Non-24-hour sleep-wake syndrome

Non-24-hour sleep-wake syndrome
Classification and external resources
ICD-10	G47.2
ICD-9	327.34
MeSH	D021081

Non-24-hour sleep-wake syndrome (Non-24) is a chronic circadian rhythm sleep disorder, classified within Chapter VI, Diseases of the Nervous System, in the ICD-10. It can be defined as "a chronic steady pattern comprising one- to two-hour daily delays in sleep onset and wake times in an individual living in society".^[1] The pattern of delay persists literally "around the clock", typically taking a few weeks to complete one cycle. This disruption of the body clock causes cyclical bouts of nighttime sleeplessness and excessive daytime fatigue and napping. People with Non-24 "resemble free-running, normal individuals living in a time-isolation facility with no external time cues".^[2]

Non-24 is a neurological sleep disorder. It is not caused by mental illness or psychological problems. It has been traced to a number of genetic abnormalities that affect specific biologic factors in the brain.

This sleep disorder primarily affects people who are totally blind. Without light sensitivity, the brain is not cued to reset the circadian clock to a 24-hour sleep-wake cycle. It has been estimated by researchers that of the 1.3 million blind people in the U.S.,^[3] 10% of them have no light perception at all.^[4] Of that group, it is estimated that approximately half to three-quarters, or 65,000 to 95,000 Americans, suffer from Non-24.^[5]

The European portal for rare diseases, Orphanet, lists Non-24 as a rare disease by their definition: 1 person per 2,000 or more.^[6] There are about 140,000 sufferers of Non-24 in the European Union; a prevalence of approximately 0.03%, or 3 per 10,000.^[7]

Though often referred to as Non-24, it is also known by the following terms:

• Free running disorder (FRD)
• Hypernychthemeral syndrome
• Circadian rhythm sleep disorder – free-running type
• Circadian rhythm sleep disorder – nonentrained type
• Non-24-hour circadian rhythm disorder
• Non-24-hour sleep-wake disorder

The disorder is an invisible disability and "is extremely debilitating in that it is incompatible with most social and professional obligations".^[8]

Characteristics

In people with this disorder, the body essentially insists that the day is longer 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 and hormone secretion. Left untreated, non-24-hour sleep-wake syndrome causes a person's sleep-wake cycle to change every day, the degree determined by how much over 24 hours the cycle lasts. The cycle progresses around the clock, eventually returning to "normal" for one or two days before going "off" again. This is known as free-running sleep. Most cases that have been reported in the medical literature have occurred in blind patients; Non-24 occurs in more than half of all people who are totally blind.^[9] Sighted people with Non-24 do exist, but are much more rare and the etiology of their circadian disorder is less well understood.^[2] At least one case of a sighted person developing Non-24 was preceded by head injury;^[10] 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 of the hypothalamus.^[11] Several other cases have been preceded by chronotherapy, a prescribed treatment for delayed sleep phase syndrome.^[12]

There have, however, been several studies of sighted people with the syndrome. McArthur et al. reported treating a sighted patient who "appeared to be subsensitive to bright light".^[13] In other words, the brain 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.^[14]) In 2002 Uchiyama et al. examined five sighted Non-24 patients who showed, during the study, a sleep-wake cycle averaging 25.12 hours.^[15] 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, younger and older, of 24.18 hours.^[16] The literature usually refers to a "one to two hour" delay per 24-hour day (i.e. a 25-26 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.^[17] (See Phase response curve, PRC.)

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.^[14]

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.^[14]

Most people with this disorder find that it severely impairs their ability to function socially and occupationally. Typically, they are "partially or totally unable to function in scheduled activities on a daily basis, and most are unable to 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. 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, i.e. sleepiness, fatigue, headache, decreased appetite, or depressed mood. Patients with Circadian Rhythm Sleep Disorder often have difficulty maintaining ordinary social lives, and some of them lose their jobs or fail to attend school.^[14]

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 1970.^[18] The related and more common DSPS wasn't described until 1981.

Symptoms

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

• Cognitive dysfunction
• Confusion
• Diarrhea
• Extreme nausea
• Extreme fatigue
• Hair loss
• Headaches
• Ideational apraxia
• Ideomotor apraxia
• Impaired balance
• Joint pain
• Kinetic apraxia
• Limb apraxia
• Loss of muscle coordination (ataxia)
• Menstrual irregularities
• Muscle pain
• Suicidal thoughts
• Verbal apraxia
• Weight gain

Comorbidity

It has been reported that about 25% of sighted people with this disorder have associated psychiatric disorders,^[19] a rate essentially the same as the 26.2% of the adult population of the US who have psychiatric disorders.^[20] Thus there is no indication of high comorbidity rates of psychiatric disorders among patients with non-24-hour sleep-wake syndrome.

