Clinical manifestations

Presentation and course

The clinical manifestations of non-24-hour sleep-wake rhythm disorder result from the lack of entrainment of the intrinsic circadian pacemaker to a 24-hour light-dark cycle (03). Patients typically present with symptoms of excessive sleepiness and insomnia alternating with normal sleep (01; 03). These symptoms vary as patients sleep in phase and out of phase with the light-dark environment. Patients may initially report delayed sleep onset and an increase in sleep latency, yet some patients may not recognize the alternating pattern. They may also report difficulty staying awake during the day and falling awake at night as they drift out of phase. As they continue to drift out of phase, they may eventually endorse sleepiness in the late afternoon and evening and further changes to their sleep onset time and short sleep latency (03).

The majority of these patients are blind; however, sighted individuals have been described (19; 23).

The free-running circadian rhythm can be associated with decreased alertness, impaired performance, and mood issues, but there may be an association between non-24-hour sleep-wake rhythm disorder and psychiatric disorders. There have been multiple reports of sighted individuals with non-24-hour sleep-wake rhythm disorder in addition to schizophrenia, bipolar disorder, depression, obsessive-compulsive disorder, and schizoid personality. Hayakawa and colleagues reported that psychiatric disorders preceded the diagnosis of non-24-hour sleep-wake rhythm disorder in 16 out of 57 patients (15). In addition, they found in their case series that 14 of the remaining patients were diagnosed with major depression following their non-24-hour sleep-wake rhythm disorder diagnosis (15). Using actigraphy in patients with affective disorders, Shou and colleagues found dysregulation of the 24-hour motor activity pattern in community-based individuals with mood disorders compared to their community-based controls, thereby adding to the complexity (30).

Prognosis and complications

Non-24-hour sleep-wake rhythm disorder is a rare condition with limited treatment options. The course is typically chronic. This disorder can result in adverse effects on school and/or work performance and psychosocial functioning. Some patients adapt with therapy; however, many normally sighted individuals with this disorder may have difficulty responding to therapy. In some sighted individuals with a non-24-hour sleep-wake rhythm disorder, the pattern is not associated with an underlying circadian dysfunction and may be behaviorally or light induced (07).

Clinical vignette

A 47-year-old sighted male with a medical history significant for bipolar disorder presented with complaint of an abnormal sleep cycle. He reported having an abnormal sleep cycle since puberty. He endorsed that ideally, he would like to be awake for 20 hours and then sleep for 10 hours. He stated that he had found the best pattern for him to be staying awake through one night and then sleeping the following night. He reported that he felt sleepy during his second day of wakefulness. As part of his diagnostic workup, he was given a daily sleep diary to complete for two weeks. He later underwent actigraphy, which showed a non-24-hour sleep-wake rhythm pattern with a circadian rhythm longer than 24 hours. His actigraphy demonstrated that the patient’s bedtime was delayed each night until his sleep period occurred during the day rather than at night. Once his scheduled cycled to the appropriate bedtime, he was instructed to have a consistent wake time, he also started melatonin two hours before bedtime, blue light blocking sunglasses after sundown, light exposure and exercise early in the morning, scheduled meal times, and change in antidepressant medication. At his follow-up visit, he reported that his sleep-wake schedule was more consistent with his work and social schedule. However, after 6 months of compliance, the patient relapsed noting that he preferred his long wake periods. A year later, the patient again tried the light therapy in the morning, avoidance of light in the evening, afternoon exercise, and melatonin with timed meals. He sustained a more consistent schedule but relapsed again with working from home. The patient was then given a trial of tasimelteon at 20 mg each night at 9 PM, approximately one hour prior to bed. The patient included the other nonpharmacological therapies, a more consistent work schedule and noted an easier ability to stay on a routine sleep-wake schedule.

Biological basis

Etiology and pathogenesis

The intrinsic human circadian rhythm is typically longer than 24 hours, yet daily time cues allow for this reorientation of the clock to the surrounding environment. The loss of the ability of the time cues to influence the clock appears to be the major factor in non-24-hour sleep-wake rhythm disorder. Those time cues include bright light, activity, food, and social interaction. Some estimate that over half of blind individuals have non-24-hour sleep-wake disorder, with 50% to 80% complaining of sleep disturbances. In a large cohort of blind women, nearly two thirds of participants with no light perception had evidence of a circadian rhythm disturbance, whereas only one third of participants with light perception were abnormally entrained (10).

