Journal of Plastic, Reconstructive & Aesthetic Surgery (2017) 70, 833e841

Review

Botulinum toxin treatment for facial palsy:

A systematic review
Lilli Cooper a,*, Michael Lui b, Charles Nduka a

a
Plastic Surgery Department, Queen Victoria Hospital, Holtye Rd, East Grinstead, RH19 3DZ, UK
b
Year 12, Brighton College, Eastern Rd, Brighton, BN2 0AL, UK

Received 2 July 2016; accepted 31 January 2017

KEYWORDS Summary Background: Facial palsy may be complicated by ipsilateral synkinesis or contra-
Botulinum toxin; lateral hyperkinesis. Botulinum toxin is increasingly used in the management of facial palsy;
Facial palsy; however, the optimum dose, treatment interval, adjunct therapy and performance as
Synkinesis; compared with alternative treatments have not been well established. This study aimed to sys-
Neuromuscular tematically review the evidence for the use of botulinum toxin in facial palsy.
retraining therapy Method: The Cochrane central register of controlled trials (CENTRAL), MEDLINE(R) (1946 to
September 2015) and Embase Classic þ Embase (1947 to September 2015) were searched for
randomised studies using botulinum toxin in facial palsy.
Results: Forty-seven studies were identified, and three included. Their physical and patient-
reported outcomes are described, and observations and cautions are discussed.
Discussion: Facial asymmetry has a strong correlation to subjective domains such as impair-
ment in social interaction and perception of self-image and appearance. Botulinum toxin in-
jections represent a minimally invasive technique that is helpful in restoring facial
symmetry at rest and during movement in chronic, and potentially acute, facial palsy. Botuli-
num toxin in combination with physical therapy may be particularly helpful. Currently, there is
a paucity of data; areas for further research are suggested. A strong body of evidence may
allow botulinum toxin treatment to be nationally standardised and recommended in the man-
agement of facial palsy.
ª 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Else-
vier Ltd. All rights reserved.

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834
Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834

* Corresponding author.
E-mail address: lillicooper@doctors.org.uk (L. Cooper).

http://dx.doi.org/10.1016/j.bjps.2017.01.009
1748-6815/ª 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
834 L. Cooper et al.

Selection of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834

Data extraction and management and assessment of bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
Data synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
Characteristics of the studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838
Mechanism of action of botulinum toxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838
Physical outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838
Subjective patient-reported outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840
Different types of botulinum toxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840
Safety concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840
The future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841
Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841

