| |

Received: 22 January 2021    Revised: 15 March 2021    Accepted: 30 March 2021

DOI: 10.1111/jocd.14133

ORIGINAL CONTRIBUTION

Respecting upper facial anatomy for treating the glabella

with neuromodulators to avoid medial brow ptosis—­A refined
3-­point injection technique

Sebastian Cotofana MD, PhD1  | Angela P. Pedraza MD2 | Joely Kaufman MD3 |

Luiz E.T. Avelar MD4 | Diana L. Gavril MD5 | Claudia A. Hernandez MD6 |
Emy C. Onishi MD7 | Andreas Nikolis MD8,9  | Thais Sakuma MD10  |
Konstantin Frank MD11
1
Department of Clinical Anatomy, Mayo
Clinic College of Medicine and Science, Abstract
Rochester, MN, USA
Background: Current injection algorithms for treating the glabella rely on a five-­ or
2
Private Practice, Bogota, Colombia
3
seven-­point injection technique with possible medial eyebrow ptosis and lateral eye-
Skin Associates of South Florida and Skin
Research Institute, Coral Gables, FL, USA brow elevation as undesirable outcomes.
4
Private Practice, Belo Horizonte, Brazil Objective: The objective of this study was to investigate the efficacy and safety profile
5
Private Practice, Cluj-­Napoca, Romania of a refined 3-­point injection technique targeting horizontal and vertical glabellar lines.
6
CH Dermatologia, Medellin, Colombia
Methods: A total of n=105 patients (27 males and 78 females) with a mean age of
7
Private Practice, Manila, Philippines
8
40.90 ± 9.2 years were investigated. The injection technique relied on targeting the
Clinical Research Unit, Erevna
Innovations Inc, Montreal, Quebec, muscular origin of the procerus and the corrugator supercilii muscles exclusively. The
Canada time of effect onset and the injection-­related outcome 120 days after the treatment
9
Division of Plastic Surgery, McGill
was evaluated using the 5-­point glabellar line severity scale.
University, Montreal, Quebec, Canada
10
Private Practice, Campo Grande, Brazil Results: The onset of the neuromodulator effect was on average 3.5 ± 1.5 days. There
11
Department for Hand, Plastic and was no statistically significant difference in the amplitude of movement before or
Aesthetic Surgery, Ludwig–­Maximilian
14 days after the treatment with 2.99 ± 4.4 mm vs. 3.39 ± 3.6 mm (p = 0.149) for the
University Munich, Munich, Germany
medial head of the eyebrow and with 3.18 ± 4.7 mm vs. 3.33 ± 4.3 mm (p = 0.510) for
Correspondence
the lateral head of the eyebrow, respectively.
Sebastian Cotofana, Department of
Clinical Anatomy, Mayo Clinic College of Conclusion: Incorporating anatomic concepts into clinical practice for glabellar frown
Medicine and Science, Mayo Clinic, Stabile
line neuromodulator treatments with the investigated 3-­point injection technique re-
Building 9-­38, 200 First Street, Rochester,
MN, 55905, USA. sulted in the absence of adverse events like eyebrow ptosis, upper eyelid ptosis, me-
Email: [email protected]
dial eyebrow ptosis, and lateral frontalis hyperactivity. This technique demonstrated
efficacy throughout the 4-­month study period.

KEYWORDS
abobotulinum toxin, corrugator supercilii muscle, glabellar frown lines, incobotulinum toxin,
onabotulinum toxin, procerus muscle

J Cosmet Dermatol. 2021;00:1–9. wileyonlinelibrary.com/journal/jocd© 2021 Wiley Periodicals LLC.     1 |

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2      COTOFANA et al.

