As a new drug treatment focuses public attention on this circadian disorder, the vice president of the Circadian Sleep Disorders Network discusses symptoms, diagnosis, and treatment options for blind and sighted patients.
Starting in 2014, television and radio ads brought sudden public awareness of a previously little known disorder: non-24-hour sleep-wake rhythm disorder, sometimes called non-24 or simply N24. An old disorder under a more user-friendly name—it was previously known as hypernychthemeral syndrome—non-24 has gained attention in the wake of discoveries of unexpectedly high prevalence among the blind population and the development of a new drug treatment.
Non-24 is a disorder of the body’s circadian rhythm or biological clock, the intricate timing system that includes the master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus, its input from ganglion cells in the retina, its connection to the pineal gland that produces melatonin, and its links to the DNA transcription/translation-based clocks that operate in cells throughout the body—all of which function to keep body processes entrained to the 24-hour day/night cycle. Non-24 has a high prevalence among the blind, but sighted persons can also have it.
Symptoms
When the circadian system is disrupted, a number of symptoms can result. Many of us have experienced jet lag—what one might call the “common cold” of circadian disorders—so we may have some understanding of what it feels like when the circadian clock is out of sync. Jet lag is by nature transient, but other circadian disorders are chronic. In non-24, the ability of the body’s internal clock to keep time with the outside world is defective. Instead of keeping a 24-hour cycle, the body clock runs out of control, following a cycle that may be, for example, 25 hours in length. Many patients compare it to having very bad jet lag every day of their lives. The most prominent symptoms of non-24 relate to the sleep-wake cycle and are manifest in two forms: free-running sleep or periodic insomnia.
Instead of sleeping at roughly the same time every day, persons with free-running non-24 will typically find their sleep time gradually delaying by minutes to hours every day. They will sleep at later and later clock times until their sleep periods go all the way around the clock. Patients’ cycles of body temperature and hormone rhythms also follow a non-24-hour rhythm. This is the characteristic symptom in sighted non-24 patients, but also occurs in many blind patients.
Other patients maintain a sleep cycle linked to the 24-hour clock, but their underlying circadian rhythms, as reflected in body temperature and hormone levels, continue to cycle with a non-24-hour period. As a result, these patients experience a periodic form of insomnia. When their body clock is aligned with their sleep cycle, they sleep normally. When the body clock is out of sync with the sleep cycle, they experience severe insomnia and daytime sleepiness. The periods of normal sleep and insomnia alternate in a periodic fashion over weeks or months. This pattern occurs mainly in blind persons with non-24 but is sometimes seen in sighted patients.
Since the abnormal circadian function in non-24 affects not only the sleep cycle but also multiple cellular and hormonal rhythms (melatonin, cortisol, testosterone, TSH, etc), other symptoms such as severe fatigue and digestive and metabolic disturbances are common.1
The prevalence of non-24 is particularly high in totally blind persons (those with no perception of light). About two-thirds of such patients suffer from non-24. Of the 1.3 million legally blind persons in the United States, about 10% (130,000) have no light perception, meaning there are about 85,000 blind persons with non-24.2 The rate of non-24 in the sighted population is unknown but is believed to be much lower than among the blind. However, since the total sighted population is much higher, there are still significant numbers of sighted persons with non-24. Due to the relative rarity of sighted non-24, it may be underdiagnosed in this population. The impact of non-24 on the lives of affected patients, both blind and sighted, is considerable. It has been described as “extremely debilitating in that it is incompatible with most social and professional obligations.”3
Causes
The cause of non-24 in blind persons is well understood. The master clock in the SCN is not a perfect timekeeper. On its own, it tends to produce a day length or “intrinsic period” slightly different from 24 hours. The SCN depends on a daily light signal from the eyes to realign the clock to the 24-hour light/dark cycle. Without this light input, the timing of the clock tends to drift out of sync.
In the case of sighted persons, the cause of non-24 is complex and multifactorial.4 Some cases follow traumatic brain injury or brain tumors. Other cases involve no obvious trauma but are due to a complex interaction of genetic and developmental factors. Recent genetic research points to polymorphisms in the gene BHLHE40, which encodes for a component of the transcription-translation feedback loop at the core of the mammalian cellular clock.5 The intrinsic period of the SCN in non-24 patients is longer than average (24.5 vs 24.1 hours) and may exceed the ability of the system to reset itself to a 24-hour cycle, even with a normal light signal.6
Dysfunction also has been noted in the linkage between the circadian cycle and the sleep-wake rhythm. Normal subjects become sleepy at the start of the declining phase of the body’s temperature cycle, whereas in non-24 the onset of sleepiness occurs much later. Because patients have a higher than normal level of arousal in their subjective evenings, they tend to be active and maintain room illumination, which further lengthens the circadian period. Other factors that may play a role in some cases include increased or decreased circadian response to light (despite normal vision) or alterations in the production of melatonin, either excessive or deficient.
