Botulinum toxin for masseter hypertrophy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of Botulinum toxin type A in the management of benign bilateral masseter hypertrophy.
Background
Aetiology and prevalence
Benign masseter muscle hypertrophy is an uncommon clinical phenomenon of uncertain aetiology. More than 250 cases of benign bilateral masseter muscle hypertrophy have been reported since its first published description (Legg 1880). Prevalence data are scarce but in a recent study (Sannomya 2006), 90 (4%) of the patients with masseter hypertrophy were less than 10yrs and 3% were over 40yrs of age (mean 30 years) with a male to female ratio of 1:1.
The aetiology of masseter muscle hypertrophy has been attributed to a number of factors; emotional stress, chronic bruxism, masseteric hyperfunction, para‐functional jaw habits and microtrauma (Wilson 1990; Serrat 1998; Harriman 1996). It reportedly occurs most frequently among pacific Asians and is associated with ethnic characteristics (prominence of the mandibular angle) and dietary habits (Jin Park 2007). The findings of several investigators suggest that the increase in size of muscle is not caused by work hypertrophy but as a result of compensatory enlargement due to lack of a certain type of muscle fibre. Tests have shown that the composition of muscle fibres in the enlarged masseter is very different from that in muscles with "work hypertrophy" as well as in normal masseter muscles (Satoh 2001), suggesting that the term 'hypertrophy' can be potentially misleading.
Other possible causes and associations have been suggested; clenbuterol induced hypertrophy, overuse of anabolic steroids (Skoura 2001), localized scleroderma and facial hemi‐atrophy (Kim 2000), and a multifactorial origin in combination with a genetic basis (Giudice 1992).
Benign masseter hypertrophy is also compatible with a rare genetic condition known as hypertrophic branchial myopathy (Kitagawa 2000).
Description of the condition
Signs and symptoms
Bilateral enlargement of the masseter muscles is often accompanied by pain, which may be intermittent and can be confused with pain arising from the parotid gland (Nishida 1995; Newton 1999). Clinical examination usually reveals a soft tissue mass over the body, near the angle of the mandible, which becomes more prominent on clenching of the teeth (Sannomya 2006).
Limitation of mouth opening has been reported in some cases and particularly where the muscles are focally dystonic with tension in the region of the hypertrophied muscle (Papapetropoulos 2006). Midline deviation has also been observed in some cases, as well as masseteric (hemi‐masticatory) spasm (Kim 2000). It has also been suggested that the hypertrophied muscles of the jaw can lead to increased pressure in the temporo‐mandibular joints (TMJ) which can generate severe pain mimicking temporo‐mandibular dysfunction syndrome (TMD) (Chikhani 2003).
Diagnosis
Diagnosis cannot solely be based on clinical findings and there are conflicting recommendations in the literature for investigating patients presenting with benign bilateral masseter hypertrophy:
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Standard radiographs are not essential but can sometimes assist in diagnosis.
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CT Scan and/or MRI Scan are considered the gold standard in confirming a clinical suspicion.
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Muscle biopsy
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Morphometric analysis.
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Ultrasonographic measurement
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Electromyographic measurement
Description of the intervention
Treatment options
A range of modalities of treatment have been reported with variable degrees of success and failure:
(1) Pharmacotherapy: anxiolytics, muscle relaxants and antidepressants.
(2) Dental restorations and occlusal adjustments to correct premature contacts and malocclusions and prevention of para‐functional habits with orthotic appliances.
(3) Botulinum toxin type A (BtA) injections into the muscle
(4) Radiofrequency volumetric reduction
(5) Intra‐oral and extra‐oral surgical reduction of masseter size, removal of mandibular angle, neurectomy of the masseteric nerve, and resection of the buccal fat pad.
How the intervention might work
Botulinum toxin type A (BtA) is a powerful neurotoxin produced by the anaerobic organism clostridium botulinum. When BtA is injected into a muscle it causes interference with the neurotransmitter mechanism producing selective paralysis and subsequent atrophy of the muscle.