1  |  I NTRO D U C TI O N injection-­related outcome 120 days after the treatment is evaluated

using the 5-­point glabellar line severity scale.11
Neuromodulator treatments of the face account for 48.2% of
all non-­surgical aesthetic procedures worldwide with more than
6 million injections performed in 2018, according to the global 2  |  M ATE R I A L S A N D M E TH O DS
survey of the International Society of Aesthetic Plastic Surgery
(ISAPS).1 Toxin injection techniques vary depending on facial re- 2.1  |  Study participants
gion treated and manufacturer guidelines which offer predefined
injection points to guide experts and novices toward predictable This clinical interventional study investigated the effects on the gla-
2-­4
outcomes. bellar frown line severity of a neuromodulator injection technique
Recent facial anatomic research findings provide for a more in a total of n = 105 patients (27 males and 78 females) with a mean
accurate estimation of the underlying muscular anatomy from skin age of 40.90 ± 9.2 years [range: 22–­59]. Of those were n = 1 (1.0%)
surface landmarks, thus influencing neuromodulator treatment al- Fitzpatrick type I, n = 19 (18.1%) type II, n = 55 (52.4%) type III, n = 27
5-­7
gorithms. In 2017, a cadaveric study related the shape of the hor- (25.7%) type IV and n = 3 type V (2.9%).
izontal forehead lines to the underlying muscle fascicle angle of the Inclusion criteria were age 21 –­60 years, glabellar line severity
frontalis muscle and formed a fundament for skin surface relation- with a score at baseline of 1 –­4 (mild to very severe) at maximum
ships.5 These results were confirmed in 2019 in a clinical study utiliz- frowning on the validated 5-­p oint (Flynn-­) scale 11
(0 –­ 4; best to
ing skin vector displacement technology and revealed that the shape worst), no glabellar or frontal neuromodulator treatment 1  year
of horizontal forehead lines are statistically significantly related to prior to the start of the study and the willingness to participate
the direction of forehead skin movement.6 Utilizing the same tech- and to adhere to the scopes of the study which included comple-
nology, in 2020 the bi-­directional movement of the frontalis muscle tion of the follow-­up period (120  days) and no additional facial
was described and an explanatory model for eyebrow ptosis after neuromodulator or facial soft tissue filler treatments during the
neuromodulator application in the lower part of the forehead was study follow-­up period.
proposed.7 The authors introduced the “Line of Convergence” which This study was performed in adherence to the Declaration
separated the frontalis muscle into an eyebrow-­elevation segment of Helsinki (1996), and in accordance with regional laws and good
(=lower forehead) and into a hairline-­depression segment (=upper clinical practice for studies in human subjects.12 IRB Approval was
7
forehead). This segmentation of the frontalis muscle provides a obtained from Biomedical Research Institute of America (Protocol
mechanism by why neuromodulators injections into the lower fore- Number: SITES01). Written and informed consent was obtained by
head may result in eyebrow ptosis. all participants prior to the inclusion into the study for the use of
Current injection algorithms for treating the glabella rely on a 5-­ their images and data for research purposes.
or 7-­point injection technique, 2,8 which target the procerus and the
medial and the lateral aspects of the corrugator supercilii muscles;
the latter is injected above the eyebrow. The reported incidence 2.2  |  Clinical centers
9
rates for eyebrow ptosis were reported to be at 3.1% and to be
independent of the product administered.10 The explanatory model Inclusion and exclusion criteria as well as a precise injection de-
for this adverse event is that the eyebrow elevation segment of the scription were established in a central protocol and distributed to
frontalis muscle is affected, which results in an inability to elevate the participating clinical centers. Participating centers were free to
the eyebrow and to act as an antagonist for the eyebrow depressors choose the amount of neuromodulator units injected and the type of
at rest. Although eyebrow ptosis is not long-­lasting, it can cause sig- toxin utilized (onabotulinum toxin type A, Allergan, Dublin, Ireland,
nificant patient dissatisfaction and should be avoided. However, cur- n = 16; incobotulinum toxin type A, Merz Pharma, Frankfurt/Main,
rent injection algorithms target the lower forehead despite its close Germany, n = 23; abobotulinum toxin type A, Galderma, Lausanne,
proximity to the upper margin of the eyebrow. A deeper understand- Switzerland, n  =  66). The treating physician could choose freely
ing of the underlying anatomy may suggest an injection algorithm based on their experience and based on each individual patient's
which would not administer neuromodulators cranial to the level of needs. Standardization across clinical centers occurred only for the
the hairy eyebrows. injection technique, that is, the injection location (2-­dimensions) and
Therefore, it is the aim of this study to present a refined 3-­point injection depth (3-­dimensions) applied. Patients were not included in
injection algorithm which is based exclusively on the anatomy of this analysis if they had neuromodulator treatment of their glabellar
the procerus and corrugator supercilii muscles. The investigated region or forehead within the last six months prior to the initiation in
injection algorithm targets the bony origin of those two muscles this study. Additionally, any soft-­tissue filler, biostimulator, or energy
without additional product administration above the level of the device-­based treatments were also regarded as exclusion criteria for
hairy eyebrow. The time to onset of neuromodulator effect and the this study.
COTOFANA et al. |
      3