Persons with developmental disorders such as autism have a higher rate of non-24 than the general population. In other cases, a psychiatric disorder (eg, schizophrenia, depression) may precede development of non-24. However, the majority of patients with non-24 do not have a history of psychiatric problems, although some do develop depression later in the course of the disorder, perhaps because it is so disabling.
Non-24 also may result from attempts to treat another circadian disorder, Delayed Sleep Phase Syndrome (DSPS), using chronotherapy, in which patients are instructed to gradually delay their sleep time until they go around the clock to a more socially acceptable schedule.3
Diagnosis
Diagnosis of non-24 starts with a detailed clinical interview focusing on the patient’s sleep patterns and timing. The patient should then be asked to keep a sleep log, reporting the times at which they fell asleep and awoke, preferably for at least a month. A pattern of a gradual delay of sleep that proceeds around the clock is indicative of non-24. Graphing sleep may make the pattern easier to see. In patients whose sleep is interrupted by social or work demands, or in blind patients who try to sleep on a 24-hour cycle, this pattern may not be apparent. They may instead show a pattern of periodic insomnia and daytime sleepiness.
If available, wrist actigraphy may help to confirm the diagnosis. In a research setting, core temperature monitoring or serial measurements of salivary melatonin or serum cortisol may be useful. Polysomnography is not required for the diagnosis of non-24 per se, as it is the timing rather than the quality of sleep that is primarily impaired (although some patients may show alpha intrusions and reduced delta sleep). It is mainly of use in differentiating non-24 from other disorders causing excessive daytime sleepiness such as narcolepsy, idiopathic hypersomnia, or sleep apnea. These disorders also may be comorbid with non-24. Most patients with non-24 go undiagnosed for years, and misdiagnosis, particularly of psychiatric disorders, is common.
Treatments
Treatment of patients with non-24 is different for blind and sighted patients. Since blind patients lack light input to serve as a timing signal to anchor the clock, an alternate signal is required that is outside the visual system. This generally means the use of melatonin or drugs that act as melatonin agonists.
The patient should take melatonin at the same time every day, usually between 7 PM and 10 PM, with the aim that entrainment will occur with a bedtime a few hours after the dose of melatonin. The recommended dose of melatonin is 0.5 mg. Dosage may need to be adjusted up or down in individual cases. Melatonin is often sold and prescribed in much higher doses, typically 3 mg to 10 mg, but such high doses are usually not more effective than 0.5 mg and in many cases may be less effective. In the case of most blind patients who exhibit periodic insomnia, treatment is best started around the point of transition from a period of good sleep into one of bad sleep, when melatonin will be most effective in preventing the circadian drift.
In January 2014, Hetlioz (tasimelteon) became the first drug approved by the FDA for the treatment of non-24. Tasimelteon is a melatonin agonist, which activates both MT1 and MT2 receptors. Two clinical trials were conducted.2 The SET (Safety and Efficacy of Tasimelteon) trial enrolled 84 patients in a double-blind placebo controlled study. In the first month, 20% of patients on active drug became entrained versus 2% on placebo. At 7 months, the entrainment rate rose to either 35% or 54% depending on how one counts dropouts. The RESET trial of 20 patients examined long-term efficacy and found that 90% of patients initially entrained on Hetlioz maintained entrainment after 3 months, versus 20% on placebo.
Hetlioz is marketed at a single dose of 20 mg. Timing of treatment is similar for that with melatonin: administration 1 or more hours before desired bedtime. As with melatonin, treatment may be more effective if started around the transition from good to bad sleep. There are no trials directly comparing the effectiveness of Hetlioz and melatonin, and the studies of each were conducted by different groups in different conditions, so it is not possible to say if either medication is more likely to work in a given patient.
A different melatonin agonist, Rozerem (ramelteon) is marketed for insomnia rather than non-24, but some non-24 patients have responded to it. Although melatonin and the synthetic agonists fall within the same general class, there are subtle differences between them. If a patient does not respond to one substance in this class, it is not unreasonable to try another or a third. In some cases, this approach has had success.
