Temukan buku favorit Anda berikutnya

Jadilah anggota hari ini dan baca gratis selama 30 hari
Sleep Disorders Part II

Sleep Disorders Part II

Baca pratinjau

Sleep Disorders Part II

1,466 pages
Nov 27, 2012


Sleep Disorders II covers various aspects of sleep disorders. These include the different classification of sleep disorders, the genetic influences of sleep disorders, abnormality in the sleeping pattern, and the circadian rhythm sleep disorder. A sleep disorder is a medical disorder that affects the sleeping patterns of humans (and sometimes animals). The disruptions in sleep can be caused by different factors, such as teeth grinding, night terrors, and the like.
The book also discusses different perspectives on insomnia and hypersomnia. According to the International Classification of Sleep Disorders, insomnia is a sleep that is low in quality or a difficulty in sleeping. On the other hand, hypersomnia is a sleeping disorder characterized by excessive daytime sleepiness (EDS) or prolonged nighttime sleep. The book discusses narcolepsy, a syndrome that is characterized by excessive daytime sleepiness that is associated with cataplexy and other REM sleep phenomena. The different medicines for this disease are also discussed.
People who are practicing neurology and internal medicine, especially those in pulmonary, cardiovascular, gastrointestinal, renal and endocrine specialties, will find this book valuable.

* A comprehensive resource for the study of sleep science, sleep medicine, and sleep disorders
* Fascinating noninvasive neuroimaging studies that demonstrate marked changes during different sleep states
* A state-of-the-art reference that summarizes the clinical features and management of many of the neurological manifestations of sleep disorders
Nov 27, 2012

Terkait dengan Sleep Disorders Part II

Judul dalam Seri Ini (65)
Buku Terkait
Artikel Terkait

Pratinjau Buku

Sleep Disorders Part II - Elsevier Science


Handbook of Clinical Neurology, Vol. 99, No. Suppl C, 2011

ISSN: 0072-9752

doi: 10.1016/B978-0-444-52007-4.00001-1

Classification of sleep disorders

Peter J. Hauri⁎E-mail address:cphauri@charter.net,

Mayo Clinic, Rochester, Minnesota, USA

⁎Correspondence to: Peter J. Hauri, Ph.D., Mayo Clinic, 422 Seventh Ave, SW, Rochester, MN 55902, USA. Tel: (507) 282-0059, Fax: (507) 266-7772

The Development of a New Sleep Disorders Classification

This chapter introduces the Second Edition of the International Classification of Sleep Disorders (ICSD-2), which was published in the summer of 2005 (American Academy of Sleep Medicine, 2005). This revision of ICSD was commissioned and supervised by the Board of the American Academy of Sleep Medicine, but it was an international group of sleep specialists who developed it. I was privileged to be appointed as chairman of this Committee to develop ICSD-2.

The committee first struggled to find a common organizing principle along which to sort the many different sleep disorders. We were unable to find one. In part this was because our knowledge about the different sleep disorders varies widely; for some, such as sleep apnea and narcolepsy, we know quite a bit and may be close to understanding the basic pathophysiological mechanisms of the disorder. For other sleep disorders we are still in the discovery phase and know very little about them, except for some of their symptoms.

ICSD-2 therefore abandoned the hope for a common framework along which to classify all sleep disorders. Rather, we decided to group these disorders into eight categories that, at present, seemed to make the most pragmatic sense. Some of these eight categories are based on a common complaint such as insomnia or hypersomnia. Others are grouped around the organ system from which the problems arise, such as the sleep-related breathing disorders and the sleep-related movement disorders. Still others are grouped around a presumed common etiology, such as the problems with the biological clock that are thought to underlie circadian rhythm disorders. Hopefully, in the future, a more overarching framework will emerge for classifying the sleep disorders, but we are not there yet.

ICSD-2 distinguishes the following eight categories of sleep disorders, each of which will be discussed in more detail later in this chapter:

1. Insomnias

2. Sleep-related breathing disorders

3. Hypersomnias of central origin not due to a circadian rhythm sleep disorder, sleep-related breathing disorder, or other cause of disturbed sleep

4. Circadian rhythm sleep disorders

5. Parasomnias

6. Sleep-related movement disorders

7. Isolated symptoms, apparently normal variants, and unresolved issues

8. Other sleep disorders.

Many sleep disorders are multifactorial. In accordance with the rules developed by the World Health Organization (WHO) for the International Classification of Diseases (ICD), these different factors are classified separately. For example, if a case of insomnia is related to anxiety, and to a restless legs syndrome, and to bad sleep habits, these three individual elements would be coded separately. Thus, the above case would carry three diagnoses.

History of the Sleep Disorders Classification System

The WHO, based in Geneva, Switzerland, maintains a list of all known human diseases. This International Classification of Diseases was published in its 10th revision (ICD-10) in 1992. ICSD-10 contains two sections especially reserved for sleep disorders.

The US Public Health Service maintains a standing committee that adapts the WHO's ICD to the needs and practices of the USA. The one that is currently still used in the USA is ICD-9-CM (International Classification of Diseases, ninth revision, Clinical Modifications). It is this committee that has authorized the five-digit code numbers that are listed for each of the individual sleep disorders discussed below.

In the 1970s, our knowledge about sleep disorders exploded. There was the discovery that sleep apnea was a common disorder, the new understanding that insomnia had many more etiologies than had been anticipated, the finding that periodic limb movements during sleep could significantly disturb sleep, etc. ICD had not foreseen this vast increase in our knowledge of sleep disorders. True, from very early versions onwards, ICD had listed some sleep disorders such as narcolepsy and the restless legs syndrome, but no room was reserved to place all the new sleep disorders that had emerged. Therefore, in the mid-1970s, Dr W. Dement appointed an ad hoc group of interested sleep specialists under the leadership of Dr H. Roffwarg to develop a Diagnostic Classification of Sleep and Arousal Disorders (DCSAD), which was published in the journal Sleep in 1979 (Association of Sleep Disorders Centers, 1979).

By the late 1980s, the field had developed beyond DCSAD. A revision and update was needed, carried out by a committee under the leadership of Dr M. Thorpe. This time the process was more formalized and international input was sought. This revision, called The International Classification of Sleep Disorders (ICSD-1), was published in 1990 and revised slightly in 1997 (American Sleep Disorders Association, 1997).

There is no question that, in the long run, any classification of sleep disorders needs to be absorbed into the WHO's International Classification of Diseases. Therefore, when developing ICSD-2, the current committee tried to move towards the goal of such a merger, mainly by adapting the thinking and structure of ICD whenever feasible. However, some significant obstacles for merger remain. Chief among them is the fact that ICD makes a fundamental distinction between the organic and the nonorganic disorders. For sleep disorders, this distinction is often very difficult to make, adds little to our understanding, and may even be counterproductive in our efforts to understand many of the sleep disorders.

The Content of ICSD-2

ICSD-2 is published as a book containing about 300 tightly written pages. Obviously, only a minimal amount of that information can be included in a chapter such as this one. The following tries briefly to characterize each of the eight sleep disorders categories and each of the over 80 individual sleep disorders that are included in ICSD-2. The goal of this chapter is to allow the reader some overview and appreciation of this nosology. No attempt is made in this chapter to provide enough information to make a diagnosis of each of the disorders.


Insomnia is defined as a complaint of unsatisfactory sleep. The sleep difficulty may lie in problems with falling asleep, in frequent awakenings during sleep, in waking too early in the morning, or in poor quality, nonrestorative sleep. To be called insomnia, according to ICSD-2, there have to be daytime consequences of this poor sleep, such as fatigue, irritability, or cognitive problems (American Academy of Sleep Medicine, 2005). The following 11 subtypes of insomnia are recognized by ICSD-2.

Adjustment insomnia (acute insomnia) (307.41)

This involves a relatively short-term insomnia (< 3 months) that is caused by an identifiable stressor (Roehrs et al., 2000).

