Melatonin

Light–dark cycles regulate the sleep–wake cycle in large part through their effect on the pineal gland’s synthesis and release of melatonin (N-acetyl-5-methoxytryptamine). In turn, melatonin regulates the suprachiasmatic nucleus, which has surface melatonin receptors.

The pineal gland synthesizes melatonin, which is an indolamine, through the following pathway:

Darkness promotes melatonin synthesis and triggers its release into the plasma. Thus, melatonin concentrations rise during the night. Similarly, because both natural and artificial light suppress melatonin synthesis and release, its concentration falls during daylight hours. Adolescents and teenagers, however, show a variation of that pattern. Their melatonin levels rise and fall at later times than in adults’ cycle. That phase shift is consistent with their tendency to remain awake into the early morning and stay asleep until the late morning or early afternoon. Some adolescents may benefit from more alertness and improved mood following a small phase delay in their school schedule.

Certain medications alter melatonin concentrations. For example, selective serotonin and norepinephrine reuptake inhibitors (SSRIs and SNRIs) and antipsychotics increase melatonin concentration. In contrast, benzodiazepines, monoamine-depleting medications, and tryptophan deficiency decrease melatonin concentration.

Given its relationship to light, melatonin secretion’s altered phase onset, concentration, and duration play a role in seasonal affective disorder (SAD), winter type. Reflecting that relationship, carefully timed bright light, melatonin, and melatonin agonists, such as ramelteon (Rozerem), correct a melatonin phase shift and reverse many SAD symptoms.

When prescribed as a medication, melatonin increases sleepiness and advances the sleep phase. It aids in the treatment of insomnia, jet lag, and the delayed sleep phase syndrome (see later), as well as SAD. In addition, it may be useful for blind individuals who benefit from medications that mimic alterations ordinarily induced by light and dark.

Using another strategy to combat insomnia and SAD, ramelteon promotes sleep by binding to melatonin receptors. (Ramelteon has a longer half-life as a melatonin agonist than melatonin itself.) Stimulation of melatonin receptors inhibits adenyl cyclase activity and thus decreases cyclic adenosine monophosphate. Because fluvoxamine inhibits CYP1A2, concurrent administration of fluvoxamine and ramelteon may lead to toxic concentrations of ramelteon.

Sleep Deprivation

Although various sleep disorders often result in excessive daytime sleepiness (EDS), sleep deprivation from social and vocation pressures is, by far, the most common cause of EDS. In quantifying sleepiness, physicians often utilize the Epworth Sleepiness Scale (Box 17-3).

When sleep deprivation interrupts a conventional sleep–wake schedule, it causes predictable sleep pattern alterations as well as EDS. Adults who have worked all night and children who skip a customary afternoon nap, for example, have a short sleep latency, increased sleep time, and additional slow-wave sleep. The compensatory period features greater depth and duration of slow-wave sleep. Simply put, after missing sleep, people are tired, fall asleep early and deeply, and sleep longer. Their PSGs will show that they immediately catch up on their slow-wave and then REM sleep.

In another response to sleep deprivation, particularly if REM sleep were selectively eliminated, sleep-deprived individuals show REM rebound. This manifestation of sleep deprivation consists of several major components: the first REM period occurs immediately after or within 10 minutes of falling asleep (sleep-onset REM period [SOREMP]); subsequent REM periods are longer than normal; and REM sleep occupies a greater proportion of sleep time. Therefore, individuals with REM rebound dream almost as soon as they fall asleep and then dream plentifully throughout the night. On some occasions, their REM is so abundant and forceful that the final REM period briefly spills into wakefulness. In those cases, REM-induced paralysis, which neurologists also call “sleep paralysis,” leaves people momentarily unable to move. The same phenomenon occurs in narcolepsy (see later).

REM rebound occurs not only after naturally occurring sleep deprivation, but also in individuals with EDS. It also follows withdrawal from REM-suppressing substances: SSRIs, TCAs, cocaine and amphetamines, opioids, many hypnotics, and, in the early night, alcohol. People who suddenly stop steadily using alcohol or another REM-suppressing substance often undergo a period of frequent, vivid dreams that can reach the severity of nightmares. In another example, during interrogations that include sleep deprivation, victims experience hallucinations, delusions, and cognitive disorganization.

Sleep deprivation is so commonplace that it is a public health problem. It leads to poor work performance. For example, medical house officers completing shifts longer than 16 hours report committing many more errors than those working fewer hours. Sleep deprivation also leads to mood swings, increased appetite, weight gain, and a prediabetic state. Sleep deprivation, perhaps in a reciprocal situation, aggravates chronic pain. It is also a risk factor for motor vehicle accidents and was implicated as a factor in the Chernobyl nuclear disaster, the Three Mile Island near nuclear meltdown, and, along with alcohol, the Exxon Valdez oil spill.

Studies have linked short sleep phase as well as frank sleep deprivation to coronary and cerebrovascular artery diseases, “all-cause” mortality, and obesity. They have not only linked sleep deprivation to anxiety, depression, and psychosis, but also to more subtle disturbances, such as impaired recognition of human emotions.

Effects of Age

Narcolepsy

Narcolepsy, the most dramatic of the Intrinsic Disorders, emerges in 90% of patients between their adolescence and 30th year. In fact, its onset peaks in the teenage years. Young people with narcolepsy often remain undiagnosed or misdiagnosed as lazy, neurotic, or depressed. It affects young men and women equally.

The most salient feature of narcolepsy, EDS, takes the form of brief, irresistible sleep episodes (attacks). The attacks initially mimic normal daytime naps because they typically occur when patients are bored, comfortable, and engaged in monotonous activities. Each attack usually lasts less than 15 minutes and can be easily interrupted by noise or movement.

As narcolepsy progresses, sleep attacks evolve into episodes that clearly differ from normal naps. They then have a relatively abrupt onset and, more strikingly, take place when patients are standing, during a lively interchange, or in the middle of activities that require constant attention, including driving. Multiple attacks occur daily. Each may cause momentary amnesia, confusion, and autonomic changes.

Despite their not appearing as normal naps, sleep attacks are not peculiar to narcolepsy. Sleep attacks may also be a manifestation of sleep deprivation, sleep apnea, Parkinson disease, or, ironically, dopamine agonist treatment for Parkinson disease.

