Betahistine for Ménière's disease or syndrome

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of betahistine in patients with either Ménière's disease or Ménière's syndrome.

Background

Description of the condition

This is a new protocol for an update of a Cochrane Review first published in theCochrane Library in Issue 1, 2001 and previously updated in 2008 (James 2001).

Ménière's disease is characterised by recurrent episodes of vertigo, hearing loss and tinnitus, often with a feeling of fullness in the ear. Vertigo attacks can occur without warning and their intensity varies, which may lead to psychological suffering and a reduction in quality of life. The disorder may be subdivided into two categories: it may be secondary to a number of established inner ear disorders (Ménière's syndrome) or idiopathic (Ménière's disease). Ménière's disease is known to be associated with endolymphatic hydrops, i.e. raised endolymph pressure in the membranous labyrinth of the inner ear (Hallpike 1938). However, hydrops per se does not explain all its clinical features. Nonetheless, both categories may be considered as one entity as with both endolymphatic hydrops is the diagnostic hallmark of the disease.

The diagnostic process may be difficult as there is great variability in clinical presentation and no reference standard exists. The American Academy of Otolaryngology ‐ Head and Neck Surgery (AAO‐HNS) has produced diagnostic guidelines (Alford 1972), which have been revised twice (AAO‐HNS 1995; Pearson 1985). The AAO‐HNS 1995 guidelines formulate that a 'definite' diagnosis can be made on the basis of at least two spontaneous episodes of rotational vertigo lasting at least 20 minutes, audiometric confirmation of sensorineural hearing loss, plus tinnitus and/or a perception of aural fullness (Appendix 1). More recent diagnostic criteria have also been proposed by the Bárány Society (Lopez 2015).

In a recent study in the USA the prevalence of Ménière's disease was estimated at 200 per 100,000 people per year (Alexander 2010). Ménière's disease is most common between 40 and 60 years of age (Harcourt 2014). Vertigo episodes tend to occur in clusters with a period of remission that may last for several months in between the clusters (Perez‐Garrigues 2008). Episodes have been observed to occur with increasing frequency over the first few years after presentation and then decrease in association with a sustained deterioration in hearing (Moffat 1997). In most cases, vertiginous episodes eventually cease completely (Silverstein 1989). The fluctuating, progressive and unpredictable natural history of Ménière's disease makes investigation of any treatment effect difficult; studies therefore need to compare interventions with placebo over an adequate time period.

The aim of treatment is:

• to reduce the number, severity and duration of attacks of vertigo;

• to prevent progression of the disease, in particular the loss of hearing; and

• to alleviate any chronic symptoms (e.g. tinnitus and aural fullness).

Description of the intervention

Betahistine dihydrochloride is an oral drug treatment that has been prescribed to an estimated 130 million people worldwide since its first launch (Jeck‐Thole 2006). Although betahistine has been used for vestibular vertigo in general (Murdin 2016), it is thought by some clinicians to be specifically effective for Ménière's disease (Nauta 2014). The recommended daily dose of betahistine is 24 mg to 48 mg per day divided into two or three single doses containing 8 mg, 16 mg or 24 mg (Jeck‐Thole 2006). Although gastrointestinal side effects are cited in many formularies, the rate of adverse effects in patients taking betahistine is not significantly different from those taking placebo in comparison studies (Murdin 2016).

How the intervention might work

Betahistine is a weak histamine H1 receptor agonist and a potent histamine H3 receptor antagonist. The mechanism of action of the drug may be via the reduction of endolymphatic pressure through improved microvascular circulation in the stria vascularis of the cochlea (Martinez 1972). In addition, inhibition of activity in the vestibular nuclei may contribute to rebalancing neural activity and expedite the recovery process (Lacour 2007; Timmerman 1994). Studies have shown that betahistine reaches a peak plasma concentration in about one hour and it has a plasma half‐life of approximately 3.5 hours. The maximal vestibular therapeutic effect will last approximately three to four hours (EMC 2015). The washout period can be calculated as four times the drug effect (Senn 1999).

These pharmacological characteristics are thought to reduce the intensity and duration of vertigo symptoms in the short term (under three months) and additionally prevent attacks in the longer term (over three months).

