Non-24-hour sleepâ€"wake disorder (non-24), is one of several types of chronic circadian rhythm sleep disorders (CRSDs). It is defined as a "complaint of insomnia or excessive sleepiness related to abnormal synchronization between the 24-hour lightâ€"dark cycle and the endogenous circadian rhythms of sleep and wake propensity." Symptoms result when the non-entrained (free-running) endogenous circadian rhythm drifts out of alignment with the desired or conventional sleepâ€"wake schedule. However, the sleep pattern can be quite variable; some individuals adopt a sleep pattern that is congruent with their free-running circadian clock, shifting their sleep times (usually later), thereby minimizing their sleep symptoms but suffering major social and occupational consequences. People with non-24 "resemble free-running, normal individuals living in a time-isolation facility with no external time cues".
The majority of patients with non-24 are totally blind, and the failure of entrainment is explained by an absence of photic input to the circadian clock. However, the disorder can also occur in sighted people for reasons that are not well understood.
Though often referred to as non-24, for example by the FDA, it is also known by the following terms:
- Non-24-hour sleepâ€"wake syndrome
- Free running disorder (FRD)
- Hypernychthemeral disorder
- Circadian rhythm sleep disorder â€" free-running type
- Circadian rhythm sleep disorder â€" nonentrained type
- N24HSWD
- Non-24-hour circadian rhythm disorder
The disorder is an invisible disability that can be "extremely debilitating in that it is incompatible with most social and professional obligations".
Mechanisms
The internal circadian clock, located in the hypothalamus of the brain, generates a signal that is slightly longer (occasionally shorter) than 24 hours. Normally, this slight deviation is corrected by exposure to environmental time cues, especially the solar 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 more (occasionally less) than 24 hours, expressing the intrinsic period of the 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, patients 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, only to recur as their clock drifts 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 24 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.
Characteristics
Sighted
In people with non-24, the body essentially insists that the day is longer than 24 hours and refuses to adjust to the external lightâ€"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. Non-24-hour sleepâ€"wake disorder causes a person's sleepâ€"wake cycle to change every day, the degree determined by how many minutes or hours 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.
People with the disorder may have an especially hard time adjusting to changes in "regular" sleepâ€"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.
Non-24 can begin at any age, not uncommonly in childhood. It is sometimes preceded by delayed sleep phase disorder.
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."
Blind
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.
Symptoms
Symptoms reported by patients forced into a 24-hour schedule are similar to those of sleep deprivation and can include:
Prevalence
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 person for every 2000.
Sighted
As of 2005, there had been fewer than 100 cases of sighted people with non-24 reported in the scientific literature.
Blind
While both sighted and blind people are diagnosed with non-24, the disorder affects more totally blind individuals than sighted. It has been 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.
Causes
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. 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 sleepâ€"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 sleepâ€"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 25â€"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.
Blind
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.
Diagnosis
Sighted
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 24.4â€"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.
Blind
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 sleepâ€"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.
Treatment
Sighted
Enforcing a 24-hour sleepâ€"wake schedule using alarm clocks or family interventions is often tried but usually unsuccessful. Bright light exposure on awakening to counteract the tendency for circadian rhythms to delay, similar to the treatment for delayed sleep phase disorder, and seasonal affective disorder (SAD) has been found to be effective in some cases, as has melatonin administration in the subjective late afternoon or evening. Light therapy involves at least 20 minutes of exposure to 3000 to 10000 lux light intensity. Going outside on a bright sunny day can accomplish the same benefit as special light fixtures (light boxes). Bright light therapy combined with the use of melatonin as a chronobiotic and avoidance of light before bedtime may be the most effective treatment. Melatonin administration shifts circadian rhythms according to a phase response curve (PRC) that is essentially the inverse of the light PRC. When taken in the late afternoon or evening, it resets the clock earlier; when taken in the morning, it shifts the clock later. Therefore, successful entrainment depends on the appropriate timing of melatonin administration. Also hypnotics and/or stimulants (to promote sleep and wakefulness, respectively) have sometimes been used. In any case, a sleep diary is requested to aid in evaluation of treatment.
Blind
In the 1980s and 90s, 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. 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. For example, Sack et al. found that 6 out of 7 patients treated with 10Â mg melatonin at bedtime were normally entrained. When the dose was gradually reduced to 0.5Â mg in three of the subjects, entrainment persisted. Subsequently, it was shown that treatment initiated with the 0.5Â mg dose produced entrainment. One subject who failed to entrain at a higher dose was successfully entrained at a lower dose. The 0.5Â mg dose produces melatonin blood levels that are similar to the concentrations naturally produced by nightly pineal secretion.
Products containing melatonin are available as dietary supplements in the United States and Canada, available over the counter. These "supplements" do not require FDA approval. As prescription drugs may be prescribed off-label, treatment recommendations for non-24 in the blind may vary.
There has been a constant growth in the field of melatonin and melatonin receptor agonists since the 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 solely for completely blind 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.
History
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.
Sighted
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 delayed sleep phase disorder was not described until 1981.
Blind
In the first detailed study of non-24 in a blind subject, 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.
Research directions
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 that there are non-photic time cues that are important for maintaining entrainment, but these cues await to be characterized.
Classifications
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 Sleepâ€"Wake Syndrome; code C.2.d
- The International Classification of Sleep Disorders, 1st & Revised eds. (ICSD), 1990, 1997: Non-24-Hour Sleepâ€"Wake Syndrome (or Non-24-Hour Sleepâ€"Wake Disorder); code 780.55-2
- The International Classification of Sleep Disorders, 2nd ed. (ICSD-2), 2005: Non-24-Hour Sleepâ€"Wake Syndrome (alternatively, Non-24-Hour Sleepâ€"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 sleepâ€"wake disorders, Non-24-hour sleepâ€"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.