Excerpt from Primary Hypersomnia

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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.

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