Primary Hypersomnia

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Background

The International Classification of Sleep Disorders (ICSD) describes primary hypersomnia as an idiopathic disorder of presumed central nervous system (CNS) cause that is associated with excessive sleepiness (ie, prolonged episodes of non–rapid eye movement [NREM] sleep). (See Etiology and Presentation.)[1]

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) defines primary (idiopathic) hypersomnia as excessive daytime sleepiness without narcolepsy or the associated features of other sleep disorders.[2]

In 1966, William Dement proposed that patients with excessive daytime sleepiness, but without cataplexy, sleep paralysis, or sleep-onset rapid eye movement (REM), should not be considered narcoleptic.[3] In 1972, Roth et al described a type of hypersomnia with sleep drunkenness that consists of difficulty coming to complete wakefulness, confusion, disorientation, poor motor coordination, and slowness, accompanied by deep and prolonged sleep.[4] The abrupt sleep attacks seen in classic narcolepsy are not present in this disorder.

In comparison with narcolepsy, which is characterized by well-defined clinical, polysomnographic, and immunogenetic features, primary hypersomnia is not well characterized.[5, 6] Moreover, while the DSM-IV-TR and the ICSD each define 2 types of idiopathic/primary hypersomnia based on the sleep time duration (ie, with or without long sleep), the presentation is often heterogeneous. (See Presentation, DDX, and Workup.)[7]

Please note that while the ICSD prefers the diagnostic label of idiopathic hypersomnia, the DSM prefers the diagnostic label of primary hypersomnia. As the terms are interchangeable, this article will refer to them alternately.

Classification

Primary hypersomnia can be classified as monosymptomatic or polysymptomatic. Isolated excessive daytime sleepiness that is not due to abnormal nocturnal awakenings characterizes the monosymptomatic form. The polysymptomatic form consists of abnormally long nocturnal sleep and signs of sleep drunkenness upon awakening.[8]

In the literature, 3 possible subgroups of idiopathic CNS hypersomnia have been suggested.

Subgroup I

These patients have a positive family history, and associated clinical symptoms suggest dysfunction of the autonomic nervous system. These symptoms include headache, syncope, orthostatic hypotension, and peripheral vasoconstriction (cold hands and feet).

Subgroup II

This group includes patients who had a viral infection associated with neurologic symptoms, such as Guillain-Barré syndrome, infectious mononucleosis, or atypical viral pneumonia. Even after their infectious disease resolves, these patients continue to require significantly more nocturnal sleep and continue to feel very tired.

Although initially these patients are fatigued, they subsequently have difficulty differentiating fatigue from sleepiness. To fight tiredness, these patients nap and eventually present with complaints of excessive daytime sleepiness. Analysis of cerebral spinal fluid demonstrates moderate lymphocytosis (30-50 cells/µL with mild to moderate elevation in protein).

Subgroup III

These patients do not have a positive family or viral infection history, and the cause of the disorder truly is idiopathic.

Recurrent primary hypersomnia

Kleine-Levin syndrome (KLS) is a rare disorder that starts during adolescence and has a male gender preference. The patients have recurrent episodes of hypersomnia, which are often associated with compulsive overeating and hypersexuality.[9] The periods of hypersomnia occur for days to weeks at a time and recur several times a year. In between the symptomatic periods, the patients have normal sleep requirements and do not have excessive daytime sleepiness. Some patients may develop symptoms of irritability, impulsive behavior, depersonalization, hallucinations, depression, and confusion. The etiology of this disorder is not known.[10, 11]

The disorder mainly affects males (68%). The median age of onset is 15 years (range, 4-82y; 81% during the second decade), and the syndrome may last up to 8 years. The episodes recur every 3-4 months and may last up to 10 days, but they may last longer in women. (See Epidemiology.)

KLS may be precipitated by infections (38.2%), head trauma (9%), or alcohol consumption (5.4%). Characteristic symptoms include the following[11] :

Menstrual-related hypersomnia is diagnosed when excessive daytime sleepiness occurs on a periodic basis over a few days preceding menstruation.[12] It is assumed that the symptoms follow hormonal changes, but the etiology of the syndrome, as well as its prevalence and course, are virtually unknown.

