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Managing Adverse Events Associated with Botulinum Toxin Type A: A Focus on

Cosmetic Procedures

Article  in  American Journal of Clinical Dermatology · February 2005

DOI: 10.2165/00128071-200506030-00001 · Source: PubMed

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Am J Clin Dermatol 2005; 6 (3): 1

LEADING ARTICLE 1175-0561/05/0003-0001/$34.95/0

 2005 Adis Data Information BV. All rights reserved.

Managing Adverse Events Associated with

Botulinum Toxin Type A
A Focus on Cosmetic Procedures
Uwe Wollina and Helga Konrad
Department of Dermatology, Hospital Dresden-Friedrichstadt, Academic Teaching Hospital, Dresden, Germany

Abstract Botulinum toxin A (BTXA) has become a widely used drug in cosmetic dermatology, not only to treat focal
hyperhidrosis but also hyperkinetic facial lines, platysma bands, décolleté bands, and other skin features. The
spectrum of possible adverse effects of BTXA is broad but fortunately those that have been observed with
cosmetic use of this product are generally mild and transient. The major tools for preventing adverse effects from
BTXA are knowledge and skill. Use of correct injection techniques are mandatory since most unwanted effects
are caused by incorrect technique. Knowledge of the target structures, e.g. the facial and extrafacial muscles,
allows physicians to select the optimal dose, time and technique. The most common adverse effects are pain and
hematoma. In the periocular region, lid and brow ptosis are important adverse effects. Adverse effects such as
pain, hematoma, ecchymosis, and bruising may also occur in the upper and lower face and at extrafacial sites.
Other possible adverse effects seen in other indications that the user of BTXA in cosmetic dermatology should be
wary of include induction headaches and possible interaction with concomitant medications. Induction of
neutralizing antibodies due to cosmetic BTXA treatment has not been observed. The article also outlines
PAGE PROOF 2

recommendations regarding use of BTXA. Of these, the most important for avoiding most unwanted adverse
effects are the proper technique of dilution, storage, and injection, as well as the careful exclusion of patients
with any contraindications. Pain, hematoma, ecchymosis, and bruising can be prevented by cooling the skin
before and after BTXA injection. Upper lid ptosis may be partly corrected using apraclonidine or phenylephrine
eyedrops. If simple rules relating to the indications for and application of BTXA are followed, this is a safe and
effective drug in cosmetic dermatology.

Botulinum toxin (BTX) is produced by Clostridium botulinum.
This was discovered in 1905 by Tchitchikine, who described the
substance as a neurotoxin.[1] BTX was purified by Sommer in
California in 1920, and 36 years later Lamanna succeeded in
further purifying BTX into crystalline form.[2] In 1949, it was
demonstrated that BTX inhibits the release of acetylcholine from
nerve endings.[3]
BTX consists of two different chains, a heavy chain that is
responsible for binding to the nerve ending and a light, toxifying
chain. Following endocytosis, the molecule is cleaved by disrup-
tion of a disulfide bond. Seven different types of BTX are known,
but only BTXA and very recently BTXB have been approved as
drugs for human use. The target for BTXA is a 25kDa
synaptosome-associated protein. The binding is rapid and stable.
BTXA, a zinc-dependent endopeptidase, cleaves the 25kDa vesi-
cle transport protein. In this way, it impedes proper binding of
acetylcholine vesicles to, and fusion with, the cell membrane.
Neurotransmitter release to the muscle endplate is inhibited and
muscle contraction prevented. The deadly dose for humans has
been estimated to be 3000U of Botox 1.[3,4]
1. Botulinum Toxin A Brands
There are two different BTXA products on the international
market – Botox (Allergan) and Dysport (Speywood/Ipsen). The
two formulations have different biological potencies.[4] However,
the exact relative potencies of the two products are still a matter of

