Dermatol Clin 22 (2004) 197 – 205
Complications with the use of botulinum toxin
Arnold W. Klein, MD
Department of Dermatology, David Geffen School of Medicine at UCLA, 435 Roxbury Drive, Suite 204,
Beverly Hills, CA 90210, USA
The treatment of hyperfunctional facial lines with
botulinum A exotoxin injection is safe, effective, and
without serious side effects. Properly used, the inci-
dence of complications is low and their severity mild.
Millions of individual clinical doses have been de-
livered without major complications. Indeed, cos-
metic use of botulinum A exotoxin has become
routine within dermatology. Initiated during the
1980s, and refined by leaders in dermatologic surgery
during the past decade [1 – 5], botulinum toxin injec-
tions have become commonplace.
The bacterium Clostridium botulinum has eight
serotypes, which produce seven serologically distinct
exotoxins. With lethal doses approximating 10!9 g/
kg body weight, these neurotoxins represent some
of the most toxic naturally occurring substances [6].
Not all, however, are associated with botulism in
humans. Although the different serotypes are struc-
turally and functionally similar, specific differences
in neuronal acceptor binding sites, intracellular en-
zymatic sites, and species sensitivities suggest that
each serotype is its own unique pharmacologic entity.
Neutralizing antibodies developed against one sero-
type have not been reported to block the biologic
activity of another serotype [7].
Although the intracellular targets of the toxins
are variable, they all ultimately prevent release of
membrane-bound acetylcholine at the neuromuscular
junction of striated muscles and produce chemical
denervation and paralysis of the muscles [8]. This
chemical denervation is effective for both striated
muscle and eccrine glands. This action may not be
complete for 2 weeks and effectively destroys the
E-mail address: awkmd1@aol.com
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doi:10.1016/S0733-8635(03)00122-0
affected neuromuscular junction, causing muscular
paralysis. There is an ongoing turnover of neuromus-
cular junctions, however, such that muscular function
begins to return at approximately 3 months and is
usually complete by 6 months.
Botulinum toxins exist as large protein complexes
consisting of the neurotoxin moiety (approximately
150 kd) and one or more nontoxic proteins, which
are stabilized through noncovalent bonds and that
function to protect the toxin molecule [9]. Botulinum
toxin type B serotype associates with the nontoxic
proteins to form a complex with a total molecular
weight of approximately 700 kd, whereas the type A
complex is estimated to be approximately 900 kd
[10]. These large botulinum toxin complexes are
most stable in the pH range of 5 to 7 [11]. At pH
values above 7, the protein subunits dissociate [12].
The mode of measuring strength of this toxin is
paralytic activity in the mouse. One unit is defined as
that amount of the toxin that kills 50% (LD50) of a
standardized mouse model when injected intraperito-
neally. This is affected by many factors: strain of
mouse, housing conditions, and so forth. Theoretically,
specific activity can be reduced by the presence
of contaminating proteins or inactive, aggregated
toxin that may have been carried through in the
purification procedures [13].
The peripheral blockade of neuromuscular activ-
ity causes muscular weakness, which produces the
therapeutic effect. There has been no evidence to
suggest any permanent degeneration or atrophy of
muscles in those patients treated for dystonic or
spastic disorders who have been injected with high-
dose, repetitive injections of botulinum toxin over
an extended period. Muscle biopsies that were taken
from patients after injections of botulinum toxin type
A two to five times those used for aesthetic improve-
198 A.W. Klein / Dermatol Clin 22 (2004) 197–205
ment failed to show any long- term evidence of
permanent degeneration or atrophy [14].
Purified toxin complexes have found a niche in
the treatment of clinical disorders involving muscle
hyperactivity. Botox (Allergan, Irvine, CA) is a toxin
type A approved for use in the United States (for
treatment of cervical dystonia, blepharospasm, and
glabellar lines) and Dysport (Speywood Pharmaceuti-
cals, London, United Kingdom) is also botulinum
toxin type A but is not approved in the United States.
Dysport is primarily used in Europe. It should be
noted that all doses in this article are of Botox unless
otherwise stated. A highly concentrated type B toxin
(Myobloc) developed by Athena Neurosciences (Fos-
ter City, CA) and manufactured by Elan Pharmaceuti-
cals (San Francisco, CA) is approved by the Food and
Drug Administration (FDA) for use in the treatment
of cervical dystonia [15].
Conditions caused by muscle spasms
Local injections of botulinum toxin type A (Botox)
directly into excessively contracting muscles have
been successful in treating dystonia, spasticity, and
other conditions characterized by inappropriate mus-
cle spasm [16,17]. Botox is considered a safe therapy
for these inappropriate muscle spasms and is gener-
ally well tolerated, with adverse effects being typi-
cally self-limited [18].
