Abstract
Background
This is an updated version of the original Cochrane review, published in 2009, Issue 2.
Kleine‐Levin syndrome (KLS) is a rare disorder that mainly affects adolescent men. It is characterised by recurrent episodes of hypersomnia, usually accompanied by hyperphagia, cognitive and mood disturbances, abnormal behaviour, 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 KLS was defined as a syndrome comprised of recurring episodes of undue sleepiness lasting some days, which may or may not be associated with hyperphagia and abnormal behaviour. According to the International Classification of Sleepiness Disorders, 3rd version (ICSD‐3), revised in 2014, the Kleine‐Levin syndrome is a disorder characterized by recurrent episodes of hypersomnia that last from two days to four weeks, with at least annual recurrence, and hyperphagia (rapid consumption of a large amount of food), usually with onset in early adolescence in males but occasionally in later life and in women. A monosymptomatic form of the disorder with hypersomnia only can occur without binge eating or hypersexuality.
The cause of Kleine‐Levin syndrome remains unknown, and several treatment strategies have been used. Some medications have been reported to provide benefit in the treatment of patients with KLS, 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 was effective and safe. 2. which drug or category of drugs was effective and safe.
Search methods
For the latest update, we searched the following sources: the Cochrane Epilepsy Group Specialized Register (7 April 2016); the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online CRSO (7 April 2016); MEDLINE (1946 to April 2016); LILACS (7 April 2016); ClinicalTrials.gov (7 April 2016); WHO International Clinical Trials Registry Platform ICTRP (7 April 2016); reference lists of sleep medicine textbooks; review articles and reference lists of articles identified by the search strategies.
Selection criteria
All randomised controlled trials (RCTs) and quasi‐randomised controlled trials looking at pharmacological interventions for Kleine‐Levin syndrome were eligible. We had planned to include both parallel‐group and cross‐over studies.
Data collection and analysis
Two review authors (MMO and CC) had planned to extract 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.
Plain language summary
Pharmacological treatment for Kleine‐Levin syndrome
Background
Kleine‐Levin syndrome (KLS) is a rare disorder that mainly affects adolescent men. It is characterised by recurrent episodes of hypersomnia (excessive sleepiness), hyperphagia (overeating), and abnormal behaviour. The frequency and nature of the attacks can disrupt the individual's social, professional, and family life. The cause of KLS is not known. Several treatments have been used, including stimulant, anti‐epileptic, anti‐depressant, and anti‐psychotic drugs, with some benefit reported, but because of the rarity of the condition, long‐term follow‐up of participants is difficult.
Objectives
The authors of this review aimed to identify and evaluate randomised controlled trials (RCTs) studying the effectiveness of pharmacological treatment for Kleine‐Levin syndrome.
Results
We were not able to find any RCTs. Good‐quality evidence is therefore lacking, and therapeutic trials with a double‐blind, placebo‐controlled design are needed.
The evidence was current to 7 April 2016.
Background
This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (2009. Issue 2) on 'Pharmacological treatment for Kleine‐Levin syndrome' (Oliveira 2013).
Kleine‐Levin syndrome (KLS) is a rare disorder with an estimated prevalence of one to five cases per million population (ISCD‐3 2014) that mainly affects adolescent men. It is characterised by recurrent episodes of hypersomnia, usually accompanied by hyperphagia, cognitive and mood disturbances, abnormal behaviour, such as hypersexuality, and signs of dysautonomia (ICSD 1990; Kleine 1925; Levin 1936; ISCD‐3 2014).
In 1815, Satterley presented the case of a 16‐year old male with hypersomnia and hyperphagia following a short period of fever and headache. Kleine‐Levin syndrome was first described by Kleine in 1925 (Kleine 1925); this description was elaborated on by Levin in 1936 (Levin 1936), but it was not named Kleine‐Levin syndrome until 1942, by Crichtley and Hoffman (Critchley 1942). Kleine‐Levin syndrome was further defined by Critchley in 1962 (Critchley 1962), and by Schmidt in 1990, who established the following diagnostic criteria:
Predominance in adolescent males;
Onset in adolescence;
Periodic hypersomnia;
Hyper/mega/polyphagia;
Association with behavioural and psychological changes;
Benign clinical course with spontaneous disappearance of clinical symptoms;
Lack of other neurological or psychiatric disease.
In 1990, the diagnostic criteria for KLS were modified in the International Classification of Sleep Disorders, where it was defined as a syndrome comprised of recurring episodes of undue sleepiness lasting some days, which may, or may not, be associated with hyperphagia and abnormal behaviour (ICSD 1990). According to the International Classification of Sleepiness Disorders, 3rd version (ICSD‐3), revised in 2014, Kleine‐Levin syndrome is a rare sleep disorder characterized by recurrent episodes of severe hypersomnia associated with cognitive and behavioral disturbances such as confusion, derealization, apathy, compulsive eating, and hypersexuality. Episodes last a few days to several weeks and are separated by weeks or months of normal sleep and behavior. KLS is categorized as a central disorder of hypersomnolence (ISCD‐3 2014).
