Quy Trình Tiêm Botulinum Toxin Trong Da Liễu Thẩm Mỹ (Cosmetic Dermatology Series)

133
19 
Platysma and the Nefertiti Lift®
Figure 19.6  Platysma (A, C) before and (B, D) 2 weeks after Nefertiti Lift®; (A, B) at rest; (C, D) contracted.
A
B
C
D
Figure 19.7  Nefertiti Lift®: modified smile caused by inadvertent
injection into the depressor labialis inferioris (DLI). Treatment in this
case consisted of injecting 1.5 units of onabotulinum toxin A into the
contralateral DLI.
Figure 19.8  Nefertiti Lift®: injection points (blue arrows) situated
under the mandible at least 1 cm posterior to the red arrow indicating
the position of the posterior fibers of the depressor labialis inferior.

134
Botulinum toxin
Carruthers J, Fagien S, Matarasso SL, the Botox Consensus Group
2004 Consensus recommendations on the use of botulinum
toxin type A in facial aesthetics. Plastic and Reconstructive
Surgery 114(6 suppl):S1–S22
Carruthers J, Carruthers A 2003 Aesthetic botulinum A toxin in
the mid and lower face and neck. Dermatologic Surgery
29:468–476
Gassia V, Beylot C, Béchaux S, et al 2009 Botulinum toxin
injection techniques in the lower third and middle of the face,
the neck and the décolleté: the ‘Nefertiti lift’. Annals of
Dermatology and Venereology 136(suppl 4):S111–S118
Hoefflin SM 1998 Anatomy of the platysma and lip depressor
muscles. Dermatologic Surgery 24:1225–1231
Levy PM 2007 The ‘Nefertiti Lift’: a new technique for specific
recontouring of the jawline. Journal of Cosmetic and Laser
Therapy 9(4):249–252
Park MY, Ahn KY, Jung DS 2003 Botulinum toxin type A treatment
for contouring of the lower face. Dermatologic Surgery
29:477–483
Rohen JW, Yokochi C, Lütjen-Drecoll E 1998 Color atlas of
anatomy, 4th edn. Lippincott Williams & Wilkins, Philadelphia
experience adverse events, which are most often linked to
excess dosage and inappropriate injection technique. Rare
adverse events include mild dysphagia, an excess ‘lifting’
effect, and slight smile modification. All adverse effects
are reversible and resolve rapidly. Treatment failure is
often due to poor candidate selection and the presence of
excess fat on the mandibular border. The Nefertiti Lift®
offers clinicians an opportunity to sharpen the jawline and
improve facial contours making it an excellent comple­
ment to other minimally invasive procedures when seeking
to achieve global facial rejuvenation.
Further reading
Brandt FS, Bellman B 1998 Cosmetic use of botulinum A exotoxin
for the aging neck. Dermatologic Surgery 24:1232–1234
Brandt FS, Boker A 2003 Botulinum toxin for the rejuvenation of
the neck. Clinics in Dermatology 21:513–520

temporalis) hypertrophy was by the latter group; this
was an unusually severe case of a 32-year-old woman
who, following a motor car accident and brain contusion,
was beginning to communicate after a prolonged coma.
Although she obeyed verbal commands, she had devel­
oped severe bruxism and ‘the teeth grinding was very loud
and almost continuous causing damage to the teeth and
annoyance to nearby patients’. In this case 25 units were
injected into each temporalis and each masseter muscle,
which is, somewhat surprisingly, a similar dose to an initial
dosing in todays cases. The treatment of masseteric hyper­
trophy soon became more widespread and today is a main­
stream treatment for this condition replacing surgery in
many cases. In the treatment of bruxism it has a definite
place alongside and in many cases replacing splints and
orthodontic techniques in selected patients.