Patients were treated according to the central protocol in six dif- 2.4.2  |  Time of onset
ferent clinical centers.
The time of onset was defined as the decrease by one grade in the
glabellar line severity scale from baseline when assessed by the
2.3  |  Injection technique treating physician. This assessment was conducted online via tel-
emedicine or via transmitted videos. Those videos were sent by the
The applied injection technique is a modified version of the pre- patient on a daily basis after the treatment to the treating physician
viously described 3-­p oint technique. 8 The modification included who documented at what day after the treatment a decrease in one
the inferior re-­p osition of all 3 injection points to match precisely grade in the glabellar severity scale was first observed.
the anatomic origin of the procerus and the corrugator supercilii
muscles.
In detail: the procerus muscle was targeted with one single in- 2.4.3  |  Eyebrow position
jection point in the midline at the level of a connecting line between
the left and right medial canthal ligaments; this injection was per- The position of the medial and the lateral head of the eyebrows was
formed at an perpendicular angle to the nasal bone surface and in measured with a standard—­flexible ruler and results were docu-
constant and direct contact with the bone. The corrugator muscles mented before the treatment and at day 14 by measuring the dis-
were targeted at the medial and inferior margin of the eyebrows tance (in mm) from the medial and the lateral canthus to the inferior
with a 45-­degree injection angle in relation to the midline and to margin of the hairy eyebrow, respectively. The same measurements
the underlying frontal bone with bone contact during the injection were conducted while asking the patient to maximally contract their
procedure. No additional (lateral) injection points were utilized forehead (frontalis muscle).
(Figures 1, 2).

2.4.4  |  Dosage
2.4  |  Outcome assessment
The dosage (measured in international units and in Speywood units)
2.4.1  |  Glabellar line severity injected into the procerus and into the left/right corrugator supercilii
muscles were documented. Speywood units were converted with
Glabellar line severity was assessed before the treatment (=day 0), 1:1 for onabotulinum toxin type A, 1:1 for incobotulinum toxin type
14  days after the treatment, 30  days after the treatment, 60  days A and 1:2.5 for abobotulinum toxin type A.13
after the treatment, 90 days after the treatment, and 120 days after
the treatment. The assessment of the glabellar line severity was
conducted in person at day 0, day 14, and at day 30; further evalu- 2.5  |  Statistical analysis
ation was performed either in person or via online assessment (tel-
emedicine) for days 90 and 120. Glabellar line severity was assessed Differences between measurements (male vs. female) were calcu-
by the treating physician only based on a previously published and lated using independent Student's t test and between baseline and
validated 5-­point scale: grade 0 = No glabellar lines, grade 1 = Mild follow-­up parameters using paired Student's t test. Differences
glabellar lines, grade 2 = Moderate glabellar lines, grade 3 = Severe with ordinal variables (glabellar line severity scale) were com-
11
glabellar lines, and grade 4 = Very severe glabellar lines. puted using Mann-­W hitney U test and Wilcoxon signed-­r ank test.

F I G U R E 1  Bar graph showing the

median values for the glabella line severity
scale at each follow-­up assessment
throughout the study period. Whiskers
represent 95% confidence interval
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4      COTOFANA et al.