The ICSD recurrent hypersomnia is classified separately to describe the recurrent form of primary hypersomnia according to the DSM-IV-TR.

Etiology

Primary hypersomnia is an idiopathic disorder. Although head injury or viral infections can cause a disorder resembling primary hypersomnia, the true causes for most cases remain unknown. No genetic, environmental, or other predisposition has been identified.[6]

Excessive daytime sleepiness has been described in a subset of patients following viral illnesses such as Guillain-Barré syndrome, hepatitis, mononucleosis, and atypical viral pneumonia. Familial cases associated with HLA-Cw2 and HLA-DR11 genotypes have also been reported.[13] However, the majority of the patients diagnosed with idiopathic hypersomnia have neither a positive family history nor a past medical history of viral illnesses.

In experimental animal studies, destruction of the nonadrenergic neurons of the rostral third of the locus ceruleus complex has produced hypersomnia. While trauma has been associated with excessive daytime sleepiness in a case series, cerebrospinal fluid (CSF) analysis for specific neurotransmitter metabolites did not differentiate patients with posttraumatic excessive daytime sleepiness from patients with narcolepsy or other patients with excessive daytime sleepiness.[14] Injury to the adrenergic neurons at the bundle of isthmus has led to hypersomnia associated with a proportional increase of both NREM and REM sleep.[15]

Evidence suggests that a dopamine system dysfunction may occur in narcolepsy, while a similar malfunction of the norepinephrine system may occur in idiopathic hypersomnia. Decreased CSF histamine levels have been reported in primary hypersomnia, as well as in narcolepsy, but not in non-CNS hypersomnias, suggesting that histamine may be an indicator of a central (versus a peripheral) origin for hypersomnias.[16]

A major advance in the understanding of the pathology of narcolepsy, a disorder closely related to primary hypersomnia, was made after the discovery of narcolepsy-associated genes in animals; ie, genes involved in the pathology of the hypocretin/orexin ligand and its receptor.[17, 18] Low CSF concentrations of hypocretin-1 and hypocretin-2 in HLA DQB1*0602 were also found in primary hypersomnia, and a generalized defect in hcrt-2 transmission may be present in this disorder. As hypocretin peptides excite the histaminergic system by the hypocretin receptor 2,[19] hypocretin deficiency may result in excessive daytime sleepiness via decreased histaminergic function.[16]

Epidemiology

Occurrence in the United States

While the rates of excessive daytime sleepiness complaints in the general population are between 0.5-5% of adults (in surveys without a specific consideration of causes/diagnoses), idiopathic hypersomnia is diagnosed in about 5-10% of individuals who are self referred to a sleep clinic with a chief complaint of daytime sleepiness.[1] A precise estimation of idiopathic hypersomnia prevalence is complicated by a lack of clear biologic markers or unambiguous diagnostic criteria.

A study by Ohayon et al suggested that excessive sleepiness is more prevalent than previously estimated. The study found that with 27.8% of 15,929 individuals from 15 US states reported excessive sleepiness. Even when using restrictive criteria of frequency at least 3 times per week for at least 3 months despite normal sleep duration, the prevalence was 4.7%.[20]

Sex- and age-related demographics

Gender ratio for idiopathic hypersomnia is unknown. Kleine-Levin syndrome affects males approximately 3 times more often than females.[1]

As with narcolepsy and Klein-Levin syndrome, onset of primary hypersomnia is most common during adolescence and rare in people older than 30 years. The diagnosis of idiopathic hypersomnia is complicated by the fact that differentiating between excessive versus long sleep or normal versus abnormal wakefulness is often difficult in this population.

Prognosis

After a typical onset between the ages 15-30 years, untreated primary hypersomnia presents a chronic, but stable, course. Idiopathic hypersomnia is a lifelong disorder with no tendency to remit spontaneously. Consequences of this disease are mostly social and professional in nature.

Daytime sleepiness can lead to depression. Of note, in children, daytime sleepiness can present as hyperactivity.[1]

Patient Education

While treating patients with primary hypersomnia, the patient's close family should be involved in the overall education and decision-making process.

