#98883: Sleep Disorders

During stage 1 sleep, individuals begin to feel drowsy but can be easily aroused. Relaxation of musculature begins, as does reduced environmental awareness [20]. Slow and rolling lateral eye movements also may occur. EEG brain activity shows interruption of the posterior dominant rhythm (i.e., alpha dropout) and the onset of a low-voltage, intermixed pattern of frequencies [35,36]. Positive occipital sharp transients of sleep (POSTS) and very brief vertex sharp waves may occur in repetitive runs. (POSTS start around 4 years of age, are common by 15 years of age, and decline after 50 years of age.) Hypnagogic hypersynchrony, or bursts of high-amplitude, diffuse, rhythmic (sinusoidal) delta activity, can arise, especially among children 3 months to 13 years of age and is considered a normal variant of drowsiness in this age group. This stage tends to last one to five minutes, consisting of around 5% of the total cycle [34].

Approximately 50% of time is spent in stage 2 sleep during an adult's normal night's sleep [20,34]. Arousal is more difficult during this phase, and the low-voltage, intermixed pattern continues. Brainwave activity slows to the theta range (4 Hz to 7 Hz). Sleep spindles (and associated K-complexes) are the defining characteristic of stage 2 sleep. Spindles are short bursts of vertex rhythmic activity between 12 and 16 Hz (typically 14 Hz) lasting about 0.5 seconds. Sleep spindles begin at 6 to 8 weeks of age and continue throughout life [34,35,36].

This is considered the deepest stage of sleep [34]. Muscle tone continues to decrease progressively through stage 3. Arousal is most difficult during these stages, which are marked by slow-wave sleep consisting of progressively increasing high-voltage, delta-range brain activity. During stage 3, delta activity comprises as much as 50% or more of brainwave activity [35,36]. Sleep spindles may still occur in these stages but are not a major feature. Over a lifetime, the amount of time spent in slow-wave sleep decreases [20]. Cognitive testing shows that individuals awakened during this stage tend to have mental performance that is moderately impaired for 30 minutes to 1 hour [34]. During N3, the body repairs and regrows tissues, builds bone and muscle, and strengthens the immune system [34].

As the name suggests, the major feature of REM sleep is rapid eye movement, but this stage is also characterized by muscle atonia and EEG desynchronization [20]. Brainwave activity returns to a low-voltage intermixed pattern and becomes faster (beta and theta range), almost resembling wakefulness. Dreaming is most likely to occur in this stage. Central activity in the theta range can produce waves with a "saw tooth" appearance on a polysomnogram display.

In healthy adults, about four or five sleep cycles, each about 90 minutes, occur in one night, each one progressing through the non-REM stages, followed by REM sleep [20]. Slow-wave sleep is lessened and REM sleep becomes more predominant with each successive sleep cycle [37].

Some individuals enter REM sleep before descending through non-REM phases, which is referred to as sleep-onset REM periods (SOREMPs). This is considered an indicator of a sleep disorder, usually narcolepsy, but it may also occur in patients with obstructive sleep apnea [33,38]. SOREMPs are uncommon in the healthy adult population but are slightly more prevalent in individuals with excessive sleepiness (e.g., adolescents and young adults, shift workers) [39]. SOREMPs are also seen with other disorders, including Prader-Willi syndrome, Kleine-Levin syndrome, Parkinson disease, and periodic limb movement disorder (PLMD) [40].

Approximately 10% of the adult population is affected by chronic insomnia disorder as defined by the ICSD-3 [2]. The disorder is more common in women than in men and affects a greater number of individuals with low socioeconomic status versus those who are economically and socially stable. Patients with medical, psychiatric, and/or substance abuse problems are disproportionately affected. Older individuals are more often diagnosed with chronic insomnia, likely due to medical conditions, medications used to treat them, and age-related sleep continuity decline [2]. Transient insomnia affects 30% to 35% of the adult population.

Prevalence of insomnia in children and adolescents is estimated at 10% to 30% and 3% to 12%, respectively, with wide variance due to definitions of insomnia used in research. It is more frequently diagnosed in adolescent girls than boys [2]. Although the specific ICSD-3 diagnosis has changed, the problems associated with childhood sleep disorders have not. Most chronic childhood insomnia cases are due to caregiver/parental behavior, bedtime interactions, and cultural influences, and the underlying difficulties are still primarily sleep-onset and/or limit-setting problems [2]. The need for and provision of nighttime contact varies among cultures, which should be taken into account. Infants do not establish a regular sleep pattern until approximately 3 to 6 months of age, and an insomnia diagnosis is typically not made before 6 months of age.

The evidence for familial occurrence of insomnia is weak, but there does appear to be some influence, particularly between mothers and daughters, monozygotic twins, and, to some extent, other first-degree relatives [2]. It is not known what the association(s) may be; theories range from learned behavior and a shared environment to genetic predisposition and the byproduct of a common psychopathology.

A diagnosis of chronic insomnia disorder is based primarily on subjective reports from adult patients and objective and subjective reports for children and adolescents. The differential diagnosis of chronic insomnia may include a sleep study, if warranted, but typically is not needed for routine evaluation.

There are three features of chronic insomnia disorder [2]. The first is frequent and persistent difficulty initiating or maintaining sleep, and this is the intrinsic essential feature of chronic insomnia disorder [2]. This repetitive failure results in the patient's general dissatisfaction with sleep and quality of life. Insomnia, though chronic, does not necessarily occur every night. Some patients will have episodes of recurrent insomnia, while others constantly struggle with sleep insufficiency. It is common for individuals with persistent insomnia to have several bad nights of sleep with an occasional good sleep [2]. Other patients who are predisposed to insomnia may experience poor sleep in relation to stressful life events. An initial episode of acute insomnia related to a stressful event will typically resolve in most individuals as they adjust to their new reality; however, this episode has the potential to become a chronic problem for some patients. The remembrance and anticipation of insomnia following a stressful event, coupled with actual sleep difficulties and daytime impairment, can lead to a cycle of disordered sleep [2].

The second feature of chronic insomnia is worry about sleep difficulties and/or academic, family, social, vocational, or other functional impairment [2]. Patients with insomnia often display excessive preoccupation with sleep, which can be problematic. Worrying about not getting enough sleep and not being able to initiate sleep following an episode of insomnia can lead to a vicious cycle of becoming tense or agitated as bedtime approaches (with corresponding adrenaline release), trying too hard to sleep (e.g., lying in bed for extended periods of time), becoming increasingly distressed and agitated at the inability to sleep, and being further unable to initiate sleep [43].

Preoccupation with general health and wellness may predispose individuals to chronic insomnia, and repression and internalization of disturbing feelings may be a common trait [2]. It may appear that patients are overly anxious, and in fact, recurrent thoughts of poor sleep performance may trouble these individuals in the morning and afternoon and attain a peak at night. However, generalized anxiety is not the norm for chronic insomnia sufferers. Screening for comorbid general anxiety is recommended when symptoms seem to extend beyond an emphasis on disordered sleep [2]. Environmental and biologic sleep cues often become triggers for heightened sleep anxiety and arousal. For example, when the sun sets and darkness falls, thoughts of poor previous nights' sleep and sleep performance anxiety may begin. In healthy individuals, feelings of drowsiness lead to increased calm, but fatigue can cause panic and distress in those with chronic insomnia. Patients may think, "I feel tired, but I know that if I go to bed I will not be able to fall asleep," or, "I feel tired now, but I am going to feel even worse tomorrow morning when I am not able to sleep tonight." This may be, or become, true as the patient ruminates about sleep and stresses.

Subjective or objective deficits with daily functioning are noticed in individuals with chronic insomnia. These may manifest as depression, lethargy, or a desire to limit activities or work. Work productivity may suffer, as may academic performance.

Patients often readily express sleep anxiety and may acknowledge their ability to sleep normally in unfamiliar settings [2]. The lack of environmental triggers in unfamiliar environments can help prevent sleep performance worry.

The third essential feature of chronic insomnia disorder is inability to sleep and remain asleep despite plenty of time to sleep, no nighttime interruptions, an adequate sleep environment, and other sufficient circumstances [2]. Practicing sleep hygiene, or maintaining an ideal sleep environment and optimum mental/physical state to promote sleep, is discussed later in this course.

