RECONSTRUCTIVE

Nonaesthetic Applications for Botulinum Toxin

in Plastic Surgery
Matthew D. Freeman, M.D.
Ilana G. Margulies, M.D.,
M.S.
Paymon Sanati-Mehrizy,
M.D.
Nikki Burish, M.D.
Peter J. Taub, M.D., M.S.
New York, N.Y.
Downloaded from http://journals.lww.com/plasreconsurg by BhDMf5ePHKbH4TTImqenVNPUfnk57qBdFPX25arJMLRLL1vVHl6YzQuD6qQDszG7 on 07/03/2020
Background: Since their introduction to clinical medicine in 1989, botulinum
toxin injections have been used for many indications. First used for nonsur-
gical management of strabismus, botulinum toxin injections are now widely
used in plastic and reconstructive surgery for aesthetic indications; however,
nonaesthetic indications of botulinum toxin have grown tremendously over
the past two decades and span numerous specialties, including urology, der-
matology, ophthalmology, otolaryngology, gynecology, plastic surgery, general
surgery, and neurology. The present review aims to highlight nonaesthetic indi-
cations of botulinum toxin that are most relevant to the plastic surgeon with

an emphasis on evidence-based practice.

Methods: A PubMed search with manual reference checking was conducted to
find the most relevant and influential articles on the nonaesthetic uses of botu-
linum toxin within the realm of adult plastic surgery. Studies were then catego-
rized into areas of use, and quality of evidence for each category was highlighted.
Results: Botulinum toxin has numerous nonaesthetic indications in plastic
surgery, including for select pain-related disorders, skeletal muscle activity dis-
orders, exocrine gland hyperfunction, wound healing, Raynaud phenomenon,
abdominal wall reconstruction, and prosthetic breast reconstruction and aug-
mentation. Although these indications have been widely reported, high-quality
evidence supporting efficacy, optimal dose, and injection protocol with ran-
domized controlled trials is lacking in many areas.
Conclusions: Botulinum toxin is widely used in plastic surgery for a variety of
nonaesthetic indications. Future studies should focus on investigating efficacy
and best practice with high level of evidence research. (Plast. Reconstr. Surg.
146: 157, 2020.)

B
otulinum toxin is a potent neurotoxin pro-
duced by the bacterium Clostridium botuli-
num. It causes muscle paralysis by blocking
the release of acetylcholine at the neuromuscular
junction.1 Botulinum toxin also affects the release
of other neurotransmitters and neuropeptides,
which has increased its uses.2 Seven different
botulinum toxin serotypes have been reported,
with several subtypes that possess unique protein
sequences and distinct molecular entities.3 Studies
have shown that variability exists in potency,4 recep-
tor occupancy,5 spread,6 and immunogenicity.7
From the Division of Plastic and Reconstructive Surgery, De-
partment of Surgery, Mount Sinai Hospital.
Received for publication January 9, 2019; accepted January
17, 2020.
Disclaimer: The American Society of Plastic Surgeons did
not provide the official level of evidence grading that the au-
thors have assigned in this article.
Copyright © 2020 by the American Society of Plastic Surgeons
DOI: 10.1097/PRS.0000000000006908
All botulinum toxin products on the market
are composed of the A1 serotype (botulinum
toxin type A), except for a single B serotype
product [Myobloc (Solstice Neurosciences, Inc.,
South San Francisco, Calif.)/NeuroBloc (Eisai
Manufacturing Limited, Herts, United Kingdom),
botulinum toxin type B], which has been shown
to have lower potency in humans than in experi-
mental animal studies.8 The three most widely
used botulinum toxin type A products, which dif-
fer in their final formulation and potency units,
Disclosure: None of the authors has a financial
­interest in any of the products, devices, or drugs
­mentioned in this manuscript.
A “Hot Topic Video” by Editor-in-Chief Rod J.
Rohrich, M.D., accompanies this article. Go to
PRSJournal.com and click on “Plastic Surgery
Hot Topics” in the “Digital Media” tab to watch.

www.PRSJournal.com 157
Copyright © 2020 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

are onabotulinumtoxinA (Botox; Allergan, Inc.,
Dublin, Ireland), abobotulinumtoxinA (Dysport;
Ipsen, Paris, France), and incobotulinumtoxinA
(Xeomin; Merz, Frankfurt am Main, Germany).9
At present, U.S. Food and Drug Administra-
tion–approved uses in aesthetic surgery include
cosmetic improvement of lines in the glabellar
and lateral canthal areas. Additional off-label aes-
thetic uses include lateral eyebrow elevation; treat-
ment for gummy smile; and improving rhytides
surrounding the forehead, nose, midface, lower
face, and neck. Nonaesthetic on-label indications
include treatment of chronic migraine, spasticity,
detrusor activity, and strabismus (Table 1); how-
ever, numerous other off-label nonaesthetic indi-
cations have arisen over the past two decades.10,11
Although prior reviews have primarily explored
indications for aesthetic botulinum toxin use,12–14
this article aims to provide a comprehensive yet
succinct review of the most common nonaesthetic
indications for botulinum toxin in the adult
population relevant to plastic surgeons, with an
emphasis on evidence-based practice using levels
of evidence to summarize the studies included in
each subsection (Fig. 1).
DISORDERS
Pain-Related Disorders
Chronic Migraine (Level of Evidence I to III)
Chronic migraine is defined as headache
on 15 days or more per month for greater than 3
months, of which 8 or more days meet the criteria
for migraine with or without aura and/or respond
to migraine-specific treatment, occurring in a
patient with a history of at least five prior migraine
attacks not attributed to another causative disor-
der or medication overuse.15 Chronic migraine
affects approximately 2 percent of the popula-
tion, leading to reduced quality of life, increased
analgesic misuse, increased health care costs, and
increased missed work days.16 Although migraine
surgery has been found to be effective for chronic
migraine,17 onabotulinumtoxinA is a U.S. Food
and Drug Administration–approved noninvasive
treatment with efficacy supported by three large-
scale studies.18 The Phase 3 Research Evaluating
Migraine Prophylaxis Therapy trial used a prospec-
tive, double-blinded, placebo-controlled study to
conclude that onabotulinumtoxinA significantly
improved all outcomes in chronic migraine, with
improvement remaining at 56 weeks’ follow-up.19
The Chronic Migraine Onabotulinum Toxin
A Prolonged Efficacy Open Label study noted
158
Copyright © 2020 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Plastic and Reconstructive Surgery • July 2020
Table 1. U.S. Food and Drug Administration
On-Label Indications for Botulinum Toxin
1. Urinary incontinence because of detrusor overactivity
associated with neurologic disorder (SCI, MS) or nonre-
sponse to anticholinergics
2. Prophylaxis of HA in adult patients with chronic migraine
(≥15 days/mo with headache lasting 4 hr/day or longer)
3. Treatment of upper limb spasticity in adult patients
4. Treatment of cervical dystonia in adult patients, to reduce
the severity of abnormal head position and neck pain
5. Treatment of severe axillary hyperhidrosis that is inad-
equately managed by topical agents in adult patients
6. Treatment of blepharospasm associated with dystonia in
patients aged 12 yr or older
7. Treatment of strabismus in patients aged 12 yr or older
SCI, spinal cord injury; MS, multiple sclerosis; HA, hyaluronic acid.
improvement after nine sessions, with favorable
results at 24 months.20 The ongoing Real-Life Use
of Botulinum Toxin for the Symptomatic Treat-
ment of Adults with Chronic Migraine, Measuring
Health Care Resource Use, and Patient-Reported
Outcomes Observed in Practice trial found long-
term benefits of onabotulinumtoxinA injections
during preliminary studies across 78 clinics in
Europe and the United States.21
Although the therapeutic mechanism of
botulinum toxin in preventing migraines is still
being elucidated, it appears that it functions both
at the injection site and at distant sites by means
of axonal transport. Botulinum toxin inhibits the
release of neurotransmitters and neuropeptides
other than acetylcholine, and reduces release
of substance P and calcitonin gene-related pep-
tide, which likely causes the therapeutic effect in
chronic migraine.2 Botulinum toxin also modi-
fies cell surface nociceptive receptors linked to
chronic migraine.2 Although botulinum toxin
has been found to decrease frequency and inten-
sity of migraines with minimal side effects in
chronic migraine patients, episodic migraine
and tension-type headache patients have not
experienced the same results, and these condi-
tions are currently not indications for botulinum
toxin.22–24
The injection protocol in the Phase 3
Research Evaluating Migraine Prophylaxis
Therapy trial involves a total of 155 to 195 U
injected as 5-U aliquots across 31 to 39 intramus-
cular sites (Table 2). A retreatment schedule of
every 12 weeks, up to five cycles, was well-toler-
ated.18,19,25 Alternative protocols exist, including
the use of a targeted peripheral nerve-directed
approach with a decreased botulinum toxin type
A dose, resulting in significant improvements
in severity and duration of migraine headaches
(Table 2).26,27
 Volume 146, Number 1 • Nonaesthetic Uses for Botulinum Toxin

Fig. 1. Overview of the wide scope of nonaesthetic botulinum toxin use. The following indications that are
less commonly performed or outside the scope of plastic surgery are included in this diagram but are not
further described in the text: vaginismus, prevention or treatment of salivary fistula in head and neck sur-
gery, rhinitis, spastic entropion, and lacrimal hypersecretion. TMJ, temporomandibular joint. Printed with
permission from © Mount Sinai Health System.