Multivariate analyses were run utilizing generalized linear models 3  |  R E S U LT S

with robust estimator and adjustment for age, gender, and total
amount of neuromodulator dosage injected. Analyses were per- 3.1  |  Dosage
formed using SPSS Statistics 23 (IBM), and differences were con-
sidered statistically significant at a probability level of ≤0.05 to The mean dose for treating the procerus muscle was 5.23 ± 2.5 I.U.
guide conclusions. (12.90 ± 6.30 S.U.), whereas the mean dose for treating each corru-
gator supercilii muscle was 13.27 ± 5.7 I.U. (33.17 ± 14.2 S.U.).

3.2  |  Glabellar line severity scale

The median glabellar wrinkle score before treatment was 3 (=severe

glabellar lines) with an IQR (=interquartile range) of 1 [range: 1–­4]. At
14 days after the treatment, the median score was 0 (=no glabellar
lines) with an IQR of 1 [range: 0–­2] representing a statistically sig-
nificant improvement with p < 0.001. At 30 days, the median score
was 0 with an IQR of 1 [range: 0–­3] with p < 0.001 (when compared
to the pre-­treatment score); at 60 days, the median score was 1 with
an IQR of 1 [range: 0 –­3] with p < 0.001 (when compared to the pre-­
treatment score); at 90 days, the median score was 2 with an IQR of
1 [range: 0 –­4] with p < 0.001 (when compared to the pre-­treatment
score); and at 120  days, the median score was 2 with an IQR of 1
[range: 0–­4] with p < 0.001 (when compared to the pre-­treatment
score). Results are shown in Figure 1.

3.3  |  Time of onset

The mean time of onset as defined by the interval in days between the
F I G U R E 2  Three injection points demonstrated on a 42-­year-­old
male patient treatment and the first observed decrease in one grade of the glabellar

F I G U R E 3  Image of a 46-­year-­old
female patient with illustration of the
measurements conducted at rest before
the treatment and 14 days after the
treatment
COTOFANA et al. |
      5

line severity scale was on average 3.5  ±  1.5  days [range: 1–­8]. No 4-­month follow-­up period of the study. No hyperactive lateral eye-
statistically significant difference in onset between genders was ob- brow elevation was observed when asking the patients to contract
served with males 3.44 ± 1.42 days and females 3.56 ± 1.60 days with their frontalis muscle leading clinically to the “Spock” or “Mephisto”
p  =  0.731. Stratification by neuromodulator type revealed that on- eyebrow shape at any follow-­up assessment (Figures 5 and 6).
abotulinum toxin type A had a mean time of onset of 2.31 ± 0.79 days,
incobotulinum toxin type A 2.74  ±  1.4  day, and abobotulinum toxin
type A 4.11 ± 1.5 days with p < 0.000 across groups. 4  |  D I S C U S S I O N

The objective of this study was to investigate the efficacy and safety
3.4  |  Eyebrow position profile of a refined 3-­point injection technique targeting horizontal
and vertical glabellar lines. The fundament for this injection tech-
The medial eyebrow increased in height 14 days after treatment (=in- nique is the muscular origin of the procerus and the corrugator su-
crease in distance between the medial canthus and the inferior margin of percilii muscles which is specifically targeted by the applied injection
the medial head of the eyebrow) by 1.21 ± 2.8 mm (p < 0.001), whereas algorithm.
the lateral head of the eyebrow increased in height by 1.06 ± 2.8 mm One strength of the present study is the innovative approach to
(p  <  0.001). When additionally asking the patient to maximally con- determine the 2-­ and 3-­dimensional location of the injection points
tract their frontalis muscle the change between baseline and day 14 purely on anatomy and on the muscular origin of the targeted mus-
in eyebrow position was 1.61 ± 2.6 mm for the medial (p < 0.001) and cles. Despite the plethora of currently available injection points and
2,8,14
1.21 ± 1.8 mm (p < 0.001) for the lateral heads of the eyebrow. algorithms, the presented injection technique is unique as it
There was no statistically significant difference in the amplitude relies exclusively on targeting the origins of the muscles responsi-
of movement (=difference in eyebrow position between frontalis ble for glabellar frown lines. Another strength of this study is the
muscle contraction and at rest) before or 14 days after the treatment long follow-­up period with 120 days (=4 months), which allows for
with 2.99 ± 4.4 mm vs. 3.39 ± 3.6 mm (p = 0.149) for the medial head evaluation of onset, duration, and the reduction in effectiveness of
of the eyebrow and with 3.18 ± 4.7 mm vs. 3.33 ± 4.3 mm (p = 0.510) the administered neuromodulators. The presentation of this cycle is
for the lateral head of the eyebrow, respectively (Figures 3 and 4). important to reveal the true effectiveness of the applied technique
as it accounts for the limited durability of the injected drug. This may
account for the confounding variables of differing drug efficacy and
3.5  |  Adverse events and additional observations injection techniques: a longer durability of the effect could be due
to the selected product rather than due to the performed injection
No ptosis of the medial or total eyebrow and no ptosis of the upper technique. Another strength of the study is the coordination across
eyelid were observed in any of the treated patients during the the six participating clinical centers via a central study protocol to

