The major change proposed is to expand and separate the various circadian rhythm sleep disorders so that each will be a subtype, but with different diagnostic codes. The rationale for this proposed change is largely based on the new data indicating not only the differences in clinical characteristics, but also the underlying pathophysiology and in some cases, genetic basis for the different types of CRSD (delayed sleep phase, advanced sleep phase, irregular sleep wake rhythm, free-running).
Delayed and Advanced Sleep Phase Disorder Pathophysiology
Based on the fundamental properties of the circadian timing system and sleep, several mechanisms could account for a persistently altered phase relationship between the sleep/wake cycle and the environment. One mechanism is that the endogenous period of the circadian pacemaker is unusually short in individuals with ASP and long in individuals with DSP. With respect to DSP, there is evidence showing a greater frequency of longer periods in adolescents, the same demographic group to show a higher prevalence of the DSP. A long period that lies outside the range of entrainment or is too long to make the necessary adjustments to maintain a 24-hour day may cause non-24-hour sleep-wake syndrome. A long endogenous cycle that is still entrained to a 24-hour day may have an altered phase angle of entrainment, delaying the sleep period in relation to the light-dark cycle. Likewise, in the case of ASP, a short period could have an effect on the phase angle of entrainment causing a subsequent advance in the sleep and wake times relative to the light-dark cycle. The report that one member with familial ASPS had a short circadian period supports this explanation and suggests that an alteration in the period of the pacemaker may be involved in the development of ASP.
Another etiology underlying the phase advance or delay seen in ASP and DSP is the influence of the delayed or advanced sleep phase on exposure to light, so that patients who are consistently awakening early are likely to be exposed to light at the region of their phase response curve (PRC) to light causing phase advances, and if they are also going to bed earlier in the evening, they are less likely to be receiving light at the delay region thereby reinforcing the advanced schedule. Similarly, DSP patients who awaken later in the morning are presumably sleeping through the phase advancing portion of their PRC and are more likely to be receiving phase delaying light in the late evening hours. A longer interval between body temperature nadir and sleep offset has been described in a few patients with DSP, suggesting that the sleep period extended into the morning may be masking the advance portion of the PRC in DSP patients and therefore preventing them from phase advancing their circadian rhythms. This behavior acts as a vicious cycle and perpetuates the already advanced or delayed schedule in ASP and DSP, respectively.
An alteration in the entraining effects of light is yet another explanation for the altered phase relationship between the sleep/wake rhythm and the light/dark cycle. This has been described as a weak or low-amplitude advanced or delayed portion of the light PRC. For example, DSP patients may have abnormally small advance portions of the light PRC explaining the inability to advance the phase of their sleep. Decreased sensitivity to the photic cues may also have an effect on the ability to synchronize an individual's sleep/wake rhythm to the environment. An increased sensitivity to nighttime light has been shown in DSP patients and a reduced response to morning light was demonstrated in subjects with a long free-running period, suggesting the possibility of an altered responsiveness to light cues in these conditions.
Finally, an alteration in the phase relationship between the circadian clock and the sleep/wake rhythm may play a role in these disorders. There have been reports of changes in the phase relationship between sleep times and measures of the circadian clock; specifically an altered phase relationship between the melatonin rhythm and that of the sleep/wake cycle. The most consistent finding was a prolonged interval between melatonin acrophase and sleep offset. A change in the phase relationship of melatonin rhythm and core body temperature with an individual's diurnal preference has also been described with an earlier circadian phase of melatonin and core temperature in morning types and a later phase in evening types. Furthermore, the interval between circadian phase and habitual wake time was longer in morning types than in evening types. Because DSP and ASP patients segregate into the two diurnal groups evening types or morning types, this supports the explanation that an alteration in the phase relationship between the clock and the sleep/wake rhythm may affect the phase of the sleep episode. Interestingly, when the morning types were divided by age, there was a difference in this phase relationship. Older morning types who also had an earlier circadian phase showed a shorter interval between core body temperature nadir and sleep offset, opposite to that seen in the young morning types. This suggests that different mechanisms may be responsible for the earlier phase seen in association with aging and ASP. Therefore, it is likely that not only changes in the free running period but also entrainment mechanisms of the circadian system contribute to the alteration in the timing of sleep in DSP and ASP.
Irregular Sleep Wake Rhythm (ISWR)
ISWR is characterized by the lack of a clearly defined circadian sleep-wake rhythm. Nocturnal and daytime sleep is often composed of multiple naps.
Pathophysiology
It has been postulated that both dysfunction of the central processes responsible for the generation of the circadian rhythm as well as decreased exposure to external synchronizing agents such as light and social activities play a role in the development and maintenance of the irregular sleep-wake rhythm. Older adults, especially those with chronic medical and neurological disorders are often exposed to lower levels of daytime light than their younger counterparts. This reduction may be exacerbated by age-related visual disorders, such as cataracts which can further attenuate the effect of ambient light on the SCN. The impact of diminished exposure to circadian synchronizing agents, such as light and activity is most pronounced in patients with AD. Low light levels and lack of structured social and physical activities in long term care facilities may further decrease the amplitude of circadian rhythms. In fact, lower daytime light levels are associated with an increase in night-time awakenings, even after controlling for the level of dementia. Finally, while there is no direct evidence for a genetic basis for ISWR, results from several studies suggest that genetic factors may play a role in the development of sleep fragmentation in AD. Longitudinal studies of AD show that the course and level of sleep deterioration appears to be associated with an inherent “trait” or genetic vulnerability in a given patient. Further studies are needed to determine if certain mutations or polymorphisms of circadian clock genes play a role in the development of ISWR.
