INTRODUCTION — Circadian rhythms are the near-24-hour rhythms that are regulated by the suprachiasmatic nucleus (SCN) in the hypothalamus. On average, the endogenous circadian rhythm is slightly longer than 24 hours. As such, daily adjustment or entrainment of the circadian clock is required to maintain alignment with the 24-hour environment, and light serves as one of the primary entraining signals.
Individuals with non-24-hour sleep-wake rhythm disorder (N24SWD) are unable to maintain appropriate alignment with the 24-hour environment, so each day their sleep-wake patterns shift (typically later) with respect to external time. N24SWD has previously been referred to as free-running disorder, non-entrained disorder, or hypernychthemeral syndrome.
The clinical features, diagnosis, and management of N24SWD will be reviewed here. Other circadian rhythm sleep-wake disorders are discussed separately. (See "Overview of circadian sleep-wake rhythm disorders" and "Delayed sleep-wake phase disorder" and "Advanced sleep-wake phase disorder" and "Jet lag" and "Sleep-wake disturbances in shift workers".)
EPIDEMIOLOGY — N24SWD primarily affects blind individuals who lack light perception. N24SWD was first recognized in blind individuals but has subsequently been recognized in rare sighted individuals.
In a study of 127 blind individuals, 63 percent of those without light perception had N24SWD, while only 31 percent of those with intact light perception had N24SWD [1]. In the largest case series of sighted individuals with N24SWD (57 patients), 72 percent of patients were male, the average age of symptom onset was approximately 20 years old, and there was a high proportion of individuals with premorbid psychiatric disorders (28 percent) [2].
By extrapolation, N24SWD is estimated to affect between 65,000 and 95,000 individuals in the United States [3].
PATHOPHYSIOLOGY — The pathophysiology of N24SWD varies depending on whether the individual is blind or has intact light perception.
●In blind individuals – The daily light-dark cycle is the most powerful environmental time cue for synchronizing the hypothalamic circadian pacemaker to the 24-hour day. The circadian resetting effect of light is required because the endogenous circadian rhythm cycles with a period that is typically longer than the environmental 24-hour light-dark cycle.
The retinohypothalamic tract carries light input from melanopsin-containing, intrinsically photosensitive ganglion cells in the retina to the circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. In blind individuals who lack these retinal ganglion cells or their projections through the optic nerve due to disorders such as glaucoma, enucleation, or optic nerve hypoplasia, this light input is no longer received by the brain. By contrast, individuals with blindness that is primarily due to rod/cone degeneration may still be able to perceive the circadian light signal.
Not all blind individuals who lack light perception develop N24SWD. Along with light, there are many other inputs to the circadian clock that can help maintain entrainment. These nonphotic time cues include endogenous or exogenous melatonin, activity, and timing of eating and social interactions. As such, some individuals are better able to maintain entrainment than others, possibly related to stronger nonphotic cues or to having an endogenous period that is closer to 24 hours.
●In sighted individuals – The pathophysiology of N24SWD in sighted individuals is likely multifactorial. Proposed mechanisms relate to progression from delayed sleep-wake phase disorder (DSWPD), lengthening of the biologic clock, impairments in the circadian response to light, and an abnormal relationship between the homeostatic drive for sleep and the circadian timing of sleep and wake.
Many individuals initially present with DSWPD, a circadian sleep-wake disorder in which individuals exhibit a stable delay in their sleep-wake patterns with respect to the environment [2]. There are also case reports of individuals with DSWPD who develop N24SWD after undergoing chronotherapy, a treatment in which the onset of sleep is deliberately delayed by several hours each day with a goal of re-entraining to an earlier sleep-wake schedule [4]. Under these conditions, a small number of individuals are unable to stop their schedule from continuing to move later each day. (See "Delayed sleep-wake phase disorder".)
In some cases, N24SWD may be the result of a biological clock that is significantly longer than 24 hours, which makes it more difficult to entrain to a 24-hour schedule. When sighted individuals with and without N24SWD are placed on a 28-hour schedule that they are unable to entrain to (referred to as a forced desynchrony protocol), the endogenous melatonin rhythm is significantly longer in those with N24SWD compared with controls [5]. Similarly, a study of fibroblast samples collected from sighted individuals with and without N24SWD used circadian clock reporter genes to demonstrate that the circadian period was approximately 0.4 hours longer in those with N24SWD compared with controls [6].
