Abstract
Precise injection technique is vital for avoiding suboptimal eyebrow position when treating glabellar lines with botulinum toxin type A.
The aim of this study was to evaluate the impact of glabellar injection technique on eyebrow position in patients treated with DaxibotulinumtoxinA for Injection (DAXI).
This retrospective post hoc analysis involved 60 adults who received a single treatment with DAXI 40 U to the glabella and had standardized facial photography. Median vertical and horizontal displacement of the brows (at rest) at baseline and 2 weeks after glabellar injection were measured. Brow position outcomes were evaluated by an oculoplastic surgeon and expert anatomist. Investigators were interviewed to ascertain individual injection techniques.
Precise injection location and depth, and median resting brow position following treatment varied between investigators. Positive brow outcomes were achieved with deep DAXI injections into the medial corrugator, superficial lateral corrugator injections placed between the midpupil and lateral limbus, and deep midline procerus injections. Glabellar injection technique that more precisely targeted the corrugator muscles resulted in longer glabellar line treatment duration compared to a less targeted technique. Medial corrugator injections above the medial brow; lateral corrugator injections administered deeply or more medially, toward the medial third of the brow; and procerus injections superior to the inferomedial brow tended to be associated with suboptimal outcomes that were more apparent during dynamic expression.
Aesthetically pleasing brow outcomes and greater duration of efficacy can be achieved with an injection pattern that precisely treats the anatomic location of the corrugator supercilii and procerus muscles, avoiding the frontalis.
The main aim of treatment with botulinum toxin type A (BoNTA) is to eliminate facial wrinkles while maintaining natural outcomes and aesthetically pleasing results at rest, and particularly with animation.1,2 Although injections into the glabella can have positive effects on the shape and elevation of the eyebrows,3-5 outcomes can vary and lead to undesirable or unnatural brow effects, including asymmetry; ptosis; hyperelevated brow shapes, including amplified displacement of the lateral region relative to the medial region; and excessive reduction in movement.6-8 To achieve aesthetically pleasing results when treating the upper face, a detailed understanding is needed of the anatomic interrelation between facial muscles and the way in which BoNTA injections in the glabella affect brow height and position.1,2
Although most injectors are aware of the effects of treatment of the frontalis on brow position, the importance of considering the frontalis when treating simple glabellar lines is not universally understood. Because the frontalis is an important contributor to brow elevation and brow position,9 a precise balance between the opposing effects of the frontalis and the glabellar complex is required to avoid negative effects on brow position.10 For example, partial inactivation of the medial region of the frontalis following administration of BoNTA at the glabella can result in compensatory overactivity of the lateral frontalis, which elevates the lateral brow.11-13 Some lateral brow elevation can enhance an individual’s appearance, but excessive elevation can produce an unnatural, surprised, or “diabolical” look.14,15 Despite the effects of individual differences in patient anatomy on the complexity of achieving consistently positive brow outcomes,10 most consensus guidelines acknowledge the importance of BoNTA injection technique on brow shape and the need to avoid negative brow outcomes.1,2,16,17 To achieve positive brow outcomes more consistently when treating upper facial lines, objective data on the effect of BoNTA injection technique on static and dynamic eyebrow position are needed.
The novel BoNTA formulation DaxibotulinumtoxinA for Injection (DAXI; Revance Therapeutics, Inc., Nashville, TN) has been extensively studied for the treatment of moderate or severe glabellar lines in the Phase 3 SAKURA clinical program.18-21 In addition to the clinical development program for treatment of glabellar lines, DAXI has been evaluated in a multicenter, open-label, dose-escalation Phase 2a study for treatment of moderate or severe dynamic forehead lines (FHLs) following treatment of the glabellar complex.22,23 This study was conducted at 4 clinical trial sites with expert injectors. Discussions with the investigators revealed that, although they followed a standard pattern for glabellar treatment, there were subtle differences in the injection point locations for each investigator. This allowed us to analyze the impact of these differences on brow position and eyebrow movement.
METHODS
Subjects
An open-label, dose-escalation Phase 2a FHL study (January 2019-March 2020)22,23 was conducted to assess the efficacy and safety of DAXI for the treatment of FHLs after the treatment of glabellar lines (NCT 03786770). The study protocol was approved by the relevant IRB (Advarra, formerly Quorum Review IRB, Columbia, MD) and independent ethics committees, and all subjects provided written informed consent.