The other cardinal features of narcolepsy, cataplexy, sleep paralysis, and sleep hallucinations, which all reflect disordered REM sleep, usually develop after sleep attacks have become frequent. In total, the symptoms form the narcoleptic tetrad:

Narcolepsy may occur with or without cataplexy, i.e., narcolepsy with cataplexy and narcolepsy without cataplexy. Even when cataplexy complicates narcolepsy, it appears about 4 years into the illness. Depending on the diagnostic criteria, age of the patients, and duration of their narcolepsy, surveys have reported a wide variability of the proportion of narcolepsy patients who have cataplexy. Most surveys give a figure of 10–70%. In any case, with the comorbidity far below 100%, neurologists do not require cataplexy for a diagnosis of narcolepsy.

Cataplexy consists of attacks, typically lasting 30 seconds or less, occurring one to four times daily, of sudden weakness precipitated by emotional situations. Patients remain alert during an attack, but immediately afterwards they may have a sleep attack.

Cataplexy-induced weakness tends to be symmetric and proximal. For example, the neck, trunk, hips, knees, or shoulders may suddenly lose their strength. Sometimes the eyelids, jaw, or face weaken alone or in combination with the trunk and limbs. The most common pattern is sudden but brief weakness of the legs or merely the knees. Physicians and patients could easily dismiss attacks when they involve only jaw dropping open or head nodding. In its most sensational form of cataplexy, which rarely occurs, patients’ entire body musculature suddenly becomes limp and they collapse to the floor.

The most common precipitant of an attack is hearing or telling a joke. Other situations or emotions that commonly provoke it are surprise, anger, fear, and arousal.

Whether a group of muscles or the entire musculature weakens, affected muscles become flaccid and areflexic – as in REM sleep. Nevertheless, also as in REM sleep, patients breathe normally and retain full ocular movement.

Sleep paralysis and hypnagogic hallucinations – other components of the tetrad – affect about 50% of narcolepsy with cataplexy patients. They develop several years after the onset of narcolepsy. In other words, only 10% of narcolepsy patients display the full narcoleptic tetrad. Sleep paralysis and sleep hallucinations may be present on awakening (hypnopompic) or while falling asleep (hypnagogic). In sleep paralysis, patients are unable to move or speak for as long as several minutes on awakening or when falling asleep, but they remain cognizant of their surroundings, breathe, and move their eyes. This situation may terrify the patients who vainly attempt to scream or move about. Although sleep paralysis is a characteristic feature of narcolepsy, it is not diagnostic because it may occur in sleep-deprived individuals and anyone with REM deprivation.

During hypnopompic or hypnagogic hallucinations, patients essentially experience vivid dreams while in a twilight state, but they are technically awake. Hypnopompic or hypnagogic hallucinations qualify as an organic cause of visual hallucinations (see Chapters 9 and 12). As with the other features of narcolepsy, hypnopompic or hypnagogic hallucinations represent REM sleep intruding into people’s wakefulness or at least the transition into wakefulness (Fig. 17-5).

FIGURE 17-5 A narcoleptic attack begins when the electroencephalogram channel shows the low-voltage fast activity of rapid eye movement sleep. The absence of chin electromyogram activity indicates that muscles are flaccid. After several seconds, REMs begin.

In addition to the narcolepsy tetrad, multiple, brief, spontaneous awakenings interrupt nighttime sleep. These interruptions cause inadequate nighttime sleep that exacerbates the EDS.

In children, EDS, whether from sleep deprivation, narcolepsy, or other disorder, leads to somewhat different symptoms than in adults. For example, instead of being merely sleepy, children typically develop inattention and “paradoxical hyperactivity” (increased, usually purposeless, activity). Children with narcolepsy also have behavioral, cognitive, and scholastic impairments that resemble learning disabilities or attention deficit hyperactivity disorder. When combined with cataplexy (see later), these children may appear to have a behavioral disorder.

Neurologists use the multiple sleep latency test (MSLT) to support a clinical diagnosis of narcolepsy. Using PSG recording techniques, the MSLT determines both sleep latency and REM latency during five “nap opportunities” offered at 2-hour intervals during daytime. The MSLT shows that, in contrast to normal adults who might take a nap, those with narcolepsy fall asleep on two or more nap opportunities and do so almost immediately. In fact, narcolepsy patients typically take only 8 minutes or less to fall asleep and have SOREMP during at least two naps.

Although sensitive for the diagnosis of narcolepsy, MSLT abnormalities are not specific. The MSLT shows shortened sleep latency and SOREMPs in EDS from almost any cause. To reduce false-positive results, patients suspected of having narcolepsy should first undergo a PSG, mostly to exclude sleep apnea and sleep deprivation.

A complementary test, the maintenance of wakefulness test (MWT), measures daytime sleepiness by assessing an individual’s ability to remain awake. Subjects undergoing the MWT attempt to remain awake in a quiet, dark room while sitting still for four 40-minute periods at 2-hour intervals during daytime. Those who fall asleep have EDS. However, such a determination does not constitute a diagnosis of a particular disorder.

Narcolepsy probably results from an interaction of a genetic predisposition and environmental factors. First-degree relatives have a 10–40-fold increased risk of developing the illness, but the concordance rate between monozygotic twins is only 25%. Almost 90% of patients with cataplexy as well as narcolepsy carry a certain major histocompatibility complex, designated human leukocyte antigen (HLA) DQB1*0602, on chromosome 6. Despite the antigen’s prevalence among narcolepsy patients, the antigen is neither sufficient nor necessary to diagnose narcolepsy-cataplexy because approximately 25% of the asymptomatic general population also carries it and most carriers do not have the illness. Curiously, antistreptococcal antibody titers are elevated in narcolepsy-cataplexy patients.

In a major medical advance that has located narcolepsy’s physiologic basis, studies have shown close association between narcolepsy and a deficiency in a pair of polypeptide excitatory neurotransmitters, hypocretin 1 and 2, which are also known as orexin A and B.

Hypocretin normally maintains wakefulness and activity and stimulates the appetite. It is also associated with arousal and, during sleep, increased REM and decreased NREM activity. Different research groups named hypocretin for its location in the hypothalamus, and orexin for orexis (Greek, appetite).

Cells in the hypothalamus synthesize hypocretin. These cells, which are the only ones in the central nervous system (CNS) that synthesize hypocretin, project to several brainstem centers involved with sleep regulation, particularly the hypothalamus and locus ceruleus. They also secrete some hypocretin into the cerebrospinal fluid (CSF).

