Information on the following diseases can be found in the Related Disorders section of this report:

• Narcolepsy
• Depression
• .

Kleine-Levin syndrome is an extremely rare disorder characterized by the need for excessive amounts of sleep (hypersomnolence), excessive eating (compulsive hyperphagia), and behavioral abnormalities.

Onset of symptoms associated with this disorder is extremely rapid. Such symptoms may persist for days to weeks. Affected individuals may have approximately two to 12 episodes per year. In most cases, no symptoms of Kleine-Levin syndrome are exhibited between episodes. Episodes become less frequent with age and may eventually disappear (spontaneous remission). However, episodes have been reported to occur in individuals well into the fourth and fifth decades of life.

Individuals with Kleine-Levin syndrome may sleep for 18 to 20 hours per day and wake only to eat, urinate, and defecate. Although affected individuals can be awakened, they may be irritable or listless (lethargic) and/or lack emotion (apathy). They may also appear confused (disoriented), or have difficulties speaking such as slurred speech. In some cases, affected individuals may experience hallucinations or sense of distorted reality in which they feel detached from their surroundings or have disconnected thinking.

In addition, individuals with Kleine-Levin syndrome may have an uncontrollable urge to eat excessively (compulsive hyperphagia). Affected individuals generally do not complain of being excessively hungry but will typically consume available food, regardless of the food's condition, quality, or appeal to their preferences. Most individuals with Kleine-Levin syndrome may experience weight gain associated with episodes of compulsive hyperphagia.

In some cases, individuals with Kleine-Levin syndrome also exhibit an abnormal sexual drive. They may be sexually uninhibited or have an abnormally increased sex drive (hypersexuality). In addition, in some cases, episodes of Kleine-Levin syndrome may be characterized by other behavioral abnormalities such as memory problems, inattentiveness, absentmindedness, and/or difficulties with concentration. Some affected individuals may show signs of depression, aggression, and/or anxiety. (For more information on Depression, see the Related Disorders section of this report.)

The exact cause of Kleine-Levin syndrome is unknown. It is speculated that symptoms may develop due to malfunction or damage to the portion of the brain that helps to regulate functions such as sleep, appetite, and body temperature (hypothalamus). As with most diseases with no known cause, some researchers have speculated that, in some cases, symptoms may develop as a result of a head injury or an infectious disease affecting the hypothalamus; however, this is unproven.

In some cases, the development of Kleine-Levin syndrome follows a flu-like illness indicating an infection leading some researchers to speculate that an underlying autoimmune process may play a role in the development of the disorder. Autoimmune disorders are caused when the body's natural defenses against "foreign" or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. A Stanford University study in 2005 determined that 72 percent of the cases studied were preceded by symptoms of infection.

In extremely rare cases, more than one family member has been affected (familial Kleine-Levin syndrome). These rare cases and the possible role of infection in the development of Kleine-Levin syndrome suggest that genetic factors may cause some individuals to have a predisposition to developing the disorder.

Kleine-Levin syndrome is a rare sleep disorder that primarily affects adolescent males, usually around the age of 16 years. However, there have been cases involving females and older men. Males appear to be affected three times as often as females (M3:F1). On average, women had a longer disease course than men.

More than 500 cases have been reported in the medical literature. However, because cases of Kleine-Levin syndrome often go unrecognized, the disorder is under-diagnosed, making it difficult to determine its true frequency in the general population.

Symptoms associated with the disorder usually become apparent during adolescence. Individuals with Kleine-Levin syndrome may have episodes that last for a few days or up to several weeks. Episodes occur approximately two to 12 times per year. Most affected individuals exhibit no symptoms of Kleine-Levin syndrome between episodes. In some cases, symptoms subside with advancing age (spontaneous remission), most often by early adult life. However, in other cases, the disorder persists throughout adulthood.

Symptoms of the following disorders can be similar to those of Kleine-Levin syndrome. Comparisons may be useful for a differential diagnosis:

Narcolepsy is a sleep disorder characterized by abnormal sleepiness during the day, sudden extreme muscle weakness (cataplexy), hallucinations, paralysis while sleeping, and disrupted sleep during the night. Excessive daytime sleepiness is usually the first symptom of narcolepsy. People with narcolepsy may also experience lack of energy (lethargy), an irresistible urge to sleep ("sleep attack"), and/or an inability to resist sleep. The symptoms of narcolepsy generally begin between the ages of 10 to 20 years. The exact cause of narcolepsy is not known. (For more information on this disorder, choose "Narcolepsy" as your search term in the Rare Disease Database.)

Numerous disorders in addition to narcolepsy are involved with disturbed sleeping patterns. A partial list of these disorders includes cataplexy, sleep apnea, delayed sleep phase syndrome, excessive daytime sleepiness, and African sleeping sickness. A recently described disorder known as idiopathic hypersomnia is characterized by excessive sleepiness (hypersomnia) that occurs for unknown reasons (idiopathic).

The following disorder may be associated with Kleine-Levin syndrome as secondary a characteristic. It is not necessary for a differential diagnosis:

Depression is a common psychiatric disorder characterized by prolonged feelings of profound sadness, unhappiness, and discouragement. Affected individuals may be irritable, have difficulty concentrating, and/or experience confusion and/or hallucinations. Some affected individuals may also experience extremes in eating behaviors: they may refuse to eat or may eat enormous amounts of food. In addition, affected individuals may sleep excessively or may be unable to sleep (insomnia). Some researchers believe that depression may be caused by a variety of factors, including diet, family history, and the interaction of many genes (polygenic inheritance), possibly in combination with environmental factors (multifactorial inheritance). (For more information on this disorder, choose "Depression" as your search term in the Rare Disease Database.)
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Kleine-Levin syndrome may be suspected based upon a thorough clinical evaluation and a detailed patient history. Kleine-Levin syndrome may be confirmed based upon excessive sleep requirements (hypersomnolence); the desire to eat all available food (compulsive hyperphagia); and hypersexuality. Certain medical tests may be performed to rule out other conditions such as epilepsy, brain lesions, meningitis or encephalitis.