Osteoarthritis (Level of Evidence II to III) A recent meta-analysis of randomized controlled

Patients with osteoarthritis often see hand
surgeons because of pain that results from inflam-
mation of the surrounding synovium, changes
to the articular cartilaginous surface, and loss of
joint space volume.28 Inhibition of substance P,
calcitonin gene-related peptide, and neurokinin
A release may allow botulinum toxin to reduce
osteoarthritis-related pain.29 A systematic review
showed a role for botulinum toxin in osteoarthritis
treatment, but the reviewed studies were too het-
erogeneous, and the optimal injection method,
dilution, and dosage need further investigation.30
trials found a significant short-term joint pain
reduction with intraarticular botulinum toxin
injection, but again noted the need for study
homogeneity and additional studies comparing
botulinum toxin with conventional treatment
modalities.31
Trigeminal and Postherpetic Neuralgia (Level
of Evidence II to V)
Trigeminal neuralgia is characterized by par-
oxysmal, sudden-onset episodes of severe pain
in the distribution of the trigeminal nerve, usu-
ally unilaterally, with a variety of potential causes,

159
Copyright © 2020 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
 Plastic and Reconstructive Surgery • July 2020

Table 2. Phase 3 Research Evaluating Migraine Temporomandibular Pain Disorders (Level

Prophylaxis Therapy Injection Protocol versus of Evidence II to IV)
Targeted Injection Protocol* Temporomandibular pain disorders, which
Total Total can be divided into myofascial or arthrogenic,
No. of No. of have a number of causes and affect up to 10
Units Sites percent of the population.43 Myofascial tem-
Muscle target poromandibular pain disorders respond well to
Corrugator 10 2 pharmacologic therapy and behavioral changes,
Procerus 5 1
Frontalis 20 4 although refractory cases can be challenging to
Temporalis 40–50 8–10 treat. Limited research into the use of botulinum
Occipitalis 30–40 6–8 toxin type A has yielded encouraging results with
Cervical paraspinal muscle group 20 4
Trapezius 30–50 6–10 effective dosing ranging from repeated injections
Targeted injection protocol† of 100 U to a single injection of 500 U of botuli-
Peripheral nerve target num toxin type A into the masseter and/or tem-
Supraorbital nerve/supratrochlear
nerve 25 2 poralis muscle.44,45 Additional case series found
Zygomaticotemporal nerve 37.5 2 that 90 U of botulinum toxin type A injected into
Greater occipital nerve 50 2 the masseter and temporalis decreased pain by at
*All muscles should be injected bilaterally with the exception of the least 50 percent in 79 percent of patients.46 Simi-
midline procerus. Dosages are in the form of onabotulinumtoxinA.
†Targeted botulinum toxin injection protocol as detailed in Janis JE, lar promising results were found with botulinum
Barker JC, Palettas M. Targeted peripheral nerve-directed onabotu- toxin type A use to correct disk displacement in
linumtoxin A injection for effective long-term therapy for migraine arthrogenic temporomandibular pain disorders
headache. Plast Reconstr Surg Glob Open 2017;5:e1270. 10.1097/
GOX.0000000000001270 through lateral pterygoid muscle injection47,48;
however, randomized prospective studies are
needed to confirm the efficacy of botulinum toxin
although in many patients it is idiopathic.32 Botu- in temporomandibular pain disorders and deter-
linum toxin use in trigeminal neuralgia was first mine optimal dosing.49
reported for pain relief in intractable trigeminal
neuralgia in 2002,33 and its efficacy in reducing Skeletal Muscle Activity
frequency and severity of episodes has been con-
firmed by a number of studies, including by means Cervical Dystonia (Level of Evidence I)
of meta-analysis, with single-dose regimens having Cervical dystonia is the most common focal
effects comparable to multiple-dose regimens. dystonia, characterized by involuntary head and
Effective doses have ranged from 70 to 100 U bot- neck posturing, potentially resulting in severe
ulinum toxin type A for single-dose regimens or pain.50 A 2017 meta-analysis showed significant
50 to 70 U botulinum toxin type A per treatment improvement in severity, disability, and pain from
for repeated dose regimens.34–36 Meta-analysis also a single injection session of botulinum toxin type
revealed the efficacy of botulinum toxin in alle- A, but with increased risk for dysphagia (9 per-
viating pain in refractory trigeminal neuralgia, cent) and generalized weakness (10 percent).50 A
although it emphasized the current lack of high- meta-analysis in 2016 showed similarly encourag-
quality studies.37 ing results for botulinum toxin type B.51 All botuli-
Postherpetic neuralgia is a neuropathic pain num toxin products are now U.S. Food and Drug
condition that results from herpes zoster–induced Administration approved for the treatment of cer-
vical dystonia, with botulinum toxin type A used
peripheral nerve damage. Although topical or sub-
as first-line management (Table 3),52,53 and botu-
cutaneous lidocaine and/or systemic therapy with
linum toxin type B used for botulinum toxin type
tricyclic antidepressants or epileptic drugs has
A–resistant patients.54
been found to be beneficial,38 these therapies are
limited by variable patient tolerance and adverse Hemifacial Spasm (Level of
effects. Several reports and randomized controlled Evidence II to III)
trials have found that up to 200 U of botulinum Hemifacial spasm, generally caused by vascular
toxin type A injected subcutaneously throughout compression of the facial nerve near its brainstem
the affected area is beneficial in postherpetic neu- origin, is characterized by facial nerve–mediated
ralgia by decreasing pain, decreasing opioid use, contractions of the face that can cause significant
and improving sleep time and quality.39–42 How- cosmetic and social disability.55,56 Although few high-
ever, additional long-term and more robust studies quality, randomized, placebo-controlled trials have
are needed to confirm these findings. been conducted for hemifacial spasm, numerous