Introduction interval, adjunct therapy and performance as compared

Facial palsy is common, affecting 1 in 60 people during the
course of their lifetime.1 Two-thirds of the patients do not
recover completely, living with chronic sequelae usually due
to aberrant facial nerve regeneration.2,3 Non-flaccid facial
palsy describes the involuntary, synchronous (synkinetic) or
overactive (hyperkinetic) movement of facial muscles.3,4
Synkinesis, the abnormal co-contraction of muscles, occurs
because of aberrant facial nerve regeneration on the
affected side of the face. It may involve muscles that typi-
cally contract together, such as orbicularis oculi contracture
on Duchenne smiling.5 Occasionally, antagonist muscles may
contract at the same time, causing an apparent paralysis,6
such as zygomaticus major and depressor anguli oris or
platysma. Hyperkinesis, the excessive contraction of a
muscle, can affect both sides of the face, either because of
aberrant nerve activity or compensatory change on the un-
affected side.7 The facial nerve has protective, aesthetic
and communicative responsibilities; its dysfunction results
in considerable social and functional impairment and affects
the quality of life.4,7,8
Non-flaccid facial palsy can be addressed through surgery,
non-surgical interventions, and biofeedback physical thera-
pies. Injected chemodenervation agents such as botulinum
toxin type A (BTX-A) temporarily paralyse muscles by blocking
acetylcholine release at the neuromuscular junction.4,9 It is
preferentially taken up by the neuromuscular junctions of
hyperactive muscles10; synkinesis and hyperkinesis can
therefore be managed through targeted injections, most
commonly to peri-ocular, peri-oral and cervical muscles,
which are paramount for communication and function.4,9,10
Where flaccid facial muscles persist, injections into the
non-paralysed side may be used to symmetrise the face.4,11
Botulinum toxin is increasingly used in the management
of facial palsy4; however, the optimum dose, treatment
with alternative treatments have not been established.
This study aims to systematically review the evidence for
the use of botulinum toxin in facial palsy.
Method
A systematic search was undertaken for randomised studies
using botulinum toxin in the treatment of facial palsy. The
Cochrane central register of controlled trials (CENTRAL),
MEDLINE(R) (1946 to September 2015) and Embase
Classic þ Embase (1947 to September 2015) using the Ovid
interface. See Box 1 for example search strategy. There
were no language or publication restrictions. Reference
searching of included papers was undertaken for appro-
priate studies.
All randomised studies that evaluated the effects and
outcomes of botulinum toxin injection, of any strength or
trade name, on patients with facial palsy were included. All
participants with facial palsy were included, irrespective of
age. Non-randomised studies, non-human subjects or sub-
jects without facial palsy were excluded.
The primary outcomes included were facial symmetry,
facial muscle paralysis, discomfort/pain or adverse effects
that were defined by the study. The secondary outcomes
included were dosage of toxin required and cost that were
defined by the study.
Selection of studies
Two authors (L.C. and M.L.) independently assessed the
titles and abstracts of all trials identified by the search. The
same two authors then independently assessed for inclusion
full-text copies of potential relevant studies. Authorship
and results were not masked. The senior author would have
arbitrated any disagreement, but this was not required.
Botulinum toxin treatment for facial palsy 835

Data extraction and management and assessment
of bias
Two review authors (L.C. and M.L.) independently extrac-
ted data and assessed the risk of bias from the included
studies using a standardised and agreed form. The authors
then independently cross-checked the data. No disagree-
ment resolution was required.
Data synthesis
RevMan 6.0 (software package) would be used for statistical
analysis, including the meta-analysis of comparable
studies, if possible.
Results
Of the 41 studies identified, three studies were included
(see Figure 1).
Characteristics of the studies
Three randomised trials were included, with a total of
105 patients. Details of these trials are presented in
Table 1.8,11,12
Included paper 1: Borodic G MM, Slattery W, et al.
Botulinum Toxin for Aberrant Facial Nerve Regeneration:
Double-blind, Placebo-controlled Trial Using Subjective
Endpoints. Plast Reconstr Surg. 2005;116:36e43.8
Borodic et al. (2005) treated 30 patients with chronic
(>6 months) facial palsy with BTX-A injections to their
synkinetic side (n Z 15) and compared the effects with
those of a placebo (n Z 15).8 There was no difference
before treatment in their vertical palpebral distance (VP,
Figure 2), corneal light reflex to upper eyelid margin dis-
tance (MCRD, Figure 2) or synkinesis physicians’ grading
scale (PGS, Table 3).
The botulinum toxin group (n Z 15) demonstrated a
significant increase in VP and MCRD for smiling (p < .015),
chewing (p < .015) and puckering (p Z .005) and in PGS
(p < .001) compared to those in the placebo injection group
(n Z 15), which showed no significant change at 2 weeks’
follow-up. Although it was not an outcome of the study, it
was noted that reflex epiphora (crocodile tears) improved
in 6/9 intervention and 0/6 placebo group patients
(p < .05) and worsened in 2/9 intervention group patients
(Table 2). As a result, there was an increased incidence of
exposure keratitis in the active drug group compared to
that in the control group (<.05, Fisher’s test), although
neither of the two patients exceeded grade 3 on the
exposure grading scale (symptoms of exposure keratitis
associated with evidence of superficial punctate keratop-
athy of less than one-eighth of the cornea; no evidence of
ciliary injection of the eye).8
Synkinesis had a negative impact on all five subjective
morbidity domains. In all five domains, improvement was
seen in the botulinum toxin group: quality of life (p Z .05),
social interaction (p Z .001), personal appearance
(p Z .001), peripheral visual impairment (p Z .01), and
perception of severity (p Z .05).8 Borodic et al. found that
impairment in quality of life, social interaction, and
perception of self-image demonstrated the highest corre-
lation to measured asymmetry in VP and MCRD. Visual
obstruction appeared less significant than impact on self-
image and impairment in social interaction. The PGS best
reflected subjective morbidity over direct videotaped
measurements.
Included paper 2: do Nascimento Remigio AF, Salles AG,
Marques de Faria JC et al. Comparison of the Efficacy of
OnabotulinumtoxinA and AbobotulinumtoxinA at the 1:3
Conversion Ratio for the Treatment of Asymmetry after
Long-Term Facial Paralysis. Plast Reconstr Surg.
2015;135:239e49.11

