Non-24-hour sleep–wake disorder
|Non-24-hour sleep–wake disorder|
|Symptoms||Progressively shifting nighttime|
|Complications||None if sleeping according to biological clock, sleep deprivation otherwise|
|Causes||Blindness, unknown for sighted|
|Diagnostic method||Sleep diary, actigraphy|
|Frequency||50% of total blind people, common in blind, rare in sighted|
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 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 half of the totally blinds, it can also affect sighted people more rarely. The American Academy of Sleep Medicine (AASM) provides guidelines since 2007 with the latest update released in 2015.
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 sleepers.
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 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 often have difficulty maintaining ordinary social lives, and some of them lose their jobs or fail to attend school."
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.
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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.
Symptoms reported by patients forced into a 24-hour schedule are similar to those of sleep deprivation and can include:
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.
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 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.
The circadian rhythm
All living animals have an internal clock, the circadian rhythm, that is close to, but different from 24 hours. For humans, the average is 24 hours 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 that is significantly different from 24 hours, up to 26 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. These people's brains may have normal circadian clocks, but the clocks 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 everyday.
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 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 disorder, circadian rhythm sleep disorder – free-running type or nonentrained type, N24HSWD, Non-24-hour circadian rhythm disorder.
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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 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 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 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 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 suggest that N24SWD might in fact be a different disorder in sighted and blind people, with different internal and external contributing factors that might affect treatment response and thus might necessitate different treatments, as thus, future studies should try to identify and assess these factors.
Non-24-hour sleep-wake disorder is diagnosed when the patient fails to follow (entrain to) a 24-hour light-dark cycle and clock times. As such, the entrainment status (defined as whether the hypothalamic circadian clock is synchronized to a 24-hour day) physiologically defines this disorder and can thus be used as the sole outcome measure. This is similar to elevated blood pressure characterizing essential hypertension. In contrast to other circadian rhythm sleep-wake disorders (CRSWD), a diagnosis of non-24 sleep-wake disorder requires the documentation of progressive shifting of the sleep-wake times over at least 14 days using sleep diaries and/or actigraphy.
This disorder can have symptomatic periods, where « the time of high sleep propensity gradually shifts, such that patients experience daytime hypersomnolence and nighttime insomnia».
In sighted people, 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 24.9 ± 0.4 hours (range 24.4–26.5). 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) or actigraphy. In addition to the sleep diary, the timing of melatonin secretion or core body temperature rhythm 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, the timing of melatonin secretion, or by analyzing the pattern of the sleep–wake schedule using actigraphy. 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.
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 C.2.d
- 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 780.55-2
- 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 780.55-2
Since 2005, the disorder has been recognized by name in the U.S. National Center for Health Statistics and the U.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, free-running type; code 327.34 became effective in October 2005. Prior to the introduction of this code, the nonspecific code 307.45, 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 G47.24 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 307.45 is recommended (no acknowledgment of 327.34 is made), and ICD-10-CM code G47.24 is recommended when it goes into effect.
Melatonin administration 1 hour before bedtime is considered an effective treatment for blind N24SWD. Indeed, 67% were successfully entrained (or synchronized) to a 24h day cycle using melatonin. The exact dosage required for efficacy remains unclear, with studies using variable amounts between 0.5mg to 10mg, with one case using 0.05mg. For sighted people with N24SWD, only a few case studies exist, so there is no recommendation.
The Food and Drug Administration (FDA) approved in January 2014 the melatonin agonist Hetlioz (tasimelteon) for the treatment of non-24 for blind people. This is the first FDA-approved drug for any circadian rhythm sleep-wake disorder, since melatonin is unregulated. Tasimelteon safely and effectively treated non-24 patients with an entrainment rate of 20%, which is lower than melatonin with 67%.
Light therapy, which involves a bright light exposure of thousands of lux of white light or about 400 lux of blue light, on awakening to counteract the tendency for circadian rhythms to delay, similar to the treatment for delayed sleep phase disorder, and seasonal affective disorder (SAD) is not currently recommended until more studies appear, although it has been found to be effective in some cases. This can be combined with dark therapy (or scototherapy) which involves filtering blue light (using softwares, screen filters or glasses) and preferring red colored lights with a low amount of lux in the few hours before bedtime to avoid melatonin suppression.
