Although many individuals make a significant effort to preserve the 24-hour circadian rhythm, the progressive appearance of sleep delays and changes in waking times, the main signs of N24SWD, are most frequently reported, mimicking insomnia [4] [8]. Specifically, sleep onset and waking times are prolonged to a 25-hour (or sometimes even to 27 hours) cycle [1] [6], manifesting as progressive delays in initiation of sleep followed by oversleeping into daytime [6]. After some time, the lack of sleep and rest over a period of days results in extreme fatigue that necessitates a very long recovery sleep of 14-24 hours [6]. Finally, an asymptomatic phase lasting for days or weeks ensues. Once the disease has appeared, patients alternate between asymptomatic and symptomatic phases and both the severity and frequency of the disorder is shown to be dependent on their internal rhythm in relation to the outside world [6].

To make the diagnosis of N24SWD and distinguish it from other sleep disorders, it is imperative to obtain a thorough patient history, especially the onset of symptoms and sleep disturbances, so that a preliminary diagnosis can be made. One of the easiest, but very effective methods for determining a circadian rhythm sleep disorder is to keep a sleep and waking log for a prolonged period of time [6]. It is important to keep a timeline of occupational and social activities during this process as well, as delayed sleep-phase syndrome may present with similar symptoms but occurs only during vacations [6]. Current diagnostic criteria for N24SWD include the mentioned signs and symptoms of sleep disturbance for at least six weeks that are confirmed by one of the following methods [6] [4] [3]:

• Polysomography or actigraphy performed for several consecutive days on a fixed daily schedule.
• Temperature monitoring for 24h for at least five days to observe its fluctuation.

Treatment principles aim to improve daytime function and overall quality of sleep by attempting to entrain patients into the 24-hour cycle [7]. Melatonin has been suggested as the mainstay of therapy in many sleep disorders, including N24SWD. Higher doses (3-5 mg) for one month 1-2 hours before sleep are recommended and once a 24-hour cycle has been established, a lower dose of 0.5 mg one hour before preferred sleeping time is used, but even lower doses (20-300 μg) in later stages may be sufficient [7]. Recently, a melatonin receptor agonist, Tasimelteon, has been approved for specific therapy of N24SWD and its main benefit is minimal interaction with other endocrine molecules and receptors [11]. Sleep-promoting medications, light therapy (which is not possible in blind patients), strategic avoidance of light, timed physical activity and prescribed sleep-wake scheduling are alternative treatment modalities for sleep disorders but have shown no effect in N24SWD [10], indicating that melatonin use is the mainstay of treatment.

Although the condition is not considered as life-threatening, sleep disorders have shown to be a significant risk factor for the development of obesity, diabetes, breast and colorectal cancer, but also depression [11], which is why their early recognition is detrimental. Unfortunately, N24SWD may be difficult to diagnose due to its disease course that comprises both symptomatic and asymptomatic stages [6]. However, irregular sleeping and waking patterns invariably reduce the ability to function on a daily basis, including social and occupational activities and many patients report symptoms at some point. Also, the continuation of melatonin therapy in blind patients is an important aspect as the symptoms of the disorder return once the melatonin therapy is stopped.

In blind people, which comprise the majority of N24SWD cases, the cause seems to be the inability of the retina to convey light stimulus to the higher structures responsible for circadian rhythm, thus impeding the normal daily cycle [2]. Other reports suggest that psychosocial factors [2], brain trauma [9], and mutations in the CK1ε gene as possible etiologies [5], but the complete pathophysiological mechanism remains unknown.

Although the condition is considered to be rare, current prevalence rates in the population are unknown [2]. The most significant risk factor for N24SWD, however, is blindness, as about 50% of all individuals who suffer from total vision loss have a diagnosis of N24SWD [7]. Isolated reports have shown that 28% of cases have some preexisting psychiatric disorder, suggesting that it may be an additional risk factor [1]. The onset of N24SWD is documented across all age groups, including infants, middle-aged adults and elderly [6]. At this moment, a familial pattern of inheritance of the disease has not been recognized. Also, this disorder is more commonly seen in males.

Under physiological conditions, the biological clock of humans (known as circadian rhythm) is designed to function in 24-hour cycles and is able to do so under tight regulation [2] [6]. One of the principal stimuli that initiate this machinery is natural light, which is conveyed by the retina into structures such as the epiphysis (pineal gland), the sympathetic plexuses of the spinal cord and the suprachiasmatic nucleus located in the hypothalamus, the main site where circadian rhythm is regulated. Depending on the amount of natural light, various concentrations of melatonin are secreted from the pineal gland through the activity of the suprachiasmatic nucleus (SCN) [7]. During daytime, the SCN will inhibit the production of melatonin, while this inhibitory effect is abolished during the night, so that sleep is not interrupted [7]. This regulatory system keeps the circadian clock in check throughout life, but in the setting of blindness and absence of light stimuli, the SCN and pineal gland do not receive adequate stimuli, resulting in a disorganized activity and appearance of disturbed sleep [2]. In addition to light deprivation, mutations of the CK1ε, with its role of phosphorylation of proteins responsible for regulation of the circadian rhythm, has been brought into discussion when attempting to find the exact mechanism of disease [5].