Effects of a localized injection of botulinum toxin
to nearby or adjacent muscles are believed to be a
result of local diffusion of toxin to that muscle
(eg, ptosis following facial injections) [19]. There is
an area of denervation associated with each point
of injection because of toxin spread of about 2.5 to
3 cm. Although there are reversible and, rarely,
irreversible histologic changes in muscles that are
denervated after Botox treatment, there have been no
irreversible clinical effects reported. There have been
few reports of clinically relevant paresis in muscles
distant from the site of injection. Subclinical effects,
however, such as increased jitter and changes in the
single fiber electromyography (EMG), have been
described [20]. The clinical significance and duration
of this effect have yet to be determined [21]. Gener-
alized reactions that have idiosyncratically occurred
include nausea, fatigue, malaise, flulike symptoms,
and rashes at sites distant from the injection. A report
documenting three cases of generalized muscular
weakness associated with the use of botulinum toxin
type A (Dysport) in patients with dystonia reinforces
the concern about the possible spread of botuli-
num toxin – induced effects [22]. There has been a
single reported case of systemic spread of botulinum
toxin A. The patient had one set of injections for
blepharospasm. After the second set, the patient
immediately went into acute myasthenic crisis. This
was a motor end plate problem. Botox should not
be used in any patient with motor neuron disease.
The main complications of treatment of strabis-
mus with botulinum toxin are ptosis and vertical
deviations [23 – 25]. Rare instances of ciliary ganglion
injury, retrobulbar hemorrhage, and scleral perfora-
tion have been reported [25].
Transient ptosis, tearing, and dry eye are the most
frequently encountered complications with the use
of botulinum toxin in the treatment of blepharo-
spasm, hemifacial spasm, and Meige’s syndrome.
Diplopia and facial weakness are seen more rarely.
Resistance to botulinum toxin
The possibility of antibody production with result-
ing immunoresistance has always been a concern
with the use of Botox [26]. Hypersensitivity reactions
to the injection of the substance do not occur. The
only consequence is that Botox no longer is effective
as a treatment. With the original Allergan batch [27],
it was recommended that not greater than 100 U be
used at treatment sessions that occur at not less than
monthly intervals. Antigenicity of a foreign material,
however, is almost uniformly proportional to protein
load and the vastly decreased amount of protein
present in the currently used batches of Botox may
allow the application of larger doses of the product
per treatment session without fear of immunogenicity.
Indeed, animal studies have supported the decreased
formation of neutralizing antibodies with these new
batches [28]. Prevalence of Botox resistance is less
than 5% [29] and is associated with dose and fre-
quency of treatment sessions but not by duration of
overall treatment regimen [30].
The intramuscular injection of botulinum toxin
type A into affected muscles is used as therapy for
the treatment of cervical dystonia. After repeated use,
however, some patients receiving high doses, as are
often required in cervical dystonia, develop second-
ary resistance to type A therapy, possibly related to
the development of neutralizing antibodies. The inci-
dence of clinical resistance to type A treatment in
cervical dystonia has been estimated to be as high
as 6.5% [31]. Some of these patients have benefited
from different preparations of Botox [32] or from
other types of botulinum toxin [33,34].
Although there have been reports in the literature
of treated patients developing resistance after a
 A.W. Klein / Dermatol Clin 22 (2004) 197–205
mean cumulative dose of 192 U of Botox [32],
communication with Allergan indicated that only
1% to 2% of treated patients evidenced resistance
(neutralizing antibodies). Furthermore, the company
could not unequivocally say that this was caused by
size or frequency of dose. The factors that predispose
patients to the development of antibodies are un-
known, but experience has shown that the risk is
increased with repetitive dosages above 300 U
[33,34]. It should be noted that most of these data
are based on older batches of Botox that had greater
amounts of protein load than the newer toxin. Dos-
ages for individual sites treated for the purpose of
minimizing hyperfunctional facial lines usually re-
quire no more than 20 to 40 U per site. To further
minimize the dose and increase the accuracy of toxin
placement, an EMG-guided technique can be used.
In regards to frequency of injection sessions,
many authorities using Botox for cosmetic indica-
tions do additional treatment, when indicated,
2 weeks post – initial treatment. With the small doses
(< 100 U) used for almost all cosmetic procedures,
the limitation of injection interval does not seem to
be crucial.
Cosmetic use of botulinum toxin
Facial wrinkles are frequently caused by repeated
muscle contraction. Botulinum A exotoxin can pro-
duce weakness or paralysis of these muscles and
offers a novel approach for the treatment of certain
facial rhytides. Botulinum toxin type A weakens the
overactive underlying muscle contraction, causing a
flattening of the facial skin and an improved cosmetic
appearance [35]. The effect, although temporary, is
extremely popular with patients, has a very low
incidence of side effects, and is a relatively easy
technique to acquire. For these reasons, botulinum
toxin A (Botox) has gained rapid and enthusiastic
acceptance [36,37]. Botulinum toxin injections have
revolutionized the cosmetic approach to rejuvenation
of the aging face.