Box 1. Example search strategy for CENTRAL database.

#1 MeSH descriptor: [Botulinum Toxins, Type A]

explode all trees
#2 MeSH descriptor: [Facial Paralysis] explode all trees
#3 MeSH descriptor: [Synkinesis] explode all trees
#4 (#2 OR #3)
#5 (#1 AND #4)
#6 (Botox or botulinum or toxin):ti,ab,kw
#7 (fac* or bell*):ti,ab,kw
#8 (pals* or paralys* or dyston*):ti,ab,kw
#9 synkinesis/
#10 (#7 AND #8)
#11 (#9 OR #10)
#12 (#6 AND #11)
#13 MeSH descriptor: [Randomized Controlled Trial] Figure 1 PRISMA diagram demonstrating the review meth-
explode all trees odology. Reasons for record exclusion (n Z 41) were non-
#14 (#12 AND #13) randomised study (n Z 1); non-human subject (n Z 1); sub-
#15 (#5 OR #14) jects without facial palsy (n Z 36); studies investigating
methods of intervention instead of effect (n Z 3).
836 L. Cooper et al.

The two main brands of BTX-A available in the United
Kingdom and Europe are onabotulinumtoxinA and abobo-
tulinumtoxinA. Each toxin has its own biochemical and
diffusion characteristics and is used equally, at a dose
conversion ratio ranging from 1:2 to 1:6. Do Nascimento
Remigio et al. (2015) compared them at a dose conversion
ratio of 1:3 (the most commonly used) for injection into the
non-paralysed side of 55 patients with long-term facial
palsy (>2 years since diagnosis or reanimation surgery). The
demographics and pre-intervention scores of the two
groups were matched. Two independent plastic surgeons
used a clinical score for facial palsy that was determined
from a regional scale for symmetry evaluation (Table 4)
before and at 1 and 6 months after the injection, and an
average was taken. Patients also completed the Facial
Disability Index at 1 and 6 months, with aspects relating to
social function/well-being and physical aspects such as
brushing teeth, eating and drinking. A subjective assess-
ment of the degree of satisfaction regarding symmetry was
performed by two independent plastic surgeons once a
month for 6 months after treatment using a 4-point scale:
1: poor, 2: fair, 3: good and 4: excellent (see Table 5).
At 1 month, the Clinical Score for Facial Palsy (Table 4)
had decreased on the non-paralysed side in both groups and
increased significantly on the paralysed side in both groups.
The facial disability index increased in group 1
(onabotulinumtoxinA) for physical function sub-scale scores
but decreased in group 2 (abobotulinumtoxinA). For the
social/well-being score, there was a progressive increase in
both groups, and on subjective evaluation, there was a sig-
nificant increase in both groups. Group 2 had a higher inci-
dence of excessive facial weakness, i.e. mild difficulty in
talking, eating or drinking, of 93.3% (64% in group 1,
p Z .007).
At 6 months, the clinical scores for the non-paralysed
and non-injected side and excessive facial weakness
returned to the pre-treatment values in both groups. The
paralysed side scores remained higher in both groups than
the pre-treatment scores at 6 months by an average of
9%. Using the Facial Disability Index, the physical function
sub-scale scores in group 1 were higher at 6 months than
the mean scores at pre-treatment and 1 month, but the
scores in group 2 did not differ before and after treat-
ment. The social/well-being score increased progressively
in both groups, but the increase was only significant in
group 1. The subjective evaluation by the plastic surgeons
remained higher than the pre-treatment score at 6
months, although it was lower than the score at 1 month
in both groups.
They concluded that both toxins were efficient in
reducing asymmetry in long-term facial palsy patients at
both 1 and 6 months after injection. The frequency of