Why it is important to do this review

The previous version of this Cochrane Review found no evidence of a benefit from the use of betahistine (James 2001). Despite this, it is still widely used and studied in clinical practice, especially in Europe. Reassessment of the effect of betahistine in the treatment of Ménière's disease is therefore now warranted.

Objectives

To assess the effects of betahistine in patients with either Ménière's disease or Ménière's syndrome.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials, including cluster‐randomised controlled trials. We will exclude quasi‐randomised studies. Cross‐over trials will be eligible if data from before the cross‐over are extractable, to avoid the potential for a carry‐over phenomenon.

Types of participants

Patients with Ménière's disease or syndrome. We will classify studies according to the diagnostic criteria used for Ménière's disease. We will rate studies using the AAO‐HNS or the Japanese Society of Equilibrium Research criteria to define probable, definite or certain Ménière's disease's as class 'I' studies and studies using other diagnostic definitions as class 'II'. We will rate studies including patients with 'possible' Ménière’s disease as class 'III'. Participants who have received betahistine previously will be eligible for inclusion.

Types of interventions

Betahistine: any dose regimes or formulations and for any duration of treatment.

The sole comparison is:

• betahistine versus placebo.

Concurrent use of other medication or other treatment will be acceptable if used equally in each group; for example, betahistine with an additional intervention versus placebo with an identical additional intervention. Where an additional intervention was used equally in both groups, we will analyse this as a separate comparison.

Types of outcome measures

We will analyse the following outcomes in the review, but we will not use them as a basis for including or excluding studies.

Based on the pharmacological properties of the drug described above, we will assess outcomes as short‐term (three months or under) or long‐term (over three months).

Primary outcomes

• Vertigo: the proportion of patients with a reduction in vertigo symptoms (considering together the intensity, frequency and duration of those symptoms).

• Significant adverse effects: upper gastrointestinal discomfort.

Secondary outcomes

• Hearing loss: the proportion of patients with progression of hearing loss (more than 15 dB), based on the four‐tone average of thresholds at 0.5 kHz, 1 kHz, 2 kHz and 3 kHz, as measured by a pure‐tone audiogram.

• Tinnitus: the proportion of patients with reduction of tinnitus, measured with patient‐reported questionnaire scores such the Tinnitus Handicap Index (THI) (Kleinstäuber 2015, see Appendix 3), the Tinnitus Functional Index (Meikel 2012), the Tinnitus Handicap Questionnaire (Kuk 1990), the Tinnitus Questionnaire (Hallam 1996), the Tinnitus Reaction Questionnaire (Wilson 1991) and the Tinnitus Severity Scale (Sweetow 1990).

• Aural fullness: the proportion of patients with reduction of aural fullness, measured using patient‐reported questionnaire scores (e.g. visual analogue scale).

• Other adverse effects: headache and allergic skin reactions (pruritis, rashes).

• Well‐being and disease‐specific health‐related quality of life: overall changes as reported particularly by the Functional Level Scale (FLS) (see Appendix 4), the Ménière's disease Patients Oriented Symptoms Severity Index (MPOSI) and the Dizziness Handicap Inventory (see Appendix 5). The FLS will be used as defined by the AAO‐HNS 1995 guideline. The questionnaires are validated and often used in trials to assess the change in dizziness‐related and Ménière's disease‐related quality of life (Duracinsky 2007).

We anticipate that various non‐validated tools (e.g. questionnaires) will be used. We will only include validated tools to ensure that the results for the effects of treatment on outcomes are as reliable as possible.

Search methods for identification of studies

The Cochrane ENT Information Specialist will conduct systematic searches for randomised controlled trials; these will be based on the searches used in the previous review (Appendix 6). There will be no language, publication year or publication status restrictions. We may contact original authors for clarification and further data if trial reports are unclear and we will arrange translations of papers where necessary.

