Complications With the Use of Botulinum Toxin

Type A for Cosmetic Applications and Hyperhidrosis

Miguel A. Pena, MD, Murad Alam, MD, and Simon S. Yoo, MD

In dermatology, botulinum toxin is now most often used to reduce dynamic facial creases
and treat primary focal hyperhidrosis. The exemplary safety record of this medication is
such that after nearly 2 decades, it is not known to have any long-term adverse events.
Transient adverse events, such as mild injection pain, are typically minor and spontane-
ously remitting. Headache, nausea and flu-like symptoms, lid and brow ptosis after upper
face injection, lower face asymmetry after perioral injection, and fine motor impairment
after palmar injection are uncommon to rare. Understanding of anatomic landmarks and
site-specific precautions can further mitigate the incidence of unwanted effects. Patients
who do experience uncommon, transient effects can be reassured that these are not
dangerous and will resolve completely without intervention.
Semin Cutan Med Surg 26:29-33 © 2007 Elsevier Inc. All rights reserved.

KEYWORDS Botulinum toxin A, Botox®, complication, rhytide, wrinkle, hyperhidrosis

B otulinum toxin A (BTX-A; Botox®, Botox Cosmetic®,

Allergan, Irvine, CA) injections have become a common
practice in a dermatologist’s office for cosmetic applications
and hyperhidrosis. The beneficial effects of BTX-A stem from
temporary chemical denervation of both striated muscle and
eccrine sweat glands. Patient and physician satisfaction with
treatment results can be surmised from the more than 3 mil-
lion cosmetic injections reported in 2005, a 16% increase
from the preceding year.1 With increasing popularity among
patients, and increasing numbers of physicians offering in-
jections, BTX-A should be periodically reviewed in regards to
its safety profile when used for esthetic reasons and hyperhi-
drosis.
Pharmacologic BTX-A has an excellent safety record that is
diametrically opposed to the devastating presentation of sys-
temic botulism secondary to food poisoning. In adult botu-
lism, afebrile patients initially develop bilateral cranial nerve
palsies causing diplopia, dysarthia, dysphagia, and dyspho-
nia, followed by a descending flaccid paralysis, which can
lead to respiratory failure and death.2 The estimated lethal
dose of BTX-A for humans falls in a range of 2500 to 3000 U.3
The severe symptoms of botulism were apparent on Novem-
ber 2004, when an unlicensed physician (operating a cos-
metic clinic in Florida) injected 3 individuals with massive
Section of Cutaneous and Aesthetic Surgery, Department of Dermatology,
Feinberg School of Medicine, Northwestern University, Chicago, IL.
Address reprint requests to Simon S. Yoo, MD, 676 N. St. Clair St., Suite
1600, Chicago, IL 60611. E-mail: simyoo@yahoo.com
doses of an unlicensed, unapproved research-grade botuli-
num toxin. The victims required mechanical ventilation for
several months. The 2004 cases serve as a common-sense
reminder to use only Food and Drug Administration-ap-
proved and licensed BTX-A medical products sold by Aller-
gan under the brand names Botox® and Botox Cosmetic®.
No cases of botulism and no deaths have been reported with
the use of Botox® for esthetic purposes.4
Injection-Site Reaction
The most common patient complaints for BTX-A are injec-
tion site pain and bruising.5 During clinical trials of BTX-A
for glabellar lines, the most frequently reported adverse
events were headache, respiratory tract infection, flu syn-
drome, blepharoptosis, and nausea. The incidence of head-
ache, respiratory tract infection, and flu syndrome were not
different from placebo.6
Mild bruising can occur with any type of injection. During
BTX-A treatment, ecchymosis occurs most frequently in the
periorbital region because of the highly vascular and fragile
tissue. A double-blind randomized, controlled study exam-
ining the treatment of patients with crow’s feet using BTX-A
reported bruising in 11% to 25% of patients, with similar
rates for the placebo arm.7 Ecchymosis can be reduced if the
patient can avoid products such as aspirin, nonsteroidal an-
tiinflammatory agents, and high-dose vitamin E for 10 days
before the procedure.8 Applying direct pressure and applying
a cold compress on the injection site also is helpful.

