Research Paper (APA STYLE)

Sleep Disorders and Fatigue Sheila C. Tsai, MD *, Teofilo Lee-Chiong Jr, MD Fatigue is defined by a lack of energy or a sensa- tion of tiredness that may improve with rest. It is essential to distinguish fatigue from sleepiness.

Fatigue can be described as lack of energy or weariness. Sleepiness, on the other hand, is commonly associated with inattention, constant yawning, frequent lapses into sleep, or struggling to stay awake. One important difference be- tween fatigue and sleepiness is that the former may improve with rest alone and without sleep, whereas the latter worsens with resting or remain- ing sedentary. 1 Fatigue is a prominent symptom in many disease conditions, and about 20% of visits to family prac- tice physicians are related to complaints of fa- tigue. 2Fatigue is frequently a predominant or associated symptom in mood disorders, particu- larly anxiety or depression. Conversely, depressive and anxiety symptoms are risk factors for new- onset or persistent fatigue among adolescents. 3–5 The etiology of fatigue is not clear. Proposed mechanisms include cortisol imbalance 6and re- lease of inflammatory mediators. 7Fatigue is as- sociated with many disease states, such as cardiovascular disease, endocrine abnormalities, multiple sclerosis, and sickness behavior, that are associated with an increased inflammatory state. 8–10 Sickness behavior, characterized by a constellation of symptoms (decreased appetite, anhedonia, decreased pain tolerance, psychomo- tor slowing, and fatigue), occurs after exposure to pathogens or cytokine administration (ie, the com- mon manifestations in individuals who are ill from microbial infections). 8It is this enhanced inflam- matory state and altered immunomodulation that may be the pathogenetic link between sleep disor- ders and fatigue. Rating scales have attempted to objectively quantify and categorize subjective complaints of fatigue. One commonly used scale is the Fatigue Severity Scale (FSS).

11 The FSS consists of a se- ries of 7 questions regarding fatigue that are rated from 1 to 9. A score of 36 or greater is considered positive for the presence of fatigue. SLEEP DISORDERS AND FATIGUE As stated earlier, it is important to properly charac- terize fatigue and sleepiness when obtaining a medical history from patients suspected of having a sleep disorder. Sleepiness is a prominent clin- ical feature of many sleep disorders including insuf- ficient sleep syndrome, narcolepsy, obstructive sleep apnea (OSA), and circadian rhythm sleep dis- orders, such as shift work disorder (SWD). In these sleep disorders, patients commonly complain of National Jewish Health, University of Colorado Denver School of Medicine, 1400 Jackson Street, Denver, CO 80206, USA * Corresponding author. National Jewish Health, 1400 Jackson Street, G012, Denver, CO 80206, USA.

E-mail address: [email protected] KEYWORDS Fatigue Narcolepsy Sleepiness Sleep disorders Insomnia KEY POINTS Fatigue is a prominent symptom in numerous medical disorders.

Many individuals with cardiovascular, endocrine, psychiatric, and neurologic disorders experience significant, sometimes debilitating, fatigue.

Although several sleep disorders are characterized by pathologic sleepiness, fatigue can be a major symptom in some sleep disorders.

Identifying and managing underlying sleep disorders may improve sleep and attenuate fatigue.

Sleep Med Clin 8 (2013) 235–239 http://dx.doi.org/10.1016/j.jsmc.2013.02.003 1556-407X/13/$ – see front matter 2013 Elsevier Inc. All rights reserved. sleep.theclinics.com Downloaded for Anonymous User (n/a) at Liberty University from ClinicalKey.com by Elsevier on April 08, 2017.

For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. difficulty staying awake and may fall asleep unin- tentionally. Importantly, sleepiness improves fol- lowing appropriate therapy (eg, sleep extension for insufficient sleep syndrome, psychostimulants for narcolepsy and idiopathic hypersomnia, and positive airway pressure therapy for OSA).Sleep disorders may also give rise to fatigue.

In addition to the sleep disorders already men- tioned, chronic sleep deprivation can result in fa- tigue and lack of motivation. Also, fatigue, either in lieu of, or in addition to sleepiness, is a prom- inent feature of insomnia and restless legs syn- drome (RLS).

INSOMNIA Insomnia refers to difficulty falling asleep, staying asleep, and/or nonrestorative sleep. It is associ- ated with daytime impairments resulting from poor sleep. 12 Patients with insomnia often de- scribe feeling physically or mentally tired or fa- tigued but often do not complain of sleepiness. 13 Imaging studies in patients with insomnia have demonstrated relative increased activity in certain brain regions during sleep, as well as areas of decreased activity during wake. 14 This suggests that fatigue may arise from inappropriate arous- ability during the sleep period and reduced brain metabolic activity during waking. In addition, it has been theorized that insomnia is associated with chronic psychophysiologic hyperarousal. 15,16 Finally, comorbid depression, anxiety, or psycho- logical distress is common in insomnia and may adversely impact daytime functioning. 17 Excessive anxiety regarding sleep may be a bet- ter predictor of daytime fatigue than objective sleep parameters. Perceptions about inadequate sleep duration and poor sleep quality can influence the severity of fatigue complaints. Decreases in slow wave sleep, rapid eye movement (REM) sleep, and total sleep time often accompany sleep fragmentation. 18Sleep fragmentation may result in more complaints of exhaustion and sleepiness, that, in turn, can lead to less physical activity.

