Pharmacological treatment for Kleine-Levin syndrome

  • Review
  • Intervention

Authors


Marcio M de Oliveira, Universidade Federal de São Paulo, Rua Pedro de Toledo, 598, São Paulo, São Paulo, 04039001, Brazil. docmmo@uol.com.br.

Abstract

Background

This is an updated version of the original Cochrane review, published in Issue 2, 2009.

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 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 KLS 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 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 is effective and safe.
2. which drug or category of drugs is effective and safe.

Search methods

We obtained relevant trials from the following sources: the Cochrane Epilepsy Group Specialized Register (2 May 2013); the Cochrane Central Register of Controlled Trials (CENTRAL Issue 4, The Cochrane Library, April 2013); MEDLINE (1946 to 2 May 2013); SCOPUS (2 May 2013); LILACS (2 May 2013); ClinicalTrials.gov (2 May 2013); WHO International Clinical Trials Registry Platform ICTRP (2 May 2013); 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 selected. We included both parallel-group and cross-over studies.

Data collection and analysis

Two review authors (MMO 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.

Résumé scientifique

Le traitement pharmacologique du syndrome de Kleine-Levin

Contexte

Ceci est une version mise à jour de la revue Cochrane originale publiée dans le numéro 2 en 2009.

Le syndrome de Kleine-Levin (KLS) est une maladie rare qui affecte principalement les adolescents de sexe masculin. Il est caractérisé par des épisodes récurrents d'hypersomnie, généralement accompagnés d'hyperphagie, de troubles cognitifs et de l'humeur, de comportements anormaux tels que l'hypersexualité et de signes de dysautonomie.

En 1990, les critères de diagnostic pour le syndrome de Kleine-Levin ont été modifiés dans la Classification internationale des troubles du sommeil où il a été défini comme un syndrome composé d'épisodes récurrents de somnolence excessive d'une durée de plusieurs jours, pouvant être ou non associés à une hyperphagie et à un comportement anormal.

L'étiologie du syndrome de Kleine-Levin reste inconnue et plusieurs stratégies de traitement ont été utilisées. Il a été rapporté à propos de certains médicaments qu'ils étaient bénéfiques pour le traitement des patients atteints du syndrome de Kleine-Levin mais, en raison de la rareté de la pathologie, aucun suivi de thérapie sur le long terme n'a encore été décrit.

Objectifs

Cette revue visait à évaluer :

1. si le traitement pharmacologique du syndrome de Kleine-Levin est efficace et sûr ; et
2. quel médicament ou catégorie de médicaments est efficace et sûr(e).

Stratégie de recherche documentaire

Nous avons trouvé des essais pertinents dans les sources suivantes : Le registre spécialisé du groupe Cochrane sur l'épilepsie (2 mai 2013), le registre Cochrane des essais contrôlés (CENTRAL numéro 4, The Cochrane Library avril 2013), MEDLINE (de 1948 au 2 mai 2013), LILACS (2 mai 2013), ClinicalTrials.gov (2 May 2013); WHO International Clinical Trials Registry Platform ICTRP (2 May 2013); les références bibliographiques de manuels de médecine du sommeil, des articles de revue et les références bibliographiques d'articles identifiés au moyen des stratégies de recherche.

Critères de sélection

Tous les essais contrôlés randomisés (ECR) et quasi-randomisés portant sur des interventions pharmacologiques pour le syndrome de Kleine-Levin. Nous avons inclus tant des études en groupes parallèles que des études croisées.

Recueil et analyse des données

Deux auteurs de la revue (MO et CC) ont extrait les données rapportées dans les articles d'origine.

Résultats principaux

Aucune étude ne répondait aux critères d'inclusion de cette revue systématique.

Conclusions des auteurs

Il est nécessaire d'effectuer des essais thérapeutiques en double-aveugle contrôlés par placebo de traitements pharmacologiques pour le syndrome de Kleine-Levin.

Plain language summary

Pharmacological treatment for Kleine-Levin syndrome

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 behavior. 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.

The authors of this review aimed to identify and evaluate randomised controlled trials (RCTs) studying the effectiveness of pharmacological treatment for Kleine-Levin syndrome. 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.