Non-entrained (free-running)
Under non-entrained conditions, the circadian period or frequency of oscillation of the clock in humans is slightly longer than 24 hours (24.2 hours) and thus sleep and wake times will drift later each day. As light is the strongest synchronizing agent of the circadian clock, most patients with non-entrained sleep/wake cycles are blind. It has been estimated that approximately 50% of blind people have disturbed sleep. However, this condition can also occur in sighted individuals. While the etiology of non-entrained type sleep disorder in blind people is likely due to lack of light perception, the etiology in sighted individuals may be multi-factorial and include living in environments with weak light/dark cycles or unstructured social and physical activity schedules, decreased responsiveness of the circadian clock to light or behavioral and social entraining agents, and/or an unusually long free-running circadian period that is outside the range of entrainment.
References
The International Classification of Sleep Disorders : Diagnostic & Coding Manual, ICSD-2. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005
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Genetic Basis for Circadian Rhythm Disorders
Our current understanding of circadian rhythm sleep disorders indicate that alterations in the interaction between circadian and homeostatic processes that regulate sleep and wakefulness play an essential role in the pathophysiology of DSP and ASP. The evidence in rodents that mutations in circadian genes can alter both circadian rhythmicity and sleep homeostasis suggest the possibility that a similar genetic predisposition could be involved in the etiology of the circadian and sleep homeostatic changes of sleep regulation seen in circadian rhythm sleep disorders. In the last few years, a genetic basis for ASP and DSP has been established. Familial cases of ASP and one published family with DSP demonstrate the heritability of these disorders. The ASP and DSP phenotypes appear to segregate with an autosomal dominant mode of transmission. Genetic analysis of a family with ASP led to the identification of a mutation in the human PER2 gene causing the disorder. However, other published cases of fASP had not been found to carry this mutation and showed heterogeneity for fASP. More recently, a mutation in the CKId gene was linked to another fASP kindred.
Association studies in idiopathic cases of circadian rhythm sleep disorders have also identified mutations in several circadian genes associated with altered circadian properties. Structural polymorphisms in the human PER3 gene have been associated with the affected status in DSP patients and different polymorphisms in the same PER3 gene were also identified and associated with DSP and eveningness. A missense mutation in the CKIe gene showed an inverse association with circadian rhythm sleep disorders DSP and non-24-hour sleep-wake syndrome. Genetic analysis of diurnal preference to identify polymorphisms in circadian genes has yielded similar results. A polymorphism in the CLOCK gene was correlated with evening type although 2 other groups did not find this association with eveningness in their study populations. More recently association studies of diurnal preference have identified polymorphisms in the human PER2 and PER3 genes associated with extreme morningness and eveningness, respectively.
References for Genetics of CRSD
Aoki, H., Ozeki, Y. and Yamada, N. (2001). Hypersensitivity of melatonin suppression in response to light in patients with delayed sleep phase syndrome. Chronobiology International 18, 263-271.
Archer, S. N., Robilliard, D. L., Skene, D. J., Smits, M., Williams, A., et al. (2003). A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep 26, 413-415.
Ebisawa, T., Uchiyama, M., Kajimura, N., Mishima, K., Inoue, Y., et al. (2001). Association of structural polymorphisms in the human Period3 gene with delayed sleep phase syndrome. EMBO Reports 2, 342-346.
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Psychopathology and CRSD
Alterations in circadian rhythms can have profound effects on sleep and mental health, and similarly, abnormalities in sleep and circadian rhythms are often observed in patients with depressive disorders, schizophrenia, bipolar disorder and anxiety disorders. High co-morbidity for psychiatric disorders has been reported in patients with CRSD and there is some evidence that individuals with a delayed circadian preference (evening-type) may also be prone to psychiatric disorders. A high rate of psychopathology, in particular depression and personality disorders have been reported in patients with DSP. The most prevalent disorders reported in patients with DSPD were depression, social phobia and obsessive-compulsive disorders. There is also some indirect evidence that having an evening-type preference is associated with depressive symptomatology.
Recent studies suggest the involvement of circadian genes in several psychiatric disorders. For example, alteration in circadian clock proteins in the circadian pacemaker is associated with mania-like behavior in mice. In addition, in a few human genetic studies, there is evidence for weak associations between circadian gene polymorphisms and mood disorders. For example, a polymorphism in NPAS2 has been associated with seasonal affective disorder, PER3, BMAL1, CLOCK have been associated with bipolar disorder.
On the other hand, it is likely that psychiatric disorders contribute to, or exacerbate circadian rhythm sleep disruption. The inability to sleep at socially acceptable times can result in quite significant impairments of waking function and personal relationship, especially in severe cases when patients are awake during most of the night, when others are sleeping. In addition to social isolation, individuals with delayed sleep phase may have difficulty maintaining regular employment.
References for Psychopathology and CRSD
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Relationship to International Classification of Diseases-10
ICD-10: Nonorganic disorder of the sleep-wake schedule F51.2, jet lag type 51.21, shift work type 51.22, delayed sleep phase type 51.23, other 51.29. Disorders of the Sleep-Wake Schedule G47.2: Delayed sleep phase type G47.21, advanced sleep phase type G47.22, irregular sleep-wake type G47.23,
Relationship to International Classification of Sleep Disorders 2nd Edition
ICSD-2: circadian rhythm sleep disorder, delayed sleep phase type 327.31, advanced sleep phase type 327.32, irregular sleep-wake type 327.33, free-running type: 327.34, jetlag type 327.35, shift work type 327.36