The connection of lack of sight to this circadian rhythm disorder is through a different pathway than the conventional pathway of vision. Light influences the retinal ganglion cell layer from which axons course along the optic nerve and leave the optic chiasm to innervate the suprachiasmatic nucleus. Interruption of these fibers, by either congenital or acquired blindness prevents information regarding light to be transmitted to the master circadian pacemaker and thus prevents light from contributing to the entrainment process. Thus, the endogenous non-24-hour rhythm is unmasked and demonstrated in the sleep-wake cycle. Individuals who are blind because of lesions posterior to the optic chiasm, such as cortical blindness, do not get the disorder. For many blind subjects who have a chiasmal or prechiasmal lesion, nonphotic (social, timed meals) cues may not be sufficient to synchronize the endogenous rhythm with the environmental.

For individuals who are sighted and have non-24-hour sleep-wake rhythm disorder, the pathology is less clear. Some of these individuals have a history of head trauma, suggesting a possible disruption of the retino-hypothalamic fibers, caused by damage to the suprachiasmatic nucleus or disrupted the secretion of melatonin. The etiology of non-24-hour sleep-wake disorder in sighted individuals is unknown, but it has been theorized to be due to prolongation of the endogenous circadian period, making it more difficult to entrain to a 24-hour day (25). In one case series, similar features of cases starting in adolescence raise the possibility of maturational changes to the inherent clocks’ responsiveness to time cues or abnormally long rhythms in which typical entrainment cues actually cause a prolongation of the rhythm (23; 24). In another case, a man underwent chemotherapy for Hodgkin lymphoma and developed a free running cycle of 25.27 hours, which did not respond to bright light and melatonin (11). Another possible contributing mechanism may be an impaired melanopsin-dependent phototransduction pathway. The melanopsin pathway does contribute to pupillary constriction to high intensity blue light. An indirect measure of this utilizes quantification of post-illumination pupil ability to sustain contraction. Abbott and colleagues showed that sighted individuals with non-24-hour sleep-wake rhythm disorder had a reduced response, indicating a possible reduction in the contribution the melanopsin pathway to entraining the circadian rhythm (02).

In another venue, Emens and colleagues reported three sighted individuals with non-24-hour sleep-wake rhythm disorder, in which one demonstrated in a prolonged time controlled environment using plasma and salivary assessment of dim light melatonin onset a normal circadian rhythm length (07). The other two individuals sleep wake cycles responded to adjustment of the schedule. From this, Emens and colleagues concluded that for these three individuals that behavior and light exposure was the underlying driver of the progressive sleep wake schedule. However, two of the individuals had depressed mood issues. The underlying driver for these patients' conditions is unclear and may represent the complex interaction of the sleep homeostatic process, the monoamine system relating to mood and the central circadian system (18). In a separate case report, a 14-year-old male developed non-24 sleep wake disorder in association pediatric autoimmune neuropsychiatric disorder associated with streptococci infection that occurred prior to the onset of symptoms (08).

Review of circadian mechanisms. All living organisms possess an inherent circadian rhythm. This near 24-hour cycle modulates a variety of physiologic and behavioral processes, such as sleep-wake cycle, body temperature, mood, hormone secretion, and many others. The paired suprachiasmatic nuclei of the hypothalamus have been established as the “master clock” that sets the timing of the mammalian circadian system. The suprachiasmatic nuclei are composed of 10,000 anterior ventromedial hypothalamic neurons that maintain a self-sustaining daily rhythm. This cycle is achieved through a complex system of timed gene expression that creates an autoregulatory feedback loop. A variety of genes are involved in this cycle, including Clock, Per, Bmal1, and Cry. This complex cycle is vulnerable to changes in these genes or genes of proteins involved in regulation of these factors (21).

The biological clocks of normal humans of all ages have a natural endogenous circadian cycle of slightly more than 24 hours, generally about 24.2 hours. Therefore, the internal body clock must be adjusted on a daily basis to align with the 24-hour day, a process called entrainment. Entrainment involves using zeitgebers (German for “time givers”) to reset the internal clock slightly each day. Common zeitgebers include light, melatonin, food intake, social interaction, and exercise. Each of these factors can independently change the timing of the circadian pacemaker, thereby altering the time of all physiologic processes that are regulated on a circadian basis.

Light is the main zeitgeber for endogenous clocks in humans. The human circadian system is more sensitive to short-wave blue-green light than to long-wave red-spectrum light. The major afferent input to the SCN consists of a melanopsin-containing subset of photosensitive retinal ganglion cells whose axons synapse on SCN cells. This retinohypothalamic tract transmits nonvisual, light-dark information to the SCN, which is mediated through glutamate and pituitary cyclase-activating peptide. In addition to a direct pathway, retinal ganglion cells also project to the intergeniculate leaflet of the lateral geniculate body, which in turn projects to the SCN. Neuropeptide Y and GABA are the main neurotransmitters. Other time clues appear to influence the SCN through serotonergic input from the brainstem raphe nuclei.