Thus, sleep quality, rather than sleep quantity, may be a more important factor in the develop- ment of fatigue in patients with insomnia. How- ever, both subjective sleep quality and objective measures of sleep are important; in one study, among persons with similar levels of fatigue, those with more severe objective sleep disruption re- ported lower quality-of-life scores. 19 OBSTRUCTIVE SLEEP APNEA OSA is a form of sleep-disordered breathing char- acterized by repetitive cessation (apnea) or reduction (hypopnea) of respiration due to com- plete (apnea) or partial (hypopnea) upper airway obstruction during sleep. OSA, if left untreated, can produce cardiovascular and neurocognitive consequences, in addition to excessive sleepiness and fatigue. 20 Daytime sleepiness and mental fa- tigue are associated with a higher risk of accidents due to lapses in alertness or vigilance. 21,22 Compared with hypersomnia, the association between OSA and fatigue is not as well defined. It is unclear what factors or mechanisms contribute to development of fatigue in persons with OSA.

Although fatigue can certainly result from sleep fragmentation and chronic sleep deprivation, studies have demonstrated that fatigue in OSA is more closely correlated with severity of depressive symptoms rather than severity of OSA. 23 Depres- sive symptoms contribute up to 50% of the vari- ance in fatigue in OSA patients, a value 10 times higher than that contributed by OSA severity. 24,25 About half of patients with OSA have at least mild depression 26,27 and almost 20% may be classified as having major depressive disorder. 28Thus, OSA can give rise to fatigue directly via sleep disruption or indirectly by its interactions with depressive symptoms. Lastly, perceived sleep quality appears to be just as important as objective measures of sleep in predicting fatigue. 17 Treatment with positive airway pressure (PAP) remains the therapy of choice for most patients with OSA. However, despite treatment with PAP devices, some patients with OSA may suffer from persistent sleepiness and fatigue. In these pa- tients, it is important to exclude suboptimal ther- apy, noncompliance, significant increases in weight, or development of new sleep or medical disorders that can give rise to fatigue. 29 RESTLESS LEGS SYNDROME Persons with RLS report an uncomfortable sensa- tion or urge to move the legs and sometimes the arms. It is worse at rest and in the evening and is usually relieved by movement. RLS affects about 5% to 15% of the population. 30 It causes sleep disruption and has been associated with fatigue.

The latter may arise from increased inflammation caused by significant sleep disruption and comor- bid depression. Complaints of lack of energy and tendency for depression have been noted in about 60% and 54% of affected individuals, respec- tively. 31 This high associated rate for depression may account for an increase in fatigue complaints.

Older adults with RLS symptoms have significantly higher depression scores compared with those without RLS. 32 Furthermore, insomnia is common among patients with RLS and may also contribute Tsai & Lee-Chiong Jr 236 Downloaded for Anonymous User (n/a) at Liberty University from ClinicalKey.com by Elsevier on April 08, 2017.

For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. to the development of fatigue. Severe RLS is asso- ciated with both poorer sleep quality, as measured using the Pittsburgh Sleep Quality Index (PSQI), and reduced sleep quantity. 33 Patients with RLS commonly have worse quality-of-life scores, with ratings similar to those with other chronic medical conditions. By worsening sleep quality, RLS may exacer- bate fatigue in certain chronic disorders, such as multiple sclerosis (MS) and diabetes mellitus (DM). In persons with type 2 DM, the presence of RLS is associated with worse sleep quality (PSQI scores), longer sleep onset latency, more daytime complaints, more depression, and greater fatigue (higher FSS scores). 34Similarly, RLS negatively af- fects sleep quality in persons with MS and can in- crease the likelihood and severity of fatigue. In 1 study, the prevalence of RLS among patients with MS was 27%. Individuals with both MS and RLS note poorer sleep quality and higher levels of fatigue than in MS without RLS. 35 Individuals with fibromyalgia (FM) generally have more complaints of sleepiness, fatigue, and in- somnia than the general population. 1They also have a higher prevalence of RLS; in 1 study, RLS was 10 times more prevalent among patients with FM than in controls. 36 Treatment of RLS, if present, may improve sleep quality and quality of life in patients with FM. SHIFT WORK Up to 25% of the US workforce has a nontraditional work schedule, working evening, rotating, or night shifts. 37This high number of shift workers is related to the increased connectedness of the world, the global nature of the economy, and 24-hour communication. Shift work disorder (SWD) is char- acterized by insomnia, excessive sleepiness, or both. In SWD, the worker’s endogenous circadian rhythm is desynchronized from the required work schedules, since they are expected to work during typical sleep times, and sleep during typical wake times. While sleepiness is a key feature of SWD, fatigue is also associated with shift work. Shift workers suffer from more fatigue-related accidents. About 30% to 40% of truck accidents are considered fa- tigue-related. 1When evaluating shift workers and their complaints of fatigue, the frequency of shift work affected symptoms of subjective fatigue. 37 The mean FSS score increased as the frequency of shift work increased. When comparing shift workers to nonshift workers, those with 3 or more shifts per week had higher FSS scores. The most fatigued patients also objectively had the worst sleep quality with lower nocturnal oxygen saturations and worse sleep efficiencies. Interest- ingly, sleepiness and fatigue did not correlate with each other. In this study, the severity of fatigue experienced by the shift workers was similar to the severity of fatigue in those with chronic dis- eases such as MS and lupus.