Electronic searches

Published, unpublished and ongoing studies will be identified by searching the following databases from their inception:

• the Cochrane Register of Studies ENT Trials Register (search to date);

• the Cochrane Register of Studies Online (search to date);

• PubMed (1946 to date);

• Ovid EMBASE (1974 to date);

• EBSCO CINAHL (1982 to date);

• Ovid CAB abstracts (1910 to date);

• LILACS (search to date);

• KoreaMed (search to date);

• IndMed (search to date);

• PakMediNet (search to date);

• Web of Knowledge, Web of Science (1945 to date);

• ClinicalTrials.gov, www.clinicaltrials.gov (search via the Cochrane Register of Studies to date);

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (search to date);

• ISRCTN, www.isrctn.com (search to date);

• Google Scholar (search to date);

• Google (search to date).

Where appropriate, the subject strategies will be combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Handbook 2011)).

Searching other resources

We will scan the reference lists of identified publications for additional trials and contact authors if necessary. In addition, the Information Specialist will search PubMed and theCochrane Library to retrieve existing systematic reviews relevant to this systematic review, so that we can scan their reference lists for additional trials. We will search for conference abstracts using the Cochrane ENT Trials Register and EMBASE.

Data collection and analysis

Selection of studies

Two authors (BE and HZ) will independently scan the initial search results to identify studies that appear to meet the inclusion criteria. Both authors will then review the full‐text articles of the retrieved trials and apply the inclusion criteria independently. We will resolve any differences in opinion about which studies to include in the review by discussion or, failing that, by consultation with one of the other authors (TB, LM, AJ, PB).

Data extraction and management

Two authors (BE and HZ) will independently extract data from the studies using standardised data forms. We will extract data so as to allow an intention‐to‐treat analysis. Where necessary or where insufficient data are provided for the study, we will contact the authors for further information.

With regard to subgroup analysis, we will extract data to allow grading of the diagnostic accuracy of the methods used to define the study population (see Types of participants), along with duration of disease and treatment protocol (dose and duration of drug treatment). For the outcome proportion of patients with a reduction in vertigo symptoms, we will independently dichotomise these into 'improved' or 'not improved'. If we find studies with more than two groups (e.g. two or more active treatments compared to placebo), we will only extract data from the intervention and placebo groups but we will make a note of the additional arm(s). If betahistine doses differ among the intervention groups within a study, we will extract data on the highest dose and compare this to placebo. Extraction of data on co‐morbidity will involve, for example, the presence of migraine and benign paroxysmal positional vertigo (BPPV).

For each study, we will extract the following information:

• study design;

• duration of study;

• randomisation;

• allocation concealment;

• number of participants;

• setting of study;

• diagnostic criteria;

• exclusion criteria;

• age and sex distribution of participants;

• country of recruitment;

• date of study;

• number of intervention groups;

• generic name of intervention;

• total dose per day (mg);

• method of administration;

• outcomes measured and definition of outcomes;

• missing data and final sample size;

• funding;

• conflict of interest (any author);

• concomitant treatment.

Assessment of risk of bias in included studies

BE and HZ will assess the risk of bias of the included studies independently as guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). The 'Risk of bias' tool addresses the following domains:

• sequence generation;

• allocation concealment;

• blinding;

• selective outcome reporting

• incomplete outcome data; and

• other sources of bias (e.g. improper statistical analysis).

The two authors will judge these domains using the Cochrane 'Risk of bias' tool in RevMan 5 (RevMan 2014), which involves describing each of these domains as reported in the trial and then assigning a judgement about the adequacy of each entry: 'low', 'high' or 'unclear' risk of bias. We will resolve differences of opinion by discussion. If no consensus is reached, we will consult the other authors.

Measures of treatment effect

The primary outcome in this review will be the proportion of participants with a reduction in vertigo symptoms, which is a dichotomised measure. For this type of data we will calculate the risk ratio (RR).

For intervention effect measures using continuous data we plan to calculate the mean difference (MD) between groups, provided that the selected studies used the same scale of measurement. If different scales having been used, we plan to calculate the standardised mean difference (SMD).

For studies with ordinal data we plan to dichotomise these data where possible.

Unit of analysis issues

Cluster‐randomised trials

We will include cluster‐RCTs with the cluster as the unit of analysis. For more recent studies, it is most likely that clusters have been taken into account in the analyses. If not, we will adjust for the clusters using the methods set out in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011).