Psychophysiological insomnia (307.42)

This is characterized by heightened arousal and learned sleep-preventing associations such as trying too hard to fall asleep, or excessive worrying about sleep (Bonnet and Arand, 1995).

Paradoxical insomnia (307.42)

This used to be called sleep state misperception syndrome. However, there is more to paradoxical insomnia than just a marked mismatch between how the patients think they slept and what objective data document about their sleep. During sleep, patients with paradoxical insomnia show either a near-constant awareness of the environment or a near-continuous pattern of conscious thoughts (Edinger and Fins, 1995).

Idiopathic insomnia (307.42)

This is a form of chronic insomnia that started in infancy or childhood, has no identifiable precipitant, and is chronic and relentless, with no periods of sustained remission. An imbalance in the neurological/neurochemical sleep/wake system has been postulated (Hauri and Olmstead, 1980).

Insomnia due to mental disorder (327.02)

This is diagnosed only in patients who have a diagnosed mental disorder. Also, this diagnosis is used only when the insomnia is an unusually predominant complaint of the underlying mental disorder or when insomnia warrants independent, clinical attention (Nofzinger et al., 1993).

Inadequate sleep hygiene (V69.4)

This involves an insomnia that is caused by maladaptive habits that cause poor sleep, such as excessive daytime napping, alcohol or caffeine near bedtime, excessively stimulating activities close to bedtime, etc. (Morin et al., 1999).

Behavioral insomnia of childhood (V69.5)

This is diagnosed when maladaptive child-rearing techniques are at the base of the insomnia, such as a lack of limit-setting throughout the day, or inadvertently teaching the child to fall asleep only when being rocked (Gaylor et al., 2001).

Insomnia due to drug or substance (292.85, or, if alcohol, 291.82)

This indicates that the insomnia is based on the use of or withdrawal from prescription or recreational drugs, or it may be caused by food items or toxins such as carbon monoxide poisoning (Schweitzer, 2000).

Insomnia due to medical condition (327.01)

This is involved when a condition such as asthma is presumed to cause the insomnia (Gislasen and Almquist, 1987).

Insomnia not due to substance or known physiological condition, unspecified (304.41)

This category is used when a patient has insomnia that is not classifiable into any of the above insomnias, but seems to be related to psychological issues. The unusually cumbersome title for this insomnia has to do with the fact that terms such as psychiatric or psychological are hard to define nowadays, except by exclusion (nonphysiological, nonsubstance induced).

Physiological (organic) insomnia, unspecified (327.00)

This is the category to use when a patient has an insomnia that clearly does not fit into any of the above-named insomnias, or when there are not enough data to diagnose the patient into any of the above disorders.

Sleep-related breathing disorders

Listed in this category are sleep problems that are characterized by disordered breathing during sleep. Other respiratory disorders that occur both during wakefulness and during sleep, such as asthma, are not classified as sleep disorders.

Central sleep apnea syndromes

These are sleep disorders where respiratory drive is repetitively either diminished (central hypopnea) or absent (central apnea) during all or parts of sleep. It appears that the patient simply stops trying to breathe adequately. These syndromes are usually based on either cardiac or neurological dysfunctions.

Primary central sleep apnea (327.21)

This involves the repeated stopping of respiratory effort during sleep. This leads to frequent awakenings (sleep fragmentation) and excessive daytime sleepiness (EDS). A high ventilatory response to carbon dioxide is often found in such patients (Xie et al., 1995).

Central sleep apnea due to a Cheyne–Stokes breathing pattern (786.04)

This breathing pattern shows repetitive crescendo–decrescendo breathing. Feedback in the respiratory system is slow. The tidal respiratory pattern gradually waxes and wanes. The repetitive hypoxic lows and the increased effort to restart breathing can disturb and fragment sleep (Xie et al., 2002).

Central sleep apnea due to high-altitude periodic breathing (327.22)

This is found in almost everyone when rapidly brought to altitudes, say over 4000 meters (Anholm et al., 1992).

Central sleep apnea due to a medical condition not Cheyne Stokes (327.27)

This is usually caused by a brainstem lesion, or by cardiac or renal disease.

Central sleep apnea due to a drug or substance (327.29)

This is usually related to taking long-acting drugs such as opioids for long periods. Such medications can also cause other sleep-related respiratory disorders such as obstructive hypoventilation or periodic breathing (Farney et al., 2003).

Primary sleep apnea of infancy (770.81)

This involves prolonged respiratory pauses that may be either central, obstructive, or mixed. This is usually a developmental problem, often caused by immaturity in the brainstem (Kahn et al., 2000).

Obstructive sleep apnea syndromes

These disorders are based on an obstruction in the upper airway that develops during sleep, e.g. by the relaxing of the muscles that keep the airway open. The patient continues to try to breathe, but during all or parts of sleep the airflow is limited or inhibited by the obstruction, and gas exchange is absent or at least curtailed until the sleeper awakens.

Obstructive sleep apnea, Adult (327.23)

This is by far the most common problem seen in sleep disorders centers. It involves repetitively either complete collapse of the upper airway during sleep, or at least a narrowing. This results in either apnea or hypopnea, or it may simply require an increased effort to move air through the upper airway (upper airway resistance syndrome). In severe obstructive sleep apnea there may be as many as 500 or more respiratory-related arousals during a night. The usual consequence of such a massive disturbance of sleep is excessive daytime somnolence (Flemons, 2002).

Obstructive sleep apnea, pediatric (327.23)

This is essentially the same condition as adult obstructive sleep apnea, except for different criteria. While an occasional obstructive apnea is acceptable for an adult, even one obstructive apnea per hour may be pathological in a child (Marcus, 2000).

Sleep-related hypoventilation/hypoxemia syndromes

These disorders show a chronically reduced oxygen and carbon dioxide exchange during sleep. Typically, this causes sleep fragmentation and nonrestorative sleep.

Sleep-related nonobstructive alveolar hypoventilation syndrome, idiopathic (327.25)

Chronically decreased alveolar ventilation during sleep results in lower arterial oxygen saturation. When this occurs in patients with otherwise normal lung properties it is called idiopathic. The condition is usually based on blunted chemoresponsiveness (Plum and Leigh, 1981).

Congenital central alveolar hypoventilation syndrome (327.24)

This is present at birth and is lifelong. It involves a failure of the automatic central control of breathing. Sleep aggravates this syndrome, and many patients may need mechanical ventilation during sleep (American Thoracic Society, 1999).

Sleep-related hypoventilation/hypoxemia due to medical condition (327.26)

This occurs in such problems as lower airway obstructions, neuromuscular and chest wall disorders. (Perez-Padilla et al., 1985).

Sleep apnea/Sleep-related breathing disorder, unspecified (327.20)

This is classified when the sleep-related breathing disorder cannot be classified into any of the above categories.

Hypersomnias of central origin not due to a circadian rhythm sleep disorder, sleep-related breathing disorder, or other cause of disturbed nocturnal sleep

The tortured title of this category tries to indicate that many sleep disturbances that are dealt with in other parts of ICSD-2 may also cause excessive daytime somnolence (EDS), but that the disorders discussed here are different. In them, EDS is a primary, not a secondary, symptom.


This group of sleep disorders has been recognized for over 100 years. Characterizing features of narcolepsy are: (1) EDS, usually associated with markedly disrupted sleep; (2) daytime naps that are refreshing for a short time only; (3) an unusual tendency to transition rapidly from wakefulness to rapid eye movement (REM) sleep without intervening nonREM sleep. This fast transition into REM sleep gives rise to cataplexy, hypnagogic hallucinations, and sleep-onset paralysis, features that are characteristic of narcolepsy but not invariably present.