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Both melatonin administration and light therapy work by shifting circadian rhythms according to a phase response curve (PRC) that is essentially the inverse of the light PRC. Furthermore, light can suppress melatonin secretion. Both have a duration of approximately 12 hours, in opposite phase: light PRC spikes at the beginning of the day and lowers throughout the day with a depression after 8 hours for the last 4 hours, whereas natural melatonin spikes at the start of the biological night and drops around the time of wake up or light perception. The first 8 hours are called the "advance zone" whereas the last few hours the "delay zone". The change from advancement to delay zones is progressive, passing through a long area of no effect (a "dead zone"), but the change from delay to advancement is abrupt, occurring a few hours before wake-up time or bedtime for light or melatonin respectively. When melatonin supplementation is taken in the melatonin PRC advance zone (i.e., the last few hours before bedtime), it resets the clock earlier; when taken in the melatonin PRC delay zone (i.e., few hours before and after wake-up time), it shifts the clock later. In other words, melatonin has most effect when it is taken at times when natural melatonin is not normally present, thus during the day: when taken in the morning, melatonin causes phase delays (shifts to a later time), and when taken in the afternoon/evening it causes phase advances (shifts to an earlier time). However, for a sleep phase delayed person, the time of biological morning and biological afternoon/evening might differ depending on the circadian clock shift the person is affected. This means that if melatonin is taken during the usual bedtime and wake-up time (i.e., usual nighttime), it has no effect. Therefore, successful entrainment depends on both the melatonin dosage and the appropriate timing of melatonin administration. The accuracy needed for successfully timing the administration of melatonin might require a period of trial and error, as does the dosage. However, entrainment was also observed when giving a dose of melatonin as low as 0.05mg and without any timing, by just continuing melatonin administration at the same time everyday until the N24 circadian rhythm shifted enough to coincide with melatonin administration (which took from 1 to 2 months).
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 stabilized cycle is achieved; such as travel, exercise, stress, alcohol or even the use of light emitting technology close to a subjective evening/night.
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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 0.03%. 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 population. The US National Organization for Rare Disorders (NORD) lists Non-24 as a rare disease by its definition.
As of 2005, there had been fewer than 100 cases of sighted people with non-24 reported in the scientific literature.
While both sighted and blind people are diagnosed with non-24, the disorder is believed to affect 50% of totally blind individuals. It is estimated by researchers that of the 1.3 million blind people in the U.S., 10% 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.
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 cues. 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 environment. 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 blind: they found that 6 out of 7 patients treated with 10mg melatonin at bedtime were normally entrained, and when the dose was gradually reduced to 0.5mg in three of the subjects, entrainment persisted. Subsequently, it was observed that treatment initiated with the 0.5mg dose could produce entrainment on some patients. Interestingly, one subject who failed to entrain at a higher dose was successfully entrained at a lower dose. A low dose produces melatonin blood levels that are similar to the concentrations naturally produced by nightly pineal secretion.
There has been a constant growth in the field of melatonin and melatonin receptor agonists since the 1980s. In 2005 Ramelteon (Rozerem®) was the first melatonin agonist to be approved in the United States (US), indicated for insomnia treatment in adults. 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 insomnia. Tasimelteon (trade name Hetlioz®) received FDA-approval in January 2014 for persons diagnosed with non-24. 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 dyskinesia.
The first report and description of a case of non-24, a man living on 26-hour days, who happened to be sighted, was "A man with too long a day" by Ann L. Eliott et al. in November 1970. The related and more common delayed sleep phase disorder was not described until 1981.
The first detailed study of non-24 in a blind subject was by Miles Le and his colleagues in 1977. The researchers reported on a 28-year-old male who had a 24.9-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 shift.
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Not all totally blind individuals have free-running rhythms, and those that do often show relative coordination as their endogenous rhythms approximate normal timing. It has been suggested[by whom?] that there are non-photic time cues that are important for maintaining entrainment, but these cues still wait to be characterized.
Very preliminary research on light sensitivity suggest that not only insensitivity but also circadian hypersensitivity to light might be at play for patients with a delayed sleep phase disorder.
NASA explored the potential impact on circadian rhythm and possible development of a sleep-wake disorder by human astronauts who would go on a mission to Mars, by assessing mission personnel who worked remotely on the Phoenix Mars Lander project and were asked to follow a Mars day of 24.65h for 78 days.
- Circadian rhythm sleep disorder, the parent spectrum of sleep disorders including non-24-hour sleep-wake disorder.
- Delayed sleep phase disorder
- Advanced sleep phase disorder
- Irregular sleep–wake rhythm
- Seasonal affective disorder (SAD)
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