Botulinum Toxin Type A for the Treatment of Masseter Muscle Prominence in Asian Populations

Abstract

 

In Asian populations, an oval face shape with a slimmer lower face is considered favorable. Botulinum toxin type A (BoNT-A) treatment of the lower face for aesthetic purposes is widely performed in Asia, although it is not officially approved for this indication in any country. In this review, the authors highlight recent research describing injection techniques, mechanism of action, clinical efficacy, and key learning points to safely treat benign masseter muscle prominence (MMP) in Asian populations using BoNT-A. To support the existing literature, clinical examples are provided that demonstrate individualized treatment plans for patients with asymmetric vs symmetric MMP and an observed complication after treatment. This review provides insights for optimizing clinical outcomes and for designing future studies investigating the safety and efficacy of BoNT-A for treating MMP.

Level of Evidence: 5

Asian individuals consider a slimmer lower face with an overall oval face shape more favorable than a square face.^1–4 A survey of Chinese women showed that 40% preferred an oval face shape compared with <2% who preferred a square face.⁵ Benign masseter muscle prominence (MMP, also known as masseter muscle hypertrophy) resulting from unilateral or bilateral enlargement of the masseter muscle is characterized by widening near the angle of the mandible that contributes to a square face shape.^2,6,7 This condition occurs in both men and women regardless of age, but it is most commonly observed in adults between the ages of 20 and 40 years.^3,8 MMP may have a negative impact on an individual's self-perception of facial attractiveness and may be associated with psychological distress, thus affecting quality of life.^2,9 In Asia, individuals usually seek MMP treatment for aesthetic contouring.^10–12

The 2 most common treatment options for MMP are surgery or injections with botulinum toxin type A (BoNT-A), including onabotulinumtoxinA (Botox; Allergan, an AbbVie Company, Dublin, Ireland).^1–4 Historically, surgical interventions have been used for individuals with underlying bony flaring in addition to MMP.¹³ This treatment, which has long recovery periods, has been replaced by minimally invasive BoNT-A injections. BoNT-A disrupts neurotransmission by producing temporary chemical denervation of the muscle, resulting in localized relaxation of the muscle and reduction in muscle activity, thus reducing the associated muscle bulk or volume.⁷

Although widely used among Asian individuals for the treatment of MMP, BoNT-A treatment has not yet been approved for this indication.^3,4,6 The use of BoNT-A for the aesthetic treatment of MMP was first described in 1994.¹⁴ Since then, several studies and smaller case series have demonstrated the efficacy and safety of onabotulinumtoxinA^12,15–17 and other formulations of BoNT-A for the reduction of MMP.^8,18–21 Consensus guidelines also recommend the use of BoNT-A for the management of MMP in Asian populations.^10,22

This evidence-based review provides a general overview of anatomy research to help optimize injections. It also reviews the clinical evidence for reduction of muscle volume with BoNT-A in MMP, including efficacy and safety data in Asian populations, which may provide insight in designing future studies. Information from the literature is supported with clinical examples that demonstrate individualized treatment plans for patients with asymmetric vs symmetric MMP and an observed complication after treatment, which can help guide current clinical practices.

ANATOMY RESEARCH IN ASIAN POPULATIONS FOR GUIDING BONT-A INJECTION

The masseter muscle is the largest of a set of facial muscles responsible for mandibular chewing motions.^23,24 The anatomic basis for MMP is enlargement of the masseter muscle, which may be influenced by ethnic background.^{4,6,8,25–28} In general, Asian individuals tend to have more developed and pronounced masseter muscles and a more protrusive angle of the mandible compared with most white individuals.^4,29,30