Narcolepsy with cataplexy (347.01)

This is the pure form of narcolepsy, involving almost daily excessive sleepiness, combined with a history of cataplexy (sudden, transient loss of muscle tone usually triggered by emotions). This form of narcolepsy is closely associated with sleep-onset REM periods, with a genetic abnormality, and 90% of these patients have abnormally low hypocretin levels (Overeem et al., 2001).

Narcolepsy without cataplexy (347.00)

This is a somewhat more heterogeneous, less clearcut group that may involve some patients whose cataplexy has not yet emerged and others who may have a milder or atypical form of the disease. In the majority of these patients, hypocretin levels are normal. Sleep-onset REM periods may or may not be present (Krahn et al., 2002).

Narcolepsy due to a medical condition

This is secondary to medical conditions such as a hypothalamic tumor or a blow to the brainstem (Scammell et al., 2001). Distinguish narcolepsy with cataplexy (347.11) from narcolepsy without cataplexy (347.10).

Narcolepsy, unspecified (347.11)

This is the category to use if enough is known about a patient to diagnose narcolepsy, but not enough to classify them into one of the other narcolepsy categories.


This group combines the various hypersomnias that are not dealt with elsewhere in ICSD-2.

Recurrent hypersomnia (327.13)

This consists of episodic hypersomnolence alternating with periods of normal sleep, such as is typical in menstrual-related hypersomnia or in the Kleine–Levin syndrome. This latter disorder involves episodes of 16–18 hours of sleep per day for a few days or weeks, alternating with long stretches of normal sleep (Dauvilliers et al., 2003).

Idiopathic hypersomnia with long sleep time (327.11)

This is diagnosed when the patient typically sleeps longer than 10 hours per night but still is excessively sleepy during the day (Billiard and Dauvilliers, 2001).

Idiopathic hypersomnia without long sleep time (327.12)

This is diagnosed when the patient sleeps a normal 6–10 hours per night but is excessively sleepy during the day.

Behaviorally induced insufficient sleep syndrome (307.44)

Some patients are required by circumstances (e.g. jobs) to get by with less sleep than needed, others believe that sleep is an unnecessary waste of time, and many consistently obtain less sleep than they require, for social, cultural, financial, or other reasons. When they then show excessive somnolence during the day from lack of sleep, they often do not recognize what causes their EDS (Von Dongen et al., 2003).

Hypersomnia due to a medical condition (327.14)

This occurs when EDS is secondary to a disease such as Parkinson's disease, a brain tumor, or an endocrine disorder.

Hypersomnia due to drug or substance (292.85, 291.82 if alcohol)

This may be based on substance abuse (e.g. abuse of sedatives, withdrawal from excessive use of stimulants) or it may be related to the use of medically required drugs such as a high dose of sedative antiepileptic medication required for seizure control (Young-McCaughan and Miaskowski, 2001).

Hypersomnia not due to substance or known physiological condition (327.15)

Nonorganic hypersomnia, not otherwise specified, may be found in certain psychiatric diseases such as atypical depression, bipolar disorder, seasonal affective disorder, or conversion disorder (Overeem et al., 2002).

Physiological (organic) hypersomnia, unspecified (327.10)

Patients in this group satisfy the diagnosis of hypersomnia but do not fit any of the above types of hypersomnia.

Circadian rhythm sleep disorders

Human functioning is regulated by an internal clock that is located in the suprachiasmatic nucleus. This clock dictates when we become sleepy and when we become alert. It may be malfunctioning. For example, it may have a periodicity that is significantly longer than 24 hours or it may be misaligned with local clock time, such as in jet lag.

Circadian rhythm sleep disorder, delayed sleep phase type (327.31)

In this disorder, also called the night owl syndrome, the internal clock of the individual lags behind the local clock time. For example, when the clock on the wall indicates midnight, the internal clock may indicate only 9 pm, and the individual is biologically not yet ready to sleep. Then, when the clock on the wall indicates 8 am, the internal clock may show only 5 am, not yet time to get up. Now, if the biological clock were running in a time-free environment, the individual would go to bed and get up progressively later each day. However, in the real world, there are countervailing forces to free running, such as bright light during the day, or social pressures requesting a steady sleep time. The result is a delayed sleep phase syndrome – an uneasy balance is reached between internal and external clock: the individual goes to bed very late and gets up late, but still much earlier than is comfortable (Baker and Zee, 2000).

Circadian rhythm sleep disorder, advanced sleep phase type (327.32)

This is the opposite of the delayed sleep phase disorder: The patient has an internal clock that is ahead of local time. This results in the early bird behavior pattern (Jones et al., 1999).

Circadian rhythm sleep disorder, irregular sleep–wake type (327.33)

This disorder is characterized by a relative weakness or total lack of a circadian rhythm, with sleeping and waking being spread almost evenly over a 24-hour period. It appears as if the internal clock has stopped altogether (Pollack and Stokes, 1997).

Circadian rhythm sleep disorder, free-running (non-entrained) type (327.34)

This usually occurs when there are not enough stimuli to synchronize the internal clock to local time. It is like the delayed or the advanced sleep phase syndrome, except that the countervailing forces discussed under delayed sleep phase are absent. This problem is most often found in totally blind people (Sack et al., 1992).

Circadian rhythm sleep disorder, jet lag type (327.35)

This is a temporary complaint of insomnia or EDS after an individual has crossed many time zones and the body clock has not yet caught up to the new local time (Spitzer et al., 1999).

Circadian rhythm sleep disorder, shift work type (327.36)

Complaints of either insomnia or EDS occur in individuals who have difficulties adjusting to shift work. The problem is aggravated by the fact that during their time off work such individuals try to sleep on a normal day/night cycle, so that the clock can never adjust to any regular 24-hour periodicity (Akerstedt, 2003).

Circadian rhythm sleep disorder due to a medical condition (327.37)

This may occur in patients with dementia, Parkinson's disease, hepatic encephalopathy, etc. (Bliwise et al., 1995).

Circadian rhythm disturbance due to drug or substance (292.85) or, if alcohol induced (291.82)

This occurs when substances such as some antidepressants affect the circadian rhythm.

Circadian rhythm sleep disorder, other (327.39)

Classified here are patients who have problems with the circadian rhythm but cannot be diagnosed into any of the above categories.


Parasomnias are undesirable events that accompany sleep. Often they seem to be purposeful and goal directed. They may result in injuries, disturb sleep (of the patient as well as of others), and they may cause untoward psychosocial developments.

Disorders of arousal (from nonREM sleep)

Confusional arousals (327.41)

Such patients are mentally or behaviorally more confused than others when awakening, usually from deep (slow-wave) sleep (Ohayon et al., 2000).

Sleepwalking (307.67)

This involves walking or other complex behaviors that are started when awakening, usually from slow-wave sleep. The person may be difficult to awaken, coordination is often impaired, and behavior is often inappropriate (Kavey et al., 1990).

Sleep terrors (307.67)

These involve sudden terrified arousals, usually with a piercing scream, usually from slow-wave sleep. There is evidence of intense autonomic activation and panic. The person is difficult to awaken and usually shows amnesia for the episode (Ohayon et al., 1999a).

Parasomnias usually associated with REM sleep

REM sleep behavior disorder (327.42)

During REM (dreaming) sleep, most of our voluntary muscles are paralyzed. This keeps us from acting out our dreams. When this paralysis is weak or fails altogether, we start enacting parts of our dreams. Shouting, grabbing, punching, and leaping are often seen, but walking is rare. Injuries to self or bed partner are of concern (Olson et al., 2000).

Recurrent isolated sleep paralysis (327.43)

This involves the inability to speak or move, either when falling asleep or when waking up. Consciousness is preserved during the paralysis, which may last up to minutes (Ohayon et al., 1999b).

Nightmare disorder (307.47)

This consists of increasingly disturbing dream sequences that are highly emotional, involving fear, panic, and anger. However, in contrast to sleep terrors, autonomic arousal is minimal and patients often retain considerable recall of their dream (Levin and Fireman, 2002).