Because these disorders may lead to marriage breakdown, extensive counseling for the patient's partners, educating them about the symptomatology and treatment options, must be part of a comprehensive management plan.

Patients with primary hypersomnia often need significant support because they are at risk of being misunderstood as being incompetent or slothful. Therefore, education of relatives, friends, and colleagues helps the patient to function much better with this incurable disease.

For patient education information, see the Sleep Disorders Center, as well as Disorders That Disrupt Sleep (Parasomnias) and Narcolepsy.

Medline Plus/National Institutes of Health (NIH) provides concise and to-the-point summaries of the diagnosis and recommendations for patients and families dealing with primary hypersomnia and Kleine-Levine syndrome.

The Mayo clinic offers an additional, more comprehensive patient resource on idiopathic/primary hypersomnia.

History

DSM-IV-TR diagnostic criteria for 307.44 primary hypersomnia

The DSM-IV-TR provides the following characteristics for primary hypersomnia:

Specify if the condition is recurrent; that is, if there are periods of excessive sleepiness that last at least 3 days, occurring several times a year for at least 2 years.[1]

ICSD criteria

The diagnostic criteria of idiopathic hypersomnia in the revised edition of the ICSD, in addition to the clinical criteria, which are similar to DSM-IV-TR criteria, include 1 or more of the following polysomnographic features[2] :

Additional characteristics

The most typical referral is for the polysymptomatic form of primary hypersomnia and is characterized by the following[5, 21] :

These patients do not feel refreshed following naps and, therefore, fight sleepiness as long as they are able. Patients are difficult to awaken from sleep or naps.

Some patients complain of headaches, fainting episodes, orthostatic hypotension, and peripheral vascular complaints of Raynaud phenomenon. Rarely, hypnagogic hallucinations and sleep paralysis may be observed. During long periods of drowsiness, patients might develop automatic behavior, during which they act in a semicontrolled fashion. (During automatic behavior episodes, these patients may endanger themselves through risk of injury.)

In patients with the recurrent form (ie, Kleine-Levine syndrome), hypersomnia occurs for days to weeks several times a year. In between, patients do not have excessive daytime sleepiness. Some patients may develop symptoms of irritability, hypersexuality, hyperphagia, impulsive behavior, depersonalization, hallucinations, depression, and disorientation.

Physical Examination

The patient may appear overtired or even fall asleep in the physician’s office. The rest of the physical examination, however, will not reveal any particular features suggesting a diagnosis of idiopathic hypersomnia.

The physical examination goal is to exclude alternate diagnoses. A diagnosis of obstructive sleep apnea rather than idiopathic hypersomnia should be considered for a patient presenting with hypersomnia associated with central obesity, micrognathia or retrognathia, macroglossia, crowded oropharynx, nasal obstruction, and tonsillar enlargement.

An underlying rheumatologic disease, such as active rheumatoid arthritis or osteoarthritis, may cause daytime hyperoxia and sleepiness associated with poor nighttime sleep due to pain. Prior head trauma sequela or a current brain tumor can leave their specific mark on the neurologic examination.

Specific findings may suggest a degenerative neurologic condition (eg, Parkinson or Huntington disease), endocrine dysfunction (eg, hypothyroidism), viral and bacterial infections (eg, hypersomnia secondary to viral encephalitis), pulmonary disease with secondary sleep-related breathing difficulties (eg, chronic bronchitis) or musculoskeletal disorders (eg, rheumatoid arthritis, fibromyalgia).

An overweight patient with primary hypersomnia should be assessed for underlying endocrine problems and sleep apnea.

If psychomotor retardation or agitation is noted, mental disorders with secondary sleep disturbance need to be ruled out before making a diagnosis of primary hypersomnia.

Mental status examination

Major depressive disorder commonly presents with decreased energy and tiredness and atypical depression presents with hypersomnia. Similarly, speech that is soft in quality, with a decreased rate of production and an increased latency of answers, might indicate excessive tiredness, but it may also indicate depression.

Mood might be “down," tired,” or even “depressed,” with mood congruent and a decreased range of affect. If this is the case, the meaning of the words needs to be carefully qualified. Is it that the patient has depression (ie, major depressive disorder) or is it that he/she feels down as a reaction to oversleeping and decreased ability to function?

