November 10, 2015; 85 (19) 

Lithium therapy in Kleine-Levin syndrome. An open-label, controlled study in 130 patients.

Smaranda Leu-Semenescu, Thibault Le Corvec, Elisabeth Groos, Sophie Lavault, Jean-Louis Golmard, Isabelle Arnulf Abstract: Objective: To compare the benefits and risks of lithium therapy vs abstention/other treatments in Kleine-Levin syndrome (KLS). Methods: In a KLS cohort followed in a single center, 130 patients regularly took lithium carbonate (median dose 1,000 mg/day; n = 71; 40 children), valproate (n = 5), contraceptive pill (n = 5), or no treatment (n = 49). The disease characteristics (frequency, mean, and longest durations of episodes, time incapacitated per year) were compared before and after follow-up in the lithium vs abstention groups. Results: The time between KLS onset and therapeutic onset was 69 ± 92 months. The patients were then followed up for a mean of 21.5 ± 17.8 months. Before treatment, the 71 patients treated with lithium tended to have a higher frequency of episodes per year (3.8 ± 2.9 vs 2.9 ± 2.6) and had a longer time spent incapacitated (57 ± 51 vs 37 ± 35 days) than the untreated patients. The mean (−8 ± 20 vs 2 ± 13 days) and longest (−18 ± 35 vs −5 ± 13) episode duration, the time spent incapacitated (−37 ± 65 days vs −10 ± 38), as well as the frequency of episodes per year (−2.6 ± 2.9 vs 1.3 ± 2.78) decreased significantly more in the treated than in the untreated patients. Side effects (reported by 50% of the patients) were mild and classical with lithium (tremor, increased drinking, diarrhea, and subclinical hypothyroidism).

July-September 2015, Indian J Psychol Med 2015;37:352-4. Successful Use of Valproate in Kleine-Levin Syndrome: A Case Report and Review of Cases Reported from India. Naresh Nebhinani, Ajit Avasthi, Manish Modi Abstract: Kleine-Levin syndrome (KLS) is characterized by recurrent episodes of hypersomnia and other symptoms and it is a really challenging for the physician, since its causes are not yet clear, and available treatment options are not having adequate support. Here, we are reporting a case with successful use of valproate in KLS and also reviewing the cases reported from India.

June 11, 2014 Preliminary results on CSF biomarkers for hypothalamic dysfunction in Kleine–Levin syndrome. Régis Lopez,  Lucie Barateau, Sofiene Chenini, Yves Dauvilliers Abstract: Objective: To measure CSF biomarkers of hypothalamic dysfunction in patients with typical Kleine– Levin syndrome (KLS) during symptomatic and asymptomatic periods. Patients/methods: Two patients with typical KLS were admitted during symptomatic and asymptomatic periods to a research Sleep Disorders Center. Cerebrospinalfluid (CSF) hypocretin-1, histamine (HA), and its major metabolite tele-methylhistamine (t-MHA) levels were measured in two KLS patients in and out of episode. Results: CSF biomarkers of hypothalamic dysfunction measured in two KLS patients in and out of episode revealed low hypocretin levels (within the narcolepsy–cataplexy range) during a hypersomnia episode in the more severe patient, and a 42% decrease (although within normal range) in the second patient. CSF HA and t-MHA measurements in and out of episode revealed a two-fold in-episode decrease in HA in the more severe patient, with no significant change for the second patient, nor for t-MHA levels. Conclusion: We reported reversible changes in CSF hypothalamic biomarkers in a typical patient with KLS that reinforces the hypothesis that in some patients KLS episodes may be caused by recurrent functional alterations of the hypothalamus.

Brain 2014: 137; 2077–2087 Feeling unreal: a functional imaging study in patients with Kleine-Levin syndrome. Aurelie Kas, Sophie Lavault, Marie-Odile Habert, Isabelle Arnulf Abstract: Kleine-Levin syndrome is characterized by relapsing-remitting episodes of severe hypersomnia, cognitive impairment, apathy, derealization and behavioural disturbances. Between episodes, patients have normal sleep, mood and behaviour. Functional imaging studies performed in small series of patients with Kleine-Levin syndrome with visual or semi-quantitative, uncontrolled analysis yielded equivocal brain changes. Using whole brain voxel-based group analysis, we compared brain perfusion scintigraphy during and between episodes in consecutive patients with Kleine-Levin syndrome versus healthy control subjects and correlated perfusion changes with disease severity and symptoms, focusing on less studied but disabling symptoms, such as apathy and derealization. During asymptomatic periods, 41 patients (mean age of 22.3 ± 8.1 years, 56.1% male) and 15 age- and sex-matched healthy control subjects underwent single-photon emission computed tomography scanning with technetium-99m ethyl cysteinate dimer. Eleven patients repeated the test during a symptomatic period. Compared with controls, patients during asymptomatic periods had persistent hypoperfusion in the hypothalamus, the thalamus (mainly the right posterior part), the caudate nucleus, and cortical associative areas, including the anterior cingulate, (Brodmann area 25), the orbito-frontal (Brodmann area 11) and the right superior temporal cortices (Brodmann area 22), extending to the insula (P < 0.001 in all area). Two additional hypoperfused areas emerged during symptomatic periods (P < 0.001), located in the right dorsomedial prefrontal cortex (Brodmann area 8) and the right parieto-temporal junction (Brodmann areas 22 and 39). These two areas were more affected between episodes, when the mean episode duration was longer (r = -0.53; P < 0.001). The score for the Depersonalization/Derealization Inventory during symptomatic periods strongly correlated with the hypoperfusion of the right (r = -0.74, P < 0.001) and left (r = -0.59, P < 0.005) parieto-temporal junctions. No hyperperfusion was found. Because the parieto-temporal junction (including the angular gyrus) is involved in cross-modal association between somatosensory (body knowledge), auditory and visual information, the robust hypoperfusions and correlations observed in this area may underlie the striking derealization reported by patients during episodes. Defects in the dorsomedial prefrontal cortex may cause apathy. Persistent hypoperfusion in the diencephalic and associative cortical area during asymptomatic periods is a marker of the disease, suggestive of a scenario wherein patients compensate for these deficient circuitries.

April 15, 2014

Further Experience using Clarithromycin in Patients with Kleine-Levin Syndrome

Lynn Marie Trotti, M.D., M.Sc., Donald L. Bliwise, Ph.D., F.A.A.S.M., David B. Rye, M.D., Ph.D., F.A.A.S.M. Introduction: We read with interest Drs. Rezvanian and Watson’s report of Kleine-Levin Syndrome (KLS) treatment with clarithromycin.¹ We appreciate their expansion upon our work using GABA-A receptor antagonists, including flumazenil and clarithromycin, for hypersomnia disorders.^2–4 Our experience treating four KLS patients with clarithromycin follows.

Published: April 3, 2014

Widespread Hypermetabolism in Symptomatic and Asymptomatic Episodes in Kleine-Levin Syndrome.

Yves Dauvilliers, Sophie Bayard, Régis Lopez, Frederic Comte, Michel Zanca, Philippe Peigneux

Abstract Background: No reliable biomarkers are identified in KLS. However, few functional neuroimaging studies suggested hypoactivity in thalamic and hypothalamic regions during symptomatic episodes. Here, we investigated relative changes in regional brain metabolism in Kleine-Levin syndrome (KLS) during symptomatic episodes and asymptomatic periods, as compared to healthy controls.

Front. Neurol., 02 April 2014 Reduced thalamic and pontine connectivity in Kleine–Levin syndrome.  Maria Engström, Thomas Karlsson, and Anne-Marie Landtblom Background: Kleine–Levin syndrome is a sleep disorder characterized by exceptionally long sleep episodes, which can endure up to several weeks and recur several times a year. During the hypersomnic periods, the KLS patients often suffer from behavioral, perceptual, and cognitive disturbances, such as binge eating, delusions, and memory problems (3, 4). Structural neuroimaging and inter-episodic EEG are usually normal. However, functional neuroimaging shows frontotemporal and thalamic abnormality that indicate complex disruptions in thalamocortical networks in episodes, but also partially between episodes (5–7). Functional MRI has shown hyperactivation in the left thalamus and abnormal coupling between the thalamus and the brain’s executive and salience networks in asymptomatic KLS patients during working memory performance (8–10). SPECT has shown hypoperfusion of the bilateral thalami during hypersomnic periods, which was not persistent during the asymptomatic periods (6, 11, 12). Despite convincing data indicating thalamic involvement, the neuropathology of KLS remains unknown. Copyright: © 2014 Engström, Karlsson and Landtblom.

J Clin Neurosci. 2012 Jan 26. [Epub ahead of print] Distribution of HLA-DQB1 alleles in patients with Kleine-Levin Syndrome. Huang CJ, Liao HT, Yeh GC, Hung KL. Department of Medical Research, Cathay General Hospital, Taipei, Taiwan; School of Medicine, Fu Jen Catholic University, New Taipei, Taiwan; Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan. Kleine-Levin syndrome (KLS) is a rare disorder characterized by recurrent episodes of hypersomnia, cognitive or behavior disturbances, compulsive eating behavior, and hypersexuality. The etiology of KLS remains unknown even though its clinical symptoms suggest an underlying autoimmune process. In this study, we analyzed the human leukocyte antigen (HLA) typing alleles in Taiwanese patients with KLS using the polymerase chain reaction sequence-specific priming technique. We report that an immunoresponsive HLA-DQB1, DQB1∗0602, was detected in significant quantities in patients with KLS (three of 12, p=0.046) and could elevate the risk of KLS (odds ratio, 1.143; 95% confidence interval, 0.0982-1.329). In conclusion, an identification of genomic susceptibility to KLS will be helpful in determining the immunospecific targeted therapies for patients with KLS. PMID: 22285112

Sleep Med. 2012 Jan 17. [Epub ahead of print] A case of PANDAS with Kleine-Levin type periodic hypersomnia. Das A, Radhakrishnan A. Comprehensive Center for Sleep Disorders, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum 695011, Kerala, India. We report on an 11-year-old girl, presenting with clinical features suggesting both pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and Kleine-Levin syndrome (KLS), who was successfully treated with penicillin prophylaxis. KLS is a sleep disorder characterized by recurrent episodes of hypersomnia and at least one of the following symptoms: (1) cognitive or mood disturbances, (2) megaphagia with compulsive eating; (3) hypersexuality with inappropriate behaviors; and (4) abnormal behavior. The etiopathogenesis is still unclear and there is no effective treatment other than symptomatic therapies. This intriguing case report suggests novel insight into the pathogenesis of this rare and enigmatic syndrome. PMID: 22261244