The diagnosis of chronic insomnia in children is somewhat different because of the strong influence of parental/caregiver and environmental factors on development. Parents should be questioned regarding their expectations for their child's sleep. Putting children to bed prematurely or allocating too much time in bed can cause sleep difficulties that may lead to chronic insomnia [2]. On the other hand, parents may not be implementing or enforcing regular bedtimes or may allow children to postpone bedtimes. As children develop greater language skills and seek individuality, limit setting becomes more important. Studies have also shown that parents of children who faced a life-threatening illness are less strict about enforcing bedtimes and allow their children greater leeway with sleeping (e.g., joining the adult bed upon waking) [2]. Abuse and unstable home environments are also known factors for insomnia in children and adults. Crowded homes (e.g., with extended family of many generations) are associated with poor limit setting and negative sleep-onset cues. Children should also be carefully screened for comorbid medical and psychiatric conditions that may have gone unnoticed. The diagnostic criteria for adults and children are shown in Table 2.

Subjective assessment with a sleepiness instrument, such as the Epworth Sleepiness Scale (Table 3), may be helpful to ascertain the patient's degree of impaired sleep, but laboratory testing to measure sleepiness (e.g., the Maintenance of Wakefulness Test) usually does not show greater sleepiness in this cohort compared with healthy individuals [44]. The Epworth Sleepiness Scale has been found to be particularly effective for identifying cases of insomnia and less useful for diagnosing other sleep disorders [45]. Sleep studies are not typically needed to make a diagnosis, but polysomnography may reveal poor sleep continuity (e.g., decreased sleep efficiency, intermittent wakefulness) and more stage 1 sleep and limited stage 3 sleep [44,46]. As noted, many persons with insomnia sleep better outside their own bed, and overnight laboratory testing may not provide significant data. Polysomnographic results also vary considerably from night to night in these patients [44]. Polysomnography is recommended for elderly individuals, as they are more prone to having identifiable etiologies of insomnia.

Approximately 7 of 10 individuals with persistent insomnia struggle with insomnia after one year of treatment, and half still have insomnia three years later [2]. Complications of chronic insomnia include increased risk of depression, hypertension, work disability, and protracted use of prescription or over-the-counter sleep aids. Therefore, effective professional therapies are needed to avoid dangerous comorbidities and adverse drug effects. Additionally, managing comorbid medical and psychologic conditions with sleep-disrupting effects is necessary for these patients.

Sleep Hygiene

Management of chronic insomnia centers on behavior and lifestyle modification combined with counseling and instruction in effective sleep hygiene practices. Some of the foremost behaviors patients should modify or adhere to include keeping a consistent sleep schedule (i.e., going to bed at the same time each night and waking up at the same time each morning), devoting at least seven to eight hours each night to sleep, and creating and maintaining a bedtime ritual [48]. The optimum sleep time varies among individuals, but those with persistent excessive daytime sleepiness should sleep a minimum of six to eight hours.

Establishing a bedtime ritual involves deciding upon an activity or series of activities that provide conditioned sleep cues and consistently repeating those activities each night. The first part of the ritual should involve quitting challenging, engaging, or stressful tasks (e.g., paying bills, playing video games, watching television) and resolving any lingering worries (e.g., quarrels, dwelling problems). Some people find that if tasks are incomplete or issues are left unresolved, making a to-do list for the next day will help to clear their mind [48]. Next, patients should focus on relaxation for 20 or 30 minutes. During this time, they might read, listen to relaxing music, take a warm bath, or practice meditation and/or deep-breathing exercises. There are many other lifestyle modifications that can reduce the likelihood of developing a sleep disorder or can lead to a reduction of symptoms of an existing disorder. The following guidelines are all components of proper sleep hygiene and should be included as part of patient education for any sleep disorder [11,48]:

The following changes to the sleeping environment have also been shown to promote sleep [48]:

A sleep hygiene regimen is a universally applicable prevention and treatment strategy that can improve sleep quality for those with and without a specific sleep disorder. Most sleep experts recommend that sleep hygiene be used as an adjunct to treatment for sleep disorders [2]. Despite limited research supporting the role of proper sleep hygiene in patients with insomnia, many patients will find these suggestions helpful. It has been found that individuals with chronic insomnia who are highly aware of poor sleep hygiene practices may be the most indifferent toward making changes [2].

Cognitive-Behavioral Therapy and Other Modalities

Certain forms of chronic insomnia tend to be less amenable to control with simple nonpharmacologic and brief sedative-hypnotic modes of treatment. Some form of cognitive-behavioral therapy (CBT), utilizing stimulus control, relaxation training, and sleep restriction therapies, sequentially or in combination, achieves the best results [46,49]. Stimulus control therapy, which is akin to maintaining strict sleep hygiene, has been extensively studied and is the most recommended modality for initial insomnia treatment [43]. However, because sleep cues and other practices learned with sleep hygiene/stimulus control may become (or may already be) a cause of arousal, it is unlikely that all clinical subtypes will benefit significantly from this form of therapy.

The effectiveness of CBT for psychophysiologic insomnia has been demonstrated in several studies [43,49,50,51]. Patients also tend to prefer CBT over pharmacologic options and other forms of psychotherapy [51]. Relaxation techniques (e.g., biofeedback, breath counting/deep breathing, meditation, progressive relaxation) can be an effective adjunct to CBT [46,52]. Progressive relaxation can be particularly effective in patients who somatize stress into physical tension. This form of therapy involves tensing and relaxing individual muscle groups while breathing deeply, starting from the toes, working progressively through the calves, thighs, stomach, shoulders, hands, arms, and neck, and ending with the facial muscles. Deep breathing exercises use slow, controlled breaths (while counting) to "quiet" racing thoughts; if the mind wanders from counting breaths, patients should resume counting and eventually they should fall asleep [52].

Sleep restriction is also a useful form of therapy [52,53]. This technique is based on the observation of deeper, more consolidated sleep in sleep-deprived test subjects. Through this paradoxical approach, patients learn to associate time spent in bed with time spent sleeping [54]. The first step is for patients to keep a sleep log for two weeks to determine their average total sleep time (i.e., average amount of time asleep in bed); 30 minutes is added to this time to establish the time they will be allowed in bed [55]. For example, if the patient's average total sleep time is 5 hours, the allowed time in bed will be 5.5 hours. Next, a wake time is set based upon when the patient needs to start their day (e.g., 6:30 a.m.), and the bed time is set by counting backward based on the time in bed allowance (e.g., 1:00 a.m.). Regardless of how sleepy the patient feels, he or she must not nap or get into bed before the prescribed bedtime. Upon waking, the patient should expose his or her eyes to bright light (daylight whenever possible) to reinforce the sleep/wake cycle [55]. If after two weeks the patient feels tired during the day, they may add 15 minutes to the sleep allowance, and every successive week they may add an additional 15 minutes until they are able to get to sleep easily, are sleeping well throughout the night, and feel rested during the day [55]. The minimum amount of sleep needed to achieve these goals is recommended, and a consistent sleep and wake time must be maintained. This therapy should be discontinued if job performance or safety is compromised due to excessive daytime sleepiness.

Pharmacologic Options

For some patients, CBT in combination with a pharmacologic agent, administered over six to eight weeks, is an effective strategy. The primary pharmacologic option for patients with chronic insomnia disorders is the administration of sedative-hypnotic drugs at night (e.g., eszopiclone, ramelteon, triazolam, zaleplon, zolpidem). However, long-term treatment with sedative-hypnotics is associated with a high incidence of adverse effects, including cognitive impairment, constipation, dizziness, headache, heartburn, the development of parasomnias (e.g., sleepwalking, sleep driving), and reduced respiratory drive [50]. If used, the lowest effective dose is recommended to reduce the incidence of these effects [50]. Additionally, AASM guidelines for the pharmacologic treatment of chronic insomnia in adults provide "weak" recommendations for the agents reviewed. AASM emphasizes that this grade does not indicate that the agents are ineffective but rather reflects a "lower degree of certainty in the outcome and appropriateness of the patient-care strategy for all patients" [56]. Patients should be cautioned not to combine these medications with alcohol or other central nervous system (CNS) depressants, as their combination can cause increased liver toxicity and drastically reduced cognitive and psychomotor functioning [57].