The cause of KLS remains unknown, although numerous atypical or incomplete causes have been hypothesised:
Diencephalic‐hypothalamic dysfunction, reported with hypothalamic and third ventricle tumours, has similar symptoms, suggesting hypothalamic or circadian dysfunction as a cause (Fulton 1929; Haugh 1983).
Abnormalities in serotonin and dopamine metabolism have been reported, suggesting a neurotransmitter imbalance in the serotonergic or dopaminergic pathway (Chesson 1991; Koerber 1984).
Inflammatory lesions in the thalamus, diencephalon and midbrain have been described in postmortem neuropathological case reports, suggesting a viral infection (Fenzi 1993; Merriam 1986; Salter 1993).
Stress status, sleep deprivation, and alcohol abuse have also been suggested as triggers of KLS (Russel 1992).
A genetic basis for the disorder has been suggested by the preponderance of cases in the Ashkenazi Jewish population, suggesting a founder effect, as well as numerous reports of familial cases. To date, however, no specific genes have been identified (ISCD‐3 2014).
Because of the frequency and the nature of the attacks a person can suffer with KLS, individuals often experience disruption to their social, family, and professional life.
Several treatment strategies have been used:
Stimulant drugs (methylphenidate, modafinil, pemoline‐piracetam‐meclofenoxate, D‐amphetamine, ephedrine, meta‐amphetamine, amphetamine, etc.);
Anti‐epileptic drugs (valproic acid, carbamazepine, amobarbital, phenobarbital, phenytoin, etc.);
Anti‐depressants (imipramine, monoamine oxidase inhibitors (MAOIs), moclobemide, clomipramine, amineptine, fluoxetine, fluvoxamine, sertraline, methysergide, trazodone, etc.);
Anti‐psychotic drugs (haloperidol, chlorpromazine, levomepromazine, trifluoperazine, thioridazine, clozapine, risperidone, etc.);
Anti‐virals (acyclovir);
Lithium;
Hydrocortisone;
Melatonin;
Benzodiazepines;
Levodopa‐benserazide.
These medications have been reported to provide some benefit in the treatment of patients with KLS, 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 was effective and safe;
(2) which drug or category of drugs was effective and safe.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) of pharmacological treatment for Kleine‐Levin syndrome. We also had planned to include quasi‐randomised controlled trials (using inadequate allocation assignment such as date of birth, day of the week or month of the year, medical record number or alternate allocation). We had planned to include both parallel‐group and cross‐over studies.
Types of participants
Inclusion criteria
We considered children and adults who met the established clinical criteria for KLS (Critchley 1962; ICSD 1990):
Recurring episodes of undue sleepiness lasting some days;
Hyperphagia (not obligatory);
Abnormal behaviour (not obligatory).
Predominance in adolescent males;
Onset in adolescence;
Periodic hypersomnia;
Hyper/mega/polyphagia;
Associated behavioural and psychological changes;
Benign clinical course with spontaneous disappearance of clinical symptoms;
Lack of other neurological or psychiatric disease.
Exclusion criteria
We excluded studies that predominantly recruited participants with narcolepsy, obstructive sleep apnoea, schizophrenia, bipolar affective disorder, obsessive‐compulsive disorder, frontal brain tumour, third ventricle tumour, drug or alcohol abuse, encephalopathies, bulimia, atypical depressive disease, and delayed sleep maturation.
Types of interventions
We included all drugs used for the treatment of KLS.
Pharmacological interventions
Stimulant drugs (methylphenidate, modafinil, pemoline‐piracetam‐meclofenoxate, D‐amphetamine, ephedrine, meta‐amphetamine, amphetamine, etc.);
Anti‐epileptic drugs (valproic acid, carbamazepine, amobarbital, phenobarbital, phenytoin, etc.);
Anti‐depressants (imipramine, MAOIs, moclobemide, clomipramine, amineptine, fluoxetine, fluvoxamine, sertraline, methylsergide, trazodone, etc.);
Anti‐psychotic drugs (haloperidol, chlorpromazine, levomepromazine, trifluoperazine, thioridazine, clozapine, risperidone, etc.);
Anti‐viral (acyclovir);
Lithium;
Hydrocortisone;
Melatonin;
Benzodiazepines;
Levodopa‐benserazide.
Comparison groups
Placebo;
No intervention;
Other drug treatments.
Types of outcome measures
Primary outcomes
Relief of KLS symptoms (hypersomnia, hyperphagia, abnormal behaviour) as measured by any objective or subjective validated scale.