Cross‐over trials

In Ménière's disease it is unlikely that symptom activity returns to its baseline level after the first treatment period. Therefore, we will only use data from cross‐over trials if data from before the cross‐over can be obtained.

Multi‐arm studies

In the event that we find studies with more than two groups (e.g. two or more active treatments being tested against placebo), we will establish which of the comparisons are relevant to the systematic review and relevant to each of the meta‐analyses that we may implement. As we anticipate that participants will have been included in several groups, there is a risk of unit of analysis error. As a result, we will ensure that participants are included only once per meta‐analysis. Where the study design used independent groups, we will treat the study as an independent comparison.

Repeated observations on participants

The unit of analysis will be the participant. We do not anticipate that by‐ear reporting will generally be available but data per ear are preferred in cases of bilateral Ménière's disease. We will regard bilateral Ménière's disease patients as 'improved' if any ear shows no deterioration of hearing loss and the proportion of patients who have a reduction in tinnitus or aural fullness increases. If studies evaluate the effect over a longer time period, we may record the results at multiple time points. To avoid unit of analysis error when combining study results in a single meta‐analysis (and therefore counting the same participants in more than one comparison), we will define different outcomes related to the periods of follow‐up and we will perform separate analyses.

Dealing with missing data

Where necessary and where sufficient data from the study are not provided, we will contact the authors of the study requesting further details about missing data and reasons for the incompleteness of the data. If no useful response is obtained, we will impute data if we judge the data to be 'missing at random'. If we judge data to be 'missing not at random', the missing data may affect the overall results; we will therefore not impute data. In the latter case, we will conduct sensitivity analysis with different assumptions.

We will be alert to potential mislabelling or non‐identification of standard errors and standard deviations. Our methods for imputation will be according to chapter 7.7.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011).

If data are missing we will use available case analysis using all data (as reported) for all randomised patients available at the end of the study/time point of interest, regardless of the actual treatment received. We will consider the quality of outcome assessment as a study limitation (GRADE) and not as a stratifying factor.

Assessment of heterogeneity

We will determine whether the selected studies suffer from clinical, statistical and methodological heterogeneity. We will quantify statistical heterogeneity using the I² statistic and the Chi² test. With respect to the I² statistic, an approximately guide to interpretation is provided in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). If the I² value is 50% or higher, the data can be considered to suffer from substantial or considerable heterogeneity. For the Chi² test, we will use the indicator that where the Chi² is greater than the degrees of freedom, then heterogeneity is likely to be present. We will consider heterogeneity to be statistically significant if the P value is less than 0.10. Subsequently, we will perform the meta‐analysis using fixed‐effect (in the absence of heterogeneity) and random‐effects modelling (in the presence of heterogeneity). If the level of heterogeneity remains unclear we will seek statistical advice.

Assessment of reporting biases

If the meta‐analysis contains at least 10 or more studies, we will assess publication bias using a funnel plot and Egger's test.

Data synthesis

We plan to analyse treatment differences as a risk ratio (RR), calculated using the Mantel‐Haenszel method. For continuous data, if different scales have been used across the studies, as we anticipate, we will use the SMD as an effect measure.

Subgroup analysis and investigation of heterogeneity

If sufficient data are available, we will carry out subgroup analyses. This will be restricted to a very small number of subgroups. We will also clearly specify the boundaries for defining inclusion and exclusion in advance and we will perform a significance test for interaction with the treatment effect. The planned subgroups are:

• stage of disease, as defined by the AAO‐HNS 1995 guidelines (see Appendix 7);

• type of Ménière's disease (see Types of participants); and

• dose of betahistine administered (minimum daily dose of 8 mg to a maximum of 148 mg).

Sensitivity analysis

We will conduct a sensitivity analysis by excluding those studies with a high risk of bias, thereby checking the robustness of the conclusion from the studies included in the meta‐analysis. In addition, we will use sensitivity analyses for studies in which data were imputed.

GRADE and 'Summary of findings' table

Two authors (BE and HZ) will independently use the GRADE approach to rate the overall quality of evidence. The quality of evidence reflects the extent to which we are confident that an estimate of effect is correct and we will apply this in the interpretation of results. There are four possible ratings of quality: high, moderate, low and very low. A rating of high quality of evidence implies that we are confident in our estimate of effect and that further research is very unlikely to change our confidence in the estimate of effect. A rating of very low quality implies that we are very uncertain about any estimate of effect obtained.