Other parasomnias

Sleep-related dissociative disorders (300.15)

These arise out of wakefulness during the sleep period. These events are similar to waking dissociative disorders, except that they are often associated with other parasomnias (Mahowald and Schenck, 2001).

Sleep-related enuresis (788.36)

While bedwetting in young children is expected, it becomes pathological if it occurs frequently after the age of about 5 years or so (Fritz and Rockney, 2004).

Sleep-related groaning (catathrenia, 327.49)

Chronic expiratory moaning and groaning during sleep usually occurs nightly and mainly during the later REM episodes of the night (Vetrugno et al., 2001b).

Exploding head syndrome (327.49)

This occurs at the transition between waking and sleeping. The person experiences either a sudden loud noise or a violent explosion in the head. Although very frightening, there is no pain, and, as far as known, the experience is benign (Pearce, 1989).

Sleep-related hallucinations (368.16)

These occur either when falling asleep or waking up. They are primarily visual and may be hard to distinguish from dreams (Silber et al., 2002), except that they occur when the patient is awake.

Sleep-related eating disorder (327.49)

In these patients there are recurrent episodes of involuntary eating and drinking during sleep. Some patients may be fully asleep during these episodes, others only partially so, or they may gradually awaken to full consciousness during the episode. Patients often consume peculiar foods such as a peanut butter/cigarette sandwich. Many patients realize that they have had an eating episode only when they enter the kitchen in the morning, finding food items displaced or missing (Winkelman, 1998).

Parasomnias due to drug or substance (292.85, if alcohol 291.82)

There are many possibilities, such as a REM behavior disorder (RBD) triggered by antidepressants or sleep-related hallucinations triggered by β-adrenergic receptor blocking agents.

Parasomnias due to a medical condition (327.44)

These may involve such parasomnias as sleep-related visual hallucinations associated with Parkinson's disease or RBD related to dementia.

Parasomnia, other or unspecified (327.40)

This is diagnosed when a given parasomnia cannot be classified into any of the above disorders.

Sleep-related movement disorders

Except for restless legs, this category of sleep disorders involves relatively simple, stereotyped movements during sleep or on the threshold between sleeping and waking. These movements cause fragmented sleep, insomnia and/or EDS.

Restless legs syndrome (333.94)

In this disorder there are very strong urges to move the legs (occasionally arms as well), often accompanied by paresthesias such as a creepy/crawly feeling in the legs. Restless legs occur mainly when resting or lying down. There is a circadian rhythm to them (nights are worst) and there is temporary relief when the extremities are moved (Allen and Earley, 2001).

Periodic limb movement sleep disorder (327.51)

This involves episodes during sleep of highly stereotyped, periodic limb movements. Such movements can also occur in good sleepers. A sleep disorder is diagnosed only when these limb twitches cause arousals and lead to a complaint of either insomnia or EDS (Coleman, 1982).

Sleep-related leg cramps (327.52)

These may arise from either sleep or wakefulness during the night, may last up to a few painful minutes and then abate spontaneously (Saskin et al., 1988).

Sleep-related bruxism (327.53)

This indicates that the patient is grinding or clenching the teeth during sleep. Considerable tooth damage may occur and sleep may become disturbed (Kato et al., 2001).

Sleep-related rhythmic movement disorders (327.59)

These may involve body rocking, head banging, head rolling, etc. during sleep. Quite normal in young children, the rhythmic movements may become a problem when they disturb sleep either in the patient or in a bed partner (Dyken et al., 1997).

Sleep-related movement disorder due to a drug or substance (327.59)

An example might be disturbed sleep secondary to tardive dyskinesia caused by dopamine receptor blocking agents.

Sleep-related movement disorder due to a medical condition (327.59)

This is diagnosed when such movements disturb sleep, an underlying condition such as Parkinson's disease is suspected, but has not yet been properly identified as the reason for the sleep disturbance.

Sleep-related movement disorder, unspecified (327.59)

This is used when there is clearly a sleep disturbance caused by muscle movements that does not fit into any of the above disorders, or when not enough is known to assign it to any of the above categories.

Isolated symptoms, apparently normal variants, and unresolved issues

Sleep clinicians frequently deal with issues that lie at the borderline between normal and abnormal sleep. Some may occur in many people without causing difficulties, but may become abnormal in excess or in highly sensitive sleepers.

1. Long sleeper is a term reserved for adults who sleep more than 10 hours per night (or for children who sleep more than 2 hours longer than age-adjusted norms). When they do not get that amount of sleep, long sleepers show signs of sleep deprivation (Aeschbach et al., 1996).

2. Short sleeper is an adult who regularly sleeps fewer than 5 hours per night, or a child who sleeps 3 hours less than age-appropriate norms, without showing daytime signs of sleep deprivation.

3. Snoring is diagnosed when there is audible, often very loud, snoring without disruption of the snorer's sleep.

4. Sleep talking is usually disruptive to a bed partner, but not to the talker.

5. Sleep starts (hypnic jerks) usually occur around sleep onset and may delay the beginning of sleep, especially when they occur frequently. A subjective feeling of falling, a sensory flash, or a dream fragment often accompanies them (Sander et al., 1998).

6. Benign sleep myoclonus of infancy involves repetitive large jerks that occur only during sleep, usually in children less than 6 months of age.

7. Hypnagogic foot tremors and alternating leg muscle activation involves benign movements in the legs and feet during sleep.

8. Propriospinal myoclonus at sleep onset consists of sudden muscular jerks occurring at sleep onset, mainly in the abdomen, trunk, or neck (Vetrugno et al., 2001a).

9. Excessive fragmentary myoclonus involves small movements or fasciculations in fingers, toes, or corners of the mouth that may disturb the relaxing patient. (Vetrugno et al., 2002).

Other sleep disorders

It seems likely that in the near future other sleep disorders will be found that do not fit into the framework of ICSD-2. The category of other sleep disorders is reserved for them. However, environmental sleep disorder is also classified here, mainly because it overlaps with so many other categories (insomnia, EDS, parasomnia).

Environmental sleep disorder (307.48)

This is diagnosed when the sleep disorder is caused by environmental factors such as noise, temperature, a bed partner, etc. It may manifest itself as insomnia, EDS, parasomnia or the patient may simply show daytime signs of sleep deprivation (Thiessen and Lapointe, 1983).

Other or unspecified sleep disorder (327.8)

This is diagnosed when there is a sleep disorder that does not fit into any of the other ICSD-2 diagnoses.

Concluding remarks

The above outline of the recognized sleep disorders gives a cursory glance at what is involved in the field of sleep disorders medicine. Clearly this field is multidisciplinary. Among others, knowledge of pulmonary medicine is needed to deal with the respiratory sleep disorders, knowledge from neurology to deal with the hypersomnias and some parasomnias, from psychiatry and psychology to deal with the insomnias.

Obviously, the field of sleep medicine is still young and evolving. It will be different in a decade or so.

For more information, the reader might contact the central office of the American Academy of Sleep Medicine, One Westbrook Corporate Center, Suite 920, Westchester, IL 60154, USA (Tel: 708 492-0930; www.aasmnet.org).


D. Aeschbach, C. Cajochen, H. Landolt, et al. Homeostatic sleep regulation in habitual short sleepers and long sleepers. Am J Physiol. 1996;270:R41-R53.

T. Akerstedt. Shift work and disturbed sleep/wakefulness. Occup Med. 2003;53:89-94.

R. Allen, C. Earley. Restless legs syndrome: a review of clinical and pathophysiologic features. J Clin Neurophysiol. 2001;18:128-147.

American Academy of Sleep Medicine. International Classification of Sleep Disorders. Diagnostic and Coding Manual., 2nd edn. Westchester, IL:American Academy of Sleep Medicine; 2005

American Sleep Disorders Association. International Classification of Sleep Disorders (Revised). In Diagnostic and Coding Manual. Rochester, MN: American Sleep Disorders Association; 1997.