The American Academy of Sleep Medicine recommends the following agents be considered for the treatment of chronic sleep-onset insomnia:

• Eszopiclone

• Zaleplon

• Zolpidem

• Temazepam

• Ramelteon

(https://jcsm.aasm.org/doi/10.5664/jcsm.6470 Last Accessed: December 7, 2021)

Strength of Recommendation: Weak (a lower degree of certainty in the outcome and appropriateness of the patient-care strategy for all patients)

Different sedative-hypnotics are indicated for various sleep difficulties. Zaleplon is fast acting, but has a short half-life; this drug may be best for patients who experience night awakenings with difficulty returning to sleep [58]. Zolpidem has a rapid onset and short-half life as well; patients with difficulty falling asleep may benefit from this drug. A controlled-release version is also available. Eszopiclone has a slow onset and long duration of action and is indicated for patients with difficulty staying asleep and with perception of poor sleep quality [57].

Hypnotic drugs are best utilized when nonpharmacologic measures do not achieve symptom reduction, when insomnia causes serious impairment, or when an immediate response is desired [54]. The following are best practice guidelines regarding the prescription and use of sedative-hypnotics [54,59]:

Herbal and Hormonal Supplements

A variety of herbal, hormonal, and dietary supplements have been marketed as sleep aides, with scant evidence of significant benefit. Melatonin, a brain hormone produced by the pineal gland, does have some function in regulating the normal sleep cycle, and melatonin supplementation may be of benefit to a subset of patients with delayed sleep phase syndrome (a disturbance of the circadian rhythm). However, it does not appear to be helpful for most people who have insomnia. It is safe when used in modest dosage (2–3 mg per night) for short periods (three months or less) [60]. Melatonin is unregulated by the U.S. Food and Drug Administration (FDA); formulations vary in strength, and higher doses can lead to adverse side effects (e.g., disrupted sleep, fatigue, headache) [57]. AASM does not recommend melatonin for sleep onset or sleep maintenance insomnia in adults [56].

Valerian is a popular herbal product commonly used to self-treat insomnia. It causes CNS sedation by inhibiting the breakdown of certain chemical mediators within the brain. Clinical trials have shown minimal effectiveness at best [61]. This product is also unregulated by the FDA. Daytime drowsiness and rare instances of liver toxicity have been observed in association with its use. AASM does not recommend valerian for sleep onset or sleep maintenance insomnia in adults [56].

Obstructive sleep apnea is by far the most common sleep-related breathing disorder [62]. Using the AASM criteria, it is estimated that 1 in 5 American adults has at least mild obstructive sleep apnea and 1 in 15 has at least moderate obstructive sleep apnea [63]. The incidence of the disorder increases with age, and it is two to three times more common in men than in women [62,63,66]. The estimated incidence among various age-groups is [62,66]:

Differences in incidence among racial and ethnic groups have not been extensively studied. Although race is thought to be an important risk factor for sleep disordered breathing, at this time it is not certain what role race or ethnicity plays in the development of obstructive sleep apnea. Researchers have attempted to link occurrence of the disorder to racial craniofacial differences and variations in body mass trends or fat distribution, with little replicable data to support their hypotheses [66]. Again, this may be due to a lack of research that accounts for race in the United States and other Western countries and limited research of the disorder in Africa, Asia, and the Pacific Islands.

Many risk factors have been theoretically linked to obstructive sleep apnea. The most widespread factors are alcohol consumption, smoking, overweight and obesity, and hormonal changes related to pregnancy, menopause, and polycystic ovary syndrome [63]. There are conflicting studies for each of these theories, and only overweight and obesity is considered a statistically significant risk factor.

Excess body weight is the strongest risk factor for obstructive sleep apnea in the general population, and most (though not all) patients who present with the disorder are heavier than normal weight [2]. The overweight and obesity epidemic in the United States has caused a concurrent rise in the prevalence of sleep disordered breathing, but the mechanisms involved are still unclear [67]. Hypotheses for the pathophysiology of overweight and obesity in the disorder include distorted upper airway structure and function (caused by altered neck morphology), an altered relationship between respiratory drive and load compensation, and intensification of apnea/hypopnea events through obesity-related decreases in functional residual capacity and increased whole-body oxygen demand [63,68,69]. Other obesity-related conditions, including insulin resistance, generalized inflammation, hypoactive hypothalamic corticotropin-releasing hormone neurons, and visceral adiposity, have been suggested as factors in the development of obstructive sleep apnea following excessive weight gain [70]. Individuals with an "apple-shaped" body (i.e., central adiposity) or who have a greater neck circumference are thought to be more affected than those who are "pear shaped" (i.e., gynoid adiposity), but there is little concrete evidence to support this idea [67].

Obesity may also be a risk factor for obstructive sleep apnea in children and adolescents. One study found a relative risk 4.59 times higher in obese children 2 to 18 years of age compared with normal weight controls [71].

Despite the lack of consensus regarding the role of excess body weight in the pathogenesis of obstructive sleep apnea, studies have shown a strong positive correlation between body mass index (BMI) and AHI [63,68,72]. A decade-long Wisconsin study of 690 randomly selected participants (mean age: 46 years) found that a 10% weight gain yielded a six-fold increase in the odds of developing moderate-to-severe sleep disordered breathing compared with individuals who maintained a steady weight [67]. Those who lost 10% of their initial weight during the study period lowered their AHI score by an average of 26% (range: 18% to 34%). Several small-scale studies have shown improvements in obstructive sleep apnea symptoms following surgical weight-loss interventions. Body mass reduction following bariatric surgery can cause the most dramatic (though possibly short-term) decrease in AHI score [63,64,68,72].

History and Physical Examination

The diagnosis of obstructive sleep apnea is usually made in one of three settings: a general, routine health evaluation, a screening of high-risk patients, or an evaluation suggestive of obstructive sleep apnea [41]. High-risk groups include individuals who are obese or are being evaluated for bariatric surgery; those with atrial fibrillation, congestive heart failure, treatment-refractory hypertension, nocturnal dysrhythmias, pulmonary hypertension, type 2 diabetes, and/or stroke; and high-risk driving populations (i.e., commercial truck drivers). During the initial evaluation, a history of snoring and daytime sleepiness should be taken, along with an assessment of BMI, blood pressure, maxillofacial irregularities (e.g., retrognathia), and upper airway restriction (e.g., large adenoids/tonsils).

A detailed sleep history should be obtained, including evaluation for [41]:

Any of the previously discussed complications associated with obstructive sleep apnea (e.g., hypertension, stroke, motor vehicle accidents) should be documented. The physical examination may reveal common physical traits associated with obstructive sleep apnea, including [41]:

The differential diagnosis of obstructive sleep apnea in adults includes nonpathologic snoring, panic attacks, laryngospasm related to gastroesophageal reflux, and dyspnea associated with pulmonary edema [2].

Testing

The American College of Physicians recommends polysomnography for diagnostic testing in patients suspected of obstructive sleep apnea. Portable sleep monitors are recommended for patients without serious comorbidities as an alternative to polysomnography when it is not available for diagnostic testing.

(https://www.acpjournals.org/doi/10.7326/M12-3187 Last Accessed: December 7, 2021)

Level of Evidence: Moderate-quality evidence (Randomized, controlled trials with important limitations)

Objective testing with a standardized method follows suspicion of obstructive sleep apnea to confirm the diagnosis and guide the initiation of treatment. In-laboratory polysomnography is the preferred method of objective sleep testing and is recommended for most patients [41]. At-home testing with portable monitors may be used prior to laboratory testing or to confirm the efficacy of treatments, but it should not be used for individuals with a high degree of comorbidity unless in-laboratory monitoring is not feasible due to safety or mobility issues.

Diagnostic Criteria for Adult Patients

The AASM has established diagnostic criteria for adults suspected of having obstructive sleep apnea. In all cases, the disorder must not be better explained by another current sleep disorder, medical or neurologic disorder, medication use, or substance use disorder. In addition, patients must display the following signs and symptoms [2]:

OR

Diagnostic Criteria for Pediatric Patients

The criteria established to diagnose obstructive sleep apnea in adults have been found to be insufficient to identify children with the disorder. For these patients, parents or caretakers must report a history of labored breathing, snoring, or both, and observation of at least one of the following must be made to diagnose pediatric obstructive sleep apnea [2]:

Differentiating obstructive sleep apnea from primary snoring requires the use of polysomnography. Further, one (or more) scorable event per hour must be recorded during the sleep study. For diagnosis of obstructive sleep apnea in children, polysomnographic findings must include [2]:

OR

The disorder must also not be better explained by any other medical condition, including another sleep disorder.

