Non-24-hour sleep–wake disorder

Non-24-hour sleep–wake disorder (non-24), is one The disorder in its extreme form is an invisible disability
of several chronic circadian rhythm sleep disorders that can be “extremely debilitating in that it is incompat(CRSDs). It is defined as a “chronic steady pattern com- ible with most social and professional obligations”.[3]
prising [...] 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.

1 Mechanisms

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 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.[4] 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 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 clock.[1] 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 The circadian clock modulates many physiological
schedule.
rhythms.[5] The most easily observed of these is the
Though often referred to as non-24, for example by the propensity for sleep and wake; thus, people with non-24
FDA,[2] the disorder is also known by the following terms: 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[1]
• Non-24-hour sleep–wake syndrome
hour day and they attempt to conform to a conventional
schedule. Eventually, their circadian rhythms will drift
• Non-24-hour sleep–wake disorder
back into normal alignment, and symptoms temporarily
• Non-24-hour sleep-wake rhythm disorder
resolve, but then their clocks drift out of alignment again.
Thus the overall pattern involves recurring symptoms on
• Free running disorder (FRD)
a weekly or monthly basis, depending on the length of the
internal circadian cycle. For example, an individual with
• Hypernychthemeral disorder
a circadian period of 24.5 hours would drift 30 minutes
• Circadian rhythm sleep disorder – free-running type later each day and would be maximally misaligned every
48 days. If patients set their own schedule for sleep and
• Circadian rhythm sleep disorder – nonentrained wake, aligned to their endogenous non-24 period (as is the
type
case for most sighted patients with this disorder), symptoms of insomnia and wake-time sleepiness are much re• N24HSWD
duced. However, such a schedule is incompatible with
• Non-24-hour circadian rhythm disorder
most occupations and social relationships.
1

illness.[10] the external light–dark cycle. 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. in employment and in their social lives. is not cued each day to synchronize the circadian rhythm to the 24-hour 2. 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 3 Symptoms alertness.000.[19] At least one .[7][8] The disorder can occur at any age. they are “partially or totally unable to function in scheduled activities on a daily basis.[9] as the photosensitive ganglion cells in the retina are also removed. 4.000 to 95. body temperature minimum. Non-24-hour sleep–wake disorder causes a person’s sleep–wake cycle to move around the Symptoms reported by patients forced into a 24-hour clock every day. a total prevalence of approximately 3 per 10. which are typically known to cause fatigue. People with the disorder may have an especially hard time adjusting to changes in “regular” sleep–wake cycles. evening activities. so incidence may be higher. It is sometimes preceded by delayed sleep phase as a rare disease by its definition.S. They also show lower sleep propensity after total sleep deprivation than do normal sleepers.3 million blind people in the U. it is estimated that approximately half to threequarters. [3] disorder. Most people with this disorder find that it severely impairs their ability to function in school. shorter) than 24 hours and refuses to adjust to night can affect the body clock. medications (especially stimulants or sedatives).[1] to the point of falling into microsleeps. decreased appetite.2 Blind It has been estimated that non-24 occurs in more than half of all people who are totally blind. and some of them lose their jobs or fail to attend school. Orphanet.e.[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. the suprachiasmatic nucleus (SCN). or 65. The European portal for rare diseases. headache. to a degree dependent on the length of schedule are similar to those of sleep deprivation and can the cycle. resulting in non-24 for many totally blind individuals. as well as myriad effects associated with acute and chronic sleep deprivation. the body essentially insists that patients who retain at least some light perception. not uncommonly in child.03%. sleepiness. Patients often have difficulty maintaining ordinary social lives.2 Blind While both sighted and blind people are diagnosed with non-24. travel to different time zones. Organization for Rare Disorders (NORD) lists Non-24 hood. or depressed mood. there had been fewer than 100 cases of sighted people with non-24 reported in the scientific literature.[17] 10% have no light perception at all.[16] 4. It has been estimated by researchers that of the 1.[7] Non-24 is rare among visually impaired In people with non-24. the disorder is believed to affect more totally blind individuals than sighted. and growth spurts. stress. or 0. Rethe length of a day (and night) is appreciably longer (or. fatigue.person for every 2000 population. time changes like daylight saving time. from birth onwards. It generally follows shortly after loss or removal of a person’s eyes. This is known as freerunning sleep. and most cannot work at conventional jobs”. i.[6] 4 Prevalence There are an estimated 140. located in the hypothalamus.1 Sighted As of 2005. suffer from non-24..[8] 5 Causes 5. eventually returning to “normal” for one or two include: days before “going off” again. metabolism and hormone secretion.2 2 5 CAUSES Characteristics Without light to the retina.[18] Of that group.1 Sighted social day. Typically. changes in daylight hours in different seasons.”[6] 2.000 Americans.000 people with N24 – both sighted and blind – in the European Union. lists Non-24 as a rare disease by their definition: fewer than 1 affected [15] The US National Non-24 can begin at any age. searchers have found that even minimal light exposure at very rarely.[14] It is unknown how many individuals with this disorder do not seek medical attention.1 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. such as vacations.