Anatomic studies using cadavers provide insights for achieving safe and effective injections in Asian populations.^31–35 The Figure shows an image of a cadaver with the masseter muscle belly located mainly below an imaginary line between the mouth angle and the earlobe. Masseter dissections (N = 3) identified 3 layers of the masseter skeletal muscle (superficial, middle, and deep layers) that are innervated by separate nerve branches originating from the nervus massetericus.³⁶ The most prominent part of the masseter muscle bulge was associated with the distribution region of the nervous massetericus in the lower third of the mandibular ramus.³⁶ Because BoNT-A targets the presynaptic nerve terminals at the motor end plate, the most prominent point of the bulging masseter muscle where the appropriate nerve innervates the affected muscle would present an ideal injection site.^36,37 The number of BoNT-A injection sites and dosage may be dependent on masseter muscle thickness and the degree of hypertrophy.³⁶ Another cadaver dissection study (N = 22) showed that 2–4 perforating nerve branches from the anteroinferior nerve group innervate the superficial layer of the masseter muscle.³⁷ The superior portion of the masseter muscle is considered unsuitable for BoNT-A injection because of the location of the parotid duct and the absence of perforating nerve branches supplying the superficial layer of the masseter muscle.^31,37

Figure.

Anatomic presentation of the masseter muscle. (A) The masseter muscle is located on the deep side of the platysma muscle and superficial musculoaponeurotic system. It arises from the zygomatic arch and inserts into the lateral surface of ramus and angle of the mandible. (B) The full exposure of the masseter muscle after the flap of the Plt and the SMAS fascia have been removed. (C) For optimal effects, BoNT-A should be injected in at least 3 points of the masseter muscle (represented by *) below the white line (safety zone). Considering the masseter muscle thickness of this individual, unilateral injection of more than 35 U BoNT-A was required; the depth of injection was >15 mm. (D) The masseter muscle was detached from the mandible bone, and the masseter muscle was flipped. The thickness of the masseter muscle was >10 mm. BoNT-A, botulinum toxin A; DAO, depressor anguli oris; MB, mandible bone; MM, masseter muscle; Plt, platysma muscle; SMAS, superficial musculoaponeurotic system; Zmj, zygomatic major.

MEASUREMENT OF MASSETER MUSCLE PROMINENCE (MMP)

Standardized approaches for assessing MMP, including masseter muscle thickness, are needed.³⁸ In the authors’ opinion, the lack of standardized approaches may be influenced by injector preferences, the distinct facial shapes of individuals, and the limited availability of simple and convenient equipment in clinical practice. Previous studies have used physical measurements, cephalometry, clinical photographs, scales, and three-dimensional facial imaging systems to measure reductions in facial volume, the degree of MMP, and the efficacy of BoNT-A in reducing the degree of MMP.^17,36,39,40 A study in Chinese patients classified MMP into 5 types based on detection by palpation of the bulging masseter muscle upon contraction.³⁶ This study found that types II (mono, a local singular longitudinal bulge) and III (double, 2 separate longitudinal bulges of equal or differing height) were the most common.³⁶ Another study used a validated MMP scale to classify the prominence into 5 types based on detection in the static state and by palpation of the bulging muscle upon contraction.³⁹

PHARMACOLOGY AND CLINICAL EFFICACY OF MMP INJECTION WITH BONT-A

BoNT-A blocks neuromuscular transmission by inhibiting the release of acetylcholine into synaptic junctions, leading to partial denervation and muscle paralysis, then to reversible muscle atrophy.^41,42 The chemical denervation produced by BoNT-A is slowly reversed over time. Repeat dosing is thus necessary to maintain the desired reduction in MMP.^1,43 A review of published studies on the use of BoNT-A for lower face contouring found that the onset of action ranged from 2–4 weeks, and its effects can last up to 12 months.⁷ In comparison, the effects of BoNT-A injection generally last 3–6 months for facial lines.^44,45 The longer duration of efficacy following treatment of MMP relative to treatment of facial lines may be related to dosing. Results from a multicentre, randomized, double-blind, placebo-controlled, Phase 2 dose-escalation study suggested that efficacy in MMP was maintained for 9 months with 72 and 96 U onabotulinumtoxinA, compared with 180 days with 24 and 48 U (Table 1).³⁹ Thus, a number of publications suggest that longer dosing intervals can be used to maintain beneficial results in MMP⁷ compared with the treatment of hyperkinetic facial lines.