There have been no long-term adverse effects or
health hazards related to the use of Botox for any
cosmetic indication thus far [38]. Botox treatments
have not been associated with any permanent clinical
effects, although histologically there are reversible
and, rarely, irreversible histologic changes in muscles
that have been injected.
In general, a higher concentration allows for
more accurate placement and greater duration of
effect and fewer side effects. Lower concentrations
encourage the spread of the toxin. One should re-
199
member that there is an area of denervation associ-
ated with each point of injection because of toxin
spread of about 2.5 to 3 cm. Large dilutions have
also resulted in larger areas of paralysis.
Botulinum toxin works best when delivered into
the muscle belly. By limiting injections to the imme-
diate subcutis, injection-related pain and risk of
bruising is lessened, and effect is maintained. Inject-
ing into the periosteum on the forehead or glabella is
painful. Around the eyes the skin is extremely thin
and injections need not be deep to reach muscle.
Seldom are botulinum injections too superficial be-
cause the toxin easily penetrates muscle and even
fascia. Pre-existing or anatomic redistribution or re-
alignment of underlying musculature can alter the
effects of Botox, and modifications in injection
technique should be made.
Exclusion criteria include pregnancy or active
nursing and pre-existing neuromuscular conditions.
Patients with neuromuscular diseases (myasthenia
gravis, Eaton-Lambert syndrome) are not suitable
candidates for Botox. Women who have inadvertently
been treated with Botox during pregnancy have had
uneventful deliveries, and no teratogenicity has been
attributed to Botox. Nevertheless, Botox is classified
as a pregnancy category C drug.
Sequelae that can occur at any site because of
injection of Botox include pain, edema, erythema,
ecchymosis, headache, and short-term hypesthesia.
Some unwanted effects are idiosyncratic, but sponta-
neously resolving. Upper eyelid swelling after fore-
head injection, lower lid swelling after injection at
this site, bruising at the injection site, mild headache,
and flulike symptoms can persist for several days
to a few weeks after treatment with botulinum toxin
[39]. Ice applied immediately after injection reduces
the pain and the edema and erythema associated with
an intramuscular injection. Ecchymosis can be min-
imized by avoiding aspirin, aspirin-containing prod-
ucts, and nonsteroidal anti-inflammatory agents for
7 days before injection. Although the onset of head-
aches has been initiated with Botox injections, they
are alleviated with standard over-the-counter analge-
sics. It is, however, more common for patients to
report that chronic tension headaches have been
improved following injections of Botox. Pain associ-
ated with injections can be minimized by infusing
slowly with a 30- or 32-gauge needle, by injecting
small volumes of relatively concentrated solutions,
and by reconstituting the toxin in preserved rather
than preservative-free saline (Alam et al, 2002).
New patients should be told of potential undesired
effects, and their low likelihood and essentially
benign nature.
200 A.W. Klein / Dermatol Clin 22 (2004) 197–205
There are, admittedly, patients who do not achieve
their desired goal and are able to contract treated
facial musculature. Combining Botox with adjunctive
therapy is often necessary to appropriately address
the aging anatomy. There are also patients who per-
ceive that the Botox was a failure and are dissatisfied.
In one instance, the muscles treated are, in fact, im-
mobilized, but in an attempt to contract their muscles
they recruit adjacent muscles. Although this can
occur anywhere, it is particularly apparent in the
glabellar area. Additionally, some patients do not
recognize the improvement caused by the Botox
and express disappointment as residual nondynamic
rhytides persist. Demonstrating muscle immobility
with a hand-held mirror or before- and after-injection
Polaroid photographs is often necessary to convince
these patients.
All Botox patients are told to stay upright for at
least 4 hours. There is some controversy as to the
necessity of this, but it is a precaution that is used
almost universally. Immediately after injection,
movement of the treated muscles is encouraged so
that the toxin is taken-up by the involved neural
end plates. Patients are to repeat this muscle move-
ment 10 times per hour for the first 90 minutes. After
that the toxin has all been taken-up.
Glabella
The most common complication in treatment of
the glabellar complex is ptosis of the upper eyelid.
Eyelid ptosis is a significant risk if injections are
placed at or under the middle of the eyebrows in the
vicinity of the mid-pupillary line. This is cause by
diffusion of the toxin through the orbital septum,
where it affects the upper eyelid levator muscle. This
can occur as early as 48 hours or as late as 7 to
10 days following injection when the aesthetic effect
is beginning to appear and can persist for 2 to
4 weeks. With proper technique, the ptosis rate is
very close to zero.