Sleep. 2012 Jan 1;35(1):123-9. Relationship between Kleine-Levin Syndrome and Upper Respiratory Infection in Taiwan. Huang YS, Guilleminault C, Lin KL, Hwang FM, Liu FY, Kung YP. STUDY OBJECTIVES: In Kleine-Levin Syndrome (KLS), new episodes of hypersomnia are often preceded by an acute flu-like syndrome or upper airway infection 3 to 5 days before onset. This study investigated the relationship between the occurrence of mild upper respiratory tract infections (URIs) in the general population and the occurrence and seasonality and hypersomnic episodes in KLS patients. DESIGN: This investigation was a longitudinal clinical study. Based on data obtained from the National Health Research Institutes between 2006 and 2007, the timing of hypersomnic episodes in 30 KLS patients were compared with calendar reports of URI events, and the results compared with age-matched general Taiwanese population. MEASUREMENTS: Clinical symptoms, physical examination, polysomnographic recording, SPECT study, and laboratory tests affirming KLS during both periods of hypersomnic attack and non-attack were collected. Every symptomatic episode was then followed up. The cross-correlation function (CCF) and bivariate correlations analysis were performed to see the relationship between KLS and URIs. RESULTS: A positive finding of CCF analysis and significant bivariate correlations were found between KLS episodes and URI in the general population (r = 0.456*). In onset of hypersomnia, significant correlations existed among “acute upper respiratory infections” (r = 0.446*), “acute bronchitis and bronchiolitis” (r = 0.462*), and “pharyngitis and nasopharyngitis” (r = 0.548*) subtypes of infections. A positive correlation between higher reports of symptomatic hypersomnia and URI also existed in a given season. A positive nonsignificant trend for “allergic rhinitis” (r = 0.400) was also found. CONCLUSION: The agent behind URI or its consequence (such as fever) is associated with increased incidence of KLS episodes and may explain periodic symptomatic recurrences. CITATION: Huang YS; Guilleminault C; Lin KL Hwang FM; Liu FY; Kung YP. Relationship between Kleine-Levin Syndrome and upper respiratory infection in Taiwan. PMID: 22215926

Lancet Neurol. 2012 Oct;11(10):918-28. doi: 10.1016/S1474-4422(12)70187-4. Diagnosis, disease course, and management of patients with Kleine-Levin syndrome. Arnulf I, Rico TJ, Mignot E. National Reference Center for Narcolepsy, Idiopathic Hypersomnia and Kleine-Levin Syndrome, Sleep Disorders Unit and Inserm U975, Pitié-Salpêtrière Hospital (APHP), Pierre and Marie Curie University, Paris, France. isabelle.arnufl@psl.aphp.fr Abstract Kleine-Levin syndrome is a rare sleep disorder that mainly affects adolescents and is characterised by relapsing-remitting episodes of severe hypersomnia, cognitive impairment, apathy, derealisation, and psychiatric and behavioural disturbances. Boys are more frequently affected than girls. Just over half of patients have hyperphagia, are hypersexual (mainly boys), or have depressed mood (mainly girls), and 30% become anxious, delusional, and have hallucinations. Although some symptoms are similar to those in patients with encephalopathy, imaging and laboratory findings are unremarkable. The first episode of hypersomnia is often triggered by an infection, with relapses occurring every 1-12 months for a median of 14 years; disease duration can be much longer with childhood or adult onset than in patients with adolescent onset. Between episodes, patients generally have normal sleep patterns, cognition, mood, and eating habits. During episodes, electroencephalography might show diffuse or local slow activity. Functional imaging studies have revealed hypoactivity in thalamic and hypothalamic regions, and in the frontal and temporal lobes. Stimulants and mood stabilisers can be beneficial in the treatment of severe cases. Copyright © 2012 Elsevier Ltd. All rights reserved. Sleep Med Rev. 2011 Aug;15(4):247-57. Epub 2010 Oct 20. Recurrent hypersomnia: a review of 339 cases. Billiard M, Jaussent I, Dauvilliers Y, Besset A. Department of Neurology, Gui de Chauliac Hospital, 80 Avenue Augustin Fliche, 34295 Montpellier cedex 5, France.  Abstract Based on 339 cases this review identifies, quantifies and compares 4 clinical forms of recurrent hypersomnia (1) Kleine-Levin syndrome (KLS) (239 cases), (2) Kleine-Levin syndrome without compulsive eating (KLS WOCE) (54 cases), (3) Menstrual related hypersomnia (MRH) (18 cases) and Recurrent hypersomnia with comorbidity (RHC) (28 cases). A second part of the review considers the main current issues on recurrent hypersomnia: the predisposing factors, including a window on family cases; the pathophysiology based on clinical patterns, neuroimaging data, neuropathological examinations and cerebrospinal fluid (CSF) hypocretin-1 measurements; the issues of recurrence and of a possible disruption of the circadian timing system; the relationships between recurrent hypersomnia and mood disorders; and a note on the atypical Kleine-Levin syndrome. The main outcomes of this study are a clear nosologic distinction of the different forms of recurrent hypersomnia, the finding that the prevalence of familial cases of KLS is in the same range as in narcolepsy, the suggestion of the possible involvement of a large set of cortical and subcortical structures in recurrent hypersomnia and some clues in favour of a relationship between recurrent hypersomnia and mood disorders. PMID: 20970360

Ceylon Med J. 2011 Sep;56(3):132-3. A case of Kleine-Levin syndrome. Wanigasinghe J, Mettananda SG, Kodikara Arachchi DS. PMID: 22164757

Sleep Med. 2011 Aug;12(7):730. Epub 2011 Jul 16. Treatment of Kleine-Levin syndrome with sodium oxybate. Ortega-Albás JJ, Díaz JR, López-Bernabé R, Vera JF, Alós M, Serrano AL. PMID: 21763197

Sleep Med Rev. 2011 Aug;15(4):247-57. Epub 2010 Oct 20. Recurrent hypersomnia: a review of 339 cases. Billiard M, Jaussent I, Dauvilliers Y, Besset A. Department of Neurology, Gui de Chauliac Hospital, 80 Avenue Augustin Fliche, 34295 Montpellier cedex 5, France. Based on 339 cases this review identifies, quantifies and compares 4 clinical forms of recurrent hypersomnia (1) Kleine-Levin syndrome (KLS) (239 cases), (2) Kleine-Levin syndrome without compulsive eating (KLS WOCE) (54 cases), (3) Menstrual related hypersomnia (MRH) (18 cases) and Recurrent hypersomnia with comorbidity (RHC) (28 cases). A second part of the review considers the main current issues on recurrent hypersomnia: the predisposing factors, including a window on family cases; the pathophysiology based on clinical patterns, neuroimaging data, neuropathological examinations and cerebrospinal fluid (CSF) hypocretin-1 measurements; the issues of recurrence and of a possible disruption of the circadian timing system; the relationships between recurrent hypersomnia and mood disorders; and a note on the atypical Kleine-Levin syndrome. The main outcomes of this study are a clear nosologic distinction of the different forms of recurrent hypersomnia, the finding that the prevalence of familial cases of KLS is in the same range as in narcolepsy, the suggestion of the possible involvement of a large set of cortical and subcortical structures in recurrent hypersomnia and some clues in favour of a relationship between recurrent hypersomnia and mood disorders. PMID: 20970360

Sleep Med. 2011 May;12(5):532. Epub 2011 Apr 13. Dynamic fMRI changes in Kleine-Levin Syndrome. Billings ME, Watson NF, Keogh BP. PMID: 21493136

Handb Clin Neurol. 2011;99:869-82. REM sleep parasomnias. Montplaisir J, Gagnon JF, Postuma RB, Vendette M. Hôpital du Sacré-Coeur de Montréal, Université de Montréal, Montreal, Canada. PMID: 21056233

Handb Clin Neurol. 2011;99:815-23. Recurrent hypersomnias. Billiard M. Department of Neurology, Gui de Chauliac Hospital, Montpellier, France. PMID: 21056229

J Clin Neurosci. 2011 Mar;18(3):439-40. Epub 2011 Jan 13. Persistent deficits of visual recall in Kleine-Levin syndrome. Körtner K, Hansen ML, Danker-Hopfe H, Neuhaus AH, Jockers-Scherübl MC. Department of Psychiatry, Campus Benjamin Franklin, Charité University Medicine, Eschenallee 3, 14050 Berlin, Germany. Kleine-Levin syndrome (KLS) is commonly described as a self-limiting disorder exhibiting episodes of hypersomnia and psychiatric symptoms but without any enduring disabilities. Recently, some authors have reported persistent or even progressive memory deficits associated with the disorder. Nevertheless, literature about cognitive disturbances in KLS is rare. Our report describes a patient with deficits of visual and verbal recall after remission of an episode, as well as selective deficits of visual recall 6 months later. Neuropsychological testing is necessary in all patients with KLS to further characterize the profile and impact of associated cognitive deficits. PMID: 21236684

Ann Indian Acad Neurol. 2011 Jan;14(1):50-2. Kleine-Levine syndrome in an adolescent female and response to modafinil. Aggarwal A, Garg A, Jiloha RC. Department of Psychiatry, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India. Kleine-Levine Syndrome (KLS) is a disorder characterized by a triad of periodic hypersomnia, hyperphagia, and hypersexuality. KLS, although more common in young males, it has also been seen in females. Treatment options available for its management include mood stabilisers like lithium, stimulants like amphetamines, antidepressants and other options including electroconvulsive therapy. Modafinil is one of the new stimulant medications approved for narcolepsy. Herein, we report a young female with KLS and showing favorable response to modafinil. More data is required to establish the effectiveness of modafinil in this syndrome. PMID: 21655207

J Neuropsychiatry Clin Neurosci. 2011 Fall;23(1):E33-4. Kleine-Levin syndrome and response to modafinil in a young woman. Aggarwal A, Garg A, Jiloha R. PMID: 21304127

J ECT. 2010 Dec;26(4):253-8. Etiopathogenesis of catatonia: generalizations and working hypotheses. Dhossche DM, Stoppelbein L, Rout UK. Department of Psychiatry & Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA. Catatonia has been rediscovered over the last 2 decades as a unique syndrome that consists of specific motor signs with a characteristic and uniform response to benzodiazepines and electroconvulsive therapy. Further inquiry into its developmental, environmental, psychological, and biological underpinnings is warranted. In this review, medical catatonia models of motor circuitry dysfunction, abnormal neurotransmitters, epilepsy, genetic risk factors, endocrine dysfunction, and immune abnormalities are discussed. Developmental, environmental, and psychological risk factors for catatonia are currently unknown. The following hypotheses need to be tested: neuroleptic malignant syndrome is a drug-induced form of malignant catatonia; Prader-Willi syndrome is a clinical GABAergic genetic-endocrine model of catatonia; Kleine-Levin syndrome represents a periodic form of adolescent catatonia; and anti-N-methyl-d-aspartate receptor encephalitis is an autoimmune type of catatonia. PMID: 21076339