Due to the chronic nature of the disorder, obstructive sleep apnea treatment is typically long-term and includes behavioral, medical, and surgical options. Patient education regarding the clinical consequences, natural history, pathophysiology, and risk factors of the disorder, and general information, such as alcohol avoidance, risk factor modification, medication effects, weight loss, sleep position, and drowsy driving, should be given upon diagnosis. The goals of treatment are to improve breathing during sleep, to lessen or prevent the sequelae associated with excessive daytime sleepiness and the disorder itself, and patient and partner satisfaction [41].

Positive Airway Pressure Therapy

According to the American College of Physicians (ACP), the principal initial treatment for obstructive sleep apnea is positive airway pressure (PAP) therapy, which uses forced air to maintain a patent pharyngeal airway [73]. This therapy may be provided in one of three modes: continuous (CPAP), bilevel (BPAP), or autotitrating (APAP), all with or without pressure relief (i.e., partial pressure reduction during expiration) [41,71]. CPAP is the standard mode of PAP therapy; BPAP and APAP are used when CPAP cannot be tolerated. CPAP therapy is also recommended for patients with mild obstructive sleep apnea who have failed to improve with behavior modification or who are unable to enact lifestyle changes and who have symptoms that affect their ability to perform daily tasks and impact their quality of life [71].

CPAP appliances consist of a mask or other device that fits over the nose or the nose and mouth, a tube that connects to the mask, and a motor that blows air into the tube [74]. A humidifier and/or heater can be used to condition the device air and lessen or prevent complications, such as throat irritation, nasal dryness, and nasal bleeding. Many patients have difficulty adjusting to wearing the mask and may feel confined during sleep. Periodically wearing the mask during the day, trying CPAP while awake, or using relaxation exercises should be recommended to help in getting comfortable with the device [74]. Newer machines have a "ramp" feature that slowly builds to the prescribed pressure level, which can help with adjusting to the unnatural feeling that CPAP can create.

The clinical effectiveness of CPAP therapy on measures of self-reported daytime sleepiness, fatigue, cognitive function, and depression is supported by evidence. However, the effect on other measures, such as hypertension and cardiovascular events, is unclear [74]. A 2012 clinical trial summary showed that 19% of patients in the CPAP study group developed hypertension, compared with 22% in the control group (dietary and sleep hygiene counseling), and 8% of patients using CPAP had a cardiovascular event, compared with 8% in the control [75]. Although the authors stated that CPAP therapy outcomes failed to reach statistical significance in reduction of these two measures, the small study size may have had limited power to detect a significant difference. A meta-analysis that included 3,780 patients found that, compared with medical therapy alone, CPAP was not associated with a reduced risk of major adverse cardiac events. Improved cardiac outcomes were observed only in a subgroup of patients who wore the CPAP mask for more than four hours at a time [76]. A 2021 meta-analysis that included 2,590 participants found a significant association between use of CPAP and reduced risk of major adverse cardiovascular events, particularly among participants with an AHI less than 30 events per hour [77]. Still, the authors concluded that more research is needed to confirm this benefit.

Oral Appliances

The American Academy of Sleep Medicine recommends sleep physicians consider prescription of oral appliances, rather than no treatment, for adult patients with obstructive sleep apnea who are intolerant of CPAP therapy or prefer alternate therapy.

(https://jcsm.aasm.org/doi/10.5664/jcsm.4858 Last Accessed: December 7, 2021)

Level of Evidence: Moderate

An oral appliance is a custom-fit, molded mouthpiece that is fitted by a dental professional to enlarge the upper airway and/or decrease upper airway collapsibility. There are two types of oral appliances: mandibular advancement devices (MADs), which advance the mandible with respect to the resting position and cover the upper and lower teeth, and tongue-retaining devices, which do not reposition the mandible but hold the tongue forward relative to the resting position. The ACP recommends MADs as an alternative for patients who cannot tolerate or would prefer not to use PAP therapy [73]. A complete dental history and dental examination for appraisal of characteristic patterns of wear from nocturnal bruxism; soft tissue, periodontal, and temporomandibular joint (TMJ) assessment; evaluation of occlusion; and resolution of dental pathology precludes the fitting of the appliance. The type employed will be based on a patient's individual anatomy, preferences, and dental assessment. MADs require satisfactory jaw range of motion, no important TMJ disorder, and enough healthy teeth upon which to seat the oral appliance.

A 2006 Cochrane Database review found that oral appliances had similar effectiveness on self-reported outcome measures (e.g., subjective sleepiness, depression) as CPAP therapy but were inferior in reducing respiratory disturbances among most patients [78]. Patients expressed a strong preference for the oral appliances. However, participants were more likely to withdraw on oral appliances than on CPAP therapy. Oral appliance therapy is recommended for patients with mild obstructive sleep apnea who fail behavioral treatments or for patients with mild-to-moderate obstructive sleep apnea who prefer the option over CPAP, who are not candidates for CPAP, or who do not respond to CPAP, or for those carefully selected patients in whom they are as effective in reducing daytime symptoms and AHI score [41,78].

Behavior Modification

There have been no large-scale clinical trials of dietary, exercise, medication, or surgical weight-loss interventions on outcomes in patients with sleep disordered breathing. However, the ACP recommends that all overweight and obese patients diagnosed with obstructive sleep apnea be encouraged to lose weight [73]. Many small-scale studies have shown that BMI reduction (by any means) is effective at reducing the number and duration of apnea and hypopnea events [64]. Other behavioral options include positional therapy and avoidance of alcohol and sedative drugs.

A 10% weight loss can considerably reduce the total number of obstructive events per night, and all patients should be strongly encouraged to achieve a BMI ≤25 through a combination of diet and exercise to improve obstructive sleep apnea symptoms and lessen the risk of comorbidities [41,67]. Subsequent to body mass reduction, AHI should be reassessed using in-lab polysomnography to determine whether PAP adjustments are needed or if PAP therapy may be discontinued altogether. Because significant and lasting weight reduction is typically not achieved by most patients, especially with a dietary component alone, other treatment strategies should be employed simultaneously [41]. Even sustained weight loss does not often fully alleviate the disorder.

A supine sleep position is most likely to affect breathing, and maintaining a non-supine position throughout sleep helps to keep the airway patent in some patients [41]. Identification of individuals who have a low AHI in a non-supine position is necessary before positional therapy is initiated. If appropriate, a device (e.g., alarm, backpack, tennis ball, pillow) may be employed to keep the patient from sleeping on his or her back.

Surgical Treatment

Before the widespread use of PAP therapy, surgery was the primary treatment for obstructive sleep apnea, and it is still indicated for certain cases. Many surgical options involving reconstruction (or bypass) of the upper airway can be used to reduce the severity of obstructive sleep apnea symptoms and increase the effectiveness of behavioral and medical treatments (Table 4); however, it is beyond the scope of this course to cover the details of each procedure. Bariatric weight-loss surgery is also considered a treatment for obstructive sleep apnea and is indicated for patients with a BMI ≥40 or BMI ≥35 with significant comorbidities and failure to achieve weight loss with diet and exercise [41].

After a diagnosis of obstructive sleep apnea has been established, it should be determined if patients are appropriate candidates for surgery as a primary, secondary, or adjunct treatment [79]. Candidates should also be screened for comorbidities that would affect the outcome of surgery. This and individual anatomy will dictate which option is chosen. Patients with obstructive sleep apnea who have gross anatomic abnormalities that are correctable (e.g., tonsillar and/or adenoidal hypertrophy, collapse or narrowing of the retropalatal or retrolingual areas) should be considered for primary surgical treatment regardless of the severity of the disorder [41]. Surgery as secondary treatment should be considered for patients who have failed to improve with PAP therapy or with an oral appliance or who cannot tolerate either modality. Upon examination of the upper airway, a patient with a gross obstruction that is deemed likely to interfere with the placement, effectiveness, or tolerance of either oral appliances or PAP should be considered a candidate for surgery as an adjunct treatment [41].