Table 1 The three studies included in the systematic review.

Citation Patients History Intervention Objective outcome Subjective outcome
Borodic, et al., 30 (1:1 control/ Chronic (>6 Botulinum toxin for 1. Corneal light reflex Questionnaire
20058 treatment) months’) facial injection was to upper lid margin validated by team
Age and gender palsy with quantified using the distance (MCRD, regarding impairment
not provided synkinesis after standard Schantz- Figure 1) of quality of life,
Bell’s palsy (20),
Kautter method of 2. Vertical palpebral social interactions,
acoustic “LD 50” (VP) distance perception of self,
neuroma (4), determination.7 (Figure 1) visual function,
Ramsay-Hunt Four peri-ocular 3. Synkinesis physi- perception of
syndrome (4), injections of 2.5 LD cians’ grading problem severity
mastoiditis (1), 50 units/0.1 cc BTX- scale (Figure 2)
meningioma (1) A to synkinetic side 4. Complications, all
of face vs placebo at 2 weeks
Do Nascimento N Z 55 Chronic facial OnabotulinumtoxinA 1. Clinical Score for Subjective
Remigio 16e67 years palsy (>2 years (0.76  0.1 ml, Facial Palsy assessment of
et al., 43 women, 12 men since diagnosis or n Z 25 patients, Gp 2. Facial Disability symmetry performed
201511 reanimation 1) vs Index (12) by two plastic
surgery) AbobotulinumtoxinA 3. Complications at 4 surgeons using a four-
(0.71  0.08 ml, weeks point scale
n Z 20 patients, Gp
2) to non-paralysed
side of face
Monini et al., N Z 20 Chronic facial BTX-A injection 10 Sunnybrook score None
201312 12 females, 8 palsy (>1 year e40 units at final pre-treatment (early
males diagnosis) with concentration of 5 stage), day 7 post
18e67 years (no residual House- units/ml then botulinum toxin
mean provided) Brackman score neuromuscular injection (post-early
>2 after Kabat retraining therapy stage), day 90 post
physical (NMRT) from 1 week botulinum toxin
rehabilitation later (group A) vs injection (late stage,
NMRT only (group B) ls)
Botulinum toxin treatment for facial palsy 837

Figure 2 Vertical palpebral distance (VP, A), corneal light reflex to upper eyelid margin distance (MCRD, B), measurements of
palpebral asymmetry with facial movement, adapted from original source.8

adverse effects was higher after abobotulinumtoxinA
when used at a dose equivalence ratio of 1:3 than those of
onabotulinumtoxinA (93.3% vs 64%, p Z .007). These
adverse effects included symptoms related to excessive
facial weakness (e.g. mild difficulty in talking, eating or
drinking), lasting for 1e33 days (mean, 15.8  2.4 days).
There was no significant difference in their duration. The
mean social/well-being function scores were higher in
both groups at both 1 and 6 months after treatment than
the pre-treatment values, but the increase was significant
only in group 1, which could be related to the adverse
incidents.
Included paper 3: Monini S, de Carlo A, Biagini M et al.
Combined protocol for treatment of secondary effects
from facial nerve palsy. Acta Oto-Laryngologica.
2011;131:882e6.12
Monini et al.12 compared patients with residual facial
palsy after Kabat physical therapy for >1 year (House-

Table 2 Outcomes using botulinum toxin in facial palsy patients.

