Elsevier

The Lancet Neurology

Volume 11, Issue 10, October 2012, Pages 918-928
The Lancet Neurology

Review
Diagnosis, disease course, and management of patients with Kleine-Levin syndrome

https://doi.org/10.1016/S1474-4422(12)70187-4Get rights and content

Summary

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.

Introduction

Kleine-Levin syndrome is characterised by the sudden occurrence of reversible but recurrent episodes of marked hypersomnia associated with cognitive and behavioural disturbances. Although it was identified as a specific disorder more than a century ago,1 the underlying pathophysiology remains unknown. Symptoms and disease course follow typical patterns, but Kleine-Levin syndrome is often misdiagnosed as depression, bipolar disorder, psychosis, seizures, or intoxication,2, 3, 4 partly because it is rare (around 1·5 cases per million population) and infrequently encountered by clinicians.

The disorder is at the interface of neurology and psychiatry. No objective biochemical, neuropathological, or structural imaging alterations have been identified. Acute onset of cognitive impairment, apathy, derealisation, altered perception of the environment, disinhibited behaviour, anxiety, visual hallucinations, and delusions suggests that the associative cortex is affected. This hypothesis is supported by functional imaging studies, which have shown decreased temporal-lobe, frontal-lobe, and thalamic activity during episodes.

Although the disorder was named Kleine-Levin syndrome in the 20th century, a case was reported in 1862 by Brierre de Boismont5 of a normally quiet child who had recurrent sleeping episodes after which he sang and played loudly and ate voraciously. Critchley2 named the syndrome in 1962 on the basis of his own patients and two earlier reports by Kleine1 and Levin6 of adolescent boys with periodic hypersomnia plus increased appetite.

We base this Review on data from two systematic analyses of case reports and findings from international case series.3, 4, 7, 8, 9, 10 Functional imaging studies of the brain are also discussed. We explore the epidemiology and pathology. We also provide a comprehensive description of the core and the wider range of symptoms of the syndrome.

Section snippets

Epidemiology

The prevalence of Kleine-Levin syndrome is unknown, but it is rare. In France, from our own experience in a national reference centre for Kleine-Levin syndrome and from various reports, prevalence is estimated to be 1·5 cases per million population.3, 4, 7, 8, 9, 10 Most cases are seen in boys and men (68–87%).4, 10 Most patients develop the disorder as adolescents, but several cases in children older than 9 years10 and adults older than 35 years11 have been reported. The syndrome has been

Disease onset and course

Kleine-Levin syndrome is classified as a periodic hypersomnia, although it presents with multiple clinical characteristics. Diagnostic criteria have been defined (panel 1).28 The first episode is frequently interpreted as an unexplained infection, as it closely resembles flu-like or encephalitis symptoms. A diagnosis is generally made only after several episodes have occurred. A typical episode progresses rapidly in severity within a few hours to days. The patient becomes increasingly tired,

Presentation and symptoms during episodes

During episodes patients are predominantly exhausted, apathetic, exhibit cognitive impairment, and report a feeling of derealisation (webvideo 1); irritability and disinhibition (hyperphagia and hypersexuality) are seen less consistently. Patients experience sudden and extreme fatigue and an irresistible need to rest. Typically, the patient withdraws to his or her bedroom and sleeps for 15–21 h per day for 1 week to several weeks.4 Sleeping can occur during the night or day with no clear

Menstruation-related hypersomnia

Episodes of hypersomnia have been reported just before or during menstruation.1, 66 They are rare, however, and have been identified in only 18 women worldwide.8 Episodes in these cases are associated with compulsive eating (12 [65%]), sexual disinhibition (in five [29%]), and depressive mood (in six [35%]).8 Episodes last 3–15 days and occur fewer than three times per year on average. A boy with Kleine-Levin syndrome had a sister affected by menstruation-related hypersomnia27 and, therefore,

Brain functional imaging studies

Brain morphology in patients with Kleine-Levin syndrome is usually normal on MRI and CT. By contrast, widespread abnormalities are frequently seen on SPECT. In 27 children with Kleine-Levin syndrome, unilateral hypoperfusion was seen in the left or right thalamus (in 18 [67%] and three [11%], respectively) and in right or left basal ganglia (six [22%] and three [11%], respectively).10 Hypoperfusion has also been seen in the mesial temporal lobe64, 71, 72, 73 and the frontal lobe.71, 74, 75 The

Management and treatment

Drug trials in Kleine-Levin syndrome have frequently shown disappointing results, and none has been placebo-controlled or blinded. Most patients benefit from reassurance, maintenance of a simple hygiene routine, and management at home (panel 4). Selected drugs might help to manage symptoms during episodes and could even prevent recurrence (table 2). During episodes, 22 (20%) of 108 patients4 and 16 (40%) of 40 physicians7 reported that stimulants (modafinil, methylphenidate, and amphetamine)

Possible pathophysiological mechanisms

Evidence suggests that a localised but multifocal encephalopathy occurs during episodes of Kleine-Levin syndrome, as functional imaging and EEG indicate thalamic, temporal-lobe, and frontal-lobe involvement.39 Temporal-lobe dysfunction might explain altered cognition and derealisation, and frontal-lobe involvement could explain apathy and disinhibition. Thalamus and hypothalamus involvement, which have been frequent findings, could explain hypersomnia or apparent sleep-like behaviour.72 Brain

Conclusions

Kleine-Levin syndrome is a unique disease entity with specific causes. The framework of core symptoms of hypersomnia, slowed cognition, apathy, and derealisation should supersede the previously recognised hypersomnia-hyperphagia-hypersexuality triad. Focus on these characteristics of the syndrome should improve disease recognition and pathophysiological research. Hyperphagia, hypersexuality, and inappropriate social behaviour should not be viewed as independent symptoms but as expressions of

Search strategy and selection criteria

References for this Review were identified through searches of PubMed with the terms “Kleine-Levin syndrome”, “periodic”, “recurrent”, and “hypersomnia”, and through searches of the authors' own files. Articles had to be published between January, 1966, and May, 2012. Papers published in any language were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope and aims of this Review.

