Research

JAMA Facial Plastic Surgery | Original Investigation

Treatment Patterns and Outcomes in Botulinum Therapy

for Patients With Facial Synkinesis
Justin R. Shinn, MD; Nkechi N. Nwabueze, BS; Liping Du, PhD; Priyesh N. Patel, MD; Kevin K. Motamedi, MD;
Cathey Norton, PT; William R. Ries, MD; Scott J. Stephan, MD

Supplemental content
IMPORTANCE In the last decade, there has been a significant increase in the number of
practitioners administering botulinum toxin for facial synkinesis. However, there are few
resources available to guide treatment patterns, and little is known about how these patterns
are associated with functional outcomes and quality of life.

OBJECTIVE To evaluate botulinum treatment patterns, including the dosing and frequency of
muscle targeting, for treatment of facial synkinesis and to quantify patient outcomes.

DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study of 99 patients treated for
facial synkinesis was conducted from January 2016 through December 2018 at the Vanderbilt
Bill Wilkerson Center in Nashville, Tennessee, a tertiary referral center.

INTERVENTION Onabotulinum toxin A treatment of facial synkinesis.

MAIN OUTCOMES AND MEASURES Patient-reported outcomes on the Synkinesis Assessment

Questionnaire and botulinum treatment patterns, including the dosages and frequency of
injection for each facial muscle, were compared at the initiation of treatment and at the end
of recorded treatment.

RESULTS In total, 99 patients (80 female patients [81%]) underwent botulinum injections for
treatment of facial synkinesis. The median (interquartile range) age was 54.0 (43.5-61.5)
years, and the median (interquartile range) follow-up was 27.1 (8.9-59.7) months. Most
patients underwent injections after receiving a diagnosis of Bell palsy (41 patients, 41%) or
after resection of vestibular schwannoma (36 patients [36%]). The patients received a total
of 441 treatment injections, and 369 pretreatment and posttreatment Synkinesis Assessment
Questionnaire scores were analyzed. The mean botulinum dose was 2 to 3 U for each facial
muscle and 9 to 10 U for the platysma muscle. The dose increased over time for the majority
Author Affiliations: Department of
of all muscles, with steady state achieved after a median of 3 treatments (interquartile range,
Otolaryngology, Vanderbilt University
2-3). Linear regression analysis for cluster data of the mean total questionnaire score Medical Center, Nashville, Tennessee
difference was −14.2 (95% CI, −17.0 to −11.5; P < .001). There was a significant association of (Shinn, Patel, Ries, Stephan);
postinjection questionnaire score with younger patients, female sex, total dose, and Vanderbilt University School of
Medicine, Nashville, Tennessee
synkinesis severity. Oculo-oral synkinesis may respond more to treatment compared with (Nwabueze); Department of
oro-ocular synkinesis. Biostatistics, Center for Quantitative
Sciences, Vanderbilt University,
Nashville, Tennessee (Du);
CONCLUSION AND RELEVANCE Patients with facial synkinesis responded significantly to
Department of Head and Neck
botulinum treatment. Treatment began with 6 core facial muscles that were injected during Surgery, Kaiser Permanente,
most treatment sessions, and dosages increased after the first injection until steady state was Lafayette, Colorado (Motamedi);
achieved. Those with a greater degree of morbidity, younger patients, and females showed Pi Beta Phi Institute, Bill Wilkerson
Center, Vanderbilt University Medical
significant improvement, and the larger the dose administered, the greater the response.
Center, Nashville, Tennessee
Oculo-oral synkinesis may be more responsive than oro-ocular synkinesis. (Norton); Division of Facial Plastics
and Reconstructive Surgery,
LEVEL OF EVIDENCE 3. Vanderbilt University Medical Center,
Nashville, Tennessee (Ries, Stephan).
Corresponding Author: Scott J.
Stephan, MD, Department of
Otolaryngology, Vanderbilt University
Medical Center, 1215 21st Ave S, 7209
Medical Center E, South Tower,
JAMA Facial Plast Surg. doi:10.1001/jamafacial.2018.1962 Nashville, TN 37232-8605
Published online January 31, 2019. (stephan@vanderbilt.edu).

