Klein-Levin syndrome

Overview
Kleine-Levin Syndrome, or KLS, is an extremely rare disorder characterized by the need for excessive amounts of sleep (hypersomnia), (e.g. up to 20 hours a day); excessive food intake (compulsive hyperphagia); and an abnormally uninhibited sexual drive. Adolescent males and females are the predominant victims of the disorder. There are only about 500 known sufferers of this condition in the world. However, because KLS is sporadic in its appearances, some doctors believe that this number is, in reality, much higher and the reason that it is not publicly noted is because this disease is extremely difficult to diagnose.

Presentation
Individual sufferers may often become irritable, lethargic, and/or apathetic. KLS patients may appear disoriented and report hallucinations. Symptoms are cyclical; with days to weeks (even up to months) of suffering interspersed by weeks or months (even up to years) symptom-free. Although resolution of the disorder may occur for some in later life, this is not universal.

Causes
While some researchers speculate that there may be a hereditary predisposition, others believe the condition may be the result of an autoimmune disorder. Both proposals need not be mutually exclusive with the result being a malfunction of the portion of the brain that helps to regulate functions such as sleep, appetite, and body temperature (hypothalamus). Recent studies also suggest that there may be a link to a deficiency of dopamine transporter density in the lower striatum.

Demographics
A 2008 study of 108 KLS patients found that the majority of cases were present in adolescent males, with a mean sex ratio of 3:1. The average age of onset was 15.7 years, with 81.7% experiencing their first episode between 10 and 20 years of age. Age ranged from 6 to 59 years when patients experienced their first episode. Females tended to be slightly older than males at first onset, even though they tended to experience puberty earlier. In the US population, KLS presents in Caucasians with three times the expected frequency, and with six times the expected frequency in those of Jewish heritage.

First Onset
About 90% of KLS patients associate an event with their first KLS episode. This event is most often a type of infection or cold, but may also be associated with stress, sleep deprivation, alcohol or marijuana use, physical exertion, traveling, or head trauma. This causes some to think that there may be some immunological link, but so far there is no clear proof of this. Only a quarter of KLS patients report events triggering subsequent episodes.

Symptoms
Hypersomnia is a primary symptom of KLS, and is present in all subjects. Subjects are often treated initially for a sleeping disorder. During a KLS episode, subjects often spend 18 hours a day asleep. Another defining symptom of KLS is an altered mental state during the episode. Subjects are hard to arouse from this sleep, and are irritable or aggressive when prevented from sleeping. Subjects also frequently show cognitive impairment, and can show confusion, amnesia for the event, hallucinations, delusions, or experience a dream-like state. About 75% of KLS patients experience changes in eating behavior during episodes, with the majority of these exhibiting megaphagia. Reports describe patients who will eat anything placed in front of them with very little discrimination. Reports also describe consumption of excessive amounts of food, but KLS is distinct from bulimia since no purging occurs after binging. Almost half of KLS patients also experience some sort of hypersexual behavior during the event, including promiscuity, excessive masturbation, inappropriate sexual advances, and other risqué, atypical behavior. Hypersexual behavior is more common in males than females, and is associated with a much longer disease course. Other unusual compulsions reported during the event are also not uncommon.

Genetics
There are no known genetic markers for KLS. There is no protein or antibody markers available for a positive diagnosis of KLS. Some researchers have explored hereditable immunity traits that may predispose individuals for KLS. One such trial focused on a family of twelve in which the father and five children were all affected by KLS. Human leukocyte antigen (HLA) typing revealed the father was identical to two of his children that were both affected by KLS. Furthermore, all of his affected children shared one-half of his HLA antigens.

Diagnosis
Diagnosis of KLS is very difficult since there are no symptoms that allow for a positive diagnosis. KLS is instead a diagnosis of exclusion, where a doctor must first eliminate a long list of other conditions that could mimic the symptoms. Because hypersomnia is the primary symptom, many patients are initially treated for a sleeping disorder. Potential KLS patients are often referred to an endocrinologist early on to check for metabolic problems including diabetes and hypothyroidism. Several neurological disorders can also mimic KLS symptoms, but those can be positively diagnosed by MRI—including ones caused by a lesion, tumor, or inflammation. Multiple sclerosis also has neurological components that can mimic the symptom profile for KLS, but this can also be detected by an MRI.

Once the origin of the problem is confirmed to be psychiatric, several more common conditions must first be considered. The depressive periods of bipolar disorder are easily mistaken for KLS episodes, but bipolar disorder is characterized by the manifestation of a manic episode. Successful diagnosis often relies on interviews with not only the patient, but their friends and family—since many bipolar patients would not characterize their own behavior as mania. Hypersexual behavior is also a difficult symptom to diagnose accurately, since this is a taboo subject to approach during an interview. Because of cultural attitudes, this information is often not communicated to the physician—and ends up being left out of the diagnosis. Narcolepsy and Klüver-Bucy syndrome also produce very similar symptom profiles, but typically have different EEG readings from a KLS patient. Before a final diagnosis can be made, all other possibilities must be carefully excluded, and the cluster of symptoms must fit with those commonly observed in KLS patients.

Treatment
There is no definitive treatment for Kleine-Levin syndrome. Stimulants, including amphetamines, methylphenidate, imipramine and modafinil, administered orally, are used to treat sleepiness. Because of similarities between Kleine-Levin syndrome and certain mood disorders, lithium and carbamazepine may be prescribed. Responses to treatment have often been limited. This disorder needs to be differentiated from cyclic re-occurrence of sleepiness during the premenstrual period in teenage girls that may be controlled with hormonal contraception. There is no treatment for Kleine-Levin syndrome as of yet however, stimulants are often used to keep the patient awake. This does not alter their mental state.

Frequency and Duration of Episodes
A 2005 study of 168 KLS patients reported that in subjects where the disease terminates, the average age is 23 and the median duration is 4 years. They reported no correlation between age at onset and disease duration. Patients experienced an average of 12 episodes lasting an average of 12 days, although the range of symptoms reported varied from 2-130 episodes and lasted between 2.5 and 80 days. Subjects experienced an average duration of 6 months between episodes, but this ranged from .5 to 72 months. Subjects typically experienced less frequent and less intense attacks towards the end of the disease course, and the subject is considered cured if they do not experience an episode for 6 or more years.

Prognosis
Living with KLS can be a very serious affair. Many patients report depression during one or more episodes. While the major symptoms may seem innocent enough to some (copious amounts of sleeping, eating, and sexual behavior) the effects can be very debilitating. At very least, KLS makes it difficult to maintain a normal job—and in some cases criminal charges have resulted from unrestrained sexual behavior. Periodic binges associated with the episode can lead to weight gain, and KLS patients often exhibit an above-average BMI, but no mention of obesity is made in the literature. KLS patients also end up suffering from other’s psychosocial stigmas because they don’t understand some of the unusual activities resulting during an episode. Many patients report embarrassing episodes from early in their adolescence before KLS was considered a viable diagnosis.

Eponym
It is named for Willi Kleine and Max Levin.