Secondary outcomes
Subjective sleep quality (any description of sleep quality; Epworth scale).
Sleep quality, as measured by night polysomnography (measured by sleep efficiency, total sleep time, arousal index).
Quality of life, as measured by a validated scale such as Short‐Form Health Survey (SF‐36), or a visual analogue scale.
Adverse events associated with treatments (to be described in terms of (i) numbers of participants withdrawing because of adverse events; and (ii) numbers of participants describing any side effect associated with the interventions).
Search methods for identification of studies
The search strategies used for the original version of this review are recorded in Appendix 1. For the most recent update of this review, we searched the following databases:
The Cochrane Epilepsy Group Specialized Register (7 April 2016), using the search strategy set out in Appendix 2;
The Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online CRSO (7 April 2016), using the search strategy set out in Appendix 3;
MEDLINE (Ovid, 1946 to 7 April 2016), using the search strategy outlined in Appendix 4;
LILACS (The Latin American and Caribbean Literature on Health Sciences Database; 7 April 2016), using the search strategy outlined in Appendix 5;
ClinicalTrials.gov (7 April 2016), using the search term: "Kleine‐Levin" OR "Kleine Levin";
WHO International Clinical Trials Registry Platform ICTRP (7 April 2016), using the search term: Kleine‐Levin OR Kleine Levin in the Condition.
Previously, we searched SCOPUS as an alternative to EMBASE, using the search strategy outlined in Appendix 6, but this is no longer necessary, because randomised and quasi‐randomised controlled trials in EMBASE are now included in CENTRAL.
We also searched the reference lists of sleep medicine textbooks, review articles, and the reference lists of articles identified by the search strategies described here.
Data collection and analysis
Selection of studies
Two review authors (MMO and CC) undertook the review. We used the broad search strategy already described to obtain the titles and abstracts of studies pertaining to KLS of any cause. The same two review authors independently screened the titles and abstracts, and discarded studies that were not applicable; however, they initially retained studies and reviews that might have included relevant data or information on trials. The same two review authors independently assessed the retrieved abstracts, and if necessary, the full text of these studies to determine which studies satisfied the inclusion criteria.
We found no studies that met the eligibility criteria for inclusion. If studies that meet the inclusion criteria are identified for future updates of this review, we will apply the following methodology.
Data extraction and management
The same two review authors will independently carry out data extraction using standard data extraction forms, and then independently enter the data into the Review Manager software (RevMan 2012). We will translate studies reported in non‐English language journals before assessment. When more than one publication of a trial exists, we will group the articles, and for each available outcome, we will extract results from the publication with the most complete data. We will request any further information required from the original author by written correspondence, and will include any relevant information obtained in this manner in the review. We will resolve disagreements in consultation with a third review when necessary.
Assessment of risk of bias in included studies
The two review authors will independently assess the risk of bias of the studies to be included, without blinding to authorship or journal, using the new Cochrane 'Risk of bias' tool (Higgins 2011). We will resolve discrepancies by discussion with GFP. 'Risk of bias' factors to be assessed include: randomisation, allocation concealment, blinding of investigators, participants and outcomes assessors, completeness of follow‐up, selective reporting,
Measures of treatment effect
Dichotomous outcomes
For dichotomous outcomes (such as frequency of adverse reactions requiring withdrawal), we will express results as relative risk (RR) with 95% confidence interval (CI). We will pool data using the random‐effects model but will also analyse the fixed‐effect model to ensure the robustness of the model chosen and susceptibility to outliers.
Continuous outcomes
When continuous scales of measurement are used to assess the effects of treatment (such as various of KLS symptoms or effects on quality of life), we will use the mean difference (MD), or the standardised mean difference (SMD) if different scales have been used.
Dealing with missing data
If possible, we will perform all analyses according to the intention‐to‐treat method, using the last reported observed response ('carry forward') and including all participants regardless of compliance or follow‐up.
Assessment of heterogeneity
We will analyse heterogeneity using the Q statistic, a Chi² test on N‐1 degrees of freedom, with an alpha of 0.10 used for statistical significance. We will also quantify inconsistency with the I² statistic, calculated by [(Q － df)/Q × 100%], which describes the percentage of variability in effect estimates caused by heterogeneity rather than by sampling error. A value greater than 50% will be considered to signify substantial heterogeneity (Higgins 2011).
When sufficient data are available, we will pool study findings according to subcategory to explore possible sources of heterogeneity. We will divide the studies according to the following:
Age of participants;
Severity of the disorder;
Type of medication given;
Methodological quality of the study (allocation concealment, blinding, intention‐to‐treat analysis).
Sensitivity analysis
We will perform 'a worst case scenario' analysis and will consider participants with missing data as treatment failures.
Results
Description of studies
We initially identified 257 studies using the search strategy.
