AUTHOR AND EDITOR INFORMATION

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• Authors and Editors
• Introduction
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• Differentials
• Workup
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• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

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. 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. The abrupt sleep attacks seen in classic narcolepsy are not present in this disorder.

According to the International Classification of Sleep Disorders (ICSD), idiopathic hypersomnia is defined as a disorder of presumed central nervous system (CNS) cause that is associated with excessive sleepiness consisting of prolonged sleep episodes of non–rapid eye movement (NREM) sleep. For the criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR) for primary hypersomnia, see DSM-IV-TR diagnostic criteria for 307.44 primary hypersomnia.

In comparison with narcolepsy, which is characterized by well-defined clinical, polysomnographic, and immunogenetic features, idiopathic hypersomnia is not well characterized. 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.

In the literature, 3 possible subgroups of idiopathic CNS hypersomnia have been suggested, as follows:

• 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 neurological 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, subsequently, they 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/mL³ or 30-50 X 10-6/L 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

Some patients have recurrent episodes of hypersomnia, which often is associated with compulsive overeating and hypersexuality. This presentation is termed Kleine-Levin syndrome, or KLS. The periods of hypersomnia occur for days to weeks at a time but 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.

Kleine-Levin syndrome is a rare disorder with symptoms that include periodic hypersomnia, cognitive and behavioral disturbances. Mostly men (68%) are affected. The median age of onset is 15 years (range, 4-82 y; 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. KLS may be precipitated by infections (38.2%), head trauma (9%), or alcohol consumption (5.4%). Characteristic symptoms include hypersomnia (100%), cognitive changes (96%, including a specific feeling of derealization), eating disturbances (80%), hypersexuality (43%), compulsions (29%), and depressed mood (48%). Somnolence decreased with stimulants (mainly amphetamines), while neuroleptics and antidepressants are of poor benefit. Lithium rather than carbamazepine or other antiepileptics had a higher success rate for stopping relapses. In secondary KLS, patients were older and had more frequent and longer episodes, but they hadclinical symptoms and treatment responses similar to those of primary cases.³

Pathophysiology

A definite mechanism of primary hypersomnia is not known. In experimental animal studies, destruction of the nonadrenergic neurons of the rostral third of the locus ceruleus complex has produced hypersomnia. Additionally, injury to the adrenergic neurons at the bundle of isthmus also has led to hypersomnia associated with a proportional increase of both NREM and REM sleep. These experiments have produced a state resembling idiopathic or primary hypersomnia. Evidence suggests that malfunction of the neurotransmitter dopamine occurs in narcolepsy, and a similar malfunction of the norepinephrine system may occur in idiopathic hypersomnia. A genetic basis for idiopathic hypersomnia is suggested, but the mode of inheritance has not been determined.

Hypocretin-1 (hcrt-1) and hypocretin-2 (hcrt-2) (also called orexin-A and orexin-B) are newly discovered neuropeptides processed from a common precursor and are involved in narcolepsy. Hypocretin-containing cells are located exclusively in the lateral hypothalamus, with widespread projections within the central nervous system. The role of the hypocretin system in other disorders causing excessive daytime sleepiness is more uncertain. Recently, very low cerebrospinal fluid concentrations of hypocretin-1 and hypocretin-2 in HLA DQB1*0602 were found in primary hypersomnia. Furthermore, a generalized defect in hcrt-2 transmission may be present in this disorder.

Frequency

United States

The prevalence of primary hypersomnia in the general population is not known. Excessive daytime sleepiness without a definite cause may be found in 0.5-5% of persons. Primary hypersomnia is diagnosed in 5-10% of all patients referred to the sleep laboratory for evaluation of excessive daytime sleepiness. From various studies, a ratio of the rate of idiopathic hypersomnia to narcolepsy is reported as 28.7:76.9%.

Mortality/Morbidity

The course of primary hypersomnia is chronic, with persistent symptoms of excessive daytime sleepiness occurring without resolution. This daytime sleepiness can lead to depression. Kleine-Levin syndrome begins during adolescence, and the disease process may continue for years, with spontaneous resolution during adult life.

Sex

Kleine-Levin syndrome affects males approximately 3 times more often than females.