For treatment of non-24 in sighted patients, there are several options. Melatonin has been reported to be effective in some cases of sighted non-24. Dosage and timing are similar to use in blind patients. There is limited data on the newer melatonin agonists, but early indications suggest they also will be effective in some, but not all, sighted patients.
The mainstay of treatment for sighted patients involves manipulation of the light/dark cycle through light therapy (phototherapy) and dark therapy (scototherapy). Use of light/dark therapy does not fix the root causes of sighted non-24 but can compensate for them and achieve entrainment in some cases.
Light therapy usually involves the use of a light box. Patients should be instructed to wait until the time of their cycle when they are waking a few hours before their desired wake-up time (for example, waking at 3 AM when the desired time is 7 AM). Then they should start using the light box at the desired wake-up time (for example, 7 AM). If treatment is successful, as the wake time of their sleep cycle approaches the time of light use, the rate of daily delay should decrease until the sleep time has stabilized. Successful results have been reported using 2,500 lux for 2 hours. Newer light boxes producing 10,000 lux are preferable but may not mean a proportional reduction in time required.
Because of the phase relationship between light therapy and sleep time, stabilization may not occur until sleep onset time is somewhat phase delayed relative to wake time. In other words, the patient may awake at 7 AM, but rather than falling asleep at 11 PM (giving 8 hours of sleep), they may not fall asleep until late at night. This may cause sleep deprivation unless the patient is able to nap on a daily basis to make up for the loss. Napping usually will not interfere with entrainment. Despite the inconvenience, some patients find this split sleep schedule preferable to free running.
Dark therapy aims to reduce the phase-delaying effect of evening light. In early studies, non-24 and DSPS patients were instructed to avoid light as much as possible after 4 PM to 6 PM. Because this regimen is extremely restrictive, an alternative approach is to avoid only blue and green light, which have the strongest circadian effect. Color restriction is achieved by the use of amber or red room light in the evening, or with goggles that block out blue and green light or similar filters fitted to computer monitors. These techniques should be used for at least 4 hours before desired bedtime.
Combined therapy, using melatonin and/or dark at night and light in the morning, is more likely to be effective than one approach alone.
Because treatment studies of sighted non-24 are few, the success rate of this approach is unknown. Treatment is very restrictive and not easy to carry out, and significant residual symptoms, such as daytime sleepiness, may remain. Nonetheless, the difficulties associated with a free-running sleep cycle provide a strong motivation for some patients to continue treatment.
Research is ongoing on the molecular basis of the circadian clock and the relation between circadian rhythms and the neurobiology of sleep. It is hoped that such research may lead to more effective treatments for severe circadian disorders such as non-24.
James S.P. Fadden is vice president of the Circadian Sleep Disorders Network (csd-n.org). He holds a degree in biochemistry from Harvard University and has been active in educating professionals and the public about circadian disorders for over 20 years. He was co-author of the official report on non-24 for the National Organization for Rare Disorders and has appeared on a special Nightline television program about light and sleep. CONTACT [email protected]
REFERENCES
1. Oren DA, Giesen HA, Wehr TA. Restoration of detectable melatonin after entrainment to a 24-hour schedule in a ‘free-running’ man. Psychoneuroendocrinology. 1997 Jan;22(1):39-52.
2. Vanda Pharmaceuticals. Presentation to FDA Advisory Committee. Silver Spring, Md. November 14, 2013.
3. Oren DA, Wehr TA. Hypernyctohemeral syndrome after chronotherapy for delayed sleep phase syndrome. N Engl J Med. 1992 Dec 10;327(24):1762.
4. Fadden JSP, Sharkey K. Non-24-Hour Sleep-Wake Disorder. National Organization for Rare Disorders. 2012. https://www.rarediseases.org/rare-disease-information/rare-diseases/byID/1275/viewFullReport
5. Kripke DF, Klimecki WT, Nievergelt CM, et al. Circadian polymorphisms in night owls, in bipolars, and in non-24-hour sleep cycles. Psychiatry Investig. 2014 Oct;11(4):345-62.
6. Kitamura S, Hida A, Enomoto M, et al. Intrinsic circadian period of sighted patients with circadian rhythm sleep disorder, free-running type. Biol Psychiatry. 2013 Jan 1;73(1):63-9.