J Med Assoc Thai. 2010 Nov;93 Suppl 6:S218-22. Kleine-Levin syndrome: the first typical case in Thailand. Sithinamsuwan P, Ruangwittayawong T, Pinroj Y, Saengpattrachai M, Chinvarun Y. Division of Neurology, Department of Medicine, Phramongkutklao Hospital and Medical College, Bangkok, Thailand. Kleine-Levin syndrome (KLS) is a rare disorder characterized by periodic hypersomnia, cognitive and behavioral disturbances. Other unique symptoms in KLS are megaphagia, hypersexuality and some psychiatric disturbances such as compulsion and depression. Definite diagnosis requires the elimination of other potential etiologies. We reported a typical case of KLS in a young Thai man who suffered from seven episodes of periodic hypersomnia within 1.5 years and eventually he was diagnosed with Kleine-Levin syndrome after excluding known possible neurological conditions and sleep disorders. PMID: 21280539

Pediatr Neurol. 2010 Nov;43(5):307-15. Catatonia is hidden in plain sight among different pediatric disorders: a review article. Dhossche DM, Wachtel LE. Department of Psychiatry, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA. Over the past two decades, catatonia has been better demarcated in adult psychiatry as a unique syndrome that consists of specific motor signs with a characteristic response to benzodiazepines and electroconvulsive therapy. Pediatric catatonia is considered rare, but may be underdiagnosed, and hence undertreated. Discussed here are the current diagnostic criteria of catatonia in individual cases of children and adolescents diagnosed with childhood disintegrative disorder, Kleine-Levin syndrome, Prader-Willi syndrome, tic disorder, and autoimmune encephalitis, and the effects of benzodiazepines and electroconvulsive therapy. In these cases, catatonia resolved safely once it was recognized and treated properly. Children and adolescents presenting with these disorders should be systematically assessed for catatonia; when the presence of catatonia is confirmed, the use of benzodiazepines and electroconvulsive therapy should be considered. The occurrence of catatonia in such a wide range of child and adolescent disorders supports the view that pediatric catatonia is not so rare, that there are shared elements in the etiology, psychopathology, and pathophysiology of these disorders, and that catatonia is best classified as a unique neurobiologic syndrome. PMID: 20933172

Ann Indian Acad Neurol. 2010 Oct;13(4):241-6. Kleine-Levin syndrome: Etiology, diagnosis, and treatment. Ramdurg S. Department of Psychiatry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India. Kleine-Levin syndrome (KLS) is a rare sleep disorder mainly affecting teenage boys in which the main features are intermittent hypersomnolence, behavioral and cognitive disturbances, hyperphagia, and in some cases hypersexuality. Each episode is of brief duration varying from a week to 1-2 months and affected people are entirely asymptomatic between episodes. No definite cause has been identified, and no effective treatments are available even though illness is having well-defined clinical features. Multiple relapses occur every few weeks or months, and the condition may last for a decade or more before spontaneous resolution. In this study, PubMed was searched and appropriate articles were reviewed to highlight etiology, clinical features, and management of KLS. On the basis of this knowledge, practical information is offered to help clinicians about how to investigate a case of KLS, and what are the possible treatment modalities available currently for the treatment during an episode and interepisodic period for prophylaxis. Comprehensive research into the etiology, pathophysiology, investigation, and treatments are required to aid the development of disease-specific targeted therapies. PMID: 21264130

J Clin Psychopharmacol. 2010 Jun;30(3):347-50. Modafinil-associated vivid visual hallucination in a patient with Kleine-Levin syndrome: case report. Hsieh CF, Lai CL, Lan SH, Liu CK, Hsu CY. PMID: 20473083

J Neuropsychiatry Clin Neurosci. 2010 Spring;22(2):E5-6. Non-convulsive status epilepticus presenting as recurrent hypersomnia. Sharma A, Singh SM, Grover S, Malhotra S, Modi M. PMID: 20463123

Med Clin North Am. 2010 May;94(3):557-62. Kleine-Levin syndrome: current status. Huang YS, Lakkis C, Guilleminault C. Sleep Center, Chang Gung Memorial Hospital and University, Taoyuan, Taiwan. Kleine-Levin Syndrome is a periodic hypersomnia characterized by recurrent episodes of hypersomnia and other symptoms. This article reviews the research to date, outlines the clinical symptoms, and describes current testing and treatment. It concludes that the cause remains unknown and no treatment is effective in preventing recurrence, although modafinil may reduce duration of symptomatic episode. PMID: 20451032

Sleep Med. 2010 Oct;11(9):959. Epub 2010 May 5. Greater reduction of striatal dopamine transporter availability during the symptomatic than asymptomatic phase of Kleine-Levin syndrome. Hoexter MQ, Shih MC, Felício AC, Tufik S, Bressan RA. PMID: 20447863

Med Clin North Am. 2010 May;94(3):557-62. Kleine-Levin syndrome: current status. Huang YS, Lakkis C, Guilleminault C. Sleep Center, Chang Gung Memorial Hospital and University, Taoyuan, Taiwan. Abstract Kleine-Levin Syndrome is a periodic hypersomnia characterized by recurrent episodes of hypersomnia and other symptoms. This article reviews the research to date, outlines the clinical symptoms, and describes current testing and treatment. It concludes that the cause remains unknown and no treatment is effective in preventing recurrence, although modafinil may reduce duration of symptomatic episode. PMID: 20451032

Sleep. 2009 May;32(5):681-8. Working memory in 8 Kleine-Levin syndrome patients: an fMRI study. Engström M, Vigren P, Karlsson T, Landtblom AM. Center for Medical Image Sciences and Visualization, Linköping University, Linköping, Sweden. Abstract STUDY OBJECTIVES: The objectives of this study were to investigate possible neuropathology behind the Kleine-Levin Syndrome (KLS), a severe form of hypersomnia with onset during adolescence. DESIGN: Functional magnetic resonance imaging (fMRI) applying a verbal working memory task was used in conjunction with a paper-and-pencil version of the task. PARTICIPANTS: Eight patients with KLS and 12 healthy volunteers participated in the study. RESULTS: The results revealed a pattern of increased thalamic activity and reduced frontal activity (involving the anterior cingulate and adjacent prefrontal cortex) while performing a reading span task. DISCUSSION: This finding may explain the clinical symptoms observed in KLS, in that the thalamus is known to be involved in the control of sleep. Given the increasing access to fMRI, this investigation may aid clinicians in the diagnosis of patients suffering from severe forms of hypersomnia. PMID: 19480235

J Child Neurol. 2010 Nov;25(11):1408-10. Epub 2010 Apr 19. Familial recurrent hypersomnia: two siblings with Kleine-Levin syndrome and menstrual-related hypersomnia. Rocamora R, Gil-Nagel A, Franch O, Vela-Bueno A. Department of Neurology, Hospital del Mar, Barcelona, Spain. Kleine-Levin syndrome and menstrual-related hypersomnia are rare idiopathic sleep disorders occurring primarily in adolescence. They are characterized by intermittent periods of excessive sleepiness, cognitive disturbances, and behavioral abnormalities. In both, the etiology remains unknown but autoimmune, hormonal, infectious, and inflammatory mechanisms have been proposed. The authors describe, for the first time, the association of Kleine-Levin syndrome and menstrual-related hypersomnia in 2 adolescent siblings who shared the human leukocyte antigen (HLA) loci DQB1*0501. The same haplotype has been associated with sleepwalking and with rapid eye movement (REM) sleep behavior disorder. This gender differences in the manifestation of a probably genetic influenced sleep disorder suggests that hormonal mechanisms could be implicated in the phenotypical expression of this sleep disorder. The male sibling with Kleine-Levin syndrome was easily controlled with carbamazepine in low doses, but his sister could be only efficaciously treated with oral contraceptives. PMID: 20404354

Sleep. 2010 Feb;33(2):169-76. Validation of the ICSD-2 criteria for CSF hypocretin-1 measurements in the diagnosis of narcolepsy in the Danish population. Knudsen S, Jennum PJ, Alving J, Sheikh SP, Gammeltoft S. Danish Center for Sleep Medicine, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark. STUDY OBJECTIVES: The International Classification of Sleep Disorders (ICSD-2) criteria for low CSF hypocretin-1 levels (CSF hcrt-1) still need validation as a diagnostic tool for narcolepsy in different populations because inter-assay variability and different definitions of hypocretin deficiency complicate direct comparisons of study results. DESIGN AND PARTICIPANTS: Interviews, polysomnography, multiple sleep latency test, HLA-typing, and CSF hcrt-1 measurements in Danish patients with narcolepsy with cataplexy (NC) and narcolepsy without cataplexy (NwC), CSF hcrt-1 measurements in other hypersomnias, neurological and normal controls. Comparisons of hypocretin deficiency and frequency of HLA-DQB1*0602-positivity in the Danish and eligible NC and NwC populations (included via MEDLINE search), by (re)calculation of study results using the ICSD-2 criterion for low CSF hcrt-1 (< 30% of normal mean). MEASUREMENTS AND RESULTS: In Danes, low CSF hcrt-1 was present in 40/46 NC, 3/14 NwC and 0/106 controls (P < 0.0001). Thirty-nine of 41 NC and 4/13 NwC patients were HLA-DQB1*0602-positive (P < 0.01). Hypocretin-deficient NC patients had higher frequency of cataplexy, shorter mean sleep latency, more sleep onset REM periods (P < 0.05) and more awakenings (NS) than did NC patients with normal CSF hcrt-1. Across populations, low CSF hcrt-1 and HLA-DQB1*0602-positivity characterized the majority of NC (80% to 100%, P = 0.53; 80% to 100%, P = 0.11) but a minority of NwC patients (11% to 29%, P = 0.75; 29% to 89%, P = 0.043). CONCLUSION: The study provides evidence that hypocretin deficiency causes a more severe NC phenotype. The ICSD-2 criterion for low CSF hcrt-1 (< 30% of normal mean) is valid for diagnosing NC, but not NwC. HLA-typing should precede CSF hcrt-1 measurements because hypocretin deficiency is rare in HLA-DQB1*0602-negative patients. PMID: 20175400