The GRADE approach rates evidence from RCTs that do not have serious limitations as high quality. However, several factors can lead to the downgrading of the evidence to moderate, low or very low. The degree of downgrading is determined by the seriousness of these factors:

• study limitations (risk of bias);

• inconsistency;

• indirectness of evidence;

• imprecision; and

• publication bias.

We will include a 'Summary of findings' table for our comparison of betahistine versus placebo, constructed according to the recommendations described in Chapter 11 of the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). We will include the following outcomes in the 'Summary of findings' table: the primary outcomes vertigo (the proportion of patients with a reduction in vertigo symptoms) and significant adverse events (upper gastrointestinal discomfort), and the secondary outcomes hearing loss, tinnitus, aural fullness, other adverse effects (headache and allergic skin reaction) and well‐being and disease‐specific health‐related quality of life.

Appendices

Appendix 1. Diagnostic criteria defined for Ménière’s disease by the American Academy of Otolaryngology ‐ Head and Neck Surgery in 1995

'Certain' Ménière's disease	'Definite' Ménière’s disease
	Histopathological confirmation
'Definite' Ménière's disease	Two or more definitive spontaneous episodes of vertigo of 20 minutes or longer
	Audiometrically documented hearing loss on one occasion
	Tinnitus or aural fullness in the treated ear
	Other causes excluded
'Probable' Ménière's disease	One definitive spontaneous episodes of vertigo of 20 minutes or longer
	Audiometrically documented hearing loss on one occasion
	Tinnitus or aural fullness in the treated ear
	Other causes excluded
'Possible' Ménière's disease	Episodic vertigo of the Ménière's type without hearing loss (or)
	Sensorineural hearing loss, fluctuating or fixed, with disequilibrium but without definitive episodes
	Other causes excluded

Source: AAO‐HNS 1995.

Appendix 2. AAO‐HNS outcome measures

The AAO‐HNS Committee on Hearing and Equilibrium proposed the "control of vertigo" as a main objective outcome measure when assessing therapy in Ménière's disease. The number of attacks six months prior to treatment is compared to the number of attacks in the period between 18 and 24 months following treatment. The resulting number indicates the extent of "control of vertigo". The AAO‐HNS further divides the control of vertigo into classes, where Class A (CoV = 100% control) is complete control and class B (CoV 99 to 60%%) is substantial control. They recommend a period of at least two years of follow‐up in order to assess fully the effect of the intervention. We will also consider studies with shorter periods of follow‐up for this review (AAO‐HNS 1995).

Appendix 3. Tinnitus Handicap Inventory

1.	Because of your tinnitus, is it difficult for you to concentrate?	Yes	Sometimes	No
2.	Does the loudness of your tinnitus make it difficult for you to hear people?	Yes	Sometimes	No
3.	Does your tinnitus make you angry?	Yes	Sometimes	No
4.	Does your tinnitus make you feel confused?	Yes	Sometimes	No
5,	Because of your tinnitus, do you feel desperate?	Yes	Sometimes	No
6.	Do you complain a great deal about your tinnitus?	Yes	Sometimes	No
7.	Because of your tinnitus, do you have trouble falling to sleep at night?	Yes	Sometimes	No
8.	Do you feel as though you cannot escape your tinnitus?	Yes	Sometimes	No
9.	Does your tinnitus interfere with your ability to enjoy your social activities (such as going out to dinner, to the movies)?	Yes	Sometimes	No
10.	Because of your tinnitus, do you feel frustrated?	Yes	Sometimes	No
11.	Because of your tinnitus, do you feel that you have a terrible disease?	Yes	Sometimes	No
12.	Does your tinnitus make it difficult for you to enjoy life?	Yes	Sometimes	No
13.	Does your tinnitus interfere with your job or household responsibilities?	Yes	Sometimes	No
14.	Because of your tinnitus, do you find that you are often irritable?	Yes	Sometimes	No
15.	Because of your tinnitus, is it difficult for you to read?	Yes	Sometimes	No
16.	Does your tinnitus make you upset?	Yes	Sometimes	No
17.	Do you feel that your tinnitus problem has placed stress on your relationships with members of your family and friends?	Yes	Sometimes	No
18.	Do you find it difficult to focus your attention away from your tinnitus and on other things?	Yes	Sometimes	No
19.	Do you feel that you have no control over your tinnitus?	Yes	Sometimes	No
20.	Because of your tinnitus, do you often feel tired?	Yes	Sometimes	No
21.	Because of your tinnitus, do you feel depressed?	Yes	Sometimes	No
22.	Does your tinnitus make you feel anxious?	Yes	Sometimes	No
23.	Do you feel that you can no longer cope with your tinnitus?	Yes	Sometimes	No
24.	Does your tinnitus get worse when you are under stress?	Yes	Sometimes	No
25.	Does your tinnitus make you feel insecure?	Yes	Sometimes	No