Evidence has begun to accumulate that the masseteric
hypertrophy has other effects besides the bulk it directly
confers because of the muscle volume. In line with theo­
ries of bone deposition and development, Wu found in
2010 that this muscle development may have effects on
the underlying bone growth and volume. Bone growth
and volume are under the influence and related to the
activity of the muscles attached to the bone. A bone
responds to the activity and strength of the muscles
attached to it by thickening and the corollary is that bone
will decrease when the muscular force acting on the bone
is decreased, as reported by Tsai et al. Molina et al found
that the masseter neuromuscular end plates are devel­
oped by 12 weeks’ fetal gestation. By restraining mouth
opening, Habib and co-workers showed by the use of
suturing that restricted fetal temporomandibular joint
movement influences the process of endochondral bone
formation of condylar cartilage. These effects on bone
may explain the trimming effect that botulinum toxin has
on the facial shape may be above and beyond the effects
of what would be expected by a decrease in muscle bulk
alone (Fig. 20.1). However, not all authors (e.g. Chang
et al) believe that bony resorption occurs after botulinum
toxin injection.
One of the great determinants of beauty is facial shape.
In males a square facial shape is considered desirable, but
this should not be a bottom- heavy face with a wider lower
face than an upper face. In females this is more of an issue,
with youth and beauty being related to an oval, triangular
or heart-shaped face.
20 
The masseters and their
treatment with botulinum toxin
Greg J. Goodman
Introduction
Botulinum toxin has been certainly an unusual drug. A
drug does not usually find itself being continually rein­
vented, popping up all over disparate branches of medi­
cine as a treatment for a seemingly never-ending number
of indications. The story of botulinum toxin in the treat­
ment of masseter hypertrophy may have started in the
medical arena with the treatment of bruxism, but now has
stepped well and truly into the cosmetic arena, establish­
ing a central role in altering facial shape – arguably one of
the most important determinants of facial beauty.
History
Following on from earlier experience by Jancovic & Orman
in treating other facial dystonias with botulinum toxin,
investigators including Lagueny et al and Van Zandijcke &
Marchau turned their attention to the treatment of
bruxism. Amongst the earliest use of botulinum toxin in
the treatment of bruxism associated with masseteric (and
Summary and Key Features
•
The masseter muscle may become hypertrophied
distorting the mandibular angle
•
Masseteric hypertrophy may be a cause of bruxism
and facial pain syndromes
•
Botulinum toxin may be used to treat both medical
pain syndromes and to change facial shape by
changing the mandibular angle
•
Botulinum toxin may replace surgical and
orthodontic techniques in selected patients in both
medical and aesthetic indications
•
Botulinum toxin may allow us to beautify patients
by altering the lower facial width and converting
the face to a more youthful triangular or heart-
shaped face

136
Botulinum toxin
Figure 20.1  (A) Pre-botulinum toxin injection for masseteric hypertrophy. (B) Result after two injection sessions. The trimming of the lower
facial shape seems here to have produced more change than would be expected from just diminution of masseteric bulk and may involve
some bony involution. This would be expected to be a temporary change with discontinued botulinum injection.
A
B
Anatomy
The bony framework
The background to the story of masseter (and temporalis)
hypertrophy is their function as a set of masticatory
muscles acting over the temporomandibular joint.
The temporomandibular joint is an engineering complex
made up of bony and ligamentous structures. The bony
parts are the anterior part of the mandibular fossa of the
temporal bone, the articular tubercle of the maxilla, and
the condyle of the mandible. The ligamentous structures
include the articular capsule and disc, and a series of
lateral ligaments.
Movements permitted the mandible by the temporo­
mandibular joint include: depression or opening of the
mouth from rest, elevation or closing of the mouth to rest,
protrusion or pushing the mandible forwards from rest,
retraction or pulling the mandible back to rest, and a small
amount of side-to-side movement.
The muscles involved in closing the jaw (elevation) are
the masseter, temporalis, and to some extent the medial
pterygoid muscles. The temporalis muscle controls the
first stage of the elevation action by initially lifting the
mandible up and back, then the medial pterygoid muscle
contracts slightly to lift the bottom of the mandible up.