Despite the fact that the mechanism of disease in blind people has been established, the exact trigger of N24SWD remains unknown and current preventive strategies do not exist.

Non-24 hour sleep-wake disorder (N24SWD) is one of the types of circadian rhythm sleep disorders that is distinguished by chronic disturbances of sleep and wake times that breach the physiological 24-hour cycle regulated by the brain [7]. Because of the fact that almost 50% of blind individuals are diagnosed with N24SWD, the underlying cause seems to be the absence of light perception that consequently disrupts the transmission of retinal signaling to the pineal gland and suprachiasmatic nucleus [2], while the mechanism of N24SWD in sighted people remains unclear [7]. Some reports show that alterations in genes that are involved in transcription of genes responsible for maintenance of the circadian rhythm, such as Casein Kinase I Epsilon (CK1ε), may also be contributing factors to the pathogenesis [5]. In most cases, the sleep-wake patterns don't follow the 24-hour circadian rhythm, causing significant issues with both initiations of sleep and awakening [6]. Insomnia and extreme fatigue may arise, which often have a major impact on daily life. Because of progressive changes in sleep patterns that eventually become "phased" with normal daily rhythm, both symptomatic and asymptomatic phases are reported in patients [7]. To make the diagnosis, clinical criteria including sleeping and waking difficulties for at least six weeks and continuous delays in the onset of sleep that results in the deviation from the 24-hour sleep-wake pattern are necessary [6]. Sleep logs, polysomnography, and actigraphy are valuable methods to confirm N24SWD and distinguish it from other sleep disorders, whereas continuous measurement of body temperature has also been proven as a valid diagnostic procedure [3]. Various treatment strategies have been implemented, but the first drug for treatment of N24SWD, tasimelteon, was recently approved and recommended in blind individuals suffering from this disorder [10]. Tasimelteon is a melatonin receptor agonist that was tailored for individuals with impaired melatonin secretion as a result of inadequate stimulation by light perception through the retina [11], while other therapeutic strategies, such as phototherapy, sleep-promoting drugs, timed physical activity and several other have not shown significant effects [10].

Non-24 hour sleep-wake disorder (N24SWD) is a rare but severely debilitating disease of altered sleep and waking patterns that most predominantly occurs in blind people, but cases in sighted people have been documented as well. In individuals who suffer from total vision loss, the cause is presumed to be a lack of brain stimulation by natural light conveyed by the eyes. Normally, the daily cycle of humans is regulated by various structures in the brain that act on the basis of exposure to light (or darkness) and the term "circadian rhythm" is used to describe the 24-hour biological clock that is maintained by the body. One of the most important substances secreted by a small gland in the brain called epiphysis (or pineal gland) is melatonin, which serves to either facilitate sleep during the night or promote wakefulness during the day and the hypothalamus is the part of the brain that regulates its activity. Melatonin is secreted in response to light perceived by the eyes and the retina, but in blind individuals, light signals are not present, thus leading to disruption of the biological clock and the appearance of altered sleeping patterns. A characteristic feature of N24SWD is that the daily biological cycle is prolonged to 25 (rarely to 27) hours, resulting in progressive changes when it comes to going to sleep and waking up, eventually causing extreme fatigue and insomnia. In this "symptomatic" phase, extreme fatigue will occur and mandate a very long sleep after some period of time (14-24 hours), followed by "asymptomatic" phase, in which little or no changes in sleeping habits will be observed. The onset of the disease has been reported across all ages, whereas gender predilection has not been established. To make the diagnosis of N24SWD, symptoms must persist for at least six weeks and diagnostic procedures such as polysomnography or actigraphy may be used for confirmation. The mainstay of therapy is the administration of melatonin before desired sleeping time, in order to entrain the individual back into the 24-hour cycle and maintain its ability to perform daily social and occupational activities. A melatonin receptor agonist, tasimelteon, has been recently introduced into medical practice and is designed specifically for treatment of N24SWD. The prognosis of patients is good with an early diagnosis and appropriate therapy, but sleep disorders, in general, are known to increase the risk for numerous diseases, including cardiovascular, malignant and diabetes. For this reason, it is imperative to recognize this condition as soon as possible, so that patients may continue their daily activities without significant limitations.

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