Causes

The etiology of Non-24 is unknown in sighted individuals. However, chronotherapy has been known to cause it in humans.^[8] "Studies in animals suggest that a hypernyctohemeral syndrome could occur as a physiologic aftereffect of lengthening the sleep-wake cycle with chronotherapy.".^[8] According to the American Academy of Sleep Medicine (AASM): "Patients with free-running (FRD) rhythms are thought to reflect a failure of entrainment".^[21]

Treatment

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

Common treatments for non-24-hour sleep-wake syndrome are similar to those for delayed sleep phase syndrome.^[22] They include light therapy with a full spectrum lamp giving—usually—10,000 lux, hypnotics and/or stimulants (to promote sleep and wakefulness, respectively) and melatonin supplements. In any case, a sleep diary should be kept to aid in evaluation of treatment.

Light therapy has been shown useful in treating DSPS; effects on patients with Non-24 are less clear. Melatonin administration has been shown to be effective for mild cases of Non-24, particularly among the blind. It often takes several treatments before any progress is noticed, and for many the treatments may only be marginally effective or not effective at all. In addition, the treatment is not a cure, and the condition may only be managed.

Bright light therapy combined with the use of melatonin as a chronobiotic (as per the PRC) may be the most effective treatment. However the timing of both is tricky and a lot of determination and experimentation is usually required.

Currently, there is no treatment approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for Non-24 in blind people without light perception, though clinical studies are underway.

Clinical Research

There are a number of clinical studies being conducted to investigate the safety and efficacy of a new treatment, a melatonin agonist, which resets the internal clock in people with circadian rhythm sleep disorders, including Non-24. ^[23][24]

See also

• Delayed sleep phase syndrome
• Advanced sleep phase syndrome
• Irregular sleep-wake rhythm
• Circadian rhythm sleep disorder
• Mars Exploration Rover^[25]

External links

• Japanese study of 57 sighted adults with Non-24
• An active mailing list for peer support and information
• The Effects of the Mars Exploration Rovers (MER) Work Schedule Regime on Locomotor Activity Circadian Rhythms, Sleep and Fatigue (PDF, 10.85 MB)
• Radio Interview with Harvard Sleep Researcher Dr. Joseph Hull on Non-24 in the Blind