The goals, benefits, risks, complications, and possible side effects of the chosen procedure(s) should be discussed, and the willingness to undergo surgical therapy should also be assessed. Although certain procedures (e.g., maxillomandibular advancement, radiofrequency ablation) seem to be effective in reducing AHI score, evidence for most procedures is of low quality and long-term data regarding effectiveness and sequelae is not available [79]. Patients should be informed that most surgeries will not cure obstructive sleep apnea but may improve clinical outcomes (e.g., cardiovascular risk, daytime sleepiness, mortality) [41]. The exception is tracheotomy, which can completely eliminate obstructive sleep apnea but not improve blood oxygen saturation or resolve other symptoms of hypoventilation syndrome. Tracheotomy for obstructive sleep apnea is typically only performed when all other options have been exhausted, when clinically urgent, or in special populations (e.g., patients with Alzheimer disease, Down syndrome, or mental and physical handicaps), as it is a radical procedure that requires a high level of care and lifestyle modification [79].

Pharmacologic and Oxygen Therapies

There are no effective pharmacotherapies for obstructive sleep apnea with the exception of medications used to treat conditions (e.g., hypothyroidism, acromegaly) that can precipitate obstructive sleep apnea or that worsen symptoms of the disorder (e.g., rhinitis) [41]. Patients with persistent daytime sleepiness (despite well-documented improvement in AHI score with PAP or other treatments) may benefit from use of the analeptic modafinil. All other causes of daytime sleepiness must be ruled out and PAP therapy should not be discontinued when taking modafinil. This drug is also used for the treatment of narcolepsy and will be discussed in detail later in this course. In 2019, two drugs, solriamfetol (Sunosi) and pitolisant (Wakix), were approved by the FDA to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. [57,80]. Solriamfetol, a dual dopamine-norepinephrine reuptake inhibitor, has exhibited robust efficacy in randomized controlled trials. Initial oral dosing is 37.5 mg once daily, titrated up to a maximum dose of 150 mg/day. The most common adverse reaction is headache [57]. Pitolisant is a histamine H3 receptor inverse agonist approved for the treatment of cataplexy or excessive daytime sleepiness in adults with narcolepsy. Initial oral dosing is 8.9 mg once daily for one week, then 17.8 mg once daily for one week. The dose may be further increased based on response and tolerability during the third week to a maximum dose of 35.6 mg once daily. As with solriamfetol, the most common adverse reaction is headache [57]. Oxygen therapy is not considered a useful treatment for obstructive sleep apnea, as it has been found that it can lengthen the duration of apneas [41]. However, it is sometimes used to relieve hypoxemia. Resolution of hypoxemia must be documented to justify continued use, especially in patients with comorbid respiratory disease who are at an increased risk of hypercapnia with oxygen therapy.

Narcolepsy is the second most common sleep-related disorder in the United States (after obstructive sleep apnea), affecting an estimated 1 in 2,000 individuals or an estimated 135,000 to 200,000 Americans [42]. Men and women are equally affected, but prevalence varies by race/ethnicity. For example, compared with the United States, narcolepsy is more common in Japan and less common in Israel. Narcolepsy with cataplexy is less common, estimated to affect 1 in 3,000 Americans [42]. The age of onset is typically between 7 and 25 years.

The causes of narcolepsy are not well known, so it is difficult to determine the influencing factors. There is a heritable component that can predispose individuals to developing the disorder. Certain gene variants of the human leukocyte antigen (HLA) complex and its receptor, T-cell receptor alpha (TCRA), are strongly associated with narcolepsy [42]. Most (though not all) narcoleptic individuals possess the HLA-DR2 or HLA-DQB1*0602 phenotype, which are risk factors for autoimmune disease. However, inflammatory markers and signs/clinical features of inflammatory processes are typically not found in narcoleptics [88,89,90]. This suggests that if the disorder does have an autoimmune origin, the pathology is confined to the nervous system.

Researchers believe that individuals with the implicated subtypes of HLA and TCRA are more prone to an immune system attack on hypocretin-producing neurons in the hypothalamus [42,82]. The neurotransmitter protein hypocretin regulates appetite, feeding, and sleep patterns, including keeping brain systems from unexpectedly shutting off while awake. People with narcolepsy with cataplexy (and a certain subset of individuals without cataplexy) typically have very low levels of hypocretin, which could explain why they develop narcolepsy and also the higher rate of obesity in this population [42,82,91].

Though a genetic predisposition does exist, it does not fully explain development of the disorder, as most individuals with the HLA/TCRA variants do not develop narcolepsy and some narcoleptics do not possess these subtypes. In certain rare instances, tumor growth or head trauma have led to narcolepsy [42]. Other factors, including environmental toxins, stress, dietary factors, changes to the sleep schedule, and hormonal changes, likely contribute to the development of the disorder. Infectious agents have been identified as triggers for narcolepsy, particularly Streptococcus spp. and the H1N1 influenza virus, but it is not yet known if the infections are direct triggers or if they indirectly increase susceptibility (e.g., due to the relaxed blood-brain barrier during fever) [42].

As discussed, the most common presentation for all sleep disorders, including narcolepsy, is excessive daytime sleepiness. Cataplexy is rare without narcolepsy and is considered a positive indicator of the disorder [42]. If cataplexy is not present, all other causes of excessive sleepiness must be ruled out by collecting a thorough medical history and conducting an exhaustive clinical examination. The Epworth Sleepiness Scale can be used to identify excessive daytime sleepiness. For the diagnosis of narcolepsy to be confirmed, polysomnography and an MSLT should be performed in a sleep clinic. A polysomnographic study for narcolepsy is similar to an obstructive sleep apnea study. The MSLT will indicate shorter sleep latency periods in patients with narcolepsy compared with healthy individuals [42].

Laboratory testing may include cerebrospinal fluid (CSF) hypocretin-1 levels, but the value of this test is debated [2,42,92]. CSF hypocretin sampling is generally not recommended unless MSLTs are inconclusive or unavailable. This is because reduced or absent levels are usually only found in patients with cataplexy [42,92]. Although most narcoleptic patients without cataplexy have normal hypocretin levels, there is a subset who is deficient, including individuals with the HLA-DR2 phenotype, those at a younger age at onset, and patients with shorter mean REM latency periods [91].

Narcolepsy is incurable, and the loss of hypocretin in patients with cataplexy is believed to be irreversible [42]. However, there are several pharmacologic and behavioral treatment options that, when combined, can greatly reduce symptoms of the disorder and help improve patients' quality of life.

Pharmacologic Therapies

Traditional drug treatment options for narcolepsy have included CNS stimulants taken during the daytime to help patients remain alert, sedatives taken at night to help patients attain more restful sleep, and tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) to help control cataplexy, sleep paralysis, and HHEs [42,93,94]. Certain drugs have been found to exert multiple effects; for example, modafinil, a stimulant drug used to treat daytime sleepiness, may also exert antidepressant effects by modulating serotonin transmission [95]. These drug classes are still recommended for prescription today, but the use of a single drug, sodium oxybate, to control all symptoms of narcolepsy (including cataplexy) is gaining favor following a series of successful clinical trials [94,96,97,98,99,100]. However, due to abuse potential, access to the drug is tightly restricted [42,57].

If a CNS stimulant is prescribed in order to combat the effects of excessive daytime sleepiness, the most common are various amphetamines and methylphenidate [42,93]. These agents can be effective in reducing daytime sleepiness and the occurrence of sleep attacks. Amphetamines (e.g., amphetamine, dextroamphetamine, methamphetamine) have been prescribed for narcolepsy since the 1930s and, at lower dosages, act primarily by causing dopamine (and noradrenaline) release [101]. They may be prescribed at 10–60 mg/day. However, amphetamine use is associated with a number of adverse effects, including headache, insomnia, irritability, nervousness, and palpitations, and less frequently, anorexia, hyperhidrosis, nausea, orofacial dyskinesia, and psychosis [93]. Abuse of prescribed amphetamines is rare among narcoleptics, but tolerance develops in one-third of patients. Due to these risks and the proven efficacy of newer drugs, amphetamines are no longer recommended as first- or second-line therapy. Methylphenidate has similar, though milder, adverse effects and a much shorter half-life [94]. It is also prescribed at 10–60 mg/day, but it is recommended only when modafinil is insufficiently active, when modafinil must be supplemented at a specific time of the day, or in situations where maximum alertness is required [42,92].