Age

As with narcolepsy and Klein-Levin syndrome, onset of this condition is most common during adolescence and rare in people older than 30 years.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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History

• The most typical referral is for the polysymptomatic form of idiopathic hypersomnia and is characterized by the following:
• • Excessive daytime sleepiness leading to prolonged naps that are not refreshing
  • Nocturnal sleep of long duration (as much as 12 h or more)
  • Sleep drunkenness

• 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. Episodes of automatic behavior also are present.
• 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 develop automatic behavior, during which they act in a semicontrolled fashion.
• 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

Upon physical examination, no particular features suggest a diagnosis of primary hypersomnia; however, physical examination findings may help exclude the alternate diagnosis of obstructive sleep apnea. Features that may suggest obstructive sleep apnea are central obesity, micrognathia or retrognathia, macroglossia, crowded oropharynx, nasal obstruction, and tonsillar enlargement.

• Upon physical examination, exclude a specific neurological disorder. An underlying rheumatological disease, such as active rheumatoid arthritis or osteoarthritis, may cause daytime hyperoxia because of poor nighttime sleep due to pain.
• Primary depression may present as hypersomnia, which may be excluded by performing a careful psychiatric evaluation.
• Patients with primary hypersomnia are at increased risk of developing a major depressive disorder (see Depression). Patients should receive a careful mental status and psychiatric evaluation for depression. Therefore, in the psychiatric evaluation, determining if any dynamic-family, work, or interpersonal issues, which may cause or contribute to the depression, is important. Clinical features of depressive disorders vary according to the severity of the illness, as follows:
• • Mild depression
    • In mild depression, a loss of interest or pleasure may be present to some degree. Social withdrawal or neglect of pleasurable activities can be present. Appetite usually is reduced, and individuals may have to force themselves to eat. These individuals also may develop a sense of worthlessness or guilt. During depressive episodes, many individuals find it hard to think, concentrate, or make decisions.

    • Patients typically complain of low mood, lack of energy and enjoyment, and poor sleep. Patients often demonstrate anxiety, phobias, and obsessive symptoms. Sleep disturbances such as difficulty in sleep initiation and sleep maintenance are common. The patient's mood may vary during the day, but the biological features occur infrequently.
  • Moderate-to-severe depression
    • In contrast, the clinical features of moderate-to-severe depression not only are more intense, but additional symptoms may be present.

    • Regarding appearance, patients who are depressed may have psychomotor changes including agitation, inability to sit still, retardation, slow speech, and slow thinking. Decreased energy, tiredness, and fatigue may occur. The patient also may appear restless and unable to relax.

    • Regarding mood, patients appear sad and depressed. The mood is described as down or depressed, which may be observed from a person's facial expressions and demeanor. Anxiety and irritability are associated features. Increased irritability and exaggerated sense of frustration over minor matters may be reported.

    • Lack of interest and enjoyment occur quite frequently, and patients stop pursuing previously enjoyed activities and loose pleasure from everyday living. Reduced energy may lead to lethargy, insufficient efforts on the patient's part, and leaving everyday tasks unfinished. Patients complain of poor concentration and poor memory. However, with effort, recall and retention usually are normal. Physical complaints also are common in patients with depressive disorders. Either new physical symptoms appear or preexisting physical disorders become more symptomatic.

    • Depressive thinking manifests as patients being pessimistic in their thinking and often having guilty thoughts. These thoughts concern both the present and the future. Patients expect the worst and foresee failure in their work, finances, and lives. These ideas of hopelessness may progress to suicide in many cases. Patients also may be concerned with their past and develop unreasonable guilt and self-blame.

    • Biological symptoms are present more commonly in severe depression. Several types of sleep disturbance may be present, and early morning awakening is quite characteristic. Patients are unable to fall asleep again. They also may develop symptoms of delay in falling asleep and waking up through the night. The other biological symptoms are loss of appetite, loss of weight, constipation, and loss of libido.

    • Other psychiatric symptoms that may develop in many patients with depressive disorders include depersonalization, obsessional symptoms, phobias, and conversion symptoms such as fugue state or loss of function of an extremity. Patients frequently report memory difficulties and suboptimal intellectual performance. Eventually, these individuals may lose the ability to function socially or occupationally.