Subjects included in this retrospective post hoc analysis were those for whom photographs were taken at rest, maximum frown, and maximum brow elevation at baseline and 2 weeks after glabellar treatment, prior to receiving frontalis treatment. Subjects included in the study had moderate or severe glabellar lines as assessed by the Investigator Global Assessment (IGA)–Frown Wrinkle Severity scale and the Patient Frown Wrinkle Severity scale, and moderate or severe FHLs during maximum brow lift as assessed by the IGA–Forehead Wrinkle Severity and IGA–Patient Forehead Wrinkle Severity scales. Patients were excluded from the study if they were pregnant or nursing, had received BoNTA treatment ≤6 months before screening, had a neurologic condition that may have placed them at increased risk with exposure to BoNTA, had muscle weakness or paralysis in the area receiving treatment, or had a history of facial nerve palsy.
Subjects received a single glabellar complex treatment with DAXI 40 U administered as intramuscular injections placed according to a prescribed 5-point pattern comprising 1 injection to the procerus, 1 into the medial region of each corrugator supercilii, and 1 into the lateral region of each corrugator supercilii. Two weeks after glabellar treatment, subjects received forehead line treatment with DAXI administered to the frontalis; however, only data from before and after glabellar treatment were included in this post hoc analysis.
Image Analysis
Quantitative analyses (Canfield Scientific, Inc., Parsippany, NJ) were conducted on photographs taken of subjects at baseline and 2 weeks after DAXI glabellar injection. Photographs were taken at rest and at maximum brow lift.
Brow Position
Objective eyebrow measurements were performed from standardized pre- and postinjection photographs, with standardized head positioning, which were captured throughout the study at maximum frown, maximum lift, and at rest.24 Blinded analyses of the position of the brow were conducted on at-rest photographs taken at baseline and at Week 2, the last time point before any treatment of the frontalis. As previously described,24 3 areas of interest were identified for each subject’s eye based on anatomic landmarks at the lateral brow, mid-brow, and medial brow. After transposing baseline at-rest images onto Week 2 at-rest images, “markerless tracking” technology was used to measure the median displacement (in the x and y axes) of each area of interest.
Brow position outcomes for all subjects underwent a blinded review and evaluation from standardized photographs taken at rest and at maximum lift by an oculoplastic surgeon and an expert anatomist. The outcomes for this analysis included the ability to lift the medial brows before and after treatment and the appearance of brows in terms of the presence of unnatural or unbalanced elevation of the medial and lateral brow before and after treatment. The ability to lift the medial brow and brow appearance were assessed by viewing changes in brow position and shape from the “at-rest” to the “maximum-lift” brow positions.
Assessment of Injection Technique
The 4 study investigators were interviewed to ascertain the specific injection technique that they used during the study. Investigators were asked to describe their injection technique by means of photographs of each subject at rest and at maximum frown according to a prespecified template (Figure 1). On each photograph, investigators were asked to estimate the precise injection depth (deep = almost to bone, bone contact, or supraperiosteal; superficial = subdermal) and location of the injection points for each subject at rest.
Assessment tool. Investigators were asked to mark the location and depth of each injection on representative baseline at-rest photographs.
Duration of Response
To assess the clinical impact of injection technique on treatment outcomes, a post hoc analysis compared the median duration of clinical response, which was assessed a priori, for subjects at 2 of the sites in the FHL study. Duration of response was calculated as the time to return to moderate/severe glabellar lines at maximum frown on both the investigator and subject rating scales. Median duration was calculated from Kaplan-Meier analysis.
RESULTS
Images from all 60 subjects in the study were analyzed (Investigator 1, 13 subjects; Investigator 2, 16 subjects; Investigator 3, 15 subjects; and Investigator 4, 16 subjects). Subjects were mostly White (96.7%), female (88.3%), and approximately 50 years of age (mean, 47.7 years; range, 26-65 years). Although the study protocol established a standardized treatment pattern, the precise injection location and depth varied somewhat between investigators. These differences are described in detail in Figure 2.
Injection technique and sites for each investigator. Filled circles denote deep injections; open circles denote superficial injections.