Why it is important to do this review
Surgery has historically been the standard treatment for cosmetic reduction of masseter hypertrophy, but injection of BtA into the muscle, which is generally considered a less invasive modality, has more recently been advocated.
Although there have been several studies and case reports to the best of our knowledge there has not been a systematic review of the effectiveness of BtA for the treatment of masseter hypertrophy.
Objectives
To assess the effects of Botulinum toxin type A in the management of benign bilateral masseter hypertrophy.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled clinical trials (RCTs) and controlled clinical trials (CCTs).
Types of participants
Individuals in any age group with bilateral benign masseter hypertrophy which has been self evaluated and confirmed by clinical and radiological examination. In view of the possible clinical diversity in presentation we will not include studies involving participants with unilateral or compensatory contra lateral masseter hypertrophy resulting from head and neck radiotherapy.
Types of interventions
Transcutaneous intra‐masseteric injections of botulinum toxin versus placebo. We will include studies in which the intervention has been administered for cosmetic facial sculpting and where the masseter hypertrophy is co‐associated with temporo‐mandibular dysfunction syndrome (TMD) Studies involving a single injection cycle will be considered in addition to those in which all participants entered in to a trial have received repeat injections at similar time periods.
Types of outcome measures
Assessment will include a follow‐up period of up to 2 years after the intervention.
Primary outcomes
(1) Self assessed improvement in facial appearance and patient satisfaction using any validated scale or questionnaire.
(2) Change in pain/discomfort (associated with the TMJs or jaw muscles): patient‐assessed using any recognized validated pain scale.
Secondary outcomes
1) Objective evaluation of the change in facial contour: involving physical measurements
(a) Clinical photography
(b) Radiologically: three‐dimensional computed tomographic (CT) scans, magnetic resonance (MR) imaging, ultrasonographic measurements of the thickness of the masseter muscle
Search methods for identification of studies
Electronic searches
For the MEDLINE search, the subject search will be run with the Cochrane Highly Sensitive Search Strategy (CHSS) for identifying randomised trials in MEDLINE: sensitivity maximising version (2008 revision) as referenced in Chapter 6.4.11.1 and detailed in box 6.4.c of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 (updated February 2008) (Higgins 2008).
Databases to be searched
The following databases will be searched:
Cochrane Movement Disorders Group Trials Register
Cochrane Central Register of Controlled Trials (CENTRAL)
MEDLINE (via Pubmed)
EMBASE (via OVID)
LILACS (via BIREME)
IndMED (http://indmed.nic.in/)
Iranmedex (www.iranmedex.com)
Details of the search strategy for searching via Medline is provided in 'appendices'. Further details of the search strategies for any other databases searched will be provided in the published review.
Searching other resources
Handsearching will be conducted of any journals that are considered appropriate and have not already been searched as part of the Cochrane Movement Disorders Group's or the Oral Health Group's handsearch programme.
We will search the reference lists of all eligible trials and relevant articles in addition to the review authors' personal database of trial reports and will also attempt to contact investigators of included studies by electronic mail to ask for details of additional published and unpublished trials.
Language
There will be no language restriction on included studies and we will arrange to translate any relevant non‐English papers.
Data collection and analysis
Selection of studies
Two review authors (Zbys Fedorowicz (ZF) and Mohammed Al Muharraqi (MAM) will independently assess the abstracts of studies resulting from the searches. Full copies of all relevant and potentially relevant studies, those appearing to meet the inclusion criteria, or for which there were insufficient data in the title and abstract to make a clear decision, will be obtained. The full text papers will be assessed independently by two review authors and any disagreement on the eligibility of included studies will be resolved through discussion and consensus or if necessary through a third party Reem Al Bareeq (RAB). All irrelevant records will be excluded and details of the studies and the reasons for their exclusion will be noted in the 'Characteristics of excluded studies' table in RevMan 5 (RevMan 2008).
Data extraction and management
Study details will be entered into the 'Characteristics of included studies' table in RevMan 5. The review authors will collect outcomes data using a pre‐determined form designed for this purpose.