Paper Flaccid/non- Objective outcome Subjective outcome Complications
flaccid facial
palsy
Borodic et al., Non-flaccid VP distance and MCRD improved Significant improvement Ocular keratitis
20058 facial palsy on smiling, puckering and in quality of life, social increased with
(synkinesis) chewing (p < .05) interaction, personal botulinum toxin (n Z 2,
appearance, peripheral <grade 3)
visual impairment,
perception of severity
Do Nascimento Flaccid or non- 1. Clinical Score decreased on Subjective assessment Adverse effects at 1
Remigio flaccid facial non-paralysed (injected) side improved at all time month higher with
et al., palsy at 1 month -> normal at points cf. pre-treatment abobotulinumtoxinA
201511 6 months (gp1 Z gp2). The scores. (group 2) at an
paralysed side scores increased AbobotulinumtoxinA equivalence ratio of 1:3
after 1 month and remained group over-paralysed at (93% vs. 64%, p Z .007)
higher than pre-treatment 1 month but equalled
scores at 6 months (gp1 Z gp2) group 2 at 6 months
2. Facial Disability Index had a
significant increase in both
groups at 1 month and
sustained increase in group
1 at 6 months
Monini et al., Non-flaccid Group A: SFGS improvement No complications No complications
201312 facial palsy of 2.1 at day 7 and 5.4 at reported reported
day 90 (p < .001). Coefficient
linear regression for botulinum
toxin efficacy was 4.95 (p < .024).
Group B, SFGS improvement of
3.8 at day 90, significantly
different to that of group A
(p < .001)
838 L. Cooper et al.

Table 3 The synkinesis physicians’ grading scale.8 Table 4 The Clinical Score for Facial Palsy, where
Grade Description 0 Z absent, 1 Z partial/moderate, 2 Z full/pronounced.11