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. to better notice trends and hypothalamus. examThe disorder can be considered very likely in a totally ined five sighted non-24 patients who showed. Specifically. one study found that they were more sensitive than the control group. a 25. the timing of melatonin secretion[23] or core body temperature rhythm[28][29] has been meaThere have been several experimental studies of sighted sured in a few patients who were enrolled in research studpeople with the disorder.are not currently available for routine clinical use. even minimal light exposure can synchronize the body clock.m. it is thought to involve abnormal functioning of the suprachiasmatic nucleus (SCN) in the hypothalamus. the diby the control subjects in that study.[21] Several other cases have been preceded by chronotherapy.[16] 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 below)[27] or actigraphy. In their clinical review in 2007. reported treat. In the research setting.2 Blind tive to light.[24] That ness.4 hours (range 24. a prescribed treatment for delayed sleep phase disorder. had earlier determined that sighted wake schedule using actigraphy. confirming the endogenous generation of the non-24ing a sighted patient who “appeared to be subsensitive to hour circadian rhythm.8 hours. Wed Thu Fri Sat Sun Mon Tue Blind As stated above.1 Sighted The diagnosis is typically made based on a history of persistently delayed sleep onset that follows a non-24-hour pattern.5).[23] In other words.02-hour average shown need to be ruled out.[22] 6 Diagnosis 6.[6] ) In 2002 Uchiyama et al. and the failure of entrainment is explained by the loss of photic input to the circadian clock.[18][26] . but are normally entrained and have an intact response to the suppressing effects of light on melatonin secretion. McArthur et al. although other causes for these common symptoms is appreciably longer than the 24.18 hours found by Charles Czeisler.9 ± 0. by periodic 24. a sleep–wake cycle averaging 25. Non24 is rare among visually impaired patients who retain at least some light perception.[25] as per the phase response curve (PRC) for light. Thu Fri Sat Sun Mon Tue Wed totally blind. val between the temperature trough and awakening makes illumination upon awakening virtually ineffective.ies.[3] According to the American Academy of Sleep Medicine (AASM): “Patients with free-running (FRD) rhythms are thought to reflect a failure of entrainment". bright light”.to 26-hour cycle).[19] “Studies in animals suggest that a hypernyctohemeral syndrome could occur as a physiologic aftereffect of lengthening the sleep–wake cycle with chronotherapy”. during the blind person with periodic insomnia and daytime sleepistudy. In their large series. and the length of the freeaverage innate cycle for healthy adults of all ages: the running circadian cycle can be ascertained. the majority of patients with Non-24 are a.12 hours. be unusually subjectively sensi6.e. These assays hours before awakening.[20] another patient diagnosed with the disorder was later found to have a “large pituitary adenoma that involved the optic chiasma".m.[1] Thus the problem appears to be neurological.2 7 Treatment p. the brain (or the retina) does not react normally to light (people with the disorder may or may not.[16] In addition to the sleep diary.4–26. which was near the agnosis can be confirmed. however.[32] Most recent research non-24 patients’ minimum core body temperature occurs has used serial measurements of melatonin metabolites in much earlier in the sleep episode than the normal two urine or melatonin concentrations in saliva.[10] A few cases have been described in which patients are subjectively blind. Hayakawa reported the average day length was 24. They suggest that the long inter.[4] The literature assessment of circadian marker rhythms. secretion.[30] the timing of melatonin day (i.[6] 5.[8][31] or by analyzing the pattern of the sleep– Uchiyama et al.3 case of a sighted person developing non-24 was preceded by head injury. such as the core usually refers to a “one to two hour” delay per 24-hour body temperature rhythm. A sleep diary with nighttime in the middle and the weekend in indicating preserved neural pathways between the retina the middle.