The Tinnitus Handicap Inventory (THI) is scaled in the following grades:

Grade	Score	Description
1	0 to 16	Slight: Only heard in quiet environment, very easily masked. No interference with sleep or daily activities.
2	18 to 36	Mild: Easily masked by environmental sounds and easily forgotten with activities. May occasionally interfere with sleep but not daily activities.
3	38 to 56	Moderate: May be noticed, even in the presence of background or environmental noise, although daily activities may still be performed.
4	58 to 76	Severe: Almost always heard, rarely, if ever, masked. Leads to disturbed sleep pattern and can interfere with ability to carry out normal daily activities. Quiet activities affected adversely.
5	78 to 100	Catastrophic: Always heard, disturbed sleep patterns, difficulty with any activity.

Appendix 4. Functional Level Scale

Regarding my current state of overall function, not just during attacks (check the ONE that best applies):

1. My dizziness has no effect on my activities at all.

2. When I am dizzy I have to stop what I am doing for a while, but it soon passes and I can resume activities. I continue to work, drive and engage in any activity I choose without restriction. I have not changed any plans or activities to accommodate my dizziness.

3. When I am dizzy, I have to stop what I am doing for a while, but it does pass and I can resume activities. I continue to work, drive and engage in most activities I choose, but I have had to change some plans and make some allowance for my dizziness.

4. I am able to work, drive, travel, take care of a family or engage in most essential activities, but I must exert a great deal of effort to do so. I must constantly make adjustments in my activities and budget my energies. I am barely making it.

5. I am unable to work, drive or take care of a family. I am unable to do most of the active things that I used to. Even essential activities must be limited. I am disabled.

6. I have been disabled for 1 year or longer and/or I receive compensation (money) because of my dizziness or balance problem.

The raw data for the Functional Level Scale should be reported for each patient at each time interval (baseline, two years, etc.). The score should also be expressed as improved, unchanged or worse for each patient.

Appendix 5. Dizziness Handicap Inventory

P1. Does looking up increase your problem?	Yes	Sometimes	No
E2. Because of your problem, do you feel frustrated?	Yes	Sometimes	No
F3. Because of your problem, do you restrict your travel for business or recreation?	Yes	Sometimes	No
P4. Does walking down the aisle of a supermarket increase your problems?	Yes	Sometimes	No
F5. Because of your problem, do you have difficulty getting into or out of bed?	Yes	Sometimes	No
F6. Does your problem significantly restrict your participation in social activities, such as going out to dinner, going to the movies, dancing, or going to parties?	Yes	Sometimes	No
F7. Because of your problem, do you have difficulty reading?	Yes	Sometimes	No
P8. Does performing more ambitious activities such as sports, dancing, household chores (sweeping or putting dishes away) increase your problems?	Yes	Sometimes	No
E9. Because of your problem, are you afraid to leave your home without having without having someone accompany you?	Yes	Sometimes	No
E10. Because of your problem have you been embarrassed in front of others?	Yes	Sometimes	No
P11. Do quick movements of your head increase your problem?	Yes	Sometimes	No
F12. Because of your problem, do you avoid heights?	Yes	Sometimes	No
P13. Does turning over in bed increase your problem?	Yes	Sometimes	No
F14. Because of your problem, is it difficult for you to do strenuous homework or yard work?	Yes	Sometimes	No
E15. Because of your problem, are you afraid people may think you are intoxicated?	Yes	Sometimes	No
F16. Because of your problem, is it difficult for you to go for a walk by yourself?	Yes	Sometimes	No
P17. Does walking down a sidewalk increase your problem?	Yes	Sometimes	No
E18.Because of your problem, is it difficult for you to concentrate	Yes	Sometimes	No
F19. Because of your problem, is it difficult for you to walk around your house in the dark?	Yes	Sometimes	No
E20. Because of your problem, are you afraid to stay home alone?	Yes	Sometimes	No
E21. Because of your problem, do you feel handicapped?	Yes	Sometimes	No
E22. Has the problem placed stress on your relationships with members of your family or friends?	Yes	Sometimes	No
E23. Because of your problem, are you depressed?	Yes	Sometimes	No
F24. Does your problem interfere with your job or household responsibilities?	Yes	Sometimes	No
P25. Does bending over increase your problem?	Yes	Sometimes	No