Distinctive findings in narcolepsy-cataplexy consist of degeneration of hypocretin-synthesizing cells in the hypothalamus and the resulting absence or near absence of hypocretin in the CSF. Low levels of CSF hypocretin correlate much more closely with narcolepsy with cataplexy than narcolepsy without cataplexy. Curiously, in both conditions serum hypocretin concentrations remain normal, which suggests that cells outside the CNS also synthesize it. Narcolepsy with the characteristic hypocretin deficiency also occurs in an autosomal recessive inheritance pattern in certain families of ponies and dogs. Their members serve as laboratory models of the disorder.

The primary goal in the treatment of narcolepsy is for the patient to remain awake during critical times, particularly when driving, attending school, and working. In one approach, methylphenidate (Ritalin) and amphetamines, which enhance adrenergic and dopaminergic activity, reduce EDS and the naps. The major problem with this approach is the potential for abuse. For example, even from the beginning, individuals may falsely report symptoms of narcolepsy-cataplexy in order to secure these stimulants. Individuals may then use or sell their drugs to others. Another potential problem is that stimulants induce tolerance and may create psychiatric side effects.

In a newer, superior approach, the nonamphetamine medication modafinil (Provigil) and its long-acting, r-enantiomer version armodafinil (Nuvigil) promote wakefulness without causing excitation or nighttime insomnia. Moreover, unlike stopping amphetamines and other stimulants, stopping them does not lead to EDS or a rebound in NREM sleep. In other words, they do not merely keep people awake by postponing sleep. Modafinil interacts with multiple neurotransmitters, including dopamine, serotonin, and gamma-aminobutyric acid (GABA).

Despite their help in counteracting narcolepsy and keeping patients awake, these medicines have little effect on cataplexy. Instead, a rapid-acting hypnotic, oxybate (Xyrem), also known as gamma-hydroxybutyrate (GHB) or the “date rape drug,” reduces cataplexy. In addition, it increases slow-wave sleep. Illicitly prepared oxybate has caused many complications, including profound amnesia, coma, seizures, and, with continued use, addiction (see Chapter 21). Even a pharmaceutical preparation in narcolepsy-cataplexy patients may lead to sleepwalking, enuresis, confusion, and sleepiness. It may also lead to depression in predisposed patients. However, it does not seem to lead to addiction or, on stopping it, rebound insomnia.

Whether or not patients use these medicines, they should arrange for regular, strategically placed daytime naps after meals and during the late afternoon (“nap therapy”). The naps should be brief because short naps provide as much rest and recuperation as long ones. Patients should also maintain regular nighttime sleep schedules.

Restless Legs Syndrome

RLS consists essentially of movement of the feet and legs in response to an irresistible urge to move and unpleasant sensations. Patients usually describe these sensations – dysesthesias – as burning or aching deep in their feet and legs. The movements occur predominantly when patients rest or try to sleep, i.e., not when they are actually asleep.

Deliberate movement of the legs alleviates the dysesthesias and quells the urge. Thus, patients typically seek relief by arising from bed and marching in place; moving their feet back and forth while sitting in a chair; or, while lying in bed, performing bicycle movements. Like patients with tics, those with RLS have psychologic discomfort if they fail to respond to the urge and a sense of relief after they comply.

When the patients are no longer able to maintain the movements, the sensations return. While the family and physicians may see movements as the problem, patients know that abnormal sensations and irrepressible urge, rather than the movements themselves, constitute the problem. Whatever the sequence, the combination of the urge, dysesthesias, and movements interfere with falling asleep. The symptoms delay the onset of sleep (prolong sleep latency), disrupt sleep, and lead to EDS for both the patient and bed partner. Moreover, in about 80% of cases, periodic leg movements (see below) accompany RLS.

Although RLS may develop in young pregnant women and other young adults, it usually first appears in individuals older than 45 years. Polyneuropathy from ischemia, diabetes, and uremia may not necessarily cause RLS, but worsens it. Many RLS patients have iron-deficiency anemia characterized by low concentrations of serum ferritin (an iron protein complex). Also, when pregnant women develop RLS, they are usually in their third trimester. During that time, their folate as well as ferritin concentrations may be low, and their expanded uterus may irritate the adjacent lumbosacral nerves. According to some studies, SSRIs, SNRIs, and antipsychotics provoke RLS.

An observation that many otherwise healthy individuals with RLS have close relatives with the same problem indicated that RLS has a genetic basis or susceptibility. Indeed, genetic studies revealed a mutation on chromosome 6 in many patients. Studies of D2 receptor binding in the striatum (see Chapter 18) have yielded contradictory results. However, decreased D2 binding in some of them is consistent with a successful therapeutic strategy (see later).

Another condition characterized by involuntary nocturnal leg movements, but lacking a sensory component, is the familiar, benign leg thrusts that occasionally appear when people “fall” asleep. These movements, sleep starts or hypnic or hypnagogic jerks, occur in the twilight of sleep. In view of their time of onset, the classifications consider them a sleep–wake transition disorder or parasomnia (Latin, para, next to; somnia, sleep).

An intriguing aspect of RLS consists of its similarity to akathisia. These conditions share features – incessant leg movement in response to an urge and common treatments (see later). On the other hand, in akathisia, restlessness but not discomfort occurs throughout the day and subsides when the patient returns to bed in the evening and sensory disturbances do not trigger the movements. Psychiatrists may also have to consider that both RLS and akathisia may mimic agitated depression.

For treatment of idiopathic RLS, dopaminergic medications suppress the movements, reduce the urge to move, and promote restful sleep. In particular, probably because of the decreased D2 receptor binding, dopamine precursors (e.g., L-dopa) and dopamine agonists (e.g., ropinirole and pramipexole) offer the greatest benefit with the least risk. With doses as low as 10% of those prescribed for Parkinson disease, dopaminergic medicines suppress RLS. Opioids will also suppress the movements. For patients with polyneuropathy-induced RLS, medicines that reduce paresthesias, such as gabapentin, reduce or alleviate symptoms and restore sleep. Correcting an iron-deficiency anemia frequently reduces the paresthesias and movements. On the other hand, TCAs, SSRIs, SNRIs, and antihistamines may precipitate or exacerbate those symptoms during the first few nights after treatment begins.