Acta Paediatr. 2010 Jun;99(6):946-8. Epub 2010 Feb 16. Onset of Kleine-Levin Syndrome in association with isotretinoin treatment. Smedje H, Schwan S, Hallberg E, Hallberg P. Child and Adolescent Psychiatric Unit, Department of Neuroscience, Uppsala University Hospital, Uppsala, Sweden. The synthetic retinoid isotretinoin is an effective treatment option for severe forms of acne vulgaris. However, several reports indicate that some patients experience altered central nervous system functions in association with treatment. We present here the first description of the onset of Kleine-Levin Syndrome (KLS), a rare disorder characterised by periodic hypersomnia and cognitive and behavioural symptoms, in close temporal relation to the start of isotretinoin treatment. We also discuss the biological potential of retinoids to affect sleep. CONCLUSIONS: In light of a documented potential of retinoids to modulate sleep-wake regulation, the present case suggests that isotretinoin may rarely trigger the onset of KLS. PMID: 20163374

Encephale. 2010 Feb;36(1):28-32. Epub 2009 Apr 2. [Kleine-Levin syndrome: a case report]. [Article in French] Richard Y, Le Galudec M, Saint-André S, Planche P, Genestet S, Lazartigues A. Jeune équipe Ethique, Professionnalisation, Santé (JE 2535), université de Bretagne occidentale, UFR médecine et sciences de la santé, Service hospitalo-universitaire de psychiatrie de l’enfant et de l’adolescent, hôpital de Bohars, CHU de Brest, France. The purpose of this article is to report an original clinical case whose symptoms suggest a very peculiar pathology, because of its rarity, symptomatic expression and unclear etiopathogenesis: the Kleine-Levin Syndrome (KLS). During the regression of tonsillitis concomitant with an emotional shock, the 15-year-old patient exhibited a dramatic change in behaviour, at odds with his previous state, and accompanied by hypersomnia and confusion, megaphagia, irritability, hypersexuality and mood disorders. We observed a spontaneous and total regression of the symptoms after 12 days, except for the incomplete amnesia that proved to be persistent. Four months later, further to an ethylic drunkenness, the patient presented with a new and similar episode. The patient benefited from no medicinal treatment, even in the course of hypersomnia episodes and asymptomatic periods. After a clinical presentation of this patient, we will consider this case study from a more psychopathological angle by questioning the existence of a facilitating psychological profile. The discovery of an IQ equal to 86 from the scores of WISC-IV, and the identification of constructive visual difficulties made us suspect neurological disorders, but these abnormalities were not found during the completion of the Rey Complex Figure Test. The personality profile issued from the scores at the MMPI-A assessment was ranked as barely significant (type 2-4): indeed, it showed nothing specific to this patient. Literature data show that most of the patients presenting with a KLS have been seen by a psychiatrist at the time of the disease and diagnosed as suffering from hysteria, or schizophrenia, or bipolar disorders… Because of diagnostic wanderings, some patients have, hence, received inappropriate treatments. One should pay close attention to this very rare syndrome, on the border between neurology and psychiatry, since its diagnosis is essentially based on clinical features, and carefully think about the implementation of a medicinal treatment. This unique case seems unable to support our working hypothesis about the identification of a particular psychological profile in the KLS, but the question of an underlying fragility is still worth considering. We personally think that, even though links between the KLS and bipolar disorders have been suggested, this disease has to be considered as a separate entity. PMID: 20159193

Sleep Med. 2010 Apr;11(4):335-6. Epub 2010 Feb 4. Insomnia: how tricky can it get? Mahowald MW, Cramer Bornemann MA, Schenck CH. Comment on Sleep Med. 2010 Apr;11(4):343-50. PMID: 20133195

Semin Neurol. 2009 Sep;29(4):354-67. Epub 2009 Sep 9. Primary hypersomnias of central origin. Frenette E, Kushida CA. Stanford Sleep Clinic, Stanford, California, USA. Hypersomnia is a frequently encountered symptom in clinical practice. The cardinal manifestation is inappropriate daytime sleepiness, common to all types of hypersomnias. Hypersomnias of central origin are a rare cause of excessive daytime sleepiness, much rarer than the hypersomnia related to other pathologies, such as sleep-disordered breathing. Narcolepsy, with or without cataplexy, remains the most well studied of the primary hypersomnias. Although recognized more than a century ago, it was not until the end of the 20th century that major breakthroughs led to a better understanding of the disease, with hope of more specific therapies. The authors review the major aspects of this disorder, including the newer treatment modalities. Idiopathic hypersomnia is also part of the primary hypersomnias. Although difficult to diagnose, certain peculiarities stand out to help us differentiate it from the more commonly seen narcolepsy. The recurrent hypersomnias, particularly the Kleine-Levin syndrome, will be discussed. This rare disorder has been studied more closely in the last few years with abundant epidemiologic data assembled through literature and worldwide case reviews. Understanding the primary central hypersomnias warrants a thorough look from the original description, as well as a peek at the future, while more efficacious diagnostic and therapeutic interventions are currently being developed. PMID: 19742411

Harefuah. 2009 May;148(5):329-32, 349, 348. [Kleine-Levin syndrome]. [Article in Hebrew] Tauman R, Greenfeld M, Sivan Y. Pediatric Sleep Disorders Center, Department of Pediatric Pulmonology, Critical Care and Sleep Medicine, Dana Children’s Hospital, Tel Aviv. Kleine-Levin Syndrome (KLS) is a rare disease characterized by recurrent episodes of hypersomnia associated with cognitive and behavioral disturbances, compulsive eating behavior and hypersexuality. Episodes are separated by weeks or months of normal sleep and behavior. The disease predominantly affects adolescent males. The median duration of the disease is eight years. Fifteen percent of the KLS population is of Jewish origin and the incidence reported in Israel is unproportionately high. The etiology and pathophysiology are unknown. The current concept is that the disease is caused by genetic predisposition combined with environmental factors. Autoimmune etiology has also been suggested.KLS poses diagnostic and therapeutic challenges. Diagnosis is usually based on clinical manifestations. Physical examination including neurological evaluation is usually normal. EEG, brain imaging and CSF examination are normal. Stimulants are partially effective on sleepiness. Lithium was reported to induce positive effects in preventing or delaying recurrences. Increased awareness to KLS among physicians in Israel is important due to the relatively higher incidence of KLS among Jewish and Israeli patients. PMID: 19630365

Intern Med. 2009;48(13):1183-5. Epub 2009 Jul 1. Gabapentin for Kleine-Levin syndrome. Itokawa K, Fukui M, Ninomiya M, Yamamoto T, Imabayashi E, Tamura N, Matsuda H, Araki N. Department of Neurology, Saitama Medical University. We describe a 17-year-old girl with Kleine-Levin syndrome (KLS), in which gabapentin was effective for the prevention of attacks. (99)mTc-ECD SPECT revealed hyperperfusion of the thalamus and nucleus accumbens presenting in the symptomatic period, suggesting epilepsy-like neuronal discharge from these structures. Treatment for KLS has not been established, although lithium has been used in limited cases with insignificant efficacy. Here, we report a case of recurrent hypersomnia in which gabapentin was effective for the prevention of attacks. We speculate that the recurrent hypersomnia and behaviour disturbance are related to epilepsy-like neuronal discharge from the thalamus due to dysfunction in GABAnergic receptors. PMID: 19571456

Epilepsy Behav. 2009 Jul;15(3):391-2. Epub 2009 Jun 16. A case of Kleine-Levin syndrome with a complete and sustained response to carbamazepine. El Hajj T, Nasreddine W, Korri H, Atweh S, Beydoun A. American University of Beirut, Medical Center, Beirut, Lebanon. We describe a patient with Kleine-Levin syndrome who was initially misdiagnosed as having epilepsy and who achieved complete remission on carbamazepine treatment. A drug effect was established when symptoms recurred after carbamazepine taper and disappeared after reintroduction of the drug. Carbamazepine, a safer drug than lithium, can be a highly effective treatment in some patients with Kleine-Levin syndrome. This syndrome can sometimes be confused with epilepsy because of the episodic nature of the symptoms and the occasional response to anticonvulsants. PMID: 19447193

Sleep. 2009 May;32(5):681-8. Working memory in 8 Kleine-Levin syndrome patients: an fMRI study. Engström M, Vigren P, Karlsson T, Landtblom AM. Center for Medical Image Sciences and Visualization, Linköping University, Linköping, Sweden. STUDY OBJECTIVES: The objectives of this study were to investigate possible neuropathology behind the Kleine-Levin Syndrome (KLS), a severe form of hypersomnia with onset during adolescence. DESIGN: Functional magnetic resonance imaging (fMRI) applying a verbal working memory task was used in conjunction with a paper-and-pencil version of the task. PARTICIPANTS: Eight patients with KLS and 12 healthy volunteers participated in the study. RESULTS: The results revealed a pattern of increased thalamic activity and reduced frontal activity (involving the anterior cingulate and adjacent prefrontal cortex) while performing a reading span task. DISCUSSION: This finding may explain the clinical symptoms observed in KLS, in that the thalamus is known to be involved in the control of sleep. Given the increasing access to fMRI, this investigation may aid clinicians in the diagnosis of patients suffering from severe forms of hypersomnia. PMID: 19480235

Cochrane Database Syst Rev. 2009 Apr 15;(2):CD006685. Pharmacological treatment for Kleine-Levin Syndrome. Oliveira MM, Conti C, Saconato H, Fernandes do Prado G. UNIFESP, Pedro de Toledo st 598, São Paulo, Brazil, 04039001 Abstract BACKGROUND: Kleine-Levin Syndrome (KLS) is a rare disorder which mainly affects adolescent men. It is characterized by recurrent episodes of hypersomnia, usually accompanied by hyperphagia, cognitive and mood disturbances, abnormal behavior such as hypersexuality, and signs of dysautonomia.In 1990 the diagnostic criteria for Kleine-Levin Syndrome were modified in the International Classification of Sleep Disorders, where it was defined as a syndrome composed of recurring episodes of undue sleepiness lasting some days, which may or may not be associated with hyperphagia and abnormal behavior. The etiology of Kleine-Levin Syndrome remains unknown and several treatment strategies have been used. Some medications have been reported to provide some benefit for the treatment of Kleine-Levin Syndrome patients, but because of the rarity of the condition no long-term follow-up therapies have yet been described. OBJECTIVES: This review aimed to evaluate: 1. whether pharmacological treatment for Kleine-Levin Syndrome is effective and safe; and 2. which drug or category of drugs is effective and safe. SEARCH STRATEGY: We obtained relevant trials from the following sources: the Cochrane Epilepsy Group Specialized Register (1 December 2007); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2007); MEDLINE (1966 to December 2007); EMBASE (1980 to December 2007); LILACS (1982 to December 2007); reference lists of sleep medicine textbooks; review articles and reference lists of articles identified by the search strategies. SELECTION CRITERIA: All randomized controlled trials (RCTs) and quasi-randomized controlled trials looking at pharmacological interventions forKleine-Levin Syndrome. We included both parallel group and cross-over studies. DATA COLLECTION AND ANALYSIS: Two review authors (MO and CC) extracted the data reported in the original articles. MAIN RESULTS: No studies met the inclusion criteria for this systematic review. AUTHORS’ CONCLUSIONS: Therapeutic trials of pharmacological treatment for Kleine-Levin Syndrome, with a double-blind, placebo-controlled design are needed.

