Sleep Disorders
Carlos A. Santana
Francisco Fernandez
Sleep disorders are common in human immunodeficiency virus (HIV) disease. Disturbance of sleep may contribute to the fatigue and excessive disability associated with HIV infection. Insomnia is underdiagnosed in HIV disease, and clinicians need to be more aware of the high prevalence of insomnia in HIV-seropositive patients. HIV-positive individuals often contend with a number of psychological stressors and social challenges, such as financial concerns, impaired autonomy, social stigma, multiple bereavements, and numerous other psychosocial stressors. Even with the discovery of newer medications, they must also cope with the complex psychosocial demands of their chronic illness and its treatment. These types of recurrent stressors may affect their sleep and their immune status.
Health care providers need to consider the factors that contribute to impaired sleep in developing effective care for HIV-infected individuals with sleep disturbance. In the context of a chronic illness such as HIV infection, achieving the balance of sleep and wakefulness can be difficult yet crucial.
Characteristics of Normal Sleep
Although sleep appears to be simply a body and mind at rest, it is actually a dynamic and complex physiologic state necessary for survival. Normal sleep is characterized by behavioral and physiologic changes, as well as two distinct sleep states—rapid eye movement (REM) and non–rapid eye movement (NREM). Through the course of a night, people cycle between NREM and REM sleep via an ultradian rhythm, with most sleep spent in NREM. Despite being highly regulated, sleep is fragile and its stages and duration may be affected by multiple factors, such as age, drugs, temperature, and medical and psychiatric disease. Variations in nighttime sleep affect subsequent sleep periods and daytime function.
During sleep, a person’s response to or engagement in his or her surroundings is diminished but not completely absent. This reduced consciousness coupled with rapid reversibility distinguishes sleep from death, coma, and hibernation.
Activity in the parasympathetic nervous system is increased during most of sleep, while sympathetic nervous system activity is similar to that of wakefulness, except for periods of REM sleep. Breathing becomes irregular and even periodic in sleep. Control of body temperature is
altered; during NREM sleep, body temperature is set and maintained at a lower temperature than during wakefulness. Temperature control seizes almost entirely during REM sleep.
altered; during NREM sleep, body temperature is set and maintained at a lower temperature than during wakefulness. Temperature control seizes almost entirely during REM sleep.
NREM and REM Sleep
During sleep, a person alternates between NREM and REM sleep.1 This NREM-REM cycle is hypothesized to be controlled by an ultradian process that lasts approximately 90 to 120 minutes. The NREM-REM cycle occurs 3 to 6 times per night in normal nocturnal sleep, with biologic sleep needs being about 8 hours on average.
During NREM sleep, cognitive activity is typically fragmented and body activity periodically occurs as a person moves through the four stages of NREM sleep, each of which is defined along electroencephalographic measures. Stage 1 lasts for 1 to 7 minutes, occurs primarily at the onset of sleep, and serves as a transitional stage throughout sleep. After stage 1 a person enters stage 2, which last 1 to 25 minutes. During stage 2, sleep spindles and k complexes occur periodically. As stage 2 progresses, high-voltage, slow-wave activity increases to the point of becoming stage 3. In the first sleep cycle the duration of stage 3 lasts only a few minutes, with the onset of stage 4 occurring as high-voltage, slow-wave activity continues to increase. When high-voltage, slow-wave activity accounts for more than 50% of the electroencephalogram (EEG), a person has entered stage 4 and stays there for 20 to 40 minutes in the first sleep cycle. Stages 3 and 4 are sometimes referred to collectively as slow- wave, delta, or deep sleep.
Unlike in NREM sleep, during REM sleep the brain exhibits fast encephalographic activity, with the body almost paralyzed except for a few muscle twitches. Thus encephalographic activation, skeletal muscle atonia, bursts of autonomic activity, and episodes of REM characterize REM sleep. The first one third of sleep is spent primarily in NREM stages 3 and 4, and the last one third is spent primarily in REM. Although a sleeping person cycles between NREM and REM every 1.5 to 2 hours, the time spent in these different sleep states is not equal. Most (75% to 85%) of sleep is spent in NREM sleep; the other 20% to 25% of sleep is REM.
Determinants of Sleep
In the brain, sleep and wakefulness are controlled via the hypothalamus through the ventro- lateral preoptic nucleus (VLPO) and the posterior lateral hypothalamus, respectively. Within the hypothalamus the VLPO has been identified as containing -aminobutyric acid (GABA) and galanin neurons, which are necessary for normal sleep.2 During sleep, the VLPO neurons have been found to fire twice as much as in the awake state. In animals with lesions in the VLPO cluster, duration of sleep was diminished by about 50%.2
Wakefulness appears to be mediated by hypocretin (also termed orexin) neurons contained in the posterior lateral hypothalamus. These neurons appear to inhibit the VLPO neurons, thereby establishing a feedback loop that offers two stable patterns, wakefulness and sleep. If either set of neurons fail to fire at its normal rate, instability occurs, with insomnia and/or daytime sleepiness. Hypocretin was discovered in 1998, and its role in sleep and narcolepsy was identified in 2001. As of yet, undiscovered transmitters are undoubtedly involved in sleep control. Most individuals with narcolepsy and cataplexy exhibit about a 90% decrease in the number of hypocretin cells.3
Insomnia
Insomnia is a pervasive condition with various causes, manifestations, and health consequences. Regardless of the initial cause, or event that precipitates insomnia, it is perpetuated into a chronic condition through learned behaviors and cognitions that foster sleeplessness.