[6] and seasonal affective disorder (SAD) has been found to be effective in some cases. several research groups showed that appropriately timed mela- 8. Going outside on a bright sunny day can accomplish the same benefit as special light fixtures (light boxes). The graphs and basic sleep diary records can be shared with a physician. graphs can now be generated using mobile phone applications. exercise. Additionally.[53] 8 History The ability of melatonin administration to entrain freerunning rhythms was first demonstrated by Redman.[33][34][35] as has melatonin administration in the subjective late afternoon or evening.[39][40][41][42] Then. was “A man with too long a day” by Ann L.[52] TIK-301 (Tikvah Therapeutics.[43] found that 6 out of 7 patients treated with 10 mg melatonin at bedtime were normally entrained.[50] Melatonin in the form of prolonged release (trade name Circadin® ) was approved in 2007 in Europe (EU) for use as a shortterm treatment. Therefore. it shifts the clock later.5 mg dose produced entrainment. as does the dosage. However. light intensity and diet are likely to affect the efficacy of melatonin and light therapies since these exogenous zeitgebers would compete for hormonal homoeostasis. Eliott et al. In addition to natural fluctuations within the circadian rhythm. in patients 55 years and older. Bright light therapy combined with the use of melatonin as a chronobiotic and avoidance of light before bedtime may be the most effective treatment. Subsequently.[47] A low dose produces melatonin blood levels that are similar to the concentrations naturally produced by nightly pineal secretion. Melatonin administration shifts circadian rhythms according to a phase response curve (PRC) that is essentially the inverse of the light PRC. entrainment persisted. indicated for insomnia treatment in adults. in November 1970. treatment recommendations for non-24 in the blind may vary. though the emergence of modern actigraphy devices can also assist in the logging of sleep data. There has been a constant growth in the field of melatonin and melatonin receptor agonists since the 1980s. . hours of daylight.[49] In 2005 Ramelteon (Rozerem® ) was the first melatonin agonist to be approved in the United States (US). similar to the treatment for delayed sleep phase disorder. et al.[54] Blind In the 1980s and 1990s. available over the counter. Further to this there are unforeseen disruptions to contend with even when a stabilised cycle is achieved.[55] The related and more common delayed sleep phase disorder was not described until 1981.4 7. Atlanta. alcohol or even the use of light emitting technology close to a subjective evening/night. When the dose was gradually reduced to 0.[6] Products containing melatonin are available as dietary supplements in the United States[48] and Canada.1 8 Sighted Enforcing a 24-hour sleep–wake schedule using alarm clocks or family interventions is often tried but usually unsuccessful.5 mg in three of the subjects. 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.[23][36][37][38] Light therapy involves at least 20 minutes of exposure to 3000 to 10000 lux light intensity. a man living on 26-hour days. Typically a sleep diary is requested to aid in evaluation of treatment.[43][44] For example. 7. These “supplements” do not require FDA approval. utilising internal accelerometers which are present in most smartphones in use today.[45][46] One subject who failed to entrain at a higher dose was successfully entrained at a lower dose. for use as a treatment for circadian rhythm sleep disorder in blind individuals without light perception as well as individuals with tardive dyskinesia. when taken in the morning. Hypnotics and/or stimulants (to promote sleep and wakefulness.1 Sighted The first report and description of a case of non-24. it was shown that treatment initiated with the 0. several trials of melatonin administration to totally blind individuals without light perception produced improvement in sleep patterns. successful entrainment depends on the appropriate timing of melatonin administration. As prescription drugs may be prescribed off-label. it resets the clock earlier. for primary insomnia. respectively) have sometimes been used. using endogenous melatonin as a marker for circadian rhythms. Bright light exposure on awakening to counteract the tendency for circadian rhythms to delay. Sack et al.[51] Tasimelteon (trade name Hetlioz® ) received FDA-approval in January 2014 for persons diagnosed with non-24. such as travel. but instead to monitor the cycle and general progress of any medications in use. The accuracy needed for successfully timing the administration of melatonin requires a period of trial and error. due to the lack of clinical accuracy they should not be used for diagnosis. When taken in the late afternoon or evening. in 1983 in rats who were maintained in a time-free environment. but it was unclear at that time if the benefits were due to entrainment from light cues.2 HISTORY tonin administration could entrain free-running rhythms in the totally blind. seasonal changes including temperature. stress.