    • Regarding delusions, patients with very severe depression usually develop delusions that intensify the nondelusional thinking disorder present in moderate depression. These patients develop delusions of worthlessness, guilt, ill health, poverty, nihilism, and persecution.

    • Hallucinations may occur. In severe depressive disorders, perceptual auditory disturbances may be present. Visual hallucinations are uncommon. Suicidal ideas may intensify, and, rarely, homicidal ideas may develop.

• DSM-IV-TR diagnostic criteria for 307.44 primary hypersomnia
• • The predominant complaint is excessive sleepiness for at least 1 month (or less if recurrent) as evidenced by either prolonged sleep episodes or daytime sleep episodes that occur almost daily.
  • The excessive sleepiness causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • The excessive sleepiness is not better accounted for by insomnia and does not occur exclusively during the course of another sleep disorder (eg, narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, parasomnias) and cannot be accounted for by an inadequate amount of sleep.
  • The disturbance does not occur exclusively during the course of another mental disorder.
  • The disturbance is not due to the direct physiological effects of a substance (eg, drug of abuse, medication) or a general medical condition.
  • For a diagnosis of recurrent primary hypersomnia, periods of excessive sleepiness last at least 3 days and occur several times a year for at least 2 years.

Causes

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.

DIFFERENTIALS

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Other Problems to be Considered

Major depressive disorder

Before a diagnosis of primary hypersomnia is considered, differentiate the following entities:

Narcolepsy: Excessive daytime sleepiness, a positive history of cataplexy, and the presence of 2 or more sleep-onset REM periods should allow differentiation of narcolepsy from idiopathic hypersomnia. In the absence of cataplexy, the disorder may be difficult to differentiate. In these patients, a positive diagnosis of narcolepsy requires the presence of 2 or more sleep-onset REM periods on the Multiple Sleep Latency Test (MSLT) and association with the human leukocyte antigen (HLA)-DR15 and HLA-DQ6 haplotype.

Chronic insufficient sleep: People generally have varying sleep requirements. An average sleep duration of less than 7 hours may suggest chronic insufficient sleep. These patients should be instructed to document their sleep duration in sleep diaries. Often, an improvement in daytime symptoms is noted following increase in sleep duration.

Hypersomnia secondary to general medical conditions: General medical conditions such as brain tumor or morbid obesity may cause excessive sleepiness. Excessive daytime hypersomnia also may occur from frequent sleep disruption, chronic pain, or repeated awakenings because of an underlying medical disorder. Use of medications and drugs of abuse or withdrawal from these also may lead to hypersomnia.

Neurological disorders: Imaging studies of the brain may identify daytime hypersomnolence seen in communicating hydrocephalus of unknown etiology. Excessive daytime sleepiness may be the first symptom of progressive hydrocephalus in the absence of other features of hydrocephalus.

Upper airway resistance syndrome: This syndrome is associated with excessive daytime sleepiness and heavy snoring causing frequent arousals during nocturnal sleep. Obesity is uncommon; patients may have anatomic abnormalities of the upper airway such as a high, narrow, arched palate; malocclusion of the mouth; or retrognathia. Polysomnographic recording shows short alpha-electroencephalogram arousals lasting 3-5 seconds. Monitoring esophageal pressure or quantifying airflow using a pneumotachometer is required to confirm the presence of this syndrome. The use of nasal continuous positive airway pressure as a therapeutic test also can help confirm the diagnosis. This syndrome must be excluded before idiopathic hypersomnia is considered as a diagnosis.

Psychiatric disorders: Hypersomnia associated with dysthymia and related mood disorders is observed frequently. The presentation usually is later in life. A low-grade chronic depression and inability to cope with stressful situations are observed. MSLT findings do not demonstrate short sleep latency. Persistent or relapsing fatigue that does not resolve with bedrest characterizes chronic fatigue syndrome. Polysomnographic recording shows reduced sleep efficiency and alpha intrusion into sleep on electroencephalogram (EEG).

Posttraumatic hypersomnia: Posttraumatic hypersomnia may mimic idiopathic hyposomnia. Symptoms usually develop 6-18 months after head trauma.

