Although the primary zeitgeber in humans is the light-dark cycle, there are other influential nonphotic cues, including exercise, temperature, and various social cues, that influence the regulation of various biologic processes (e.g., body temperature, hormone production) [23,26,27]. Researchers propose that sleep patterns may be influenced by other important zeitgebers, including sound, temperature, and the earth's magnetic field, that are as yet unproven or only considered weak factors [28,29]. Given that light is such a powerful influence and that humans are sensitive to very low levels of light, it is difficult to study the effects of these other possible cues. (Blind individuals typically have "free running" circadian rhythms ≥25 hours and are often the subject of zeitgeber investigations.) Some zeitgebers, such as aberrant work schedules, alarm clocks, artificial light, radio, television, and time-zone change, are known to cause disruptions to the natural sleep-wake cycle.

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].

As discussed, there are more than 80 official sleep disorders defined in the current AASM diagnostic and coding manual, the ICSD-3 [2]. The ICSD-3 uses a pragmatic framework for categorizing sleep disorders based primarily on pathophysiology, if known, and also phenomenology and organ system methodology [2]. Unlike in original versions, disorders are no longer grouped into three major classes: dyssomnias, parasomnias, and sleep disturbances associated with mental, neurologic, or other medical disorders. Instead, the ICSD-3 contains seven major categories of sleep disorders [2]:

The term insomnia is defined generally as difficulty with initiation, duration, consolidation, or quality of sleep. It is commonly applied when three conditions are satisfied: ample time and opportunity for sleep, persistent sleep difficulty, and daytime dysfunction associated with sleep deficit [2].

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]:

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]:

Only obstructive sleep apnea syndrome will be discussed in detail in this section, as the other sleep-related breathing disorders are comparatively rare and/or mainly associated with other medical conditions. For example, central sleep apnea due to Cheyne-Stokes breathing is primarily associated with congestive heart failure and stroke, and primary central sleep apneas of infancy or prematurity are associated with premature birth and low birth weight, occurring in 25% of infants weighing <2,500 g and 84% of infants weighing <1,000 g [2]. Others are extremely rare. It is estimated that there are perhaps a total of 200 congenital central alveolar hypoventilation syndrome cases worldwide [2].

If a patient presents with complaints of excessive daytime sleepiness or non-restful sleep and a history of snoring, obstructive sleep apnea should be suspected. A comprehensive medical history and physical evaluation should be obtained, and various objective sleep studies (e.g., polysomnography, portable monitors, MSLT) should be completed to confirm the diagnosis. The AHI scale has been developed to quantify and standardize the degree of obstructive sleep apnea severity. The score is determined by adding the number of apnea and hypopnea events during a patient's overnight sleep study, dividing the total number of events by the minutes of sleep, and finally multiplying the result by 60. For example, if a patient sleeps 8 hours (480 minutes) and has 120 apnea events and 80 hypopnea events (200 total events), the calculation for this patient would be 200 events ÷ 480 minutes × 60, for an AHI score of 25. A normal cutoff for AHI has never been defined in an epidemiologic study of healthy people. Most sleep centers use a cutoff of 5 to 10 episodes per hour. The severity of obstructive sleep apnea is arbitrarily defined and differs widely between centers. Recommendations for cutoff levels on AHI include 5 to 15 episodes per hour for mild, 15 to 30 episodes per hour for moderate, and more than 30 episodes per hour for severe [65]. In the example, the patient has an AHI score of 25, or moderate obstructive sleep apnea.

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.

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.

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].

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].

Narcolepsy is a primary disorder of the CNS characterized by recurring episodes (every two to three hours) of extreme sleepiness, sudden and irresistible sleep attacks, disturbed nighttime sleep, and memory problems resulting from sleep deficit [2,81]. Sleep spells (or attacks) usually occur during activities or situations in which sleepiness is common (e.g., as a passenger, in a class with no participation, during movies) and last 10 to 20 minutes, on average. However, they may also occur at times when sleeping is not normal (e.g., while driving, eating, walking, or talking). Individuals will feel rested when they awake, but this sense of refreshment does not last long. Sleepiness soon returns, and the cycle repeats. The disorder strongly features SOREMPs and is associated with several pathologic REM sleep phenomena, including cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations [82].

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.

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].

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.

Staying up late, with activity and indoor bright lights, can promote the disorder, as can a corresponding reduction in bright morning light [2]. Shift work, changes in schedules, and frequent travel across time zones can also precipitate the disorder. Attempts at retraining, using sleep hygiene and bright light therapy may work, but patients usually maintain a strong desire for "eveningness" despite intervention [2].

Sleepwalking typically occurs during non-REM sleep stage 3 (slow-wave sleep), which is more common early in the night (during the first-third of sleep) [110]. Episodes last an average of 10 minutes but range from a few minutes to more than 30 minutes. Patients usually return to bed before waking, but some may fall asleep in another location or awaken while sleepwalking [2]. Sleep talking may also be exhibited by these individuals, and sleep terrors may occur at other times. Sleepwalking episodes may occur frequently (several times per night, for several nights) or only rarely or when precipitating factors are present [2].

Restless legs syndrome, also known as Willis-Ekbom disease, is a neurologic sleep disorder characterized by disagreeable leg sensations that worsen when individuals are at rest (e.g., when seated) and/or at night before bedtime [2]. There is an accompanying urge to move the legs to relieve the unpleasant sensations, which are described as aching, bubbling, creeping, crawling, pulling, searing, and/or tingling; walking, stretching, or shaking usually provides relief [128]. The area between the ankle and the knee is most often affected (usually bilaterally), but the thighs, feet, and, to a lesser extent, the arms may also be affected [2]. Pathologic changes in efficiency of central dopamine neurotransmission are thought to cause the disorder, based on the observation that restless legs syndrome symptoms are relieved by the use of dopaminergic drugs [127]. The secondary (non-idiopathic) form of restless legs syndrome can be caused by a variety of medical conditions. Iron deficiency and uremia are common causes; others include chronic kidney disease, cobalamin (vitamin B12) deficiency, folate deficiency, diabetes, fibromyalgia, Parkinson disease, peripheral neuropathy, pregnancy, radiculopathy, rheumatoid arthritis, Sjögren syndrome, use of certain drugs (e.g., caffeine, calcium channel blockers, lithium, neuroleptics), and withdrawal from sedatives [128,129].