The patient is asked to answer each question as it pertains to dizziness or unsteadiness problems, specifically considering their condition during the last month. Questions are designed to incorporate functional (F), physical (P) and emotional (E) impacts on disability. To each item, the following scores can be assigned: no = 0, sometimes = 2, yes = 4. Scores greater than 10 points should be referred to balance specialists for further evaluation: 16 to 34 points (mild handicap), 36 to 52 points (moderate handicap), 54+ points (severe handicap).

Appendix 6. Search strategies

CENTRAL	PubMed	EMBASE (Ovid)
#1 MeSH descriptor Meniere Disease explode all trees #2 meniere* #3 (ENDOLYMPHATIC and HYDROPS) or (LABYRINTH and HYDROPS) or (LABYRINTH and SYNDROME) or (aural and vertigo) or (labyrinth and vertigo) or (cochlea and hydrops) #4 (#1 OR #2 OR #3) #5 MeSH descriptor Betahistine explode all trees #6 BETAHISTIN* or BETAISTINA or SERC or AEQUAMEN or BETASERC or BETASERK or BEATSERKA or EXTOVYL or FIDIUM or LECTIL or LOBIONE or MEGINALISK or MELOPAT or MENIACE or MERISLON or MICROSER or RIBRAIN or VASOMOTAL #7 (#5 OR #6) #8 (#4 AND #7) #9 MeSH descriptor: [Meniere Disease] explode all trees and with qualifiers: [Drug therapy ‐ DT] #10 (#8 OR #9)	#9 #7 OR #8 #8 "Meniere Disease/drug therapy"[Mesh] #7 #3 AND #6 #6 #4 OR #5 #5 Betahistin* [tiab] OR BETAISTINA [tiab] OR SERC [tiab] OR AEQUAMEN [tiab] OR BETASERC [tiab] OR BETASERK [tiab] OR BEATSERKA [tiab] OR EXTOVYL [tiab] OR FIDIUM [tiab] OR LECTIL [tiab] OR LOBIONE [tiab] OR MEGINALISK [tiab] OR MELOPAT [tiab] OR MENIACE [tiab] OR MERISLON [tiab] OR MICROSER [tiab] OR RIBRAIN [tiab] OR VASOMOTAL [tiab] #4 "Betahistine" [Mesh] #3 #1 OR #2 #2 meniere* [tiab] OR (ENDOLYMPHATIC [tiab] AND HYDROPS [tiab]) OR (LABYRINTH [tiab] AND HYDROPS [tiab]) OR (LABYRINTH [tiab] AND SYNDROME [tiab]) OR (aural [tiab] AND vertigo [tiab]) OR (labyrinth [tiab] AND vertigo [tiab]) OR (cochlea [tiab] AND hydrops [tiab]) #1 "ENDOLYMPHATIC HYDROPS" [Mesh]	1 MENIERE DISEASE/ 2 meniere*.tw. 3 ((ENDOLYMPHATIC and HYDROPS) or (LABYRINTH and HYDROPS) or (LABYRINTH and SYNDROME) or (aural and vertigo) or (labyrinth and vertigo) or (cochlea and hydrops)).tw. 4 1 or 3 or 2 5 Betahistine/ 6 (BETAHISTIN* or BETAISTINA or SERC or AEQUAMEN or BETASERC or BETASERK or BEATSERKA or EXTOVYL or FIDIUM or LECTIL or LOBIONE or MEGINALISK or MELOPAT or MENIACE or MERISLON or MICROSER or RIBRAIN or VASOMOTAL).tw. 7 6 or 5 8 4 and 7 9 Meniere disease/dt [Drug Therapy] 10 8 or 9
Web of Science	CINAHL (EBSCO)	ICTRP
#3 #1 AND #2 #2 TS=(BETAHISTIN* or BETAISTINA or SERC or AEQUAMEN or BETASERC or BETASERK or BEATSERKA or EXTOVYL or FIDIUM or LECTIL or LOBIONE or MEGINALISK or MELOPAT or MENIACE or MERISLON or MICROSER or RIBRAIN or VASOMOTAL) #1 TS=(meniere* OR (ENDOLYMPHATIC and HYDROPS) or (LABYRINTH and HYDROPS) or (LABYRINTH and SYNDROME) or (aural and vertigo) or (labyrinth and vertigo) or (cochlea and hydrops))	S6 S4 and S5 S5 TX BETAHISTIN* or BETAISTINA or SERC or AEQUAMEN or BETASERC or BETASERK or BEATSERKA or EXTOVYL or FIDIUM or LECTIL or LOBIONE or MEGINALISK or MELOPAT or MENIACE or MERISLON or MICROSER or RIBRAIN or VASOMOTAL S4 S1 or S2 or S3 S3 TX (ENDOLYMPHATIC and HYDROPS) or (LABYRINTH and HYDROPS) or (LABYRINTH and SYNDROME) or (aural and vertigo) or (labyrinth and vertigo) or (cochlea and hydrops) S2 TX meniere* S1 (MH "Meniere's Disease")	BETAHISTIN* or BETAISTINA or SERC or AEQUAMEN or BETASERC or BETASERK or BEATSERKA or EXTOVYL or FIDIUM or LECTIL or LOBIONE or MEGINALISK or MELOPAT or MENIACE or MERISLON or MICROSER or RIBRAIN or VASOMOTAL