Lastly the masseter completes the elevation by contract­
ing producing the final stage of mouth closure. Contrac­
tion can be seen in the muscle flowing from the anterior
to the posterior portion of the muscle.
Masseter muscle
The masseter comprises three overlapping layers, all of
which originate from the zygomatic arch and insert into the
ascending ramus of the mandible thus allowing it to fulfill
its function of elevating the mandible to close the jaw.
Specifically:
1. The superficial part arises from the zygomatic process
of the maxilla and from the anterior two-thirds of
the lower border of the zygomatic arch
2. The middle part originates from the deep surface of
the anterior two-thirds of the zygomatic arch and
from the lower border of the posterior one-third of
the arch
3. The deep part arises from the deep surface of the
zygomatic arch.
The three layers merge as the fibers pass downward and
backwards to insert into the lateral surface of the angle,

137
20 
The masseters and their treatment with botulinum toxin
Raison d’être for botulinum injection of
the masseters in the lower face
Most often botulinum toxin is injected into the masseter
muscles to decrease the effect of masseter hypertrophy.
This hypertrophy may occur from many reasons; there is
probably some genetic component, with East Asians seem­
ingly over-represented in the severe end of the spectrum
of muscle excess. In some, the development of masseteric
hypertrophy is as simple as developing a habit of chewing
a food item such as chewing gum or dried foodstuffs
recurrently, but in many it is a side effect of the common
psychosocial habit of jaw clenching or bruxism. Some­
times bruxism will be seen without a lot of masseter
hypertrophy and attention should be directed elsewhere
in the search of its cause, such as the temporalis muscle
or disorders of the temporomandibular joint or malocclu­
sion issues, which are beyond the scope of this chapter.
Bruxism
Masticatory muscle activities can be normal or abnormal
in nature and were categorized by Ahrlberg et al as func­
tional (e.g. chewing, swallowing, and speaking) or para­
functional (e.g. tooth clenching, grinding, and various oral
habits). Bruxism (the nonfunctional gnashing and grinding
of the teeth) is one such parafunctional activity commonly
seen in humans. It had been primarily viewed as a dental
phenomenon, but thinking has changed and it is now
viewed as a psychophysiological disorder. It may be diurnal,
where it has a prevalence of about 20% and is usually just
jaw clenching, or nocturnal with a prevalence of clenching
of about 10% and that of grinding of the teeth during
sleep ranging from 8 to 16% (as reported by Lavigne &
Montplaisir and Santamato et al). Bruxism appears to be
equally common in males and females, but appears to
occur more often in adults than in children.
Bruxism may lead to masseter muscle hypertrophy by
the effect of recurrent action of the muscle over time. In
this context, relief may be as simple as the use of adequate
dosing of botulinum toxin over time to the masseter muscle.
ramus and coronoid process of the mandible. Where these
layers overlap is the thickest palpable region when the
patients clench their teeth. This maximum bulk is usually
inferiorly placed nearer the jawline than the zygoma.
The masseteric nerve from the anterior division of the
mandibular nerve innervates the muscle and the vascular
supply derives from the transverse facial branch of the
superficial temporal, the masseteric branch of the maxil­
lary artery, and the facial arteries.
Temporalis muscle
The temporalis muscle arises from the floor of the tem­
poral fossa and from the overlying temporal fascia and its
fibers converge towards their insertion at the apex, the
anterior and posterior borders, and the medial surface of
the coronoid process. In order to reach the coronoid
process, the temporalis muscle runs beneath the zygo­
matic arch. Its function is to elevate the mandible (ante­
rior or vertical fibers), but also by way of its posterior or
horizontal fibers to retract it.
Surface anatomy of the masseter muscle
The muscle is easily outlined, with the superior border
represented by the zygomatic arch and the inferior border
being the inferior border of the mandible, The posterior
border is the posterior border of the mandible, and the
anterior border is easily seen in those with hypertrophy
by asking the patient to clench their teeth. Anteriorly,
along the jawline the masseter muscle will give way to a
gap where often the arterial pulsation of the facial artery
may be felt, and superior to this the hardness of the con­
tracting masseter muscle may be contrasted with the
softer connective tissue of the face anterior to the con­
tracting muscle (Fig. 20.2).