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 Volume 146, Number 1 • Nonaesthetic Uses for Botulinum Toxin
Table 3. OnabotulinumtoxinA Dosages and Injection
Sites in Cervical Dystonia*
Recommended
Muscle Dosage (U)
Splenius capitis 15–100
Splenius cervicis 20–60
Sternocleidomastoid 15–100
Scalene complex 15–50
Semispinalis capitis 30–100
Trapezius 20–100
Longissimus 30–100
Levator scapulae 20–100
*All injections should be guided by results of electromyographic
studies. As recommended dosages are provided in a wide range for
each involved muscle, dosing should be individualized based on
patient head and neck positioning, localization of pain, and muscu-
lar hypertrophy.
lower quality publications have supported the use
of botulinum toxin as a first-line treatment. Success
rates in those studies ranged from 76 to 100 per-
cent, with effect lasting between 2.6 and 4 months.
No systemic side effects were noted and minor side
effects were transitory.55 Although microvascular
decompression of the facial nerve may be a cura-
tive procedure, studies comparing botulinum toxin
versus surgical cohorts are lacking. Despite the
lack of high-quality studies, hemifacial spasm is an
on-label indication for botulinum toxin injection
because of clinical experience.
Blepharospasm (Level of Evidence I)
Blepharospasm is a dystonia affecting the
orbicularis oculi muscle, causing excessive eyelid
closure. It may be unilateral at onset, but usually
progresses to bilateral involvement. Patient edu-
cation, avoidance of causal agents (such as dopa-
mine blockers), and avoidance of corneal injury
have been fundamental in blepharospasm man-
agement.57 Oral medications including benzodi-
azepines, baclofen, tetrabenazine, and clozapine
have shown therapeutic effects because of their
activities at gamma aminobutyric acid or dopami-
nergic receptors.58 Facial nerve lysis and orbicu-
laris myotomies were once used extensively but
have been replaced by chemodenervation. Mul-
tiple clinical trials and two large evidence-based
reviews have demonstrated that botulinum toxin
is a safe and effective treatment choice (Fig. 2).59–61
Benign Masseteric Hypertrophy (Level of
Evidence III to IV)
Benign masseteric hypertrophy is enlarge-
ment of the muscles responsible for mastication.
The cause is unknown.62 Although it is rarely a
health risk, patients present with pain and/or aes-
thetic concerns. Conservative management can
include oral muscle relaxants or intraoral splints
Copyright © 2020 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
to adjust occlusion. Although partial myomec-
tomy is possible, intramuscular botulinum toxin
injection causing selective loss of muscle func-
tion and decrease in muscle mass is an alternative
treatment option (Fig. 3).63–65 Although studies
have illustrated the efficacy of botulinum toxin in
decreasing muscle volume and have established
a tailored injection protocol based on masseter
bulge type,66–68 high-quality studies that evaluate
the efficacy of botulinum toxin particularly in
Western patient populations are needed.62,64
Bruxism (Level of Evidence II)
A recent placebo-controlled pilot trial tested
the safety and efficacy of onabotulinumtoxinA
injections into the masseter and temporalis mus-
cles in patients with symptomatic sleep bruxism.69
Participants with sleep bruxism confirmed by
polysomnography were injected with either ona-
botulinumtoxinA 200 U (60 U into each masse-
ter and 40 U into each temporalis) or placebo.
They were evaluated at 4- to 8-week time points by
multiple questionnaires, polysomnographic data,
and electromyographic recordings. None of the
exploratory endpoints changed significantly, but
total sleep time and number/duration of bruxing
episodes favored the onabotulinumtoxinA group,
indicating an improvement in sleep quality.
Synkinesia and Symmetrization of
Nonaffected Face after Facial Palsy (Level of
Evidence I to V)
Synkinesia, which involves abnormal involun-
tary muscle activation that occurs with voluntary
activation of a different muscle group, is most
commonly caused by idiopathic Bell palsy and
likely secondary to aberrant regeneration of axons
with abnormal muscle activation.70–72 The use of
botulinum toxin in the 1980s for hemifacial spasm
and blepharospasm was extrapolated to synkine-
sia in the 1990s, and it has been applied to several
affected muscles, including platysma, orbicularis
oculi, and depressor anguli oris.73–75 The use of
40 to 120 U of botulinum toxin type A for eyelid
synkinesia showed equivalent results for the 40-U
subgroup, indicating that low-dose injections are
effective.76 Indeed, another study using 0.5 to 1.25
U of botulinum toxin type A per injection site for
an average of 5.76 U total resulted in effective elim-
ination of ocular synkinesis.77 Furthermore, 64 per-
cent of patients examined had complete resolution
of their synkinesis with three or fewer treatments,
raising the possibility of definitive management
with botulinum toxin injections. Botulinum toxin
use in synkinesia has also been found to improve
patient-reported outcomes and blinded-physician
161
 Plastic and Reconstructive Surgery • July 2020

Fig. 2. Injection sites and protocol for botulinum toxin use in the
treatment of blepharospasm. Current guidelines for treatment of
blepharospasm include three injection sites in the orbicularis oculi:
(A) lateral pretarsal orbicularis oculi of the upper lid; (B) medial pre-
tarsal orbicularis oculi of the upper lid; (C) lateral pretarsal orbicu-
laris oculi of the lower lid. Dosages at each site range from 1.25 to
2.5 U, with recommended dilutions of 100 U/8 ml to 100 U/4 ml. At
repeated treatments, these doses may be increased up to twofold
if necessary. To minimize the risk of brow ptosis, providers should
avoid injection near the elevator palpebrae superioris. To minimize
the risk of diplopia from inadvertent inferior oblique muscle injec-
tion, careful technique is warranted in the medial lower lid.

evaluations, and may also improve responsiveness
to adjunct treatment modalities such as neuromus-
cular retraining therapy.78,79
Patients with facial palsy with or without subse-
quent synkinesia commonly present with contra-
lateral hyperkinesis or facial asymmetry involving
the brow, periocular, and lateral oral commissure
areas.75 Contralateral botulinum toxin injection
with or without physical therapy has been found to
improve asymmetry and contralateral hyperkinesis
even in patients with long-term facial paralysis.80,81
For instance, Azuma et al. used 112.5 U of botuli-
num toxin type A to the contralateral face in synki-
nesia with mirror biofeedback therapy and observed
significant, long-lasting improvements in facial sym-
metry.82 Systematic review found botulinum toxin
injection to improve facial asymmetry, particularly if
used in combination with physical therapy, but noted
the need for additional high-quality evidence.83
Exocrine Gland Hyperfunction
Sialorrhea (Level of Evidence I to IV)
The use of botulinum toxin in the manage-
ment of sialorrhea originally stemmed from
observations in patients with botulism exhib-
iting severe dry mouth. Furthermore, studies
on botulinum toxin injection for other indica-
tions have shown dry mouth as one of the more
common side effects.84 Although sialorrhea has
a multitude of acute and chronic causes, botu-
linum toxin is usually indicated for chronic
drooling caused by neurologic disorders such
as cerebral palsy, amyotrophic lateral sclerosis,
and Parkinson disease. A 2006 systematic review
produced two randomized controlled trials that
both showed a statistically significant improve-
ment in sialorrhea.84 A prospective, double-
blind, crossover pilot study in amyotrophic
lateral sclerosis and Parkinson disease patients
showed that both types of botulinum toxin are
effective for the treatment of sialorrhea.85 A sys-
tematic review in 2011 regarding motoneuron
disease did not identify additional experimental
trials.86 Another 2013 meta-analysis reinforced
the need for further high-quality studies to com-
pare botulinum toxin with surgical management
and to determine the optimal dosage and injec-
tion location.87

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 Volume 146, Number 1 • Nonaesthetic Uses for Botulinum Toxin

Fig. 3. Injection sites and protocol for botulinum toxin use in the treat-
ment of masseter hypertrophy. First, draw a line from the corner of the
angle of the lip to the lower part of the external auditory meatus. All injec-
tions should be kept below this line (horizontal line). Second, palpate the
masseter muscle while asking the patient to clench their teeth tightly.
Third, mark the anterior and posterior borders of the masseter muscle.
Fourth, mark the following three points: point of maximum bulge (A), infe-
rior point 1 cm lateral to anterior border of muscle (B), and inferior point
1 cm medial to the lateral border of the muscle (C). Fifth, depending on the
bulk of the muscle, 5 to 15 U may be injected at each point, for a total of
15 to 45 U per side. The needle tip is introduced in a perpendicular fashion
and is used to palpate the mandible and then retracted 1 to 2 mm before
injection, thus avoiding the superficial facial musculature.

Treatment of sialorrhea consists of botulinum Multiple randomized, double-blind, placebo-

toxin injection into the parotid and subman-
dibular glands. Review of the literature identi-
fied one article with direct injection into the
sublingual gland, which resulted in dysphagia in
50 percent of patients with no improvement in
sialorrhea.88–90 Injection into the parotid gland
requires caution to minimize injection into the
facial nerve. Injection regimens vary greatly in
the literature, with ranges of reported injection
sites (one to nine) and sites of injection (parotid
gland versus subcutaneous to minimize risk of
facial nerve palsy). Dosing per parotid gland is
typically started at 30 U and can be up-titrated
to 50 U.88–90
Axillary Hyperhidrosis (Level of Evidence I)
Axillary hyperhidrosis is a result of sympa-
thetic-mediated overactive eccrine glands and
can cause significant social embarrassment.91,92
controlled studies have found botulinum toxin
type A to be effective in reducing hyperhidrosis
as reported by patients and as seen on ninhydrin-
stained sheets.93,94 However, botulinum toxin
injection into the axilla is associated with sig-
nificant pain. Multiple analgesic modalities have
been attempted, such as icing before injection,
topical anesthetics, and regional nerve blockade.
A randomized placebo-controlled study investigat-
ing reconstituting onabotulinumtoxinA in lido-
caine rather than normal saline showed improved
pain during injection with similar improvement
in symptoms.95
Identification of areas requiring treatment
in axillary hyperhidrosis requires evaluation with
the Minor iodine-starch test procedure. Patients
should be instructed to shave their underarms
and abstain from deodorant and antiperspirants