Thought processes should be coherent and goal directed. While suicidal ideation is not typical for primary hypersomnia, because of the overlap between sleeping and affective disorders, standard questioning about the presence of suicidal and homicidal ideation is recommended.

Insight and judgment are most times good. Mild cognitive changes in the domains of attention, concentration and short-term memory are occasionally present, but most often the cognitive examination should not reveal any significant deficits.

Recurrent hypersomnia

On the neurologic examination, patients with Klein-Levin syndrome may present with a number of nonspecific findings including nystagmus, dysarthria, and generalized hyperreflexia.

For secondary Kleine-Levin syndrome, patients tend to be older and have more frequent and longer episodes, but they present with clinical symptoms and treatment responses similar to those of primary cases.[11]

Approach Considerations

Primary hypersomnia is a diagnosis of exclusion. Other causes of excessive daytime somnolence should be ruled out before a diagnosis of primary hypersomnia is made.

Patients should receive a complete blood count (CBC), screening biochemistry tests, and thyroid-stimulating hormone tests to exclude common physical disorders that may present with complaints of excessive tiredness, often expressed as excessive sleepiness by patients. A drug screen is indicated if substance-induced sleep disorder needs to be ruled out.

As excessive sleepiness is essentially a self-reported, subjective complaint, a number of tests have been created with the goal of increasing the data collection validity and reliability. Commonly used scales for a quantitative, systematic assessment of excessive sleepiness are the Epworth Sleepiness Scale and the Stanford Sleepiness Scale. While helpful, these scales remain essentially subjective in nature, which raises questions about the characteristics of sleepiness as assessed by subjective methods (eg, the Epworth and Stanford sleepiness scales) versus objective ones (eg, polysomnography and the Multiple Sleep Latency Test).[24, 25]

Polysomnography and Multiple Sleep Latency Test

Complete in-laboratory polysomnography (PSG) studies are essential to exclude other sleep disorders, particularly sleep breathing disorder, periodic limb movement disorder, and narcolepsy. Nocturnal PSG findings in primary hypersomnia include a short sleep latency, absence of arousals or awakenings, normal distribution of REM and NREM sleep, and normal to prolonged sleep duration.[26, 27]

A PSG study completion is required prior to the Multiple Sleep Latency Test to objectively characterize preceding sleep and uncover potential causes of sleep fragmentation. The PSG must have confirmed at least 6 hours of sleep for the Multiple Sleep Latency Test results to be considered in diagnosing primary hypersomnia.

Sleep latency on the Multiple Sleep Latency Test is usually short (8-10 min or less). In addition, in contrast to narcolepsy, sleep-onset REM periods (the occurrence of REM sleep within 20 minutes of sleep onset) are not typically seen.

Breathing-related sleep disturbances and frequent limb movements disrupting sleep are not present.

The following PSG features are required for the diagnosis of primary hypersomnia:

The Multiple Sleep Latency Test is performed to evaluate the presence of pathologic sleepiness. The subject is studied during 5 daytime naps taken 2 hours apart. According to 2 studies, the mean Multiple Sleep Latency Test score in primary hypersomnia is slightly higher than the score in narcolepsy. The mean Multiple Sleep Latency Test score was found to be 6.5 ± 3.2 minutes for idiopathic hypersomnolence versus 3.3 ± 3.3 minutes for narcolepsy. Narcolepsy is excluded by the absence of sleep-onset REM periods on the 5-nap Multiple Sleep Latency Test.

Electroencephalography

In recurrent primary hypersomnia (ie, Kleine-Levin syndrome), routine electroencephalographic studies performed during hypersomnia show a general slowing of the background rhythm and paroxysmal bursts of theta activity. Nocturnal PSG shows prolonged sleep duration and decreased sleep latency (< 10 min). In addition, sleep-onset REM has been reported during symptomatic periods. (See the images below.)[1]


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Primary hypersomnia. Polysomnographic study demonstrates apnea (absence of carbon dioxide fluctuation indicating no flow), chest wall paradox, abrupt ....


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Primary hypersomnia. In contrast to obstructive sleep apnea, mixed apnea shows absence of respiratory efforts in the first segment of the apnea.


