The characterization and pathology of circadian rhythm sleep disorders.
* Being alert to excessive sleepiness and/or insomnia in shift workers may prevent comorbidities and accidents that can occur as a consequence of shift-worker disorder (SWD) (SOR: B).
* Not all shift workers develop SWD. Thus, identification of sensitivity to shift work may be facilitated by asking patients whether they find it difficult to function in the absence of consolidated sleep, prefer to be active early in the day, or have previously experienced insomnia due to sleep challenges (SOR: B).
Organisms demonstrate predictable daily patterns in neuroendocrine function and behavior. The archetypal example is the sleep/wake cycle, although daily fluctuations are evident in nearly all physiological processes, including heart rate, blood pressure, and the release of digestive enzymes. (1,2) Such characteristics are controlled by circadian rhythms under the command of the organism's circadian pacemaker, also referred to as the "biological clock" The word circadian is taken from the Latin circa dies, meaning "around a day" and, in this instance, refers to the endogenous flee-running clock within the hypothalamus. This clock functions on a cycle of approximately 24.2 hours, (3) although daylight and social cues serve to entrain (synchronize) the circadian pacemaker to the 24-hour day ascribed by the rotation of the Earth. This article aims to characterize the current understanding of the mammalian circadian system and describes the features of the 6 recognized circadian rhythm sleep disorders (CRSDs), including shift-work disorder (SWD).
The circadian system
The circadian system consists of 3 parts: (1) input pathways, (2) a central oscillator, and (3) output pathways. (4) The mammalian sleep/wake cycle is governed by the circadian clock as follows: (1) light is transferred from the retina via melanopsin in ganglion cells of the retinohypothalamic tract to (2) the 2 suprachiasmatic nuclei (SCN) in the hypothalamus, which interpret these data regarding day length and signal them to (3) the pineal gland, which secretes melatonin nocturnally for a duration corresponding to the habitual period of darkness (scotoperiod) experienced by the organism (5-8) (FIGURE 1). The SCN also activate further output pathways, including the adrenal gland, which releases the stress hormone cortisol in the morning prior to waking; production of cortisol assists with arousal from sleep. (9)
The SCN are capable of maintaining oscillatory patterns of rhythmic gene expression and electrical and metabolic activity even when cultured in vitro. (10-13) Ablation of the SCN results in disruption of activity/rest cycles in some mammals. (14) These findings demonstrate the robustness of the central oscillator and its vital role in preserving important mammalian behaviors such as the sleep/wake cycle. Each of the 2 SCN comprises approximately 10,000 neurons, a proportion of which fire rhythmically to synchronize cellular activity throughout the body via the neuroendocrine and autonomic nervous systems.
Target cells and the SCN rhythmically transcribe clock genes. Expression of such genes is controlled by autoregulatory feedback, ensuring that the circadian rhythm of each cell can work autonomously while remaining capable of responding to entrainment from extrinsic cues--predominantly the light/dark cycle. Examples of clock genes that have been characterized in humans are hPer (period bomolog)l, hPer2, hPer3, hCLOCK (circadian locomotor output cycles kaput), hCK (casein kinase)1[delta], and hCKl[epsilon]. Mutations in these genes are thought to be responsible for a variety of intrinsic CRSDs and also confer individual preferences for activity early or late in the day (morningness or eveningness, respectively). For example, a single nucleotide polymorphism in the hCLOCKgene is associated with a more delayed, evening-type, individual-phase preference, whereas a polymorphism in the hPer2 gene is associated with more of an advanced-phase preference characterized by going to sleep and awakening earlier. (15, 16)
The homeostatic system
The sleep/wake cycle is not governed solely by the circadian system; successive hours of wakefulness produce an increasing sleep pressure referred to as the homeostatic sleep drive. These 2 systems typically interact in a synergistic way, with the homeostatic system increasing the drive to sleep as the day progresses, while the circadian signal counteracts this process by promoting wakefulness (FIGURE 2A). The circadian alertness signal dissipates in the evening, making way for homeostatic sleep pressure to give rise to sleep onset. (17,18) However, when the internal circadian phase is shifted or behaviors change relative to circadian timing--as occurs in individuals with a CRSD--the homeostatic and circadian systems no longer interact synergistically to maintain appropriate sleep/wake behavior. For example, shift workers may struggle to stay awake at night in the face of increased homeostatic pressure for sleep, without the benefit of a wake-promoting signal from the SCN (FIGURE 25) (see "Shift-work disorder" on page S15 of this article for a more detailed explanation of the sleep challenges that give rise to this CRSD). (19) This situation is diametrically opposed to normal sleep/wake behaviors in terms of the circadian timing of physiological processes and has potentially dire consequences. Indeed, circadian desynchronization in animals has been shown to decrease survival rate, (20) and numerous studies in humans have demonstrated increased morbidity associated with circadian misalignment (see "The social and economic burden of shift-work disorder" on page S3 of this supplement).
