Non-24-hour sleep-wake disorder

Non-24-hour sleep-wake disorder (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 has been traced to a number of genetic abnormalities that affect specific biologic factors in the brain. While both sighted and blind people are diagnosed with Non-24, the disorder affects proportionately more totally blind individuals than sighted.

Though often referred to as Non-24, it is also known by the following terms:
 * Free running disorder (FRD)
 * Hypernychthemeral disorder
 * 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".

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. 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.

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.

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 a majority of 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 can synchronize the body clock.

Sighted people with Non-24 do exist, but are much more rare and the etiology of their circadian disorder is less well understood. As of 2005, there were fewer than 100 cases of sighted people with N24 reported in the scientific literature. 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. Several other cases have been preceded by chronotherapy, a prescribed treatment for delayed sleep phase syndrome.

There have been several 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 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, 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.

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 lowered 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 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 often have difficulty maintaining ordinary social lives, and some of them lose their jobs or fail to attend school."

The impact of Non-24 on daily life is affected by the extent to which the body clock drifts. For instance, a person with a 25-hour body clock would have a 25-day cycle with two weeks of good sleep and two weeks of poor sleep. But a person with a 24.1-hour circadian rhythm would drift only six minutes per day and take 241 days, or eight months, to go around the clock. They may have four months of good sleep and four months of bad sleep, when the cycle would begin again.

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.

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

Prevalence
While both sighted and blind people are diagnosed with Non-24, the disorder affects more totally blind individuals than sighted.

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.

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
The etiology of Non-24 is unknown in sighted individuals. However, chronotherapy 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".

In the blind without any light sensitivity, the brain is not cued to reset the circadian clock to a 24-hour sleep-wake cycle.

Treatment
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.

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. A year-long (2011-2012) study at Harvard and at 26 other sites in the U.S. and Germany, is testing the use of tasimelteon in blind subjects with non-24-hour sleep-wake disorder.