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A Case Report of Kleine-Levin Syndrome in an Adolescent Girl

Received September 12, 2000; revised February 13, 2001; accepted February 23, 2001. From the Department of Psychiatry, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195. Address reprint requests to Dr. Franco.

Key Words: Kleine-Levin Syndrome

Kleine-Levin Syndrome (KLS) comprises a triad of symptoms, including hypersomnia, hyperphagia, and hypersexuality. Although Kleine knew of an earlier case of hypersomnia with possible hyperphagia, the first two cases he definitely attributed to the disorder were reported in 1925.¹ His patients were adolescent boys who exhibited periodic hypersomnia, excessive food consumption, and confusion. Over a decade later, Max Levin described a similar adolescent male patient with pathological hunger and unusually long periods of sleep.² Additional reports confirmed a higher prevalence in boys.^3–5 KLS remains particularly rare in girls and is challenging to diagnose, as most patients have no prior physical, neurological, or psychiatric history.

Case Report

Ms. C., an 18-year-old white girl with no previous psychiatric and medical history, was evaluated for episodic hypersomnia. Her neurologic history began 4 months before this evaluation when she was hit on the head while playing in a high school varsity basketball game. She did not lose consciousness but requested to be removed from the game. That evening she attended a social event where she consumed vodka, her first-ever exposure to alcohol, and she later appeared confused and very sleepy. During the following 3-week period she experienced hypersomnia, sleeping for 18–20 hours at a time and awakening for only 2 hours each day. Rather than her usual pleasant demeanor, Ms. C.'s family described her as "stone-faced" and argumentative. After awakening, she craved large quantities of "junk food," which she avoided in the past. She did not verbalize hunger, yet her mother would have to take food away from her to get her to stop.

Ms. C. was seen by several neurologists who described a normal MRI and EEG during the initial 3 weeks of this behavior and who diagnosed her as having postconcussive syndrome. By the 4th week, Ms. C.'s symptoms subsided and her normal sleep/wake cycle and eating pattern returned, as well as her congenial attitude. Her teachers' comments indicated that her intellectual capabilities seemed fully intact, yet she was unusually anxious with her peers. Although she continued to improve over the next several weeks, Ms. C. required daily naps of 2–3 hours. Six weeks after her first hypersomnolent episode, Ms. C. went on an overseas school trip where she again consumed vodka but did not experience any of her previous symptoms.

By 3 months Ms. C. was notably improved but had decreased energy, a weight gain of 10 pounds, and three episodes of urinary incontinence. Her dress was more provocative, but she denied any sexual activity. Reintegrating as a senior in high school, she graduated as salutatorian of her class.

Immediately after graduation Ms. C. left on a vacation with friends, participating in recreational activities requiring great physical exertion and again drinking alcohol. Toward the end of her trip, Ms. C. exhibited unusual behavior: "cranky", lethargic, and "not acting like herself." Her friends attributed her "sleepiness" to vodka initially. On the trip home, she developed hypersomnolence, which persisted for the next week and led to her admission.

Ms. C. was distressed at being brought to the hospital by her parents. After arriving, she said she was depressed and would kill herself if she were not allowed to go home. It was at this point that we were asked to evaluate her. When admitted to the hospital, she was argumentative, irritable, and barely cooperative. She also exhibited flat affect, poor eye contact, and psychomotor retardation. Her speech was slow and her responses to questions were abbreviated. She denied any prior depression or suicidal ideation, and she did not exhibit hallucinations, paranoid thought, or delusions. She was sleepy but arousable, and she was again consuming large amounts of food. Her mother did note that Ms. C. had normal menstrual cycles and that both episodes had occurred during her menses.

The patient's family history is remarkable for increased frequency of sleep-related disorders among close family members. Most striking is the fact that a 15-year-old male cousin on her father's side of the family developed KLS at age 10, which had continued to the present. He had exhibited five discrete episodes, with symptoms similar to his cousin, including hypersomnia, hyperphagia, irritability, and neglect of relationships. These episodes lasted from 3 to 10 weeks. One paternal aunt had narcolepsy, another had severe hypothyroidism, and a paternal uncle had been diagnosed with chronic fatigue syndrome. Ms. C.'s maternal grandfather had what the family described as an "allergy" to alcohol, exhibiting bizarre behavior after just one drink but without hyperphagia or hypersomnia.

Laboratory assessments for thyroid stimulating hormone, melatonin, 24-hour urine for cortisol, fasting blood glucose, insulin level, follicular stimulating hormone, luteinizing hormone, estradiol, urinalysis, and basic metabolic panel were normal. However, one day earlier Ms. C. had a low blood glucose of 62 mg/dL after consuming large amounts of "junk food." Her neurological exam and lumbar puncture were normal; an EEG showed intermittent left frontal temporal lobe slowing, rhythmic, without epileptiform activity. A geneticist, who interviewed and examined her, believed she did not have a mitochondrial disorder, although her serum carnitine was low.

Ms. C. was discharged 1 week after admission without medication. Her symptoms gradually subsided by 2 weeks after their onset. At 1-month follow-up, Ms. C. was "acting like herself again." She had not experienced any further episodes. Although she exercised, she had not engaged in as much strenuous physical activity, had reduced her alcohol to an "occasional drink," and was looking forward to attending college in the fall.