Figure 20.2  Markings on the face showing the masseter muscle
outlined and the position of the facial artery along the jawline
anteriorly.
Pearl 1 
Injection of the masseter muscle requires knowledge of its
surface anatomy and the trilaminar nature of the muscle.
Pearl 2 
The masseter muscle is often the seat of both lower facial
pain syndromes and tooth damage due to clenching and
grinding.
Treatment of the masseter muscle for
shaping and beautification of the lower face
Aesthetic recontouring of the lower face has been gradu­
ally developing as a concept initially with East Asian

138
Botulinum toxin
There are many surgical procedures that have been
described to decrease width of the lower third of the
face, for example by Yang et al and Ying et al, and there
is general agreement that attractiveness in female faces
has as one of its components an aesthetically pleasing
angles of the lower third of the face. In 2011 Liew looked
at the similarities in truly beautiful people in different
racial groups, and found that if one transposes a vertical
line from the midline to intersect with the angle cast
between the line drawn along the body of the mandible
and tissue overlying the ascending ramus of the mandible
it will form an acute angle (Fig. 20.4A–C). This angle is
more acute (a lower angle) if the facial shape is square,
such as one cast with masseter hypertrophy or parotid
enlargement. It is less acute or greater if the facial shape
is more triangular or the lower facial width is decreased.
Hence, in Figure 20.3, one can see the improvement in
attractiveness as one moves towards a greater ‘angle of
beauty’, the ideal being 9–12°.
Wu has also published results on the role of trimming
parotid enlargement (which sits posterior to the enlarge­
ment produced by masseteric bulk) to further refine the
cosmetic appearance of the lower face. Kwon et al
reported that injection into the masseter has no effect
on salivary flow rates, but injection into the parotid
directly would certainly be expected to diminish salivary
output. Wu noted that none of his patients suffered
from symptoms of dry mouth after the parotids were
injected for hypertrophy; the fullness shown by parotid
enlargement may be missed as it may merge with the
posterior border of the masseteric hypertrophy and
be apparent only after masseter injection. Rarely, as
Reddy et al found, masseteric hypertrophy may be asso­
ciated with obstructive parotitis from obstruction of
Stensen’s duct.
Figure 20.3  ‘Heart-shaped face’, which is stated to have the
appearance of youth.
Figure 20.4  (A) Before treatment showing Liew’s ‘angle of beauty’ at 6°. (B) Interim result at 3 weeks following masseter injection with 25 units
botulinum toxin with improved lower facial angle of 8°. (C) Final result with a more ideal angle of 10° at 15 weeks following injection.
A
B
C
Pearl 3 
A bulky masseter muscle squares the face and is often a
negative influence in female facial beauty. Bulky masseters
are very common in East Asian patients, but it affects all
patient groups.
patients, but more recently also in Western patients.
There has been a gradual increase in understanding of the
use of botulinum toxin in the treatment of masseteric
hypertrophy to promote a better facial appearance and
enhance beauty. However, there is a definite gender dif­
ference in what is perceived to be attractive. Male facial
shape is ideally full of sharp angles. The ideal facial female
shape has been stated to be heart shaped, oval or base-up
triangular or similar (Fig. 20.3).

139
20 
The masseters and their treatment with botulinum toxin
The dose depends on the bulk of the muscle being
treated. In general Caucasian patients will require less
than East Asian patients (Liew and Dart 2010) and males
more than females. Most often, Caucasian females will
require 15–25 units per side, whereas East Asian females
may require 30–50 units per side. Males may need 10
units or so more than their female counterparts.