F I G U R E 4  Image of a 46-­year-­old
female patient with illustration of the
measurements conducted upon maximal
eyebrow elevation before the treatment
and 14 days after the treatment
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6      COTOFANA et al.

F I G U R E 5  Clinical image series of a 38-­year-­old female patient. The upper row images are facial expressions before treatment and
the lower row 14 days after the treatment. The facial expressions evaluated were at rest (left column), at maximal glabellar frown (middle
column), and at maximal eyebrow elevation (right column)

limit the injector bias on the study outcome. This central protocol by the treating physician but would be disregarded by a rigid study
was designed independently and in absence of the individual pref- protocol.
erences of the participating injecting physicians to increase objec- A limitation of the study is that glabellar line severity was semi-­
tivity when assessing the performed injection technique, that is, a quantitatively assessed by the treating physician only and not by
difference in effectiveness could be due to variability in injection blinded and independent additional observers. This setup was spe-
technique performed at each study center. Another strength of the cifically chosen to best capture the nuances in change in glabellar
study is the freedom of choice of the participating clinical centers for line formation which would be potentially limited by non-­involved
neuromodulator type and the amount of toxin injected per patient. experts. This could however also result in a bias toward a more pos-
A study protocol providing regulations for product choice or amount itive outcome which has to be acknowledged here. Another limita-
of neuromodulator injected per injection location would limit the tion of the study is relatively small sample size with n  =  105. This
ability of the treating physician to use their experience to customize sample size results from the study design where patients were en-
the treatment for each patient. In the present study, this freedom of rolled during continuous clinical routine and products were donated
choice was opted in to account for each patient's individuals needs by the participating clinical centers and not by funding sources from
to exclude the influence of the “patient factor,” that is, variation in industry.
muscular anatomy, soft tissue thickness, patients age, gender, and Understanding and targeting precisely the underlying anatomy;
ethnic background on the study outcome by allowing the treating this concept was utilized in the present study to eliminate the poten-
physician to best adjust the treatment. In this way, it is hoped to tial of eyebrow ptosis after neuromodulator treatment. No injections
exclude the bias of the “patient factor” on the study outcome and were performed at the upper margin or above the hairy eyebrow;
to emphasize exclusively the effectiveness of the applied injection only inside or inferior to the eyebrow the product was administered.
technique: a difference in effectiveness could be due to anatomic The results of the performed analyses confirm the validity of previ-
variation of each patient which can be observed and adjusted for ously published anatomic concepts as no eyebrow ptosis (0%) and no
COTOFANA et al. |
      7