Theoretically, an impaired circadian response to light could interfere with entrainment to environmental light, even in the presence of normal subjective light perception. In support of this hypothesis, there is evidence from case reports that the normal suppression of melatonin in response to light is decreased in patients with N24SWD [7]. In addition, one study found that sighted patients with N24SWD exhibited an impaired pupillary response to light compared with controls [8]. N24SWD has also been described in children with developmental delay due to Rett syndrome, autism, and Angelman syndrome, who may have difficulty either perceiving or responding to environmental time cues [9].
CLINICAL FEATURES — The clinical manifestations of N24SWD reflect varying degrees of misalignment between the patient's circadian timing and the external 24-hour environment.
At times when endogenous circadian sleep-wake times are out of phase with the environment, patients may complain of insomnia when they are trying to sleep at night and/or of excessive sleepiness when trying to maintain alertness during the day. As the patient's sleep-wake timing drifts steadily later, there will be times when they are well aligned with the environment and can sleep and wake easily at the appropriate times. Thus, it is important to focus on sleep-wake patterns over several weeks, rather than on a single night.
Sighted patients, in particular, will often initially present with a sleep-wake pattern more consistent with delayed sleep-wake phase disorder (DSWPD). In DSWPD, affected individuals habitually fall asleep significantly later, and wake up significantly later, than conventional or desired times. They experience insomnia when they attempt to go to bed earlier in the evening, and they have difficulty waking up when they need to arise in the morning. As N24SWD emerges, these sleep-wake patterns move progressively later with respect to the external environment. (See "Delayed sleep-wake phase disorder", section on 'Clinical features'.)
EVALUATION AND DIAGNOSIS — N24SWD should be suspected in blind individuals with sleep-wake disturbances that are cyclic in nature, alternating between periods of relatively good nighttime sleep and daytime alertness and periods of insomnia and excessive daytime sleepiness. The diagnosis is confirmed by demonstration of a gradual daily shift in rest-activity patterns by sleep logs or actigraphy.
The diagnosis requires a higher index of suspicion in sighted individuals, as N24SWD is rare in this population, particularly when compared with other more common causes of sleep-wake disturbances, such as chronic insomnia or delayed sleep-wake phase disorder (DSWPD). (See 'Differential diagnosis' below.)
Clinical history — Initial assessment for suspected N24SWD begins with an accurate clinical history. Insomnia and excessive daytime sleepiness are nonspecific complaints, and recognition of an underlying circadian sleep-wake rhythm disorder requires attention to the timing of the individual's sleep-wake cycle and especially to patterns over time.
Clinicians should determine whether complaints of insomnia or excessive sleepiness fluctuate, with time periods of normal sleep alternating with time periods when the patient is unable to sleep at night and feels excessively tired during the day. These patterns are often more apparent in individuals with significantly prolonged circadian periods (ie, much greater than 24 hours) and may be more subtle if the daily drift is much shorter. Clinicians should have a higher index of suspicion for N24SWD in individuals who lack light perception.
Daily sleep logs and actigraphy — The presence of N24SWD can be confirmed by self-reported sleep diaries (form 1 and table 1 and table 2) or by actigraphy for a minimum of two weeks. Longer periods of assessment (eg, three to four weeks) may be indicated if there is strong clinical suspicion for N24SWD, as patients can sometimes exhibit patterns of intermittent stable entrainment followed by periods of progressive delays [9].
Actigraphy is a wrist-worn noninvasive accelerometer that provides objective data on rest-activity patterns from activity-based monitoring. An actigraphy log (table 3) should be completed daily during the monitoring period to improve the accuracy of the data analysis. (See "Actigraphy in the evaluation of sleep disorders".)
In patients with N24SWD, the typical finding on actigraphy and sleep logs is a daily delay in sleep onset and offset of approximately one hour, although some sighted individuals will exhibit "jumps" of more than four hours per day when sleeping during the daytime (figure 1) [2].
