Non-24-hour sleep-wake syndrome
Encyclopedia
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". 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".
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., 10% of them 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, suffer from Non-24.
The European portal for rare diseases, Orphanet
, lists Non-24 as a rare disease by their definition: 1 person per 2,000 or more. There are about 140,000 sufferers of Non-24 in the European Union
; a prevalence of approximately 0.03%, or 3 per 10,000.
Though often referred to as Non-24, it is also known by the following terms:
The disorder is an invisible disability
and "is extremely debilitating in that it is incompatible with most social and professional obligations".
s 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. Sighted people with Non-24 do exist, but are much more rare 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
of the hypothalamus
.See also subsequent:
* Several other cases have been preceded by chronotherapy, a prescribed treatment for delayed sleep phase syndrome
.
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". 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.) 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, younger and older, of 24.18 hours. 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. (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.
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.
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". 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 microsleep
s, 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.
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. The related and more common DSPS
wasn't described until 1981.
and can include:
has been known to cause it in humans. "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
".
Common treatments for non-24-hour sleep-wake syndrome are similar to those for delayed sleep phase syndrome
. 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.
Circadian rhythm sleep disorder
Circadian rhythm sleep disorders are a family of sleep disorders affecting, among other things, the timing of sleep. People with circadian rhythm sleep disorders are unable to sleep and wake at the times required for normal work, school, and social needs. They are generally able to get enough sleep...
, classified within Chapter VI, Diseases of the Nervous System, in the ICD-10
ICD-10
The International Statistical Classification of Diseases and Related Health Problems, 10th Revision is a medical classification list for the coding of diseases, signs and symptoms, abnormal findings, complaints, social circumstances, and external causes of injury or diseases, as maintained by the...
. 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". 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".
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., 10% of them 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, suffer from Non-24.
The European portal for rare diseases, Orphanet
Orphanet
Orphanet is a European website providing information about orphan drugs and rare diseases. It contains content both for physicians and for patients. Its administrative office is in Paris. The organisation also publishes the open-access online journal Orphanet Journal of Rare Diseases.-External...
, lists Non-24 as a rare disease by their definition: 1 person per 2,000 or more. There are about 140,000 sufferers of Non-24 in the European Union
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
; a prevalence of approximately 0.03%, or 3 per 10,000.
Though often referred to as Non-24, it is also known by the following terms:
- Free running disorder (FRD)
- Hypernychthemeral syndrome
- Circadian rhythm sleep disorderCircadian rhythm sleep disorderCircadian rhythm sleep disorders are a family of sleep disorders affecting, among other things, the timing of sleep. People with circadian rhythm sleep disorders are unable to sleep and wake at the times required for normal work, school, and social needs. They are generally able to get enough sleep...
– free-runningFree-running sleepFree-running sleep experiments can involve any organism which sleeps. Free-running sleep is sleep which is not adjusted, entrained, to the 24-hour cycle in nature nor to any artificial cycle. Such experiments are used in the study of circadian and other rhythms in biology...
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
Invisible disability
Invisible disabilities are disabilities that are not immediately apparent. Some people with visual or auditory disabilities who do not wear glasses or hearing aids, or discreet hearing aids, may not be obviously disabled. Some people who have vision loss may wear contacts...
and "is extremely debilitating in that it is incompatible with most social and professional obligations".
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 rhythmCircadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
s 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
Free-running sleep
Free-running sleep experiments can involve any organism which sleeps. Free-running sleep is sleep which is not adjusted, entrained, to the 24-hour cycle in nature nor to any artificial cycle. Such experiments are used in the study of circadian and other rhythms in biology...
. Most cases that have been reported in the medical literature have occurred in blind
Blindness
Blindness is the condition of lacking visual perception due to physiological or neurological factors.Various scales have been developed to describe the extent of vision loss and define blindness...
patients; Non-24 occurs in more than half of all people who are totally blind. Sighted people with Non-24 do exist, but are much more rare 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
Suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...
of the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
.See also subsequent:
* Several other cases have been preceded by chronotherapy, a prescribed treatment for delayed sleep phase syndrome
Delayed sleep phase syndrome
Delayed sleep-phase syndrome , also known as delayed sleep-phase disorder or delayed sleep-phase type , is a circadian rhythm sleep disorder, a chronic disorder of the timing of sleep, peak period of alertness, the core body temperature rhythm, hormonal and other daily rhythms, compared to the...