References

1. ^ ^{a b c d} International Classification of Sleep Disorders Diagnostic and Coding Manual
2. ^ ^{a b} El-Ad, Baruch (2009-04-09). "Non-24-hour sleep-wake syndrome" (Clinical Summary). MedLink Neurology. http://www.medlink.com/medlinkcontent.asp. Retrieved 2009-08-08. "(search, upper left, for "non-24")" 
3. ^ National Federation of the Blind. Blindness Statistics. Retrieved 2011-10-27.
4. ^ Czeisler, C.A., Shanahan, T.L., Klerman, E.B., Martens, H., Bortman, D.J., Emens, J.S., Klein, T., & Risso, J.F. (1995), "Suppression of Melatonin Secretion in Some Blind Patients by Exposure to Bright Light," N Engl J Med 332, 6-11.
5. ^ Sack, R.L., Lewy, A.J., Blood, M.L., Keith, D., & Nakagawa, H. (1992), "Circadian rhythm abnormalities in totally blind people: incidence and clinical significance," J Clin Endocrinol Metab 75, 127-134.
6. ^ Orphanet (April 2006). "Hypernychthemeral syndrome". Inserm: Institut national de la santé et de la recherche médicale. http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=11045&Disease_Disease_Search_diseaseGroup=non-24&Disease_Disease_Search_diseaseType=Pat&Disease(s)%20concerned=Hypernychthemeral-syndrome--Non-24-Hour-Sleep-Wake-syndrome-&title=Hypernychthemeral-syndrome--Non-24-Hour-Sleep-Wake-syndrome-&search=Disease_Search_Simple. Retrieved 2009-08-08. 
7. ^ "New Drugs Online Report for tasimelteon". UK Medicines Information, National Health Service. http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=5145. Retrieved 2011-05-17. 
8. ^ ^{a b c} Oren, Dan A.; Thomas A. Wehr (10 December 1992). "Hypernyctohemeral Syndrome after Chronotherapy for Delayed Sleep Phase Syndrome" (Letter to the Editor). New England Journal of Medicine (Massachusetts Medical Society) 327 (24): 1762. doi:10.1056/NEJM199212103272417. PMID 1435929. 
9. ^ "Circadian Rhythm Sleep Disorder" (PDF). American Academy of Sleep Medicine. 2008. http://www.aasmnet.org/resources/factsheets/crsd.pdf. Retrieved 2009-08-08. 
10. ^ Boivin et al. (2003). "Non-24-hour sleep-wake syndrome following a car accident". Neurology 60 (11): 1841–3. 
11. ^ Stores G (2003). "Misdiagnosing sleep disorders as primary psychiatric conditions" (Full text). Advances in Psychiatric Treatment 9 (1): 69–77. doi:10.1192/apt.9.1.69. http://apt.rcpsych.org/cgi/content/full/9/1/69. 
    See also subsequent:
    * Stores G (2007). "Clinical diagnosis and misdiagnosis of sleep disorders". J. Neurol. Neurosurg. Psychiatr. 78 (12): 1293–7. doi:10.1136/jnnp.2006.111179. PMC 2095611. PMID 18024690. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2095611. 
12. ^ Wilkins J (1990). "Treatment of DSPS in 7 chronic patient". New England Journal of Medicine 7: 161–67. 
13. ^ McArthur AJ, Lewy AJ, Sack RL (1996). "Non-24-hour sleep-wake syndrome in a sighted man: circadian rhythm studies and efficacy of melatonin treatment". Sleep 19 (7): 544–53. PMID 8899933. 
14. ^ ^{a b c d} Okawa, Masako; Uchiyama, Makoto (2007). "Clinical Review. Circadian Rhythm Sleep Disorder: Characteristics and entrainment pathology in delayed sleep phase and non-24-h sleep-wake syndrome" (PDF). Sleep Medicine (Elsevier Ltd) (11): 485–496. http://www.chronobiology.ch/chronobiology.data/Dokumente/PDF/PDF_Chrono_Psychiatry/Okawa_07.pdf. Retrieved 2008-03-13. 
15. ^ Uchiyama M, Shibui K, Hayakawa T, Kamei Y, Ebisawa T, Tagaya H, Okawa M, Takahashi K (2002). "Larger phase angle between sleep propensity and melatonin rhythms in sighted humans with non-24-hour sleep-wake syndrome". Sleep 25 (1): 83–88. PMID 11833864. 
16. ^ "Human Biological Clock Set Back an Hour". 1999. http://news.harvard.edu/gazette/1999/07.15/bioclock24.html. Retrieved 2007-12-09. 
17. ^ Uchiyama M et al. (2000). "Altered phase relation between sleep timing and core body temperature rhythm in delayed sleep phase syndrome and non-24-hour sleep–wake syndrome in humans". Neuroscience Letters 294 (2): 101–104. doi:10.1016/S0304-3940(00)01551-2. PMID 11058797. 
18. ^ Billiard, Michel; Angela Kent (2003) (Page view, Google books). Sleep: Physiology, Investigations, and Medicine. New York: Springer. pp. 495–97, 502. ISBN 0306474069. http://books.google.com/?id=IorPrIY6dOYC&pg=PA505&lpg=PA505&dq=hypernychthemeral+syndrome&q=hypernychthemeral%20syndrome. Retrieved 2009-11-08. 
19. ^ Hayakawa, T, Kamei, Y, Urata, J, Shibui, K, Ozaki, S, Uchiyama, M, and Okawa, M. Trials of bright light exposure and melatonin administration in a patient with non-24 hour sleep-wake syndrome. Psychiatry & Clinical Neurosciences 1998;52:261-2.
20. ^ "The Numbers Count: Mental Disorders in America". 2009. http://www.nimh.nih.gov/health/publications/the-numbers-count-mental-disorders-in-america/index.shtml. Retrieved 2009-11-27. 
21. ^ Moegenthaler, TI; T Lee-Chiong et al (November 2007). "Standards of Practice Committee of the AASM. Practice Parameters for the Clinical Evaluation and Treatment of Circadian Rhythm Sleep Disorder" (Full text). SLEEP (Associated Professional Sleep Societies, LLC) 30 (11): 1445–59. PMC 2082098. PMID 18041479. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2082098. Retrieved 2010-26-9. 
22. ^ Okawa, Masako; Uchiyama, Makoto (2007). "Clinical Review. Circadian Rhythm Sleep Disorder: Characteristics and entrainment pathology in delayed sleep phase and non-24-h sleep-wake syndrome" (PDF). Sleep Medicine (Elsevier Ltd) (11): 485–496. http://www.chronobiology.ch/chronobiology.data/Dokumente/PDF/PDF_Chrono_Psychiatry/Okawa_07.pdf. Retrieved 2008-04-16. "Bright-light therapy and melatonin are known to be effective for DSPS and non-24. However, many patients do not properly respond to these treatments." 
23. ^ U.S. National Institutes of Health, Clinical Trials database. Retrieved 2011-10-27
24. ^ European Medicines Agency, EU Clinical Trials Register. Retrieved 2011-10-27.
25. ^ Mallis, Melissa (December 4, 2003). "Working a Mars Sol (24.65-hr) Schedule on Earth". National Aeronautics and Space Administration. Human Systems Integration Division. http://human-factors.arc.nasa.gov/awards_pubs/news_view.php?news_id=13. Retrieved 9 July 2011.