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Copyright © 2020 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

for 24 hours before the procedure. The underarm
is painted with iodine solution, and starch powder
is applied once the iodine has dried. Regions of
hyperhidrosis in the underarm will then develop
a darkened appearance, marking the region for
toxin injection. The recommended manufactur-
er’s dosage for onabotulinumtoxinA in axillary
hyperhidrosis is 50 U per axilla, typically diluted
in 2 ml of solution. Aliquots of 0.1 to 0.2 ml are
injected intradermally approximately 1 to 2 cm
apart.11
Plantar/Palmar Hyperhidrosis (Level of
Evidence II to IV)
Although plantar/palmar hyperhidrosis is
less common than hyperhidrosis of the axilla, it
can cause significant social impairment, and act
as a risk factor for skin infection and eczema.96
Current treatments include aluminum chloride,
oral medications such as clonidine, iontopho-
resis, and occasionally surgical sympathectomy;
however, botulinum toxin injection (off-label)
is a promising alternative. Although limited
studies exist, both botulinum toxin type A and
botulinum toxin type B have been found to be
effective for palmar hyperhidrosis, and botu-
linum toxin type A has further been found to
decrease plantar hyperhidrosis in adolescent
patients, with minimal side effects.96,97 Treat-
ment complications include motor weakness
and significant pain. In a placebo-controlled
trial, three of 11 patients (27 percent) exhib-
ited motor weakness lasting up to 5 weeks.98 The
treatment paradigm involves over 30 injections
into the palm. Icing or wrist nerve blockade
should be used.
The protocol for botulinum toxin injections
for palmar/plantar hyperhidrosis is similar to that
described for axillary hyperhidrosis. If avoiding
the Minor iodine-starch test, a 1 × 1-cm grid is
created on the palm or sole. A total of 100 U of
botulinum toxin type A is then injected subcuta-
neously across the palm (150 U in the sole), with
an attempt to evenly distribute the toxin across
the grid.99
Frey Syndrome (Level of Evidence IV)
Frey syndrome, characterized by gustatory
sweating, results from injury to the auriculotem-
poral branch of the trigeminal nerve as it courses
through the parotid gland. Innervation to the
parotid to produce saliva is instead routed to the
sweat glands of the scalp, causing sweating in the
presence of gustatory stimuli. It is most common
after surgery to the parotid gland.100
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Plastic and Reconstructive Surgery • July 2020
Botulinum toxin injections for Frey syn-
drome have been used since 1995. A systematic
review in 2015 evaluating 22 published case
studies showed that botulinum toxin type A was
effective 98.5 percent of the time, with a com-
plication incidence of 3.6 percent, which mostly
consisted of dry mouth or transient muscular
weakness in the area of injection.100 Random-
ized, multicenter, placebo-controlled trials are
needed to improve evidence quality. Although
Frey syndrome is an off-label indication, botuli-
num toxin injections are considered first-line by
many providers.
The Minor iodine-starch test can identify the
cutaneous area requiring treatment. As in the
management of hyperhidrosis, a 1 × 1-cm grid is
marked, and 1 U of botulinum toxin is injected
subcutaneously at each point. The total number
of units required is dependent on each patient,
with reported dosages between 16 and 80 U of
botulinum toxin type A.101,102
Other Uses
Wound Healing (Level of Evidence II)
Botulinum toxin injection for wound healing,
keloids, and hypertrophic scarring has shown
promising early results. A prospective random-
ized study found that facial wounds treated with
botulinum toxin type A within 3 days of repair
had significant scar improvement using a visual
analogue scale as compared to those not treated
with botulinum toxin type A.103 However, when
measures other than the visual analogue scale
were used, no significant differences were noted.
Other studies have shown some benefit but
were too heterogeneous to support widespread
use.104 Potential mechanisms of action include
chemodenervation of the muscles at the wound
periphery, which allows healing in a tension-
free environment, and reduction of transform-
ing growth factor-β1, potentially a key mediator
in hypertrophic scar development. Botulinum
toxin for wound healing is currently an off-label
indication.
Currently, no consensus exists on botulinum
toxin dosing and injection patterns in the treat-
ment of existing or anticipated scars. A recent
prospective, double-blind, randomized, con-
trolled trial used 10 U/cm of forehead scar at the
time of closure as originally described by Gassner
et al.105,106 Timing of botulinum toxin injection
also varies within the literature, including imme-
diately before skin closure to greater than 1 week
after surgery, with research suggesting that earlier
injection is more effective.107
 Volume 146, Number 1 • Nonaesthetic Uses for Botulinum Toxin

Table 4. Review of the Literature on Botulinum Toxin Use in Abdominal Wall Reconstruction*
Time of Injection and
Total Dose of BT Technical Considera- Level of
Reference Defect per Patient tions Reported Outcomes Evidence
Elstner et al., Complex 300 U† or 150 U† • Injected 1–4 wk • Fascial closure achieved in II
2017124 ventral if unilateral preoperatively all cases
hernia‡ • Increase in mean abdomi-
nal wall length from
16.4 cm to 20.4 cm per side
Ibarra-Hurtado Midline 500 U§ injected • EMG instead of US • Mean hernia reduction of 5.25 II
et al., 2009117 incisional through 5 points guidance used ± 2.32 cm before repair
hernia on each side • Injected at least 4 wk • No hernia recurrences at
between exter- preoperatively mean follow-up of 9.08 mo
nal and internal
oblique muscles
Ibarra-Hurtado Midline 500 U§ injected • Injected at least 4 wk • Reduction in muscle thick- II
et al., 2014118 incisional through 5 points preoperatively ness and increase in muscle
hernia on each side in length
between exter- • No hernia recurrences at
nal and internal mean follow-up of 49 mo
oblique muscles
Farooque Midline or 300 U† or 150 U† • Injected 2 wk preop- • Fascial closure with mesh in II
et al., right-side if unilateral eratively all cases
2016115 incisional • Increase in mean
hernia abdominal wall length from
18.5 cm to 21.3 cm per side
Zielinski et Open 300 U† • Injected when • 83% primary fascial closure III
al., 2013123 abdomen patients achieved rate, 6% partial fascial
hemodynamic stabil- closure rate, 11% planned
ity after OA opera- ventral hernia rate
tion
Rodriguez- Complex 200–300 U† • Injected 7–14 days • Increase in mean lateral II
Acevedo ventral preoperatively, with abdominal wall length from
et al., herniaǁ or without PPP 16.1 cm to 20.1 cm per side
2018119 • Primary closure achieved in
all cases
• 2% hernia recurrence
Bueno-Lledo Large incisional 500 U§ injected • EMG guidance with • 14% decrease in VIH/VAC II
et al., hernia (VIH/ through 5 points US ratio
2017126 VAC >20%) on each side • Injected 40 days • 4.4% hernia recurrence
preoperatively, plus after 40.5 ± 19 mo
PPP
Bueno-Lledo, Incisional 500 U§ injected • EMG guidance with • 16.6% decrease of II
2018115 hernia with through 5 points US VIH-to-VAC ratio
LOD on each side • Injected 4 wk preop- • 5.7% hernia recurrence
eratively, plus PPP after 34.5 ± 22.3 mo
Zendejas et Incisional 300 U† injected • 41% were injected • Decreased postoperative III
al., 2013122 hernia through 5 points at median of 6 days opioid use and pain scores
on each side preoperatively, 59% • No difference in hernia
were injected on the recurrence as compared to
day of surgery matched controls
Smoot et al., Ventral hernia 300 U† • Injected >3 wk • Improvement of pain per- V
2011120 postoperatively sisting to 3-mo follow-up
BT, botulinum toxin; EMG, electromyographic; US, ultrasound; OA, open abdomen; PPP, preoperative progression pneumoperitoneum; VIH,
volume of incisional hernia; VAC, volume of abdominal cavity; LOD, loss of domain.
*All injections of BT were performed under ultrasound guidance at three sites in external oblique, internal oblique, and transversus abdominis
muscles unless otherwise specified. Timing of injection is described with respect to hernia repair.
†OnabotulinumtoxinA.
‡As defined by Slater NJ, Montgomery A, Berrevoet F, et al. Criteria for definition of a complex abdominal wall hernia. Hernia 2014;18:7–17.
10.1007/s10029-013-1168-6
§AbobotulinumtoxinA.
ǁAs defined by >20% loss of domain or recurrent/traumatic defect(s) >6 cm.