Periodic Limb Movement Disorder

Periodic limb movement disorder consists of regular (periodic), episodic stereotyped movements of the legs or, less often, arms during sleep. Most often individuals with periodic limb movements repetitively jerk both feet upward (dorsiflex at the ankle) in brief (0.5–5.0-second) thrusts. When the movements are confined to the legs, neurologists call the disorder periodic leg movements. In a more extensive variation, all the limbs simultaneously jerk. Whatever the pattern, the feet always move and EMG leads of the PSG show regular muscle contractions.

Movements take place at 20–40-second intervals, for episodes of 10 minutes to several hours primarily, but not exclusively, during stages of NREM sleep (Fig. 17-7). Periodic limb movements generally do not arouse patients. Thus, the movements rarely lead to EDS.

FIGURE 17-7 In periodic limb movements, approximately 30-second intervals of synchronous anterior tibialis contractions cause the patient’s ankles to dorsiflex and the electromyogram activity.

The disorder usually develops in individuals older than 55 years. It occurs in close association with RLS, with use of antidepressants, withdrawal from various medications, and the onset of certain medical illnesses, particularly anemia and uremia. A genetic variation on chromosome 6 is a risk factor. A disorder of dopamine physiology in either the brain or spinal cord may give rise to periodic limb movements.

Despite the frequent comorbidity of RLS and periodic movements, these conditions differ in many respects. Periodic limb movements occur at regular intervals, appear only during sleep, and do not arise as a response to either dysesthesias or an urge.

Neurologists usually do not treat periodic movements unless RLS is also present because they do not interrupt sleep, cause EDS, or create other problems. On the other hand, the movements may disrupt the sleep of a bed partner who may then develop EDS. When the movements require treatment, benzodiazepines and dopaminergic medications suppress them.

Kleine–Levin Syndrome

In the rare Kleine–Levin syndrome, periodic hypersomnia, patients, who are predominantly adolescent males, have episodes lasting 1–4 weeks of prolonged, intense sleep (hypersomnia), lasting on average 18 hours daily, recurring three to four times a year until spontaneously disappearing after about 8 years. Even more remarkable than the hypersomnia is the patients’ state when they emerge from their bedroom. As if in a trance for about one to several hours, they eat voluminous amounts of food (show hyperphagia or “morbid hunger”), display rudimentary sexuality (e.g., masturbate or expose themselves), and, when questioned, are confused, withdrawn, and surly. Undisturbed, they return to bed to resume sleeping. After the episodes, Kleine–Levin patients have no overt neurologic disorder. Infections, unusual stress, alcohol use, and traumatic brain injury precede many episodes, but most arise spontaneously.

PSGs show only nonspecific frequent awakenings from light NREM sleep during hypersomnia episodes and no abnormalities during sleep between them. No endocrinologic or other physiologic study reveals a consistent, significant abnormality.

Neither antiepileptic drugs (AEDs) nor antidepressants prevent or shorten episodes. Amphetamines and lithium help, but only in a minority of cases. Modafinil may counteract the hypersomnia.

In other words, no physical finding, PSG data, laboratory, or response to medication result can confirm a diagnosis of the Kleine–Levin syndrome. Thus, when consulting in cases of suspected Kleine–Levin syndrome or hypersomnia in general, psychiatrists might consider alternatives: depression, bipolar disorder, drug or alcohol abuse, complex partial seizures, encephalitis, hypothalamic tumors, and traumatic brain injury. The diagnosis still rests on observing patients through several episodes and excluding alternative diagnoses.

Caffeine

Caffeine, the world’s most commonly used stimulant, is a major ingredient in coffee, tea, and soft drinks; chocolate and other foodstuffs; and over-the-counter medicines (Table 17-2). It most likely combats sleepiness by acting as an antagonist to adenosine (see before).

TABLE 17-2 Caffeine Content of Popular Beverages, Medicines, and Foods

^*For coffees and teas, caffeine content varies by the type of bean or leaf, preparation, and duration of brewing as well as by the size of the serving.

^†1.5–2 oz.

^‡One bar, approximately 1.5 oz.

Neurologists routinely prescribe caffeine as a critical ingredient in antimigraine medicines. In addition, they prescribe ones that magnify caffeine’s effects, such as dopaminergics, steroids, and amphetamines. Individuals who deliberately or unknowingly ingest excessive caffeine (250 mg or more daily) frequently develop caffeinism, which consists of restlessness, nervousness, and excitement in combination with diuresis, gastrointestinal disturbance, tachycardia, and cardiac arrhythmia, as well as insomnia. Even with mild consumption, caffeine reduces slow-wave sleep and total sleep time. On the other hand, when habitual coffee drinkers abruptly stop taking caffeine, they experience headache, anxiety, and psychological agitation, as well as EDS.

Not only does caffeine cause or exacerbate psychiatric symptoms, it alters the metabolism of several psychotropics. Probably because cytochrome P-450 liver enzyme CYP1A2 metabolizes almost all caffeine, its use may potentiate antidepressants (monoamine oxidase inhibitors [MAOIs], TCAs, SSRIs, and duloxetine) and antipsychotics (clozapine, haloperidol, and olanzapine). In the opposite direction, some psychiatric medicines, such as fluvoxamine, a powerful 1A2 inhibitor, may increase caffeine levels.

Jet Lag

Extrinsic factors can alter a conventional sleep–wake schedule to produce circadian rhythm disorders. In jet lag (time zone change syndrome), the best-known example, travelers between at least two time zones develop insomnia and the resultant EDS. Their temperature fluctuations and hormone secretions, as well as their sleep–wake schedule, temporarily remain pegged to their home city.

East-to-west (westward) trips create fewer problems than west-to-east (eastward) ones because travelers can more easily postpone (delay) their night’s sleep than fall asleep earlier (advance it). For example, travelers from New York to Los Angeles can, with little effort, postpone their sleep time by several hours, but those traveling in the opposite direction cannot so easily fall asleep several hours earlier.