0 Not present Force of voluntary movement Right side Left side

1 Mild; upper lid closure <1.5 mm Eyebrow raise 0 1 2 0 1 2
2 Mild-moderate; upper eyelid closure to within Eyelid closure 0 1 2 0 1 2
1 mm of the corneal light reflex Upper lip elevation (‘sniff’) 0 1 2 0 1 2
3 Moderate; upper eyelid moves to the position Upper lateral traction of lips 0 1 2 0 1 2
of the corneal light reflex Horizontal traction of lips 0 1 2 0 1 2
4 Moderate-severe; corneal light reflex is obliterated Lip closure 0 1 2 0 1 2
by upper eyelid movement Lower lip depression 0 1 2 0 1 2
5 Severe; upper lid moves to the position of the Subtotal
inferior limbus at the 6 o’clock position with Force of involuntary movement
evidence of scleral show Eyelid closure when blinking 0 1 2 0 1 2
6 Very severe; eye closes complete with lower facial When speaking 0 1 2 0 1 2
movement When smiling (spontaneously) 0 1 2 0 1 2
Subtotal
Negative findings
Eyelid deformity at rest 0 1 2 0 1 2
Brackmann score 2e3) who received BTX-A treatment fol-
Lip deformity at rest 0 1 2 0 1 2
lowed by NMRT to those who received NMRT alone. NMRT is
Synkinesis/spasms 0 1 2 0 1 2
an exercise programme to minimise synchronic mobilisation
Subtotal
and disrupt synkinesis by redirective cortical projections to
Final total
non-synkinetic motoneurons only. No demographic differ-
ence between the two groups was stated. Up to 40 units of
BTX-A was injected to the synkinetic side of the face
(orbicularis oculi, orbicularis oris and frontalis) and NMRT regarding its implementation in facial palsy. We performed
commenced 1 week later at an unspecified frequency for an a systematic review of randomised trials to distil the high-
unspecified length of time. est quality evidence in this field.
Monini et al. reported that BTX-A is a useful treatment
to improve synkinesis in the short and long term because
Mechanism of action of botulinum toxin
the SFGS significantly reduced in group A (the intervention
group) at day 90 compared to that in the control group (3.5
cf. 5.6, p < .001). They also noted that BTX-A therapy Botulinum toxin is a protein derived from the bacterium
optimises NMRT because although there was an improve- Clostridium botulinum and exists in seven serologic types,
ment in synkinesis in both groups, this was significantly namely A-G.3 BTX-A has been developed for therapeutic use
more in group A (p < .001). They recommend intervention in the face after its initial approval by the FDA in 1979 for
with BTX-A as soon as synkinesis has been noted. use in strabismus patients.3,8,11,12 Since 1987, it has been
reported to be successful in the temporary relief of non-
flaccid facial palsy.3,8 It blocks the pre-synaptic release of
Data analysis acetylcholine, temporarily stopping motor end-plates from
transmitting action potentials, with effects clinically
The outcomes differed between studies, and therefore, the evident at weeks 1e27,13 and optimal effects at approxi-
results could not be directly compared. mately 1 month, depending on the type and size of muscles
and degree of hyperkinesia.7 Collateral sprouting occurs
after 3e6 months, which clinically re-establishes the
Discussion
pathological state.3,7,11 As expected, botulinum toxin
therapy improved facial symmetry in all three studies.8,11,12
Facial palsy can result in wide-ranging consequences for the The follow-up by Borodic et al. was relatively short at 2
patient. Emotional expression is profoundly interrupted, weeks,8 but in the other two studies, it was interesting that
and there are functional consequences such as impaired the results were sustained beyond the 6 months that we
vision resulting from ocular synkinesis and peri-oral synki- would expect botulinum toxin to work.11,12
nesis causing difficulties with speech or oral continence.3,7
Aesthetic concerns with asymmetry correlate strongly with
impairment in social interaction and perception of self- Physical outcomes
image. Interestingly, aesthetic concerns rate higher than
functional concerns such as peripheral visual function.8 Do Nascimento Remigio et al. demonstrated that after
There is a mounting body of evidence that supports botu- botulinum toxin injections into the non-paralysed side of
linum toxin as an important treatment for facial asymme- the face, there was a sustained 9% reduction in facial
try, in ameliorating synkinesis on the affected side and for asymmetry at 6 months.11 This phenomenon has been
minimising hyperkinesis of the face on the unaffected side. demonstrated in a study on rats, where buccalebuccal
Despite its widespread use, there is limited evidence for nerve anastomosis with contralateral BTX-A injec-
how best to use botulinum toxin and no accepted guidelines tions showed a significantly higher degree of correct
Botulinum toxin treatment for facial palsy 839

Table 5 Risk of bias table.

Paper Adequate sequence Allocation Blinding Incomplete Free of Free of other
generation concealment outcome data selective bias
addressed reporting
Borodic et al., Unclear Unclear Yes Yes Yes Yes
2005 Patients were treated Not specified Six patients were Thirty patients Overall, The study
with either the active in the study included in an participated in there is appears to be
drug or placebo in this open-label pilot this limb of the no selective free of other
randomised study, study design and study reporting of sources of bias
but the method of 30 patients were and there were outcomes
sequence generation in a multi-centre, no drop-outs
was not specified double-blinded,
placebo-
controlled trial.
In the double-
blinded study,
measurements
were obtained by
blinded physician
observers
Do Nascimento Unclear Yes Yes Unclear Yes Yes
Remigio Patients were The first author Double blinded, It is not clearly Overall, The study
et al., 2015 randomly treated and the resident- both the patient reported if all there is no appears to be
with either in-training blindly and the physician participants selective free of other
onabotulinumtoxinA performed the who gave the included in the reporting of sources of bias
or patient intervention were trial attended outcomes
abobotulinumtoxinA evaluations; the unaware of the the follow-up
but the method of second author brand of Botox assessments
sequence generation was the only one used
was not clear aware of the
brand used by
each patient to
allow for
determination of
the dose and
technique
Monini et al., Unclear Unclear Unclear Yes Yes Yes
2013 The 20 patients were Not specified in Not specified in All 20 patients Overall, The study
randomly and equally the study the study attended the there is no appears to be
distributed into group follow-up selective free of other
a and b, both with ten assessment 90 reporting of sources of bias
patients, but the days after outcomes
method of sequence treatment
generation was
not clear