Modafinil, a stimulant, was approved for use in the United States in 1998 and is the treatment of choice for narcolepsy when the most serious symptom is excessive daytime sleepiness due to its efficacy, limited adverse effects, and easiness of manipulation [42,92]. To date, researchers have been unable to determine the exact mechanism(s) of action, but modafinil is known to increase the release of monoamines (e.g., dopamine, norepinephrine, histamine) from synapses [93,102]. Therefore, the central histaminergic and dopaminergic systems are suspected to be involved. Unlike with classic CNS stimulants, the coadministration of a dopamine antagonist only partially weakens the effectiveness of modafinil, leading researchers to describe the drug as a wakefulness promoting agent [57,103]. The starting dose is 200 mg, and the usual effective dose is 200–400 mg taken as a single morning dose or as a split dose (first in the morning and then around noon). However, evidence of benefit with a dose greater than 200 mg/day is lacking [57]. There is a low prevalence of common side effects, including headache (13%), nervousness (8%), nausea (5%), and rhinitis, all of which are typically mild [92,94]. More serious side effects have been noted and are mainly allergic/inflammatory reactions, including hives, rash, and swelling. Other severe dermatologic reactions have occurred, such as drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN), prompting the FDA to issue a safety labeling change in 2007 [57]. There have been very few instances of DRESS, Stevens-Johnson syndrome, and TEN (less than 10 since 1998), and modafinil is considered a safe treatment for excessive daytime sleepiness.

For patients with excessive daytime sleepiness with poor nighttime sleep and cataplexy, the first-line treatment is sodium oxybate [92]. This drug, also known as gamma hydroxybutyrate (GHB), is a powerful sedative that has been burdened by the stigma as a party or "date-rape" drug and a performance-enhancing drug [94]. Misuse of the drug can be life-threatening, and steps should be taken to ensure no other sedatives (including alcohol), muscle relaxants, or respiratory depressants are taken concurrently and that sleep disordered breathing is not present or does not develop. Sodium oxybate is restricted and can only be prescribed by those enrolled in the Xyrem Patient Success Program and dispensed by the designated centralized pharmacy [57]. The initial dose is 4.5 g/night in two equal doses [57]. The first dose is taken sitting upright in bed just before sleep; the patient should lie down immediately after dose one; the second dose is taken 2.5 to 4 hours later. (An alarm may be necessary.) The dose can be increased by 1.5 g at two-week intervals up to a maximum dose of 9 g/night [57,92]. Patients usually begin to improve after the first few nights, but the optimal response (even at the starting dose) can take up to 8 to 12 weeks. Adverse effects are common and include headache (9% to 37%), dizziness (8% to 37%), nausea (8% to 40%), vomiting (2% to 23%), pain (9% to 20%), confusion (3% to 17%), sleep disorder (6% to 14%), somnolence (1% to 14%), abdominal pain (3% to 11%), enuresis (3% to 17%), and urinary incontinence (<1% to 14%, usually nocturnal) [57].

Antidepressants are considered second-line agents for cataplexy and are also an effective treatment for sleep paralysis and HHEs [92]. The most potent anticataplectic drugs are tricyclic antidepressants, especially clomipramine (10–75 mg). However, these agents have the disadvantage of anticholinergic side effects. SSRIs have fewer side effects but are slightly less active [92]. Venlafaxine, a norepinephrine/serotonin reuptake inhibitor, is widely prescribed despite a lack of published clinical evidence to support its use. The same paucity of data exists for norepinephrine reuptake inhibitors (e.g., reboxetine, atomoxetine) [92]. Other pharmacologic agents are no longer recommended for use based on either a lack of clinical efficacy data or on their undesirable adverse effects and safety profiles [92].

Caution should be given when treating patients with comorbid psychiatric disorders. Sodium oxybate should not be used in patients with depression. Instead, antidepressants should be prescribed along with a referral to a psychiatrist or mental health provider [92].

Behavioral Therapies

The European Academy of Neurology, the European Sleep Research Society, and the European Narcolepsy Network recommend planned daytime naps to improve immediate subjective and objective sleepiness both in drug-naïve patients with narcolepsy and in those taking stimulant medication, at any age.

(https://onlinelibrary.wiley.com/doi/10.1111/ene.14888 Last Accessed: December 7, 2021)

Level of Evidence: Expert Opinion/Consensus Statement

There are several lifestyle and dietary changes that may help reduce the symptoms and risks of narcolepsy, although there are no accepted behavioral treatments for cataplexy [92]. Behavior modification is useful as medications cannot ensure a consistent state of alertness in individuals with the disorder. Practicing strict sleep hygiene is important, and engaging in relaxation exercises or taking a bath before bedtime may offer a benefit [42]. Daytime napping has been shown to improve alertness and shorten reaction times [42]. Regular exercise (20 minutes/day, four to five hours before bedtime) can lead to better sleep and help prevent or reduce narcolepsy-related weight gain. Alcohol and caffeine should be avoided, especially at night.

One of the major risks of narcolepsy is falling asleep while performing hazardous tasks (e.g., driving, operating machinery) or collapsing due to cataplexy at an ill-timed moment (e.g., while descending a stairway). Automobile accidents are 10 times more common in individuals with untreated narcoleptic symptoms, but when medication and behavioral therapies are being used, the accident rates are similar to healthy individuals [42]. Scheduled naps are recommended to reduce the likelihood of falling asleep unexpectedly. The Americans with Disabilities Act guarantees equal opportunity for narcoleptic students and workers, and reasonable adjustments to school and work schedules should be encouraged to accommodate periodic naps [42].

Support groups for narcolepsy are helpful for many patients. Overcoming feelings of isolation by connecting with other people with the disorder and lessening the sense of judgment by outsiders are important both for those who have just received a diagnosis and experienced patients alike. It may be difficult for individuals living in non-metropolitan areas to find a support group, and for these patients online groups can be useful. More information about narcolepsy support groups is available at https://www.narcolepsynetwork.org. The Narcolepsy Network offers meetings in several U.S. cities and hosts online support groups as well [104].

There are many medical conditions that can cause hypersomnia, including Kleine-Levin syndrome, Parkinson disease, dementia, and post-traumatic stress disorder, all of which should be ruled out with a complete medical history, physical examination, and diagnostic workup. Standard sleep studies are used to confirm the diagnosis of idiopathic hypersomnia, including MSLT and polysomnography. The absence of multiple SOREMPs (one or fewer) during MSLT and greater time spent in slow-wave sleep during polysomnography suggest idiopathic hypersomnia [105]. On the other hand, multiple SOREMPs (two or more) are indicative of narcolepsy.

The same array of pharmacologic options used to treat excessive daytime sleepiness in narcolepsy may be prescribed for idiopathic hypersomnia, but the level of effectiveness is typically not replicated [105,106]. Only half of patients treated report any improvement of symptoms. In 2021, the FDA expanded approval of oxybate salts (calcium, magnesium, potassium, and sodium) to include treatment of idiopathic hypersomnia [149]. It is the first and only medication approved for this indication; all other pharmacologic options are prescribed off label. Although sleep hygiene practices are usually not helpful for idiopathic hypersomnia patients, they should be discussed because there are virtually no risks or drawbacks [105]. Patients should be advised to avoid sedative drugs and alcohol.

The prevalence of sleepwalking ranges from 4% in adults to 17% in children [2]. The disorder may begin as soon as a child is able to walk, but the age of onset is usually between 4 and 8 years. The disorder is most common in children 5 to 12 years of age [2,110]. A 2004 National Sleep Foundation poll found that sleepwalking a few nights per week occurs in 1% of preschoolers and 2% of school-age children [113]. Sleepwalking is more common in children with sleep enuresis (chronic bedwetting). Symptoms of sleepwalking disappear after adolescence in most patients; however, the disorder can occur at any age [2,110]. Approximately one-third of cases develop after adolescence [2]. Girls and boys are affected equally in childhood, but the gender distribution in adults is not well defined [2]. One study of an adult population of sleepwalkers in Nigeria found prevalence roughly three times higher in men than in women [114].

Sleepwalking may occur in isolated cases, but there is a known genetic susceptibility and a familial pattern [2,115]. The incidence in children is 60% when both parents have the disorder and 45% when one parent is affected. The incidence is 22% if neither parent has the disorder but when sleepwalking is familial (i.e., occurs in more distant relatives) [2]. A 2012 Stanford School of Medicine study found that the self-reported yearly incidence of sleepwalking was 3.6%, equating to about 8.5 million Americans [116]. According to the study, the lifetime prevalence of a sleepwalking episode was estimated at 29.2%, with 30.5% of participants reporting a family history of the disorder. Twin studies support the role of genetic susceptibility in at least 65% of cases [2].