1 The use of trade names is for product identification purposes only and does not imply endorsement.
 2 Wollina & Konrad
debate. While the potency of both BTXA products is expressed in
LD50 mouse units (the amount of toxin required to kill 50% of test
mice), the assays used for each are different. However, one vial of
Botox contains 100U, whereas one vial of Dysport contains
500U, suggesting a conversion factor of 1:5 (Botox vs
Dysport). Indeed, a single-blind, randomized, parallel study con-
ducted in patients with blepharospasm or hemifacial spasm sup-
ported this conversion factor.[5] Other double-blind studies in
cervical dystonia patients suggested a conversion factor of 1:3 to
1:4 (Botox vs Dysport).[6,7] Unfortunately, no comparative
study in BTXA for hyperkinetic wrinkles or hyperhidrosis has
been published as yet. Nor has it been proven that the above-
mentioned conversion factor for Botox vs Dysport is stable for
all indications.
Because of the different potencies of the two available BTXA
preparations, there is a risk of over- or under-treatment when
different brands of BTXA are used in the same office. To mini-
mize this risk, the reconstitution of lyophilized BTXA and the
preparation of syringes for the individual patient should be carried
out by the physician who administers the injections.
2. Use in Cosmetic Dermatology
Use of BTXA in cosmetic medicine has arisen from observa-
PAGE PROOF 2
tions that treatment of blepharospasm by BTXA also improved
periocular lines.[8] Standard procedures for BTXA injection to
improve mimic lines and wrinkles target frown lines, glabellar
(horizontal) lines, and crow’s feet.
Evaluation of BTXA in double-blind, placebo-controlled stud-
ies of patients with glabellar folds[9,10] and crow’s feet[11,12] has
resulted in recognition of this agent as an evidence-based cosmetic
medicine for these indications. For other lines and wrinkles, the
evidence for use of BTXA is based on uncontrolled studies.[8,13]
More advanced techniques involve use of BTXA for perioral lines,
sad lines, marionette lines, nasal (bunny) lines and the poppy
chin.[8] BTXA has also been used for brow lift, eye opening
(injection into the lower lid), gingival smile, platysmal bands, neck
bands, sleeping lines and décolleté lines.[8]
Knowledge of the pharmacology and toxicology of BTXA, and
of the anatomy and physiology of treatment targets (i.e. the facial
and extrafacial muscles), are the keys to successful use of BTXA.
Development of expertise in the use of the appropriate injection
techniques, dosages, and dilutions requires training. To avoid
common mistakes, we recommend that practitioners who wish to
administer BTXA attend at least a course and workshop given by
an experienced user of BTXA. We advise that beginners in this
field should not start with advanced techniques; rather, gradual
progression from easier to more sophisticated applications is rec-
 2005 Adis Data Information BV. All rights reserved.
ommended. When basic guidelines are adhered to, use of BTXA
for cosmetic reasons and hyperhidrosis is safe, predictable, has no
serious complications, and delivers general patient satisfac-
tion.[13,14]
3. Dosage and Administration
BTXA should not be administered as large volumes of low-
dose toxin. Dilutions should be as recommended in the product
information. Higher dilutions are associated with a risk of instabil-
ity since the protein concentrations are in the range of nanograms.
Furthermore, duration of response might be shortened with higher
dilutions because of increased diffusion of BTXA and a lower
effective concentration at the target site.[15] The use of concentra-
tions according to the product information in small volumes (i.e.
0.1–0.2ml per injection site) will ensure that the toxin does not
diffuse to unwanted sites.[15]
In general, patients who have undergone previous facial sur-
gery or show facial asymmetries require a dose adaption and
probably modifications of the injection sites. The injection sites in
general are placed in a symmetrical pattern, but any asymmetry of
the facial musculature requires either a dose reduction on one site
or an asymmetric placement of the injection sites.[8,13,15]
Botox must be used within 4 hours of reconstitution, and
Dysport within 8 hours, when kept at a temperature of between
2°C and 8°C.[16]
4. Contraindications and Precautions
Patient selection is a crucial step toward prevention of patient
dissatisfaction. Every patient needs an extensive informative con-
sultation that covers not only the BTXA option but also all
alternative methods and procedures. Patients should be made
aware that facial asymmetry is common, and that use of BTXA
cannot guarantee facial symmetry; however, asymmetry caused by
hyperactive muscles can be smoothened.[17] BTXA should not be
used for facial rejuvenation in patients that have a pre-existent lid
ptosis or those who have undergone surgical procedures that may
have repositioned or weakened the muscles.[18]
Poor candidates for BTXA include patients with unrealistic
expectations and psychiatric disease, in whom BXTA should be
used with caution. There is also a small group of patients who fear
the possibility of sustaining systemic botulism after BTXA injec-
tion and it should also be used with caution in these patients. In
addition, patients who are normally rather demonstrative, such as
politicians and actors, may fear that BTXA might leave them with
a mask-like, non-emotive face.[15,19] In such cases, fillers might be
a better alternative.
Am J Clin Dermatol 2005; 6 (3)
 Managing Adverse Events of Botulinum Toxin Type A
Contraindications to use of BTXA include pregnancy or lacta-
tion.[8,15] Patients with neuromuscular diseases such as Lambert-
Eaton syndrome, amyotrophic lateral sclerosis or myasthenia
gravis are also not suitable for BTXA therapy since even low
doses of the toxin may cause a neuromuscular crisis.[14]
BTXA should not be used in patients taking concomitant ami-
noglycoside antibacterials, such as streptomycin, dihydrostrepto-
mycin, gentamicin, neomycin, netilmicin, kanamycin or spectino-
mycin.((Author: why not?)) ((Author: Please provide a refer-
ence)) When administered for cosmetic reasons or hyperhidrosis
therapy, BTXA should also be avoided in patients taking one of
the following medications: polymyxins, tetracyclines, lincomycin,
penicillamine, quinine, cyclosporin, chloroquine and hydrox-
ychloroquine, gallamine, pancuronium, tubocurarine, calcium
channel antagonists, and local anesthetics((Author: why should
BTXA be avoided in patients taking these agents?)).[4,14,19]
Since conditions like diabetes, alcoholism, polymyositis and
other immunocompromising conditions are risk factors for severe
infectious disease, BTXA injections for either cosmetic reasons or
hyperhidrosis should generally be avoided in patients with these
conditions.
5. Adverse Effects
The most common adverse effects of BTXA in cosmetic indica-