Raynaud Phenomenon (Level of
Evidence II to IV)
Raynaud phenomenon, classified as primary
idiopathic or secondary disease, involves vasospas-
tic episodes affecting cutaneous arterial inflow in
localized areas including fingers and toes leading
to pain, ischemia, ulceration, and potential ampu-
tation.108 The efficacy of pharmacologic treatment
for severe disease is variable, with some patients
requiring sympathectomy for symptomatic relief.

165
Copyright © 2020 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.

Botulinum toxin has been found to be an effective
treatment option through an unclear mechanism,
which may be related to its increase in vasodilation
through sympathetic blockade.109,110 A recent sys-
tematic review found a wide dosage range in prior
reports from 12 to 300 U per hand primarily into
digital neurovascular bundles and/or superficial
palmar arch, and they largely showed improve-
ments relating to digital temperature; pain; Dis-
abilities of the Arm, Shoulder and Hand score;
and ulcer healing.111 Further efforts through clini-
cal trials to produce high-quality evidence on bot-
ulinum toxin use in primary or secondary disease
are ongoing.112,113
Abdominal Wall Reconstruction (Level of
Evidence II to V)
The efficacy of botulinum toxin in abdominal
wall reconstruction was first evaluated in vivo, where
botulinum toxin–mediated paralysis of abdominal
wall muscles was found to increase intraabdominal
volume and decrease pressure.114 The clinical use
of botulinum toxin in abdominal wall reconstruc-
tion has subsequently been evaluated in a number
of studies, with a range of 200 to 500 U (minimum
of 150 U if unilateral) injected into abdominal wall
muscles showing overall efficacy in aiding closure
of abdominal wall defects with or without compo-
nent separation (Table 4).115–127 A recent systematic
review cited the need for randomized controlled
trials to further evaluate efficacy, dose, and timing
of administration, and to define criteria for opti-
mal candidates.121
Prosthetic Breast Reconstruction and
Augmentation (Level of Evidence II to IV)
The use of botulinum toxin has been inves-
tigated for a number of purposes in prosthetic
breast reconstruction, including to decrease post-
operative pain, increase tissue expander volume
expansion, and attenuate the development of
capsular contracture; however, discordant study
results exist. With respect to decreasing post-
operative pain, 40 to 100 U of botulinum toxin
type A injected into the pectoralis major with or
without serratus anterior and rectus abdominis
injections showed increased volume of expansion
with decreased postoperative pain and narcotic
use.128,129 However, others showed that intraopera-
tive injection of 100 U of botulinum toxin into
the pectoralis muscle was not effective in decreas-
ing postoperative pain.130 Additional high-quality
studies are needed to determine efficacy and eval-
uate optimal dosage.131
Botulinum toxin has also been found to be poten-
tially therapeutic in capsular contracture in both in
166
Copyright © 2020 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Plastic and Reconstructive Surgery • July 2020
vivo and in vitro studies by preventing implant cap-
sular formation though the inhibition of fibroblast
differentiation by means of a transforming growth
factor-β1/Smad–mediated mechanism.132–134 Clini-
cal investigation found that intraoperative injection
of 100 U of botulinum toxin type A into the pec-
toralis major in breast augmentation resulted in a
decreased incidence of capsular contracture and
decreased thickness of the capsule.135 Additional
prospective studies are needed to further elucidate
this therapeutic effect.136
CONCLUSIONS
The indications for botulinum toxin have
evolved enormously since 1989. With research
continuously exploring toxin subtypes and mech-
anisms of action, we may observe further increases
in the indications for botulinum toxin. The toxin
is a powerful tool, and plastic surgeons should be
aware of the other indications for its use outside
of improving facial aesthetics.
Matthew D. Freeman, M.D.
5 East 98th Street, 15th Floor
New York, N.Y. 10029
matthew.freeman@mountsinai.org
instagram: @matthew.freeman.md
PATIENT CONSENT
The patient provided written consent for the use of
her image.
ACKNOWLEDGMENT
The authors wish to thank Amy Zhong, M.A.,
and Jill Gregory, M.F.A., C.M.I., for their illustration
included in this article.
REFERENCES
1. Pellizzari R, Rossetto O, Schiavo G, Montecucco C. Tetanus
and botulinum neurotoxins: Mechanism of action and thera-
peutic uses. Philos Trans R Soc Lond B Biol Sci. 1999;354:259–268.
2. Do TP, Hvedstrup J, Schytz HW. Botulinum toxin: A review
of the mode of action in migraine. Acta Neurol Scand.
2018;137:442–451.
3. Hill KK, Smith TJ. Genetic diversity within Clostridium botu-
linum serotypes, botulinum neurotoxin gene clusters and
toxin subtypes. Curr Top Microbiol Immunol. 2013;364:1–20.
4. Pier CL, Chen C, Tepp WH, et al. Botulinum neurotoxin
subtype A2 enters neuronal cells faster than subtype A1.
FEBS Lett. 2011;585:199–206.
5. Kroken AR, Blum FC, Zuverink M, et al. Entry of botulinum
neurotoxin subtypes A1 and A2 into neurons. Infect Immun.
2017;85;e00795-16.
6. Torii Y, Kiyota N, Sugimoto N, et al. Comparison of effects
of botulinum toxin subtype A1 and A2 using twitch tension
assay and rat grip strength test. Toxicon 2011;57:93–99.
 Volume 146, Number 1 • Nonaesthetic Uses for Botulinum Toxin
7. Torii Y, Goto Y, Nakahira S, Kozaki S, Ginnaga A. Comparison
of the immunogenicity of botulinum toxin type A and the
efficacy of A1 and A2 neurotoxins in animals with A1 toxin
antibodies. Toxicon 2014;77:114–120.
8. Peng L, Berntsson RP, Tepp WH, et al. Botulinum neuro-
toxin D-C uses synaptotagmin I and II as receptors, and
human synaptotagmin II is not an effective receptor for type
B, D-C and G toxins. J Cell Sci. 2012;125:3233–3242.
9. Brin MF, James C, Maltman J. Botulinum toxin type A prod-
ucts are not interchangeable: A review of the evidence.
Biologics 2014;8:227–241.
10. Chen S. Clinical uses of botulinum neurotoxins: Current
indications, limitations and future developments. Toxins
(Basel) 2012;4:913–939.
11. Allergan, Inc. Highlights of prescribing information for
BOTOX. Dublin, Ireland: Allergan, Inc; 2018.
12. Noland ME, Lalonde DH, Yee GJ, Rohrich RJ. Current uses
of botulinum neurotoxins in plastic surgery. Plast Reconstr
Surg. 2016;138:519e–530e.
13. Rohrich RJ, Janis JE, Fagien S, et al. Botulinum toxin:
Expanding role in medicine. Plast Reconstr Surg.
2003;112(Suppl):1S–3S.
14. Rohrich RJ, Janis JE, Fagien S, et al. The cosmetic use of
botulinum toxin. Plast Reconstr Surg. 2003;112(Suppl):177S–
188S; quiz 188S, 192S; discussion 189S–191S.
15. Headache Classification Committee of the International
Headache Society (IHS). The International Classification of
Headache Disorders, 3rd edition (beta version). Cephalalgia
2013;33:629–808.
16. Baigi K, Stewart WF. Headache and migraine: A lead-
ing cause of absenteeism. Handb Clin Neurol. 2015;131:
447–463.
17. Janis JE, Barker JC, Javadi C, et al. A review of current evi-
dence in the surgical treatment of migraine headaches. Plast
Reconstr Surg. 2014;134(Suppl 2):131S–141S.
18. Frampton JE, Silberstein S. OnabotulinumtoxinA: A review in
the prevention of chronic migraine. Drugs 2018;78:589–600.
19. Aurora SK, Winner P, Freeman MC, et al.
OnabotulinumtoxinA for treatment of chronic migraine:
Pooled analyses of the 56-week PREEMPT clinical program.
Headache 2011;51:1358–1373.
20. Blumenfeld AM, Stark RJ, Freeman MC, Orejudos A, Manack
Adams A. Long-term study of the efficacy and safety of ona-
botulinumtoxinA for the prevention of chronic migraine:
COMPEL study. J Headache Pain 2018;19:13.
21. Davies B, Gaul C, Martelletti P, García-Moncó JC, Brown S.
Real-life use of onabotulinumtoxinA for symptom relief in
patients with chronic migraine: REPOSE study methodology
and baseline data. J Headache Pain 2017;18:93.
22. Simpson DM, Hallett M, Ashman EJ, et al. Practice guide-
line update summary: Botulinum neurotoxin for the
treatment of blepharospasm, cervical dystonia, adult spas-
ticity, and headache. Report of the Guideline Development
Subcommittee of the American Academy of Neurology.
Neurology 2016;86:1818–1826.
23. Relja M, Telarović S. Botulinum toxin in tension-type head-
ache. J Neurol. 2004;251(Suppl 1):I12–I14.
24. Padberg M, de Bruijn SF, de Haan RJ, Tavy DL. Treatment
of chronic tension-type headache with botulinum toxin: A
double-blind, placebo-controlled clinical trial. Cephalalgia
2004;24:675–680.
25. Diener HC, Dodick DW, Aurora SK, et al.; PREEMPT 2
Chronic Migraine Study Group. OnabotulinumtoxinA
for treatment of chronic migraine: Results from the dou-
ble-blind, randomized, placebo-controlled phase of the
PREEMPT 2 trial. Cephalalgia 2010;30:804–814.
Copyright © 2020 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
26. Janis JE, Barker JC, Palettas M. Targeted peripheral nerve-
directed onabotulinumtoxin A injection for effective long-
term therapy for migraine headache. Plast Reconstr Surg Glob
Open 2017;5:e1270.
27. Nahabet E, Janis JE, Guyuron B. Neurotoxins: Expanding
uses of neuromodulators in medicine—Headache. Plast
Reconstr Surg. 2015;136(Suppl):104S–110S.
28. Loeser RF, Goldring SR, Scanzello CR, Goldring MB.
Osteoarthritis: A disease of the joint as an organ. Arthritis
Rheum. 2012;64:1697–1707.
29. Martel-Pelletier J, Barr AJ, Cicuttini FM, et al. Osteoarthritis.
Nat Rev Dis Primers 2016;2:16072.
30. Khenioui H, Houvenagel E, Catanzariti JF, Guyot MA,
Agnani O, Donze C. Usefulness of intra-articular botuli-
num toxin injections: A systematic review. Joint Bone Spine
2016;83:149–154.
31. Courseau M, Salle PV, Ranoux D, de Pouilly Lachatre A.
Efficacy of intra-articular botulinum toxin in osteoarticular
joint pain: A meta-analysis of randomized controlled trials.
Clin J Pain 2018;34:383–389.
32. Sabalys G, Juodzbalys G, Wang HL. Aetiology and pathogen-
esis of trigeminal neuralgia: A comprehensive review. J Oral
Maxillofac Res. 2013;3:e2.
33. Micheli F, Scorticati MC, Raina G. Beneficial effects of botu-
linum toxin type a for patients with painful tic convulsif. Clin
Neuropharmacol. 2002;25:260–262.
34. Wu CJ, Lian YJ, Zheng YK, et al. Botulinum toxin type A for
the treatment of trigeminal neuralgia: Results from a ran-
domized, double-blind, placebo-controlled trial. Cephalalgia
2012;32:443–450.
35. Zhang H, Lian Y, Xie N, Chen C, Zheng Y. Single-dose botu-
linum toxin type a compared with repeated-dose for treat-
ment of trigeminal neuralgia: A pilot study. J Headache Pain
2017;18:81.
36. Yang F, Lin Q, Dong L, Gao X, Zhang S. Efficacy of 8 dif-
ferent drug treatments for patients with trigeminal neu-
ralgia: A network meta-analysis. Clin J Pain 2018;34:
685–690.
37. Sridharan K, Sivaramakrishnan G. Interventions for refrac-
tory trigeminal neuralgia: A Bayesian mixed treatment com-
parison network meta-analysis of randomized controlled
clinical trials. Clin Drug Investig. 2017;37:819–831.
38. Johnson RW, Rice AS. Clinical practice: Postherpetic neural-
gia. N Engl J Med. 2014;371:1526–1533.
39. Liu HT, Tsai SK, Kao MC, Hu JS. Botulinum toxin A relieved
neuropathic pain in a case of post-herpetic neuralgia. Pain
Med. 2006;7:89–91.
40. Shackleton T, Ram S, Black M, Ryder J, Clark GT, Enciso
R. The efficacy of botulinum toxin for the treatment of
trigeminal and postherpetic neuralgia: A systematic review
with meta-analyses. Oral Surg Oral Med Oral Pathol Oral Radiol.
2016;122:61–71.
41. Sotiriou E, Apalla Z, Panagiotidou D, Ioannidis D. Severe
post-herpetic neuralgia successfully treated with botu-
linum toxin A: Three case reports. Acta Derm Venereol.
2009;89:214–215.
42. Xiao L, Mackey S, Hui H, Xong D, Zhang Q, Zhang D.
Subcutaneous injection of botulinum toxin a is beneficial in
postherpetic neuralgia. Pain Med. 2010;11:1827–1833.
43. Slade GD, Bair E, By K, et al. Study methods, recruit-
ment, sociodemographic findings, and demographic
representativeness in the OPPERA study. J Pain 2011;12
(Suppl):T12–T26.
44. Khawaja SN, Scrivani SJ, Holland N, Keith DA. Effectiveness,
safety, and predictors of response to botulinum toxin type
167