Ptosis, should it occur, can be treated with eye-
drops to the affected side. a-Adrenergic agonists
ophthalmic eyedrops apraclonidine 0.5% (Iopidine)
and phenylephrine hydrochloride 2.5% (Neo-
Synephrine) are mydriatic agents. This causes con-
traction of an adrenergic muscle (Müller’s muscle),
which is situated beneath the levator muscle of the
upper eyelid. This treatment causes 1 to 2 mm of
elevation of the eyelid, which is usually sufficient to
make the individual symmetric. The treatment is
symptomatic and 1 to 2 drops three times a day must
be continued until the ptosis resolves [40].
To avoid eyelid ptosis, it is prudent to be con-
servative when treating elderly patients who may
have a reduced or absent orbital septum. Injecting
the Botox accurately and with low volume can also
decrease the risk for ptosis. Increasing the volume
injected increases the spread of the toxin from the
injection site and increases the possibility of affect-
ing unwanted muscles, and decreasing the volume
allows more accurate placement of the toxin. To
avoid ptosis, injections should be 1 cm above the
eyebrow and for more precise intramuscular injec-
tion, EMG guidance can be helpful [35,41].
The site of deposition of the toxin, not the ap-
proach to it, is important. After injection of the pro-
cerus, one should massage this site horizontally
across the upper nasal bridge to massage the toxin
toward the depressor supercilii. Complications have
not followed the massaging of this area. In the
glabellar area, digital pressure at the border of the
supraorbital ridge while injecting the corrugator also
reduces the potential for extravasation of Botox,
avoiding inadvertent weakening of the levator muscle
and resulting eyelid ptosis. It is important that this
injection site be 1 cm above the bony rim because
lower placement of the toxin in this site is the most
likely cause of ptosis.
In Allergan’s multicenter FDA study, ptosis
occurred in 12 (5.4%) of 263 patients, most of whom
were in one center where the injecting physician had
little experience with the technique.
Individuals treated in the glabellar area are more
likely to complain of an inadequate response than
those treated in other areas. The usual cause is
inadequate dosage.
Brow
The most significant complication of treatment
of the frontalis is brow ptosis. Botulinum A exotoxin
should not be injected above the middle brow so as to
avoid brow ptosis. Injection should also be avoided
within 1 cm of the bony superior orbital rim for the
same reason. Botox works best in younger female
patients (20 to 45 years of age). In some older
patients and in some male patients, redundant skin
can be created under the brow (pseudoptosis), so such
patients should be approached with caution. Treat-
ment of the brow depressors may be necessary,
however, after brow ptosis has become manifest.
Lack of expressivity may be caused by injection
of frontalis lateral to the mid-pupillary line. One
should remember that the brow shape can be changed
because of relaxing the major muscle responsible for
 A.W. Klein / Dermatol Clin 22 (2004) 197–205
elevating the brow. If the patient has a low eyebrow,
treatment of the forehead lines should be avoided,
or limited to that portion of the forehead 4 cm or
more above the brow. The lower 2.5 to 4 cm of the
frontalis muscle moves cephalad to elevate the eye-
brows. Older people use this to raise their eyebrows
to see. One must always cautiously address the lower
frontalis and stay 2 cm above the brow in all
individuals. One should never try to inject the gla-
bella and the entire forehead during the same session.
This invariably produces brow ptosis. The upper half
of the forehead and the frown, however, can be done
at the same time. Not rendering the frontalis muscle
completely immobile and paralyzed but weakened
can achieve the comparable goal of reducing the folds
while maintaining some forehead movement.
In individuals who have significant brow ptosis,
the possible effects of frontalis injection should be
discussed with the individual and injection of the
brow depressors (the glabellar complex) performed.
The brow depressors should also be treated in indi-
viduals with low-set brows or mild brow ptosis.
There is upward diffusion of toxin, which addresses
the lower forehead lines.
Brow elevation is usually achieved during treat-
ment of the glabella or may be necessary to prevent
or correct brow ptosis caused by treatment of hori-
zontal forehead lines (frontalis) and hence unopposed
action of the brow depressors. Chemodenervation
of all the brow depressors, corrugator supercilii,
depressor supercilii, procerus, and orbicularis oculi
(the glabellar complex) with Botox alone (ie, no
surgery) can elevate the brow from 1 to 2 mm [42].
An equally aesthetically unfavorable outcome
is the brow that assumes a quizzical or ‘‘cockeyed’’
appearance [40]. That is, the lateral eyebrows may
arch upward to an excessive extent because of the
unopposed pull of the frontalis. This occurs when the
lateral fibers of the frontalis muscle have not been
appropriately injected. This may be corrected by in-
jecting 3 U about 2 cm above each brow medial to the
temporal fusion line.
Ptosis of the upper eyelid (levator ptosis), al-
though less likely, can also occur. This is secondary
to downward diffusion of the injected material and
often caused by poor technique.
Before injecting the forehead of a patient for the
first time, it may be best to clarify the anatomic
boundaries. The width of the forehead and location
of the temporal fusion line vary from patient to
patient, and botulinum toxin treatment of the fore-
head needs to be individualized. The high-narrow
forehead must be treated differently than the short
and wide forehead.