When going in either direction, travelers can minimize jet lag by adopting the schedule of their destination several days to a week before their trip. For important events, travelers should arrive several days ahead of time. When going from New York to Los Angeles, for example, travelers should remain in sunlight as long as possible in the late afternoon on the West Coast to maintain their alertness. Those arriving in New York from the West Coast, the more taxing trip, should seek a sun-exposed location and drink a strong cup of coffee in the early morning. If they wish to go to sleep at a conventional East Coast time, they should avoid bright lights after sunset. In addition, once they reach their destination on long west-to-east flights, travelers can take melatonin, zolpidem, or another hypnotic to adopt the earlier local sleep time. On long east-to-west trips, travelers may adjust more easily if they nap.

Shift-Work Sleep Disorder

A related cause of insomnia and EDS due to extrinsic factors is the shift-work sleep disorder. It plagues medical house staff, police officers, factory workers, and other individuals who must work daytime shifts and then rotate to evening or nighttime shifts. Almost 20% of American workers have schedules that change on a weekly, monthly, or seasonal basis.

Workers starting a new shift typically suffer fatigue and then an inability to fall asleep. Although most workers can make the transition after several days, some may be unsuccessful because their internal schedule is deeply ingrained or, during weekends or holidays, they revert to their old schedule. While working a midnight shift, for example, their “daytime sleepiness” tends to occur at 4 AM. To supplement drinking coffee and exposure to bright light, affected individuals may benefit from taking modafinil just before their shift. Although imperfect, this medicine reduces extreme sleepiness and improves performance.

Delayed Sleep Phase Syndrome

In contrast to the previous disorders, a perpetual phase delay in falling asleep (prolonged sleep latency) characterizes the delayed sleep phase syndrome. In this disorder, sleep starts late, but thereafter it has a normal quality and duration. Body temperature and melatonin concentration even have the normal correlates with the sleep–wake cycle. The entire sleep cycle, otherwise quite ordinary, merely seems to begin and then extend later than usual.

This syndrome most commonly first develops in adolescents during a long vacation when they remain active until the early morning. Working into the early-morning hours persists in many adults, particularly those in the entertainment industry. Adolescents and adults with this disorder work and socialize late into the night, and their late bedtime necessarily postpones the time that they awaken.

Although the delay may seem benign during a vacation, afterwards adolescents cling to that sleep–wake schedule. With their unconventional timing, they cannot attend either to school or work without being tardy. When forced to awake “on time,” they remain perpetually sleep-deprived. Their delayed sleep–wake schedule, which gives rise to truancy as well as EDS, resists the usual sleep-altering interventions, such as hypnotics and instruction to go to bed earlier. This disorder is one of the most common causes of insomnia in teenagers.

Chronotherapy delays patients’ sleep phase by 1–3 hours successively each night. Using activities, coffee, sunlight, or strong artificial light, this strategy eventually postpones (delays) the sleep onset time by almost 24 hours. Patients eventually fall asleep at a conventional time, such as 11 PM, and, with effort, maintain that schedule (Fig. 17-8). Once patients reach a conventional schedule, taking melatonin at bedtime helps them maintain it.

FIGURE 17-8 A 17-year-old high-school student who has the delayed sleep phase syndrome does not fall asleep before 1:00 AM or arise before 9:00 AM. He has been unable to attend school on a regular basis and has gathered friends who have no curfews. Brought into a sleep laboratory, his sleep graph demonstrates a delayed sleep phase during the first week of study. Then each succeeding night, the staff encourage him to remain awake for an additional 30 minutes. By the end of 6 weeks, the staff have postponed (delayed) his sleep time to 2300 hours (11:00 PM) and his awakening time to 8:00 AM. For the next week, the staff reinforce the 11:00 PM to 8:00 AM schedule. The young man holds to this schedule for many months. This strategy, chronotherapy, did not require hypnotics, stimulants, or other medication; a sleep laboratory; or trained personnel.

Light therapy (phototherapy), an alternative approach, advances patients’ sleep–wake schedule. Using it, parents shine a bright, artificial light to awaken the patient in the morning, but they dim the lights in the evening, and extinguish all light at midnight. Phototherapy relies on the light suppressing melatonin release and dark promoting its release. This strategy requires about 2 weeks and then sometimes a melatonin supplement to fix the new schedule.

Advanced Sleep Phase Syndrome

In the advanced sleep phase syndrome, the less frequently occurring counterpart of the delayed sleep phase syndrome, patients awake and fall asleep earlier than normal times. Their sleep, which follows an unconventional schedule, is nevertheless restful and its hypnogram displays the normal architecture (see Fig. 17-3). Individuals self-entrained to follow this schedule go to sleep, for example, at 8 PM and awaken at 5 AM. Some individuals accommodate their propensity to this schedule by seeking work in occupations that require full early-morning activity, such as living in California and following the New York Stock Exchange. Many normal older individuals who awake early in the morning have this variation. However, depressed individuals who sleep and awake early also have an advanced sleep phase syndrome.

Confusional Arousals

Confusional arousals consist of disorientation and incoherence when something partially, rather than fully, awakens an individual from slow-wave sleep. They typically cause children, with eyes open or closed, to speak incoherently, i.e., have sleeptalking or somniloquy. Children with open eyes stare blankly.

Confusional arousals may affect adults as well as children. For example, if a telephone call stirs house officers from deep sleep, they may remain confused during the beginning or throughout the conversation. Their cognition may be uncertain and illogical, and, in the morning, they will have no recall of the conversation.

Sleepwalking

Sleepwalking (somnambulism) usually consists of an episode lasting several seconds to 10 minutes of abruptly sitting, standing, or walking, but occasionally more complex activities, including sleeptalking, in the midst of sleep. The sleepwalker rarely displays any emotion. In a typical episode, a child walks slowly, with eyes open and a blank facial expression, along familiar pathways. Although sleepwalking children appear partially awake, their parents cannot completely awaken them or capture their attention. When questioned during their trip, children cannot recall their whereabouts, remember recent events, or even converse sensibly; however, they will follow a lead back to bed. As with other parasomnias, in the morning children will have no recall of their journey. Treatment of an episode is usually neither necessary nor, in view of its brevity, practical.

Sleepwalkers do not walk zombie-like with their eyes closed and their arms stuck out in front of themselves: That behavior occurs in play.

Unlike episodes of sleepwalking in children, sleepwalking episodes in adults often arise during early NREM sleep and not until the latter half of the night’s sleep. Their episodes also lead to injuries. In another distinction, various psychiatric disturbances, a history of violence, CNS pathology, and use of hypnotics, particularly, zolpidem (Ambien), are risk factors for sleepwalking in adults.