Résumé simplifié

Le traitement pharmacologique du syndrome de Kleine-Levin

Le syndrome de Kleine-Levin (KLS) est une maladie rare qui affecte principalement les adolescents de sexe masculin. Il est caractérisé par des épisodes récurrents d'hypersomnie (somnolence excessive), d'hyperphagie (alimentation excessive) et de comportement anormal. La fréquence et la nature des attaques peuvent perturber la vie sociale, professionnelle et familiale de la personne. La cause du syndrome de Kleine-Levin n'est pas connue. Plusieurs traitements ont été utilisés, dont des médicaments stimulants, antiépileptiques, antidépresseurs et antipsychotiques, avec un certain bénéfice signalé, mais le suivi à long terme des patients est difficile en raison de la rareté de la maladie.

Les auteurs de cette étude avaient pour but d'identifier et d'évaluer des essais contrôlés randomisés (ECR) étudiant l'efficacité d'un traitement pharmacologique pour le syndrome de Kleine-Levin. Nous n'avons pu trouver d'ECR. On manque donc d'éléments probants de bonne qualité et des essais thérapeutiques en double-aveugle contrôlés par placebo sont nécessaires.

Notes de traduction

Traduit par: French Cochrane Centre 1st June, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Background

This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 2, 2009) on 'Pharmacological treatment for Kleine-Levin syndrome'.

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 behavior such as hypersexuality and signs of dysautonomia (ICSD 1990; Kleine 1925; Levin 1936).

In 1815 Satterley presented the case of a 16-year-old male with hypersomnia and hyperphagia after a short period of fever and headache. Kleine-Levin syndrome was first described by Kleine in 1925 (Kleine 1925), and 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). KLS 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 composed of recurring episodes of undue sleepiness lasting some days, which may or may not be associated with hyperphagia and abnormal behaviour (ICSD 1990).

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).

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 is effective and safe;

(2) which drug or category of drugs is 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 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 included 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):

ICSD 1990:

  • Recurring episodes of undue sleepiness lasting some days.

  • Hyperphagia (not obligatory).

  • Abnormal behaviour (not obligatory).

Critchley 1962:

  • 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 predominantly recruiting participants with narcolepsy, obstructive sleep apnoea, schizophrenia, bipolar affective disorder, obsessive-compulsive disorder, frontal brain tumour, third ventricle tumour, drug/alcohol abuse, encephalopathies, bulimia, atypical depression 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) and 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 (2 May 2013) using the search strategy set out in Appendix 2.

  • The Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4, The Cochrane Library, April 2013) using the search strategy set out in Appendix 3.

  • MEDLINE (Ovid, 1946 to 2 May 2013) using the search strategy outlined in Appendix 4.

  • SCOPUS (2 May 2013) using the search strategy set out in Appendix 5.

  • LILACS (The Latin American and Caribbean Literature on Health Sciences Database) (2 May 2013) using the search strategy outlined in Appendix 6.

  • ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform ICTRP (2 May 2013) using the search term Kleine-Levin OR Kleine Levin.

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. MMO and CC 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 criteria.

The same two authors will independently carry out data extraction using standard data extraction forms. The two review authors will 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 together 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 in the review any relevant information obtained in this manner. We will resolve disagreements in consultation with a third review author (GFP).

Study quality

MMO and CC will independently assess the quality of studies to be included, without blinding to authorship or journal, using the checklist developed by the Cochrane Epilepsy Group. We will resolve discrepancies by discussion with GFP. Quality items to be assessed include allocation concealment, intention-to-treat analysis, completeness of follow-up and blinding of investigators, participants and outcomes assessors.

Quality checklist
(1) Allocation concealment
  • 'A' adequate: randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant was enrolled in the study.

  • 'B' unclear: randomisation stated but no information provided on method used.

  • 'C' inadequate: method of randomisation given, such as use of alternate medical record numbers or unsealed envelopes; any information provided indicating that investigators or participants could influence intervention group.

(2) Blinding
  • Blinding of investigators: yes/no/not stated.

  • Blinding of participants: yes/no/not stated.

  • Blinding of outcomes assessor: yes/no/not stated.

  • Blinding of data analysis: yes/no/not stated.

(3) Intention-to-treat analysis
  • Yes: specifically reported by authors that intention-to-treat analysis was undertaken and that this was confirmed on study assessment.

  • Yes: not specifically stated but confirmed upon study assessment.

  • No: not reported and lack of intention-to-treat analysis confirmed on study assessment (participants who were randomly assigned were not included in the analysis because they did not receive the study intervention, they withdrew from the study or they had violated the protocol).

  • No: stated but not confirmed upon study assessment.

  • Not stated.

(4) Completeness of follow-up
  • Percentage of participants lost to follow-up.