innervation than after nerve anastomosis alone (61% vs
27%).14 It would suggest in this context that botulinum
toxin not only inhibits exaggerated movements on the
non-pathological side but also improves the movement on
the paralysed side.11
Monini et al. attributed their sustained effects to the
ability of botulinum toxin to optimise neuromuscular
retraining therapy.12 In this study, botulinum toxin to the
affected side is believed to create a ‘window of opportu-
nity’ for the patient to train with relatively normal move-
ment patterns, without synkinetic interference.12 Azuma
et al. also reported this using mirror biofeedback tech-
niques, 30 min per day for 10 months after botulinum toxin
injections.10 In this study, the ‘window of opportunity’ was
visual clarity for the patient, where the botulinum toxin
injection overcomes aberrant facial movement that would
disturb patients’ concentration on facial asymmetry. In
their series of 18 patients with 0.9 ml (112.5 units) of BTX-A
injected to the non-affected (hyperkinetic) side, the eye
opening with pursing of lips, baring of teeth and puffing out
of cheeks before botulinum toxin was 38%, 33% and 20%,
which improved to 74%, 84% and 74% after botulinum toxin
and 80%, 60% and 67%, respectively, after 10 months.10
Botulinum toxin appears to be very effective as a com-
bined treatment with physical therapies. It may be wise to
start with therapy so as not to rely on botulinum toxin to
840
achieve all the benefits and to assess where it is most
required.
Subjective patient-reported outcomes
All three included studies identified considerable subjec-
tive improvements in patients after treatment with botu-
linum toxin, with improvements in quality of life, social
interaction, personal appearance, peripheral visual
impairment and perception of severity.8,11 Patient satis-
faction increased over time and did not correlate directly
to the clinical effect, which peaks at approximately 1
month.7 For example, do Nascimento Remigio et al. re-
ported mean social/well-being scores that were signifi-
cantly higher than pre-treatment scores at 1 and 6 months;
however, the chemical effects of the botulinum toxin
therapy as reported by the Clinical Score peaked at 1 month
and had largely worn off by 6 months. In group 2 (abobo-
tulinumtoxinA), although the score was significantly higher
at 1 month, it was non-significant by 6 months, which the
authors attributed to the adverse effects in group 2.11 In
general, patient satisfaction with botulinum toxin therapy
seems to increase over time.13
Different types of botulinum toxin
Only the study by do Nascimento Remigio et al. compared
two types of botulinum toxin: onabotulinumtoxinA and
abobotulinumtoxinA.11 Both types produced objectively
reduced movement on the injected (unaffected) side of the
face and an improvement on the paralysed side. Onabotu-
linumtoxinA produced longer lasting patient-reported
improvement using the Facial Disability Scale and less
excessive facial weakness, i.e. mild difficulty in talking,
eating, or drinking, of 93.3% (64% in Group 1, p Z .007).11
They concluded that both toxins were efficient in
reducing asymmetry in long-term facial palsy patients at
both 1 and 6 months after injection; however, they rec-
ommended a lower dose equivalence ratio, than the 1:3
that they used, of a maximum of 1:2.5.11
Safety concerns
Botulinum toxin treatment is less invasive than surgery, but
care must be exercised in its use. Box 2 shows the contra-
indications from the studies, combined.
Significant incidences of side effects reported by Bod-
ovic et al. were induced lagophthalmos (8/15 patients) and
<grade 3 exposure keratitis (7/15 patients) in the botuli-
num toxin group.8 Do Nascimento Remiglio et al. found a
higher incidence of excessive facial weakness in the abo-