(1) Excluded studies
The search identified 36 potentially eligible studies from the sources previously described. Of these, none were ultimately included in the review. All 36 studies were excluded because of study design: all were case reports or reviews. See the table of 'Characteristics of excluded studies' for details.
(2) Ongoing studies
The review authors know of no ongoing studies.
(3) Included studies
No studies met the eligibility criteria for inclusion.
Risk of bias in included studies
No studies met the eligibility criteria for inclusion.
Effects of interventions
No studies met the eligibility criteria for inclusion.
Discussion
We found no randomised, placebo‐controlled trials of pharmacological treatments for KLS, and no studies could be included in this review. Kleine‐Levin syndrome has a benign clinical course with spontaneous disappearance of symptoms; the findings of case reports excluded from this review were unpredictable. However, some case reports have described improvement in specific symptoms of KLS as follows:
Stimulant drugs, especially amphetamines, significantly improved sleepiness but did not improve other symptoms (Gallinek 1962).
Anti‐depressant drugs had no effect on preventing relapse, except in one case, in which a monoamine oxidase inhibitor (moclobemide) was used (Chaudhry 1992).
Anti‐epileptic drugs showed, in a single case, improvement in abnormal behaviour when carbamazepine was used (Mukaddes 1999).
Lithium significantly improved abnormal behaviour and recovery of symptoms (reducing the duration of episodes and decreasing relapses) (Kellet 1977; Poppe 2003; Smolik 1988).
Unfortunately, no evidence was available to support the use of these therapies.
It is important to remember that the frequent occurrence of attacks and of severe behavioural disorders incapacitates patients with KLS both professionally and socially. We believe that double‐blind, placebo‐controlled therapeutical trials of drugs that can prevent or improve all symptoms of KLS are warranted, and that because of the rarity of the condition, these trials should have a multicentre design.
Authors' conclusions
Implications for practice.
No evidence indicated that pharmacological treatment for Kleine‐Levin syndrome was effective and safe.
Implications for research.
Therapeutic, double‐blind, placebo‐controlled drug trials for Kleine‐Levin syndrome are needed that use a robust methodology, and in the light of the rarity of this condition, a multicentre design.
What's new
| Date | Event | Description |
|---|---|---|
| 7 April 2016 | New search has been performed | Searches updated 7 April 2016. |
| 7 April 2016 | New citation required but conclusions have not changed | No new studies identified; conclusions are unchanged. |
History
Protocol first published: Issue 3, 2007 Review first published: Issue 2, 2009
| Date | Event | Description |
|---|---|---|
| 7 May 2013 | New citation required but conclusions have not changed | Conclusions unchanged. |
| 2 May 2013 | New search has been performed | Searches updated; no new studies identified. |
| 13 March 2012 | New search has been performed | Searches updated 24 October 2011; no new studies identified. |
| 5 March 2010 | New search has been performed | Searches updated 5 March 2010; no new trials identified. |
| 19 August 2008 | Amended | Converted to new review format. |
Acknowledgements
We would like to acknowledge Humberto Saconato who was on the review author team for the original protocol and review.
Appendices
Appendix 1. Search strategies for original version of this review
We searched the Cochrane Epilepsy Group Specialized Register (1 December 2007) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2007) using the following terms
:#1 KLEINE‐LEVIN SYNDROME #2 (Kleine‐Levin* next syndrome*) #3 (periodic next hypersomnia next sleep*) #4 (compulsive next eating*) #5 (hyperphagia or megaphagia or polyphagia*) #6 (hypersexuality) #7 (KLS) #8 (#1 or #2 or #3 or #4 or #5 or #6 or #7)
We also searched the following electronic databases.
‐ MEDLINE (1966 to December 2007) using the optimally sensitive strategy developed for the Cochrane Collaboration for the identification of randomized controlled trials (Dickersin 1994).
‐ EMBASE (1980 to December 2007) using a search strategy adapted from that developed for the Cochrane Collaboration for the identification of randomized controlled clinical trials (Lefebvre 1996).
‐ LILACS (1982 to December 2007) using a search strategy adapted for the identification of randomized controlled clinical trials.