American Thoracic Society. Idiopathic congenital central hypoventilation syndrome: diagnosis and management. Am J Respir Crit Care Med. 1999;160:368-373.

J. Anholm, A. Powles, R. Downey, et al. Operation Everest II: arterial oxygen saturation and sleep at extreme simulated altitude. Am Rev Respir Dis. 1992;145:817-826.

Association of Sleep Disorders Centers. Diagnostic Classification of Sleep and Arousal Disorders. In Prepared by the Sleep Disorders Classification Committee, 1st edn, Roffwarg HP; 1979:1-127. Chairman. Sleep 2

S. Baker, P. Zee. Circadian disorders of the sleep–wake cycle. In: M.H. Kryger, T. Roth, W.C. Dement, editors. Principles and Practice of Sleep Medicine. 3rd edn. Philadelphia: WB Saunders; 2000:606-614.

M. Billiard, Y. Dauvilliers. Idiopathic hypersomnia. Sleep Med Rev. 2001;5:351-360.

D. Bliwise, R. Watts, N. Watts, et al. Disruptive nocturnal behavior in Parkinson's disease and Alzheimer's disease. J Geriatr Psychiatry Neurol. 1995;8:107-110.

M.H. Bonnet, D.L. Arand. 24-Hour metabolic rate in insomniacs and matched normal sleepers. Sleep. 1995;18:581-588.

R. Coleman. Periodic movements in sleep (nocturnal myoclonus) and restless legs syndrome. In: C. Guilleminault, editor. Sleeping and Waking Disorders: Indications and Techniques. Menlo Park: Addison Wesley; 1982:265-295.

Y. Dauvilliers, C. Baumann, B. Carlander, et al. CSF hypocretin-1 levels in narcolepsy, Kleine–Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry. 2003;74:1667-1673.

M. Dyken, D. Lin-Dyken, T. Yamada. Diagnosing rhythmic movement disorder with video-polysomnography. Pediatr Neurol. 1997;16:37-41.

J.D. Edinger, A.L. Fins. The distribution and clinical significance of sleep time misperceptions. Sleep. 1995;18:232-239.

R.J. Farney, J.M. Walker, T.V. Cloward, et al. Sleep-disordered breathing associated with long-term opioid therapy. Chest. 2003;123:632-639.

W.W. Flemons. Clinical practice. Obstructive sleep apnea. N Engl J Med. 2002;347:498-504.

G. Fritz, R. Rockney. Summary of the practice parameter for the assessment and treatment of children and adolescents with enuresis. J Am Acad Child Adolesc Psychiatry. 2004;43:123-125.

E. Gaylor, B. Goodlin-Jones, T. Anders. Classification of young children's sleep problems. J Am Acad Child Adolesc Psychiatry. 2001;40:60-67.

T. Gislason, M. Almquist. Somatic disease and sleep complaints: an epidemiological study of 3201 Swedish Men. Acta Med Scand. 1987;22:475-481.

P. Hauri, E. Olmstead. Childhood-onset insomnia. Sleep. 1980;3:59-65.

C. Jones, S. Campbell, S. Zone, et al. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat Med. 1999;5:1062-1065.

A. Kahn, J. Groswasser, P. Franco. Breathing during sleep in infancy. G. Loughlin, J. Carroll, C. Marcus, editors. Sleep and Breathing in Children. New York:Marcel Dekker; 2000;Vol. 147:405-422

T. Kato, N. Thie, J. Montplaisir, G. Lavigne. Bruxism and orofacial movements during sleep. Dent Clin North Am. 2001;45:657-684.

N.B. Kavey, J. Whyte, S.R. Resor, S. Gidro-Frank. Somnambulism in adults. Neurology. 1990;49:749-752.

L.E. Krahn, V.S. Pankratz, L. Oliver, et al. Hypocretin (orexin) levels in cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLA DQB1*0602 status. Sleep. 2002;25:733-736.

R. Levin, G. Fireman. Nightmare prevalence, nightmare distress, and self-reported psychological disturbance. Sleep. 2002;25:205-212.

M. Mahowald, C. Schenck. Nocturnal dissociation – Awake? Asleep? Both? Or Neither? Sleep Hypnosis. 2001;3:129-130.

C.L. Marcus. Pathophysiology of childhood obstructive sleep apnea: current concepts. Respir Physiol. 2000;119:143-154.

C.M. Morin, P.J. Hauri, C.A. Espie, et al. Nonpharmacologic treatment of chronic insomnia. Sleep. 1999;22:1134-1156.

E. Nofzinger, D.J. Buysse, C.F. Reynolds3rd, et al. Sleep disorders related to another mental disorder (nonsubstance/primary): a DSM-IV literature review. J Clin Psychiatry. 1993;54:244-255.

M. Ohayon, C. Guilleminault, R. Priest. Night terrors, sleepwalking, and confusional arousals in the general population: their frequency and relationship to other sleep and mental disorders. J Clin Psychiatry. 1999;60:268-276.

M. Ohayon, J. Zulley, C. Guilleminault, et al. Prevalence and pathologic associations of sleep paralysis in the general population. Neurology. 1999;52:1194-1200.

M. Ohayon, R. Priest, J. Zulley, et al. The place of confusional arousals in sleep and mental disorders: findings in a general population sample of 13,057 subjects. J Nerv Ment Dis. 2000;188:340-348.

E. Olson, B. Boeve, M. Silber. Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain. 2000;123:331-339.

S. Overeem, E. Mignot, J.G. van Dijk, et al. Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives. J Clin Neurophysiol. 2001;18:78-105.

S. Overeem, J.J. van Hilten, B. Ripley, et al. Normal hypocretin-1 levels in Parkinson's disease patients with excessive daytime sleepiness. Neurology. 2002;58:498-499.

J. Pearce. Clinical features of the exploding head syndrome. J Neurol Neurosurg Psychiatry. 1989;52:907-910.

R. Perez-Padilla, P. West, M. Lertzman, et al. Breathing during sleep in patients with interstitial lung disease. Am Rev Respir Dis. 1985;132:224-229.

F. Plum, R. Leigh. Abnormalities of central mechanisms. T. Hornbein, editor. Regulation of Breathing. Part II. Lung Biology in Health and Disease. New York:Marcel Dekker; 1981;Vol. 17:989-1067

C. Pollack, P. Stokes. Circadian rest–activity rhythms in demented and non-demented older community residents and their caregivers. J Am Geriatr Soc. 1997;6:452.

T. Roehrs, F. Zorick, T. Roth. Transient and short-term insomnias. In Principles and Practice of Sleep Medicine, 3rd edn, Philadelphia: WB Saunders; 2000:624-632.

R. Sack, A. Lewy, M. Blood, et al. Circadian rhythm abnormalities in totally blind people: incidence and clinical significance. J Clin Endocrinol Metabol. 1992;75:127-134.

H.W. Sander, H. Geisse, C. Quinto, et al. Sensory sleep starts. J Neurol Neurosurg Psychiatry. 1998;64:690.

P. Saskin, C. Whelton, H. Moldofsky, et al. Sleep and nocturnal leg cramps. Sleep. 1988;11:307-308.

T.E. Scammell, S. Nishino, E. Mignot, et al. Narcolepsy and low CSF orexin (hypocretin) concentration after a diencephalic stroke. Neurology. 2001;56:1751-1753.

P. Schweitzer. Drugs that disturb sleep and wakefulness. In: M.H. Kryger, T. Roth, W.C. Dement, editors. Principles and Practice of Sleep Medicine. 3rd edn. Philadelphia: WB Saunders; 2000:1176-1196.

M.H. Silber, M. Hansen, M. Girish. Complex nocturnal visual hallucinations. Sleep. 2002;25:484.

R. Spitzer, M. Terman, J. Williams, et al. Jet lag: clinical features, validation of new syndrome-specific scale, and lack of response to melatonin in a randomized, double-blind trial. Am J Psychiatry. 1999;156:1392-1396.