PAGE PROOF 2
tions are listed in table I.
5.1 Allergies
Patients with known hypersensitivity to any of the components
of commercially available BTXA, such as human albumin, lac-
tose, saline and BTXA itself, are not suitable candidates for BTXA
treatment. However, in two large studies involving more than 300
patients, most of whom received multiple treatments of BTXA,
only four experienced generalized pruritus (n = 3) or an unspeci-
fied rash (n = 1).[20] As yet, there have been no published reports of
BTXA allergy.
A single case of fixed drug eruption has been observed follow-
ing BTXA injection.[21] However, the cause of the eruption was
lactose, not the toxin or the non-toxic proteins. Lactose is a rare
cause of fixed drug eruptions.[22]
Table I. The most common adverse effects of botulinum toxin A (BTXA) in
cosmetic indications
Symptom Management
Pain Usually needs no treatment
Bruising Pressure and cooling
Lid ptosis Apraclonidine or phenylephrine eyedrops
Brow ptosis BTXA for a brow lift
 2005 Adis Data Information BV. All rights reserved.
3
A so-called localized anaphylactic reaction was described fol-
lowing BTXA injection into leg muscles, although the allergic
nature of the reaction was not proved.[23] To date, no anaphylaxis
or deaths attributable to BTXA have been reported.[3]
5.2 Cardiovascular System
BTXA is a powerful presynaptic neuromuscular blocking agent
which interferes with cholinergic parasympathetic terminals. In
order to evaluate whether BTXA has an influence on the cardio-
vascular system, the short-term cardiovascular effects of BTXA
were evaluated in 26 patients with torticollis.[24] The dosage was
BTX (Dysport) 12ng (almost 500U) administered intramuscular-
ly. No significant influence on respiratory heart variation was
observed after one injection. After a second injection, a significant
attenuation of selected parameters was seen, and this response was
noted with each subsequent injection over several months. Howev-
er, no clinically manifest remote adverse effects or cardiac hy-
pokinetic arrhythmias were seen over this period.[24]
Nevertheless, fatal heart block has been described following
treatment with BTXA for achalasia.[25] A 91-year-old man with
pre-existent heart disease, first degree atrioventricular block, right
bundle branch block, and incomplete left bundle branch block was
treated for achalasia with Botox 80U. He died 3 weeks later as a
consequence of complete atrioventricular block and sepsis. It is
rare for people of this age and with cardiovascular problems of this
kind to ask for BTXA to treat cosmetic conditions. However, it is
important to be aware of the possibility that BTXA may worsen a
pre-existent bradycardia. In an animal model it was investigated
whether BTXA injected into the sinoatrial fat pad inhibits de-
creases in heart rate induced by stimulation of the preganglionic
parasympathetic nerves in the heart of the anesthetized dog.[26]
Stimulation of the parasympathetic nerves in the sinoatrial fat pad
(SAP stimulation) prolonged the atrial interval but not the atrio-
ventricular interval, and cervical vagus nerve stimulation pro-
longed both atrial and atrioventricular intervals. After BTXA (20
or 25 Botox U) was injected into the sinoatrial fat pad, it
gradually inhibited the prolongation of the atrial interval evoked
by SAP and cervical vagus nerve stimulations but not the prolon-
gation of the atrioventricular interval evoked by cervical vagus
nerve stimulation. Conditioning successive stimulation of the cer-
vical vagus nerves accelerated the inhibition by BTXA of the
chronotropic response to cervical vagus nerve stimulation. These
results indicate that selective injection of botulinum toxin into the
sinoatrial fat pad blocks bradycardia mediated by parasympathetic
ganglionic activation in the dog heart.[26]
Importantly, the dosages of BTXA used in cosmetic procedures
are in general much lower than those used in the treatment of
Am J Clin Dermatol 2005; 6 (3)
 4 Wollina & Konrad
achalasia, dystonia or spasticity. Furthermore, there has been no
report of cardiovascular adverse effects following BTXA treat-
ment for cosmetic reasons.
5.3 Generalized Reactions
As shown by electromyographic investigations conducted at
sites distant from the BTXA injection site, small amounts of the
toxin may diffuse into the circulation.[8] Generalized reactions
have been observed in rare cases following intramuscular BTXA
injection for spastic disorders and cosmetic reasons.[15] These
reactions include nausea, fatigue, malaise, flu-like reactions, and
rashes at distant sites. Symptomatic treatment only is required for
these adverse effects.
5.4 Headaches
While headaches can be induced by injection of BTXA, espe-
cially in the forehead, it is more common for patients to report that
chronic tension headaches have improved after injection of
BTXA.[8,10,27] Furthermore, pericranial injection of BTXA has
been found to be a safe and well-tolerated treatment that reduces
migraine frequency, severity, acute medication use, and associated
vomiting.[28]
In a study of 264 patients treated with BTXA (Botox) for
PAGE PROOF 2
glabellar lines, 15.3% reported headaches. Of these, over 90%
were rated as mild and two-thirds disappeared within a few
hours.[10] In a prospective randomized trial of Botox combined
with collagen for glabellar furrows, no difference in headache rate
was observed between Botox/collagen and placebo recipients.[29]
No specific therapy is generally required in patients who report
headaches following Botox injection. Local application of cold
compresses is beneficial in most cases.[8,15]
Recently, severe headache after BTXA application for cosmetic
reasons or palmar hyperhidrosis was reported in five patients.[30]
The headaches lasted for 1–4 weeks. No infection or any other sign
of adverse reaction to BTXA was documented. The reason for
these headaches is not known and risk factors have not been
defined. Painkillers are necessary in these rare cases.
5.5 Hematoma, Ecchymosis and Bruising
Intramuscular injections may cause hematomas. Ecchymosis of
mucous membranes is another possible adverse effect of BTXA
injection. However, the available evidence suggests that hemato-
ma and ecchymosis at injection sites occur in less than 1% of
BTXA injections.[31,32] Nevertheless, patients with bleeding disor-
ders or medications that affect hemostasis and thrombostasis
should not be treated with intramuscular (BTXA) injection-
 2005 Adis Data Information BV. All rights reserved.
s.((Author: should this sentence be included in the Contraindi-
cations and Precautions section?))
Even with proper technique, ecchymosis occurs easily in the
soft eyelid tissue and the periorbital tissue of patients receiving
BTXA injections in these areas. In a placebo-controlled trial of
BTXA for crow’s feet, bruising was seen in 11–25% of patients,