Table 1.

Summary of Efficacy Findings From the Phase II Study of OnabotulinumtoxinA for Masseter Muscle Prominence³⁹

Outcome	Study group
	Placebo (n = 37)	OnabotA 24 U (n = 36)	OnabotA 48 U (n = 36)	OnabotA 72 U (n = 38)	OnabotA 96 U (n = 38)
Primary efficacy measure  LS mean change in lower facial volume calculated from VECTRA M3 (Parsippany-Troy Hills, NJ) photography at day 90, cm3	−0.52a	−4.40a,b	−6.84a	−7.41a	−8.20a
Other efficacy measures  Responders achieving MMPS grade ≤3 at day 90, %	35.1	66.7c	83.3c	89.5c	89.5c
Responders achieving ≥2-grade change in MMPS at day 90, %	8.1	47.2a	47.2a	73.7a,d	65.8a
Change in masseter volume in a defined region at day 90 as measured by CT, cm3	−0.6e	−5.4a	−6.0a	−7.0a	−7.2a

ANOVA, analysis of variance; CT, computed tomography; LS, least squares; MMPS, Masseter Muscle Prominence Scale; onabotA, onabotulinumtoxinA. ^aP < .001 vs placebo from ANOVA (effects in ANOVA include treatment and baseline MMPS grade, where type III sum of squares is used). ^bP = .006, onabotA 48 U vs 24 U. ^cP ≤ .008 vs placebo from ANOVA. ^dP = .016 onabotA 72 U vs 48 U. ^en = 36.

In studies on Asian individuals, the total dose varied between 10 and 45 U of BoNT-A injection per side (Table 2).^1,12,15,19 Similar to previous studies,²⁸ the authors’ experiences show that higher doses (40 U or more of onabotulinumtoxinA per side) may be more appropriate for patients with moderate to severe MMP, and the contouring effect could last longer. These injection dose recommendations are further validated by a recent phase II dose-escalation study to assess the safety and efficacy of onabotulinumtoxinA for treatment of MMP.³⁹ A significant difference (P < .05 vs placebo) in lower facial volume reduction was maintained at all timepoints through day 180 after a single treatment in all onabotulinumtoxinA dose groups (48, 72, and 96 U) and for up to 6 months after 2 treatments with onabotulinumtoxinA.³⁹ Dose-ranging studies conducted in female and male adult patients with glabellar lines demonstrated that efficacy and duration of onabotulinumtoxinA response may increase with doses higher than 20 U.^45,46

Table 2.

Effective Doses of Botulinum Toxin Type A for Masseter Muscle Prominence in Asian Populations

Study (year)	Patients, N	Dose per masseter muscle, U	Maximum follow–up, months
Park et al (2003)	45	25-30	10
Choe et al (2005)	22	10-30	9
Liew and Dart (2008)	48	40-45	24
Shim et al (2010)	15	25	6

Both sides of the masseter muscle are commonly injected with the same dose. However, for individuals with different lower facial volumes in the left and right sides of their face, dose adjustments may be required to achieve symmetry.^24,47 The side of the face with a larger volume or masseter thickness is usually injected with a higher dose than the side with less volume/thickness.³⁶

SAFETY OF BONT-A FOR THE REDUCTION OF MMP

Previous studies have reported the safety and tolerability of BoNT-A to treat MMP in Asian populations, with common adverse events (AEs) that include mild chewing weakness/temporary mastication force decrease, injection site pain, headaches, and sunken cheeks (ie, hollowing of the middle face).^20,24,39,48 Most AEs were mild, expected, and transitory.³⁹ A dose-escalation study reported no incidence of AEs indicative of distant spread of toxin and no safety signals as revealed by computed tomography scan (ie, clinically relevant mandibular bone changes) or dental exams.³⁹