At 2 weeks following DAXI treatment, the median resting brow position was found to vary by investigator (Figure 3). For Investigator 1, there was a small (right, 0.32 mm; left, 0.50 mm) elevation in the medial brows and a larger degree of elevation in the midbrow and lateral brow. On average, after treatment, the lateral brow rested 0.83 mm (right) and 0.88 mm (left) higher than the medial brow. For Investigator 2, there were little to no changes in the medial brow (right, –0.02 mm; left, 0.1 mm) and a small elevation in the midbrow and lateral brow. On average after treatment, the lateral brow rested 0.42 mm (right) and 0.58 mm (left) higher than the medial brow. For Investigator 3, there was a decrease in brow position across all areas of interest, with the greatest decreases in the midbrow (right, –0.59 mm; left, –0.53 mm). On average, after treatment, the lateral brow was at a similar height (right, –1.10 mm lower; left, 0.02 mm higher) to the medial brow. For Investigator 4, there was a balanced elevation in brow position across all areas of interest, with an increase of 0.84 mm (right) and 0.59 mm (left) in the medial brows. On average, after treatment, the lateral brow rested 0.32 mm (right) and 0.17 mm (left) higher than the medial brow.
Injection site technique at baseline and median brow displacement (mm) at rest 2 weeks following glabellar injection of DaxibotulinumtoxinA for Injection for each investigator group. Filled circles denote deep injections; open circles denote superficial injections.
Subjective evaluation of the posttreatment photographs at rest and at maximum lift by 2 expert assessors found, in subjects treated by Investigators 1 and 2, a greater occurrence of increased lateral brow arch, frequently coupled with an inability to elevate the medial brow following DAXI treatment (Figure 4). However, this was rarely observed in subjects treated by Investigator 4 (Figure 4). This finding remains to be further quantified and will be addressed in subsequent publications.
Brow positions at rest and at maximum lift for representative subjects in each investigator group. Images were taken at baseline and at 2 weeks following glabellar injection of DaxibotulinumtoxinA for Injection. The injection site technique for each investigator is shown at baseline, and values shown are for brow displacement (mm) at 2 weeks following glabellar injection of DaxibotulinumtoxinA for Injection for each subject, at rest. Filled circles denote deep injections; open circles denote superficial injections. Representative images are shown for a 36-year-old female (Inv 1), a 46-year-old female (Inv 2), a 52-year-old female (Inv 3), and a 54-year-old female (Inv 4). Inv, investigator.
A post hoc analysis compared the duration of clinical efficacy observed in subjects treated by Investigator 4 with that of subjects treated by Investigator 3. In this study, the median time to return to moderate or severe glabellar lines was 26.25 weeks (95% CI: 22.0, 26.7 weeks) for the 16 subjects treated by Investigator 4 compared with 20.1 weeks (95% CI: 10.7, 22.1 weeks) for the 15 subjects treated by Investigator 3.
DISCUSSION
Findings from our previous analysis showed an overall average elevation of eyebrow position 2 weeks after DAXI treatment of glabellar lines. This outcome reflected a mild increase in the lateral arch resulting in improved eyebrow shape.24 The current by-investigator analysis of the posttreatment changes in resting eyebrow position showed that certain injection techniques appeared to be associated with specific eyebrow outcomes. In this analysis, positive brow position outcomes at rest and at maximum brow lift were most commonly associated with quite specific injection sites of DAXI into the glabellar musculature (Figure 5)—namely, (1) when placed as a deep injection into the inferomedial aspect of the natural hair-bearing eyebrow, near the origin of the corrugator supercilii; (2) as a superficial injection into the lateral corrugator, between the midpupillary and lateral limbal lines and within 1 mm of the natural hair-bearing eyebrow; and (3) as a deep midline injection to the procerus, at or below the horizontal line connecting the inferior region of the medial brows. In contrast, medial corrugator injection sites that were above the medial brow, lateral corrugator injection sites that were administered deeply or more medially toward the medial third of the brow, and procerus injection sites that were superior to the horizontal line connecting the inferior region of the medial brows tended to be associated with less aesthetically pleasing outcomes that were more apparent during dynamic expression. Combined with anatomic studies of the location of facial muscles13,25-27 and a recent analysis of a 3-point glabellar injection technique designed to target the true anatomic origin of the procerus and the corrugator supercilii,28 these findings suggest that injection locations that more precisely target the intended muscles and are more remote from the frontalis are likely to result in more consistently aesthetically pleasing brow outcomes (Figure 6).
