Non-24-hour sleep-wake syndrome (ORPHA:73267)
A rare neurological disease which is a circadian rhythm sleep disorder characterized by non-synchronization to a 24-hour day leading to insomnia and daytime sleepiness with sometimes severe associated manifestations.
Epidemiology
Approximately half of all people with complete blindness are thought to be affected by non-24 hour disorder. Rare cases are found in partially blind subjects. The disorder may be largely underdiagnosed in blind individuals. Sighted individuals with the disorder are far less numerous and about 100 cases have been reported in the medical literature to date.
Clinical description
Non-24 hour sleep-wake syndrome can occur at any age in sighted individuals but often develops in childhood. In blind people, it can occur at any age. In affected patients, the circadian system does not synchronize with the 24-hour day. Patients have gradual delays in sleep onset time from one day to the next. Sleep onset therefore occurs later and later during the night and then eventually during the daytime. In rare cases, sleep onset time moves backward from one day to the next. Constant and changing misalignment between the patient's circadian rhythm and standard times can result in fragmented sleep and signs of sleepiness when the patient attempts to maintain a regular 24h sleep-wake cycle. These manifestations include diurnal sleepiness, nocturnal insomnia, and fatigue. Other repercussions may include headaches, depression, difficulty concentrating, confusion, memory disorders, decreased appetite, ataxia, and psychological difficulties (loneliness, isolation). At certain times, the sleep pattern coincides with standard times providing temporary remission of symptoms.
Etiology
Defective functioning of the suprachiasmatic nucleus (SCN) located in the hypothalamus, which controls circadian rhythms, is thought to underlie the disorder, especially in sighted patients. The circadian clock has a slight deviation from 24h (generally 24.2h) which is corrected in healthy people by environmental time cues (including the solar light-dark cycle). Core body temperature cycle and production of melatonin are also affected. Absence of perception of light in completely blind subjects is thought to lead to failed sleep training. Abnormal development of the brain, trauma, and iatrogenic factors may play a role in sighted patients with non-24 disorder.
Diagnostic methods
The diagnosis is based on recurrent or relapsing insomnia and daytime drowsiness. The disorder should be suspected in blind individuals with recurrent insomnia and daytime sleepiness. At certain times, the sleep pattern coincides with standard times due to misalignment between the 24-hour light-dark cycle and the undeveloped endogeneous circadian rhythm. Symptoms persist for at least 3 months. Daily sleep logs and actigraphy, for at least 14 days, demonstrates a pattern of sleep and wake times that delay each day with a circadian period that is usually longer than 24 hours. A non-24-hour pattern of cortisol or melatonin secretion may assist diagnosis.
Differential diagnosis
Differential diagnoses include delayed sleep phase disorder, irregular sleep-wake disorder, sleep apnea syndrome, Kleine Levin syndrome, and idiopathic hypersomnia.
Management and treatment
Some patients may find relief by following their own changing sleep-wake cycle. This is however generally not compatible with regular occupational and social constraints. Phototherapy in the morning and scototherapy late in the day has been found to successfully improve sleep cycles in some sighted patients. Melatonin can also be used to this end in both sighted and blind patients. Hypnotics and/or stimulants may also play a role in the management. Tasimelteon, a melatonin-receptor agonist, is used for treatment of non-24 hour disorder in blind patients without light perception.
Prognosis
Without treatment, this disorder disrupts social, emotional and occupational functioning and may be severely debilitating.

                            Last update: 
                            November 2020


                            - Expert reviewer(s): 
                            Pr Yves DAUVILLIERS