F I G U R E 6  Clinical image series of a 42-­year-­old male patient. The upper row images are facial expressions before treatment and the
lower row 14 days after the treatment. The facial expressions evaluated were at rest (left column), at maximal glabellar frown (middle
column), and at maximal eyebrow elevation (right column)

upper eyelid ptosis (0%) were observed in any of the treated individ- follow-­up (p = 0.149); this provides numerical evidence for the unaf-
uals during the study follow-­up period. fected mobility of the medial eyebrow. The increase in amplitude by
The bony origin of the procerus muscle is located in the midline 0.4 mm can be explained by the reduction of the inferior-­pull of the
of the nasal bone whereas its insertion is the dermis and the fron- procerus muscle which acts as an eyebrow depressor. The analysis
talis muscle at the level of the upper margin of the medial heads of of the amplitude additionally provides evidence that the function of
the eyebrows. The muscle majorly determines the position of the the frontalis muscle remained intact as it was not affected by the
medial eyebrows and is at a muscular balance with the eyebrow el- neuromodulator.
evating frontalis muscle. Injections cranial to the superior margin of The corrugator supercilii muscle originates from the supercil-
the eyebrows can therefore affect the eyebrow elevation segment iary arch of the frontal bone around 0.5  cm lateral to the midline
of the frontalis muscle and result in medial eyebrow ptosis. This is a slightly medial and inferior to the most common location of the su-
relatively frequent adverse event after forehead and glabella neuro- pratrochlear notch/foramen. From this location, the muscle courses
modulator treatments and can also be seen with a hyper-­elevation of laterally and cranially to insert in the middle and/or lateral third of
the lateral eyebrow. 9,10 Targeting the origin of the procerus muscle the skin of the eyebrow. Its cranial boundary is formed by the infe-
exclusively at its bony insertion eliminates the possibility of medial rior frontal septum which corresponds to the upper margin of the
eyebrow ptosis as no frontalis muscles will be affected. This was hairy eyebrow.15 At its dermal insertion, orbicularis oculi and fron-
confirmed by the measurements conducted; the amplitude of me- talis muscle fibers merge and connect additionally to the overly-
dial eyebrow elevation exerted by the eyebrow elevation segment ing skin comparable to the perioral subcutaneous architecture.15-­17
of the frontalis muscle remained unaffected. The amplitude of the Most commonly performed injection techniques target this mus-
medial eyebrows was 3.0 mm at baseline and was 3.4 mm at 14-­day cle in two or three locations of which the medial injection is aimed
 |
8      COTOFANA et al.

at the muscle belly and the lateral injection at its dermal insertion AU T H O R C O N T R I B U T I O N S
2
above the eyebrow or even further lateral and cranial. The lateral S.C., A.P, J.K, L.A, D.G., C.H., E.O, A.N., T.S., and KF contributed sub-
injections have the potential to drop the eyebrow as the eyebrow-­ stantially to the conception, the acquisition, analysis, and interpreta-
elevating segment of the frontalis muscle can be affected resulting tion of data for the work. The work was drafted and revised critically
in an unbalance favoring the inferior-­pull of the eyebrow depres- by all authors.
sors. The performed injection technique targeted exclusively the
bony origin of the corrugator supercilii muscle without a lateral in- DATA AVA I L A B I L I T Y S TAT E M E N T
jection component. This resulted in an elevation of the lateral head The data that support the findings of this study are available from
of the eyebrow in the resting position of 1.06 mm between baseline the corresponding author upon reasonable request.
and 14 days after the treatment (p < 0.001). This can be explained
by the reduction of the medial and inferior-­pull of the corrugator su- ORCID
percilii muscle which favored the increase in eyebrow height after Sebastian Cotofana  https://orcid.org/0000-0001-7210-6566
the onset of the neuromodulator effect. The eyebrow-­elevation Andreas Nikolis  https://orcid.org/0000-0002-2927-5564
segment of the frontalis muscle was not affected by the treatment Thais Sakuma  https://orcid.org/0000-0002-6390-1223
(medial injection only); this was confirmed by the similar amplitude Konstantin Frank  https://orcid.org/0000-0001-6994-8877
in eyebrow elevation upon frontalis contraction with 3.18 ± 4.7 mm
before the treatment and with 3.33  ±  4.3  mm 14  days after the REFERENCES
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