currently available for routine clinical use


A sleep diary with nighttime in the middle and the weekend in the middle, to better notice trends


Enforcing a 24-hour sleep–wake schedule using alarm clocks or family interventions is often tried but usually unsuccessful Bright light exposure on awakening to counteract the tendency for circadian rhythms to delay, similar to the treatment for delayed sleep phase disorder,6 and seasonal affective disorder SAD has been found to be effective in some cases,333435 as has melatonin administration in the subjective late afternoon or evening23363738 Light therapy involves at least 20 minutes of exposure to 3000 to 10000 lux light intensity Going outside on a bright sunny day can accomplish the same benefit as special light fixtures light boxes Bright light therapy combined with the use of melatonin as a chronobiotic and avoidance of light before bedtime may be the most effective treatment Melatonin administration shifts circadian rhythms according to a phase response curve PRC that is essentially the inverse of the light PRC When taken in the late afternoon or evening, it resets the clock earlier; when taken in the morning, it shifts the clock later Therefore, successful entrainment depends on the appropriate timing of melatonin administration The accuracy needed for successfully timing the administration of melatonin requires a period of trial and error, as does the dosage 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 homoeostasis Further to this there are unforeseen disruptions to contend with even when a stabilised cycle is achieved; such as travel, exercise, stress, alcohol or even the use of light emitting technology close to a subjective evening/night

Hypnotics and/or stimulants to promote sleep and wakefulness, respectively have sometimes been used Typically a sleep diary is requested to aid in evaluation of treatment, though the emergence of modern actigraphy devices can also assist in the logging of sleep data Additionally, graphs can now be generated using mobile phone applications, utilising internal accelerometers which are present in most smartphones in use today The graphs and basic sleep diary records can be shared with a physician However, due to the lack of clinical accuracy they should not be used for diagnosis, but instead to monitor the cycle and general progress of any medications in use


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 cues39404142 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 blind4344 For example, Sack et al43 found that 6 out of 7 patients treated with 10 mg melatonin at bedtime were normally entrained When the dose was gradually reduced to 05 mg in three of the subjects, entrainment persisted Subsequently, it was shown that treatment initiated with the 05 mg dose produced entrainment4546 One subject who failed to entrain at a higher dose was successfully entrained at a lower dose47 A low dose produces melatonin blood levels that are similar to the concentrations naturally produced by nightly pineal secretion6

Products containing melatonin are available as dietary supplements in the United States48 and Canada, available over the counter These "supplements" do not require FDA approval As prescription drugs may be prescribed off-label, treatment recommendations for non-24 in the blind may vary

There has been a constant growth in the field of melatonin and melatonin receptor agonists since the 1980s49 In 2005 Ramelteon Rozerem® was the first melatonin agonist to be approved in the United States US, indicated for insomnia treatment in adults50 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 insomnia51 Tasimelteon trade name Hetlioz® received FDA-approval in January 2014 for persons diagnosed with non-2452 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 dyskinesia53


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 environment54


The first report and description of a case of non-24, a man living on 26-hour days, was "A man with too long a day" by Ann L Eliott et al in November 197055 The related and more common delayed sleep phase disorder was not described until 1981


In the first detailed study of non-24 in a blind subject, researchers reported on a 28-year-old male who had a 249-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 shift56

Research directionsedit

Not all totally blind individuals have free-running rhythms, and those that do often show relative coordination as their endogenous rhythms approximate normal timing57 It has been suggested that there are non-photic time cues that are important for maintaining entrainment, but these cues await to be characterized


Since 1979, the disorder has been recognized by the American Academy of Sleep Medicine:

  • Diagnostic Classification of Sleep and Arousal Disorders DCSAD, 1979: Non-24-Hour Sleep–Wake Syndrome; code C2d1
  • The International Classification of Sleep Disorders, 1st & Revised eds ICSD, 1990, 1997: Non-24-Hour Sleep–Wake Syndrome or Non-24-Hour Sleep–Wake Disorder; code 78055-21
  • The International Classification of Sleep Disorders, 2nd ed ICSD-2, 2005: Non-24-Hour Sleep–Wake Syndrome alternatively, Non-24-Hour Sleep–Wake Disorder; code 78055-21

Since 2005, the disorder has been recognized by name in the US National Center for Health Statistics and the US 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 32734 became effective in October 2005 Prior to the introduction of this code, the nonspecific code 30745, Circadian rhythm sleep disorder of nonorganic 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 G4724 is 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 30745 is recommended no acknowledgment of 32734 is made, and ICD-10-CM code G4724 is recommended when it goes into effect58

See alsoedit

  • Delayed sleep phase disorder
  • Advanced sleep phase disorder
  • Irregular sleep–wake rhythm
  • Circadian rhythm sleep disorder
  • Seasonal affective disorder SAD


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  56. ^ Miles LE, Raynal DM, Wilson MA October 1977 "Blind man living in normal society has circadian rhythms of 249 hours" Science 198 4315: 421–3 doi:101126/science910139 PMID 910139 
  57. ^ Emens JS, Laurie AL, Songer JB, Lewy AJ 2013 "Non-24-Hour Disorder in Blind Individuals Revisited: Variability and the Influence of Environmental Time Cues" Sleep 36 7: 1091–1100 doi:105665/sleep2818 PMC 3669071 PMID 23814347 
  58. ^ DSM-5 2013, p 390: "For ICD-9-CM, code 30745 for all subtypes For ICD-10-CM, code is based on subtype"

External linksedit

  • Circadian Sleep Disorders Organization
  • An active mailing list for peer support and information
  • DeRoshia, Charles W; Colletti, Laura C; Mallis, Melissa M 2008 "The Effects of the Mars Exploration Rovers MER Work Schedule Regime on Locomotor Activity Circadian Rhythms, Sleep and Fatigue" PDF 1085MB NASA Ames Research Center NASA/TM-2008-214560 
  • "Improving Sleep in the Blind: It's Not Just Insomnia" Matilda Ziegler Magazine for the Blind October 5, 2011 
  • National Organization for Rare Disorders NORD: Non-24-Hour Sleep–wake Disorder

non-24-hour sleep–wake disorder, non-24-hour sleep–wake disorders

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