(Reprinted) E1
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 Research Original Investigation
C
oinnervation of facial musculature by misdirected axo-
nal guidance can result in static and dynamic aber-
rancy and hypertonicity. Facial synkinesis and hyper-
kinesis, which have been reported to occur in as many as 50%
of those with longstanding facial weakness, results in psycho-
logical, aesthetic, and functional consequences.1-9 Although
this manifests as various functional challenges, the impair-
ment to social interaction, personal appearance, and percep-
tion may contribute more significantly to the morbidity of
disease.10
Given the variability of the involved mimetic muscula-
ture and resulting symptomology, the treatment of synkine-
sis is multimodal and tailored to individual patient concerns.
Treatment options include musculature retraining with physi-
cal therapy, targeted chemodenervation, and select surgical
procedures.9,11-18 Onabotulinum toxin type A (BT) is the stan-
dard for chemodenervation and has the capacity to produce
objective and subjective results, including improved facial sym-
metry, reduced involuntary muscle contractions, and en-
hanced quality of life.16,17,19-25
Current literature, however, fails to elucidate patient- and
injection-specific factors that predict BT responses, and many
health care professionals administer BT with irregular or ca-
pricious dosing. The intent of the present study was, there-
fore, to (1) describe the systematic use and experience with BT
injections at a tertiary referral center that has been using elec-
tromyography (EMG)–guided muscle targeting for 18 years to
help guide other clinicians; (2) describe BT treatment pat-
terns over time; (3) evaluate BT outcomes using the validated
Synkinesis Assessment Questionnaire (SAQ); and (4) identify
factors contributing to patient-reported outcomes.26,27
Methods
Patients were included if they were treated with BT for facial
synkinesis and had completed both pretreatment and post-
treatment SAQs between January 2016 and February 2018. Pa-
tients were excluded if they received BT for reasons other than
facial synkinesis or were treated with other botulinum formu-
lations. Institutional review board approval was obtained from
Vanderbilt University Medical Center to perform a prospec-
tive cohort study in conjunction with a retrospective data-
base review of patients with facial synkinesis who were treated
at the Bill Wilkerson Center Pi Beta Phi Rehabilitation Insti-
tute and the Department of Otolaryngology at Vanderbilt Uni-
versity Medical Center (Nashville, Tennessee). Written in-
formed consent was obtained from patients for botulinum
injections at each visit; the SAQ questionnaires were used in
the routine care of patients as a clinical tool and for treatment
decision making (not solely for research).
Clinic Setup and Procedure
Patients are traditionally offered chemodenervation 3 to 6
months after initiation of rigorous facial physical therapy un-
der the supervision of a therapist who specializes in facial re-
habilitation. In our clinic in general, including for the present
study, BT treatments are performed every 3 months on
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Treatment Patterns and Outcomes in Botulinum Therapy for Patients With Facial Synkinesis
Key Points
Question What are the dosing patterns and outcomes of
onabotulinum toxin A therapy for patients with facial synkinesis?
Findings In this cohort study of 99 patients, 6 facial muscles were
commonly injected and the dose progressively increased until a
steady state was achieved after 3 consecutive treatment sessions.
Younger patients, females, and those with oral symptoms and
greater overall disease severity responded significantly and most
substantially.
Meaning In facial synkinesis, onabotulinum toxin A injections
begin with the treatment of a group of core facial muscles at lower
doses and progressively increase until a steady state is achieved,
resulting in improved patient-reported outcomes.
designated treatment days. Topical anesthetic containing ben-
zocaine, 20%, lidocaine, 6%, and tetracaine, 4%, is applied to
potential injection sites, and EMG leads are placed while await-
ing appropriate anesthetic time. Patients are taken to a treat-
ment room where they are examined by both the treating phy-
sician (W.R. or S.S.) and a facial physical therapist (C.N.).
Injections are performed with a 1.5-inch × 27-gauge hypoder-
mic needle electrode having a Luer lock hub and a BT dilu-
tion of 2.5 U/0.1 mL. A 1-mL syringe is used to facilitate pre-
cise dosing. During the injection, a portable EMG system
(Nicolet VikingQuest; Natus Neurology Inc) monitors the pres-
ence of muscle hypertonicity and synkinesis at rest and with
volitional movements.
Data Collection
Routine collection of SAQ data was introduced in 2016, and pa-
tients complete the survey on the day of treatment and 2 weeks
after treatment through RedCap, a secure, Health Insurance
Portability and Accountability Act–compliant, online data-
base. The cause of facial paralysis, muscles treated, reported
duration of response, and dosages for patients completing an
SAQ were retrospectively collected.
Given the evolving nature of facial synkinesis and the need
to titrate dosing in the early phases of treatment, it was
expected that patients would reach a stable treatment course
after several visits. A preliminary analysis was therefore
performed to evaluate when steady state was achieved
(Table 1). The novel algorithm is sum = (|Δdose|) + (|ΔCMs|) +
(|ΔOMs|) = [|Δdose|/(CMs × 2) + OMs] = [(ΔCMs × 4)/10)] +
[(|ΔOMs|)/10], where changes in dose are in units of botuli-
num, CMs represent core muscles, and OMs represent other
muscles, was generated to compare the intertreatment changes
in dosing and muscles targeted with the following 2 consid-
erations. First, several muscles were treated considerably more
frequently at our center (termed herein core muscles), and
changes in these muscles were more heavily weighted than
those of the other muscles. Second, dosing and facial muscle
treatments were weighted using a correctional denominator
to balance the expressions within the algorithm. A value less
than 1 was classified as minimal fluctuation between treat-
ment sessions, whereas a value of 1 or greater was considered
substantial fluctuation. Steady state was defined as the first
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 Treatment Patterns and Outcomes in Botulinum Therapy for Patients With Facial Synkinesis Original Investigation Research

