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Kleine-Levin Syndrome: a Systematic Study of 108 Patients

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Kleine-Levin Syndrome: a Systematic Study of 108 Patients Kleine–Levin Syndrome: A Systematic Study of 108 Patients Isabelle Arnulf, MD, PhD,1,2 Ling Lin, MD, PhD,1 Nathan Gadoth, MD,3 Jennifer File, DO,1 Michel Lecendreux, MD,2 Patricia Franco, MD, PhD,2 Jamie Zeitzer, PhD,1 Betty Lo, PhD,1 Juliette H. Faraco, PhD,1 and Emmanuel Mignot, MD, PhD1 Objective: Kleine–Levin syndrome is a rare disorder characterized by relapsing-remitting episodes of hypersomnia, cognitive disturbances, and behavioral disturbances, such as hyperphagia and hypersexuality. Methods: We collected detailed clinical data and blood samples on 108 patients, 79 parent pairs, and 108 matched control subjects. We measured biological markers and typed human leukocyte antigen genes DR and DQ. Results: Novel predisposing factors were identified including increased birth and developmental problems (odds ratio, 6.5). Jewish heritage was overrepresented, and five multiplex families were identified. Human leukocyte antigen typing was unre- markable. Patients were 78% male (mean age at onset, 15.7 Ϯ 6.0 years), averaged 19 episodes of 13 days, and were incapac- itated 8 months over 14 years. The disease course was longer in men, in patients with hypersexuality, and when onset was after age 20. During episodes, all patients had hypersomnia, cognitive impairment, and derealization; 66% had megaphagia; 53% reported hypersexuality (principally men); and 53% reported a depressed mood (predominantly women). Patients were remark- ably similar to control subjects between episodes regarding sleep, mood, and eating attitude, but had increased body mass index. We found marginal efficacy for amantadine and mood stabilizers, but found no increased family history for neuropsychiatric disorders. Interpretation: The similarity of the clinical and demographic features across studies strongly suggests that Kleine–Levin syn- drome is a genuine disease entity. Familial clustering and increased prevalence in the Jewish population support a role for a major genetic susceptibility factor. Considering the inefficacy of available treatments, we propose that disease management should primarily be supportive and educational. Ann Neurol 2008;63:482–492 Kleine–Levin syndrome (KLS) was first described more is notable in most cases during episodes, without epi- than 80 years ago.1–3 The disorder is characterized by leptic activity. Diffuse brain hypoperfusion, mostly fo- recurrent episodes of hypersomnia associated with cog- cused on the thalamic and frontotemporal areas, has nitive and behavioral abnormalities, such as megapha- been reported.6 Viral and autoimmune causative fac- gia (eating increased amounts of food) and hypersexu- tors have been suggested, based on the frequent report ality. Episodes are separated by weeks or months of of flu-like symptoms at onset and a significant associ- normal sleep and behavior.4 KLS primarily affects ad- ation with DQB1*02.7 olescent boys and has an unpredictable course of recur- KLS poses diagnostic and therapeutic challenges. rence and remission that lasts for years and most often The identity of KLS as a disorder is often questioned, mysteriously disappears in young adults.5 and cases are frequently misdiagnosed. Therapies are An underlying hypothalamic pathology is suggested marginally helpful and have not been systematically by the critical role of this structure in regulating sleep, evaluated. Stimulants are partially effective on sleepi- appetite, and sexual behaviors; however, no consistent ness but not on cognitive and behavioral abnormalities. hypothalamic abnormalities have been identified. Lithium showed positive effects on preventing or de- Structural brain imaging and evaluation of the cerebro- laying recurrences in a few reported cases.8 spinal fluid and serological inflammatory markers are Published work on KLS primarily consists of single- unremarkable. Electroencephalographic (EEG) slowing case reports and retrospective, uncontrolled series that From the 1Stanford Center for Narcolepsy and Howard Hughes This article includes supplementary materials available via the Inter- Medical Institute, Stanford University, Palo Alto, CA; 2National net at http://www.interscience.wiley.com/jpages/0364-5134/supp- Center for Rare Diseases-Narcolepsy, Hypersomnia and Kleine- mat Levin Syndrome and Assistance Publique-Hoˆpitaux de Paris, Paris, France; and 3Department of Neurology, Meier General Hospital, Published online in Wiley InterScience (www.interscience.wiley.com). Kfar Saba and the Sackler Faculty of Medicine, Tel Aviv University, DOI: 10.1002/ana.21333 Tel Aviv, Israel. Address correspondence to Dr Arnulf, Fe´de´ration des Pathologies du Received Jul 18, 2007, and in revised form Oct 24. Accepted for Sommeil, Hoˆpital Pitie´-Salpeˆtrie`re, 47-83 Boulevard de l’Hoˆpital, publication Dec 10, 2007. 