Pract Neurol. 2009 Feb;9(1):42-5. Kleine-Levin syndrome. Lisk DR. Basildon University Hospital, Basildon, UK. Kleine-Levin syndrome, sometimes referred to as Rip van Winkle disease, is a rare sleep disorder mainly affecting teenage boys in which the main features are intermittent hypersomnolence, behavioural and cognitive disturbances, hyperphagia and in some cases hypersexuality. Each episode lasts for one or two weeks, and affected people are entirely asymptomatic between episodes. No definite cause has been identified but hypothalamic dysfunction seems likely. Relapses may occur every few weeks or months, and the condition may last for a decade or more before spontaneous resolution. There is no effective treatment but stimulants such as methylphenidate and modafinil as well as the mood stabiliser lithium carbonate have been tried with varying success. PMID: 19151238

Sleep Med. 2009 Mar;10(3):391-3. Epub 2008 Dec 4. An adult onset patient with Kleine-Levin Syndrome responding to valproate. Adlakha A, Chokroverty S. NJ Neuroscience Institute, Neurology, 65 James Street, Edison, NJ 08818, USA.<ashishadlakha@gmail.com> PMID: 19062339

Indian Pediatr. 2008 Dec;45(12):1007. Kleine-Levin syndrome. Ramnath B, Kalaniti K. PMID: 19129573

J Psychosom Res. 2008 Nov;65(5):505-6. Sibutramine-induced psychotic episode in an adolescent. Dogangun B, Bolat N, Rustamov I, Kayaalp L. PMID: 18940382

Rev Neurol. 2008 Sep 16-30;47(6):333-4. [Kleine-Levin syndrome. A description of a case in a teenage girl]. [Article in Spanish] Vasconcelos M, Falcon A, Campistol J. Servicio de Neurología, Hospital Universitari SantJoan de Déu, Esplugues de Llobregat, Barcelona, Spain. PMID: 18803165

Sarcoidosis Vasc Diffuse Lung Dis. 2008 Sep;25(1):60-3. Sarcoidosis: a rare cause of Kleine-Levine-Critchley syndrome. Afshar K, Engelfried K, Sharma OP. Division of Pulmonary and Critical Care Medicine, University of Southern California, 1200 North State Street, Room 11900, Los Angeles, CA 90033, USA. Hypothalamic sarcoidosis is a rare entity that can alter the hypothalamic-pituitary axis and induce various combinations of endocrine changes. We present a case of neurosarcoidosis with uncommon features of hypersomnolense and hyperphagia. Current strategies to increase awareness and prevention of the harmful effects of obesity require clinicians to be cognizant of potential disorders that produce these features The mechanism, differential diagnosis and therapeutic options of this organic etiology are reviewed. PMID: 19070262

Nat Clin Pract Neurol. 2008 Oct;4(10):534-5. Epub 2008 Sep 16. Kleine-Levin syndrome: a disease in its own right? Taylor J, Watkins C, Kaplin A. Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD 21287 Comment on Ann Neurol. 2008 Apr;63(4):482-93. PMID: 18797439

Acta Paediatr. 2008 Dec;97(12):1749-51. Epub 2008 Aug 27. Diagnostic pitfalls in children with sleep disorders: two cases with hypersomnia. Yilmaz K, Uyar M, Adaletli H, Kilincaslan A. Department of Pediatrics, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey. Sleep disorders are common in children, yet several clinical pitfalls give rise to the unrecognition or improper management of those children. Here, we present diagnostic difficulties in two adolescents with narcolepsy and Kleine-Levin syndrome. The first patient was a 12-year-old girl who had been given Na-valproate for nearly a year because hypersomnia was initially perceived as unconsciousness periods of epileptic spells, and later attributed to the antiepileptic drug. The other patient was a 14-year-old boy who had been managed as a specific psychiatric disorder for several months despite the characteristic symptoms of Kleine-Levin syndrome (hypersomnia, hyperphagia, hypersexuality, behavioural and cognitive dysfunction). Both cases emphasize that sleep disorders could be manifested with various clinics and that there are several diagnostic challenges in children. CONCLUSION: Sleep medicine needs to be given larger role in both training curriculum and post-graduate education for paediatricians. PMID: 18754824

Eur Neurol. 2008;60(4):212-4. Epub 2008 Jul 30. Kleine-Levin syndrome: history and brief review. Pearce JM. Department of Neurology, Hull Royal Infirmary, Hull, UK. Abstract Episodic hypersomnia, compulsive excessive eating and erotic behaviour, with schizophrenic-like mental symptoms are the hallmarks of the rare Kleine-Levin syndrome. This paper traces the origins of its description back to the 18th century and the changing concepts of its complex organic-psychogenic aetiology. The eventual, spontaneous disappearance of the syndrome is unexplained. PMID: 18667831

Ann Neurol. 2008 Apr;63(4):482-93. Kleine-Levin syndrome: a systematic study of 108 patients. Arnulf I, Lin L, Gadoth N, File J, Lecendreux M, Franco P, Zeitzer J, Lo B, Faraco JH, Mignot E. Stanford Center for Narcolepsy and Howard Hughes Medical Institute, Stanford University, Palo Alto, CA, USA.  Abstract 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 unremarkable. Patients were 78% male (mean age at onset, 15.7 +/- 6.0 years), averaged 19 episodes of 13 days, and were incapacitated 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 remarkably 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 syndrome 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. PMID:  18438947

Rev Neurol (Paris). 2008 Aug-Sep;164(8-9):658-68. Epub 2008 Jul 23. [Kleine-Levin syndrome: state of the art]. [Article in French] Arnulf I, Lecendreux M, Franco P, Dauvilliers Y. Centre de référence maladies rares : narcolepsie, hypersomnie et syndrome de Kleine-Levin, France. INTRODUCTION: Kleine-Levin syndrome is a rare neurological disorder (1-2 cases per million inhabitants) primarily affecting young subjects. It is characterized by relapsing-remitting episodes of hypersomnia in association with cognitive and behavioral disturbances. Case-reports, small series, meta-analysis and a recent large, prospective trio study are consistent with a homogeneous, genuine disease entity. STATE OF THE ART: Patients are mostly male (68-78%) and adolescents (81%), with mean onset at 15 years (range 4-82 years). The first episode is triggered by an infection in 72% of patients. Patients experience an average of 7-19 episodes of 10-13 days each, relapsing every 3.5 months. Episodes recur more quickly in patients with childhood onset. The median disease course is 8-14 years, with longer course in men, in patients with hypersexuality, and when onset is after age 20. During episodes, all patients have hypersomnia (with sleep lasting 15-21 hours per day), cognitive impairment (apathy, confusion, slowness, amnesia) and a specific feeling of derealization (dreamy state, altered perception). Less frequently, patients experience hyperphagia (66%), hypersexuality (53%, principally men) and depressed mood (53%, predominantly women). Patients are remarkably similar to controls between episodes regarding sleep, vigilance, mood, and eating attitude, but have increased body mass index. Structural brain imaging, evaluation of the cerebrospinal fluid and serological inflammatory markers are unremarkable. EEG slowing is notable in 70% of cases during episodes, without epileptic activity. Sleep structure varies from harmonious hypersomnia to hypo-arousal with low sleep efficiency. The brain scintigraphy may show hypoperfusion, mostly focused on the thalamic, hypothalamic and fronto-temporal areas, especially when contrasted to images obtained between episodes. Newly identified factors include increased birth and developmental problems, Jewish heritage, genetics (5% multiplex families, suggesting autosomal recessive transmission). The association of KLS with HLA-DQ2, found in a small series, is not replicated in a larger independent sample. There is no increased family history for neuropsychiatric disorders. Some stimulants (amantadine, but more rarely modafinil or amphetamines) and mood stabilizers (lithium, valproate, but not carbamazepine) have marginal efficacy. In the 10% KLS cases secondary to various genetic, inflammatory, vascular or paraneoplasic conditions, patients are older, have more frequent and longer episodes, but their clinical symptoms, disease course and treatment response are similar to primary cases. PERSPECTIVE: The most promising findings are the familial clustering and a potential Jewish founder effect, supporting a role for genetic susceptibility factors. CONCLUSION: KLS is a puzzling and disabling disease. Until its cause will be identified, disease management should be primarily supportive and educational. PMID: 18653203

World J Biol Psychiatry. 2009;10(4 Pt 3):969-72. Kleine-Levin syndrome in two subjects with diagnosis of autistic disorder. Mukaddes NM, Fateh R, Kilincaslan A. Child and Adolescent Psychiatry Department, Istanbul School of Medicine, Istanbul University, Turkey. Kleine-Levin syndrome (KLS) is a rare disease characterized by recurrent episodes of hypersomnia, cognitive and behavioural disturbances, compulsive eating and hypersexuality. The disease is predominantly described in typically developed adolescents. Here, we present two cases with the diagnosis of KLS and autistic disorder. The aim of this presentation is to illustrate the clinical expression and differential diagnosis of KLS in this group. PMID: 18609443

Sleep Med. 2009 Mar;10(3):394. Epub 2008 May 29. A case of late-onset Kleine-Levin syndrome responding to lamotrigine. Surges R, Walker MC. PMID: 18514022