[FIGURE 1 OMITTED]
Types of circadian rhythm sleep disorder
The 6 main CRSDs can be broadly classified into 2 types: intrinsic and extrinsic (TABLE 1). (21) Intrinsic CRSDs are characterized by asynchrony between the patient's sleep/wake cycle and the external day/night cycle, due to dysregulation within the internal circadian system. Some intrinsic CRSDs have a heritable component, while other intrinsic CRSDs are caused by the absence of the transmission of light/dark signals to the brain or by maturational changes. (22-25)
Extrinsic CRSDs result from an imposed change in the behavioral timing of sleep and wakefulness relative to internal circadian timing. Not everyone who is exposed to changes in their sleep/wake pattern will develop an extrinsic CRSD; rather, these conditions act as a trigger for individuals who are susceptible to the circadian challenges of shift work or jet lag. (Factors that may cause a vulnerability to extrinsic CRSDs are discussed in detail in "Shift-work disorder" on page S15 of this article.)
[FIGURE 2 OMITTED]
In addition to the CRSDs listed above, the second edition of the International Classification of Sleep Disorders also recognizes CRSDs that occur due to a medical condition, or drug or substance abuse, or are not otherwise specified. (21) Potential causes/triggers of CRSDs include stroke, depression, intracranial infection, or head injury. Central nervous system stimulants and depressants may also contribute to drug-induced circadian phase disturbances. (22)
Intrinsic circadian rhythm sleep disorders
Delayed sleep-phase disorder
Delayed sleep-phase disorder leads to a postponement of the rest period and a late awakening compared with societal norms, and is the most common intrinsic CRSD. (23) An overwhelming majority (90%) of these patients report that the onset of their symptoms occurred before or during adolescence. (23) Functional alterations in some clock genes may lead to maladaptation of the sleep/wake cycle to entrainment by light, (26) and several different mutations in the hPer3 gene have been found to result in the delayed sleep-phase disorder phenotype. (27, 28) Individuals with this heritable form of delayed sleep-phase disorder may have a lengthened intrinsic circadian period even in the presence of normal entrainment cues. Other patients with delayed sleep-phase-disorder demonstrate hypersensitivity to light. (29)
Advanced sleep-phase disorder
Individuals with advanced sleep-phase disorder experience a circadian pressure for early initiation of sleep and early awakening. (30) This disorder is uncommon, being diagnosed in <2% of patients with an intrinsic CRSD. (23) Patients with advanced sleep-phase disorder tend to be elderly. (23,24) As sleeping and awakening early are less likely to interfere with work and social interactions than consistently sleeping and rising later in the day, it may be that advanced sleep-phase disorder is underreported. Advanced sleep-phase disorder has a heritable pathology in some individuals (familial advanced sleep-phase disorder). Two different gene mutations (in hPer2 and hCKl[delta]) in separate families have been reported to result in a shortened circadian pacemaker oscillation period in the presence of normal entrainment, resulting in advanced melatonin, temperature, and sleep/wake rhythms. (31-34)
Patients with free-running disorder--also referred to as non-24-hour sleep/wake syndrome--demonstrate a progressive pattern of 1- to 2-hour delays in the onset of sleep and the subsequent waking time. Free-running disorder is diagnosed in <2% of individuals with an intrinsic CRSD (23) and most often occurs in totally blind individuals with no light perception due to the absence of photoentrainment of the sleep/wake cycle. (25) Without entrainment, the behavioral sleep/wake cycle persists with a period similar to that of the internal circadian period of slightly more than 24 hours, resulting in a small but continual off-setting of sleep/wake times compared with the 24-hour day/night cycle. (35)