Although there is a strong heritable factor for sleepwalking, the pathology of sleepwalking is not known [2,110]. Individuals who are predisposed to sleepwalking may become active sleepwalkers when priming factors exist and a precipitating factor triggers an episode [2,115]. Priming factors deepen and increase slow-wave sleep and include anxiety, fatigue, fever, the premenstrual period, sleep deprivation, and physical or emotional stress. Alcohol use and certain medications may also be priming factors, but it is unclear if the many case reports of "sleepwalking" under the influence of substances are due to extreme intoxication or complex medication interactions (or medication/psychopathologic interactions) [2,110,115]. Precipitating factors, or triggers, identified in primed individuals in sleep laboratories include light, noise, periodic leg movements, sleep disordered breathing, and touch.

Certain mental disorders (e.g., obsessive-compulsive disorder) and medical conditions (e.g., organic brain syndrome, partial complex seizures) are associated with sleepwalking, as is obstructive sleep apnea [2,110,116]. Medication-related sleepwalking may occur, most commonly in individuals with a complex medical and psychiatric history associated with multiple medications [115]. The 2012 study found a higher risk of frequent sleepwalking episodes (two or more times/month) with obstructive sleep apnea syndrome (odds ratio [OR]: 3.9), obsessive-compulsive disorder (OR: 3.9), alcohol abuse/dependence (OR: 3.5), major depressive disorder (OR: 3.5), circadian rhythm sleep disorder (OR: 3.4), SSRI antidepressant use (OR: 3.0), over-the-counter sleep aid use (OR: 2.5), and insomnia disorder (OR: 2.1) [116].

Steps should be taken to ensure that sleepwalking is not the result of a medication side effect or an underlying medical or psychiatric condition. Specific medications and their dosages should be reviewed. In cases of pediatric sleepwalking, parents or caretakers will have witnessed one or more behaviors associated with the disorder, including [110,111]:

Adult patients with no history of the disorder may similarly present with no recollection of any episode of sleepwalking or associated behaviors, which may have instead been witnessed by another person. Sleep studies and other tests and procedures are typically not needed to confirm a diagnosis in patients with known good health [2,110]. However, testing to rule out other medical conditions (e.g., partial complex seizures, obstructive sleep apnea) in patients with a limited medical history is recommended.

There is no cure or specific treatment for sleepwalking [110,113]. As a first step in the management of sleepwalking, conditions or medications that may cause somnambulism should be identified and treated or discontinued, which may eliminate or greatly reduce sleepwalking episodes. For patients with sleepwalking as the primary diagnosis, identifying the priming and precipitating factor(s) is a cornerstone of management. Patients (or parents) should be instructed to keep a journal that includes daily activities, level of daytime sleepiness, total hours of sleep, and any illnesses or triggers of stress or anxiety to help to determine possible triggers, though dedication to observation and journaling lessens and more omissions occur over time [117].

Again, there is no high-quality evidence to support any specific sleepwalking treatment [113,118]. A tailored approach to therapy, including improvements in sleep hygiene, should be made on a patient-by-patient basis. Although medication is not usually required and is not recommended as a first-line therapy, sedative-hypnotics, tricyclic antidepressants, or SSRIs may be prescribed if sleepwalking interferes significantly with the patient's or the family's quality of life (e.g., excessive daytime sleepiness, high risk of injury, unusual symptoms, inappropriate behaviors causing family distress) [110,113]. However, the usefulness of these medications is not certain [119,120]. Care must be taken when prescribing tricyclic antidepressants, as they have many serious side effects (especially in children) and can exacerbate sleepwalking [121]. Benzodiazepines (e.g., clonazepam, diazepam) were initially prescribed for sleepwalking, with only limited benefit [119,120]. A 2021 review reports that benzodiazepines are effective at controlling sleepwalking [122]. One study of individuals with either isolated sleepwalking or sleepwalking related to psychiatric conditions or obstructive sleep apnea found that benzodiazepines and psychiatric medications were not effective in reducing sleepwalking episodes. Nasal CPAP therapy for participants with obstructive sleep apnea eliminated sleepwalking in all individuals who remained compliant throughout each of the follow-up periods [120].

Hypnosis has been used as a low-cost, safe therapy for various parasomnias, including sleepwalking [113,123]. One small-scale study (27 participants) conducted by Hurwitz and colleagues showed a 74% success rate for long-term reduction of sleepwalking and night terror episodes ("much" or "very much" improvement on self-report) following one to six office visits and continued with at-home self-hypnotic exercises [124]. A five-year follow-up study of 36 parasomnia patients (modeled on the Hurwitz study) found a 45.4% success rate after 1 month (symptom free or "much improved"), which diminished slightly to 42.2% at 18 months and 40.5% at 5 years [125]. In this study, participants underwent one or two 50-minute hypnosis sessions, described as "deep physical relaxation but with retention of an active and focused mind, so possible new thoughts could be evaluated and incorporated into the hypnotized person's thinking" [125].

One behavioral approach, anticipatory awakenings, can be effective in reducing sleepwalking episodes. This method requires parents or caretakers to wake the patient three hours into the night and 15 minutes before the usual sleepwalking time. The patient is kept awake for 30 minutes and then may return to sleep. Anecdotal reports have found this intervention to be successful; however, it requires a significant commitment on the part of those involved [121,126].

Another key to treatment is the maintenance of a safe living environment. Patient/parent education should cover precautions to be taken, including [113,121]:

Approximately 5% to 15% of the adult U.S. population is affected by restless legs syndrome, and women are affected twice as often as men [2,130]. The disorder is more common in certain groups, including pregnant women (11%), uremic patients (15% to 20%), and patients with rheumatoid arthritis (up to 30%). In general, restless legs syndrome is associated with advancing age; however, the age of onset is younger than 20 years in one-quarter of patients. Among children 8 to 11 years of age and adolescents 12 to 17 years of age, the prevalence is 1.9% and 2.0%, respectively [109]. Restless legs syndrome symptoms usually appear after the 20th week when associated with pregnancy [2].

The exact incidence of PLMD alone is unknown in adults [2]. However, it is very uncommon in children and is more prevalent after middle age, with approximately 44% of adults 65 years of age or older found to have symptoms of the disorder [2,129]. It is unclear if the prevalence among older adults differentiates symptoms indicative of idiopathic PLMD and limb movements related to other conditions, but some questions have been raised as to whether PLMD is a true sleep disorder based on the high prevalence in this population [129].

There is a strong heritable risk factor for restless legs syndrome [128,130]. One study found that more than 70% of pediatric patients with restless legs syndrome had at least one parent with the disorder [109]. As noted, restless legs syndrome is more common in women, but race does not appear to be a factor [2]. Overall, prevalence and incidence have not been well defined [109,127].

Medical or psychiatric conditions and certain medications have been associated with an increased incidence of restless legs syndrome and/or PLMD. Children with attention deficit hyperactivity disorder are more likely to have both restless legs syndrome and PLMD. Uremia and other metabolic disorders are known to cause periodic limb movements during sleep [2]. Monoamine oxidase inhibitors and tricyclic antidepressants can cause or worsen the disorder, as can withdrawal from certain drugs, including anticonvulsants, benzodiazepines, barbiturates, and other hypnotic agents. PLMD may be associated with an underlying arousal disorder [128].

The history and physical examination should focus on differentiating restless legs syndrome from other conditions with shared features, including akathisia, anxiety disorders, chronic myelopathy, erythromelalgia, leg compartment syndromes, muscular pain fasciculation syndromes, myokymia, and peripheral neuropathy [2]. Subclinical hypopneas can also trigger limb movements. Iron-deficiency anemia, caffeinism, and uremia should also be considered as possible causes of secondary restless legs syndrome. The use of and withdrawal from high-risk medications should also be identified from the medical history. All conditions known to cause the symptoms indicative of the disorder should be ruled out, and serology should be obtained (e.g., cobalamin, creatinine, ferritin, folate, iron, urea) [127,129,130]. Additional serology and electrodiagnostic testing may be considered if peripheral neuropathy is suspected. The presence of periodic limb movements during sleep is a strong indication of restless legs syndrome. Several instruments are available to measure restless legs syndrome severity, including the Johns Hopkins Restless Legs Syndrome Severity Scale (Table 5) and the Restless Legs Syndrome Quality of Life Instrument (RLS-QLI) [131]. The RLS-QLI consists of 17 items that assess the patient's social function, daily function, sleep quality, and emotional well-being, while the Johns Hopkins measure focuses on timing of symptoms [132,133].