with similar rates being seen in the placebo group.[11] This adverse
effect can be minimized by immediately applying pressure at the
injection site after every injection, alone or in combination with a
cold compress.
Patients should discontinue nonsteroidal anti-inflammatory
agents such as aspirin, but also tocopherol (vitamin E) or gingko
biloba, 10 days before BTXA injections.[19,32] Furthermore, be-
cause smokers tend to have more bruising after BTXA injection, it
has been recommended that smoking should be stopped at least 7
days before injection.[32]
5.6 Infection
Every kind of septic and antiseptic care is necessary and
recommended when handling and storing BTXA. Injection sites
must be disinfected, and BTXA injection should not be given in
any area of active infection.[10]((Author: should this sentence be
included in the Contraindications and Precautions section?))
To date, infections have not been reported in patients seeking
cosmetic treatment with BTXA.[30]
5.7 Interactions with Concomitant Medications
BXTA should not be used in patients taking the medications
listed in section 4. In addition, Fiacchino et al. (1997) reported that
BTXA interferes with other neuromuscular blockers like vecuroni-
um and may cause tolerance to the effects of vecuronium.[33]
5.8 Muscles
In general, the main adverse effects of BTXA in cosmetic
dermatology and the treatment of hyperhidrosis are a loss of facial
expression, incomplete muscle paralysis with residual rhytides,
and unwanted muscle paralysis resulting from spread of toxin to
adjacent sites.[34] Asymmetry can result from either using exces-
sively high (loss of facial expression) or excessively low (incom-
plete muscle paralysis with residual rhytides) doses of injected
BXTA.[35] Unwanted paralysis can be due to incorrect injection
site or high-volume low-concentration injections. Patients with
previous facial surgery or palsy need special attention (see section
3).
Muscular weakness at the site of BTXA injection is a desirable
effect when treating lines and wrinkles. Correct injection tech-
nique will ensure that this weakness is limited to those muscles
Am J Clin Dermatol 2005; 6 (3)
 Managing Adverse Events of Botulinum Toxin Type A
where the effect is needed. Local spread of BTXA occurs by
diffusion up to 3cm in diameter from the injection point.[4]
There is one published report of a 70-year-old woman who
developed esotropia, hypertropia, ptosis of the upper lid, and
double vision after BTXA injections around the eyelids.[36] The
adverse effects described mimicked myasthenia gravis. Muscular
adverse effects in indications other than cosmetic use have also
been reported. Recently, two patients with paraplegia or te-
traplegia who were treated with BTXA for neurogenic detrusor
overactivity were reported to have developed muscular weakness
at distant sites lasting for approximately 3 months.[37] One patient
received Dysport (total dosage 1500U), the other Botox (total
dosage 300U). The authors suggested that these two patients did
not develop the expected tight binding of BTXA locally, which
would normally prevent passage of BTXA into the circulatory
system.[37] Another study of patients with cervical dystonia sug-
gested that Dysport was associated with more swallowing
problems than Botox.[38] These types of adverse effects have not
been observed in cases of cosmetic use of BTXA. However, we
recommend that participation in any activity that increases local
blood flow, such as massage, sauna, steam bath or sun bath, should
be avoided within a few hours of BTXA injection.[8,15,19]
5.8.1 Upper Face
PAGE PROOF 2
Transient eyelid ptosis is the most significant complication of
BTXA injection in the glabellar area and occurs in about 2% of
injections.[39] Lid ptosis was seen in 5.4% of 264 patients treated
for glabellar lines in one study.[10] The upper eyelid levator muscle
can be affected as BTXA migrates through the orbital septum,
leading to ptosis within 2 to 10 days of injection.[14] When frown
lines are being treated with BTXA, a distance of at least 1cm
above the bony supraorbital margin at the lateral injection site
should be left to avoid brow or lid ptosis.[40] Lid ptosis can also
occur if injection of the nasal bridge is too lateral.
The lateral brow lift is performed by injection in the outer third
of the brow about 0.5cm above the upper orbital margin. Brow lift
by injection at the level of the lateral canthus can produce lid ptosis
if it is not directed above the orbital rim.[41,42] The medial brow lift
is performed by injecting below the medial part of the brow. The
dosage of BTXA used should be as little as Botox 2–6U or
Dysport ≤6U for medial brow lift and about Botox 3.5U or
Dysport 5–10U for lateral brow lift.[43] At a recent German
consensus conference on BTXA, a single injection point was
recommended for brow lift procedures.[43] However, previously,
Ahn et al. (1999) had suggested injection of a total of 7–10U of
Botox at three injection points into the superolateral part of the
orbicularis oculi below the lateral third of the brow.[44] Again,
injection should be superior and lateral to the orbital rim to
 2005 Adis Data Information BV. All rights reserved.
5
minimize the risk of diffusion of toxin through the orbital septum.
Based on published data from open studies, the risk of lid ptosis
seems to be higher for Dysport (6.6%) than for Botox
(1.4%).[45,46] Several investigators have noted that caution is war-
ranted when treating older patients who may have reduced or
absent orbital septum as this causes the risk of a wider spreading of
BTXA and thereby an increased risk of lid ptosis.[14,18,47]
In patients with lid ptosis, apraclonidine 0.5% (Iopidine) or
phenylephrine hydrochloride 2.5% (Neosynephrine) stimulate
Mueller’s muscle and thereby elevate the upper eyelid;
apraclonidine has the advantage of not affecting the pupil.[14]
Over-treatment of horizontal lines with BTXA can cause a
mask-like appearance and brow ptosis. Indeed, transient brow
ptosis, particularly involving the lateral brow, has been reported in
up to 5% of patients treated with BTXA for horizontal lines.[48,49]
Brow ptosis can also be aggravated by injection of the forehead, as
documented in 22 of 25 patients in a study by Bulstrode and
Grobbelaar (2002).[50] Patients with pre-existent brow ptosis
should not be treated with BTXA because of the possibility of
developing a hooded appearance.[15] Injections for horizontal lines
should be made at least 2.5cm distant from the upper brow line.[14]
The injections should also be within the midpupillary lines of both
eyes. If the lateral part of the venter frontalis is well developed, a
quizzical brow lift known as ‘Spock’s’ or ‘Jack Nicholson’s’
brows might occur. Some patients like this type of brow lift but not
everybody is happy with it.[41] In the latter case, correction can be
performed by injecting Botox 1–2U or Dysport 5U into the