Irregular sleep/wake rhythm
Individuals with irregular sleep/wake rhythm experience disorganized and variable rest and wake times, sleeping multiple times throughout the day and night. This disorder is diagnosed in 12% of patients with an intrinsic CRSD and occurs most frequently in the neurologically impaired who have damage to the SCN. (23,30) In addition, older age is associated with irregular sleep/wake rhythm due to the increasing prevalence of neurologic conditions such as dementia. (30)
Extrinsic circadian rhythm sleep disorders
Jet lag disorder
The circadian clock cannot adjust quickly enough to accommodate long-distance travel across multiple time zones, often leading to jet lag disorder. Symptoms of jet lag disorder include difficulty in initiating or maintaining sleep, excessive sleepiness, and gastrointestinal disturbances, as the body struggles to accommodate sudden shifts in the timing of activities relative to internal circadian rhythms. (21) Because environmental cues at the flight destination support phase adaptation of the circadian clock to local time, symptoms of jet lag disorder are usually transitory, however, objective measurements of hormone levels, sleep architecture, and body temperature have indicated that a complete phase shift after a long-haul flight can take up to 2 weeks. (36)
The characteristics and severity of jet lag disorder are largely dependent on the direction of travel and the number of time zones crossed. (37) Westward travel is more easily accommodated by the circadian system, as it allows the passenger to delay the onset of sleep instead of advancing sleep times, as required when traveling east. This occurs because the human circadian system runs at an internal period (tau) of slightly longer than 24 hours, a period that is conducive to phase delays in circadian timing? Older age and individual vulnerability to phase shifts also affect sensitivity to jet lag disorder. (37,38)
SWD is an extrinsic circadian rhythm sleep disorder with far-reaching implications in terms of associated morbidity, occupational and traffic accidents, and reduced work productivity (see "The social and economic burden of shift-work disorder" on page S3 of this supplement). (39) SWD occurs when an individual's occupation requires that he or she function at times that are in opposition to the body's normal circadian-controlled periods of sleep and wake. Most individuals will experience some degree of difficulty in attempting to work at unusual times within the 24-hour day, and current diagnostic criteria do not clearly differentiate this group from individuals who have a pathologic response to shift work and develop SWD. (37) Broadly, workers with SWD can be defined as those experiencing persistent insomnia when trying to sleep and/or excessive sleepiness when trying to remain awake. Sleep in patients with SWD is typically fragmented, with frequent awakenings during the daytime rest period. Although appropriate scheduling of light exposure can improve circadian adaptation, even permanent night workers find it difficult to adapt their internal circadian rhythms to the timing of their new sleep/wake schedule. (40)
[FIGURE 3 OMITTED]
Accumulated sleep loss over successive nights as a result of shift work creates a growing sleep debt that increases the homeostatic sleep drive. (41) Over a series of night shifts, the natural circadian drive for sleep during the night interacts with this increasing sleep debt (FIGURE 2B), resulting in further exacerbation of excessive sleepiness, impaired work performance, and increased risk of accidents in individuals with SWD. (19) Thus, both sleep loss as well as circadian pressure for sleep independently contribute to excessive sleepiness in patients with SWD.