Recommended 5-point injection pattern for treatment of the glabellar complex with botulinum toxin type A. (A) As shown on the left, medial corrugator injection sites above the medial brow, lateral corrugator injection sites administered deeply or more medially toward the medial third of the brow, and procerus injection sites superior to the horizontal line connecting the inferior region of the medial brows are not recommended. (B) The recommended 5-point injection pattern is shown on the right and comprises deep injections into the inferomedial aspect of the natural hair-bearing eyebrow, near the origin of the corrugator supercilii, superficial injections into the lateral corrugator, between the midpupillary and lateral limbal lines and within 1 mm of the natural hair-bearing eyebrow, and a deep midline injection to the procerus, at or below the horizontal line connecting the inferior region of the medial brows. Representative images are shown for a 54-year-old female.
Illustration of glabellar injection sites with botulinum toxin type A when treating upper facial lines. Colored circles and segments represent the locations of the facial muscles in most patients.13,25-27 Yellow and green dashed lines denote the medial and lateral corrugator supercilii, respectively, red dashed lines and shading denote the frontalis muscle, blue dashed lines denote the procerus, and pink lines and shading denote the orbicularis oculi. The recommended technique includes superficial injections to the lateral corrugator (A), which overlies the frontalis; deep injections to the inferior medial corrugator (B), which underlies the frontalis and where the bulk of medial corrugator mass is located for most patients; and deep injections to the lower procerus (C), where the bulk of the muscle mass is located. Injection sites more likely to be at risk of exposing the central frontalis to botulinum toxin type A include the superior medial corrugator (D), which may also include the frontalis and procerus, irrespective of injection depth, and the superior procerus (E), which may also include the frontalis and orbicularis oculi.
Furthermore, post hoc analysis indicates that a glabellar injection technique that more precisely targets the corrugator muscles may also result in a longer duration of clinical benefit in glabellar lines treatment when contrasted with a less targeted approach. This finding is not unexpected given that delivering more of the neurotoxin directly into the target muscle should result in a greater pharmacologic effect. However, it should be noted that FHLs were treated after treatment of the glabellar complex (at the 2-week visit) and it is unclear what, if any, effect concomitant FHL treatment had on treatment duration. Nonetheless, to our knowledge, this is the first time the effect of glabellar injection technique on treatment duration has been analyzed, and the result suggests that further and more complete investigation should be the focus of future studies.
In contrast to images commonly shown in anatomic drawings, findings from anatomic studies in White and Asian individuals have shown that the corrugators originate below the superciliary arch and extend laterally, typically to the line of the lateral limbus, and rarely extend above the upper margin of the hair-bearing brow.25,27 Although the anatomic extent of the corrugators varies somewhat between individuals, the bulk of muscle mass has been shown to be consistently located at the inferomedial aspect of the natural hair-bearing brow.25-27 Hence, BoNTA injections placed 1 cm above the medial brow, as historically recommended, are above the bulk of the corrugator muscle and may be at risk of affecting the central frontalis (Figure 6). This was demonstrated in the current analysis, where injection sites that were placed above the medial brow were associated with a drop in the medial brow, which manifested in the appearance of a peak in the lateral brow at rest (Investigator 2). Lateral corrugator injections that were more medial and may have left the lateral frontalis unopposed resulted in excessive elevation of the lateral brow and a possible drop in the medial brow in some subjects (Investigator 1). Clinicians may attempt to correct for excessive lateral elevation by administering additional injections to the frontalis, but there is a risk that this approach may result in an overall decrease across all brow regions because a drop in the medial brow has already occurred with the first treatment. As shown by Investigator 4, lateral corrugator injections that were midway along the brow, between the midpupil and the lateral limbus, are likely to result in a more balanced effect on the frontalis and brow outcomes.