Treatment method
Injecting masseters
In the author’s method, 100 units of botulinum toxin
(abobotulinum toxin) were dissolved in 2 mL of sterile
normal saline, yielding a concentration of 5 units per
0.1 mL. The intended dose was drawn into a 1 mL syringe
and the solution was injected with a 32 mm long (114 inch)
30-gauge hypodermic needle.
The patient is asked to clench the jaw and the masseter
palpated, outlining the anterior and posterior borders of
the masseter muscle. Three to five injection points are
used depending on the masseter bulk and markings placed
at the site of maximum bulge, which is usually in the
lower half of the muscle. The injection points are placed
below a line drawn from the tragus to the angle of the
mouth (see Fig. 20.2) and at least 1 cm from the borders
of the muscles. Injecting outside these limits may inter­
fere with other masticatory muscles, especially superolat­
erally, and the salivary glands posteriorly and inferiorly.
The injections are placed deeply, as superficial placement
may not reach the deeper heads of the muscle and produce
n appearance of a chipmunk chewing on nuts when the
patient is eating. Possibly this is due to the action of the
functional deep head pushing against a treated and flaccid
superficial head.
Figure 20.5  (A–C) Treatment showing effective treatment of a patient in two stages – initially 20 units bilaterally then a top-up of 10 units to
the right side only according to symptoms and palpation.
A
B
C
Pearl 6 
Dose will depend on muscle bulk, but 15–40 units of
onabotulinum toxin may be required per side.
Pearl 5 
Injections should be deep and inferior to a line between the
tragus and the angle of the mouth.
Masseter treatments may be repeated at 1–3-monthly
intervals until the desired shape is attained (Fig. 20.5).
Patients will readily report most often that their jaw
clenching, morning headaches, sore teeth or other symp­
toms are better even after the first injection session.
However, if symptoms are not improved or substantially
settled this is a sign for reinjection of similar dose, other­
wise often a lower dose than initially may be used.
Pearl 4 
Three to five injections should be centered on the maximum
muscle bulk assessed by palpating the muscle on clenching
of the jaw.
Pearl 7 
Injections may be repeated until the desired change is seen
(a decline in clenching or facial shape change) and then
reassessed at 3–4 months.

140
Botulinum toxin
2. Weakness when chewing foods that require powerful
biting and grinding such as an apple or steak (can be
limited to some degree if the injections are kept to
the lower part of the muscular bulk)
3. Injecting especially older patients with large muscle
bulk may allow a redundancy to develop anteriorly,
with jowling and sagging due to the volume reduction
of the skin envelope overlying the masseters
4. Over-hollowing of the infrazygomatic area causing a
somewhat haggard appearance
5. Intramuscular or subcutaneous hematoma
6. Muscle bulging on mastication (usually temporary
and mostly avoided by deep injection).
Conclusion
The masseter muscle is the seat of physical pain syn­
dromes and potential tooth damage, a set of medical con­
ditions that may be alleviated by the use of botulinum
toxin. However, in the process of helping masseteric
hypertrophy, which is often a prime offender in these
disorders, it has become apparent that the change in facial
shape from square to triangular is a very pleasing one. This
has begun to provide us a powerful weapon to non-
surgically reshape the lower face in much the same way
that along with filling agents they have allowed us tools to
reshape the upper face.
Quite often there will be asymmetry to the masseteric
hypertrophy or even unilateral hypertrophy. Doses should
be tailored to this event but, unless it is totally unilateral,
often it is better to inject some on both sides but more
obviously on the palpably stronger and visibly bigger side
(Fig. 20.6).
Whether or not one treats the temporalis muscle
depends on a number of factors. One should observe the
patient’s temporal fossa area when clenching or chewing
for obvious signs of hypertrophy. If it is not obviously
hypertrophic at rest with a marked convexity to the
temple and bulging on mastication, I do not inject this at
the first injection session. However, if it is then, similar
to the masseter, it is injected according to its bulk in a
number of injection points (usually three) in the area of
maximum projection. However, unlike the change of
facial shape produced by masseter injection, a hollow
temple looks cadaveric and unattractive whereas a flat or
slightly convex one is quite youthful. If a patient is com­
plaining of bruxism and injection of apparent masseteric
hypertrophy is insufficient to settle symptoms then injec­
tion of hypertrophic temporalis is indicated.