Travel Med Infect Dis. 2008 May;6(3):114-24. Epub 2008 May 7. Influenza-associated central nervous system dysfunction: a literature review. Toovey S. F. Hoffmann-La Roche Ltd., Basel, Switzerland. CONTEXT: Influenza is a viral pathogen that imposes an under-recognized burden of central nervous system (CNS) disease. OBJECTIVE: To describe the epidemiology, clinical features and etiology of the CNS disease entities associated with influenza. DATA SOURCES: English-language publications from MEDLINE. DATA EXTRACTION: Articles were identified using “influenza, human”[Mesh] AND “nervous system diseases”[Mesh] and screened for inclusion based on relevance and scientific rigor. RESULTS: Febrile seizure is the most frequently encountered influenza-associated CNS complication, with one in five children hospitalized with influenza experiencing one or more events. In most instances, symptoms resolve without neurological sequelae, although the risk for subsequent afebrile seizure may be increased. Influenza-associated encephalitis/encephalopathy is a less common but potentially more serious complication that is widely reported in Japanese populations, although cases from other East Asian countries, North America, and Europe have been described. Clinical manifestations are diverse, and typically involve febrile seizures and abnormal behaviors in mild cases, with rapid evolution through decreased consciousness to coma in severe forms. In cases of serious disease, the prognosis is often poor, with outcomes including death or severe neurological sequelae. Influenza is also a known trigger for a number of rarely encountered, yet often serious, CNS diseases, including the encephalopathic condition of Reye’s syndrome, the peripheral neuropathy known as Guillain-Barré syndrome, and the lesser known complaints of Kleine-Levin syndrome and post-encephalitic Parkinson’s disease. CONCLUSIONS: Influenza imposes a sizeable burden of CNS disease. Increased awareness and monitoring of CNS function is indicated, especially in infants and young children. PMID: 18486065

Comment in Nat Clin Pract Neurol. 2008 Oct;4(10):534-5. Neurology. 2008 Mar 4;70(10):795-801. Polysomnography in Kleine-Levin syndrome. Huang YS, Lin YH, Guilleminault C. Sleep Center and Child Psychiatry Department, Chang Gung Memorial Hospital Taipei, Taiwan. Abstract BACKGROUND: Cause and pathogenesis of the Kleine-Levin syndrome (KLS), a recurrent hypersomnia affecting mainly male adolescents, remain unknown, with only scant information on the sleep characteristics during episodes. We describe findings obtained with polysomnography (PSG) and Multiple Sleep Latency Test (MSLT) and correlation obtained between clinical and PSG findings from different episodes. METHOD: Nineteen patients (17 male) were investigated with PSG and MSLT. Ten patients had data during both symptomatic episode and asymptomatic interval. The analyses considered day of onset of symptoms and relationship between this time of onset and day of recording during the symptomatic period. RESULTS: When PSG was performed early (before the end of the first half of the symptomatic period), an important reduction in slow wave sleep (SWS) was always present with progressive return to normal during the second half (with percentages very similar to those monitored during the asymptomatic period) despite persistence of clinical symptoms. REM sleep remained normal in the first half of the episode but decreased in the second half: the differences between first and second half of episodes were significant for SWS (p = 0.014) and REM sleep (p = 0.027). The overall mean sleep latency at MSLT was 9.51 +/- 4.82 minutes and 7 of 17 patients had two or more sleep onset REM periods during the symptomatic period. CONCLUSION: Important changes in sleep occur over time during the symptomatic period, with clear impairment of slow wave sleep at symptom onset. But Multiple Sleep Latency Test (MSLT) is of little help in defining sleep problems and findings from the MSLT do not correlate with symptom onset. PMID: 18316691

Ann Neurol. 2008 Apr;63(4):482-93. Kleine-Levin syndrome: a systematic study of 108 patients. Arnulf I, Lin L, Gadoth N, File J, Lecendreux M, Franco P, Zeitzer J, Lo B, Faraco JH, Mignot E. Stanford Center for Narcolepsy and Howard Hughes Medical Institute, Stanford University, Palo Alto, CA, USA. 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 unremarkable. Patients were 78% male (mean age at onset, 15.7 +/- 6.0 years), averaged 19 episodes of 13 days, and were incapacitated 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 remarkably 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 syndrome 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. Comment in Nat Clin Pract Neurol. 2008 Oct;4(10):534-5. PMID: 18438947

Neurology. 2008 Mar 4;70(10):795-801. Polysomnography in Kleine-Levin syndrome. Huang YS, Lin YH, Guilleminault C. Sleep Center and Child Psychiatry Department, Chang Gung Memorial Hospital Taipei, Taiwan. BACKGROUND: Cause and pathogenesis of the Kleine-Levin syndrome (KLS), a recurrent hypersomnia affecting mainly male adolescents, remain unknown, with only scant information on the sleep characteristics during episodes. We describe findings obtained with polysomnography (PSG) and Multiple Sleep Latency Test (MSLT) and correlation obtained between clinical and PSG findings from different episodes. METHOD: Nineteen patients (17 male) were investigated with PSG and MSLT. Ten patients had data during both symptomatic episode and asymptomatic interval. The analyses considered day of onset of symptoms and relationship between this time of onset and day of recording during the symptomatic period. RESULTS: When PSG was performed early (before the end of the first half of the symptomatic period), an important reduction in slow wave sleep (SWS) was always present with progressive return to normal during the second half (with percentages very similar to those monitored during the asymptomatic period) despite persistence of clinical symptoms. REM sleep remained normal in the first half of the episode but decreased in the second half: the differences between first and second half of episodes were significant for SWS (p = 0.014) and REM sleep (p = 0.027). The overall mean sleep latency at MSLT was 9.51 +/- 4.82 minutes and 7 of 17 patients had two or more sleep onset REM periods during the symptomatic period. CONCLUSION: Important changes in sleep occur over time during the symptomatic period, with clear impairment of slow wave sleep at symptom onset. But Multiple Sleep Latency Test (MSLT) is of little help in defining sleep problems and findings from the MSLT do not correlate with symptom onset. PMID: 18316691

J Dev Behav Pediatr. 2007 Dec;28(6):475-7. Episodic hypersomnia and unusual behaviors in a 14-year old adolescent. Hirst J, Mignot E, Stein MT Developmental and Behavioral Pediatrics, University of California, San Diego, CA CASE: John, a 14-year old white male of European Jewish descent without a prior history of medical or psychiatric problems, presented following several days of increased need for sleep (16-20 hours per day), disorientation, difficulty maintaining attention and concentration, bizarre behaviors. He was sexually inappropriate toward his mother, sister, and housekeeper, masturbated in public, and sang nonsense lyrics. In addition, he had brief periods of agitation, paranoia (including fear that he was being followed and that he would be hurt by the physicians), and periods of distraction by auditory and visual hallucinations. His appetite increased significantly during this time. One week prior to the onset of these symptoms, he traveled to the Midwest where he experienced several days of nausea, vomiting, and diarrhea. John’s physical and neurological examinations were normal except for the behaviors noted above. A medical evaluation revealed a normal brain computerized tomogram (CT) and magnetic resonance imaging (MRI). Urine toxicology screen, a comprehensive metabolic blood panel, and a complete blood count were normal. A lumbar puncture demonstrated a slightly elevated opening pressure (24 centimeters); the cerebrospinal fluid examination was unremarkable for cells, protein and glucose. Following the lumbar puncture, for which he had received midazolam, he had a brief, 30-45 minute episode of lucidity in which he was able to describe feeling like he was “in a fog.“John was transferred to a psychiatric hospital where he recovered over several days and was discharged home. After three weeks of complete recovery, he acutely developed profound fatigue and the previously seen bizarre behaviors returned and persisted for 2 weeks. Following a 2-week period without symptoms, a similar behavior pattern recurred for the third time. The third episode differed from the first two in that he initially developed mental status changes and then developed symptoms of hypersomnolence. John has now been completely recovered from the third two week episode for one week and is taking summer school classes and enjoying socializing with his friends. PMID: 18091094

J Neuropsychiatry Clin Neurosci. 2007 Fall;19(4):413-9. Hypocretin/Orexin: a molecular link between sleep, energy regulation, and pleasure. Ganjavi H, Shapiro CM. University of Toronto, Toronto, Canada. Hypocretin (Hcrt) is a neurotransmitter of the dorsal and lateral hypothalamus that regulates sleep, appetite, and energy consumption. Recent evidence indicates that it is also involved in pleasure/reward-seeking. Mutation of the Hcrt-receptor gene causes narcolepsy in canines, and Hcrt knockout mice exhibit narcolepsy-like symptoms. Human narcoleptics do not commonly have mutations in the ligand or receptor but do have degeneration of Hcrt-containing neurons, possibly through an autoimmune mechanism. When Hcrt neurons degenerate in mice, hypophagia and obesity are observed, symptoms that are also present in some human narcoleptics. This article reviews the recent literature with regard to the many functions of this single molecule. The authors suggest that eating habits and impulsivity may be topics worth exploring in the evaluation of narcoleptic patients. PMID: 18070844

Acta Neurol Scand. 2008 May;117(5):370-3. Epub 2007 Nov 20. Lower dopamine transporter density in an asymptomatic patient with Kleine-Levin syndrome. Hoexter MQ, Shih MC, Mendes DD, Godeiro-Junior C, Felicio AC, Fu YK, Tufik S, Bressan RA. LiNC-Laboratório Interdisciplinar de Neurociências Clínicas, Universidade Federal de São Paulo, São Paulo, Brazil. BACKGROUND: Kleine-Levin syndrome (KLS) is a rare disorder whose pathophysiological mechanisms remain unknown. PATIENTS AND METHODS: To investigate dopamine abnormalities in KLS, a [99mTc]-TRODAT-1 single photon emission computerized tomography (SPECT) was performed in a patient with KLS during the asymptomatic period and compared with three matched healthy controls. RESULTS: The patient had 14% lower striatal dopamine transporter binding potential (DAT-BP) compared to the mean DAT-BP of three healthy controls. CONCLUSION: This study provides in vivo evidence for abnormalities in the DAT-BP, suggesting an involvement of the dopaminergic system in the pathophysiology of KLS. PMID: 18028505

J Neurol. 2007 Oct;254(10):1445-6. Epub 2007 Oct 15. Magnetic resonance spectroscopy in a patient with Kleine-Levin syndrome, Poryazova R, Schnepf B, Boesiger P, Bassetti CL. PMID: 179327

J Neurol Neurosurg Psychiatry. 2007 Sep;78(9):975-6. Observation of a nervous disease attended by disturbed sleep, at times lethargic and at times convulsive. Edmé Chauvot de Beauchêne (1786). Walusinski O. PMID: 17702777