A in refractory masticatory myalgia: A retrospective study. J
Oral Maxillofac Surg. 2017;75:2307–2315.
45. Kim HS, Yun PY, Kim YK. A clinical evaluation of botulinum
toxin-A injections in the temporomandibular disorder treat-
ment. Maxillofac Plast Reconstr Surg. 2016;38:5.
46. Baker JS, Nolan PJ. Effectiveness of botulinum toxin type A
for the treatment of chronic masticatory myofascial pain: A
case series. J Am Dent Assoc. 2017;148:33–39.
47. Arinci A, Güven E, Yazar M, Başaran K, Keklik B. Effect of
injection of botulinum toxin on lateral pterygoid muscle
used together with the arthroscopy in patients with anterior
disk displacement of the temporomandibular joint. Kulak
Burun Bogaz Ihtis Derg. 2009;19:122–129.
48. Karacalar A, Yilmaz N, Bilgici A, Baş B, Akan H. Botulinum
toxin for the treatment of temporomandibular joint
disk disfigurement: Clinical experience. J Craniofac Surg.
2005;16:476–481.
49. Chen YW, Chiu YW, Chen CY, Chuang SK. Botulinum toxin
therapy for temporomandibular joint disorders: A systematic
review of randomized controlled trials. Int J Oral Maxillofac
Surg. 2015;44:1018–1026.
50. Castelão M, Marques RE, Duarte GS, et al. Botulinum toxin
type A therapy for cervical dystonia. Cochrane Database Syst
Rev. 2017;12:CD003633.
51. Marques RE, Duarte GS, Rodrigues FB, et al. Botulinum
toxin type B for cervical dystonia. Cochrane Database Syst Rev.
2016;5:CD004315.
52. Charles D, Gill CE. Neurotoxin injection for movement
disorders. Continuum (Minneap Minn.) 2010;16(Movement
Disorders):131–157.
53. Allergan, Inc. Muscle selection and approved dosing in
cervical dystonia. Available at: https://www.botoxmedical.
com/cervicaldystonia/dosingandadministration. Accessed
October 8, 2018.
54. Costa J, Borges A, Espirito-Santo C, et al. Botulinum toxin
type A versus botulinum toxin type B for cervical dystonia.
Cochrane Database Syst Rev. 2005;1:CD004314.
55. Costa J, Espirito-Santo C, Borges A, et al. Botulinum toxin
type A therapy for hemifacial spasm. Cochrane Database Syst
Rev. 2005;1:CD004899.
56. Hyun SJ, Kong DS, Park K. Microvascular decompression for
treating hemifacial spasm: Lessons learned from a prospec-
tive study of 1,174 operations. Neurosurg Rev. 2010;33:325–
334; discussion 334.
57. Kennedy RH, Bartley GB, Flanagan JC, Waller RR. Treatment
of blepharospasm with botulinum toxin. Mayo Clin Proc.
1989;64:1085–1090.
58. Jankovic J. Treatment of hyperkinetic movement disorders
with tetrabenazine: A double-blind crossover study. Ann
Neurol. 1982;11:41–47.
59. Simpson DM, Blitzer A, Brashear A, et al.; Therapeutics and
Technology Assessment Subcommittee of the American
Academy of Neurology. Assessment: Botulinum neurotoxin
for the treatment of movement disorders (an evidence-
based review). Report of the Therapeutics and Technology
Assessment Subcommittee of the American Academy of
Neurology. Neurology 2008;70:1699–1706.
60. Hallett M, Albanese A, Dressler D, et al. Evidence-based
review and assessment of botulinum neurotoxin for the
treatment of movement disorders. Toxicon 2013;67:94–114.
61. Allergan, Inc. Blepharospasm injection sites. Available
at: https://www.botoxmedical.com/Blepharospasm/
DosingAndAdministration. Accessed October 8, 2018.
62. Fedorowicz Z, van Zuuren EJ, Schoones J. Botulinum
toxin for masseter hypertrophy. Cochrane Database Syst Rev.
2013;9:CD007510.
168
Copyright © 2020 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Plastic and Reconstructive Surgery • July 2020
63. Ahn J, Horn C, Blitzer A. Botulinum toxin for masseter reduc-
tion in Asian patients. Arch Facial Plast Surg. 2004;6:188–191.
64. Almukhtar RM, Fabi SG. The masseter muscle and its role
in facial contouring, aging, and quality of life: A literature
review. Plast Reconstr Surg. 2019;143:39e–48e.
65. Ahn BK, Kim YS, Kim HJ, Rho NK, Kim HS. Consensus rec-
ommendations on the aesthetic usage of botulinum toxin
type A in Asians. Dermatol Surg. 2013;39:1843–1860.
66. Kim NH, Park RH, Park JB. Botulinum toxin type A for
the treatment of hypertrophy of the masseter muscle. Plast
Reconstr Surg. 2010;125:1693–1705.
67. Kim NH, Chung JH, Park RH, Park JB. The use of botuli-
num toxin type A in aesthetic mandibular contouring. Plast
Reconstr Surg. 2005;115:919–930.
68. Xie Y, Zhou J, Li H, Cheng C, Herrler T, Li Q. Classification
of masseter hypertrophy for tailored botulinum toxin type A
treatment. Plast Reconstr Surg. 2014;134:209e–218e.
69. Ondo WG, Simmons JH, Shahid MH, Hashem V, Hunter
C, Jankovic J. Onabotulinum toxin-A injections for sleep
bruxism: A double-blind, placebo-controlled study. Neurology
2018;90:e559–e564.
70. Coulson SE, O’dwyer NJ, Adams RD, Croxson GR. Expression
of emotion and quality of life after facial nerve paralysis. Otol
Neurotol. 2004;25:1014–1019.
71. Peitersen E. Bell’s palsy: The spontaneous course of 2,500
peripheral facial nerve palsies of different etiologies. Acta
Otolaryngol Suppl. 2002;549:4–30.
72. Crumley RL. Mechanisms of synkinesis. Laryngoscope
1979;89:1847–1854.
73. Clark RP, Berris CE. Botulinum toxin: A treatment for facial
asymmetry caused by facial nerve paralysis. Plast Reconstr
Surg. 1989;84:353–355.
74. Roggenkämper P, Laskawi R, Damenz W, Schröder M,
Nüssgens Z. Botulinum toxin treatment of synkinesia
following facial paralysis (in German). HNO 1990;38:
295–297.
75. Mehdizadeh OB, Diels J, White WM. Botulinum toxin in the
treatment of facial paralysis. Facial Plast Surg Clin North Am.
2016;24:11–20.
76. Chua CN, Quhill F, Jones E, Voon LW, Ahad M, Rowson N.
Treatment of aberrant facial nerve regeneration with botuli-
num toxin A. Orbit 2004;23:213–218.
77. Ito H, Ito H, Nakano S, Kusaka H. Low-dose subcutane-
ous injection of botulinum toxin type A for facial synki-
nesis and hyperlacrimation. Acta Neurol Scand. 2007;115:
271–274.
78. Monini S, De Carlo A, Biagini M, et al. Combined protocol
for treatment of secondary effects from facial nerve palsy.
Acta Otolaryngol. 2011;131:882–886.
79. Borodic G, Bartley M, Slattery W, et al. Botulinum toxin for
aberrant facial nerve regeneration: Double-blind, placebo-
controlled trial using subjective endpoints. Plast Reconstr
Surg. 2005;116:36–43.
80. do Nascimento Remigio AF, Salles AG, de Faria JC, Ferreira
MC. 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;135:239–249.
81. Kim J. Contralateral botulinum toxin injection to improve
facial asymmetry after acute facial paralysis. Otol Neurotol.
2013;34:319–324.
82. Azuma T, Nakamura K, Takahashi M, et al. Mirror biofeed-
back rehabilitation after administration of single-dose botuli-
num toxin for treatment of facial synkinesis. Otolaryngol Head
Neck Surg. 2012;146:40–45.
