KLS Medical Publications

Most published articles on KLS in the medical and scientific literature are reports of one or two KLS cases by an attending physician. While helpful in confirming and sometimes reporting new observations, these ‘case reports’ usually do not significantly contribute to a better understanding of KLS.

In the last few years, there have been a few more informative studies and review articles based on observations and conclusions from a larger cohort of KLS cases.

Below are papers published in English where 5 or more KLS patients were studied as a group.


May 2020-present.
What is this project? The basis of this research is testing for the presence of
antibodies in patient sera that react with tissue proteins from the hypothalamus, thalamus, caudate nucleus, and portion of the parietotemporal region. This will be found through the biochemical methods called SDS-PAGE and immunohistochemistry. SDS-PAGE uses electrophoresis in which an electrical current is applied to a gel,
separating proteins by their mass (otherwise known as western blotting). Protein extraction from brain cells and tissues will be applied to the electrophoretic gel, followed by repeating this with patient sera at several concentrations. This leads to the ability to detect proteins in patients’ sera (antibodies) that react with the proteins from the brain extract. Following this method, immunohistochemistry will be completed. Sections of normal brain tissue will be cut micrometers thin, and patient sera will be applied to these sections of brain tissue. Normal brain tissue is chosen because it is a proper aspect of control and serum would inevitable bind to abnormal tissue. Patients are predominately normal with regard to neurological function…until the onset of KLS. Both of these are
readily used in biochemistry and immunology, and have been successful in studying many other diseases and disorders. Patient sera will be obtained from collaborator Dr. Arnulf, as well as a positive control of narcolepsy. Brain tissue will be obtained from one of the repositories through the Neurobiobank of the NIH. Why? Most prior studies on KLS have focused on analyzing brain function through imaging, blood and spinal fluid analysis, and treatment trials for patients. There have been very few projects that explore the pathophysiology of this disorder, and none have been performed using both patient serum and brain tissue. This project has the potential to provide critical insights into the immunopathology and etiology mechanisms of KLS patients.

IV steroids during long episodes of Kleine-Levin syndrome.

Abstract: Objective: To retrospectively compare the benefits (episode cessation) and risks of IV methylprednisolone (IV-MP) vs abstention during prolonged Kleine-Levin syndrome (KLS) episodes. Methods: A total of 26 patients with KLS received 1 g/d IV-MP for 3 days during 1 to 6 episodes each (totaling 43 IV-MP sessions). The change of episode duration with IV-MP (vs previous episode duration) was compared with the change duration between 2 consecutive episodes in 48 untreated patients matched for age, sex, age at KLS onset, number of episodes, and disease duration (more treated than untreated patients had long episodes). Results: Eleven patients (42.3%) had an episode that was at least 1 week shorter than the preceding one when they received IV-MP therapy, whereas shorter episodes were significantly less frequent (10.4%) in the untreated group. This benefit was more marked (65.5% responders, 12 fewer days in an episode vs 0 days in the untreated patients) when IV-MP was infused before the 10th day of the episode. Mild, transient adverse effects (insomnia, muscle pain, nervousness/restlessness, but no manic switching) were reported by 61.3% of patients. No specific responder profile was identified.


March 12, 2018; 22(3): 613–623.
Department of Internal Medicine, College of Medicine, Al Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia, Division of Medicine and Therapeutics, Ipswich Hospital NHS Trust and University of Suffolk, Heath Road, Ipswich, Suffolk, IP4 5PD UK, The University Sleep Disorders Center and National Plan for Science and Technology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
Abstract: Kleine-Levin syndrome (KLS) is the commonest recurrent sleep disorder, with a prevalence of 1–2 per million population. Clear diagnostic criteria are now defined, but effective treatment remains elusive. The significant body of published literature allows consideration of possible aetiological mechanisms, an understanding of which could guide the development of therapeutic strategies. Functional imaging studies have been inconclusive; although diencephalic abnormalities are a common finding, no consistent pattern has emerged, and these studies have not revealed the mechanism(s) underlying the development of the abnormalities detected. An autoimmune aetiology is consistent with the available data. In this review, we argue that, in order to further our understanding of KLS, there needs to be a co-ordinated international effort to standardise approaches to functional imaging studies, genetic analyses that specifically address the possibility of an autoimmune aetiology, and clinical trials of immunosuppressive therapies.