MEDLINE search strategy (1966 to December 2007)
((kleine[All Fields] AND levin[All Fields]) OR ("kleine‐levin syndrome"[MeSH Terms] OR kleine levin syndrome[Text Word])) AND (megaphagia[All Fields] OR (("disorders of excessive somnolence"[TIAB] NOT Medline[SB]) OR "disorders of excessive somnolence"[MeSH Terms] OR hypersomnia[Text Word]) OR hypersexuality[All Fields] OR ("hyperphagia"[MeSH Terms] OR hyperphagia[Text Word]))
EMBASE search strategy (1980 to December 2007)
'kleine levin' AND ('syndrome'/exp OR 'syndrome') AND 'kleine levin' AND ('hyperphagia'/exp OR 'hyperphagia') AND megaphagia AND ('polyphagia'/exp OR 'polyphagia') AND ('hypersomnia'/exp OR 'hypersomnia') AND periodic AND ('hypersomnia'/exp OR 'hypersomnia') AND ('hypersexuality'/exp OR 'hypersexuality') AND kls
LILACS search strategy (1982 to December 2007)
"sindrome de KLEINE‐levin" or (tw kleine and tw levin) [Descritor de assunto]
Appendix 2. Cochrane Epilepsy Group Specialized Register search strategy
#1 MeSH DESCRIPTOR Kleine‐Levin Syndrome Explode All
#2 Kleine‐Levin* next syndrome*
#3 periodic next hypersomnia next sleep*
#4 compulsive next eating*
#5 hyperphagia or megaphagia or polyphagia*
#6 hypersexuality
#7 KLS
#8 (#1 or #2 or #3 or #4 or #5 or #6 or #7) AND INREGISTER AND >02/05/2013:CRSCREATED
Appendix 3. CENTRAL via CRSO search strategy
#1 MESH DESCRIPTOR Kleine‐Levin Syndrome EXPLODE ALL TREES
#2 (Kleine AND Levin):TI,AB,KY
#3 #1 OR #2
#4 31/05/2013 TO 31/07/2015:DL
#5 #3 AND #4
Appendix 4. MEDLINE search strategy
This strategy is based on the Cochrane Highly Sensitive Search Strategy for identifying randomized trials published in Lefebvre 2011.
1. exp Kleine‐Levin Syndrome/
2. (Kleine and Levin).tw.
3. 1 or 2
4. (randomized controlled trial or controlled clinical trial).pt. or (randomi?ed or placebo or randomly).ab.
5. clinical trials as topic.sh.
6. trial.ti.
7. 4 or 5 or 6
8. exp animals/ not humans.sh.
9. 7 not 8
10. 3 and 9
11. limit 10 to ed=20130502‐20150707
Appendix 5. LILACS search strategy
(tw:("kleine levin")) OR (mh:("kleine‐levin syndrome")) AND (instance:"regional") AND ( type_of_study:("case_control" OR "cohort"))
Appendix 6. SCOPUS search strategy
(TITLE("Kleine‐Levin") OR ABS("Kleine‐Levin")) AND (TITLE((randomiz* OR randomis* OR controlled OR placebo OR blind* OR unblind* OR "parallel group" OR crossover OR "cross over" OR cluster OR "head to head") PRE/2 (trial OR method OR procedure OR study)) OR ABS((randomiz* OR randomis* OR controlled OR placebo OR blind* OR unblind* OR "parallel group" OR crossover OR "cross over" OR cluster OR "head to head") PRE/2 (trial OR method OR procedure OR study)))
Characteristics of studies
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Billiard 1998 | Review. |
| Billiard 2001 | Review. |
| Brouns SH 2012 | Case report |
| Chaudhry 1992 | Case report. |
| Chiles 1976 | Case report. |
| Crumley 1997 | Case report. |
| Crumley 1998 | Case report. |
| Duffy 1968 | Case report. |
| El Otmani H 2013 | Case Report |
| Gallinek 1962 | Case report. |
| Goldberg 1983 | Case report. |
| Hart 1985 | Case report. |
| Kapson B 2014 | Case Report |
| Kellet 1977 | Case report. |
| Kornreich 2000 | Case report. |
| Lenz 1980 | Case report. |
| Mapari 2005 | Case report. |
| Masi 2000 | Case report. |
| Minvielle 2000 | Case report. |
| Mukaddes 1999 | Case report. |
| Muratori 2002 | Case report. |
| Pike 1994 | Case report. |
| Poppe 2003 | Case report and review. |
| Reimao 1998 | Case report. |
| Rezvanian E 2013 | Case Report |
| Roth 1980 | Case report. |
| Savet 1986 | Case report. |
| Smolik 1986 | Case report and review. |
| Smolik 1988 | Case report. |
| Suzuki 1998 | Review. |
| Vlach 1962 | Case report. |
| Wenzel 1976 | Case report. |
| Will 1988 | Case report. |
| Wurthmann 1989 | Case report. |
| Yassa 1978 | Case report. |
| Yılmaz S 2015 | Case report |
Contributions of authors
Marcio M de Oliveira: protocol development, literature searching, study selection, data extraction, statistical analysis, drafting of written submissions, development of final review. Cristiane Conti: protocol development, literature searching, study selection, data extraction, statistical analysis, development of final review. Gilmar F Prado: protocol development, literature searching, study selection, data extraction, statistical analysis, development of final review.
Sources of support
Internal sources
No sources of support supplied
External sources
-
National Institute for Health Research (NIHR), UK, UK.
This review was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Epilepsy Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.
Declarations of interest
None known.