visit after at least 3 consecutive visits of algorithmic outputs

Table 1. Steady State Outcomes
less than 1. Steady state deviance was defined as a substantial
change in BT pattern (≥1) after achieving steady state. To un- Steady State Outcome Mean Value (Range)
derstand how treatment patterns evolved with time, we com- Injections 13.7 (5.0-29.0)

pared initial mean injection doses and muscles targeted with Injections until steady state 3.7 (2.0-12.0)
those of the last 3 treatments. This comparison was per- Never reaching steady state, No. (%) 6 (8.5)
formed only in patients with pretreatment and posttreat- Injections in those never reaching steady state 5.5 (5.0-6.0)
ment SAQ data who had received at least 5 injections. The study Mean deviation from steady state 1.0 (0.0-4.0)
design and the analyses performed are illustrated in eFigure 1
in the Supplement.
Table 2. Patient Demographics and Injection Data
Statistical Analysis Characteristic No. (%)
Patient demographics and characteristics of treatment are Total patients, No. 99
summarized using medians and interquartile ranges (IQRs) Age, median (IQR) 54.0 (43.5-61.5)
for continuous variables and using frequencies for categori- Follow-up, median (IQR), mo 27.1 (8.9-59.7)
cal variables. Wilcoxon signed rank tests were used to com-
Sex
pare the paired preinjection and 2-week postinjection
Male 19 (19)
scores, treating multiple treatments and injections indepen-
Female 80 (81)
dently. The median of the difference and 95% CI were esti-
Race/ethnicity
mated nonparametrically. To account for the difference of
White 85 (86)
multiple injections within a single patient, linear regression
Other 14 (14)
for clustered data without covariate (R package “miceadds”)
Cause
using the calculated preinjection and postinjection score
Bell palsy 41 (41)
difference of each injection was performed to estimate the
mean and 95% CI of the difference. Further subgroup analy- Vestibular schwannoma 36 (36)

sis was performed using SAQ questions 1 through 3 as a sur- Trauma 4 (4)

rogate for oro-ocular synkinesis (ie, inappropriate eye clo- Ramsay Hunt 9 (9)
sure in synchrony with volitional perioral movement) and Other 9 (9)
questions 5 through 7 for oculo-oral synkinesis (inappropri- Total injections, No. 441
ate facial or neck movement with volitional eye closure). Laterality
The postinjection score associations with preinjection score, Left 171 (46)
age, sex, dose, and time since first injection were studied Right 158 (43)
using multivariable linear regression with robust standard Bilateral 40 (11)
errors (to account for multiple injections within a patient). Time between injections, median (IQR), d 91 (84-98)
Bonferroni correction for multiple comparisons was applied Total dose, median (IQR) 20.0 (12.5-32.5)
when appropriate, and a 2-sided P < .05 was considered sta- Duration of response, median (IQR), d 69 (62-76)
tistically significant. All analysis was carried out using R,
Abbreviation: IQR, interquartile range.
version 3.5.0 (The R Project for Statistical Computing).