Ms. C.'s differential diagnosis included possible seizure, alcohol intoxication, long QTC interval, depression, and KLS, with the preponderance of evidence supporting the latter.

Discussion

One theory suggests that KLS occurs after pugilistic encounters or other head injury, such as Ms. C. sustained during a basketball game.^4–7 The hypothalamus, susceptible to hemorrhage and infarction in head injury, may be responsible for inducing hypersomnolence and hyperphagia.⁶ Behavioral changes seen in KLS are similar to those patients with pituitary or hypothalamic tumors.

Hypothesizing hypothalamic involvement, Fernandez⁷ described two patients with consistently low adrenocorticotropic hormone and diminished cortisol responses to insulin-induced hypoglycemia. Malhotra, however, reported hormonal differences only during symptomatic periods.⁸ During this episode, all endocrine studies for Ms. C. were within normal limits. Repeating blood and 24-hour urine testing with future episodes is planned, as well as monitoring for low blood glucose. A blunted response to glucose load has been seen in another KLS patient who exhibited no other abnormal laboratory findings.⁹

Several case reports of female patients implicate a temporal relation with menstrual cycle in the onset of KLS episodes. In one report, the appearance of an adolescent girl's KLS symptoms coincided with menarche.¹⁰ Another patient experienced episodes that occurred 12–18 hours before the onset of menses and subsided 48 hours after the end of menses.¹¹ In one 48-year-old woman, attacks began and ended with menses.¹² Although Ms. C.'s mother was not able to recall the first day of Ms. C.'s recent menses, she was certain that her daughter's two episodes had started during her "period."

Patients with KLS may share a common HLA-DR1 and may have an absence of HLA-DR2, the classic narcoleptic-associated gene.²⁴ Currently Ms. C. has not undergone genetic testing, but her family is hoping to have genetic testing done. Physical exhaustion, similar to that experienced by Ms. C., has been shown to precede the onset of KLS in at least one other patient.¹³ It is possible that dehydration, whether a consequence of exercise or not, may be a trigger. In one 58-year-old woman, an acute episode of diarrhea with dehydration and physical exhaustion may have triggered KLS.¹⁴ Other cases have noted the onset of KLS after an alcohol binge as occurred with Ms. C., another possible precipitant of dehydration.¹⁵

Ms. C.'s case supports numerous theories proposed in the literature regarding the etiology of KLS, including a positive family history, head trauma, menses, alcohol consumption, and physical exhaustion, or a combination of which might amplify the symptoms. This case adds to the body of information on KLS in female patients, a group that historically has been less often afflicted or reported, and describes a confluence of events rather than one factor alone definitely triggering KLS.

Because there are very few cases of this disorder, it is difficult to collect sufficient amounts of data to devise a consistent method of treatment for patients with KLS. Additionally, KLS seems to subside by the time most patients reach age 30.

Patients desire to alleviate the symptoms of KLS, if at all possible, because of the crippling nature of the symptoms and the fact that episodes can stretch on for weeks or months at a time. Intravenous administration of methylphenidate, which is believed to increase the activity of the ascending reticular formation, has been used to limit the length of KLS episodes when administered to symptomatic patients.¹⁶ Intravenous Methedrine (10 mg) followed by oral dextroamphetamine (20 mg/day) also alleviated symptoms in one patient.¹⁷ Carbamazepine and lithium have been the traditional drugs of choice for suppression of KLS symptoms.^18–20 Lithium (400–900 mg/day, usually bid or at night) shifts melatonin cycles forward, thus modifying hypersomnolence.¹⁸ Chronic treatment with carbamazepine (400 mg/day) does not significantly modify nocturnal sleep; however, carbamazepine has, in the same cases, alleviated and prevented the recurrence of hyperphagia, daytime hypersomnia, and hypersexuality.^19–21 Although some researchers have shown carbamazepine to be an effective treatment for KLS, two reported patients did not respond at all to the drug but were treated successfully with lithium.³

Innovative therapies for KLS have recently been attempted, including a combination of melatonin (5 mg/day) and both lithium and carbamazepine, which augments the effect of lithium, to move circadian cycles forward more dramatically.¹³ Valproic acid (1,500 mg/day) and lithium (900 mg/day) together, followed by valproic acid alone, yielded favorable results in one adolescent boy with KLS.²² This same patient later elected to stop all pharmaceutical treatment for KLS and was treated with light therapy alone, again supporting a role for modulating circadian rhythm in this disorder.²³

Conclusion

KLS is a complex syndrome with a triad of hypersomnolence, hyperphagia, and hypersexuality. Head trauma, physical exhaustion, dehydration, alcohol consumption, and menstruation may play a role in the etiology of this syndrome and may coexist. There may be a hereditary basis for this syndrome as demonstrated by the family history of our case. Treatments include psychostimulants, mood stabilizers, and light therapy.

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				I. Arnulf, J. M. Zeitzer, J. File, N. Farber, and E. Mignot Kleine-Levin syndrome: a systematic review of 186 cases in the literature Brain, December 1, 2005; 128(12): 2763 - 2776. [Abstract] [Full Text] [PDF]

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