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Primary hypersomnia. Periodic limb movements show intermittent leg electromyogram activity accompanied by electroencephalogram arousals.

Approach Considerations

Severe idiopathic hypersomnia is a disabling problem that often leads to permanent unemployment and responds poorly to medical treatment.[9, 8] Moreover, because the underlying cause of idiopathic hypersomnia is unknown, treatment remains symptomatic in nature.

The American Academy of Sleep Medicine practice parameters state that successful treatment of hypersomnia of central origin requires an accurate diagnosis, individual tailoring of therapy to produce maximum possible return of function, and regular follow-up to monitor response to therapy.

Modafinil, sodium oxybate, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, and selegiline are effective treatments for excessive sleepiness associated with narcolepsy and primary hypersomnias. Scheduled naps can be beneficial to combat sleepiness in these patients.[28]

Behavioral approaches and sleep hygiene techniques are recommended, although they have little overall positive impact on this disease.

Consultations

The diagnosis of primary hypersomnia is made after excluding neurologic, pulmonary, and psychiatric disorders known to cause excessive sleepiness. Therefore, if an underlying cause is suggested, appropriate consultations with a neurologist, pulmonologist, and psychiatrist should be obtained.

Activity

Caution is recommended in activities in which hypersomnolence may be hazardous.

Pharmacologic Therapy

Medications that have been used in the treatment of this disorder include tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), clonidine, levodopa, bromocriptine, amantadine, methysergide, pemoline (as of October 2005, this is no longer available in the United States; risk of liver toxicity outweighs benefits), and modafinil. (Patients develop tolerance to their medications; exercise caution in prescribing drugs.)

Therapy for idiopathic hypersomnolence involves maintaining the patient on a daily use of stimulants. The drug dose is titrated so that the patient stays alert during the day, but adverse effects should be avoided.

Methylphenidate (Ritalin), mazindol (withdrawn from the US market in 2001), and dextroamphetamine are the most commonly prescribed medications.

Modafinil

Modafinil has proved clinically useful in the treatment of narcolepsy and other causes of excessive daytime sleepiness, such as idiopathic hypersomnolence.[29] It is a psychostimulant that enhances wakefulness and vigilance, but its pharmacologic profile is notably different from the amphetamines, methylphenidate, or cocaine. Modafinil is less likely to produce side effects such as jitteriness, anxiety, or excess locomotor activity or to lead to a hypersomnolent rebound effect. It is long-acting; the normal elimination half-life of modafinil in humans is between 12-15 hours.[3, 30]

The mechanism of action of modafinil is not fully understood. Modafinil induces wakefulness in part by its action in the anterior hypothalamus. Its dopamine-releasing action in the nucleus accumbens is weak and dose dependent; the likelihood of a euphoric response, and, therefore, the abuse potential and tolerance, is small.

Modafinil has central alpha 1-adrenergic agonist effects (ie, it directly stimulates the receptors). Modafinil inhibits the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO). More significant, perhaps, is its ability to increase excitatory glutaminergic transmission and reduce local gamma-aminobutyric acid (GABA)–ergic transmission, thereby diminishing GABA(A) receptor signaling on the mesolimbic dopamine terminals.[30, 31]

Physician Legal Responsibilities

Physicians have a legal responsibility to know which medical conditions may impede driving ability, to diagnose these conditions in their patients, and to discuss the implications of these conditions.

The requirement to report unfit drivers varies among different jurisdictions, and interpretations of the law vary among the courts. Therefore, a physician’s risk of liability is unclear. Physicians may face legal action by their patients if they fail to counsel the patients on the dangers of driving associated with certain medications or medical conditions.

Physicians’ legal responsibilities to report patients with certain medical conditions, when required by law, override their ethical responsibilities to keep patients’ medical information confidential.

Medication Summary

Patients often require drug therapy to treat daytime hypersomnolence. Prior to initiating therapy with stimulants, clearly establish a diagnosis and consider potential for abuse.[8, 23]

Modafinil, a wake-promoting agent, is approved for treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea-hypopnea syndrome (OSAHS), and shift-work sleep disorder (SWSD).[30, 31] The studies have shown significant benefits on various objective measures and subjective estimates of excessive sleepiness.