On the basis of only the parents’ description, partial complex seizures, especially nocturnal frontal lobe seizures (see Chapter 10), may vaguely mimic sleepwalking or sleep terrors. However, seizures are stereotyped, not precipitated by arousals, prone to secondary generalization, and are often followed by (postictal) confusion. In any case, PSG supplemented by EEG-video monitoring can distinguish sleepwalking and other parasomnias from seizures. Indications for PSG with parasomnias include frequent episodes, adult onset, and potentially dangerous behavior, as well as suspicion of partial complex seizures.

Sleep Terrors

Sleep terrors, which differ completely from nightmares (see later), consist of episodes in which children suddenly, after a partial awakening from slow-wave sleep, behave as though they were threatened by great danger. During a sleep terror, children stare, moan, and sometimes scream incessantly with their eyes fully open and their pupils dilated. They sweat, hyperventilate, and have tachycardia. Their parents cannot fully wake them, put them back to bed, or comfort them. The children often leave their parents’ arms to walk aimlessly, which constitutes simultaneous sleepwalking. Although the night terrors seem interminable to the parents, who are usually distraught, the episodes usually last 1–10 minutes and end abruptly with a return to deep sleep. Despite the episode’s vivid and awesome features, children characteristically do not recall it in the morning.

As with other parasomnias, sleep terrors usually develop within several hours after bedtime and particularly after sleep deprivation. PSG studies show that they arise in slow-wave rather than REM sleep. Noises or other disruptions during slow-wave sleep arouse children and precipitate episodes. In contrast, frightening events of the day may cause nightmares, which, like other dreams, occur during REM instead of NREM sleep (Table 17-3). The preliminary version of the DSM-5 has a similar definition for Sleep Terrors, as for Confusional Arousals and Sleepwalking.

TABLE 17-3 Sleep Terrors Compared to Nightmares

REM, rapid eye movement.

^*Other parasomnias frequently accompany terrors.

Sleep Sexual Behavior

Better known among physicians as sexsomnia and the lay public as sleepsex, sleep sexual behavior consists of any variety of sexual activity during sleep. The partner may be known, an acquaintance, or someone of either sex. Sometimes it consists of self-pleasure. Typically a bed partner is receptive; however, especially in the case of an unsuspecting acquaintance, the intended partner is sometimes unwilling and shocked. The individual who experienced the parasomnia remains amnestic for the episode, i.e., the sexual aggressor justifiably has little or no recollection of the sexual behavior after awakening.

Episodes usually occur during NREM sleep, where little or no imagery occurs but voluntary muscles are potentially fully mobile. As with the other parasomnias, sleep deprivation often precedes them. Unlike other parasomnias, physical contact and alcohol consumption are frequent precipitants. Also unlike other parasomnias, sexsomnia begins during adolescence and tapers off during the fifth decade, and they occur more frequently in men than women.

To a certain extent, the manifestations of complex partial seizures may overlap those of sexsomnia episodes. One clinical difference is that these seizures are rudimentary, stereotyped, nonaggressive, and usually not confined to the night. Another diagnostic consideration is REM behavior disorder, which occurs during dreaming (see later). Finally, the Kleine–Levin syndrome includes sexual activity during sleep or sleepiness, but it typically consists only of masturbation and the sleep periods extend for days or weeks (see before). The diagnosis of sexsomnia and its alternatives requires PSG or long-term video-EEG monitoring.

Avoiding sleep deprivation and eliminating alcohol consumption usually reduce the episodes. To avoid legal repercussions, individuals prone to sexsomnia should sleep only near someone willing to share sexual experiences.

Sleep–Wake Transition Disorders

Certain parasomnias have a predilection for appearing during transitions between wakefulness and sleep. In one condition, rhythmic movement disorder, infants, children, and occasionally adults have rhythmic, repetitive, stereotyped movements of their head, trunk, or entire body while lying in bed during the initial stages of falling asleep at night or during daytime naps. The condition usually begins in infancy and disappears by age 5 years. The movements usually consist merely of infants slowly rocking their head on the pillow; however, they sometimes increase in forcefulness until they reach the point of head–banging. Rhythmic movement disorder, especially in mentally retarded individuals, can persist into the teenage years and evolve into relatively violent side-to-side rocking of the entire body.

Sleeptalking, a common sleep–wake transition disorder, usually consists of adults or children saying a few words, but rarely speaking coherently, in their sleep. It takes place in all sleep stages and occurs along with dreams, REM sleep behavior disorder, and other parasomnias.

Nightmare Disorder

In contrast to sleep terrors, nightmares are essentially dreams with frightening content and complex imagery (“bad dreams”). Children and adults who experience nightmares typically recall them and reorient themselves when awakened. Nightmares cause tachycardia but no bodily movements, except for crying. Typically, a nightmare ends by itself, but awakening the dreamer can abort it. After becoming fully awake, the dreamer has a slow, difficult return to sleep.

In adults, as in children, nightmares occur during REM periods. Adults tend to have frequent and intense nightmares as a part of REM rebound or simply abundant REM. Therefore, an evaluation of nightmares in adults should explore not only the circumstances and content of the dreams, but also the patient’s use of alcohol, drugs, and medications that may have led to excessive REM and the patient’s withdrawal from REM-suppressing medicines.

The preliminary version of the DSM-5 lists nightmares under Nightmare Disorder, and requires that the nightmares cause impairment in social, occupational, or other important areas, and not be related to any substance abuse. Adults also have nightmares as a symptom of Posttraumatic Stress Disorder (PTSD). Successful treatment of the nightmares reduces the overall burden of PTSD – if only by allowing a restful night’s sleep. Psychological interventions, such as imagery rehearsal therapy, rather than medications or insight psychotherapy, may effectively suppress nightmares in these patients.

In addition to distinguishing nightmares from night terrors, physicians might consider nocturnal panic attacks, also known as sleep panic arousals. Anxiety disorder and PTSD may cause nocturnal as well as daytime panic attacks, and either may cause panic attacks primarily or exclusively during sleep. When they occur, nocturnal panic attacks arise from NREM sleep. Most often they strike during the transition from drowsiness into light NREM rather than during deep NREM sleep. They usually contain no visual imagery, but they fully awaken the patient who is able to recall the fears. Patients with anxiety sometimes fear sleeping, in part for fear of panic attacks.