New search for studies and content updated (no change to conclusions)
References
References to studies excluded from this review
Billiard 1998 {published data only}
- Billiard M, Carlander B. Wake disorders. I. Primary wake disorders. Revue Neurologique (Paris) 1998;154(2):111‐29. [PubMed] [Google Scholar]
Billiard 2001 {published data only}
- Billiard M, Dauvilliers Y. Idiopathic hypersomnia. Sleep Medicine Reviews 2001;5(5):349‐58. [DOI] [PubMed] [Google Scholar]
Brouns SH 2012 {published data only}
- Brouns SH, Schieveld J, Leue C. The Kleine‐Levin syndrome and the treatment with methylphenidate.. Tijdschr Psychiatr. 2012;54(8):747‐51. [PubMed] [Google Scholar]
Chaudhry 1992 {published data only}
- Chaudhry HR. Clinical use of moclobemide in Kleine‐Levin syndrome. British Journal of Psychiatry 1992;161:720. [DOI] [PubMed] [Google Scholar]
Chiles 1976 {published data only}
- Chiles JA, Wilkus RJ. Behavioural manifestations of Kleine‐Levin syndrome. Diseases of the Nervous System 1976;37:646‐8. [PubMed] [Google Scholar]
Crumley 1997 {published data only}
- Crumley FE. Valproic acid for Kleine‐Levin syndrome. Journal of the American Academy of Child and Adolescent Psychiatry 1997;36:868‐9. [DOI] [PubMed] [Google Scholar]
Crumley 1998 {published data only}
- Crumley FE. Light therapy for Kleine‐Levin syndrome. Journal of the American Academy of Child and Adolescent Psychiatry 1998;37(12):1245. [DOI] [PubMed] [Google Scholar]
Duffy 1968 {published data only}
- Duffy JP, Davison K. A female case of the Kleine‐Levin syndrome. British Journal of Psychiatry 1968;114:77‐84. [DOI] [PubMed] [Google Scholar]
El Otmani H 2013 {published data only}
- Otmani H, Lahlou I, Moutaouakil F, Moutawakil B, Rafii MA, Slassi I. Invasive Kleine‐Levin syndrome responding to valproate. Rev Neurol (Paris). 2013;169(1):94‐5.. [DOI: 10.1016/j.neurol.2012.04.009] [DOI] [PubMed] [Google Scholar]
Gallinek 1962 {published data only}
- Gallinek A. The Kleine‐Levin syndrome: hypersomnia, bulimia, and abnormal mental states. World Neurology 1962;3:235‐43. [PubMed] [Google Scholar]
Goldberg 1983 {published data only}
- Goldberg MA. The treatment of Kleine‐Levin syndrome with lithium. Canadian Journal of Psychiatry 1983;28:491‐3. [DOI] [PubMed] [Google Scholar]
Hart 1985 {published data only}
- Hart EJ. Kleine‐Levin syndrome: normal CSF monoamines and response to lithium therapy. Neurology 1985;35:1395‐6. [DOI] [PubMed] [Google Scholar]
Kapson B 2014 {published data only}
- Kapson B, Nayar S, Spiegel R. Treatment of Kleine‐Levin syndrome with acetazolamide.. J Clin Sleep Med. 2014;10(10):1153‐4.. [DOI: 10.5664/jcsm.4124.] [DOI] [PMC free article] [PubMed] [Google Scholar]
Kellet 1977 {published data only}
- Kellet J. Lithium prophylaxis of periodic hypersomnia. British Journal of Psychiatry 1977;130:312‐6. [DOI] [PubMed] [Google Scholar]
Kornreich 2000 {published data only}
- Kornreich C, Fossion P, Hoffmann G, Baleriaux M, Pelc I. Treatment of Kleine‐Levin syndrome: melatonin on the starting block. Journal of Clinical Psychiatry 2000;61(3):215. [DOI] [PubMed] [Google Scholar]
Lenz 1980 {published data only}
- Lenz H. Kleine‐Levin‐syndrome. Wiener Medizinische Wochenschrift 1980;130(11):373‐5. [PubMed] [Google Scholar]
Mapari 2005 {published data only}
- Mapari UU, Khealani BA, Ali S, Syed NA. Kleine‐Levin syndrome. Journal of the College of Physicians and Surgeons － Pakistan 2005;15(1):46‐7. [PubMed] [Google Scholar]
Masi 2000 {published data only}
- Masi G, Favilla L, Millepiedi S. The Kleine‐Levin syndrome as a neuropsychiatric disorder: a case report. Psychiatry 2000;63(1):93‐100. [DOI] [PubMed] [Google Scholar]
Minvielle 2000 {published data only}
- Minvielle S. Klein‐Levin syndrome: a neurological disease with psychiatric symptoms. Encephale 2000;26(4):71‐4. [PubMed] [Google Scholar]
Mukaddes 1999 {published data only}