Results
Of 103 patients completing the SAQ, 99 patients (80 female
[80%]; median [IQR] age, 54 [43.5-61.5] years) met the inclu-
sion criteria. The median (IQR) follow-up, was 27.1 (8.9-59.7)
months. Baseline characteristics and a summary of the 441
treatments and injections are given in Table 2. Specific con-
siderations and the treatment paradigm for each facial muscle
is described in the eAppendix in the Supplement.
Steady State
Steady state (defined above) data are shown in Table 1. For 71
patients who received at least 5 injections, the median num-
ber of treatments was 13.5 (IQR, 9.3-17) and steady state was
achieved in a median of 3 treatment sessions (IQR, 2-3). One
patient had 29 total treatment sessions, and 1 patient re-
quired 12 sessions prior to achieving steady state. The mean
number of steady state deviations was 1 (range, 0-4).
Treatment Patterns
The 71 patients who underwent at least 5 injections were in-
cluded in the evaluation of the initial and final treatment pat-
terns. The 6 muscles most frequently targeted both at initial
and final treatments were the corrugator, orbicularis oculi su-
perioris, orbicularis oculi inferioris, risorius, mentalis, and pla-
tysma (Figure and eFigure 2 in the Supplement). Each muscle
was targeted more commonly at each treatment session. The
mean botulinum dose was 2 to 3 U for each facial muscle, and
9 to 10 U for the platysma muscle. Increases in mean (range)
doses between initial and final treatments were observed in
the upper face (5.2 [1.3-17.5] vs 8.1 [1.3-35.0] U), midface (2.8
[0.8-8.3] vs 4.5 [0.8-37.5] U), and neck (9.8 [2.5-30.0] vs 12.0
[2.5-32.5] U), while dosing in the lower face remained stable
(3.3 [1.3-10.0] vs 3.3 [1.3-12.5] U).
Of the 71 patients undergoing at least 5 injections, 53 com-
pleted paired pretreatment and posttreatment SAQ surveys at
their most recent treatment session. Therefore, the correla-
tion analysis with SAQ outcomes at latter phases of treatment

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 Research Original Investigation Treatment Patterns and Outcomes in Botulinum Therapy for Patients With Facial Synkinesis