REM Sleep Behavior Disorder

During normal REM sleep, even during nightmares, the peri-locus ceruleus nucleus induces quadriparesis, flaccidity, and areflexia in limb and trunk muscles. This normal immobility, among other purposes, protects people from acting out their dreams.

In comparison to the normal situation, REM sleep behavior disorder or simply REM behavior disorder releases individuals from the constraints of REM sleep. Uninhibited during dreaming, these individuals retain their ability to move and maintain their normal muscle tone. In this disorder, dreaming individuals thrash, hit, or make running movements. Like other dreaming individuals, their eyes are closed. Sleep experts have called their activity “dream enactment behavior.”

When awakened from an episode, which can be violent, patients typically either recall a dream involving activity or explain that they were only defending themselves against an attack. Their recall contrasts with that of patients with NREM-related parasomnias, such as night terrors, who typically remain amnestic for the episode. Individuals with REM sleep behavior disorder, who are usually men older than 65 years, may injure themselves and their bed partner.

REM sleep behavior disorder often develops along with or up to 15 years before the onset of either Parkinson disease or dementia with Lewy bodies. It ultimately affects almost one-third of Parkinson disease patients. In both of these illnesses, which neurologists classify as synucleinopathies (see Chapters 7 and 18), REM sleep behavior disorder correlates with cognitive impairment.

Although SSRIs, SNRIs, TCAs, and mirtazapine suppress REM sleep, they may paradoxically induce REM sleep behavior disorder. One possible explanation is that these medicines allow persistent muscle activity during REM sleep. The REM rebound that follows medication withdrawal may also precipitate attacks.

In terms of treatment, clonazepam taken at night reduces or eliminates REM sleep behavior disorder. In fact, clonazepam suppresses it so consistently that successful treatment empirically supports the diagnosis.

Enuresis

Recurrent involuntary bed-wetting (enuresis), while normal in infants, is a parasomnia in girls older than 5 years, boys older than 6 years, and all adults. Enuresis affects boys twice as often as girls – about 50% of children when one parent had the disorder, and 75% of children when both parents had the disorder. Enuresis occurs during any stage of sleep.

Compared to regular nighttime medications, such as imipramine, behavior modification therapy and bladder control training more effectively reduce enuresis. Evening water restriction, urinary retention control exercises, and “bell and pad” wetness alarm devices – alone or in combination – suppress enuresis in about 75% of cases and their benefits extend beyond the time of the treatment. For refractory cases or to avoid potentially embarrassing situations, such as enuresis during a “sleep-over,” single injections or nasal sprays of desmopressin (DDAVP), a synthetic form of the antidiuretic hormone vasopressin, promote enough water retention to prevent enuresis for a single night. However, excessive DDAVP may lead to water retention, even to the point of water intoxication.

Sleep-Related Eating Disorder

Teenagers and adults who are asleep, while dreaming or not, may have recurrent episodes of eating during the night. Depending on many factors, the eating may constitute either a sleep disorder (Sleep-Related Eating Disorder) or an eating disorder (Night Eating Syndrome, Nocturnal Eating, or Nighttime Eating). In many cases, the clinical features and PSG results lead neurologists to diagnose it as an REM or NREM parasomnia.

Individuals with the Sleep-Related Eating Disorder have one or more episodes during either NREM or, occasionally, REM sleep, each usually lasting 5 minutes or less, of partial arousal during which they eat variable amounts of food. They consume not only high-calorie (“junk”) food, but they may eat barely edible foods, such as frozen pizza or raw meat. Sometimes they prepare a relatively elaborate meal, but most often they leave food on their nightstand. Although these individuals may binge, they do not purge. Probably because they remain asleep while preparing food, they tend to cut or burn themselves accidentally. As with other parasomnias, they have little or no recollection of the night’s events in the morning, i.e., they have partial or complete amnesia. However, debris from the food or scattered kitchenware may prompt them to reconsider their night’s foraging.

Other parasomnias, particularly sleepwalking, RLS, and various psychiatric illnesses, are comorbidities of Sleep-Related Eating Disorder. In addition, major life stressors are associated with it. Zolpidem may precipitate or cause episodes of this and other abnormal nocturnal behavior.

In contrast to Sleep-Related Eating Disorder, Night Eating Syndrome, which neurologists often simply call nocturnal eating or nighttime eating, consists of individuals awakening from sleep, eating while awake, and then resuming sleep. They eat their customary foods, but often in large quantities. In the morning, because they have been awake during the night, individuals can recall their binge. Although both of these sleep-related eating disorders are associated with obesity, night eating syndrome is more closely tied to it. Also, night eating syndrome is comorbid with depression. Physicians should distinguish Sleep-Related Eating Disorders from other disorders that provoke nocturnal eating, Prader–Willi syndrome and Kleine–Levin syndrome.

Dementia

Dementia from Alzheimer disease and related disorders (see Chapter 7), at least in their moderate stages, disrupts patients’ sleep–wake cycle and produces nighttime thought and behavioral disturbances. During the night, patients tend toward confusion, agitation, and disorientation, especially when brought to new surroundings.

PSGs do not correlate with any particular etiology of dementia. In dementia, they show increased light sleep, fragmentations, and decreased efficiency. Patients typically take many naps of variable length during the day, leading to a “polyphasic sleep” pattern.

Parkinson Disease

During sleep, Parkinson disease tremor (see Chapter 18) characteristically disappears; however, the disease or medications treating it – dopamine agonists and L-dopa – frequently cause frightening vivid dreams, thought disorders, hallucinations, and agitation. Parkinson disease itself induces REM sleep behavior disorder; sleeping during the day and remaining awake at night (sleep reversal); fragmented sleep; and insomnia or hypersomnia. Dopamine agonists, more so than L-dopa, may cause episodes of irresistible sleep (sleep attacks) that interrupt activities and preclude driving. When depression complicates Parkinson disease, it compounds the sleep disturbances.

As a general rule, sleep disorders affect most Parkinson patients who have moderately advanced disease with comorbid dementia. Also, of the various symptoms of the disease, it is disruptive sleep disturbances that most often force caregivers to place patients in nursing homes.