.
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". 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
Photophobia
Photophobia is a symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of actual physical photosensitivity of the eyes, though the term...
; 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, younger and older, of 24.18 hours. 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. (See Phase response curve
Phase response curve
A phase response curve illustrates the transient change in the cycle period of an oscillation induced by a perturbation as a function of the phase at which it is received...
, 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.
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
Daylight saving time
Daylight saving time —also summer time in several countries including in British English and European official terminology —is the practice of temporarily advancing clocks during the summertime so that afternoons have more daylight and mornings have less...
, 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.
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". Attempts to keep conventional hours by people with the disorder generally result in insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
(which is not a normal feature of the disorder itself) and excessive sleepiness, to the point of falling into microsleep
Microsleep
A microsleep is an episode of sleep which may last for a fraction of a second or up to thirty seconds. Often, it is the result of sleep deprivation, mental fatigue, depression, sleep apnea, hypoxia, narcolepsy, or hypersomnia...
s, as well as myriad effects associated with acute and chronic sleep deprivation
Sleep deprivation
Sleep deprivation is the condition of not having enough sleep; it can be either chronic or acute. A chronic sleep-restricted state can cause fatigue, daytime sleepiness, clumsiness and weight loss or weight gain. It adversely affects the brain and cognitive function. Few studies have compared the...
. 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
Circadian rhythm sleep disorder
Circadian rhythm sleep disorders are a family of sleep disorders affecting, among other things, the timing of sleep. People with circadian rhythm sleep disorders are unable to sleep and wake at the times required for normal work, school, and social needs. They are generally able to get enough sleep...
often have difficulty maintaining ordinary social lives, and some of them lose their jobs or fail to attend school.
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. The related and more common DSPS
Delayed sleep phase syndrome
Delayed sleep-phase syndrome , also known as delayed sleep-phase disorder or delayed sleep-phase type , is a circadian rhythm sleep disorder, a chronic disorder of the timing of sleep, peak period of alertness, the core body temperature rhythm, hormonal and other daily rhythms, compared to the...
wasn't described until 1981.
Symptoms
Symptoms reported by patients forced into a 24-hour schedule are similar to those of sleep deprivationSleep deprivation
Sleep deprivation is the condition of not having enough sleep; it can be either chronic or acute. A chronic sleep-restricted state can cause fatigue, daytime sleepiness, clumsiness and weight loss or weight gain. It adversely affects the brain and cognitive function. Few studies have compared the...
and can include:
- Cognitive dysfunctionCognitive dysfunctionCognitive dysfunction is defined as unusually poor mental function, associated with confusion, forgetfulness and difficulty concentrating...
- ConfusionConFusionConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
- Diarrhea
- Extreme nauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
- Extreme fatigue
- Hair loss
- Headaches
- Ideational apraxiaIdeational apraxiaIdeational apraxia is a neurological disorder which explains the loss of ability to conceptualize, plan, and execute the complex sequence of motor actions involving the use of tools or objects in everyday life. Ideational apraxia is a condition in which an individual is unable to plan movement...
- Ideomotor apraxiaIdeomotor apraxiaIdeomotor Apraxia, often IMA, is a neurological disorder characterized by the inability to correctly imitate hand gestures and voluntarily pantomime tool use, e.g. pretend to brush one's hair. The ability to spontaneously use tools, such as brushing one's hair in the morning without being...
- Impaired balanceBalance- Equipment :* Balance beam, a piece of gymnastics apparatus.* Balance board, a piece of training equipment.* Balancing machine, a machine that balances mechanical rotating parts to lessen vibration.* Balance wheel, a watch component....