1085-5629/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. 29

doi:10.1016/j.sder.2006.12.004
Semin Cutan Med Surg 2007;26(1):29-33 THIS MATERIAL MAY BE
PROTECTED BY COPYRIGHT

2007030445
LAW (17 USC)
30
Injection site pain also can be reduced by applying a cold
compress over the injection site before and after treatment.
Pain can be minimized by using a small 30- to 34-gauge
needle, infusing the solution slowly, and avoiding subcuta-
neous injections.5 The thin periorbital sites are particularly
sensitive, and a superficial injection is sufficient for the toxin
to easily penetrate muscle. Visualizing small cutaneous ves-
sels and capillaries prior to injection by completely removing
make-up can reduce the likelihood of impinging upon peri-
orbital vessels. Application of topical lidocaine before injec-
tion can significantly reduce the amount of discomfort asso-
ciated with injections.9 The type of saline used to reconstitute
BTX-A also affects the level of pain. The package insert rec-
ommends that Botox® should be reconstituted only with
sterile, nonpreserved saline.6 However, reconstitution with
preserved saline solution does not impair the stability of bot-
ulinum toxin A and the benzyl alcohol preservative acts as an
anesthetic agent, resulting in less painful injections than
when reconstituted with nonpreserved saline.10 Additionally,
it has been shown that when BTX-A is reconstituted with
preserved saline, prolonged storage and reuse of previously
opened vials does not increase the risk of bacterial contami-
nation.11
The typical mild headaches occasionally reported after
BTX-A injection require no specific therapy, but a small sub-
set of patients may develop more severe, debilitating head-
aches that may be related to BTX-A injections or perhaps to
micro-trauma from needle inserted into the forehead. While
it was initially estimated that up to 1% of patients may expe-
rience severe headaches after receiving BTX-A,12 the current
incidence is believed to be much lower. Even severe head-
aches are invariably benign, and without exception, they
spontaneously remit completely within days to weeks.13 In
these cases, symptomatic treatment with an analgesic can be
initiated and patient reassurance would be appropriate.
Contraindications
Contraindications for BTX-A based on theoretical concerns
include preexisting neuromuscular disorders (eg, myasthe-
nia gravis, amyotrophic lateral sclerosis); local infection at
the expected injection site; known hypersensitivity to any
component of the formulation; pregnancy; and lactation.
BTX-A should be avoided in patients taking concomitant
aminoglycosides or other substances interfering with neuro-
muscular transmission (eg, curare-type nondepolarizing
blockers, quinidine, magnesium sulfate, succinylcholine).6
Caution should be exercised when considering a candidate
with unrealistic expectations, unrealistic fears of the toxin, or
an unstable psychological status.
Complications With the
Treatment of Glabellar Rhytides
The most significant complication that can occur with BTX-A
injection to the glabellar area is upper eyelid ptosis. Unin-
tended paralysis of neighboring muscles is not surprising,
M.A. Pena, M. Alam, and S.S. Yoo
Figure 1 Corrugator supercilii is grasped between thumb and index
finger and injecetion is placed directly into belly of muscle. (Color
version of figures is available online.)
because local diffusion of BTX-A has been demonstrated to
reach up to a 3-cm diameter from the injection point.3 The
Botox Cosmetic® package insert reports blepharoptosis oc-
curring in 3% of 405 subjects.6 One multicenter study noted
lid ptosis in 5.4% of 264 patients treated for glabellar rhy-
tides.14 Injections of the procerus muscle and the corrugator
supercilli muscles create the potential for BTX-A diffusion
through the orbital septum to the levator palpebrae superio-
ris muscle. The resulting lid ptosis can become apparent
within 2 to10 days, and can last approximately 2 to 4
weeks.15
A few simple steps can be taken to minimize the occur-
rence of lid ptosis during the treatment of glabellar lines.
Applying digital pressure during the injection may help to
reduce spread of the solution.16 The lateral borders of the
procerus muscle can be grasped at the upper nasal bridge
between the thumb and index finger of one hand. This pres-
sure reduces diffusion inferolaterally to the orbits. Simulta-
neously, the free hand can be used to inject. Similarly, a
corrugator muscle can be grasped between two fingers at the
border of the supaorbital ridge during injection (Fig. 1). Cor-
rugator injections should be placed at least 1 cm above the
level of the bony rim.14 The single injection site of the pro-
cerus can be massaged horizontally across the upper nasal
bridge toward the depressor supercilii, avoiding any massage
directed inferiorly.16
Besides accurate injection sites, using smaller injection
volumes will also reduce solution spread. A conservative ap-
proach is always prefered. Particular care must be given to the
elderly patient who tends to have loose skin and an attenu-
ated orbital septum. These two factors may allow easier dif-
fusion leading to ptosis.16