Sleep studies are not typically needed for a diagnosis of restless legs syndrome to be made; however, periodic limb movements during sleep may be confirmed using polysomnography, if necessary [2,127]. Polysomnographic features of PLMD are recorded using bilateral anterior tibialis EMG. Patterns of movement include repetitive contractions (four or more, with a duration of 0.5 to 5 seconds)—typically a leg jerk, followed by a short interval (milliseconds) and a tonic contraction—spaced apart by 20 to 40 seconds of relaxed muscle tone [2]. Both legs are involved in the majority of patients, but there may be inconsistent and random alternation between the left and right limbs or a unilateral, predominant pattern. The periodic limb movement arousal index measures the number of limb movements associated with EEG arousals per hour. Mild PLMD is defined as 5 to 25 movements per hour, moderate as 25 to 50 per hour, and severe as more than 50 movements per hour or more than 25 movements associated with arousals per hour [129].

Anticonvulsants, dopamine agonists, tranquilizers, and opioid narcotics are used to manage symptoms of restless legs syndrome, and iron supplements are used when indicated [127,128]. Dopamine agonists considered effective for restless legs syndrome management include pramipexole and ropinirole, but rotigotine is recommended for long-term therapy [128,134]. These and other antiparkinsonian drugs are also first-line therapies for PLMD and may improve sleep in patients with both disorders. The anticonvulsants gabapentin and pregabalin reduce movement symptoms and neuropathic pain in patients with either restless legs syndrome or PLMD and may also help to improve sleep; however, use of these medications for restless legs syndrome and PLMD is off-label [57,128]. Gabapentin enacarbil is on-label and is preferred over gabapentin for long-term treatment [57,134]. Other treatments for these sleep disorders include stress management, muscle relaxation exercises, and sleep hygiene.

The initial dosage of pramipexole (immediate-release) is 0.125 mg once daily, two to three hours before bedtime, but higher doses (up to 0.5 mg) are typically required in order to be effective [57]. The maximum recommended dose is 0.5 mg, but doses up to 2 mg daily are occasionally used. The most frequent side effects are nausea (11% to 27%), particularly early in treatment, and headache (16%) [57]. There is no evidence that doses higher than 0.5 mg/day offer benefit [135].

The American Academy of Sleep Medicine has identified pramipexole and ropinirole as the agents with the highest level of evidence supporting their use in the treatment of patients with restless legs syndrome.

(https://aasm.org/resources/practiceparameters/updateto.pdf Last Accessed: December 7, 2021)

Strength of Recommendation/Level of Evidence: Standard (High or moderate evidence that benefits clearly outweigh harm/burden)

The initial dose of ropinirole (immediate-release) is 0.25 mg taken one to three hours before bedtime; the dose may be increased to 0.5 mg after two days, to 1 mg after one week, and to a maximum dose of 4 mg at week 7. Common adverse effects include dizziness (6% to 40%), fatigue (8% to 11%), nausea (40% to 60%), somnolence (11% to 40%), syncope (1% to 12%), and viral infection (11%) [57].

The rotigotine (transdermal patch) initial dose is 1 mg/24 hours (one patch per day). The daily dose may be increased by 1 mg/24 hours each week, to a maximum daily dose of 3 mg/24 hours [57]. Dose-related application site reactions are common (21% to 46%), as are gastrointestinal complications such as nausea (15% to 48%) and vomiting (2% to 20%), and CNS reactions (e.g., somnolence, dizziness, headache, fatigue, orthostatic hypotension, hallucinations) [57]. Therefore, an extended low-dose trial is recommended.

Higher doses of gabapentin (2,000–2,400 mg daily) have been found to be significantly more effective than placebo in reducing moderate-to-severe restless legs syndrome symptoms, but higher doses are also associated with a high prevalence of adverse effects (e.g., dizziness, fatigue, nausea, pain, weakness) [57,136]. The recommended initial dose for restless legs syndrome treatment (off-label) is 300 mg taken two hours before bedtime; the dose may be titrated every two weeks, until desired response is achieved, to a maximum dose of 1,800 mg [57]. (Dosages of up to 3,600 mg have been tolerated in short-term studies but are not recommended.) A combination of lower-dose gabapentin (300–1,000 mg daily) and ropinirole (0.25–1.5 mg daily) is also effective for treating restless legs syndrome and is associated with a lower incidence of adverse effects than high-dose gabapentin alone [136].

Gabapentin enacarbil is FDA-approved for the treatment of restless legs syndrome and is preferred over gabapentin due to longer duration of action and improved absorption [57,134,137]. The dosage is 300-600 mg once daily at approximately 5 p.m. Worsening side effects are seen at higher doses, and no benefit is reported at a dose of 1,200 mg compared with 600 mg [57]. Adverse effects (at a 600-mg daily dose) include dizziness (13% to 17%), headache (10% to 12%), and somnolence (20%), and a low rate of gastrointestinal effects are also observed (e.g., nausea, 6% to 8%) [57]. Pooled analysis of long-term use of gabapentin and other antiepileptic drugs has validated concerns regarding suicidal ideation and behavior (0.43%) compared with placebo (0.24%) [57]. Human data regarding pancreatic cancer risk have yet to be compiled, although gabapentin is associated with pancreatic adenocarcinoma in rats [57,137].

Multiple studies have shown that pregabalin is effective for managing sensory and motor symptoms of restless legs syndrome and has a low rate of mild adverse effects across a wide dosage range [138,139]. A reduction of periodic limb movements and sleep architecture improvements (e.g., increase in slow-wave sleep, decrease in waking after sleep onset and during sleep stages 1 and 2) were noted. In one study, the mean effective dose for pregabalin was approximately 350 mg/day, but in another study, a dose of 125 mg/day was shown to be effective in 90% of participants [138,139]. Pregabalin is usually taken in divided doses, either two or three times a day [57]. Dizziness (3% to 45%) and somnolence (17% to 26%) are the most frequent adverse effects [57,138].

Lifestyle Modifications and Alternative Therapies

Stress reduction, muscle relaxation techniques, and physical activity are important components of a restless legs syndrome management strategy, along with improved nutrition, proper sleep hygiene, and elimination of caffeine and alcohol intake [128,129,130,131]. Supplementation with specific vitamins and minerals known to support the nervous system and improve blood circulation (e.g., vitamins B12, C, D, and E; glucosamine; magnesium; zinc) may be considered for patients with inadequate nutritional intake, but little research exists apart from small studies showing some degree of symptom reduction with supplementation with vitamins B and E [131]. Other alternative therapies with little or no scientific support include acupuncture, meditation, and prayer.

Moderate aerobic exercise and lower-body resistance training are recommended to both assist in the relief of psychologic stress and lessen the severity of symptoms [128]. Endorphin release, dopamine production, and increased blood flow to leg muscles are believed to mediate symptoms [131]. Massage, warm baths, and heating pads may also be used to relieve and/or prevent restless legs syndrome symptoms, though there is a lack of strong efficacy data for these therapies [130]. Case studies have shown a positive effect with massage (and a return of symptoms after cessation of massage therapy regimens), but the mechanisms involved are unclear [131]. Theories include improved blood circulation, dopamine release, counterstimulation of the cerebral cortex, and modulated thalamic neural activity as a response to tactile and temperature stimulus. Pulsed pneumatic compression devices have also been shown to reduce symptom severity; the proposed beneficial mechanisms are similar to those of massage [131]. Near-infrared light therapy has also successfully reduced restless legs syndrome symptom severity in small-scale studies [140].

There is a strong placebo effect in restless legs syndrome therapy [131]. A 2008 meta-analysis of 36 clinical trials found that one-third of patients had a significant improvement while receiving placebo medications [141]. In 24 of the trials, 40% of participants had a placebo response. However, this level of response was based on a reduction in the International Restless Legs Severity Scale score alone, and the placebo response was only moderate for other measures (e.g., daytime functioning, other restless legs syndrome measures). The placebo effect was found to be small for PLMD therapy [141].

In 2014, the FDA cleared the first device to improve sleep quality in patients with restless legs syndrome [142]. The device, marketed as Relaxis, consists of a vibrating pad that provides counterstimulation to a patient's legs as he or she sleeps. The manufacturer cautions that this device should not be used on patients who have had deep venous thrombosis in either leg in the six months prior to the initiation of therapy.