CI, −14.6 to −7.9) and oculo-oral (mean difference, −15.7; 95%

Figure. Initial and Steady-State Treatment Patterns
CI, −19.4 to −12.1) scores; significance was maintained after
A Initial injection pattern B Steady-state injection pattern Bonferroni correction (all P < .001) (Table 3).
Table 4 summarizes the results of the multivariable
regression analysis. In these regression models, besides the
main effect, the interactions between preinjection score and
other covariates were included. Total postinjection SAQ–
2.8 (13%) 2.8 (35%)
derived scores were significantly associated with baseline
severity (P < .001), younger patients (P = .03), female sex
(P = .03), and total dose administered (P = .01). For 2 groups
2.7 (56%) 3.2 (76%) of patients with the same synkinesis severity (baseline score
2.1 (42%) 3.2 (69%)
of 50), the estimated mean postinjection score decreased
2.2 points (95% CI, 0.2-4.2 points) for the group that was 10
years younger; the score was 8.3 points (95% CI, 0.9-15.6
points) lower for females than males; and the score was 3.5
2.4 (64%) 3.1 (75%)
points (95% CI, 0.8-6.2) lower for the group with a higher
1.5 1.8 dose of 20 U. For male patients aged 53 years, if the baseline
(7%) (14%)
1.0 (5%) 1.0 (20%) score 33 months after the first injection increased by 30.6
points, the mean postinjection score after a total dose of 20
2.4 (72%) 2.7 (62%)
U increased 22.7 points (95% CI, 15.1-30.3). The oro-ocular
synkinesis outcome was significantly associated with base-
2.9 (14%) 2.0 (14%) line severity (P < .001). For male patients aged 53 years, if
3.2 3.1 the baseline score 33 months after the first injection
(78%) (94%)
increased by 42 points, the mean postinjection score after
an eye dose of 5 U and a mouth dose of 5 U increased 30.6
9.8 (71%) 12.0 (86%)
points (95% CI, 23.3-37.9). The oculo-oral synkinesis out-
come was significantly associated with baseline severity
Typical location Less frequent, patient-specific location (P < .001) and perioral dose (P = .02), and perioral dose sig-
nificantly modified baseline severity (P = .01). For male
Color transparency reflects the frequency a muscle is injected in each new patients aged 53 years, if the baseline score 33 months after
patient (A) and after the botulinum toxin dose is titrated (B). The mean dose in the first injection increased by 41.7 points, the mean postin-
units of botulinum is shown, along with the frequency a muscle is injected jection score after an eye dose of 5 U and a mouth dose of 5
(shown in parentheses).
U increased 31.3 points (95% CI, 24.0-38.5). For every 3.8 U
increase in perioral dose for patients with baseline score of
was limited to these 53 patients. Most patients began their treat- 58.3, the estimated mean difference in the postinjection
ment prior to the SAQ collection period (January 2016); there- score was 1.04 (95% CI, −0.27 to 2.34), and this effect
fore, analysis of initial SAQ outcomes was limited to the 27 pa- depended on the baseline score (for every 3.8 U increase
tients who completed pretreatment and posttreatment SAQs for a baseline score of 20, the mean difference in the post-
for their first treatment visit. The SAQ score improved by a injection score was 3.66 [95% CI, 1.08-6.24], P = .01 for
mean of 13.3 points (range, −44.4 to 13.3 points) at initial vis- interaction).
its and by a mean of 15.6 points (range, −37.8 to 17.8 points) at
final treatments (P = .38).

Overall Outcomes
Mean pretreatment and posttreatment total SAQ scores were
57.9 and 46.9, respectively (P < .001). Overall and individual
patient SAQ scores are summarized in Table 3, and eTables 1
and 2 in the Supplement. The results of Wilcoxon signed rank
tests revealed significant improvement in overall, (median
difference, −15.3; 95% CI, −16.7 to −12.5), oro-ocular (median
difference, −16.7; 95% CI, −16.7 to −12.5) and oculo-oral (me-
dian difference, −20.8; 95% CI, −25.0 to −16.7) synkinesis scores
after BT treatment (all P < .001). When stratified by each of the
9 individual survey questions, similar results were found. Af-
ter accounting for the dependence of multiple injections for a
patient, linear regression analyses indicated a significantly im-
proved total score (mean difference, −14.2; 95% CI, −17.0 to
−11.5) as well individual oro-ocular (mean difference, −11.3; 95%
Discussion
Onabotulinum toxin type A is widely used in the treatment of
f a c i a l s y n k i n e s i s a n d h a s b e e n s h ow n to i m p rove
outcomes.26,28,29 In the absence of treatment guidelines, the
pattern of use and dosing is variable. This may be due to the
dynamic and evolving nature of synkinesis, multitude of fa-
cial muscles and their complex interplay, patient-reported vari-
ance of effected muscle involvement and severity, and physi-
cian preferences.
At our center, BT dosing increased with time and there was
purposeful targeting of prolific effector muscles. A core group
of 6 muscles, the corrugator, orbicularis oculi superioris and
orbicularis oculi inferioris, mentalis, risorius, and platysma,
were consistently treated, and these muscles, which provide
a large degree of facial muscle mass, were targeted more