G. Thiessen, A. Lapointe. Effect of continuous traffic noise on percentage of deep sleep, waking, and sleep latency. Acoustic Soc Am. 1983;73:225-229.

R. Vetrugno, F. Provini, S. Meletti, et al. Propriospinal myoclonus at the sleep–wake transition: a new type of parasomnia. Sleep. 2001;24:835-843.

R. Vetrugno, F. Provini, G. Plazzi, et al. Catathrenia (nocturnal groaning): a new type of parasomnia. Neurology. 2001;56:681-683.

R. Vetrugno, G. Plazzi, F. Provini, et al. Excessive fragmentary hypnic myoclonus: clinical and neurophysiological findings. Sleep Med. 2002;3:73-76.

H.P. Von Dongen, G. Maislin, J.M. Mullington, et al. The cumulative cost of additional wakefulness: dose–response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep. 2003;26:117-126.

J. Winkelman. Clinical and polysomnographic features of sleep-related eating disorder. J Clin Psychiatry. 1998;59:14-19.

A. Xie, R. Ruthford, F. Rankin, et al. Hypocapnia and increased ventilatory responsiveness in patients with idiopathic central sleep apnea. Am J Respir Crit Care Med. 1995;152:1950-1955.

A. Xie, J. Skatrud, D. Puleao, et al. Apnea–hypopnea threshold for CO2 in patients with congestive heart failure. Am J Respir Crit Care Med. 2002;165:1245-1250.

S. Young-McCaughan, C. Miaskowski. Measurement of opioid-induced sedation. Pain Manage Nurs. 2001;2:132-149.

Handbook of Clinical Neurology, Vol. 99, No. Suppl C, 2011

ISSN: 0072-9752

doi: 10.1016/B978-0-444-52007-4.00002-3

Genetics of sleep disorders

Juliane Winkelmann¹⁎E-mail address:winkelmann@lrz.tu-muenchen.de, Mayumi Kimura²

¹ Department of Neurology, Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München and Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany

² Max Planck Institute of Psychiatry, Munich, Germany

⁎Correspondence to: Dr Juliane Winkelmann, Klinik für Neurologie und Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München (TUM), Ismaninger Strasse 22, 81675 München, Germany. Tel: +49-89-4140-4688


In recent years, genetic approaches have became very popular in many fields of science. Finding causative genes specific for disorders and a variety of quantitative phenotypes is the hottest target in biomedical sciences, and such effort has also been made in the field of sleep research (Franken and Tafti, 2003; Lavie, 2005; Cirelli, 2009). One of the most successful findings in terms of sleep genetics so far is the discovery of the hypocretins/orexins, internal ligands of G-coupled orphan receptors in the hypothalamus. Hypocretins/orexins, when first discovered, were thought to function as appetite promoters (Sakurai et al., 1998), and it was then found that their impaired system initiates narcoleptic symptoms (Chemelli et al., 1999; Lin et al., 1999; Mieda and Yanagisawa, 2002; Sutcliffe and de Lecea, 2002; Sakurai, 2005; Nishino, 2007). However, as familial clustering had been observed in narcolepsy with a close association of human leukocyte antigens (e.g., HLA-DQB1 and HLA-DQA1), the discovery of gene products triggering or blocking narcolepsy was expected earlier (Peyron et al., 2000; Miyagawa et al., 2008). Thus, identifying a gene or its products responsible for sleep disorders will be difficult because of the complexity of these conditions.

However, there is an increasing demand for the discovery of genetic factors in sleep pathology (Taheri and Mignot, 2002; Dauvilliers et al., 2005; Dauvilliers and Tafti, 2008; Kimura and Winkelmann, 2007). It is known that several sleep problems can be inherited. Further, twin studies have demonstrated that sleep components are influenced significantly by genetic background. Thus, sleep regulation or dysregulation must be closely linked to genetic control. To prescreen a risk factor, find an adequate cure, or even classify the complexity of sleep phenotypes for further treatments, genetic information contributes to an in-depth understanding of the pathophysiology of major sleep disorders. Indeed, several mutations in particular genes are reported to be involved in certain sleep disorders. These sleep-related genes or mutations have mostly been demonstrated in animal models (Andretic et al., 2008), but, with the help of advanced molecular genetic approaches, sleep genetics will soon expand into a search among human models and lead to pharmacogenomic development for individualized sleep medicine.

In this chapter, we first describe the genetic influence on normal sleep and its regulatory mechanism, and then discuss recent clinical discoveries regarding the role of genetic factors in selected sleep disorders.

A Genetic Influence on Normal Sleep and Sleep–Wake Regulation

Evidence for genes

The various genetic aspects in normal sleep of healthy subjects are evident from earlier studies employing twin pairs (Linkowski, 1999). Under visual inspection, monozygotic (MZ) twins show a very similar hypnogram if they have not been exposed to similar environmental factors. The similarities of their sleep patterns are observed particularly in sleep latency, duration of sleep cycles, and appearance of rapid eye movement (REM) sleep (Webb and Campbell, 1983). The majority of twin studies have been based on questionnaire analyses, comparing sleep habits, subjective mood after night sleep, etc., and most demonstrate higher concordance for sleep characteristics in MZ than in dizygotic (DZ) twins (Partinen et al., 1983; Heath et al., 1990). However, more advanced polygraphic analyses show a stronger impact of the influence on genes in sleep regulation of twins (van Beijsterveldt and van Baal, 2002). In a previous study, alpha rhythms during waking were reported to be similar only in MZ twin pairs (Davis and Davis, 1936; Lennox et al., 1945). Recently, quantitative EEG measures revealed that spectral power during nonREM sleep showed significantly higher concordance than in DZ twin pairs, especially in the range of alpha and sigma bands (Ambrosius et al., 2008; De Gennaro et al., 2008). Furthermore, even MZ twins who were discordant for schizophrenia demonstrated almost identical spectra profiles (Brunner et al., 2001) (Figure 43.1). Apart from the strong evidence of similarity between MZ twins, more general findings of similarities in siblings suggest broader genetic heredity in sleep architecture (de Castro, 2002).

Fig. 43.1 Comparison of spectral profiles in nonREM and REM sleep (A) and temporal dynamics of delta and sigma EEG activity during nonREM sleep (B) in five monozygotic twin pairs who were discordant for schizophrenia (black line, affected twin; grey line, unaffected twin) (Brunner et al., 2001).

(Reprinted with permission from Kimura and Winkelmann, 2007. © Birkhauser.)

Genetic factors do affect sleep architecture. Whether sleep disorders can be transmitted within families is a moot question. In the case of insomnia, familial occurrence is common (Bastien and Morin, 2000). Although not every sibling experiences insomniac symptoms, they show similar power spectral distribution in their EEGs (Brunner et al., 2001). Therefore, genetic vulnerability to insomnia would be hidden even in normal sleep cycles, and the signs for potential sleep problems could be assessed by polysomnography. According to our local survey, vulnerability has been found in healthy probands who have family members diagnosed with insomnia associated with anxiety or depression (Modell et al., 2002; Friess et al., 2008); affected and nonaffected family members all showed higher REM density. However, this is controversial because insomnia begins prior to the onset of affective disorders, which are also inheritable. We cannot really separate which genomic factor influences the most or primarily, but it is worth recalling that sleep is a complex of phenotypes. Many gene factors may be involved in sleep, and balancing or counterbalancing their functions maintains homeostasis of sleep–wake regulation. Thus, there must be many possible genetic avenues for sleep disturbances.

Genetic aspects of the human and animal EEG


EEG is the most useful and convenient tool available at present to examine genetic influences on individual differences in CNS functioning and human behaviors. EEG records reflect rhythmic electrical activity of the brain and provide a direct measure of the functional state of the brain and its different levels of arousal. EEGs are described by various parameters, such as amplitude (power in μV²) and rhythm (frequency in Hz). These EEG variants can reflect genetic traits.