201
Crow’s-feet
Reported complications in this area are bruising,
diplopia, ectropion, or a drooping lateral lower eyelid
and an asymmetric smile caused by injection of
zygomaticus major. To avoid these complications,
one should inject at least 1 cm outside the bony orbit
or 1.5 cm lateral to the lateral canthus, and not inject
close to the inferior margin of the zygoma. Just as
it is important not to inject too close to the eye,
injections should not be placed too far below it or too
deep, because the orbicularis oculi are very superfi-
cial muscles. Lip ptosis can occur if botulinum toxin
is delivered below the zygoma and deeply into the
zygomaticus major, an important elevator of the
upper lip and mouth. Paralyzing the zygomaticus
major can cause an appearance similar to a Bell’s
palsy. Resolution is gradual and often slower than
that of toxin-induced eyelid ptosis.
Medial movement of the toxin from the lateral
canthus can result in diplopia caused by lateral rectus
muscle paralysis. Strabismus can also occur. Both
diplopia and strabismus are exceedingly uncommon
side effects. If they manifest, referral to an ophthal-
mologist is imperative for appropriate management.
If a patient has redundant skin, one should be
careful because the skin can fold on the zygomatic
arch, producing an undesirable cosmetic result. Ec-
chymoses have been common in the past when
treating periorbital wrinkles. This can be almost
totally avoided by injecting the Botox in a wheal or
a series of continuous blebs with each injection at
the advancing border of the previous injection to
avoid hitting blood vessels with resultant bruising.
Injection of 2 to 4 U under the eye, especially
when combined with treatment of the crows’ feet, can
increase the aperture of the eye in a cosmetically
pleasing manner. Tissue should be handled gently,
and superficial vessels identified and avoided. Blebs
should be placed immediately under the epidermis
because the periocular muscles are extremely super-
ficial at this site. Injections under the eye must be
approached cautiously and should not be attempted
if the patient exhibits a significant degree of scleral
show pretreatment; if the patient has had signifi-
cant surgery under the eye previously; or if the pa-
tient has a great deal of redundant skin under the eye
as exhibited by a snap test of the lower eyelid (ie, if
the lid does not return to its previous position when
manually pulled down).
Deeper zygomaticus lines often connect to the
lower crow’s feet lines. Treatment of the crow’s feet
can paradoxically worsen the zygomaticus lines be-
cause the redundant cheek skin gravitates downward.
202 A.W. Klein / Dermatol Clin 22 (2004) 197–205
If a patient has redundant skin, one should be careful
because the skin can fold on the zygomatic arch,
producing an undesirable cosmetic result.
Nasolabial folds
Some physicians have treated levator labii supe-
rioris alaeque nasi to soften the superomedial part
of the nasolabial fold. They have used relatively low
doses (2 to 3 U of Botox per side) including EMG
localization of the site but report unimpressive re-
sponse. In those individuals who did get softening
of the folds, some showed lengthening of the upper
lip, which of itself is aging. Initially, several nasola-
bial injections were given. Although they reduced the
nasolabial groove, they also diminished the elevation
of the lip for smiling, which was not an acceptable
cosmetic outcome for most patients. This procedure
has mostly been abandoned.
Injecting the lower face and neck
Many of the muscles in the lower central face,
especially those used in facial expression, are also
involved in the functions of the mouth and cheeks.
An asymmetric smile, biting the inside of a flaccid
cheek, or incompetence of the mouth manifest by
drooling and dribbling are possible complications
of the overly enthusiastic use of Botox in the lower
face. Small doses, however, can be used satisfactorily
(eg, into mentalis, nasalis, and levator labii superioris
alaeque nasi). More recently Botox has been used for
depressor anguli oris and upper lip wrinkles.
For the upper lip lines, some injectors are using
small doses of Botox, 1 to 3 U per wrinkle to a total
of two to three wrinkles. They claim surprising
effectiveness in the treatment of this annoying con-
dition. Because of the importance of the competence
of the mouth, however, it is necessary to be extremely
gentle with the Botox, injecting more superficially
rather than deeply. Although techniques vary, it is
imperative to inject small quantities and maintain
symmetric spacing relative to the facial midline.
Failure to adhere to these rules can result in asym-
metry. The mouth may appear lopsided at rest, and
talking and chewing may accentuate this unat-
tractive appearance. Functional deficits may include
inability to sip from a straw, pucker, put on lipstick,
clearly enunciate Ps and Ss, whistle, kiss with pas-
sion, or play a wind or brass instrument. In severe
cases, drooling may be seen.