References (90)

  • SS Papacostas et al.

    The Kleine-Levin syndrome. Report of a case and review of the literature

    Eur Psychiatry

    (2000)
  • I Arnulf et al.

    Kleine-Levin syndrome: state of the art

    Rev Neurol (Paris)

    (2008)
  • S Malhotra et al.

    A clinical study of Kleine-Levin syndrome with evidence for hypothalamic-pituitary axis dysfunction

    Biol Psychiatry

    (1997)
  • F Muratori et al.

    Efficacy of lithium treatment in Kleine-Levin syndrome

    Eur Psychiatry

    (2002)
  • NM Mukaddes et al.

    Carbamazepine for Kleine-Levin syndrome

    J Am Acad Child Adolesc Psychiatry

    (1999)
  • MI Boulos et al.

    Recurrent hypersomnia due to occult hepatic encephalopathy

    Sleep Med

    (2012)
  • P Cortelli et al.

    Endozepines in recurrent stupor

    Sleep Med Rev

    (2005)
  • YC Lo et al.

    PET finding in Kleine-Levin syndrome

    Sleep Med

    (2012)
  • ME Billings et al.

    Dynamic fMRI changes in Kleine-Levin syndrome

    Sleep Med

    (2011)
  • MQ Hoexter et al.

    Greater reduction of striatal dopamine transporter availability during the symptomatic than asymptomatic phase of Kleine-Levin syndrome

    Sleep Med

    (2010)
  • C Podesta et al.

    Kleine-Levin syndrome in a 14-year-old girl: CSF hypocretin-1 measurements

    Sleep Med

    (2006)
  • P Bourgin et al.

    CSF hypocretin-1 assessment in sleep and neurological disorders

    Lancet Neurol

    (2008)
  • W Kleine

    Periodische Schlafsucht

    Mschr Psychiat Neurol

    (1925)
  • M Critchley

    Periodic hypersomnia and megaphagia in adolescent males

    Brain

    (1962)
  • Y Dauvilliers et al.

    Kleine-Levin syndrome: an autoimmune hypothesis based on clinical and genetic analyses

    Neurology

    (2002)
  • I Arnulf et al.

    Kleine-Levin syndrome: a systematic study of 108 patients

    Ann Neurol

    (2008)
  • A Brierre de Boismont

    Des hallucinations ou histoire raisonnée des apparitions, des visions, des songes, de l'extase, des rêves, du magnétisme et du somnambulisme

    (1862)
  • M Levin

    Periodic somnolence and morbid hunger: a new syndrome

    Brain

    (1936)
  • I Arnulf et al.

    Kleine-Levin syndrome: a systematic review of 186 cases in the literature

    Brain

    (2005)
  • N Gadoth et al.

    Clinical and polysomnographic characteristics of 34 patients with Kleine-Levin syndrome

    J Sleep Res

    (2001)
  • Y Huang et al.

    Relationship between Kleine-Levin syndrome and upper respiratory infection in Taiwan

    Sleep

    (2012)
  • A Hegarty et al.

    Autonomic events in Kleine-Levin syndrome

    Am J Psychiatry

    (1990)
  • A Kesler et al.

    Kleine-Levin syndrome (KLS) in young females

    Sleep

    (2000)
  • A Gallinek

    The Kleine-Levin syndrome: hypersomnia, bulimia, and abnormal mental states

    World Neurol

    (1962)
  • F Rosenow et al.

    Multiple sleep latency test and polysomnography in diagnosing Kleine-Levin syndrome and periodic hypersomnia

    J Clin Neurophysiol

    (2000)
  • RS Sagar et al.

    Interepisodic morbidity in Kleine-Levin syndrome

    Br J Psychiatry

    (1990)
  • NM Mukaddes et al.

    The psychiatric symptomatology in Kleine-Levin syndrome

    Child Psychiatry Hum Dev

    (1999)
  • Q Zhou

    Kleine-Levin syndrome

    Chin Clin Neurol

    (2004)
  • J Russell et al.

    Kleine-Levin syndrome: a case report

    Aust N Z J Psychiatry

    (1992)
  • IO Malomo et al.

    Kleine-Levin syndrome: case report

    East Afr Med J

    (1998)
  • R Peraita-Adrados et al.

    Monozygotic twins affected with Kleine-Levin syndrome

    Sleep

    (2012)
  • T Ueno et al.

    Monozygotic twins concordant for Kleine-Levin syndrome

    BMC Neurol

    (2012)
  • JD Katz et al.

    Familial Kleine-Levin syndrome: two siblings with unusually long hypersomnic spells

    Arch Neurol

    (2002)
  • R Rocamora et al.

    Familial recurrent hypersomnia: two siblings with Kleine-Levin syndrome and menstrual-related hypersomnia

    J Child Neurol

    (2010)
  • The international classification of sleep disorders—second edition (ICSD-2)

    (2005)
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