more lateral frontal fibers, i.e., above the outer third of the eye-
brow.[19,43]
Appearance or aggravation of nasal lines after glabellar BTXA
injection can become obvious when the patient smiles. This is
known as the ‘botulinum toxin sign’ and can be corrected by the
application of Botox 2U or Dysport 10U into the lateral face of
the nose, i.e. the levator nasi muscle.[31,32]
We do not recommend that beginners in the field treat horizon-
tal and frowning lines at the same time. In the authors’ opinion,
this would tend to result in use of a higher volume and dosage of
BTXA than would be used in sequential therapy. Use of higher
volumes of BTXA is more likely to result in brow or lid ptosis.[15]
For the experienced user, the risk benefit ratio is balanced. There-
fore, some authors recommend that experienced physicians use a
combined approach of glabella and forehead injection to maximize
effects.[43]
5.8.2 Mid-Face
Lateral brow ptosis was reported to occur in about 5% of
patients who were injected for crow’s feet with BTXA.[51] The
cause is denervation of the lateral frontalis muscle, which can be
Am J Clin Dermatol 2005; 6 (3)
 6 Wollina & Konrad
avoided by injecting below the eyebrow. It is also important to
respect the horizontal line between the cheeks (os zygomaticus)
when treating crow’s feet; not staying above this line can result in
lip or cheek ptosis.[15] In addition, paralysis of the zygomaticus
muscles can cause a Bell palsy appearance.[41]
To ensure the treatment of crow’s lines is safe, the volumes
injected should be small (0.1–0.2mL per injection point). The
needle should be placed at least 1–2cm lateral to the lateral bony
margin of the orbita to avoid lid ptosis, diplopia and strabis-
mus.[15,41] Lateral rectus palsy is a potential complication of BTXA
for crow’s feet when the injection is too medial and deep.[51]
Zygomatic lines that accompany periorbital wrinkles may persist
or worsen when only the crow’s feet are treated.[15,41] To improve
appearance, tissue augmentation using fillers or skin resurfacing
techniques can be utilized.[18] Injection of crow’s feet with a lateral
canthus injection has been used to lessen rhytides and widen the
eyes.[52] Some authors have found that intradermal injections are
helpful for decreasing spread of BTXA, especially in the peri-
orbital region.[52]
Caution is necessary when treating patients who have had
previous eye surgery, particularly lower eyelid blepharoplasty. In
these patients, the balance between the tarsoligamentous complex
and pretarsal orbicularis of the lower lid can be tipped in favor of
the tarsoligamentous complex. The muscular pumping action of
PAGE PROOF 2
the lower lid is weakened, resulting in transient localized
lymphedema and festooning that disappears within 3–4 weeks.[53]
BTXA injections into the lower eyelid to improve the puffy
appearance caused by horizontal bands due to the pretarsal inferior
orbicularis muscle should be given only in patients with normal
skin elasticity.[43,54]((Author: why?)) This can be demonstrated
using a simple snap test. The dosage of BTXA should be as low as
≤2U Botox or 2–6U Dysport.[43,54] There is a synergistic effect
when treatment of the lower lid is combined with injection for
crow’s feet (optimal dosage Botox 12U for crow’s feet plus
Botox ≤4U for the lower eyelid).[54]
Lower eyelid injections in the midpupillary line about 3mm
distant to the lid margin are used to open the eyes. The results of
the snap test can be used to identify patients with impaired skin
elasticity, who should not receive the injection. Patients who have
had previous surgery of the eyelids should also be excluded.
Dosages used may be as low as Botox 1U or Dysport 2U.[43]
Because patients with fat herniation will develop a prominence
of pseudoherniating infraorbital fat pads following BTXA injec-
tions of the lower eyelid, infraorbital injections are best avoided in
these patients.[52]
Some authors do not recommend BTXA for the lower eyelid at
all because of the risk of subsequent ectropium, entropium, and
 2005 Adis Data Information BV. All rights reserved.
pupillary changes like Adie’s pupil.[48] The latter is thought to be
due to ciliary ganglion damage.[48]
Injections too distant from the recommended injection sites for
bunny lines or lower eyelids can compromise the levator labii
superioris and zygomaticus major muscles. This may lead to lip
ptosis. In a study involving 485 patients treated with BTXA for
cosmetic reasons, lip ptosis was seen in two patients injected in the
upper lip for attenuation of the nasolabial sulcus.[54] In the authors’
opinion, treatment of a mental crease is more successful using a
filler than BTXA.
5.8.3 Lower Face
Treatment of the vermilion line to improve vertical rhytides is
achieved by injecting low-dose BTXA (Botox 1U or Dysport
2U) about 1mm above the upper lip. However, even with proper
injection technique, this can impair the function of orbicularis oris,
which is undesirable in actors and musicians.[43,49] Fillers may be
more appropriate in such patients.
Sad lines (with ptosis of the oral margins) can be improved by
injection into depressor anguli oris about 1cm laterally and caudal
from the lip margin.[18,43] Injections too close to the mouth should
be avoided because of the danger of producing a flaccid cheek, an
incompetent mouth, or an asymmetric smile.[55]
The poppy chin can easily be treated with a single or double
injection into the mentalis muscle. The usual dosage should not
exceed Botox 5U or Dysport 10–15U.[18,43] Application closer
to the mouth may induce a lower lip ptosis. Injections into the
mental fold may induce an incompetent mouth.[55]
Asian women tend to prefer almond-shaped faces. However,
masseter hypertrophy, which is recognized as an asymptomatic
enlargement of one or both masseter muscles, may lead to a square
jaw contour. Masseter hypertrophy can be treated with BTXA
injections. To contour the lower face, injections are given 1cm
below and above a reference line drawn from the tragus of the ear
to the corner of mouth. The usual dosage is 25–30U of
Botox.[56,57] A common adverse effect is reduction of mastication
strength, which is seen in up to 44% of patients treated.[57]
5.8.4 Extrafacial Sites
Platysma bands can be improved by BTXA.[8] Serial injections
for platysma bands should be given directly into the anterior part
of the muscle belly in a superficial way and not directed to the
throat (median part of the neck). Three to five injections should be
spaced at 1–2cm intervals from the jawline to the lower neck. The
sternocleidomastoid muscle and the pharynx region should be
spared. The dosage should be limited to ≤40U Botox because
even 60U of Botox can affect swallowing.[40]
Horizontal neck lines can be softened with injections of Botox
1–2U administered along the lines.[40] If injections are given too
Am J Clin Dermatol 2005; 6 (3)
 Managing Adverse Events of Botulinum Toxin Type A 7