A common concern is a downturn at the corner of
the mouth producing a dejected appearance. This is
often treated by the use of fillers, such as injectable
collagen. Brandt and Bellman [43] have suggested
that injection of platysma may produce improvement
in this area. Botulinum toxin may also be used to
correct downward curl in the corners of the lip. For
this, injections of 3 U per side are given into the
depressor anguli oris at the jaw edge lateral to the
first fold. Injecting within the obicularis oris causes
unusual lip movement. Some practitioners inject
depressor anguli oris directly to achieve improve-
ment. They maintain that 2 to 3 U of Botox weaken
this muscle and allow the elevators of the corner
of the mouth to act with less opposition. The treat-
ment may be repeated to increase the effect. One must
be extremely cautious using Botox close to the
mouth, however, because of the danger of producing
a flaccid cheek, an incompetent mouth, or an asym-
metric smile.
On the chin, a prominent mentalis muscle can
cause a horizontal crease or a cobblestoned appear-
ance, which may be reduced by a single injection
of 5 to 10 U directly into the point of the chin with
massage. It is important to keep well away from the
mental fold, although this may be softened by the
injection. Injection into the mental fold area easily
can produce an incompetent mouth. Massage after
this injection is important.
Prominent hypertrophic vertical bands and fine
horizontal lines of the neck may develop with the
aging of the underlying platysma muscles. This mus-
cle is large, originating in the upper chest, and inserts
and blends variably with muscles on the mandible,
face, and ultimately the submusculoaponeurotic
system. Botox has been injected into platysma for
some years to alleviate these platysmal bands and
horizontal neck lines. The use of larger doses also to
improve the lower face and perhaps postpone a
surgical rhytidectomy is more controversial. This
technique has not produced any significant compli-
cations but the use of larger doses (75 to 100 U) can
produce weakness of the neck flexors and dysphagia.
In the neck, the platysma muscle bands can be
reduced by a series of Botox injections into the
anterior aspects of the platysma muscle bands. A
total of 21 U of Botox is injected into the offending
platysmal band at four separate sites: 3 U 1 cm below
the mandibular margin and then three injections
of 6 U each spaced 2.5 cm apart along the band.
Usually 2 to 4 bands are injected per treatment
session for a total dose of 42 to 84 U. This technique
has not produced any significant complications, but
the use of larger doses can produce weakness of the
 A.W. Klein / Dermatol Clin 22 (2004) 197–205
neck flexors and dysphagia. It is advised that no more
than 100 U be injected into these bands in total.
Brandt and Bellman [43] have expanded this
use to treat platysma more widely and with doses
up to 200 U Botox per treatment session. Injection
of large quantities or inadvertent injection or diffu-
sion into the adjacent sternocleidomastoid and
laryngeal muscles can, however, precipitate dyspha-
gia and neck weakness, which is more apparent
when an attempt is made at raising the head from
a supine position. By affecting the strap muscles,
botulinum toxin may cause singers to have diffi-
culty reaching high notes, and doses should be
limited in this case. Severe overtreatment of the
neck can result in patients having trouble holding
their heads erect.
Complications in treating hyperhidrosis
Chronically sweaty palms are uncomfortable and
socially debilitating. Superficial injection of botu-
linum toxin can provide dramatic relief from this
disorder. Injections should be at the level of the
superficial dermis and no deeper. Given the ability
of Botox to diffuse radially in the axillary skin in a
1.5-cm radius, the physician must first identify the
surface area of involvement using the starch-iodine
test. Intercurrent doses of intradermal botulinum
toxin can then be placed spaced at intervals to allow
overlap of the diffusion patterns. This serves to
maximize the paralytic effect on the eccrine units
while minimizing the total dose needed to achieve
dryness. A total dose of 50 U per axilla is normal in
treating axillary hyperhidrosis. In treating palmar
hyperhidrosis, a total dose of 100 U per hand is
common. A degree of weakness in the hands is a
common consequence of this therapy [44]. Because
of the large quantities injected and the proximity of
the small muscles of the hand, undesired outcomes
can also be seen, particularly if the injections are
too deep. Some impairment of fine motor function is
common, and this may occasionally be clinically
significant. Firm gripping with the distal digits and
rotational motions of the whole hand may be difficult.
This weakness is temporary and resolves after a few
weeks. Because of this weakness in grip strength,
however, it is advisable to only treat one hand per
treatment session.
It is also common to have to do touch-ups on
areas of the axillae or palms that are still sweating
after treatment. These touch-ups can be done 2 weeks
after initial treatment.
203
Treatment of migraine headaches
In a double-blind clinical study of migraine head-
ache treatment conducted by Silberstein et al [45],
there were no reported cases of true eyelid ptosis,
diplopia, facial nerve or expression problems, kera-
topathy, or idiosyncratic or allergic reactions attrib-
utable to Botox treatment. Two subjects reported
transient brow ptosis; other adverse effects were
limited to transient local pain and ecchymosis at the
injection site [45].