Key to understanding the zeitgebers is that the response of the circadian rhythm depends on when the stimulus is delivered. For example, light delivered prior to the temperature nadir (typically 4:00 AM in normal phase individuals) will cause a delay in the body clock. Light delivered after the body temperature nadir will advance the clock. Thus, for light therapy to be appropriately used, understanding the true timing of the circadian rhythm is essential. The temperature nadir is typically 1.5 to 2 hours before the undisturbed natural wake up time. Therefore, if a person is naturally waking at 11 AM without an alarm, the temperature nadir would most likely be between 9:00 and 9:30 AM.

Similar to light, melatonin also has a time-dependent effect on the phase of the circadian rhythm. However, melatonin has the opposite effect of light, such that melatonin delivered in the evening causes a phase advance whereas morning use may cause a mild phase delay. The SCN exhibit dense melatonin receptors, probably establishing a feedback mechanism for the sleep-wake cycle. Melatonin and potentially other factors such as light help synchronize the multitude of endogenous rhythms in the brain and other organs. Synchronization of these endogenous rhythms is important to optimal body function. Isolated delay in an endogenous rhythm has been implicated in individuals with nocturnal eating syndrome, which appears to be a delay in the feeding rhythm. Although appearing benign, in this disorder the timing of food intake can impact insulin sensitivity and metabolism, as well as potentially lead to weight gain (17). Meals also appear helpful in aligning peripheral cocks, such as in the liver, to the new schedule.

Epidemiology

Non-24-hour sleep-wake rhythm disorder has been reported in both blind and sighted individuals, though it is believed to be more common in blind individuals compared to sighted individuals, with at least 50% of totally blind individuals believed to have non-24-hour sleep-wake rhythm disorder. Unfortunately, few studies exist to delineate the true prevalence. In a telephone survey of sleep patterns in visually-impaired Japanese, nearly 27% noted non-24 hour or irregular sleep wake rhythm (32). Although this is lower that other reports, part of the lower reporting may be in the recognition of the sleep wake issue. Non-24-hour sleep-wake rhythm disorder has been described in both children and adults. However, the prevalence of non-24-hour sleep-wake rhythm disorder as well as the gender and racial differences are unknown (03).

In one of the larger case series of sighted individuals with non-24-hour sleep-wake rhythm disorder, 72% of the patients were male and onset of symptoms began in the teenage years in 63% of the patients (15).

Prevention

Non-24-hour sleep-wake rhythm disorder has been described in both sighted and blind individuals. Factors that may predispose sighted individuals to non-24-hour sleep-wake rhythm disorder include delayed sleep-wake phase disorder and certain environment conditions (03). In blind individuals, it is thought that the likelihood of non-24-hour sleep-wake rhythm disorder increases with eye disorders that damage the ganglion cell layer, damage to the optic nerve, or removal of the eye (34). Although there are no studies indicating the prevention of this disorder, targeted exposure of time cues, such as meals, physical activity, and social interaction, to individuals susceptible to this disorder would help reinforce the synchronization of the circadian rhythm. In one study Yamanaka and colleagues showed that a single fixed meal per day would prevent free running of the circadian cycle in individuals who are undergoing temporal isolation (35). Although these were normal individuals, this raises the prospect that regular time cues may bolster the adjustment of the circadian rhythm to the societal day.

Differential diagnosis

The differential diagnoses for non-24-hour sleep-wake rhythm disorder include delayed sleep-wake phase disorder and irregular sleep-wake rhythm disorder. Patients with delayed sleep-wake phase disorder will present with delay of sleep relative to their required time or desired time. These patients often experience difficulty falling asleep and waking up at times that are considered typical. Despite these issues, their sleep quality when they are allowed to sleep at the delayed times is normal (04). In contrast, patients with irregular sleep-wake rhythm disorder do not have a clear sleep-wake pattern. Instead, these patients experience excessive sleepiness and sleep during daytime hours and wakefulness during nocturnal hours. In addition, their sleep is often insufficient and fragmented (04).

Neurologic disorders such as dementia or static encephalopathies may play a role in the appearance of non-24-hour sleep-wake rhythm disorder. Similarly, patients with bipolar disorder may have non-24-hour sleep-wake rhythm disorder but should be distinguished from rapid cycling bipolar disorder. Key features in bipolar disorder are the characteristics of periods of mania or hypomania alternating with depression as opposed to the lack of these mood issues alternating in the sleep-wake rhythm.

Confusing conditions

Other conditions that, at times, may be confusing are other circadian rhythm disorders. Some individuals with severe delayed sleep phase may acquire significant sleep deprivation and have a prolonged period of sleep in a periodic fashion, which appears as if there is a free-running cycle. These individuals do not have an abnormally long circadian rhythm, but their body clocks and behavior are not synchronized (24; 07). Similarly, some patients with irregular sleep-wake rhythm, such as those with neurodegenerative disease, may have shifting periods of sleep and wake that may be confused with a non-24-hour cycle. In both of these cases, longer observation periods with actigraphy and sleep diaries can help distinguish the underlying circadian rhythm issues.

