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.
ReviewDiagnosis, disease course, and management of patients with Kleine-Levin syndrome
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 (90)
- et al.
Recurrent hypersomnia: a review of 339 cases
Sleep Med Rev
(2011) - et al.
Sleep patterns in Kleine-Levin syndrome
Electroencephalogr Clin Neurophysiol
(1979) - et al.
Clinical characteristics and HLA typing of a family with Kleine-Levin syndrome
Sleep Med
(2008) - et al.
The EEG in a case of periodic hypersomnia
Electroencephalogr Clin Neurophysiol
(1969) - et al.
A case report of Kleine-Levin syndrome in an adolescent girl
Psychosomatics
(2001) - et al.
A case of PANDAS with Kleine-Levin type periodic hypersomnia
Sleep Med
(2012) Valproic acid for Kleine-Levin syndrome
J Am Acad Child Adolesc Psychiatry
(1997)- et al.
Persistent deficits of visual recall in Kleine-Levin syndrome
J Clin Neurosci
(2011) - et al.
Posttraumatic Kleine-Levin syndrome: a case report
Eur Psychiatry
(2004) - et al.
Recurrent hypersomnia in two adolescent males with Asperger's syndrome
J Am Acad Child Adolesc Psychiatry
(1992)
The Kleine-Levin syndrome. Report of a case and review of the literature
Eur Psychiatry
Kleine-Levin syndrome: state of the art
Rev Neurol (Paris)
A clinical study of Kleine-Levin syndrome with evidence for hypothalamic-pituitary axis dysfunction
Biol Psychiatry
Efficacy of lithium treatment in Kleine-Levin syndrome
Eur Psychiatry
Carbamazepine for Kleine-Levin syndrome
J Am Acad Child Adolesc Psychiatry
Recurrent hypersomnia due to occult hepatic encephalopathy
Sleep Med
Endozepines in recurrent stupor
Sleep Med Rev
PET finding in Kleine-Levin syndrome
Sleep Med
Dynamic fMRI changes in Kleine-Levin syndrome
Sleep Med
Greater reduction of striatal dopamine transporter availability during the symptomatic than asymptomatic phase of Kleine-Levin syndrome
Sleep Med
Kleine-Levin syndrome in a 14-year-old girl: CSF hypocretin-1 measurements
Sleep Med
CSF hypocretin-1 assessment in sleep and neurological disorders
Lancet Neurol
Periodische Schlafsucht
Mschr Psychiat Neurol
Periodic hypersomnia and megaphagia in adolescent males
Brain
Kleine-Levin syndrome: an autoimmune hypothesis based on clinical and genetic analyses
Neurology
Kleine-Levin syndrome: a systematic study of 108 patients
Ann Neurol
Des hallucinations ou histoire raisonnée des apparitions, des visions, des songes, de l'extase, des rêves, du magnétisme et du somnambulisme
Periodic somnolence and morbid hunger: a new syndrome
Brain
Kleine-Levin syndrome: a systematic review of 186 cases in the literature
Brain
Clinical and polysomnographic characteristics of 34 patients with Kleine-Levin syndrome
J Sleep Res
Relationship between Kleine-Levin syndrome and upper respiratory infection in Taiwan
Sleep
Autonomic events in Kleine-Levin syndrome
Am J Psychiatry
Kleine-Levin syndrome (KLS) in young females
Sleep
The Kleine-Levin syndrome: hypersomnia, bulimia, and abnormal mental states
World Neurol
Multiple sleep latency test and polysomnography in diagnosing Kleine-Levin syndrome and periodic hypersomnia
J Clin Neurophysiol
Interepisodic morbidity in Kleine-Levin syndrome
Br J Psychiatry
The psychiatric symptomatology in Kleine-Levin syndrome
Child Psychiatry Hum Dev
Kleine-Levin syndrome
Chin Clin Neurol
Kleine-Levin syndrome: a case report
Aust N Z J Psychiatry
Kleine-Levin syndrome: case report
East Afr Med J
Monozygotic twins affected with Kleine-Levin syndrome
Sleep
Monozygotic twins concordant for Kleine-Levin syndrome
BMC Neurol
Familial Kleine-Levin syndrome: two siblings with unusually long hypersomnic spells
Arch Neurol
Familial recurrent hypersomnia: two siblings with Kleine-Levin syndrome and menstrual-related hypersomnia
J Child Neurol
The international classification of sleep disorders—second edition (ICSD-2)
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