Other circadian phase markers — Melatonin sampling is another way to determine an individual's endogenous circadian phase. While not required for the diagnosis of N24SWD, this assessment can provide additional confirmation of the daily drift of circadian time in cases where actigraphy and sleep logs are not clearly diagnostic, and it can be used to provide an objective measure of the response to treatment over time.
Measuring the melatonin profile on a single day is of limited value in the clinical diagnosis of N24SWD. However, serial melatonin assessments can be useful to demonstrate a change in the timing of melatonin over time. Patients can collect urine samples every four hours over a 24-hour window (every eight hours overnight), and the acrophase, or peak time of melatonin secretion, can be determined from this profile. In patients with N24SWD, the time of the acrophase will typically move later when measured serially, while in control individuals, the time of the acrophase will remain constant [10].
Melatonin is synthesized by the pineal gland in a circadian manner, with levels typically rising a few hours prior to sleep onset and remaining high throughout the biological night. Melatonin can be sampled directly in the serum and saliva and as the metabolite 6-sulfatoxymelatonin (aMT6s) in the urine [11]. The pattern of daily melatonin secretion is analyzed in relation to sleep timing obtained from sleep diaries or actigraphy. In individuals with normal sleep-wake timing, melatonin levels typically begin to rise two to three hours prior to sleep onset; however, in patients with N24SWD, the time window between the rise of melatonin and sleep onset is often much larger [12].
Questionnaires — An eight-item questionnaire was developed for use in blind individuals and has a positive and negative predictive value of 88 and 79 percent, respectively, for the presence of N24SWD [13]. Questions focus on characterizing the patient's vision loss, sleep patterns, and sleep quality (table 4).
Diagnostic criteria — According to the International Classification of Sleep Disorders, Third Edition (ICSD-3), the diagnosis of N24SWD requires all four of the following criteria (table 5) [9]:
●A history of insomnia, excessive daytime sleepiness, or both, that alternates with time periods of being asymptomatic, as the individual rotates between alignment and misalignment with the environmental light-dark schedule
●Symptoms must be present for at least three months
●Daily sleep logs and actigraphy for at least 14 days (though preferably longer) demonstrate a gradual daily drift (typically later) in rest-activity patterns
●The symptoms are not better explained by another current sleep, medical, neurologic, mental, or substance abuse disorder; or medication use
DIFFERENTIAL DIAGNOSIS — Insomnia and daytime sleepiness can be caused by a myriad of primary sleep, medical, and psychiatric disorders in both blind and sighted individuals (table 6 and table 7). (See "Evaluation and diagnosis of insomnia in adults" and "Approach to the patient with excessive daytime sleepiness".)
The key distinguishing feature of non-24-hour sleep-wake rhythm disorder (N24SWD) is the cyclic nature of the sleep-wake complaints. In blind individuals with a circadian period close to 24 hours, the time over which the circadian rhythm cycles in and out of phase may extend over several weeks, and neither the patient nor clinician may recognize the sleep disorder as cyclic, at least initially. An incorrect diagnosis of insomnia is often given during periods of poor sleep, when the individual's internal circadian rhythm is maximally out of phase with the 24-hour light-dark cycle.
In addition to clinical clues (eg, complete blindness, pre-existing psychiatric disease), sleep logs or actigraphy over long periods of time and melatonin sampling are the key tools to help distinguish N24SWD from insomnia as well as other circadian sleep-wake rhythm disorders, such as delayed sleep-wake phase disorder (DSWPD). (See "Evaluation and diagnosis of insomnia in adults" and "Delayed sleep-wake phase disorder".)
In DSWPD, individuals exhibit a stable but delayed pattern of sleep-wake behaviors with respect to the environmental light-dark schedule. However, many of these individuals may either intentionally or unintentionally delay their sleep-wake patterns in order to try to adjust their schedule to be more closely entrained to the environment, resulting in patterns of daily delay of sleep-wake behaviors, similar to those seen in N24SWD. However, in N24SWD, individuals are typically unable to maintain a 24-hour schedule without treatment.