deeply and the dosages are too high (>40U Botox), dysphagia cannot overcome secondary therapy failure due to the presence of
and neck muscle weakness may develop.[14] A floppy neck may neutralizing antibodies.[65] The incidence of secondary resistance
develop when fibers of the sternocleidomastoid muscle are affect- to the effect of the toxin has been dramatically diminished by the
ed by BTXA.[19] Therefore, it is recommended that, in general, the reduction of non-toxic proteins in current batches of Botox.[66]
dosage should not exceed Botox 100U.[55] To date, induction of neutralizing antibodies has not been
Decolleté wrinkles can be improved by injection of BTXA observed with use of BTXA for cosmetic purposes.
either in a V-shape along the upper, medium, and lower decolleté
or in a half-moon shape in the upper part alone, depending on the 5.11 Ophthalmologic Adverse Effects
topography of the muscles and wrinkles.[43] A dosage of about
Botox 5U or Dysport 10U should be used at each injection site. Diplopia has been reported in 3% of patients treated for facial
muscle spasm with BTXA.[67] It was suggested that the extraocular
5.9 Neurologic Adverse Effects muscles of some patients may be more susceptible to BTXA than
others, or that BTXA may diffuse more easily in some patients.
In animal studies, BTXA injection into the sympathetic ganglia
To maintain the safety of treating crow’s lines, only small
of rabbits resulted in a sympathetic ganglion effect for more than 1
volumes (0.1–0.2mL per injection point) of BTXA should be
month without causing considerable pathologic changes.[58] Injec-
injected and dosages should not exceed 4U of Botox or 10U of
tion of BTXA in the sciatic nerves of rats also did not cause
Dysport. The needle should be placed at least 1–2cm lateral to
inflammation or damage.[59]
the lateral bony margin of the orbita to avoid lid ptosis, diplopia
In theory, three types of nerve injury can take place when
and strabismus.[43,68]
injecting BTXA into the glabellar area: neuropraxia, axontomesis,
Because injections of BTXA for blepharospasm can also in-
and neurontomesis. For example, when a 40-year-old man with
duce lid ptosis,[15,69] Scott[69] investigated whether injection of
cervical dystonia was treated with BTXA, he developed an acute
human botulinum immune globulin could prevent this adverse
inflammatory demyelinating polyradiculoneuritis.[60] While no
effect. He found that 3.2 × 10–3 IU of human botulinum immune
causal relationship between BTXA and this adverse event could be
globulin per 1U of Botox was effective in blocking the toxin
firmly established, patients with such an adverse effect should not
PAGE PROOF 2