To alleviate some of the problems, reducing the number and dosage of dopaminergic medications and administering the remaining ones in the early, rather than the late, evening reduce the frightening vivid dreams, thought disorders, hallucinations, and agitation; however, that strategy may worsen the morning rigidity and bradykinesia. If tolerated, TCAs may help the patient sleep through the night. Antipsychotic agents may reduce nighttime hallucinations and agitation, but they generally worsen rigidity and bradykinesia.

Other Movement Disorders

As with Parkinson disease tremor, other basal ganglia-related involuntary movements, such as athetosis and chorea, typically disappear during sleep. In contrast, several involuntary movements occur primarily or exclusively during sleep, such as periodic limb movements, RLS, and hypnic jerks (occasional near-universal, sudden contraction of antigravity muscles during the wake-to-sleep transition).

In one special group, disorders commonly evident during the day continue in sleep. This group includes generalized dystonia, tics, blepharospasm, and hemifacial spasm (see Chapter 18). Although partial arousals may precipitate these movements, most of them are not confined to a particular sleep stage.

Stereotyped, forceful teeth grinding or clenching, bruxism, also falls into the category of sleep movement disorders and one that persists during sleep. Bruxism makes a loud, disconcerting sound and leads to wearing away of teeth, headaches, and temporomandibular joint dysfunction. Although bruxism occurs in all sleep stages, it develops generally in the transition from wakefulness to sleep and during light sleep. Individuals with dementia, mental retardation, and Parkinson disease often have bruxism while awake, as well as when asleep. Use of SSRIs, cocaine, or other psychotropic substances may also precede transient bruxism. Nighttime dental devices help by cushioning the teeth.

Fatal Familial Insomnia

A recently described illness, fatal familial insomnia (FFI) consists of a progressively severe insomnia, refractory to hypnotics, that appears on the average at 50 years of age. Neuropsychologic impairments, including inattentiveness, amnesia, sequencing problems, and confusion, develop and worsen along with the insomnia. Later in their course, patients also suffer hyperactive ANS activity (tachycardia, hyperhidrosis, for example), endocrine abnormalities (elevated catecholamine and other hormone levels), and motor abnormalities (myoclonus, ataxia). FFI follows a relentless fatal 6–36-month course.

Like Creutzfeldt–Jakob disease (see Chapter 7), FFI is a hereditary prion disease caused by a mutation of the prion protein gene (PRNP) that results in accumulation of abnormal prion protein (PrP^Sc). Individuals who are homozygous for the FFI mutation, compared to those who are heterozygous, tend to run a fulminant course characterized by severe sleep disturbances and profound ANS abnormalities. Heterozygous individuals, in contrast, run a longer course with predominantly motor deficits.

Both FFI and Creutzfeldt–Jakob disease present with mental status changes in individuals 50 years old, which is younger than the onset of Alzheimer disease. In contrast to the pathology of Creutzfeldt–Jakob disease, the thalamus in FFI patients undergoes atrophy. Another difference is that the mutation entirely determines FFI rather than, as in the case of Creutzfeldt–Jakob disease, merely placing individuals at risk.

Epilepsy

In primary generalized epilepsy compared to partial epilepsy (see Chapter 10), sleep and particularly its NREM stages have a greater role in provoking seizures. About 45% of patients with primary generalized epilepsy have seizures predominantly during sleep. Primary generalized seizures most often develop within N1 and N2 sleep – usually during the first 2 hours of sleep. They also tend to occur at the other end of the sleep cycle – on awakening. REM sleep, in contrast, remains relatively seizure-free.

Partial seizures, compared to primary generalized ones, occur less frequently during sleep. In addition, when partial seizures occur during sleep, they are less restricted to NREM sleep. When a partial seizure, especially a frontal lobe seizure, develops during sleep, it may resemble a sleep-related disorder, such as a parasomnia, REM sleep behavioral disorder episode, or a nocturnal panic attack. The PSG may require extra EEG electrodes to distinguish between sleep disturbances and seizures.

Sleep deprivation precipitates seizures in individuals with and sometimes without a history of epilepsy. For example, individuals who have worked all night remain susceptible to tonic-clonic seizures throughout the next day. In more than one-third of patients with epilepsy who have no EEG abnormalities on routine daytime studies, an EEG obtained during sleep deprivation typically shows sharp waves and spike- and sharp-wave activity.

Another aspect of epilepsy’s interaction with sleep involves AEDs. Among their many actions, AEDs usually promote normal sleep. They tend to raise the efficiency of sleep by reducing arousals and increasing slow-wave sleep. On the other hand, even at therapeutic blood concentrations, AEDs may lead to EDS. Moreover, in children and some adults, sedating AEDs may paradoxically lead to hyperactivity.

Headaches

In some migraine patients, headaches arise only during sleep (nocturnal migraines, see Chapter 9). REM sleep coincides with the onset of migraine and, even more closely, cluster headache. Migraines often begin during early-morning REM sleep as well as during the day. Naturally occurring or medication-induced sleep characteristically aborts them.

Excessive sleep or other conditions that increase REM sleep may exacerbate migraines. As a potential tool, medications that suppress REM sleep, such as TCAs, reduce them.

Other Disorders

Sleep may also trigger life-threatening cardiovascular disorders. Angina pectoris and myocardial infarctions take place much more often during REM sleep, when pulse and blood pressure often fluctuate, than during NREM sleep. Strokes have a predilection for the hours just before awakening. Thus, a family often discovers that an elderly member has sustained a stroke only when the individual awakes.

Attacks of asthma, exacerbation of chronic obstructive lung disease, gastroesophageal reflux, and peptic ulcer disease tend to develop during sleep; however, attacks occur with equal frequency in both sleep phases and may be determined by the patient’s sleeping position. Whatever their cause, these nighttime disturbances interrupt sleep and lead to EDS. In cases of “nocturnal asthma,” physicians must not overlook the alternative diagnosis of nocturnal panic attacks.

Violence – in the broadest sense – occurs as an aspect of several sleep-related conditions: REM sleep behavior disorder, nocturnal focal seizures, head-banging, sleepwalking and other parasomnias, and dementia-induced wandering. In these cases, the physical activity ordinarily consists, at most, of poorly directed or self-inflicted flailing or banging but almost never purposeful violence directed at another individual, i.e., aggression. For physicians to accept violence as a manifestation of a sleep-related condition, it should have occurred in an individual who has an established history of a sleep disorder. Also, the violence should begin abruptly without provocation, last several minutes or less, and leave little or no residual memory.