Statistical assessment

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 irrespective of compliance or follow-up. In addition, we will perform 'a worst case scenario' analysis and will consider participants with missing data as treatment failures.

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 weighted mean difference (WMD), or the standardised mean difference (SMD) if different scales have been used.

Heterogeneity analysis

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 (Higgins 2003), 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.

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).

Results

Description of studies

(1) Excluded studies

The search identified 31 potentially eligible studies from the sources previously described. Of these, none were ultimately included in the review. All 31 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

Two hundred fifty-seven studies were initially identified using the search strategy. Of this total, only 31 had the potential to be included; however after further examination, all of these studies had to be excluded because they did not meet the eligibility criteria for inclusion. Only case reports and reviews were identified.

Discussion

We found no randomised, placebo-controlled trials of pharmacological treatments for KLS, and no studies could be included in this review. KLS has a benign clinical course with spontaneous disappearance of symptoms, and 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 an MAOI (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 is 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 to 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 indicates that pharmacological treatment for Kleine-Levin syndrome is 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.

Acknowledgements

We would like to acknowledge Humberto Saconato who was on the review author team for the original protocol and review.

Data and analyses

Download statistical data

This review has no analyses.

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 WITH BL CF CI CL CO CN DI DH DT EC EM EN EP EH ET GE HI IM ME MI MO NU PS PA PP PC PX RA RI RT RH SU TH US UR VE VI

#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)

Appendix 3. CENTRAL search strategy

#1         MeSH descriptor Kleine-Levin Syndrome explode all trees

#2         (Kleine-Levin)

#3         (periodic hypersomnia)

#4         MeSH descriptor Disorders of Excessive Somnolence explode all trees

#5         MeSH descriptor Hyperphagia, this term only

#6         (compulsive eating)

#7         (hyperphagia) or (megaphagia) or (polyphagia)

#8         (hypersexuality)

#9         (KLS)

#10       (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9)

Appendix 4. MEDLINE search strategy

This strategy is based on the Cochrane Highly Sensitive Search Strategy for identifying randomized trials published in Lefebvre 2009.

1. randomized controlled trial.pt.

2. controlled clinical trial.pt.

3. randomized.ab.

4. placebo.ab.

5. clinical trials as topic.sh.

6. randomly.ab.

7. trial.ti.

8. 1 or 2 or 3 or 4 or 5 or 6 or 7

9. exp animals/ not humans.sh.

10. 8 not 9

11. exp Kleine-Levin Syndrome/

12. Kleine Levin.tw.

13. megaphagia.tw.

14. *"Disorders of Excessive Somnolence"/

15. hypersomnia.tw.

16. hypersexuality.tw.

17. *Hyperphagia/

18. hyperphagia.tw.

19. KLS.tw.

20. 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19

21. 10 and 20

Appendix 5. 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)))

Appendix 6. LILACS search strategy

Kleine-Levin [Words] or ( kleine-levin syndrome ) [Subject descriptor]

What's new

Last assessed as up-to-date: 7 August 2013.

DateEventDescription
7 May 2013New citation required but conclusions have not changedConclusions unchanged.
2 May 2013New search has been performedSearches updated; no new studies identified.

History

Protocol first published: Issue 3, 2007
Review first published: Issue 2, 2009

DateEventDescription
13 March 2012New search has been performedSearches updated 24 October 2011; no new studies identified.
5 March 2010New search has been performedSearches updated 5 March 2010; no new trials identified.
19 August 2008AmendedConverted to new review format.

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.

Declarations of interest

None known.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Billiard 1998Review.
Billiard 2001Review.
Chaudhry 1992Case report.
Chiles 1976Case report.
Crumley 1997Case report.
Crumley 1998Case report.
Duffy 1968Case report.
Gallinek 1962Case report.
Goldberg 1983Case report.
Hart 1985Case report.
Kellet 1977Case report.
Kornreich 2000Case report.
Lenz 1980Case report.
Mapari 2005Case report.
Masi 2000Case report.
Minvielle 2000Case report.
Mukaddes 1999Case report.
Muratori 2002Case report.
Pike 1994Case report.
Poppe 2003Case report and review.
Reimao 1998Case report.
Roth 1980Case report.
Savet 1986Case report.
Smolik 1986Case report and review.
Smolik 1988Case report.
Suzuki 1998Review.
Vlach 1962Case report.
Wenzel 1976Case report.
Will 1988Case report.
Wurthmann 1989Case report.
Yassa 1978Case report.

Ancillary