Sleep Med. 2008 Jul;9(5):575-8. Epub 2007 Aug 29. Clinical characteristics and HLA typing of a family with Kleine-Levin syndrome. BaHammam AS, GadElRab MO, Owais SM, Alswat K, Hamam KD. Sleep Disorders Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia. BACKGROUND: Kleine-Levin syndrome (KLS) is a rare disorder of unknown etiology. To date, only four familial cases have been described. The possible presence of genetic and autoimmune processes has been postulated recently. Our objective was to report for the first time a multiplex KLS Saudi family with 6 out of 12 family members affected. METHODS: The demographic and clinical features of the six affected family members are described. KLS was diagnosed according to the International Classification of Sleep Disorders (ICSD). Human leukocyte antigen (HLA) typing was performed for both affected and unaffected family members and compared to previous studies. RESULTS: The father and three male and two female children were affected. Age of onset ranged from 15 to 21 years. Symptoms disappeared in four family members. HLA typing was identical in the father and two children (1F and 5M). All affected members shared one-half of HLA antigens. HLA typing revealed that four members out of the six affected members are homozygous at DQB1 *02 loci. CONCLUSIONS: This report provides a description of a multiplex KLS family with six members affected. HLA-DQB1 *02 homozygosity was present in 4/6 affected and 2/6 unaffected family members. The family studied presents an invaluable opportunity for further DNA and genetic studies, which may help in finding the mutation in the future. PMID: 17761456

Sleep Med. 2008 Jan;9(2):172-6. Epub 2007 Jul 20. Atypical Kleine—Levin syndrome: can insomnia and anorexia be features too? Shukla G, Bhatia M, Singh S, Goyal V, Srivastava T, Behari M. Department of Neurology, Neurosciences Center, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. BACKGROUND: Kleine-Levin syndrome is an uncommon disorder with recurrent episodes of hypersomnia, clearly associated with behavioral abnormalities like binge eating, hypersexuality and abnormal behavior. Many patients may not necessarily fulfill minimum criteria described for diagnosis. We aim to report such patients with atypical presentation resembling the Kleine-Levin syndrome. METHOD: We evaluated all patients at our clinic who had episodic disturbance in sleep and/or appetite lasting a few days to weeks, not necessarily fulfilling the International Classification of Sleep Disorders (ICSD) criteria for a diagnosis of Kleine-Levin syndrome, over 4 years. All clinical details, especially regarding sleep, appetite and behaviour during episodes, about prior and co-existing illnesses were noted. All patients were investigated with brain magnetic resonance imaging (MRI), electroencephalogram (EEG) and some with polysomnography. RESULTS: Eighteen patients (5 females, 13 males) ranging in age from 12 to 55 years (median 18 years) were included in the study. The median duration of symptoms was 1.5 years, and the median number of episodes in each patient was six. The range of episode length was 18-300 h with a mean of 91.2h. Fourteen patients had a history of hypersomnia, 3 had only insomnia and 3 had both during their episodes, while 5 patients reported hyperphagia, 11 reduced appetite and 2 no change in appetite. Ictal EEG revealed evidence of sleep, while polysomnography showed reduced rapid eye movement (REM) latency and normal sleep architecture during the episode. MRI was normal in all patients, except one who showed non-specific abnormalities. All patients showed improvement with carbamazepine. CONCLUSION: There are many patients with episodic alteration in sleep, appetite and behaviour with a course and treatment response similar to the classical Kleine-Levin syndrome, who otherwise do not fit the classical description for diagnosis of this condition. PMID: 17644478

Sleep. 2007 Jun;30(6):683-702. Sleep and sex: what can go wrong? A review of the literature on sleep related disorders and abnormal sexual behaviors and experiences. Schenck CH, Arnulf I, Mahowald MW Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center, USA. STUDY OBJECTIVES: To formulate the first classification of sleep related disorders and abnormal sexual behaviors and experiences. DESIGN: A computerized literature search was conducted, and other sources, such as textbooks, were searched. RESULTS: Many categories of sleep related disorders were represented in the classification: parasomnias (confusional arousals/sleepwalking, with or without obstructive sleep apnea; REM sleep behavior disorder); sleep related seizures; Kleine-Levin syndrome (KLS); severe chronic insomnia; restless legs syndrome; narcolepsy; sleep exacerbation of persistent sexual arousal syndrome; sleep related painful erections; sleep related dissociative disorders; nocturnal psychotic disorders; miscellaneous states. Kleine-Levin syndrome (78 cases) and parasomnias (31 cases) were most frequently reported. Parasomnias and sleep related seizures had overlapping and divergent clinical features. Thirty-one cases of parasomnias (25 males; mean age, 32 years) and 7 cases of sleep related seizures (4 males; mean age, 38 years) were identified. A full range of sleep related sexual behaviors with self and/or bed partners or others were reported, including masturbation, sexual vocalizations, fondling, sexual intercourse with climax, sexual assault/rape, ictal sexual hyperarousal, ictal orgasm, and ictal automatism. Adverse physical and/or psychosocial effects from the sleepsex were present in all parasomnia and sleep related seizure cases, but pleasurable effects were reported by 5 bed partners and by 3 patients with sleep related seizures. Forensic consequences were common, occurring in 35.5% (11/31) of parasomnia cases, with most (9/11) involving minors. All parasomnias cases reported amnesia for the sleep-sex, in contrast to 28.6% (2/7) of sleep related seizure cases. Polysomnography (without penile tumescence monitoring), performed in 26 of 31 parasomnia cases, documented sexual moaning from slow wave sleep in 3 cases and sexual intercourse during stage 1 sleep/wakefulness in one case (with sex provoked by the bed partner). Confusional arousals (CAs) were diagnosed as the cause of “sleepsex” (“sexsomnia”) in 26 cases (with obstructive sleep apnea [OSA] comorbidity in 4 cases), and sleepwalking in 2 cases, totaling 90.3% (28/31) of cases being NREM sleep parasomnias. REM behavior disorder was the presumed cause in the other 3 cases. Bedtime clonazepam therapy was effective in 90% (9/10) of treated parasomnia cases; nasal continuous positive airway pressure therapy was effective in controlling comorbid OSA and CAs in both treated cases. All five treated patients with sleep related sexual seizures responded to anticonvulsant therapy. The hypersexuality in KLS, which was twice as common in males compared to females, had no reported effective therapy. CONCLUSIONS: A broad range of sleep related disorders associated with abnormal sexual behaviors and experiences exists, with major clinical and forensic consequences. PMID: 17580590

J Am Acad Child Adolesc Psychiatry. 2007 May;46(5):551-2 Kleine-Levin syndrome mimicking mania. Masi G, Mucci M, D’Acunto G. Type: Letter Orv Hetil. 2007 Apr 22;148(16):723-30. [Some neurological and psychiatric complications of the disorders of the hypothalamo-hypophyseal system] [Article in Hungarian] Aszalós Z. Semmelweis Egyetem, Altalános Orvostudományi Kar, II. Belgyógyászati Klinika, Connection between the central nervous system and the endocrine system is extremely complex. The hypothalamus serves as a crucial centre for the integration and coordination of autonomic functions by neuronal and hormonal pathways. It plays a central role in the homeostatic regulation of internal physiological conditions. It controls growth and reproduction, stress reactions, and determines rhythmicity, periodicity and timing of physiological processes. Beside its well-known functions, antidiuretic hormone has a role in social behavior as it enhances aggression via vasopressin receptor 1A. Oxitocin is affected in the formation of maternal behavior, and in other social interactions, like the pair bounding, as well as in analgesia and pain modulation. The corticotrop-releasing hormone acts as a neurotransmitter, it has a special role in stress-behavior, anxiety, and depression, and it blocks deep sleeping. Among the neurotransmitters and neuropeptids of the hypothalamus, serotonin, norepinephrine, GABA, cholecystokinin, neuropeptide-Y, Agouti-related protein, alpha-MSH and ghrelin have essential importance in the eating disorders. The levels of leptin and galanin determine whether formation of anabolic or catabolic neurotransmitters should take place. In the thermoregulation the central thermoreceptors play role, and suprachiasmatic nucleus is responsible for circadian rhythm, through “timing genes”. The diseases of the hypothalamus cause most frequently bulimia or anorexia, hypersomnia, impotency, and attacks of anxiety. The most common expansive process of the hypothalamus is craniopharyngioma. The lack or diminution of vasopressin causes diabetes insipidus, while inappropriate antidiuretic hormone secretion induces Schwartz-Barter syndrome. Fröhlich-, Kleine-Levin- or Prader-Willi syndromes have characteristic neuropsychiatric features. The main psychiatric symptom of hypopituitarism is a combination of dementia and delirium. The most characteristic neurological sign of pituitary adenoma is the visual field defect. Carpal tunnel syndrome, obstructive sleeping apnoe and headache are typical neurological features in somatotrop adenomas. Publication Type: Review

Brain. 2005 Dec;128(Pt 12):2763-76. Epub 2005 Oct 17. Kleine-Levin syndrome: a systematic review of 186 cases in the literature. Arnulf I, Zeitzer JM, File J, Farber N, Mignot E. Stanford University Center for Narcolepsy, Palo Alto, CA, USA Abstract Kleine-Levin syndrome (KLS) is a rare disorder with symptoms that include periodic hypersomnia, cognitive and behavioural disturbances. Large series of patients are lacking. In order to report on various KLS symptoms, identify risk factors and analyse treatment response, we performed a systematic review of 195 articles, written in English and non-English languages, which are available on Medline dating from 1962 to 2004. Doubtful or duplicate cases, case series without individual details and reviews (n = 56 articles) were excluded. In addition, the details of 186 patients from 139 articles were compiled. Primary KLS cases (n = 168) were found mostly in men (68%) and occurred sporadically worldwide. The median age of onset was 15 years (range 4-82 years, 81% during the second decade) and the syndrome lasted 8 years, with seven episodes of 10 days, recurring every 3.5 months (median values) with the disease lasting longer in women and in patients with less frequent episodes during the first year. It was precipitated most frequently by infections (38.2%), head trauma (9%), or alcohol consumption (5.4%). Common symptoms were hypersomnia (100%), cognitive changes (96%, including a specific feeling of derealization), eating disturbances (80%), hypersexuality (43%), compulsions (29%), and depressed mood (48%). In 75 treated patients (213 trials), somnolence decreased using stimulants (mainly amphetamines) in 40% of cases, while neuroleptics and antidepressants were of poor benefit. Only lithium (but not carbamazepine or other antiepileptics) had a higher reported response rate (41%) for stopping relapses when compared to medical abstention (19%). Secondary KLS (n = 18) patients were older and had more frequent and longer episodes, but had clinical symptoms and treatment responses similar to primary cases. In conclusion, KLS is a unique disease which may be more severe in female and secondary cases. PMID:  16230322

Arq Neuropsiquiatr. 2007 Mar;65(1):150-2. Kleine-Levin syndrome: interface between neurology and psychiatry. Justo LP, Calil HM, Prado-Bolognani SA, Muszkat M. Department of Psychobiology, Federal University of São Paulo, 01333-000 São Paulo, SP, Brazil. We report the first episode of Kleine-Levin (KLS) syndrome in a 17-year-old male. The illness onset, clinical features, neuropsychological evaluation and polysomnographic recording are described. Typical symptoms hypersomnia, hyperphagia and sexual disinhibition were observed besides behavioral disturbances, polysomnographic and neuropsychological alterations. Behavioral disturbances similar to a manic episode including psychotic symptoms were relevant. The pharmacologic treatment included lithium, methylphenidate and risperidone. The introduction of risperidone aimed the control of psychotic symptoms and the persistent manifestations of hypersexuality after sleepiness control and to the best of our knowledge there are no other reports regarding risperidone use for KLS in the literature.