 Volume 146, Number 1 • Nonaesthetic Uses for Botulinum Toxin
83. Cooper L, Lui M, Nduka C. Botulinum toxin treatment for
facial palsy: A systematic review. J Plast Reconstr Aesthet Surg.
2017;70:833–841.
84. Lim M, Mace A, Nouraei SA, Sandhu G. Botulinum toxin
in the management of sialorrhoea: A systematic review. Clin
Otolaryngol. 2006;31:267–272.
85. Guidubaldi A, Fasano A, Ialongo T, et al. Botulinum
toxin A versus B in sialorrhea: A prospective, randomized,
double-blind, crossover pilot study in patients with amyo-
trophic lateral sclerosis or Parkinson’s disease. Mov Disord.
2011;26:313–319.
86. Young CA, Ellis C, Johnson J, et al. Treatment for sialorrhea
(excessive saliva) in people with motor neuron disease/
amyotrophic lateral sclerosis. Cochrane Database Syst Rev.
2011;5:CD006981.
87. Vashishta R, Nguyen SA, White DR, Gillespie MB.
Botulinum toxin for the treatment of sialorrhea: A meta-
analysis. Otolaryngol Head Neck Surg. 2013;148:191–196.
88. Lagalla G, Millevolte M, Capecci M, Provinciali L,
Ceravolo MG. Long-lasting benefits of botulinum toxin
type B in Parkinson’s disease-related drooling. J Neurol.
2009;256:563–567.
89. Martinez-Poles J, Nedkova-Hristova V, Escribano-Paredes
JB, et al. Incobotulinumtoxin A for sialorrhea in neu-
rological disorders: A real-life experience. Toxins (Basel)
2018;10:E217.
90. Lakraj AA, Moghimi N, Jabbari B. Sialorrhea: Anatomy,
pathophysiology and treatment with emphasis on the role
of botulinum toxins. Toxins (Basel) 2013;5:1010–1031.
91. Weber A, Heger S, Sinkgraven R, Heckmann M, Elsner P,
Rzany B. Psychosocial aspects of patients with focal hyper-
hidrosis: Marked reduction of social phobia, anxiety and
depression and increased quality of life after treatment with
botulinum toxin A. Br J Dermatol. 2005;152:342–345.
92. Sato K, Kang WH, Saga K, Sato KT. Biology of sweat glands
and their disorders: II. Disorders of sweat gland function. J
Am Acad Dermatol. 1989;20:713–726.
93. Schnider P, Binder M, Kittler H, et al. A randomized,
double-blind, placebo-controlled trial of botulinum A
toxin for severe axillary hyperhidrosis. Br J Dermatol.
1999;140:677–680.
94. Naumann M, Lowe NJ. Botulinum toxin type A in treatment
of bilateral primary axillary hyperhidrosis: Randomised,
parallel group, double blind, placebo controlled trial. BMJ
2001;323:596–599.
95. Vadoud-Seyedi J, Simonart T. Treatment of axillary hyper-
hidrosis with botulinum toxin type A reconstituted in
lidocaine or in normal saline: A randomized, side-by-side,
double-blind study. Br J Dermatol. 2007;156:986–989.
96. Weinberg T, Solish N, Murray C. Botulinum neurotoxin
treatment of palmar and plantar hyperhidrosis. Dermatol
Clin. 2014;32:505–515.
97. Bernhard MK, Krause M, Syrbe S. Sweaty feet in adoles-
cents: Early use of botulinum type A toxin in juvenile plan-
tar hyperhidrosis. Pediatr Dermatol. 2018;35:784–786.
98. Schnider P, Binder M, Auff E, Kittler H, Berger T, Wolff
K. Double-blind trial of botulinum A toxin for the treat-
ment of focal hyperhidrosis of the palms. Br J Dermatol.
1997;136:548–552.
99. Doft MA, Hardy KL, Ascherman JA. Treatment of hyper-
hidrosis with botulinum toxin. Aesthet Surg J. 2012;32:
238–244.
100. Xie S, Wang K, Xu T, Guo XS, Shan XF, Cai ZG. Efficacy
and safety of botulinum toxin type A for treatment of Frey’s
syndrome: Evidence from 22 published articles. Cancer Med.
2015;4:1639–1650.
Copyright © 2020 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
101. Gualberto GV, Sampaio FMS, Madureira NAB. Use of botu-
linum toxin type A in Frey’s syndrome. An Bras Dermatol.
2017;92:891–892.
102. Eckardt A, Kuettner C. Treatment of gustatory sweat-
ing (Frey’s syndrome) with botulinum toxin A. Head Neck
2003;25:624–628.
103. Ziade M, Domergue S, Batifol D, et al. Use of botulinum
toxin type A to improve treatment of facial wounds: A
prospective randomised study. J Plast Reconstr Aesthet Surg.
2013;66:209–214.
104. Prodromidou A, Frountzas M, Vlachos DE, et al. Botulinum
toxin for the prevention and healing of wound scars:
A systematic review of the literature. Plast Surg (Oakv.)
2015;23:260–264.
105. Hu L, Zou Y, Chang SJ, et al. Effects of botulinum toxin
on improving facial surgical scars: A prospective, split-scar,
double-blind, randomized controlled trial. Plast Reconstr
Surg. 2018;141:646–650.
106. Gassner HG, Brissett AE, Otley CC, et al. Botulinum
toxin to improve facial wound healing: A prospec-
tive, blinded, placebo-controlled study. Mayo Clin Proc.
2006;81:1023–1028.
107. Kim YS, Lee HJ, Cho SH, Lee JD, Kim HS. Early postop-
erative treatment of thyroidectomy scars using botulinum
toxin: A split-scar, double-blind randomized controlled
trial. Wound Repair Regen. 2014;22:605–612.
108. Wigley FM, Flavahan NA. Raynaud’s phenomenon. N Engl J
Med. 2016;375:556–565.
109. Neumeister MW, Webb KN, Romanelli M. Minimally inva-
sive treatment of Raynaud phenomenon: The role of botu-
linum type A. Hand Clin. 2014;30:17–24.
110. Stone AV, Koman LA, Callahan MF, et al. The effect of
botulinum neurotoxin-A on blood flow in rats: A potential
mechanism for treatment of Raynaud phenomenon. J Hand
Surg Am. 2012;37:795–802.
111. Żebryk P, Puszczewicz MJ. Botulinum toxin A in the treat-
ment of Raynaud’s phenomenon: A systematic review. Arch
Med Sci. 2016;12:864–870.
112. Southern Illinois University. A two-part study of BOTOX
therapy for ischemic digits. Available at: https://clinicaltri-
als.gov/ct2/show/NCT01309802. Accessed May 1, 2019.
113. Johns Hopkins University. Efficacy of botulinum toxin in
scleroderma-associated Raynaud’s syndrome. Available
at: https://clinicaltrials.gov/ct2/show/NCT02165111.
Accessed May 30, 2019.
114. Cakmak M, Caglayan F, Somuncu S, et al. Effect of paraly-
sis of the abdominal wall muscles by botulinum A toxin to
intraabdominal pressure: An experimental study. J Pediatr
Surg. 2006;41:821–825.
115. Bueno-Lledó J, Torregrosa A, Jiménez R, Pastor PG.
Preoperative combination of progressive pneumoperito-
neum and botulinum toxin type A in patients with loss of
domain hernia. Surg Endosc. 2018;32:3599–3608.
116. Farooque F, Jacombs AS, Roussos E, et al. Preoperative
abdominal muscle elongation with botulinum toxin A
for complex incisional ventral hernia repair. ANZ J Surg.
2016;86:79–83.
117. Ibarra-Hurtado TR, Nuño-Guzmán CM, Echeagaray-
Herrera JE, Robles-Vélez E, de Jesús González-Jaime J. Use
of botulinum toxin type a before abdominal wall hernia
reconstruction. World J Surg. 2009;33:2553–2556.
118. Ibarra-Hurtado TR, Nuño-Guzmán CM, Miranda-Díaz
AG, Troyo-Sanromán R, Navarro-Ibarra R, Bravo-Cuéllar
L. Effect of botulinum toxin type A in lateral abdominal
wall muscles thickness and length of patients with midline
169