From the EEG recordings for three consecutive nights in 26 twin pairs living apart, Linkowski and associates (1989, 1991) found heritable signs in stages 2 and 4 of nonREM sleep, but not in REM sleep. In their study, variance in REM sleep appeared to be influenced substantially by environmental rather than genetic components. However, when heritability of EEGs was investigated in 213 twin pairs across four main frequency bands, van Beijsterveldt et al. (1996) reported that all delta, theta, alpha, and beta frequencies showed significantly high heritability. However, Vogel (1970) performed extensive earlier studies and, in the 1970s, had already proposed a hypothesis that the normal EEG rhythm is influenced by many genes. His group focused on the low-voltage EEG (lack of α waves) in 17 families with 191 individuals, and identified a linkage region for a putative gene underlying the normal human EEG variant to chromosome 20q (Steinlein et al., 1992). Their results indicate strong evidence for close linkage with the high polymorphic marker CMM6 (D20S19) and for genetic heterogeneity to the low-voltage EEG. Recently, Rétey et al. (2005) demonstrated a functional polymorphism of the gene encoding adenosine deaminase on chromosome 20, revealing an association with interindividual variability in sleep architecture and the sleep EEG. Their healthy young subjects, who possess a G to A transition at nucleoside 22 (G/A genotype compared with G/G), were characterized by more slow-wave sleep (SWS) and of greater intensity, indicating a direct role for a single gene in homeostatic human sleep regulation. Furthermore, recently Viloa, Archer and their collaborators have reported the significance of a variable-number tandem-repeat polymorphism in the PERIOD3 (PER3) gene on individual differences in sleep structure (Viola et al., 2007; Archer et al., 2008). This polymorphism was found earlier in association with diurnal preferences and delayed sleep phase syndrome (Ebisawa et al., 2001; Archer et al., 2003). The later studies have revealed that individuals with the longer PER3⁵ allele than the others who are homozygous for the PER3⁴ allele show higher delta power during nonREM sleep, and also higher theta and alpha power during REM sleep and wakefulness. Taken together, PER3 polymorphism seems to affect susceptibility to sleep loss, resulting from its influences on sleep homeostasis.

Regarding polymorphisms, it is known that a cause of fatal familial insomnia (FFI; see below for details) is a mutation at codon 178 of the prion protein gene, located on human chromosome 20, cosegregating with the methionine polymorphism at codon 129 (129M) of the mutated allele (Goldfarb et al., 1992; Montagna et al., 1998). These mutations are also found in another prion disease, Creutzfeldt–Jakob disease (CJD), in which a valine residue segregates at codon 129 (129V). Although the polymorphism at codon 129 is critical in distinguishing between FFI and CJD, the 129 polymorphism without the mutation at codon 178 occurs commonly in the general population, and does not result in prion disease. One study recently conducted EEG recordings and insomnia questionnaires in 884 middle-aged men and women to examine whether the 129V/M polymorphism influences sleep, with special emphasis on items related to insomnia complaints and any sleep disruption (Pedrazzoli et al., 2002). The results failed to clarify any differences in polysomnographic measures among three genotypes (129VV, 129MV, and 129MM), indicating that the prion 129 polymorphism does not really affect normal sleep. Other pathogenic mechanisms, implicating the normal allele of prion protein gene, need to be considered.


A role for the prion protein in sleep regulation has been also investigated in a genetically modified animal model, the prion protein null mouse (Tobler et al., 1996). Involvement of the prion protein in the neuropathogenesis of human and animal transmissible spongiform encephalopathies has been well documented (Prusiner, 1997); the normal function of this protein is still unknown. Compared with wild-types (129/Ola mice or 129/Sv and C57BL/6J mixture, Prn-p+/+), prion gene-disrupted homozygous mice (Prn-p⁰/⁰) display abnormalities in circadian activity rhythm and sleep structure; none of the mice differed particularly in their behavior or sleeping time. EEG studies have revealed that Prn-p⁰/⁰ mice exhibit a larger degree of sleep fragmentation and a larger response to sleep deprivation. The response to sleep deprivation is often indicated by the magnitude of EEG slow-wave activity (SWA, power density in the delta band) during and after sleep deprivation (Tobler and Borbély, 1986; Dijk et al., 1987). SWA in Prn-p⁰/⁰ mice during recovery sleep is twice than that in Prn-p+/+ mice after 6 hours of sleep deprivation. Data from the gene-knockout model suggest that the prion protein may participate in maintaining sleep continuity and regulating sleep intensity (Huber et al., 1999). More recently, a study by Dossena et al. (2008) confirmed its impact on sleep regulation, characterizing EEG abnormalities (e.g., sawtooth waves in the range of 3–4   Hz), and showed significantly reduced REM sleep in transgenic mice expressing the mouse homolog of the D178N/V129 mutation in the prion protein gene.

In mouse strains, systematic and quantitative studies of sleep EEG can also distinguish a genetic background that influences particular rhythmic brain activity (Valatx et al., 1972; Friedmann, 1974), as described above in the determination of zygosity in twins. Franken and Tafti's group screened many inbred mice and categorized them according to spectral dynamics of their EEG activity (Franken et al., 1998). First, time spent in each vigilance state was compared across six commonly used inbred strains (Figure 43.2). There were slight but significant differences in the amount of sleep and wakefulness, in which the relative amount of wakefulness appeared to be counterbalanced by that of SWS (=   nonREM sleep). Among these six strains, AKR/J (AK) mice had most SWS (least wakefulness), whereas DBA/2J (D2) mice had least SWS (most wakefulness) per day. When spectral profiles were compared, delta power (c. 1.5–4.0   Hz) typical for SWS was highest in AK and lowest in D2 mice respectively, whereas the distribution of peak delta frequencies was similar among the six strains. However, the peak frequency for theta band (c. 5.5–8.5   Hz) during paradoxical sleep (PS   =   REM sleep) was distributed in a strain-dependent manner, which did not coincide proportionally with relative power or episode duration of PS (Figure 43.3). Therefore, it is plausible that the theta peak frequency (TPF) associated with PS varies with genotype. Based on these findings, Tafti and colleagues (2003) performed quantitative trait loci (QTL) analysis, crossing a slow-theta strain (BALB/cByJ, C) with a fast-theta strain (C57BL/6J, B6), and demonstrated a chromosomal region that segregates with TPF. Finally, a single autosomal recessive gene, which contributes to controlling theta oscillations during REM sleep, was identified as the acylcoenzyme-A dehydrogenase for short-chain fatty acids (encoded by Acads). Demonstrating this gene with reference to TPF suggests also that brain fatty acid metabolism is important for cognitive function, and sleep represents a condition favoring or requiring β-oxidation.

Fig. 43.2 Comparison of time spent in each vigilance state across six inbred mouse strains: (A) Wake; (B) slow-wave sleep (SWS); (C) paradoxical sleep (PS). AK, AKR/J; C, BALB/cByJ; B6, C57BL/6J; BR, C57BR/6J; D2, DBA/2J; 129, 129/Ola mice. Hatched bars represent significant differences from other strains.

(Redrawn from Franken et al., 1998. Reprinted with permission from Kimura and Winkelmann, 2007. © Birkhauser.)

Fig. 43.3 Distributions of peak frequency in paradoxical sleep of six inbred mouse strains. AK, AKR/J; C, BALB/cByJ; B6, C57BL/6J; BR, C57BR/6J; D2, DBA/2J; 129, 129/Ola mice. Curves illustrate changes in maximum power spectra for each frequency bin.

(Modified from Franken et al., 1998. Reprinted with permission from Kimura and Winkelmann, 2007. © Birkhauser.)