- Mukaddes NM, Kora ME, Bilge S. Carbamazepine for Kleine‐Levin syndrome. Journal of the American Academy of Child and Adolescent Psychiatry 1999;38:791‐2. [DOI] [PubMed] [Google Scholar]
Muratori 2002 {published data only}
- Muratori F, Bertini N, Masi G. Efficacy of lithium treatment in Kleine‐Levin syndrome. European Psychiatry 2002;17:232‐3. [DOI] [PubMed] [Google Scholar]
Pike 1994 {published data only}
- Pike M, Stores G. Kleine‐Levin syndrome: a cause of diagnostic confusion. Archives of Disease in Childhood 1994;71:355‐7. [DOI] [PMC free article] [PubMed] [Google Scholar]
Poppe 2003 {published data only}
- Poppe M, Friebel D, Reuner U, Todt H, Koch R, Heubner G. The Kleine‐Levin syndrome－effects of treatment with lithium. Neuropediatrics 2003;34:113‐9. [DOI] [PubMed] [Google Scholar]
Reimao 1998 {published data only}
- Reimao R, Shimizu MH. Kleine‐Levin syndrome: clinical course, polysomnography and multiple sleep latency test: case report. Arquivos de Neuro‐psiquiatria 1998;56(3B):650‐4. [DOI] [PubMed] [Google Scholar]
Rezvanian E 2013 {published data only}
- Rezvanian E, Watson NF. Kleine‐levin syndrome treated with clarithromycin.. J Clin Sleep Med. 2013;9(11):1211‐2.. [DOI: 10.5664/jcsm.3176] [DOI] [PMC free article] [PubMed] [Google Scholar]
Roth 1980 {published data only}
- Roth B, Smolik P, Soucek K. Kleine‐Levin syndrome－lithium prophylaxis. Ceskoslovenská Psychiatrie 1980;76:156‐62. [PubMed] [Google Scholar]
Savet 1986 {published data only}
- Savet JF, Robert H, Angeli C. A case of Kleine‐Levin syndrome stabilized for over 1 year with carbamazepine. La Presse Médicale 1986;15:1281. [PubMed] [Google Scholar]
Smolik 1986 {published data only}
- Smolik P, Roth B. Diagnosis, etiopathogenesis and treatment of Kleine‐Levin syndrome. Ceskoslovenská Psychiatrie 1986;82(2):127‐30. [PubMed] [Google Scholar]
Smolik 1988 {published data only}
- Smolik P, Roth B. Kleine‐Levin syndrome: etiopathogenesis and treatment. Acta Universitatis Carolinae. Medica Monographia 1988;128:5‐94. [PubMed] [Google Scholar]
Suzuki 1998 {published data only}
- Suzuki H. Recurrent hypersomnia. Nippon Rinsho. Japanese Journal of Clinical Medicine 1998;56(2):365‐70. [PubMed] [Google Scholar]
Vlach 1962 {published data only}
- Vlach V. Periodical somnolence, bulimia and mental changes (Kleine‐Levin syndrome). Ceskoslovenská Psychiatrie 1962;25:401‐5. [PubMed] [Google Scholar]
Wenzel 1976 {published data only}
- Wenzel U. Kleine‐Levin syndrome. Female cases and catamneses. Fortschritte der Neurologie, Psychiatrie, und ihrer Grenzgebiete 1976;44(4):137‐50. [PubMed] [Google Scholar]
Will 1988 {published data only}
- Will RG, Young JP, Thomas DJ. Kleine‐Levin syndrome: report of two cases with onset of symptoms precipitated by head trauma. British Journal of Psychiatry 1988;152:410‐2. [DOI] [PubMed] [Google Scholar]
Wurthmann 1989 {published data only}
- Wurthmann C, Hartung HP, Dengler W, Gerhardt P. Kleine‐Levin syndrome. The provocation of manic symptoms by an antidepressant and a therapeutic trial of carbamazepine. Deutsche Medizinische Wochenschrift 1989;114(40):1528‐31. [DOI] [PubMed] [Google Scholar]
Yassa 1978 {published data only}
- Yassa R, Nair NP. The Kleine‐Levin syndrome－a variant?. The Journal of Clinical Psychiatry 1978;39:254‐9. [PubMed] [Google Scholar]
Yılmaz S 2015 {published data only}
- Yılmaz S, Akça ÖF, Bilgiç A. Treatment of Kleine‐Levin Syndrome with Aripiprazole.. J Child Adolesc Psychopharmacol. 2015;25(5):450‐1. [DOI: 10.1089/cap.2014.0169] [DOI] [PubMed] [Google Scholar]
Additional references
Chesson 1991
- Chesson A, Levine S, Kong LS, Lee S. Neuroendocrine evaluation in Kleine‐Levin syndrome: Evidence of reduced dopaminergic tone during periods of hypersomnolence. Sleep 1991;14:226‐32. [PubMed] [Google Scholar]
Critchley 1942