effect when injected into the same tissue site within 4 hours. The
be treated with BTXA again. In another case report, Cobb et al.[61]
limited temporary lid ptosis seen with use of BTXA for cosmetic
reported the first instance of botulism-like syndrome with respira-
indications may be improved with apraclonidine 0.5% (Iopidine)
tory arrest after intramuscular injection of BTXA for muscular
or phenylephrine 2.5% (Neosynephrine) eyedrops. These act on
spasm. The probable explanation was incomplete receptor binding
the Mueller muscle of the upper lid and can lift the lid up to
or arrested pinocytosis of BTXA-receptor complexes. However,
1.0mm.[14]
hard data have not been published to explain this phenomenon.
Injections around the eye should always be performed laterally
Importantly, no nerve injuries have been observed with cosmetic
with the needle pointing away from the eyeball. There have been
use of BTXA. Furthermore, BTXA does not cross the blood-brain
reports of blindness after centripetal injection of fat and collagen
barrier and therefore has no CNS effects.[62,63]
in this area.[70,71] Theoretically, needle penetration of the orbit can
There has been a single case report of a 44-year old non-smoker
occur, leading to retrobulbar hemorrhage.[48]
who, after treatment for glabellar frown and crow’s feet with
Injections of BTXA into the medial part of the lower eyelid
Botox 49U, repeatedly reported a metallic taste after injections;
decrease the mean blink-out rate (a measure of the frequency of lid
these disappeared within 2 weeks.[64] Other reports of dysgeusia
movement).((Author: please provide a reference)) This can
due to BTXA have also been published after injection into the
cause a problem in patients exposed to dust or other airborne
masseter muscle.[56] The pathogenesis of such adverse reactions
material that may necessitate rapid lid closure. On the other hand,
remains unclear.
this effect may be beneficial in patients with dry eye conditions,
5.10 Neutralizing Antibodies
since every movement may cause burning or even pain.[72,73]
However, reduced blinking can also lead to corneal exposure and
It is well known from BTXA treatment of patients with muscle corneal ulcers.[48]
spasm that neutralizing antibodies may develop during a course of According to a recent report, incorrect injection of BTXA into
repeated injections.[3] The frequency of neutralizing antibodies in the pretarsal portion of the orbicularis oculi muscle in an attempt
patients with cervical dystonia treated with BTXA has been esti- to correct lateral canthal rhytides resulted in abnormal lacrimation,
mated to be as high as 6.5%.[3] Increasing the dose of BTXA as shown by Schirmer‘s test.[73] The condition was treated with