The treatment of Kleine-Levin syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, psychiatrists, psychologists, neurologists, and other health care professionals may need to systematically and comprehensively plan an affected adolescent's treatment.

Specific therapies for the treatment of Kleine-Levin syndrome are symptomatic and supportive. In some cases, stimulants may provide temporary relief from the need for excessive amounts of sleep. Amphetamines were most successful in reducing sleepiness in affected individuals, but had no effect on other associated symptoms (e.g., behavioral changes).

In some cases, individuals with Kleine-Levin syndrome have appeared to respond to treatment with phenytoin, an anticonvulsant drug used to treat epilepsy. In another case reported in the medical literature, an affected individual was treated with the combination of an antidepressant and the drug carbamazepine. More research is needed to determine the long-term safety and effectiveness of these drugs for the treatment of Kleine-Levin syndrome.

Lithium, a drug used to treat serious mood disorders (affective) disorders, has been effective in some cases. One report detailed five adolescents with Kleine-Levin syndrome who received treatment with lithium. Episodes of excessive sleep were shortened by treatment with lithium and no behavioral symptoms were present. All five adolescents had relapses while on lithium treatment. More research is necessary to determine the long-term safety and effectiveness of lithium as a treatment option for individuals with Kleine-Levin syndrome.

Researchers at the Stanford University Center for Narcolepsy will be conducting a study on Kleine-Levin syndrome. The study is designed to “measure the HLA group and possible other genetic factors predisposing to KLS in all (200 cases are planned) volunteers KLS patients, their parents (50 pairs of parents are planed), and compare it to the HLA group in age, sex and ethnic-matched controls (200 cases are planed). The study includes questionnaire and blood sampling.” For more information on this study, contact:

Dr. Isabelle Arnulf
Stanford Center for Narcolepsy
701B Welch Road
Palo Alto CA 94304
Email: arnulf@stanford.edu
Phone: (650) 724-8839
Fax (650) 725-4913
Homepage: http://med.stanford.edu/school/Psychiatry/narcolepsy/KLS.html

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov



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McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:148840; Last Update:11/5/94.

TEXTBOOKS
Glaze DG. Kleine-Levin Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:544.

Adams, RD, et al, eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill, Companies; 1997:569.

Kaplan HI & Sadock BJ, eds. Comprehensive Textbook of Psychiatry. 5th Ed.: Baltimore, MD: Williams & Wilkins; 1989:1117.

JOURNAL ARTICLES
Arnulf I, et al., Kleine-Levin syndrome: a systemic review of 186 cases in the literature. Brain. 2005;128:2763-76.

Poppe M, et al. The Kleine-Levin syndrome – effects of treatment with lithium. Neuropediatrics. 2003;34:113-9.

Dauvilliers Y, et al. Kleine-Levin syndrome: an autoimmune hypothesis based on clinical and genetic analyses. Neurology. 2002;59:1739-45.

Katz JD, Ropper AH. Familial Kleine-Levin syndrome: two siblings with unusually long hypersomnic spells. Arch Neurol. 2002;59:1959-61.

Muratori F, et al. Efficacy of lithium treatment in Kleine-Levin syndrome. Eur Psychiatry. 2002;17:232-33.

Billiard M, Dauvilliers Y. Idiopathic hypersomnia. Sleep Med Rev. 2001;5:349-358.

Minvielle S, et al. Klein-Levin syndrome: a neurological disease with psychiatric symptoms. Encephale. 2000;26:71-74.

Papacostas SS, et al. The Kleine-Levin syndrome. Report of a case and review of the literature. Eur Psychiatry. 2000;15:231-35.

Kesler A, et al. Kleine Levin syndrome (KLS) in young females. Sleep. 2000;15:563-37.

Fontenelle L, et al. Neuropsychological sequelae in Kleine-Levin syndrome: case report. Arq Neurosiquiatr. 2000;58:531-34.

Masi G, et al. The Kleine-Levin syndrome as a neuropsychiatric disorder: a case report. Psychiatry. 2000;63:93-100.

Pike M, et al. Kleine-Levin syndrome: a case of diagnostic confusion. Arch Disease Child. 1994;71:355-57.

Wurthmann C, et al. Kleine-Levin syndrome. Fortschr Neurol Psychiatr. 1991;59:190-94.

Chiu HF, et al. Kleine-Levin syndrome 15 years later. Aust N Z J Psychiatry. 1989;23:425-27.

Visscher F, et al. The Kleine-Levin syndrome. Tijdschr Kindergeneeskd. 1989;57:218-21.

Fukunishi I, et al. A female case with the Kleine-Levin syndrome and its physiopathologic aspects. Jpn J Psychiatry Neurol. 1989;43:45-49.

Smolik P, et al. Kleine-Levin syndrome ethiopathogenesis and treatment. Acta Univ Carol. 1988;128:5-94.

Will RG, et al. Kleine-Levin syndrome: report of two cases with onset of symptoms precipitated by head trauma. Br J Psychiatry. 1988;152:410-12.