SLEEP, Vol. 39, No. 2, 2016
Ginevra Uguccioni, MS, Sophie Lavault, MS, Charlotte Chaumereuil, MS, Jean-Louis Golmard, MD, PhD,  Jean-François Gagnon, PhD, Isabelle Arnulf, MD, PhD
Abstract: Study Objectives: In Kleine-Levin syndrome (KLS), episodes of hypersomnia, cognitive, and behavioral disturbances alternate with asymptomatic periods. Because 50% of patients report decreased academic performances, we evaluated their cognitive status during asymptomatic periods, determinants of deficits, and changes during follow-up. Methods: The cognitive assessment during asymptomatic periods in all consecutive patients with typical KLS and healthy controls included the non-verbal intelligence quotient (Raven Progressive Matrices), the Trail Making Test, the Stroop Color-Word Test, the Wechsler Memory Test, verbal fluencies, the Free and Cued Learning Memory Test, and the Rey-Osterreith Complex Figure. Cognitive status was reevaluated after 0.5 to 2 y in 44 patients. Results: At baseline, compared with the 42 controls, the 122 patients with KLS exhibited lower non-verbal intelligence quotient, speed of processing, attention, and reduced retrieval strategies in episodic memory. Higher episode frequency, shorter episode duration, shorter time since last episode, deeper sleep, and megaphagia during episodes predicted impaired memory. The visuoconstructional abilities and non-verbal memory were intact. After a mean follow-up of 1.7 ± 1.0 y, the episode frequency decreased from 4.6 ± 4.8 to 1.7 ± 1.9/y. The logical reasoning and attention improved, the processing speed
remained low, and the retrieval strategies in verbal memory further worsened. Conclusions: In this field study, one-third of patients with KLS have long-term cognitive deficits affecting retrieval and processing speed. Cognitive function should be systematically tested in patients with KLS, which appears important to help patients in their academic studies.

Apr 1, 2016; 39(4): 855–860

Cerebrospinal Fluid Orexin A Levels and Autonomic Function in Kleine-Levin Syndrome.

Jing Yu Wang, MD, Fang Han, MD, Song X. Dong, MD, Jing Li, BS, Pei An, BS, Xiao Zhe Zhang, MD, Yuan Chang, MD, Long Zhao, BS, Xue Li Zhang, BS, Ya Nan Liu, MD, Han Yan, MD, Qing Hua Li, MD, Yan Hu, MD, Chang Jun Lv, MD, Zhan Cheng Gao, MD, and Kingman P. Strohl, MD

Abstract: Study Objectives: Kleine-Levin syndrome (KLS) is a rare disorder of relapsing sleepiness. The hypothesis was that the syndrome is related to a change in the vigilance peptide orexin A. Methods: From 2002 to 2013, 57 patients with relapsing hypersomnolence were clinically assessed in a referral academic center in Beijing, China, and 44 (28 males and 16 females; mean age 18.3 ± 8.9 y (mean ± standard deviation, range 9–57 y) were determined to have clinical and behavioral criteria consistent with KLS. Cerebrospinal fluid orexin A levels and diurnal blood pressure were measured in relapse versus remission in a subgroup of patients. Results: Presenting symptoms included relapsing or remitting excessive sleepiness–associated parallel complaints of cognitive changes (82%), eating disorders (84%); depression (45%); irritability (36%); hypersexuality (18%); and compulsions (11%). Episodes were 8.2 ± 3.3 days in duration. In relapse, diurnal values for blood pressure and heart rate were lower (P < 0.001). In a subgroup (n = 34), cerebrospinal fluid orexin A levels were ∼31% lower in a relapse versus remission (215.7 ± 81.5 versus 319.2 ± 95.92 pg/ml, P < 0.001); in three patients a pattern of lower levels during subsequent relapses was documented.


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

Smaranda Leu-SemenescuThibault Le CorvecElisabeth GroosSophie LavaultJean-Louis GolmardIsabelle 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.24 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 (34). 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 (57). 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 (810). SPECT has shown hypoperfusion of the bilateral thalami during hypersomnic periods, which was not persistent during the asymptomatic periods (61112). Despite convincing data indicating thalamic involvement, the neuropathology of KLS remains unknown.

Copyright: © 2014 Engström, Karlsson and Landtblom.


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


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


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.


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


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


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


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/

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