Currently, BoNTA injections in the lateral corrugators tend to be administered more superficially, whereas the medial corrugator injection tends to be placed deeper. The aim of this technique is to avoid injecting directly into the frontalis, which overlies the medial corrugator and lies deep to the lateral corrugator.13 However, as shown by the outcomes from Investigators 2 and 3, irrespective of injection depth, if the medial corrugator injection was placed above the medial brow, it was likely that the central frontalis may still be affected. Similarly, as shown by Investigator 3, lateral corrugator injections that were placed deep in the midbrow were likely to have exposed the frontalis to the neuromodulator, resulting in a drop in brow height across all areas of interest.
Although the procerus is considered the most straightforward of the glabellar injections, when the procerus was injected above the horizontal line connecting the superior region of the medial brows (Investigator 1), depression of the medial brow was observed at rest, and a lack of elevation was observed on animation. These effects were most likely due to placement of the product in the area where the procerus interdigitates with the frontalis,26 leading to unintended relaxation of the central frontalis. When coupled with residual activity from the inadequately treated procerus, this allowed the unopposed depressors to lower the medial brow. On animation, the brow moved asynchronously, with a greater elevation of the lateral brow against an immobile medial brow.13
Traditionally, clinicians have been reluctant to inject BoNTAs at or inferior to the medial brow because of an assumed risk of eyelid ptosis arising from diffusion of the neuromodulator into the orbital septum, resulting in a weakening of the levator palpebrae superioris muscle.29 However, the gravity-influenced diffusion zone of BoNT from the inferomedial region of the brow is relatively distant from the levator palpebrae superioris and, thus, a greater imperative is to avoid inadvertently weakening the frontalis, which has the potential to drop the eyebrow and may unmask underlying eyelid ptosis.10,25 Of the 4 investigators in the study, the injection approach taken by Investigator 4 resulted in a balanced increase in brow elevation across all regions of the brow at rest and on brow elevation. This approach involved placing corrugator injections into the inferomedial aspect of the natural hair-bearing brow, precisely targeting the belly of the muscle, and procerus injections inferior to the horizontal line connecting the medial brows, which is closer to the origin of the procerus muscle (Figure 6). The resulting relaxation of the depressors, including the medial corrugator and procerus, with minimal to no effects on the frontalis, most likely accounts for the quality of the outcomes observed with this treatment approach.13
Achieving natural-looking eyebrows is not only important for aesthetic reasons, but also because of the role the eyebrow plays in nonverbal communication and emotional expression.6,30 In this analysis, we showed that differences in glabellar injection technique can cause significant changes in brow position, and, furthermore, even small changes in eyebrow position can be amplified when viewed at maximum lift. This is clinically important because clinicians may not be aware of the true aesthetic outcome if patients treated for glabellar lines are only assessed at rest or at maximum frown. In addition, because patients rarely view themselves at maximum eyebrow lift, they also may not be fully aware of the effect of elevation in eyebrow position on their aesthetic outcomes. It is conceivable that the negative association of BoNTA use and unnatural-looking outcomes among the general public can be perpetuated, at least in part, by small elevations in the lateral brow that become exaggerated when patients are viewed during dynamic facial expressions that involve movement of the eyebrow. Administration of more precise BoNTA injections is likely to contribute to optimized brow position outcomes for patients and, therefore, perhaps a more positive perception of aesthetic BoNTA treatment. Hence, posttreatment analyses of treatment response to injection location and depth are likely to optimize outcomes and reduce negative effects, and posttreatment consultations that include both static and dynamic assessments will allow for a full assessment of eyebrow outcomes. These consultations can be conducted in office or virtually and can provide clinicians with information to identify adjustments to injection location and depth that will improve outcomes at subsequent treatments.2