botulinumtoxinA group, i.e. mild difficulty in talking,
eating, or drinking, of 93.3% vs 64% (with onabotuli-
numtoxinA) (p Z .007).11 Monini et al. did not report any
complications.
Issues of technique were highlighted to reduce adverse
events and optimise efficacy, which correlate with those
reported in other literature. The precise area or point and
depth of infiltration are important3; for example, around the
eye, it was recommended to inject orbicularis oculi centrally
in the upper lid to avoid a ptosis and to avoid injecting too
L. Cooper et al.
Box 2. Contraindications to the use of botulinum
toxin.3,8,11
- Hypersensitivity to any type of botulinum toxin
- Patients who are pregnant or lactating
- Neuromuscular junction disorders, e.g. myasthenia
gravis
- Active infections, e.g. keratitis
- Symptomatic dry eye syndrome (Schirmer test
<5 mm after 5 min without topical anaesthetic)
- Myopathic or severe involutional ptosis
- Concurrent aminoglycoside therapy
- Severe systemic diseases
- Use of anticoagulants, aminoglycosides and calcium
channel blockers
medially in the lower lid, which might cause diplopia or
epiphora (paralytic ectropion). Filipo et al. (2012) invited
their patients to look straight ahead to establish the upper
and lower lids corresponding to the iris, and infiltrated out
5 mm from the superior and inferior lid margins.3 A 45 angle
of the needle was advised to avoid diplopia or ptosis through
inadvertent extrinsic muscular or levator injection.3,8
Adverse effects around the mouth can include buccal in-
continence for liquids and/or solid or difficulties speaking,
chewing, swallowing, singing, whistling, applying lipstick
and kissing. These tend to be worst at day 147 and resolve
over time as the botulinum toxin wears off and the patient
adapts.13 There were common and mild issues reported with
drinking, chewing, speaking and smiling in 50% of patients at
day 14 in a previous series of 18 patients.7 As adverse effects
may be dose related,3,7 de Maio et al. suggested that a lower
dose treatment, with a second treatment at day 15, may
minimise the risk of adverse side effects.7
The future
While the accumulating body of evidence supports the use of
botulinum toxin in facial palsy, some questions have
remained unanswered. Gaps include the relative effect of
botulinum toxin on different types of physical rehabilitation
therapies, precision delivery including optimal doses, tech-
nique and locations, the longer term outcomes of patients
after botulinum toxin therapy (follow-up ranged only from 2
weeks to 6 months in these three studies), and the potential
for use in acute facial palsy.10,12 Kim reported encouraging
results in reducing facial asymmetry after contralateral
botulinum toxin injections in acute facial palsy,15 which is
supported by rat models.14 Further research should facili-
tate and validate the development of objective dynamics,
statistics and measures to enable quantitative research.
More work is also required on the subjective and quality of
life measures in patients with facial palsy, which will enable
better treatments to be developed.16
Conclusion
Botulinum toxin injections represent a minimally invasive
technique that is helpful in restoring facial symmetry at
Botulinum toxin treatment for facial palsy
rest and during movement in chronic, and potentially
acute, facial palsy. Botulinum toxin in combination with
physical therapy may be particularly helpful.10 Currently,
there is a paucity of large RCTs, which could help stan-
dardise the timing, dosage and protocols for treating this
neglected patient group.
Funding
N/A.
Conflict of interests
N/A.
Acknowledgements
We thank Patricia Rey for her help with the systematic
literature search and Margot Cooper for her illustrations.
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