Sleep Med. 2006 Dec;7(8):649-51. Epub 2006 Nov 13. Kleine-Levin syndrome in a 14-year-old girl: CSF hypocretin-1 measurements Podestá C, Ferreras M, Mozzi M, Bassetti C, Dauvilliers Y, Billiard M. Department of Neurology FLENI, Sleep Laboratory, Buenos-Aires, Argentina. CSF hypocretin-1 measurements were performed during a period of hypersomnia and during an asymptomatic interval in a 14-year-old girl affected with severe Kleine-Levin syndrome. A twofold decrease in hypocretin-1 was evidenced during the period of hypersomnia in comparison with the asymptomatic interval. Together with previous data, this result is in favour of recurrent dysfunction at the hypothalamic level in Kleine-Levin syndrome. Publication Type: Case Report

Curr Opin Pulm Med. 2006 Nov;12(6):383-9. Gender differences in sleep disorders. Krishnan V, Collop NA. Division of Pulmonary and Critical Care, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. PURPOSE OF REVIEW: To evaluate recent evidence regarding gender differences in sleep. RECENT FINDINGS: Women have better sleep quality compared with men, with longer sleep times, shorter sleep-onset latency and higher sleep efficiency. Despite this, women have more sleep-related complaints than men. The amount of slow-wave sleep decreases with age in men and women. Normal physiologic periods, including puberty, menstruation, pregnancy, and menopause, are associated with alterations in sleep patterns. Gender differences in normal sleep may underlie the observed differences in risk of sle

Publication Type:  Review Sleep. 2005 Aug 1;28(8):955-60. SPECT findings in the Kleine-Levin syndrome. Huang YS, Guilleminault C, Kao PF, Liu FY. Department of Psychiatry, Chang Gung Memorial University Hospital, Taipei, Taiwan. Abstract STUDY OBJECTIVES: The Kleine-Levin Syndrome, is a rare disorder with onset during teenage years, but little is known on etiopathogenesis. Seven subjects with Kleine-Levin Syndrome accumulated over time had systematic SPECT studies during (n=5) and out (n=7) of the symptomatic period. SUBJECTS: Seven boys with symptom onset between 11 and 17 years of age and at least 2 episodes per year were followed for a mean of 6 years. METHODS: Electroencephalogram awake-asleep, computed tomography scan, and magnetic resonance imaging studies were performed before Tc-99m ECD single photon emission tomography (SPECT) obtained during day 4 or 5 (n=5) and at least 1 month away from the symptomatic period (n=7). RESULTS: All imaging tests except SPECT were normal. Hypoperfusion of both thalami were seen during the symptomatic period that completely disappeared during the asymptomatic period. Hypoperfusion in other regions were also noted in some, but not all subjects. They persisted during the asymptomatic period in 2 cases over the temporal lobe (2/7 cases), frontal lobe (1/7 cases), and basal ganglia (1/7 cases). The largest amount of persistent hypoperfusion was seen in the subject with longest clinical evolution. CONCLUSION: Hypoperfusion of the thalamus is a consistent finding during the symptomatic period, but perfusion abnormalities may persist even during the asymptomatic period. The longer the duration of the syndrome, the more extended the hypoperfusion regions during the asymptomatic period. PMID: 16218078

Comment in Sleep. 2005 Aug 1;28(8):915-6. The Kleine-Levin syndrome: a paramedian thalamic dysfunction? Billiard M. Neurology. 2002 Dec 10;59(11):1739-45. Kleine-Levin Syndrome: an autoimmune hypothesis based on clinical and genetic analyses. Dauvilliers Y, Mayer G, Lecendreux M, Neidhart E, Peraita-Adrados R, Sonka K, Billiard M, Tafti M. Neurologie B, Hôpital Gui-de-Chauliac, Montpellier, France. Abstract BACKGROUND: Kleine-Levin syndrome (KLS) is a rare disorder of unknown etiology. Pathophysiologic hypotheses include a hypothalamic dysfunction and abnormalities in the central serotonin and dopamine metabolism. Several clinical symptoms also suggest an underlying autoimmune process. OBJECTIVE: To systematically investigate patients with KLS with reference to the available hypotheses. METHODS: The authors collected clinical, polysomnographic, CSF, CT, and MRI records and analyzed gene polymorphisms of HLA-DQB1, tryptophan hydroxylase (TpH), and catechol-O-methyltransferase (COMT) in 30 unrelated patients with KLS and their families. The genotype data were contrasted with data from a normal control population. RESULTS: Only human leukocyte antigen (HLA)-DQB1*0201 allele frequency was significantly increased in patients with KLS. Three patients with KLS but none of the control subjects were DQB1*0201 homozygous. Two affected subjects from the same family were DQB1*0201 homozygous. In 17 DQB1*0201 heterozygous parents, 11 (64.7%) had transmitted this allele, suggesting a preferential transmission. CONCLUSION: These findings, together with the young age at onset, the recurrence of symptoms, and the frequent infectious precipitating factors, suggest an autoimmune etiology for Kleine-Levin syndrome. PMID:  12473762

J Sleep Res. 2001 Dec;10(4):337-41. Clinical and polysomnographic characteristics of 34 patients with Kleine-Levin syndrome. Gadoth N, Kesler A, Vainstein G, Peled R, Lavie P. Department of Neurology, Sapir Medical Center, Meir General Hospital, Kfar Saba and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Abstract There is only scant information on sleep characteristics and long-term follow-up in patients with Kleine-Levin syndrome (KLS). This study describes the clinical course, results of polysomnography and long-term follow-up in a relatively large group of patients with KLS. During the years 1982-97, we encountered 34 patients (26 males and eight females) with KLS. We were able to obtain the original polysomnographs from 28 males and four females. In 25 patients, data regarding their present state of health were obtained. Fourteen agreed to be present at a detailed interview and examination while 11 gave the information by phone. The mean age at onset was 15.8 +/- 2.8 years and the mean diagnostic delay, 3.8 +/- 4.2 years. The mean duration of a single hypersomnolent attack was 11.5 +/- 6.6 days. The main abnormal findings extracted out of 35 polysomnographs obtained from 32 patients during and/or in-between attacks included: decreased sleep efficiency, and frequent awakenings from sleep stage 2. All 25 patients reported present perfect health, with no evidence of behavioral or endocrine dysfunction. In adolescents with periodic hypersomnia, the diagnosis of KLS should be explored. Sleep recordings during a hypersomnolent period will often show frequent awakenings from sleep stage 2. The long-term prognosis is excellent. PMID:  11903864

Sleep. 2000 Jun 15;23(4):563-7. Kleine Levin syndrome (KLS) in young females. Kesler A, Gadoth N, Vainstein G, Peled R, Lavie P. Department of Neurology, Sapir Medical Center, Meir General Hospital, Kfar Saba, the Sackler Faculty of Medicine, Tel-Aviv University, Israel. Abstract During the years 1982-1998, we encountered 7 adolescents and one young woman suffering from KLS. In 4 patients, hypersomnolence was accompanied by hyperphagia and hypersexuality, while in the remaining 4, recurrent hypersomnia was the only symptom. Mean age at onset of hypersomnolent attacks was 15.1+/-3.5 yrs. The mean duration of a hypersomnolent attack was 9.9+/-5.4 days, and the number of attacks per patient was 6.2+/-3.4. Polysomnographic recordings from 3 patients inbetween attacks, and from one patient during an attack, showed relatively normal sleep structure with decreased sleep efficiency due to numerous awakenings from sleep stage 2. Besides the recurrent hypersomnia, all patients enjoyed good health, with no evidence of behavioral or endocrine dysfunction. Similarly aged males with KLS from our clinic and previously reported females, had similar clinical features. PMID:  10875563

Sleep 1998 May 1;21(3):278-84 Endocrinological and polysomnographic findings in Kleine-Levin syndrome: no evidence for hypothalamic and circadian dysfunction. Mayer G, Leonhard E, Krieg J, Meier-Ewert K Hephata Klinik Schwalmstadt-Treysa, Germany. Abstract:  Five subjects—four men, ages 17-28, and one woman, age 30—with Kleine-Levin syndrome were investigated during symptomatic (SP) and asymptomatic (ASP) periods. Investigations comprised medical history, MRI, polysomnography, 24-hour hormone profile of human growth hormone, melatonin, TSH, cortisol and FSH (in the woman only) assessed every 2 hours, actimetry, and sleep logs. Medical history confirmed presence of the three symptoms diagnostic of typical Kleine-Levin syndrome: hypersomnia, excessive food intake, and psychic alteration. MRIs of the brain were normal in all patients. Symptomatic periods were triggered by unspecific events, such as infection, sleep deprivation, and alcohol. Polysomnography revealed low sleep efficiency during SPs, decreased amount of slow-wave sleep, and high frequency of stage shifts, indicating sleep fragmentation. Mean 24-hour growth hormone levels were reduced during the SPs in only two patients. Their hGH peaks were dissociated from slow-wave sleep during attacks and intervals, often occurring during wake time. Twenty-four-hour melatonin levels were increased during the SPs in all patients, but were lower in two patients during the nocturnal sleep period. Cortisol, TSH and FSH did not reveal important differences between attacks and intervals. Except for hGH, all hormones had normal circadian excretion during symptomatic and asymptomatic periods. Amplitude of nocturnal activity as assessed by actimetry was significantly increased in two patients, whereas amplitude of daytime activity was significantly reduced in three patients. Actimetry and sleep logs demonstrated prolonged sleep phases during SPs. Our investigation could confirm changes of sleep structure described in the literature. The neuroendocrinological findings could not confirm decreased hGH and cortisol and increased TSH levels during SPs, as previously reported in single cases by many authors. Endocrinological findings did not support an underlying circadian disorder in KLS. An updated search can be done at the US National Library of Medicine, National Institute of Health (NIH) on-line resource: http://www.ncbi.nlm.nih.gov/pubmed/