Interpretation of the findings should consider that the FHL study was not a priori conducted with the intent of assessing brow position or to identify the most precise injection technique that resulted in optimal brow outcomes. As such, injection technique was not assessed objectively during the study, and further research is required to confirm the relationship between injection technique and brow outcomes. As the optimal technique was unknown at the time of the analysis, it was not feasible to include a control group; therefore, we conducted a between-group analysis to compare brow outcomes with the different injection techniques that were observed in the study. It would be neither practical nor ethical to prospectively compare a precise injection control group with imprecise injection techniques because doing so could potentially result in adverse outcomes. Further, it should be noted that only a small number of investigators were evaluated and that these analyses reflect a single time point (approximately peak efficacy) and that the effects observed may differ over time. In addition, it is not possible to draw conclusions on the effects of injection technique on long-term changes to brow position, especially as the effects on brow position are likely to soften with time. Because patients are seeking aesthetic improvement, it is important to ensure that treatment patterns/techniques avoid negative effects, irrespective of duration. As such, we were interested in identifying treatment patterns/techniques that will help avoid negative brow outcomes after glabellar treatment, reducing potential patient dissatisfaction and potentially limiting the need for touch-up treatments. Finally, because this study was only focused on a single time point, we did not include any safety data in this analysis. As previously reported, most treatment-related adverse events with DAXI for aesthetic indications are mild and of limited duration, and no serious treatment-related events have been reported.18,21 Of relevance to this study, the most frequently reported treatment-related adverse events following glabellar treatment in the FHL study were injection-site edema (8.2% of patients), injection-site erythema (6.6% of patients), and headache (3.3% of patients); 1 patient experienced eyelid ptosis (site 3) and no patients experienced eyebrow ptosis.23
CONCLUSIONS
This is the first study to objectively link anatomic localization of the glabellar injection points with clinical eyebrow outcomes. The results suggest that injection technique in the glabella, including the procerus, may significantly impact both the static and dynamic appearance of the eyebrow. By incorporating current understanding of the functional anatomy of the corrugator supercilii and procerus muscles into standard treatment patterns, clinicians can deliver more accurate injections that avoid the frontalis and more consistently achieve aesthetically pleasing eyebrow outcomes for their patients.
Disclosures
Dr Bertucci has been an investigator and consultant for Evolus, Inc. (Newport Beach, CA) and a speaker, investigator, and consultant for Allergan Aesthetics, an AbbVie Company (Irvine, CA), Galderma (Lausanne, Switzerland), Merz Aesthetics (Frankfurt, Germany), and Revance Therapeutics, Inc. (Nashville, TN). Dr Green has served as clinical trial investigator for Revance Therapeutics, Inc., Allergan Aesthetics, Galderma, and Merz Aesthetics and as a consultant for Revance Therapeutics, Inc., Allergan Aesthetics, Galderma, and Merz Aesthetics. Dr Fezza is a consultant, speaker, and principal investigator for Allergan Aesthetics, a principal investigator for Merz Aesthetics and Revance Therapeutics, Inc., a patent holder and equity owner with Visant Medical (Menlo Park, CA), and a speaker for Senté Skincare (Carlsbad, CA). Drs Gallagher and Brown are employees of, and hold stock/stock options in, Revance Therapeutics, Inc. Dr Solish is a clinical investigator and consultant for Allergan Aesthetics, an AbbVie Company (Dublin, Ireland), Galderma (Lausanne, Switzerland), Merz Aesthetics (Frankfurt, Germany), Croma-Pharma (Leobendorf, Austria), and Revance Therapeutics, Inc. (Nashville, TN); and is a speaker for Allergan Aesthetics and Galderma.
Funding
This analysis was supported by Revance Therapeutics, Inc. Writing and editorial assistance was provided to the authors by Evidence Scientific Solutions (Philadelphia, PA) and was funded by Revance Therapeutics, Inc. Revance Therapeutics, Inc. was involved in the study design, collection, analysis, and interpretation of the data; writing of the report; and decision to submit the report for publication. The authors did not receive honoraria or payments for authorship.
Supplement Sponsorship
This article appears as part of the supplement “Looking Beyond the Glabellar Lines: A Comprehensive Guide for Optimizing Outcomes,” sponsored by Revance Therapeutics, Inc.
REFERENCES
Author notes
Dr Bertucci is a physician, Division of Dermatology, University of Toronto, Toronto, ON, Canada; Private Practice, Woodbridge, ON, Canada.
Dr Green is a physician in private practice in Coral Gables, FL, USA.
Dr Fezza is a cosmetic facial surgeon, Center for Sight, Sarasota, FL, USA.
Dr Brown is the director, Department of Medical Affairs, Revance Therapeutics, Inc., Nashville, TN, USA.
Dr Gallagher is the vice president, Department of Medical Affairs, Revance Therapeutics, Inc., Nashville, TN, USA.
Dr Solish is an assistant professor, Division of Dermatology, University of Toronto, Toronto, ON, Canada.