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 Treatment Patterns and Outcomes in Botulinum Therapy for Patients With Facial Synkinesis
Table 3. Wilcoxon Signed Rank Test and Simple Linear Regression Results
Patient Outcome
Wilcoxon Signed Rank
Item Median Difference (95% CI)a P Value
Total survey score −15.3 (−16.7 to −12.5) <.001
Oro-ocular synkinesis (Q1-Q3) −16.7 (−16.7 to −12.5) <.001
Oculo-oral synkinesis (Q5-Q7) −20.8 (−25.0 to −16.7) <.001
consistently and at increased doses over time. This is con-
trary to the results of Risoud and colleagues,30 who initially
increased dosing after the first injection, with decreased dos-
ing on subsequent treatments. We not only increased indi-
vidual muscle dose and frequency but also found that higher
doses resulted in improved SAQ outcomes; therefore, the doses
were increased as tolerated. Each muscle has a unique toler-
ance of BT, and at later phases of treatment, doses as high as
35, 37.5, 12.5, and 32.5 U were tolerated in the upper face, mid-
face, lower face, and neck, respectively. Overall, mean dosing
increased over time for the upper face, midface, and neck while
remaining stable for the lower face.
For BT-naive patients, initial treatment on the whole and
for each muscle group began at a lower dose and then in-
creased over subsequent treatment sessions. Although BT
doses were progressively increased, patients did reach a “steady
state” (minimal deviance from prior treatment regimen) af-
ter an initial exploratory period, similar to titrating blood pres-
sure medication to effect after initiating therapy. This steady
state was achieved after 3 treatment sessions, and most pa-
tients did not deviate from this result. Six patients never
reached steady state, all of whom discontinued treatment,
which constituted 40% of the 15 total patients who withdrew
from therapy.
Although the risorius is a common target, dosing and con-
sistency decreased over time for this muscle. This decrease was
likely due to the recent implementation of buccinator muscle
treatment, which has been shown to improve midface tight-
ness, oral commissure retraction, cheek biting, and control of
oral competence.28,29,31 During the last 2 years, the mean buc-
cinator dose increased from 4.0 to 5.5 U and is now used in 39%
of treatments, rather than 10% of earlier treatments.
There are concerns regarding complications and adverse
effects of high-dose BT, and some have advocated for lower
botulinum dosing.10,20,32,33 In the present study, there were no
major complications, and higher doses provided statistically
significant benefits when performed by skilled facial plastic
surgeons with a thorough understanding of anatomy. More-
over, although not all centers implement EMG guidance for ad-
ministration of BT, we find it a helpful adjunct that allows ac-
curate administration while reducing risks.
With initial therapy starting at low doses, the core facial
muscles were injected with a mean of 2 to 3 U each, and the
platysma with 9 to 10 U, with an emphasis to improve peri-
ocular and perioral symptoms while minimizing risk. Lower
doses initially help minimize the risk of ptosis and lagoph-
thalmos with periocular injections, lip droop when injecting
the nasalis and zygomaticus muscles, oral incompetence
with overtreatment of the risorius muscles, lip biting with
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Original Investigation Research
Abbreviation: Q, question.
Linear Regression a
Derived total score median of
Mean Difference (95% CI)b P Value difference (postscore minus
−14.2 (−17.0 to −11.5) <.001 prescore).
b
−11.3 (−14.6 to −7.9) <.001 Estimated mean difference
(postscore minus prescore) of
−15.7 (−19.4 to −12.1) <.001
derived total score.
the depressor anguli oris, and speech changes relative to
excessive buccinator treatment. The treatment of additional
and contralateral muscles was implemented at the health
care professional’s discretion to customize treatment for
each patient.
When delivering very low doses to select muscle groups
that are not immediately subdermal (eg, nasalis, zygomati-
cus, depressor anguli oris, or buccinator), confirmation of ex-
act placement in the target muscle by EMG reduces intertreat-
ment variability. The EMG can also provide immediate feedback
on which mimetic muscles exhibit purely synkinetic patterns
when the patient performs isolated facial movements of un-
related muscle groups and also to identify subclinical hyper-
kinetic or synkinetic movements.25,34 Moreover, we used EMG
to assess the degree of hyperkinesis for a select muscle at rest
in comparison with the contralateral, unaffected muscle to
guide treatment dosing and the overall regimen.
The laterality of treatment has been debated, with some
advocating for focused treatment of the synkinetic side only
and others suggesting benefit from contralateral treatment.
Eleven percent of our injections were bilateral, and the con-
tralateral muscles most commonly treated included the fron-
talis (mean, 4.6 U), corrugator (mean, 3.6 U), depressor an-
guli oris (mean, 0.75 U), zygomaticus (mean, 1.4 U), and
mentalis (mean, 3.9 U) muscles. The relatively larger fronta-
lis, corrugator, and mentalis muscles received higher doses on
the contralateral side, whereas the depressor anguli oris and
zygomaticus muscles received smaller doses. We found this
approach to improve facial symmetry and ameliorate notice-
able discrepancies in mimetic expression.
At our center, the SAQ survey helped guide treatments to
assess how previous injections benefited a patient and how to
tailor subsequent injections. Similar to overall SAQ out-
comes, we found similar positive responses for each survey
component. Notably, however, in approximately 10% of treat-
ments, a patient did not respond positively on their SAQ. Many
times this was followed by subsequent improvements; there-
fore, these fluctuations should not deter additional treat-
ment attempts. In general, patients greatly valued BT treat-
ment with a median follow-up of 27 months and a median
interval between injections of 91 days, and 85% of the pa-
tients at our center continue routine treatment sessions.
Compared with oro-ocular synkinesis, oculo-oral synki-
nesis is more common, is associated with hyperkinetic move-
ments that are more obvious to the human eye, and may be
more amenable to BT treatment.35 The findings of the present
study support these statements, as shown by the greater
absolute improvements in SAQ scores in oculo-oral (20.8)
compared with oro-ocular (16.7) synkinesis. In addition,
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 Research Original Investigation Treatment Patterns and Outcomes in Botulinum Therapy for Patients With Facial Synkinesis