Furthermore, with recombinant inbred mice, changes in the accumulation of EEG delta power can be used to detect a trace of genetic factors. As described above, and in other chapters in this volume, delta power increases proportionally over the course of recovery sleep after a certain period of sleep loss (or prior wakefulness). Therefore, requirement of SWS is predictive through the magnitude of delta power that indicates SWS intensity, i.e., homeostatic drive for nonREM sleep. Using QTL analysis, Franken et al. (1999) examined 25 BXD (B6   ×   D2 mice) recombinant inbred strains and looked for genomic regions that might affect the increase of delta power after 6 hours of sleep deprivation. One significant locus was identified on chromosome 13 that accounted for 49% of the genetic variance in this trait. In contrast, the decrease in delta power afterwards did not vary with genotype. These results indicate that the homeostatic regulation of SWS need is under genetic control (Franken et al., 2001). In addition, QTL analysis has also demonstrated PS-related loci on chromosome 7 during the light period, chromosome 5 during the dark period, and chromosomes 2, 17, and 19 across the 24-hour period from CXB (C   ×   B6 recombinant mice) lines (Tafti et al., 1997).

Differences in the level of delta power during nonREM sleep can also indicate a sign of gene mutation when compared with respective wild-types. For example, double knockout mice lacking both cryptochromes 1 and 2 (cry1,2−/−) show greater delta power during nonREM sleep across 24 hours (Wisor et al., 2002). The cryptochrome genes, as well as period genes (per), are mainly involved in circadian rhythm generation under the control of transcriptional factors such as CLOCK and BMAL1; therefore, genetic inactivation of cryptochromes results in circadian arrhythmicity (for details see Chapter 60). Although cryptochromes are clock-related genes, the experimental data from cry1,2−/− mice suggest their noncircadian role in the homeostatic regulation of sleep (Dudley et al., 2003; Franken et al., 2007). In this mutant mouse, per 1 and 2 genes are overexpressed reversely; therefore, it is not yet clear which genes or gene products are responsible for high nonREM sleep drive. However, their more recent study demonstrates increased gene expression of both per 1 and 2 in the mouse forebrain after 6 hours of sleep deprivation (Franken et al., 2007). Although upregulation of these genes does not show a linear parallel with the accumulation of process S (see below) among different strains, the results further support the hypothesis that clock-related genes participate in controlling sleep homeostasis.

On the other hand, low nonREM sleep drive is seen in mouse mutants with T-type calcium channel deficiency (Lee et al., 2004; Cueni et al., 2008). In a model (α1G−/−), low-threshold spikes in the thalamocortical relay neurons are absent, suggesting that the α1G subunit of T-type calcium channels is critical for the genesis of sleep spindles and delta oscillations (Kim et al., 2001). In fact, Lee et al. (2004) reported lack of delta waves with much lower power density during nonREM sleep in α1G−/− mice compared with wild-types, and sleep disturbances were significantly characterized by brief awakening interrupting nonREM but not REM stages. Similar sleep fragmentation was also observed in potassium channel-related mutant mice that do not have functional Kv3 potassium channels (double knockout of Kv3.1 and Kv3.3 encoding genes) (Espinosa et al., 2004). In this Kv3.1- and Kv3.3-deficient mouse model, significant sleep loss of nearly 40% was detected during the light period owing to a reduced mean duration of SWS episodes (Joho et al., 2006). Furthermore, the double mutant mice displayed dramatically reduced spectral power in the delta band and fewer sleep spindles (Espinosa et al., 2008), resembling the sleep phenotypes of the above-mentioned calcium channel-related mutants. According to these studies, genes related to influx–efflux ion channels in brain regions implicated in the modulation of the sleep–wake cycle appear to influence thalamocortical oscillations and contribute to the stabilization of nonREM sleep.

Regarding REM sleep regulation, using a gene-modified (transgenic) mouse model in which corticotropin-releasing hormone (CRH) was site-specifically overexpressed in the brain, we demonstrated that CNS-restricted CRH overexpression produces a strong drive towards REM sleep (Kimura et al., 2010). In this model, theta power during REM sleep is not particularly affected under baseline conditions. However, in response to sleep deprivation, even heterozygous CRH-overexpressing mice that fail to show increased baseline REM sleep demonstrate more REM sleep rebound than is seen in respective control and wild-type animals. The results indicate that homeostatic control in REM sleep can be detected in a particular model and only a single gene manipulation could possibly contribute to changes in REM sleep.


During the past several years, microarray technology has become a significant trend in the genetics of sleep research and opens up an opportunity for new discoveries in this field. Most of the related studies so far have been done under conditions of sleep deprivation, and then cDNA arrays are applied to find genes in the whole brain that are upregulated or downregulated, particularly during the process of sleep loss (Tononi and Cirelli, 2001; O’Hara et al., 2007). In the past, sleep-inducing factors were hypothesized to accumulate in the brain during prolonged wakefulness, and some of the putative sleep-promoting substances were isolated from the brain of sleep-deprived animals. When sleep pressure (power densities in delta waves = process S) is enhanced, the expression of related mRNAs either increases or decreases. cDNA microarrays would be able to detect such an intensified transcription of particular genes in relation to sleep needs. Earlier studies in rats (Cirelli and Tononi, 2000) and fruit flies (Cirelli et al., 2005; Zimmerman et al., 2006) showed that either 3, 6, or 8 hours of sleep deprivation increases the expression of several genes that can be categorized as: immediate early genes/transcription factors, energy balance-related genes, growth factors, heat shock proteins (chaperons), neurotransmitter/hormone receptors, kinases, etc. (Terao et al., 2003; Cirelli et al., 2004).

Most of the properties and functions of these molecules have not yet been clearly defined in association with sleep regulation. However, amongst these encoding genes, Homer1a is the most promising candidate that reflects sleep need, depending on the duration of sleep loss (Maret et al., 2007). The expression of Homer1a can be induced in the brain of D2, B6, and AK mice by sleep deprivation in a dose-dependent manner. It has been hypothesized that sleep plays a key role in synaptic plasticity (Krueger and Obál, 1993; Tononi and Cirelli, 2006). As the Homer1 gene contributes to recovery from glutamate-induced neuronal hyperactivity, its involvement in sleep homeostasis is quite reasonable, suggesting that sleep has a function in protecting neurons from the consistent activation imposed by wakefulness.

In any case, such transcriptome profilings have the potential to identify a gene or gene product that may lead to the development of personalized sleep medicine. As QTL analysis reveals, a small difference in genotypes may result in a large difference in phenotypes in terms of the characteristics of sleep patterns, including EEG modulation. cDNA array studies will provide a novel direction for searching for a central alteration that causes sleep disorders, and suggest a sleep cure on an individual basis. At present, gene hunting for human sleep disorders is not yet established; however, the microarray technique has been used to demonstrate gene traits in selectively bred animals for short or long sleepers (Xu et al., 2001). In the near future, perhaps using this gene technology, differences in sleep architecture seen in different ethnic groups may also be explained (Profant et al., 2002; Stepnowsky et al., 2003).

Familial Sleep Disorders

Restless legs syndrome

The restless legs syndrome (RLS) is probably one of the prime examples of a sleep disorder demonstrating a strong genetic component. RLS is characterized by unpleasant sensation and an urge to move the lower limbs, occurring exclusively at rest in the evening or at night. Moving the affected extremity improves the symptoms. The diagnosis is based on the clinical description of the symptoms by the patient and the presence of four essential diagnostic criteria, including the core clinical features of the disease (Allen et al., 2003). It has been reported that 40–60% of patients with RLS have a positive family history (Montplaisir et al., 1997; Winkelmann et al., 2000). Similar figures with heritability estimates of 0.6 derived from twin studies further support

Anda telah mencapai akhir pratinjau ini. Daftar untuk membaca lebih lanjut!
Halaman 1 dari 1


Pendapat orang tentang Sleep Disorders Part II

0 peringkat / 0 Ulasan
Apa pendapat Anda?
Penilaian: 0 dari 5 bintang

Ulasan pembaca