75651 Paris Cedex 13, France. E-mail: [email protected] 482 © 2008 American Neurological Association Published by Wiley-Liss, Inc., through Wiley Subscription Services contain few patients.5,7 In a recent review of these patients had been under the care of one of us, and 51 pro- studies,9 we found the disorder to be less benign than vided medical records. We did not find face-to-face interview generally recognized, with a median disease duration of of patients more accurate than phone interview because the 8 years. We also observed that megaphagia was over- description of KLS was always retrospective. No patient was emphasized. In this study, we sought to obtain a rep- self-diagnosed. resentative picture of the disorder through a cross- Based on the criteria above, differential diagnosis that could mimic KLS, mostly of psychiatric (eg, bipolar disorder, sectional, systematic evaluation of more than 100 new drugs, medications), metabolic (recurrent metabolic enceph- cases and comparison with matched control subjects. alopathies), or neurological nature (eg, a Klu¨ver–Bucy or par- tial complex seizures of neurological origin) were always con- Subjects and Methods sidered and excluded. Because KLS is a rare diagnosis, these Recruitment of Patients subjects always had been explored intensively for other po- tential causes, including often multiple EEGs and magnetic One hundred twenty-one potential subjects were aggressively resonance images, and blood, endocrine, and metabolic identified using four different routes of ascertainment. First workup; this information was available to us. and foremost, we took advantage of a list of contacts avail- Thirteen patients were excluded based on death (1), in- able through the Kleine–Levin Syndrome Foundation (n ϭ complete data (6), or incorrect diagnosis (menstrual recur- 81). Second, we personally contacted clinicians who have rent hypersomnia [1], sleep-related eating disorder [1], de- published or have reported one or several KLS cases in the layed phase sleep syndrome [2], acute disseminated literature, or large centers that are likely to treat such spe- encephalomyelitis [1], and narcolepsy [1]). Completed ques- cialized and difficult patients. These include sleep centers tionnaires and blood samples were provided by 79 parent from Barcelona, Madrid, Milano, Innsbruck, Munich, Mon- couples of 81 patients. We also recruited 108 control sub- tre´al, Toronto, all French and Israeli sleep centers (via na- jects matched for age, sex, ethnicity, demographics, and tional sleep associations), Turkey, India, and Iran. Third, we country of origin (local friends for non-US patients). A series attempted to identify patients with KLS worldwide by ad- of 377 US subjects with unexplained central nervous system– dressing letters to all members of the American Academy of mediated excessive daytime sleepiness (sleep apnea excluded Sleep Medicine, including the international members (3,534 before referral) enrolled at Stanford between 2002 and 2006 diplomats). These 2 methods led to recruiting 31 additional was also used for comparison. The Stanford Human Subjects patients. Finally, we created a Stanford University KLS Web Committee review board approved the study. All participants site and responded to patients and family members who con- gave informed consent. tacted us through this site (nine patients were identified us- ing this source). Questionnaire Because there was no existing questionnaire on KLS, we de- Confirmation of the Diagnosis in Identified Subjects veloped a specific questionnaire, using the International A semistandardized medical telephone interview focusing on Classification of Sleep Disorders criteria for KLS, our per- medical history, symptoms, and evolution of KLS and con- sonal experience with KLS patients, and all the symptoms comitant disease was conducted in all families. These inter- found in our previous review of 186 KLS published cases.4 views were all conducted by a medical professional (MD or The prefinal version was submitted to external sleep experts DO, with involvement of a psychiatrist and a neurologist) (Yves Dauvilliers, Nathan Gadoth, Richard P. Allen), to the from February 2005 to June 2005. Of 121 patients con- KLS Foundation, and to a panel of KLS patients, leading to tacted, 108 met three inclusion criteria. The first criterion minor corrections. The final questionnaire included 280 was International Classification of Sleep Disorders II revised questions on onset, course, sleep, cognition, psychiatric criteria for KLS both by phone interview and by question- symptoms, eating attitude, sexual behavior, response to ther- naire: (1) episodes of excessive sleepiness lasting more than 2 apies, personal and family history (see supplementary
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