Table 4. Multivariable Regression Results Using the Derived Total Score

Mean difference P Value for
Variable (95% CI)a P Value Interaction
Total synkinesis
Baseline SAQ <.001
Every 31-point increase for males aged 53, 22.73 (15.14 to 30.32)
total dose 20 U, 33 mo after injection
Age .03 .58
Every 10-y increase for a baseline score of 50 2.21 (0.18 to 4.23)
Sex .03 .42
Male vs female with the same baseline score of 50 8.27 (0.94 to 15.60)
Time .55 .71
Every 48-mo increase for a baseline score of 50 -1.69 (−4.72 to 1.35)
Total dose .01 .37
Every 20-U increase for a baseline score of 50 3.54 (0.82 to 6.25)
Oro-ocular synkinesis (Q1-Q3)
Baseline SAQ <.001
Every 42-point increase for males aged 53, eye dose 30.58 (23.26 to 37.90)
5 U, mouth dose 5 U, 33 mo after injection
Age .66 .76
Every 10-y increase for a baseline score of 58.3 1.16 (−1.43 to 3.76)
Sex .14 .09
Male vs female with the same baseline score of 58.3 7.77 (−1.12 to 16.66)
Time .41 .48
Every 48-mo increase for baseline score of 58.3 −1.72 (−5.57 to 2.14)
Periocular dose .25 .10
Every 7.5 U increase for a baseline score of 58.3 1.10 (−2.82 to 5.01)
Perioral dose .41 .89
Every 3.75-U increase for a baseline score of 58.3 1.23 (−1.22 to 3.67)
Oculo-oral synkinesis (Q5-Q7)
Baseline SAQ <.001
Every 42-point increase for males aged 53 y, 31.29 (24.05 to 38.52)
eye dose of 5 U, mouth dose of 5 U,
33 mo after injection
Age .26 .77
Every 10-y increase with a baseline score of 58.3 1.76 (−1.20 to 4.72)
Sex .13 .10
Male vs female with the same baseline score of 58.3 9.02 (−0.07 to 18.11)
Time .90 .65
Every 48-mo increase for a baseline score of 58.3 0.33 (−3.65 to 4.31)
Periocular dose .09 .47
Every 7.5-U increase for a baseline score of 58.3 2.98 (0.31 to 5.65) Abbreviations: Q, question;
Perioral Dose .02 .01 SAQ, Synkinesis Assessment
Questionnaire.
Every 3.75-U increase for a baseline score of 58.3 1.04 (−0.27 to 2.34)
a
Mean difference in postinjection
Every 3.75-U increase for a baseline score of 20.0 3.66 (1.08 to 6.24)
derived score.