MANAGEMENT — Treatment of N24SWD is aimed at entraining, or synchronizing, the patient's circadian pacemaker to the 24-hour day in order to decrease or eliminate the cyclic pattern of insomnia and daytime sleepiness.
In blind individuals, treatment options include melatonin and melatonin receptor agonists. In sighted individuals, melatonin is typically used in combination with behavioral strategies, including appropriately timed light exposure.
Symptomatic therapies (eg, sleeping aides for insomnia, stimulants for daytime sleepiness) may achieve short-term benefits but are not an effective long-term strategy, as they do not affect circadian alignment.
Blind individuals — Use of melatonin or a melatonin receptor agonist is the primary means to help align the endogenous circadian rhythm with the environment. We typically start with melatonin because it is inexpensive and readily available over-the-counter; however, because it is a supplement, there can be significant variability in the actual melatonin content [14].
Melatonin — Appropriately timed melatonin can help shift the endogenous circadian rhythm so that it is synchronized, or entrained, to a 24-hour schedule. This is the mainstay of therapy for blind individuals with N24SWD.
We instruct patients to take 0.5 mg of melatonin either one hour prior to their preferred bedtime or at a fixed clock time (eg, 9:00 PM) [15]. The lowest commercially available dose of melatonin in tablet form is often 1 mg, which can be cut in half. Liquid formulations of melatonin are often best for low-dose titration.
Circadian adjustments to achieve synchronization (entrainment) can take up to two and a half months, depending on the individual and the time at which melatonin is administered. Entrainment may be faster if the sleep-wake timing of the patient is allowed to drift until the preferred bedtime (and melatonin administration) falls between 6 and 18 hours after biological wake time, falling within the phase-advance portion of the melatonin phase response curve [16]. If not obvious to the patient, the optimal start time should be apparent upon review of the sleep log. (See 'Daily sleep logs and actigraphy' above.)
Melatonin is considered a nutritional supplement and not regulated as a prescription medication in most countries; although long-term safety data are not available, short-term studies suggest that it is a relatively safe drug in most patient groups [17,18].
Evidence to support the use of melatonin for N24SWD in blind individuals consists of small placebo-controlled studies and case series at varying doses of melatonin. Doses used in initial studies ranged from 5 to 10 mg [19,20]; however, subsequent studies have demonstrated effective entrainment of 70 percent of individuals with doses as low as 0.5 mg [16,21]. In the only placebo-controlled trial of the use of melatonin for the treatment of N24SWD, total sleep time improved by 27 minutes, sleep latency decreased by 29 minutes, and daytime napping decreased in the melatonin group compared with the placebo group [22].
Melatonin agonists — Tasimelteon is an oral melatonin agonist that was developed for treatment of circadian sleep-wake rhythm disorders. It is our preferred agent in patients who do not respond to over-the-counter melatonin and is an alternative first-line agent in patients who are not comfortable taking an over-the-counter supplement.
Supporting evidence for tasimelteon consists of the Safety and Efficacy of Tasimelteon (SET) trial, in which 84 patients with N24SWD were randomly assigned to receive daily tasimelteon (20 mg taken at a fixed clock time, one hour before target bedtime) or placebo [3]. Compared with patients assigned to placebo, those assigned to tasimelteon were more likely to be entrained at one month (20 versus 3 percent). Subjective sleep outcomes also improved.
Importantly, 80 percent of the tasimelteon-treated individuals did not entrain, emphasizing the challenges in treating this population. Entrainment rates did improve to 50 percent in individuals who were assessed at six weeks rather than at four weeks [3], which may reflect the fact that a longer observation period is needed before determining whether a patient is or is not responding to a treatment intervention.
Tasimelteon is generally well tolerated; the most common adverse effects observed in the randomized trial were headache (17 versus 7 percent), elevated liver function tests (10 versus 5 percent), and nightmares or abnormal dreams (10 versus 0 percent) [3]. Drug-drug interactions should be considered, as tasimelteon is a major substrate of cytochrome P450 3A4 and 1A2. Specific drug interactions may be determined by use of the Lexicomp drug interactions tool.