Both (ZF and MAM) will enter extracted data into RevMan 5. The review authors will only include data if there is an independently reached consensus, any disagreements will be resolved by consulting with a third review author (RAB).
The following details will be extracted.
(1) Trial methods:
(a) method of allocation.
(b) masking of participants, trialists and outcomes assessors.
(c) exclusion of participants after randomization and proportion and reasons for losses at follow up.
(2) Participants:
(a) country of origin and location: private clinic or academic institute.
(b) sample size
(c) age
(d) sex
(e) inclusion and exclusion criteria
(3) Intervention:
(a) type; dosage location
(b) length of time in follow up.
(4) Control:
(a) type; dosage location
(b) length of time in follow up.
(5) Outcomes:
(a) primary and secondary outcomes mentioned in the outcome measures section of this review.
If stated, the sources of funding of any of the included studies will be recorded.
The review authors will use this information to help them assess heterogeneity and the external validity of the trials.
Assessment of risk of bias in included studies
Each review author will grade the selected trials and every trial will be assessed using a simple contingency form and will follow the domain‐based evaluation described in the Cochrane Handbook for Systematic Reviews of Interventions 5.0.0 (Higgins 2008). The evaluations will be compared and any inconsistencies between the review authors in the interpretation of inclusion criteria and their significance to the selected trials will be discussed and resolved.
We will assess the following domains as 'Yes' (i.e. low risk of bias), 'Unclear' (uncertain risk of bias) or 'No' (i.e. high risk of bias):
1. Sequence generation
2. Allocation concealment
3. Blinding (of participants, personnel and outcome assessors)
4. Incomplete outcome data
5. Selective outcome reporting
These assessments will be reported for each individual study in the 'Risk of bias table' under the 'Characteristics of included studies'.
Measures of treatment effect
Analysis will be conducted at the same level as the allocation.
Risk ratios and their 95% confidence intervals (CIs) will be calculated for all dichotomous data and as weighted mean difference (and 95% confidence intervals) for continuous outcomes, using the Peto fixed‐effect method.
As it is likely that the timing of outcome assessment will vary between studies we will consider grouping the data according to the following time‐points: 6 months and 1,2 years.
Unit of analysis issues
We expect to include trials conducted on participants with bilateral hypertrophy in which the masseter muscles of an individual participant were the units of randomization and subsequent analysis.
Dealing with missing data
We will attempt to retrieve missing data from the investigators in any of the included trials and if unsuccessful or the discrepancies are significant we will provide a narrative synthesis of the data as reported.
Assessment of heterogeneity
We plan to assess clinical heterogeneity by examining the characteristics of the studies, the similarity between the types of participants, the interventions and the outcomes as specified in the criteria for included studies. As we are expecting a level of clinical heterogeneity between the studies we plan to use the random‐effects model with studies grouped by action. Statistical heterogeneity will be assessed using a chi‐squared test and the I2 test where I2 values over 50% indicate moderate to high heterogeneity (Higgins 2003).
Assessment of reporting biases
To assess publication bias we will follow the recommendations on testing for funnel plot asymmetry as described in section 10.4.3.1 of the Cochrane Handbook for Systematic Reviews of Interventions 5.0.0 (Higgins 2008), and these will be explored in the discussion if appropraite.
Data synthesis
We will seek statistical support from the Cochrane Movement Disorders Group. Two review authors ZF and MAM will analyze the data and report them as specified in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 (Higgins 2008).
In the event that there are insufficient clinically homogeneous trials for any specific intervention or insufficient study data that can be pooled, a narrative synthesis will be presented.
Subgroup analysis and investigation of heterogeneity
If data are available we will analyse the data by splitting it into sub‐categories by dose i.e. a total low dose of BtA ≤150U per muscle and a medium to high dose of BtA >150U per muscle.
Sensitivity analysis
If there are sufficient included studies we plan to conduct sensitivity analyses to assess the robustness of our review results by repeating the analysis with the following adjustments: exclusion of studies with unclear or inadequate allocation concealment, unclear or inadequate blinding of outcomes assessment and completeness of follow up.