Preventing and Managing AEs Associated With BoNT-A in the Treatment of MMP

The incidence of AEs can be mitigated through several approaches. Sunken cheeks, which may occur more often in Asian individuals who have a more prominent zygoma than White individuals, can be minimized by lowering the dose, as well as injecting over the lower part of the masseter and not too close to its anterior border.^16,20,24 As mentioned in the sections above, injecting below a line drawn between the mouth corner and earlobe (safety zone) can decrease complications.²⁴ Inadvertent injection of BoNT-A into the risorius muscle may result in an unnatural facial expression, such as a reduction in mouth width upon smiling.³⁴ By asking the patient to clench his or her teeth, thereby contracting the masseter muscle, the injector can mitigate the risk of inadvertently injecting and temporarily paralyzing the risorius muscle.⁴⁹ Post-treatment asymmetry may result from the failure to recognize differences between masseter muscles in each side of the face; it can be minimized with appropriate pretreatment assessments and dose adjustments.^24,47 Bruising can be mitigated by applying immediate local compression after injection until bleeding has stopped.²⁴ Rest is recommended for patients who experience dizziness or headache.²⁴ Sagging that may result from rapid volume reduction of the overlying skin can be reduced by lowering the injection dose and distributing the treatment over multiple sessions to decelerate muscle atrophy.^24,47 Injection of toxin into the depressor muscles of the lower face and neck (eg, the platysma muscle) may also be considered to prevent this complication.²⁴ Potentially, in rare cases, paradoxical bulging may occur.

Besides uneven distribution of injection points, another potential source of paradoxical bulging may be the deep inferior tendon (DIT) located in the superficial layer of the masseter muscle, which could prevent diffusion of BoNT-A from the deep layer to the superficial layer of the masseter muscle.³³ In such a scenario, the superficial muscle could remain active, exhibiting a superficial bulge.^33,35 To prevent paradoxical bulging, ultrasound imaging can be used to confirm DIT morphology and to guide BoNT-A injections.³⁵ If paradoxical bulging does not resolve within 2 weeks, injection of a more superficial booster dose (5 to 10 U) is recommended.²⁴ In individuals with a history of paradoxical bulging, a combination of injections to the superficial and deep masseter muscle layers may be appropriate.²⁴

CONCLUSIONS

Asian aesthetics favor a slimmer lower face yet volumized middle face.^1,3–5 Ideal conditions for individualized treatment, including injecting BoNT-A in the safety zone, using the minimum dose required to achieve the desired effects, understanding the anatomy and classifications of MMP especially in Asian populations, and clearly communicating individual clinical history and expectations, are important factors for optimizing outcomes and overall treatment satisfaction. Clinical observations from published studies and case reports suggest that BoNT-A is an efficacious, durable, and well-tolerated treatment option for individuals with benign MMP.^1,7,39 AEs observed with BoNT-A treatment were often transient, and these events can be mitigated through selection of appropriate patients for treatment and optimizing injection sites and doses.^1,24,39 It should be noted that dose recommendations are not interchangeable among BoNT-A products, and dosing cannot be converted using any dose ratio.

Despite a growing body of research, gaps remain in our understanding of how to use BoNT-A to safely achieve desired outcomes in treating benign MMP in Asian populations. More research is needed to broaden our knowledge of the mechanism of BoNT-A in reducing lower facial volume in MMP and to inform clinical practice on the optimal dosing and injection techniques necessary to safely achieve patient aesthetic goals.

Disclosures

The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.

Funding

Research and editorial support for this manuscript was funded by Allergan plc (prior to its acquisition by AbbVie) (Dublin, Ireland). Medical writing and editorial support were provided by Adrienne Drinkwater, PhD, for Peloton Advantage, LLC, an OPEN Health company (Parsippany, NJ) and funded by Allergan plc (prior to its acquisition by AbbVie). Allergan had no involvement in the study design or collection, analysis, and interpretation of data.