Ramelteon, another melatonin agonist approved in some countries for treatment of insomnia, has not been studied specifically in patients with N24SWD, but has been shown to shift circadian phase in individuals with jet lag [23] and might be expected to have similar effects as tasimelteon in patients with N24SWD.
Behavioral modifications — In addition to pharmacological interventions, general recommendations include trying to maintain a regular sleep-wake schedule and strengthening other daily time cues, including social interactions, activity, and food timing.
Role of caffeine and other symptomatic therapies — Other interventions, such as caffeine, do improve alertness but have no impact on entraining individuals with N24SWD. Similarly, the use of hypnotics is not recommended as a primary intervention to address the sleep-wake complaints in this population [24].
Sighted individuals — Treatment of N24SWD in sighted individuals can be much more challenging and typically relies on multiple treatment modalities. Treatment strategies are based largely on case studies and indirect evidence in blind individuals and in patients with other circadian rhythm sleep-wake disorders. As in blind patients, the primary goal of therapy is to align the circadian timing of sleep and wake with the 24-hour day.
As with blind individuals with N24SWD, sighted individuals can be treated with melatonin. The best time to administer melatonin in sighted patients with N24SWD is still unclear; we generally suggest administering 0.5 to 1 mg two hours prior to bedtime [25].
Timed bright light can also be used to try to shift the circadian clock in order to maintain entrainment. Bright light exposure after the core body temperature nadir (typically occurring approximately two hours prior to wake) will move the circadian clock earlier. There has been some success in stabilizing the daily drift seen in N24SWD by administering bright light therapy immediately after awakening [26,27].
We instruct patients to use an alarm clock to maintain a fixed rise time and seek exposure to natural sunlight (when available) or light box for at least 30 minutes upon awakening every morning for several weeks. In addition, we advise patients to avoid bright light exposure prior to bedtime, a time when light can potentially exacerbate the disorder by moving the circadian rhythm later.
Light boxes are commercially available in various wavelengths and intensities. We generally advise patients to use a broad spectrum white light box. The recommended distance from the source is dependent on the intensity of emitted light, and instructions for distance are typically provided by the manufacturer (eg, 10,000 lux at 5 feet).
Unfortunately, long-term compliance with therapy is often challenging, and further research is needed to determine whether addition of other time cues, such as activity and eating, may provide additional benefit.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Parasomnias, hypersomnias, and circadian rhythm disorders".)
SUMMARY AND RECOMMENDATIONS
●Non-24-hour sleep-wake disorder (N24SWD) is a rare circadian rhythm sleep-wake rhythm disorder in which patients are unable to maintain appropriate alignment between their endogenous circadian rhythm and the 24-hour environment. The disorder primarily affects blind individuals who lack light perception. (See 'Epidemiology' above.)
●In blind individuals, N24SWD is caused by the loss of light signals from the environment; in sighted individuals, the disorder may be caused by multiple factors including a lengthening or delay of the circadian clock, impaired response to circadian light signals, and a lack of strong timekeeping signals. (See 'Pathophysiology' above.)
●Symptoms of N24SWD reflect varying degrees of misalignment between the patient's circadian timing and the external 24-hour environment. Patients cycle through periods of relative normal sleep alternating with periods of insomnia at night and excessive sleepiness during the day. (See 'Clinical features' above.)
●N24SWD is a clinical diagnosis that should be suspected in blind individuals with cyclic complaints of insomnia and daytime sleepiness and confirmed through sleep logs and actigraphy for two weeks or longer (table 5). (See 'Evaluation and diagnosis' above.)
●Treatment of N24SWD is aimed at entraining, or synchronizing, the patient's circadian pacemaker to the 24-hour day in order to eliminate the cyclic pattern of insomnia and daytime sleepiness.
•In blind individuals with N24SWD, we suggest use of nightly melatonin (Grade 2C). Tasimelteon, a melatonin agonist, is a reasonable alternative to melatonin. (See 'Blind individuals' above.)
•In sighted individuals with N24SWD, we suggest use of nightly melatonin as well as morning light therapy (Grade 2C). (See 'Sighted individuals' above.)