In another double-blind clinical study conducted
by Brin et al [46], the 75-U Botox group had a
higher incidence of treatment-related adverse events
than the vehicle group (50% versus 24%, P = .02),
whereas the 25-U Botox and vehicle groups were
similar in adverse event incidence. All adverse
events were transient and included blepharoptosis,
diplopia, and injection site weakness.
Informed consent
In the informed consent, it must be brought to
the patient’s attention that Botox has been approved
by the FDA as a safe and effective therapy since 1989
for use in blepharospasm, strabismus, and hemifa-
cial spasm and since 1992 for glabellar lines. The
National Institutes of Health consensus conference of
1990 also included Botox as safe and effective ther-
apy for the treatment of adductor spasmodic dyspho-
nia, oromandibular dystonia, and cervical dystonia.
The treatment of facial wrinkles other than the gla-
bellar lines is considered an off-label use. Other off-
label uses include the treatment of Meige’s syndrome,
sphincter dysfunction, migraine headaches, hyperhi-
drosis, tremor disorders, and juvenile cerebral palsy
and other spasticity disorders for which patients are
currently receiving benefit from Botox.
References
[1] Carruthers A, Carruthers J. History of the cosmetic
use of botulinum A exotoxin. Dermatol Surg 1998;
24:1168 – 70.
[2] Carruthers A, Carruthers J. Clinical indications and
injection technique for the cosmetic use of botulinum
A exotoxin. Dermatol Surg 1998;24:1189 – 94.
[3] Klein AW, Mantell A. Electromyographic guidance
in injecting botulinum toxin. Dermatol Surg 1998;24:
1184 – 6.
[4] Binder WJ, Blitzer A, Brin MF. Treatment of hyper-
functional lines of the face with botulinum toxin A.
Dermatol Surg 1998;24:1198 – 205.
204 A.W. Klein / Dermatol Clin 22 (2004) 197–205
[5] Klein AW, Glogau RG. Botulinum toxin: beyond
cosmesis. Arch Dermatol 2000;136:539 – 41.
[6] Lamanns C. The most poisonous poison. Science 1969;
130:763 – 72.
[7] Dertzbaugh MT, West MW. Mapping of protective
and cross-reactive domains of the type A neurotoxin
of Clostridium botulinum. Vaccine 1996;16:1538 – 44.
[8] Keen M, Blitzer A, Aviv J, et al. Botulinum toxin A
therapy for hyperkinetic facial lines: results of a
double-blind, placebo-controlled study. Plast Reconstr
Surg 1994;94:94 – 9.
[9] Somers E, DasGupta BR. Clostridium botulinum type
A, B, C1 and E produce proteins with or without hemag-
glutinating activity: Do they share common amino
acid sequences and genes? J Protein Chem 1991;10:
415 – 25.
[10] Sakaguchi G. Clostridium botulinum toxins. Pharma-
col Ther 1983;19:165 – 94.
[11] Bonventre PF, Kempe LL. Physiology of toxin produc-
tion by Clostridium botulinum types A and B. III. Effect
of pH and temperature during incubation on growth,
autolysis, and toxin production. Appl Microbiol 1959;
7:374 – 7.
[12] Townsend CT, Yee L, Mercer WA. Inhibition of the
growth of Clostridium botulinum by acidification.
Food Res 1954;19:1 – 7.
[13] Baffi RA, Garnick RL. Quality control issues in the
analysis of lyophilized proteins. Dev Biol (Basel) 1991;
74:181 – 4.
[14] Borodic GE, Ferranter R. Orbicularis muscle histology
after repetitive injections of botulinum A toxin. Pre-
sented at the annual meeting of American Academy
of Ophthalmology. Atlanta, Georgia, October 28 –
November 1, 1990.
[15] Sloop RR, Cole BA, Escutin RO. Human response to
botulinum toxin injection: type B compared with type
A. Neurology 1999;49:189 – 94.
[16] Jankovic J, Brin MF. Botulinum toxin: historical per-
spective and potential new indications. Muscle Nerve
1997;20(Supp 6):S129 – 45.
[17] Brin MF. Botulinum toxin: new and expanded indica-
tions. Eur J Neurol 1997;4:59 – 66.
[18] Mahant N, Clouston PD, Lorentz IT. The current use
of botulinum toxin. J Clin Neurosci 2000;7:389 – 94.
[19] Lange DI, Brin MF, Warner CL, et al. Distant effects
of local injection of botulinum toxin. Muscle Nerve
1987;10:552 – 5.
[20] Olney RK, Aminoff MJ, Gelb DJ, et al. Neuromuscular
effects distant from the site of botulinum neurotoxin
injection. Neurology 1988;38:1780 – 3.
[21] Report of the Therapeutics in Technology Assessment
Subcommittee of the American Academy of Neu-
rology. Assessment: the clinical usefulness of botuli-
num toxin A in treating neurologic disorders.
Neurology 1990;40:1332 – 6.