Insomnia comprises various manifestations of sleep disturbances and has numerous origins. For some patients, insomnia consists of inadequate sleep duration at night, whereas others experience poor sleep efficiency or poor sleep quality. Complaints from patients with insomnia include difficulties falling or staying asleep during the night, an inability to fall asleep again after nighttime arousals, and awakening too early in the morning.
Insomnia comprises various manifestations of sleep disturbances and has numerous origins. For some patients, insomnia consists of inadequate sleep duration at night, whereas others experience poor sleep efficiency or poor sleep quality. Complaints from patients with insomnia include difficulties falling or staying asleep during the night, an inability to fall asleep again after nighttime arousals, and awakening too early in the morning.
Insomnia may be acute or chronic and primary or secondary. Acute insomnia usually lasts less than 1 month and is often directly attributable to known causes, such as jet lag, medications, or poor sleep environment. Insomnia that lasts 1 to 6 months is considered short term or subacute. Chronic insomnia generally lasts more than 6 months and may be recurrent over many years. Primary or intrinsic insomnia is a condition autonomous from other disorders and may be idiopathic. Secondary or extrinsic insomnia is caused by other medical or psychiatric disorders, alcohol or drug dependence, sleep-induced respiratory disorders, movement disorders, circadian rhythm sleep disorders, environmental factors, or parasomnias.4
When assessing the patient with sleep disorder, we should start with the simple questions: is your sleep restorative and does sleep or fatigue intrude in your daily activity. We should then establish the duration of the sleep problem and determine whether another condition might be the cause of the sleep complaint, modifies a sleep complaint, or affects possible treatments. Because common sleep disorders are frequently secondary to underlying causes, treatment should be directed at underlying medical, psychiatric, pharmacologic, psychosocial, or other disorders.
The evaluation of chronic sleep complaints should include the following:
A detailed history exploring predisposing, precipitating, and perpetuating factors
A detailed review of difficulties in falling asleep, maintaining sleep, and awakening early
Timing of sleep and wakefulness in a 24-hour day
Evidence of excessive daytime sleepiness and fatigue
Bedtime routines, sleep settings, preoccupations, anxiety, beliefs about sleep and sleep loss, and fears about consequences of sleep loss
Medical and neurologic history and examination, routine laboratory examinations
Social and occupational history and level of physical activity
A self-report 2-week sleep–wake diary
Careful assessment of the use of prescription, nonprescription, and illegal drugs and alcohol and caffeine intake
Careful evaluation of any pain complaint
Interview with bed partners or persons who observe the patient during sleep, if possible
Insomnia in HIV Infection and Polysomnographic Changes
The early clinical reports of HIV infection highlighted sleep disturbances as a prominent complaint.5 Insomnia has been described in all stages of reported HIV illness and may lead to chronic fatigue, reduced physical and social function, and an overall reduction of quality of life.6 A number of studies have reported on factors thought to contribute to the development of insomnia in people with HIV disease and acquired immunodeficiency syndrome (AIDS). Early investigations were primarily laboratory based, analyzing sleep architecture through the use of polysomnography and with a focus on biologic correlates, in particular central nervous system (CNS) manifestations of HIV infection and altered immune response. This emphasis has subsequently shifted, with epidemiologic studies evaluating subjectively reported insomnia and its associations. As well as the direct effects of HIV infection on sleep, some studies have considered the effects of other variables, including antiretroviral medication, psychiatric illness, and drug and alcohol use.
The most frequently reported change in the sleep profile of HIV-positive subjects has been a significant increase in slow-wave sleep (SWS), particularly during later sleep cycles.7 It has
been suggested that changes in SWS may be dependent on illness progression, although other factors such as age, psychiatric illness, and use of psychotropic medication are potential confounders. One case control study found that CD4 count was a determining factor.8 Uncontrolled studies suggested an increase in the number of REM periods in HIV-positive subjects, with a reduction in their duration.9
been suggested that changes in SWS may be dependent on illness progression, although other factors such as age, psychiatric illness, and use of psychotropic medication are potential confounders. One case control study found that CD4 count was a determining factor.8 Uncontrolled studies suggested an increase in the number of REM periods in HIV-positive subjects, with a reduction in their duration.9
Rubinstein and Selwyn10 found that in 10% of their sample with cognitive impairment, reports of insomnias were universal, and multivariate analysis found that cognitive impairment was the best predictor of insomnia, suggesting an effect of CNS infiltration. A significant association has also been reported with reduced CD8 cells,11 suggesting that psychological morbidity may influence CD8 count by its effect on sleep quality. Norman et al.7 proposed that a possible explanation for the observed relationship between HIV infection and sleep disorders may lie in the relationship between immune mediators and sleep. Elevated levels of interferon, tumor necrosis factor, and interlukin-1 have been detected in HIV-seropositive patients.5 These substances have been shown to affect sleep physiology by enhancing SWS, thereby disrupting normal REM and NREM sleep cycles.
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