- Joint pain
- Kinetic apraxia
- Limb apraxia
- Loss of muscle coordination (ataxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
) - Menstrual irregularities
- Muscle pain
- Suicidal thoughts
- Verbal apraxiaApraxia of speechApraxia of Speech is a motor speech disorder affecting an individual's ability to translate conscious speech plans into motor plans and is caused by illness or injury in adults. Like other apraxias, it only affects volitional movement patterns...
- Weight gain
Comorbidity
It has been reported that about 25% of sighted people with this disorder have associated psychiatric disorders, a rate essentially the same as the 26.2% of the adult population of the US who have psychiatric disorders. 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, chronotherapyChronotherapy
People who suffer from delayed sleep phase syndrome are generally unable to reset their circadian rhythm by moving their bedtime and rising time earlier...
has been known to cause it in humans. "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
Entrainment (chronobiology)
Entrainment, within the study of chronobiology, occurs when rhythmic physiological or behavioral events match their period and phase to that of an environmental oscillation. A common example is the entrainment of circadian rhythms to the daily light–dark cycle, which ultimately is determined by...
".
Treatment
Delayed sleep phase syndrome
Delayed sleep-phase syndrome , also known as delayed sleep-phase disorder or delayed sleep-phase type , is a circadian rhythm sleep disorder, a chronic disorder of the timing of sleep, peak period of alertness, the core body temperature rhythm, hormonal and other daily rhythms, compared to the...
. They include light therapy
Light therapy
Light therapy or phototherapy consists of exposure to daylight or to specific wavelengths of light using lasers, light-emitting diodes, fluorescent lamps, dichroic lamps or very bright, full-spectrum light, usually controlled with various devices...
with a full spectrum lamp giving—usually—10,000 lux
Lux
The lux is the SI unit of illuminance and luminous emittance, measuring luminous flux per unit area. It is used in photometry as a measure of the intensity, as perceived by the human eye, of light that hits or passes through a surface...
, hypnotics and/or stimulants (to promote sleep and wakefulness, respectively) and melatonin
Melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
supplements. In any case, a sleep diary
Sleep diary
A sleep diary is a record of an individual's sleeping and waking times with related information, usually over a period of several weeks. It is self-reported or can be recorded by a care-giver....
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
Chronobiotic
Chronobiotic is a substance that is capable of therapeutically re-entering short - term dissociated or long - term desynchronized circadian rhythms, or prophylactically preventing their disruption following an environmental insult. In more simple words, chronobiotic is defined as the agent causes...
(as per the PRC
Phase response curve
A phase response curve illustrates the transient change in the cycle period of an oscillation induced by a perturbation as a function of the phase at which it is received...
) 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.See also
- Delayed sleep phase syndromeDelayed sleep phase syndromeDelayed sleep-phase syndrome , also known as delayed sleep-phase disorder or delayed sleep-phase type , is a circadian rhythm sleep disorder, a chronic disorder of the timing of sleep, peak period of alertness, the core body temperature rhythm, hormonal and other daily rhythms, compared to the...
- Advanced sleep phase syndromeAdvanced sleep phase syndromeAdvanced sleep phase syndrome , also known as the advanced sleep-phase type of circadian rhythm sleep disorder, is a condition in which patients feel very sleepy and go to bed early in the evening and wake up very early in the morning Advanced sleep phase syndrome (ASPS), also known as the...
- Irregular sleep-wake rhythmIrregular sleep-wake rhythmIrregular sleep–wake rhythm is a rare form of circadian rhythm sleep disorder. It is characterized by numerous naps throughout the 24-hour period, no main nighttime sleep episode and irregularity from day to day. Sufferers have no pattern of when they are awake or asleep, may have poor quality...
- Circadian rhythm sleep disorderCircadian rhythm sleep disorderCircadian rhythm sleep disorders are a family of sleep disorders affecting, among other things, the timing of sleep. People with circadian rhythm sleep disorders are unable to sleep and wake at the times required for normal work, school, and social needs. They are generally able to get enough sleep...
- Mars Exploration RoverMars Exploration RoverNASA's Mars Exploration Rover Mission is an ongoing robotic space mission involving two rovers, Spirit and Opportunity, exploring the planet Mars...
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