If upper lid ptosis occurs, alpha-adrenergic agonist eye
drops can be used to counteract this temporary problem.
Apraclonidine 0.5% (Iopidine, Alcon Laboratories Inc, Fort
Worth, TX) or phenyleprine 2.5% ophthalmic solution stim-
ulate Mueller’s muscle to elevate the upper eyelid by 1 to 2
mm.14 Symptomatic treatment is typically begun at 2 drops,
Complications with the use of Botulinum toxin type A
twice a day until ptosis is resolved. If necessary, the frequency
of dosage can be increased to three times per day.14
Complications
With the Treatment of
Horizontal Forehead Rhytides
Paralysis of the frontalis muscles with BTX-A reduces fine
horizontal forehead rhytides but may produce the complica-
tions of brow ptosis, upper eyelid ptosis, and a mask-like
appearance. To maximize the reduction of horizontal lines
with BTX-A, the brow position will usually be slightly and
unnoticeably lowered. Apparent brow ptosis occurs when
overaggressive treatment with BTX-A leaves the brow depres-
sors unopposed. The occurrence of brow ptosis varies from
one study to another, falling in a range of 1% to 5%.17 Brow
ptosis can be treated with BTX-A injections to the glabella
and brow depressors, including corrugator supercilli, pro-
cerus, depressor supercilli, and orbicularis oculi muscles.
BTX-A correction can potentially raise the brow by 1 to
2 mm.16
When treating forehead rhytides in one session, brow pto-
sis and upper eyelid ptosis can be avoided by keeping all
injections at least 2 cm above the brow. Injections should be
placed within the lateral boundaries created by the midpu-
pillary lines of both eyes to maintain facial expression and
prevent ptosis. Treatment of the glabella and the entire fore-
head in one sitting can be avoided. Complete paralysis of the
frontalis muscles will leave the patient with a lack of facial
animation and brow ptosis, despite treating the glabela and
brow depressors. However, an experienced physician may
treat the upper forehead lines (at least 4 cm above the brow),
as well as the frown lines in one session.16 In patients who
have preexisting brow ptosis, BTX-A injection of forehead
lines should be avoided.5
An additional complication that may occur during the
treatment of forhead rhytides is an unintended quizzical
brow lift. This complication can occur in a subset of patients
with lateral frontalis muscle hyperactivity. The lateral fibers
of the frontalis muscle are left with an excessive pull on the
lateral portion of the brow, creating an extreme upward arch
of the lateral eyebrows. The resulting “Jack Nicholson’s”
brow or “joker face” can be corrected by injecting BTX-A 1 to
2 units into the lateral frontalis fibers, above the outer third of
the eyebrow.5,17
Complications With the
Treatment of Crow’s Feet
Complications involved in the treatment of crow’s feet in-
clude ectropion, diplopia, and lip ptosis. Weakening the or-
bicularis oculli can reduce the appearance of crow’s feet, but
overtreatment with BTX-A can cause ectropion. Withholding
treatment or cautious BTX-A injection is recommended for
elderly patients, patients who have had previous lower eyelid
surgery, and patients with preexisting lower lid laxity.16 Be-
fore BTX-A treatment, one can perform a snap test by pulling
31
the lower lid gently down and away from the eye for 3 sec-
onds and assessing the speed of return to evaluate eyelid
tone. Diplopia resulting from a weakening of the lateral rec-
tus can occur if the injection is too close to the outer bony
orbit, and the injection is too deep. Lip and cheek ptosis can
occur if the zygomaticus major is paralyzed by injecting a
periorbital site that is below the inferior margin of the zygo-
matic arch.16
The complications of lip and cheek ptosis, diplopia and,
ectropion can be reduced by using small injection volumes of
0.1 to 0.2 mL per injection point.5 All injections should be
kept 1.5 cm lateral to the lateral canthus. All injections
should be above the level of the inferior margin of the zygo-
matic arch.
Combining the treatment of crow’s feet with inferior eyelid
injections can provide a cosmetically appealing opening of
the eyes. However, certain subsets of patients should be ex-
cluded from lower eyelid injections due to likely complica-
tions. Patients with lower-lid laxity noted with a snap test
should avoid lower eyelid treatment.18 Patients with previous
surgery under the eye may also be excluded. Patients with
preexisting fat herniations should be excluded to avoid
pseudoherniating infraorbital fat pads after injections.19
Complications
With the Treatment
of Lower Face Rhytides
BTX-A treatment of lower face rhytides can produce perioral
complications. Upper lip weakness has been associated with
treatment of the superomedial aspects of the nasolabial folds.
Injections of the levator labii superioris alaeque nasi at these
sites has produced an unacceptable occurrence of upper lip
ptosis and an inability to smile. As a result, most physicians
have chosen soft tissue fillers and laser resurfacing, rather
than BTX-A, to treat those sites.20
Injection of radial upper lip lines can also result in lip
weakness. Subclincal compromise of the obicularis oris may
be noted when a patient has difficulty with actions such as