 2005 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2005; 6 (3)
 8 Wollina & Konrad
ocular lubrication. However, use of the correct injection technique
should have prevented this adverse effect.
When treating horizontal lines, it is important to avoid causing
brow ptosis and asymmetry. These adverse effects were seen in 22
of 25 and 2 of 25 patients, respectively, in a study by Bulstrode and
Grobbelaar.[74] We recommend maintaining a distance of at least
2.5cm between the upper line of the brow and any injection point.
Bilateral ptosis has been reported after injections of BTXA into
neck muscles.[55]
5.12 Pain
Adverse effects that can occur at any injection site (not only
with BTXA) include pain, burning sensations, edema, redness, and
short-time hypoesthesia.[15] Pain during BTXA injection is varia-
ble and depends on individual sensitivity.[31] However, the smaller
the needles used, the better the tolerance. We recommend use of
30–34 gauge needles. The injection should be delivered slowly
while pinching the skin to reduce injection-related pain.[14]
In some countries, isotonic sodium chloride can contain pre-
servatives. It has been shown that preservatives in the solution
used for reconstitution of BTXA can significantly decrease patient
discomfort on injection.[75] However, in their package leaflets,
both Speywood/Ipsen and Allergan recommend against use of
preservative-containing isotonic sodium chloride solutions for
PAGE PROOF 2
reconstituting BTXA.
Topical application of anesthetic EMLA cream may help
decrease injection pain.[76] Application of ice or a frozen gel-filled
mask 5 minutes before BTXA injection also decreases pain in
about 45% of recipients.[77] In special cases, local analgesia is
helpful.[15]
5.13 Psychiatric Disorders
Botulinophilia is a dysmorphic disorder, in which patients seem
to be obsessed about getting BTXA treatment for complaints that
are either non-existent or still in remission, so they objectively do
not need a (repeat of) treatment. Botulinophilia is not caused by
BTXA but rather should be considered a contraindication for the
use of BTXA.[78] Acute anxiety and depression have been ob-
served in a spastic patient after intramuscular injection of BTXA,
but it is doubtful whether these mood disturbances were caused by
BTXA.[79]
5.14 Skin
Cutaneous adverse effects of BTXA are extremely rare.[4,8,13,15]
Only case reports of dermatologic adverse events have been pub-
lished and the causative role of BTXA in these conditions remains
mostly speculative.
 2005 Adis Data Information BV. All rights reserved.
In dark-skinned patients, injection-related inflammation may
cause pigmentation changes.[80] However, in a study of 26 African
American patients receiving repeated periocular BTXA injections,
no evidence of any pigmentary disorder was noted.[80] Persistent
rash arising from (lactose) allergy may develop at the site of
repeated BTXA injections.[21]
Repeated BTXA injections to the forehead have been reported
to cause dryness and flakiness of the frontal area in 2 of 52
patients.[48] This can be explained by the antihydrotic activity of
BTXA, even in the case of intramuscular injection. Most female
patients will not experience this mild adverse effect if they usually
use facial moisturizers. However, some male patients may suffer
from this minor discomfort. Regular use of a moisturizer will
diminish BTXA-induced dryness.[55]
A case of human herpes virus type 8-positive facial angi-
osarcoma developing at the site of BTXA injection for blepharos-
pasm has been reported.[81] The role of BTXA in this case remains
unclear.
An 80-year-old woman with chronic myeloid leukemia who
underwent BTXA injections for blepharospasm developed a nec-
rotizing fasciitis.[82]
A psoriasiform eruption has been observed after intramuscular
injection of BTSA.[83] In patients with skin diseases likely to show
Koebnerization, such as psoriasis, lichen planus etc, patients
should be informed that skin lesions may develop at the site of
injection.
5.15 Therapeutic Failure
Although sporadic, there is anecdotal evidence that some pa-
tients do not respond to BTXA. For example, patients with severe
actinic damage and poorly developed musculature will not benefit
greatly from BTXA.[68]
In patients who develop neutralizing antibodies as a result of
non-cosmetic use of BTXA, a change to BTXB may be necessary.
However, there is no standardized commercially available assay
for testing neutralizing antibodies. Not all patients with neutraliz-
ing antibodies experience a loss of activity of the compound.
Furthermore, there is an imprecise correlation between antibody
levels and the number of injections, length of treatment, or cumu-
lative BTXA dose.[3,4] Although immunologic and treatment resis-
tance have yet to be reported in patients treated for cosmetic
reasons or hyperhidrosis, it may be necessary to warn patients of
this as one of the possible complications of BTXA therapy.
However, this adverse effect can be avoided by keeping injected
volumes low, avoiding intravascular injections, and spacing injec-
tions at intervals of at least 1 month.[14]
Am J Clin Dermatol 2005; 6 (3)
 Managing Adverse Events of Botulinum Toxin Type A
Administration of suboptimal doses and use of incorrect injec-
tion techniques will lead to treatment failure. Electromyography
has been recommended by some authors as a means of improving
localization of injection points for hyperkinetic facial lines.[84]
6. Conclusions
BTXA is safe for cosmetic indications and treatment of hyper-
hidrosis when simple treatment guidelines are followed. The main
complications are technique-dependent. They can be minimized
by adequate training, detailed knowledge of the anatomy and
physiology of injection targets, and an understanding of the phar-
macology and toxicology of BTXA. To ensure a safe and satisfy-
ing treatment outcome, serious attention needs to be paid to the
following points:
• obtaining a detailed medical history from the patient;
• performing a careful physical examination;
• excluding contraindications, if necessary by laboratory and
other investigations;
• using accurate techniques of injection, dilution, and storage of
BTXA;
• injecting concentrated small volumes;
• avoiding injections in unsuitable areas;
• educating the patient and providing complete documentation
about how BTXA works, when it is indicated, its potential
PAGE PROOF 2
risks, the nature of the procedure, and your recommendations
about use of the drug;
• obtaining the patient’s written consent.
We believe that BTXA therapy is a medical procedure that
should be administered only by skilled, experienced and well-
trained physicians. Application of BTXA by non-medical person-
nel is unethical and dangerous. Adherence to these recommenda-
tions listed above can only increase the chance that patients
receiving BTXA injections will benefit from the procedure.
Acknowledgements
No sources of funding were used to assist in the preparation of this
manuscript. The authors have no conflicts of interest that are directly relevant
to the content of this manuscript.
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Correspondence and offprints: Dr Uwe Wollina, Department of Dermatolo-
gy, Hospital Dresden-Friedrichstadt, Academic Teaching Hospital,
Friedrichstrasse 41, Dresden, 01067, Germany.
E-mail: Wollina-Uw@khdf.de
Am J Clin Dermatol 2005; 6 (3)