Circadian rhythm sleep disorders: Delayed sleep phase syndrome is a diagnostic consideration in some patients whose main complaints are extreme difficulty awakening at a desired time and excessive morning sleepiness. These patients do not have excessive daytime sleepiness in the later half of the day and are not able to fall asleep until late at night.

WORKUP

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Lab Studies

• Elimination of other causes of excessive daytime somnolence helps diagnose primary hypersomnia. Patients should receive a complete blood cell count, screening biochemistry tests, and thyroid-stimulating hormone tests to help exclude common physical disorders that may present with complaints of excessive tiredness, which often is expressed as excessive sleepiness by patients. Other laboratory tests are not useful in the workup of primary hypersomnia, except polysomnography.

Other Tests

• Polysomnography and MSLT
• • Complete in-laboratory polysomnographic studies performed by qualified technicians are essential to exclude other sleep disorders, particularly sleep breathing disorder, periodic limb movement disorder, and narcolepsy. Findings that may be observed on nocturnal polysomnographic study in primary insomnia include a short sleep latency, absence of arousals or awakenings, normal distribution of REM and NREM sleep, and prolonged sleep duration.
  • The MSLT is performed to evaluate the presence of pathological sleepiness. These individuals are studied during 5 daytime naps taken 2 hours apart. According to 2 studies, the mean MSLT score in primary hypersomnia is slightly higher than the score in narcolepsy. Mean MSLT 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 MSLT.

• In recurrent primary hypersomnia (ie, Kleine-Levin syndrome), if the EEG study is performed during hypersomnia, an outburst of theta activity may be seen. The polysomnographic study shows prolonged sleep duration and pathological sleepiness during daytime nap studies.

TREATMENT

Section 6 of 11  

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Medical Care

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

• Behavioral approaches and sleep hygiene techniques are recommended, although they have little overall positive impact on this disease.
• 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.
• • The only medications that have brought partial and often intermittent relief are the stimulant drugs.
  • Methylphenidate, mazindol (withdrawn from the US market in 2001), and dextroamphetamine are the most commonly prescribed medications.
  • Recently, a new compound, modafinil was shown to produce good results in patients with idiopathic hypersomnia. Its mechanism of action remains unclear.
  • 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.

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

During automatic behavior episodes, these patients may endanger themselves through risk of injury. Use caution in activities where hypersomnolence may be hazardous.

MEDICATION

Section 7 of 11  

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

Modafinil, a wake-promoting agent, is approved for treatment of excessive sleepiness (ES) associated with narcolepsy, obstructive sleep apnea-hypopnea syndrome (OSAHS), and shift-work sleep disorder (SWSD). The studies have shown significant benefits on various objective measures and subjective estimates of ES. The clinical efficacy of modafinil, combined with improved safety over CNS stimulants, has made it the most prescribed medication for the treatment of ES associated with narcolepsy. Unlike many other medications used for ES, 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.

Drug Category: Central nervous system stimulants

CNS stimulating effects and are effective by keeping patient alert during the daytime.

FOLLOW-UP

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• Follow-up
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Prognosis

• Idiopathic hypersomnia is a lifelong disorder with no tendency to remit spontaneously.
• Consequences of this disease are mostly social and professional in nature.

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 function much better with this incurable disease.
• For excellent patient education resources, visit eMedicine's Sleep Disorders Center. Also, see eMedicine's patient education articles Disorders That Disrupt Sleep (Parasomnias) and Narcolepsy.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Distinguish primary hypersomnia from sleep-related breathing disorders, particularly upper airway resistance syndrome.
• During automatic behavior episodes, these patients may endanger themselves through risk of injury.
• Patients develop tolerance to their medications; exercise caution in prescribing medications.

Special Concerns

• The ICSD describes primary hypersomnia as idiopathic hypersomnia. Recurrent hypersomnia is classified separately to describe the recurrent form of primary hypersomnia according to the DSM-IV.
• Kleine-Levine syndrome (See Background.)

MULTIMEDIA

Section 10 of 11  

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Media file 1:  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.
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Media file 2:  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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Media file 3:  Primary hypersomnia. Periodic limb movements show intermittent leg electromyogram activity accompanied by electroencephalogram arousals.
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Media type:  Graph

REFERENCES

Section 11 of 11

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Article Last Updated: Jun 29, 2007