drinking through a straw or whistling. Patients who require
complete mouth competence, such as wind instrument play-
ers, singers, and scuba divers, should avoid lip treatment. In
extreme cases of lip weakening, asymmetry of the mouth and
drooling can occur. These complications can be reduced by
spacing injections symmetrically with respect to the facial
midline and by utilizing superficial injections of low doses
(BTX-A 1 to 2 units per lip quadrant).16,20
Treating sad lines that include downturned corners of the
mouth involves microparesis of the depressor anguli oris,
allowing the zygomaticus to subtly elevate the oral commis-
ure. Injection of each depressor anguli oris may be safest
immediately above the angle of the mandible and 1 cm later-
ally from the oral commissure.20 Injections that are too me-
dial and involve the depressor labii can cause lower lip dys-
function. Treatment too close to the mouth can produce the
complications of a flaccid cheek, incompetent mouth, and
asymmetric smile.16
32
Perioral complications can also occur with treatment of a
mental crease or with treatment of multiple dimple rhytides
of the chin. Both rhytides can be reduced with injections of
the medial mentalis at the bony mentum. Injections that are
too lateral may affect the depressor labii muscles, inducing a
lower lip ptosis. Injection into the mental crease can produce
an incompetent mouth.20
Complications
With the Treatment
of Neck Lines and Neck Bands
The treatment of vertical platysmal bands and horizontal
neck lines involves higher doses of BTX-A (40 units and
higher) than those used on the face. In general, each
platysmal band is injected in spaced intervals starting at
the jawline and descending to the clavicular border. Re-
maining horizontal neck lines can be treated with 1 to 2
units administered along the lines.5 Potential complica-
tions include temporary dysphagia, neck weakness, and
rarely, hoarseness. These risks can be minimized by uti-
lizing the least amount of BTX-A necessary, with a recom-
mended maximum in most patients of 100 U for treatment
of the entire neck.16 Injections should be placed into the
deep dermis and not subcutaneously, due to increased risk
of affecting other cholinergic muscular structures.21 The
pharynx region and the sternocleidomastoid muscle
should be avoided.
Complications
With the Treatment
of Primary Focal Hyperhidrosis
Focal hyperhidrosis can be a distressing condition that can
dramatically impair daily activities, social interactions, and
employment activities.22 If palmar and axillary hyperhidrosis
fail to be managed by topical agents, BTX-A may provide
relief. Typically, each axilla requires 50 units and each palm
requires 100 units; however, the total dose and number of
injections is dependent on the surface area to be treated.23,24
Before beginning injections, the exact surface area of active
sweating is mapped by using starch-iodine testing. Using this
map, injections on both the palm and axilla can be placed 1.5
cm across the surface area being treated. The goal is to place
injections in a pattern so that diffusion provides overlapping
coverage for the entire surface.16 Injections should be kept to
the superficial dermis.
The most significant complication of treatment is a varying
degree of temporary hand weakness as the result of BTX-A
diffusion to lumbrical muscles and other unintended targets.
As many as two thirds of patients experience a temporary
minor weakening of finger grip strength that is noted a week
after treatment and may last for 3 to 5 weeks.25 Patients may
have difficulty with fine motor tasks, such as pushing a but-
ton through a tight button hole or using chop sticks to hold a
heavy object. Patients can usually write and type without
M.A. Pena, M. Alam, and S.S. Yoo
difficulty but may find that opening a tight jar is difficult for
a few weeks.16 Dentists, surgeons, musicians, and others in
professions that require precise hand control should be
alerted prior to injection to the possibility of transient func-
tional impediment. Superficial blebs of injectant placed high
in the dermis can reduce muscle effects. For patient comfort,
one hand should be treated per session, with a 2-week inter-
val. The frequency and severity of hand weakness complica-
tions can be reduced by following an accurate starch-iodine
map to utilize the least amount of BTX-A injections. Avoiding
subcutaneous injections is also essential. Injections for pal-
mar hyperhidrosis can be painful. Pain may be mitigated by
pre- or postoperative application of ice, concurrent use of a
vibratory device to the wrist, or nerve blocks to minimize
palmar sensory activation.
Conclusion
BTX-A has a favorable safety profile for cosmetic applications
and hyperhidrosis. The observed clinical complications are
temporary and tend to be dependent on the technique used.
With adequate physician training, the incidence of these
complications can be reduced. Proper training includes a
thorough anatomical knowledge of the target structures, op-
timal BTX-A dosing practices, and precise injection tech-
niques incorporating digital pressure.
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