Appendix 7. Staging of definite and certain Ménière's disease

Stage	Four‐tone average (dB)
1	≤ 25
2	26 to 40
3	41 to 70
4	70

Staging is based on the four‐tone average (arithmetic mean rounded to the nearest whole number) of the pure‐tone thresholds at 0.5 kHz, 1 kHz, 2 kHz and 3 kHz of the worst audiogram during the interval six months before treatment. This is the same audiogram that is used as the baseline evaluation to determine hearing outcome from treatment. Staging should be applied only to cases of definite or certain Ménière's disease.

Contributions of authors

All authors were involved in the drafting of the protocol.

Babette van Esch: BE will select and obtain studies, extract data and assess risk of bias. BE will enter data into RevMan 5 and carry out and interpret the analyses. BE will draft the final review and will have responsibility for updating and maintaining the review.

Tjasse Bruintjes: TB will provide advice as needed throughout and draft the final review.

Hester J Van der Zaag‐Loonen: HZ will select studies, extract data, assess risk of bias and help interpret the analyses. HZ will provide advice as needed throughout and draft the final review.

Louisa Murdin: LM will provide advice as needed throughout and will draft the final review.

Adrian James: AJ will provide advice as needed throughout and will draft the final review.

Peter Paul van Benthem: PB will provide advice as needed throughout and draft the final review.

Sources of support

Internal sources

• No sources of support supplied

External sources

• National Institute for Health Research, UK.

  Infrastructure funding for Cochrane ENT

Declarations of interest

Babette van Esch: none known.

Tjasse Bruintjes: none known.

Hester J Van der Zaag‐Loonen: none known.

Louisa Murdin: none known.

Adrian James: none known.

Peter Paul van Benthem: none known.

Notes

This is a new protocol for the update of the out of date review 'Betahistine for Ménière's disease or syndrome' (James 2001), which will be superseded by this review.

New