incisional hernia secondary to open abdomen manage-
ment. Hernia 2014;18:647–652.
119. Rodriguez-Acevedo O, Elstner KE, Jacombs ASW, et al.
Preoperative botulinum toxin A enabling defect closure
and laparoscopic repair of complex ventral hernia. Surg
Endosc. 2018;32:831–839.
120. Smoot D, Zielinski M, Jenkins D, Schiller H. Botox A injec-
tion for pain after laparoscopic ventral hernia: A case
report. Pain Med. 2011;12:1121–1123.
121. Soltanizadeh S, Helgstrand F, Jorgensen LN. Botulinum
toxin A as an adjunct to abdominal wall reconstruction for
incisional hernia. Plast Reconstr Surg Glob Open 2017;5:e1358.
122. Zendejas B, Khasawneh MA, Srvantstyan B, Jenkins DH,
Schiller HJ, Zielinski MD. Outcomes of chemical compo-
nent paralysis using botulinum toxin for incisional hernia
repairs. World J Surg. 2013;37:2830–2837.
123. Zielinski MD, Goussous N, Schiller HJ, Jenkins D. Chemical
components separation with botulinum toxin A: A novel
technique to improve primary fascial closure rates of the
open abdomen. Hernia 2013;17:101–107.
124. Elstner KE, Read JW, Rodriguez-Acevedo O, et al.
Preoperative chemical component relaxation using botuli-
num toxin A: Enabling laparoscopic repair of complex ven-
tral hernia. Surg Endosc. 2017;31:761–768.
125. Slater NJ, Montgomery A, Berrevoet F, et al. Criteria for
definition of a complex abdominal wall hernia. Hernia
2014;18:7–17.
126. Bueno-Lledó J, Torregrosa A, Ballester N, et al. Preoperative
progressive pneumoperitoneum and botulinum toxin type A in
patients with large incisional hernia. Hernia 2017;21:233–243.
127. Motz BM, Schlosser KA, Heniford BT. Chemical compo-
nents separation: Concepts, evidence, and outcomes. Plast
Reconstr Surg. 2018;142(Suppl):58S–63S.
170
Copyright © 2020 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Plastic and Reconstructive Surgery • July 2020
128. Layeeque R, Hochberg J, Siegel E, et al. Botulinum toxin infil-
tration for pain control after mastectomy and expander recon-
struction. Ann Surg. 2004;240:608–613; discussion 613–614.
129. Gabriel A, Champaneria MC, Maxwell GP. The efficacy of
botulinum toxin A in post-mastectomy breast reconstruc-
tion: A pilot study. Aesthet Surg J. 2015;35:402–409.
130. Lo KK, Aycock JK. A blinded randomized controlled trial
to evaluate the use of botulinum toxin for pain control in
breast reconstruction with tissue expanders. Ann Plast Surg.
2015;74:281–283.
131. Winocour S, Murad MH, Bidgoli-Moghaddam M, et al. A
systematic review of the use of botulinum toxin type A with
subpectoral breast implants. J Plast Reconstr Aesthet Surg.
2014;67:34–41.
132. Irkoren S, Ozkan HS, Ceylan E, Sivrioglu N, Tataroglu C,
Durum Y. The effect of Botox on the implant stabilization
and capsular formation: An experimental study. Ann Plast
Surg. 2015;75:91–97.
133. Lee SD, Yi MH, Kim DW, Lee Y, Choi Y, Oh SH. The effect of
botulinum neurotoxin type A on capsule formation around
silicone implants: The in vivo and in vitro study. Int Wound
J. 2016;13:65–71.
134. Kim S, Ahn M, Piao Y, et al. Effect of botulinum toxin type
A on TGF-β/Smad pathway signaling: Implications for
silicone-induced capsule formation. Plast Reconstr Surg.
2016;138:821e–829e.
135. Xiao Z. Effect of botulinum toxin type A on the capsule
around a subpectoral implant for breast augmentation.
Aesthetic Plast Surg. 2009;33:782–783.
136. Li T, Liu Y, Zhang W. Botulinum toxin A plays an important
role in the placement of implants deep within the pectora-
lis major muscle for mammaplasty: A systematic review and
meta-analysis. Aesthetic Plast Surg. 2018;42:1519–1530.