The clinical efficacy of modafinil, combined with its improved safety over CNS stimulants, has made it the most prescribed medication for the treatment of excessive sleepiness associated with narcolepsy. Unlike many other medications used for excessive sleepiness, modafinil is not known to be abused. The most common adverse event reported in clinical studies was headaches; most were transient and mild to moderate in severity. Modafinil also has the potential for interactions with other drugs metabolized via cytochrome P450 enzyme pathways.

For Kleine-Levin syndrome, somnolence can decrease with stimulants (mainly amphetamines), while neuroleptics and antidepressants are of poor benefit. Lithium, rather than carbamazepine or other antiepileptics, was found to have a higher success rate for stopping relapses.[32]

Modafinil (Provigil)

Clinical Context:  Modafinil may exert stimulant effects by decreasing GABA-mediated neurotransmission. It has wake-promoting actions similar to those of sympathomimetic agents. Modafinil improves wakefulness in patients with excessive daytime hypersomnolence. It has been used in narcolepsy and primary hypersomnia. Its mechanism of action is unclear.

Methylphenidate (Ritalin, Daytrana, Methylin, Concerta)

Clinical Context:  Methylphenidate is used for symptomatic management of primary hypersomnolence whenever the patient needs to be alert or engages in activities in which hypersomnolence may be hazardous. The drug blocks the reuptake mechanism of dopaminergic neurons. Methylphenidate stimulates the cerebral cortex and subcortical structures.

Dextroamphetamine (Procentra, Dexedrine Spansules)

Clinical Context:  This agent increases the amount of circulating dopamine and norepinephrine in the cerebral cortex by blocking the reuptake of norepinephrine or dopamine from the synapse.

Dextroamphetamine and amphetamine mixtures (Adderall XR)

Clinical Context:  This agent produces CNS and respiratory stimulation. The CNS effect may occur in the cerebral cortex and reticular activating system. Dextroamphetamine-amphetamine mixture may have a direct effect on alpha- and beta-receptor sites in the peripheral system and may also release stores of norepinephrine in adrenergic nerve terminals. The mixture contains various salts of amphetamine and dextroamphetamine. It is available as 5-, 7.5-, 10-, 12.5-, 15-, 20-, and 30mg scored tablets.

Class Summary

These agents have wake-promoting activities.

Author

Adrian Preda, MD, Health Sciences Associate Professor of Psychiatry and Human Behavior, University of California Irvine School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Iqbal Ahmed, MBBS, FRCPsych (UK), Faculty, Department of Psychiatry, Tripler Army Medical Center; Clinical Professor of Psychiatry, Uniformed Services University of Health Sciences: Clinical Professor of Psychiatry, Clinical Professor of Geriatric Medicine, University of Hawaii, John A Burns School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Jennifer S Morse, MD Associate Medical Director, Optum Health

Jennifer S Morse, MD is a member of the following medical societies: Academy of Psychosomatic Medicine, Aerospace Medical Association, and American Psychiatric Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Primary hypersomnia. Polysomnographic study demonstrates apnea (absence of carbon dioxide fluctuation indicating no flow), chest wall paradox, abrupt increase in tidal volume at the end of apnea, and oxygen desaturation. All of these features are consistent with obstructive sleep apnea.

Primary hypersomnia. In contrast to obstructive sleep apnea, mixed apnea shows absence of respiratory efforts in the first segment of the apnea.

Primary hypersomnia. Periodic limb movements show intermittent leg electromyogram activity accompanied by electroencephalogram arousals.

Primary hypersomnia. Polysomnographic study demonstrates apnea (absence of carbon dioxide fluctuation indicating no flow), chest wall paradox, abrupt increase in tidal volume at the end of apnea, and oxygen desaturation. All of these features are consistent with obstructive sleep apnea.

Primary hypersomnia. In contrast to obstructive sleep apnea, mixed apnea shows absence of respiratory efforts in the first segment of the apnea.

Primary hypersomnia. Periodic limb movements show intermittent leg electromyogram activity accompanied by electroencephalogram arousals.