Medical personnel, including nurses, frequently engage in shift work. Among nurses, both working more shifts and having more frequent shifts in- crease severity of fatigue. 38 In this group, poor sleep quality is the factor most closely associated with complaints of fatigue. 39,40 Anxiety and mood disorders also play a role in fatigue among these shift workers.

Various mechanisms for the fatigue noted in shift workers have been proposed. In contrast to normal individuals, in whom cortisol levels are highest upon awakening in the morning and decrease over the course of the day, morning cortisol levels were lower in night shift nurses than in their day shift counterparts. 38 It has been theorized that high cortisol concentrations and low melatonin levels during the day contribute to difficulty sleeping and poor sleep quality following night shifts. Fatigue may also be related to chronic sleep loss, circadian desynchrony, and comorbid sleep disorders. 41 It is estimated that 70% of fatigued shift workers have an underlying coexist- ing sleep disorder, such as OSA or RLS. 36 NARCOLEPSY Narcolepsy is a neurologic disorder characterized by chronic excessive daytime sleepiness. Other associated features include cataplexy, sleep pa- ralysis, sleep hallucinations, and sleep distur- bance. Patients with narcolepsy also often have significant fatigue. 42Using the Checklist Individual Strength (CIS) test as a measure of fatigue, inves- tigators have reported a prevalence of severe fa- tigue of 62.5% in patients with narcolepsy.

Fatigue in this population was associated with greater functional impairment, more depressive symptoms, and worse quality of life. Interestingly, fatigued and nonfatigued subjects did not differ in subjective sleepiness as determined using the Epworth sleepiness scale. Use of stimulant medi- cations was greater among fatigued subjects compared with those without fatigue. 43 Many patients with narcolepsy–cataplexy pos- sess the human leukocyte antigen (HLA) DQB1*0602 allele. Positivity for this allele may explain, in part, differences in fatigue, sleepiness, and sleep requirements among healthy individ- uals.

44 Treatment with modafinil for excessive sleepiness has also been shown to reduce fatigue and improve vigor in patients with narcolepsy. 45 Sleep Disorders and Fatigue 237 Downloaded for Anonymous User (n/a) at Liberty University from ClinicalKey.com by Elsevier on April 08, 2017.

For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. NEUROLOGIC DISORDERS Sleep quality and duration play important roles in the development and progression of fatigue in several chronic neurologic conditions. Among pa- tients with traumatic brain injuries (TBIs), poor sleep and anxiety were among the top 3 most important independent factors associated with fatigue. 46 Fatigue is a major feature of MS and negatively impacts quality of life. In these patients, fatigue is related, in large part, to inflammatory mediators.

In addition, medications used to treat MS and depression can contribute to fatigue. Patients with MS often complain of sleep disturbance and poor sleep quality, and have higher rates of chronic insomnia. These sleep problems, in turn, may worsen underlying fatigue. 47 Due to disrup- tion of dopaminergic pathways, patients with MS may experience RLS. The presence of RLS can, as mentioned previously, worsen fatigue. Finally, patients with MS may have higher risks for central sleep apnea and OSA, both of which can lead to fatigue. Poor sleep quality, including reduced total sleep times, decreased sleep efficiency, and increased prevalence of sleep apnea can contribute to fa- tigue in patients with amyotrophic lateral sclerosis (ALS). 48Conversely, ALS patients with fatigue can experience more difficulty with sleep, have more problems with staying asleep, and report more nocturnal complaints than ALS patients without fatigue. SUMMARY Fatigue is a prominent symptom in numerous disorders. Many individuals with cardiovascular, endocrine, psychiatric (anxiety and depression), and neurologic (MS) disorders complain of signifi- cant, sometimes debilitating, fatigue. Although several sleep disorders are characterized by path- ologic sleepiness, fatigue can also be a major fac- tor in some sleep disorders. A good sleep history, including sleep quality, sleep quantity, work schedule, and perceptions regarding sleep is needed when patients present with complaints of fatigue. Identifying and managing underlying sleep disorders may help attenuate the fatigue experi- enced by these patients. Improving sleep may also reduce the severity of fatigue in persons suffering from other chronic underlying disorders.

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