- Critchley M, Hoffman HL. The syndrome of periodic somnolence and morbid hunger (Kleine‐Levin). British Medical Journal 1942;1:137‐9. [DOI] [PMC free article] [PubMed] [Google Scholar]
Critchley 1962
- Critchley M. Periodic hypersomnia and megaphagia in adolescent males. Brain 1962;85:627‐56. [DOI] [PubMed] [Google Scholar]
Dickersin 1994
- Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ 1994;309(6964):1286‐91. [DOI] [PMC free article] [PubMed] [Google Scholar]
Fenzi 1993
- Fenzi F, Simonati A, Crosato F, Ghersini L, Rizzuto N. Clinical features of Kleine‐Levin syndrome with localized encephalitis. Neuropediatrics 1993;24:292‐5. [DOI] [PubMed] [Google Scholar]
Fulton 1929
- Fulton JF, Bailey P. Tumors in the region of the third ventricle: their diagnosis and relation to pathological sleep. The Journal of Nervous and Mental Disease 1929;69:1‐25. [Google Scholar]
Haugh 1983
- Haugh RM, Markesbery WR. Hypothalamic astrocytoma. Syndrome of hyperphagia, obesity, and disturbances of behaviour and endocrine and autonomic function. Archives of Neurology 1983;40:560‐3. [DOI] [PubMed] [Google Scholar]
Higgins 2011
- Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available from www.cochrane‐handbook.org 2011.
ICSD 1990
- Thorpy MJ, Chairman. International Classification of Sleep Disorders: Diagnostic and Coding Manual. Diagnostic Classification Steering Committee. American Sleep Disorders Association, 1990. [Google Scholar]
ISCD‐3 2014
- Darien, IL: American Academy of Sleep Medicine. American Academy of Sleep Medicine.. International Classification of Sleep Disorders.3rd ed 2014. [Google Scholar]
Kleine 1925
- Kleine W. Periodische Schlafsucht. Monatsschrift für Psychiatrie und Neurologie 1925;57:285. [Google Scholar]
Koerber 1984
- Koerber RK, Torkelson R, Haven G, Donaldson J, Cohen SM, Case M. Increased cerebrospinal fluid 5‐hydroxytryptamine and 5‐hydroxyindoleacetic acid in Kleine‐Levin syndrome. Neurology 1984;34:1597‐600. [DOI] [PubMed] [Google Scholar]
Lefebvre 1996
- Lefebvre C, McDonald S. Development of a sensitive search strategy for reports of randomized controlled trials in EMBASE. Fourth International Cochrane Colloquium. 1996 Oct 20‐24; Adelaide (Australia).
Lefebvre 2011
- Lefebvre C, Manheimer E, Glanville J . Chapter 6: Searching for studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from: http://handbook.cochrane.org/.
Levin 1936
- Levin M. Periodic somnolence and morbid hunger: a new syndrome. Brain 1936;59:494‐504. [Google Scholar]
Merriam 1986
- Merriam AE. Kleine‐Levin syndrome following acute viral encephalitis. Biological Psychiatry 1986;21:1301‐4. [DOI] [PubMed] [Google Scholar]
RevMan 2012 [Computer program]
- The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.
Russel 1992
- Russel J, Grunstein R. Kleine‐Levin syndrome: a case report. The Australian and New Zealand Journal of Psychiatry 1992;26(1):119‐23. [DOI] [PubMed] [Google Scholar]
Salter 1993
- Salter MS, White PD. A variant of Kleine‐Levin syndrome precipitated by both Epstein‐Barr and varicella‐zoster virus infections. Biological Psychiatry 1993;33:388‐90. [DOI] [PubMed] [Google Scholar]
References to other published versions of this review
Oliveira 2007
- Oliveira MM, Conti C, Saconato H, Fernandes do Prado G. Pharmacological treatment for Kleine‐Levin Syndrome. Cochrane Database of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/14651858.CD006685] [DOI] [PubMed] [Google Scholar]
Oliveira 2009
- Oliveira MM, Conti C, Saconato H, Prado GF. Pharmacological treatment for Kleine‐Levin Syndrome. Cochrane Database of Systematic Reviews 2009, Issue 2. [DOI: 10.1002/14651858.CD006685.pub2] [DOI] [PubMed] [Google Scholar]
Oliveira 2013
- Oliveira MM, Conti C, Prado GF. Pharmacological treatment for Kleine‐Levin syndrome. Cochrane Database of Systematic Reviews 2013, Issue 8. [DOI: 10.1002/14651858.CD006685.pub3] [DOI] [PubMed] [Google Scholar]