[22] Bhatia KP, Münchau A, Thompson PD, et al. Gener-
alised muscular weakness after botulinum toxin injec-
tions for dystonia: a report of three cases. J Neurol
Neurosurg Psychiatry 1999;67:90 – 3.
[23] Lingua RW. Sequelae of botulinum toxin injection.
Am J Ophthalmol 1985;100:305 – 7.
[24] Burns CL, Gammon JA, Gemmill MC. Ptosis asso-
ciated with botulinum toxin treatment of strabismus
and blepharospasm. Ophthalmology 1986;93:1621 – 7.
[25] Scott AB. Botulinum toxin treatment of strabismus
(Focal Points 1989 Clinical Modules for Ophthalmolo-
gists, No. 7). San Francisco: American Academy of
Ophthalmology; 1989.
[26] Jankovic J, Schwartz K. Response and immuno-
resistance to botulinum toxin injections. Neurology
1995;45:1743 – 6.
[27] Gonnering RS. Negative antibody response to long-
term treatment of facial spasm with botulinum toxin.
Am J Ophthalmol 1988;105:313 – 5.
[28] Mezaki T, Kaji R, Kohara N, et al. Comparison of
therapeutic efficacies of type A and F botulinum toxins
for blepharospasm: a double-blind, controlled study.
Neurology 1995;45:506 – 8.
[29] Ludlow CL, Hallett M, Rhew K, et al. Therapeutic
use of type F botulinum toxin [letter]. N Engl J Med
1992;326:349 – 50.
[30] Sankhla C, Jankovic J, Duane D. Variability of the
immunologic and clinical response in dystonic patients
immunoresistant to botulinum toxin injections. Mov
Disord 1998;13:150 – 4.
[31] Brin MF, Lew MF, Adler CH, et al. Safety and efficacy
of NeuroBloc (botulinum toxin type B) in type A-
resistant cervical dystonia. Neurology 1999;53:1431.
[32] Göschel H, Wohlfaqrth K, Frevert J, et al. Botulinum A
toxin therapy: neutralizing and nonneutralizing anti-
bodies—therapeutic consequences. Exp Neurol 1997;
147:96 – 102.
[33] NIH. Clinical use of botulinum toxin. National Insti-
tutes of Health Consensus Development Conference.
NIH Consens Statement, November 12 – 14, 1990;
8:1 – 20.
[34] Borodic G, Johnson E, Goodnough M, et al. Botulinum
toxin therapy, immunologic resistance and problems
with available materials. Neurology 1996;46:26 – 9.
[35] Klein A. Cosmetic therapy with botulinum toxin:
anecdotal memoirs. Dermatol Surg 1996;22:757 – 9.
[36] Blitzer A, Brin MF, et al. Botulinum toxin for the
treatment of hyperfunctional lines of the face. Arch
Otolaryngol Head Neck Surg 1993;119:1018 – 22.
[37] Carruthers JDA, Carruthers JA. Treatment of glabellar
frown lines with C. botulinum-A exotoxin. J Dermatol
Surg Oncol 1992;18:17 – 21.
[38] Hambleton P, Moore AP. Botulinum neurotoxins:
origin, structure, molecular actions, and antibody.
In: Moore P, editor. Handbook of botulinum toxin treat-
ment. Oxford: Blackwell Science; 1995. p. 16 – 27.
[39] Alam M, Arndt KA, Dover JS. Severe, intractable
headache following injection with botulinum A exo-
toxin. J Am Acad Dermatol 2002;46(1):62 – 5.
[40] Burns RL. Complications of botulinum exotoxin.
Presented at the 25th Annual Clinical and Scientific
Meeting of the ASDS. Portland, OR, May 13 – 17, 1998.
[41] Foster JA, Barnhorst D, Papay F, et al. The use of
 A.W. Klein / Dermatol Clin 22 (2004) 197–205
botulinum A toxin to ameliorate facial kinetic frown
lines. Ophthalmology 1996;103:618 – 22.
[42] Fraenkel AS, Kamer FM. Chemical brow lift. Arch
Otolaryngol Head Neck Surg 1998;124:321 – 3.
[43] Brandt FS, Bellman B. Cosmetic use of botulinum A
exotoxin for the aging neck. Dermatol Surg 1998;24:
1232 – 4.
[44] Bushara KO, Jones JW, Park DM, et al. Botulinum
toxin and sweating [abstract]. Mov Disord 1995;10:391.
205
[45] Silberstein S, Mathew N, Saper J, et al. Botulinum
toxin type A as a migraine preventive treatment. Head-
ache 2000;40:445 – 50.
[46] Brin MF, Swope DM, Abassi S, et al. Botulinum toxin
type A (Botox) for migraine: double blind, placebo
controlled, region specific evaluation [poster 1196].
Poster presented at the Headache World 2000. London,
September 3 – 7, 2000.