2014. PMID 1435929.[57] It has been suggested that there are non-photic time cues that are important for maintaining entrainment. Uchiyama M (December 2007). Retrieved 30 April 2016. • ICD-10-CM: Circadian rhythm sleep disorder.45 is recommended (no acknowledgment of 327.2 Blind In the first detailed study of non-24 in a blind subject. Even while adhering to a typical 24-hour schedule for bedtime. Retrieved August 8. and meals. code 327. Retrieved December 9. as PDF [7] “Circadian Rhythm Sleep Disorder” (PDF). 2007. National Center for Health Statistics and the U. and other parameters. American Academy of Sleep Medicine. 2008. 2014. .1056/NEJM199212103272417. code G47. doi:10. researchers reported on a 28-year-old male who had a 24. (ICSD-2). New England Journal of Medicine (Letter to the Editor) (Massachusetts Medical Society) 327 (24): 1762.34 became effective in October 2005. [2] “Peripheral and Central Nervous System Drugs Advisory Committee Meeting. Retrieved 6 May 2016. rise time.24 is recommended when it goes into effect. 2005: Non-24Hour Sleep–Wake Syndrome (alternatively. code C. and those that do often show relative coordination as their endogenous rhythms approximate normal timing. 10 Classifications Since 1979. free running type. [5] Fadden. PMID 17964201.2007. Katherine.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. “Circadian rhythm sleep disorders: characteristics and entrainment pathology in delayed sleep phase and non-24-h sleep–wake syndrome”. (ICSD). Sleep Med Rev 11 (6): 485–96. [6] Okawa M. 1999.[56] 9 Research directions Not all totally blind individuals have free-running rhythms. FDA. and ICD-10-CM code G47. 2nd ed. Harvard University Gazette.[58] 11 See also • Delayed sleep phase disorder • Advanced sleep phase disorder • Irregular sleep–wake rhythm • Circadian rhythm sleep disorder • Seasonal affective disorder (SAD) 12 References Notes [1] American Academy of Sleep Medicine (2001). [4] “Human Biological Clock Set Back an Hour”.08. “Hypernyctohemeral Syndrome after Chronotherapy for Delayed Sleep Phase Syndrome”.55-2[1] • The International Classification of Sleep Disorders.. 1979: Non-24-Hour Sleep–Wake Syndrome. James S.9hour rhythm in sleep. the disorder has been recognized by the American Psychiatric Association: • DSM-5. “Non-24-Hour Sleep-Wake Disorder”. 1st & Revised eds. Non-24-hour sleep–wake type. Thomas A.34 is made). the man’s body rhythms continued to shift. ISBN 0-9657220-1-5. Sharkey.d[1] • The International Classification of Sleep Disorders. and as of 2014 remains the code recommended by the DSM-5. 1992). doi:10. the nonspecific code 307. Tasimelteon. Revised (ICSDR) (PDF). 1990. the disorder has been recognized by name in the U. National Organization for Rare Disorders. 2013. 2013: Circadian rhythm sleep–wake disorders. 1997: Non24-Hour Sleep–Wake Syndrome (or Non-24-Hour Sleep–Wake Disorder).24 is due to take effect October 1. 2009.2. Since 2013. Circadian rhythm sleep disorder of nonorganic origin.. code 780.” (PDF).001. but these cues await to be characterized. plasma cortisol. Dan A.S. work.5 8. Non24-Hour Sleep–Wake Disorder). freerunning type.smrv. November 14. ICD-9-CM code 307. July 15.P. code 780. [3] Oren. the disorder has been recognized by the American Academy of Sleep Medicine: • Diagnostic Classification of Sleep and Arousal Disorders (DCSAD).1016/j. The International Classification of Sleep Disorders. Prior to the introduction of this code.45.55-2[1] Since 2005. Retrieved May 7. Wehr (December 10. was available.

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Raynal DM.” 13 External links • Circadian Sleep Disorders Organization • An active mailing list for peer support and information • DeRoshia. • “Improving Sleep in the Blind: It’s Not Just Insomnia”. Laurie AL. • National Organization for Rare Disorders (NORD): Non-24-Hour Sleep–wake Disorder EXTERNAL LINKS . Colletti.8 13 [56] Miles LE. doi:10. For ICD-10-CM..85MB).45 for all subtypes. Matilda Ziegler Magazine for the Blind. code is based on subtype. NASA/TM-2008-214560..910139. Songer JB. [58] DSM-5 (2013). [57] Emens JS. Laura C. 390: “For ICD-9-CM. p. “Non24-Hour Disorder in Blind Individuals Revisited: Variability and the Influence of Environmental Time Cues”. “Blind man living in normal society has circadian rhythms of 24. “The Effects of the Mars Exploration Rovers (MER) Work Schedule Regime on Locomotor Activity Circadian Rhythms. 2011. (2008).5665/sleep. October 5. Mallis. Lewy AJ (2013). NASA Ames Research Center. Melissa M. Science 198 (4315): 421–3.9 hours”. code 307. Sleep and Fatigue” (PDF 10. Charles W. Wilson MA (October 1977).2818. PMID 23814347. doi:10. PMID 910139. Sleep 36 (7): 1091–1100. PMC 3669071.1126/science.

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