multivariable regression analyses showed significantly im-
proved outcomes in oculo-oral synkinesis with worse pretreat-
ment facial synkinesis and higher perioral BT doses. The peri-
oral mouth dose was also an effect modifier, and patients
receiving higher perioral BT dosing in oculo-oral synkinesis
may have responded to an even greater extent. The reason for
these findings is unclear although they may be associated with
the small and spread out muscle mass of the orbicularis oculi;
the disproportionate impact on patient quality of life that ac-
companies constant eye closure, visual field obstruction, and
facial disfigurement; and the capacity for increased BT doses
of the midface and lower face, whereas the contributory ocu-
lar muscles have a limited dose capacity given the risk of
lagophthalmos.
It has been previously postulated that older patients and
males develop worse synkinesis, and sex and age contribu-
tions were observed in the present study when controlling for
baseline SAQ-reported severity.36 Younger patients and fe-
males had significantly improved outcomes when compared
with their older male counterparts. Because females typi-
cally possess less facial muscle bulk than males, similar doses
of BT would theoretically result in relatively greater tissue

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 Treatment Patterns and Outcomes in Botulinum Therapy for Patients With Facial Synkinesis Original Investigation Research

concentrations and therefore greater effects. One would then Limitations

expect older patients to improve more substantially than
younger patients for similar reasons; however, this expecta-
tion was not supported by data in the present study.
We chose the SAQ to longitudinally measure patient-
reported outcomes because patient perception is crucial for
successful treatment. Reduced social interaction and poor self-
perception may contribute to reduced quality of life more so
than the functional consequences of facial synkinesis. In fact,
85% of the patients at our center have continued regular BT
treatments since we began collecting injection data, and we
have a 90% retention rate since we began collecting SAQ data.
If patient retention can be used as a surrogate measure of value,
then there was a clear trend of continuing long-term BT treat-
ments for reasons beyond what may be captured by the SAQ.
Moreover, the SAQ is obtained prior to and 2 weeks after BT
treatments, which captures the most severe symptomology
compared with the near maximal associated treatment re-
sponse. Nonetheless, the SAQ is not inclusive and lacks the abil-
ity to evaluate hyperkinesia and other facial dyskinesia and also
relies on patient compliance and 2-week SAQ responses.
Similar to prior reports, the median age of the present co-
hort was 54 years, with a predominance of females (80%) and
Bell palsy as the most common cause (41%).22,26,29,32,37 Ves-
tibular schwannomas comprised a relatively high proportion
(36%), likely owing to our neurotology referral pattern. Regard-
less, patients are enrolled in facial retraining by a dedicated fa-
cial rehabilitative therapist prior to initiating BT therapy. This
is an integral part of the treatment process and helps identify
those patients who are refractory to physical therapy alone.
The majority of patients were referred after the onset of syn-
kinesis, and we were not able to assess the development, in-
cidence, or potential for prevention of the disorder, which has
been previously reported. 4,38,39 We collected patient-
reported synkinetic outcomes without objective, physician-
guided assessments, such as the Sunnybrook Facial Grading
System. This is in part due to our emphasis on patient per-
ceived severity rather than on physician interpretations, and
further study is required to correlate objective and subjective
assessments. Future directions of inquiry may also include de-
termining optimal BT dosing, EMG data to elucidate best prac-
tice management for muscles demonstrating hyperkinesis vs
pure synkinesis, BT treatment value and cost analysis, patho-
physiology of outcome discrepancies of female sex and younger
patients, and the mechanism of botulinum resistance.
Conclusions
In facial synkinesis, botulinum dosing and muscle targeting
increased after the first treatment session until steady state was
achieved. A group of core facial muscles was treated most com-
monly, with customization depending on specific patient
symptoms. Patients with facial synkinesis responded signifi-
cantly to therapy, especially younger patients, females, and
those with greater disease severity. Higher doses were signifi-
cantly associated with improved outcomes, and oculo-oral syn-
kinesis may be more responsive to treatment than oro-ocular
synkinesis.

ARTICLE INFORMATION
Accepted for Publication: September 27, 2018.
Published Online: January 31, 2019.
doi:10.1001/jamafacial.2018.1962
Author Contributions: Drs Shinn and Stephan had
full access to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Shinn, Patel, Motamedi,
Norton, Ries, Stephan.
Acquisition, analysis, or interpretation of data:
Shinn, Nwabueze, Du, Patel, Motamedi, Stephan.
Drafting of the manuscript: Shinn, Nwabueze, Patel,
Motamedi, Stephan.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Shinn, Du.
Administrative, technical, or material support:
Shinn, Patel, Motamedi.
Supervision: Shinn, Motamedi, Norton, Ries,
Stephan.
Conflict of Interest Disclosures: None reported.
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