Although a change in sleep/wake relative to circadian timing can trigger SWD, not all shift workers develop this CRSD. The high degree of variation between individuals in terms of the severity of symptoms associated with shift work is a complex issue that has not yet been fully elucidated. However, it seems likely that there are a number of innate factors that may increase an individual's susceptibility to SWD, including vulnerability to insomnia, sensitivity to sleep loss, or variation within the circadian system (TABLE 2). (15,16,42-46)
Studies of melatonin rhythms in night-shift workers have shown that many workers do not completely adapt their circadian rhythms to their new pattern of sleep and wake (47,48) (FIGURE 3). "Ibis may be due to an inherent inability to adapt their circadian rhythms or due to behaviors that preclude adaptation. A recent study has shown that a significantly greater (P < .0001) number of shift-intolerant vs shift-tolerant workers have a circadian period that is longer or shorter than 24 hours, indicative of circadian desynchronization and an inability to adapt to their new work schedule. (49) In addition, adaptation cannot occur in night-shift workers who persistently revert to a night-time sleep schedule on their days off and who, therefore, do not experience consistent circadian sleep/wake alignment with the light/dark cycle. Night-shift workers who do not adapt to their new shift schedule have been reported to experience reduced sleep during the daytime, putting them at increased risk of developing SWD compared with colleagues who demonstrated a rapid phase shift to accommodate their new work schedule. (50)
The presence of noise in the home, poor sleep hygiene, and social obligations may make it difficult for some shift workers to obtain a sufficient amount of sleep. In these instances, it may be that shift work is incompatible with the patient's lifestyle, resulting in behaviorally induced insufficient sleep syndrome. In patients with SWD, however, insomnia and/or excessive sleepiness persist despite attempts to fitly accommodate the altered work schedule.
The mammalian circadian clock is complex and is responsible for ensuring the rhythmic nature of numerous behaviors and processes. In recent years, there have been frequent and impressive advances in our understanding of the structure and properties of the mammalian central circadian oscillator--the SCN--and the molecular machinery that it controls.
Of the 6 main CRSDs recognized by the International Classification of Sleep Disorders (TABLE 1), (21) 4 are due to intrinsic problems with the circadian pacemaker, caused by damage to the SCN, maturational changes, lack of appropriate entrainment, or genetically inherited traits. The 2 remaining CRSDs--jet lag disorder and SWD--are triggered by behavioral changes, as they occur as a direct result of human activity, ie, long-distance air travel in a short time and working outside usual hours, respectively. However, not everyone develops jet lag disorder or SWD under these conditions, and the interindividual variation in susceptibility to intrinsic and extrinsic CRSDs is an area of ongoing research.
In a round-the-clock, global society, shift-working individuals perform vital tasks, so it is imperative to find simple ways to diagnose and treat SWD. The following articles discuss how this may be achieved.
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Christopher L. Drake, PhD
Henry Ford Hospital
Sleep Disorders and Research Center
Dr Drake reports that he has received research support from Cephalon, Inc., Takeda Pharmaceuticals North America, Inc, and Zeo, Inc., and has served on the speakers bureaus of Cephalon, Inc., and as a consultant to sanofi-aventis.
TABLE 1 Circadian rhythm sleep disorders (CRSDs) recognized in the ICSD-2 (21) Intrinsic Extrinsic * Delayed sleep-phase * Shift-work disorder disorder * Jet lag disorder * Advanced sleep-phase disorder * Free-running disorder (non-24-hour sleep/wake syndrome) * Irregular sleep/wake rhythm ICSD-2, International Classification of Sleep Disorders, 2nd edition. The ICSD-2 also recognizes CRSDs that are secondary to medical conditions and drug or substance abuse as well as CRSDs that are not otherwise specified. TABLE 2 Innate factors that may trigger shift-work disorder Factor Supporting evidence Predisposition to An increased chance of developing developing insomnia insomnia has been shown to have a heritable component; this vulnera- bility to insomnia is then unmasked by sleep challenges such as shift work. (42-44) Genetic vulnerability Reductions in waking performance to sleep-loss induced as a result of sleep loss vary in performance healthy individuals with different decrement polymorphisms of the hPer3 gene. (45) Circadian variation Genetic polymorphisms result in individual morningness or eveningness preferences; morning- type individuals are more likely to develop SWD. (15,16) Wide intersubject variation has been reported in the expression of genes related to the circadian system after a simulated night shift. (46) SWD, shift-work disorder.
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|Author:||Drake, Christopher L.|
|Publication:||Journal of Family Practice|
|Date:||Jan 1, 2010|
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