Diagnostic workup

Non-24-hour sleep-wake rhythm disorder is diagnosed by demonstrating a non-24-hour pattern of sleep-wake. This is accomplished using daily sleep logs and actigraphy for at least 14 days (03). In blind individuals, it is preferable to have an even longer duration for the daily sleep logs and actigraphy (03). Logs such as those for CPAP compliance may also demonstrate the non-24 hour pattern for the sleep wake cycle (33). Other circadian phase makers, such as dim light melatonin onset or urinary 6-sulfatoxymelatonin rhythm may also be used. In the case of circadian phase markers, these should be obtained at two different time points approximately 2 to 4 weeks apart (28; 05; 03). A prescreening questionnaire with eight questions can be used as a screening tool to predict non-24-hour sleep-wake disorder among blind patients and thus identifying those who need further evaluation (09).

Polysomnography may be performed to rule out another primary sleep disorder, but it is not indicated for the diagnosis of non-24-hour sleep-wake rhythm disorder (28; 03).

Management

Treatment options for non-24-hour sleep-wake rhythm disorder follow the general principles of entraining the circadian rhythm using light therapy, melatonin therapy, and melatonin agonist therapy. For individuals with ability to respond to light, light therapy has been used to phase advance the circadian pacemaker to offset the phase delay typically seen in individuals with non-24-hour sleep-wake rhythm disorder. Typically, light therapy may come in the form of a light box, light emitting glasses, or direct exposure to sunshine. This light exposure should be at least 1500 lux and may be from 15 to 45 minutes in duration. Light therapy exposure should occur after the body temperature nadir (which typically is 1.5 to 2 hours before the typical awakening time) and morning light therapy should be coupled with fixed wake times (34).

Regardless of the patient’s light response abilities, melatonin and melatonin agonist therapy have also been used to phase shift the circadian pacemaker, in addition to their ability to shift the circadian pacemaker, indicating that darkness has started. When used to treat non-24-hour sleep-wake rhythm disorder, melatonin is administered at a fixed time approximately 2 hours prior to the desired bedtime. Low dose melatonin (0.5 -1.0 mg) has been shown to be equally as effective as higher doses in entrainment of the circadian pacemaker (04; 34).

The United States Food and Drug Administration approved the use of tasimelteon, a melatonin MT1/MT2 agonist, for the treatment of non-24-hour sleep-wake rhythm disorder in blind individuals. The Safety and Efficacy of Tasimelteon (SET) study demonstrated that 6 months of daily tasimelteon treatment entrained the circadian pacemaker and improved daytime and nighttime sleep as compared to the placebo (20). The Randomized withdrawal on the Efficacy and Safety of Tasimelteon (RESET) study revealed that tasimelteon therapy needed to be continued to maintain entrainment of the circadian pacemaker (22; 34). Tasimelteon, as a 20 mg dose in adults, is given in the evening within one hour of the set time for bed (29). Some patients find administration slightly in advance of bedtime a helpful strategy.

The other melatonin agonist, ramelteon, has not been studied in non-24-hour sleep-wake disorder. In a case report, ramelteon at 8 mg in the evening in addition to nightly suvorexant improved the sleep-wake cycle in a patient with autism spectrum and non-24-hour sleep-wake disorder (16).

Other potential therapeutic options for patients with non-24-hour sleep-wake rhythm disorder include prescribed sleep-wake scheduling, timed physical activity and exercise, and strategic avoidance of light (34). Part of the issues with this combination therapy may be the initiation of the schedule. Although some advocate waiting for the patient’s inherent schedule to reach a typical sleep wake timing, Guichard and colleagues reported that total sleep deprivation followed by regimented schedule of morning light and nocturnal melatonin returned stable sleep schedule in a sighted young man with non-24-hour sleep-wake rhythm disorder (13). The subject returned to a stable 24-hour cycle after 6 months of combination therapy. In another case report, a 34-year-old male with non-24 hour sleep wake disorder experienced recurrence of his 25.5 hour cycle after consecutive heat waves, demonstrating the influence of the environmental temperature on the condition (12).

Patients should be allowed to rotate their schedule to start therapy when their natural schedule slightly advanced to the desired schedule. Patients should then be instructed to start the light avoidance (such as blue light blocking sunglasses in the evening with the melatonin therapy and bright light therapy after waking). Patients should keep a set wake 7 days a week and plan on regular timed meals and exercise. Meals appear to help synchronize other peripheral clocks; however, caffeine does not appear to have an effect (31). These patients should also keep a sleep diary to help assess the progress.

Outcomes

There are currently no long-term safety data for melatonin or tasimelteon (34).