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.
Lancet Neurol. 2012 Oct;11(10):918-28. doi: 10.1016/S1474-4422(12)70187-4.
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. firstname.lastname@example.org
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.
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.
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.
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.
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.
Functional magnetic resonance imaging (fMRI) applying a verbal working memory task was used in conjunction with a paper-and-pencil version of the task.
Eight patients with KLS and 12 healthy volunteers participated in the study.
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.
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.
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
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.
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.
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.
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.
No studies met the inclusion criteria for this systematic review.
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.
Department of Neurology, Hull Royal Infirmary, Hull, UK.
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.
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.
Kleine-Levin syndrome is a rare disorder characterized by relapsing-remitting episodes of hypersomnia, cognitive disturbances, and behavioral disturbances, such as hyperphagia and hypersexuality.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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).
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.
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.
Comment in Sleep. 2005 Aug 1;28(8):915-6.
The Kleine-Levin syndrome: a paramedian thalamic dysfunction?
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.
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.
To systematically investigate patients with KLS with reference to the available hypotheses.
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.
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.
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.
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.
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.
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.
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.
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/