If there is a reversible element in the history such as a
chewing habit (chewing gum, dried foods or other food
oddities) then ceasing this and injecting the masseters a
couple of times may be all that is required to change things
in the long term.
Complications
These include:
1. Occasionally the botulinum toxin will drift into
anterior and superficial muscles especially the risorius
limiting the smile somewhat
Figure 20.6  (A–C) Significant asymmetry of masseteric hypertrophy: (A) treated with 10 units to the right side and 15 units to the left on
the first treatment, then (B) treated with 15 units to the left and 5 units to the right and (C) the final result.
A
B
C
Pearl 8 
Injection of the masseter muscle should be considered
whenever one is assessing alteration of facial shape in search
of aesthetic improvement.

141
20 
The masseters and their treatment with botulinum toxin
Liew S, Dart A 2008 Nonsurgical reshaping of the lower face.
Aesthetic Surgery Journal 28:251–257
Molina W, Reyes E, Joshi N, et al 2010 Maturation of the
neuromuscular junction in masseters of human fetus. Romanian
Journal of Morphology and Embryology 51:537–541
Moore AP, Wood GD 1994 The medical management of masseteric
hypertrophy with botulinum toxin type A. British Journal of
Oral and Maxillofacial Surgery 32:26–28
Reddy R, White DR, Gillespie MB 2012 Obstructive parotitis
secondary to an acute masseteric bend. ORL Journal of
Otorhinolaryngology and its Related Specialties 74(1):12–15.
Epub 2011 Dec 8
Santamato A, Panza F, Di Venere D, et al 2010 Effectiveness of
botulinum toxin type A treatment of neck pain related to
nocturnal bruxism: a case report. Journal of Chiropractic
Medicine 9(3):132–137
Smyth AG 1994 Botulinum toxin type A treatment of bilateral
masseteric hypertrophy. British Journal of Oral and Maxillofacial
Surgery 32:29–33
Tsai CY, Chiu WC, Liao YH, et al 2009 Effects on craniofacial
growth and development of unilateral botulinum neurotoxin
injection into the masseter muscle. American Journal of
Orthodontal and Dentofacial Orthopedics 135(2):142.e1–142.
e6; discussion 142–143
Tsai CY, Shyr YM, Chiu WC, et al 2011 Bone changes in the
mandible following botulinum neurotoxin injections. European
Journal of Orthodontics 33(2):132–138. Epub 2010 Sep 30
Van Zandijcke M, Marchau MM 1990 Treatment of bruxism with
botulinum toxin injections. Journal of Neurology, Neurosurgery,
and Psychiatry 53:530
Wu WT 2010 Botox facial slimming / facial sculpting: the role of
botulinum toxin-A in the treatment of hypertrophic masseteric
muscle and parotid enlargement to narrow the lower facial
width. Facial Plastic Surgery Clinics of North America
18:133–140
Yang J, Wang L, Xu H, et al 2009 Mandibular oblique ostectomy:
an alternative procedure to reduce the width of the lower face.
Journal of Craniofacial Surgery 20(suppl 2):1822–1826
Ying B, Wu S, Yan S, et al 2011 Intraoral multistage mandibular
angle ostectomy: 10 years’ experience in mandibular contouring
in Asians. Journal of Craniofacial Surgery 22(1):230–232
Further reading
Ahlberg J, Rantala M, Savolainen A, et al 2002 Reported bruxism
and stress experience. Community Dentistry and Oral
Epidemiology 30:405–408
Ahn J, Horn C, Blitzer A 2004 Botulinum toxin for masseter
reduction in Asian patients. Archives of Facial Plastic Surgery
6:188–191
Berkovitz B, Kirsch C, Moxham BJ, et al 2003 Interactive Head
and Neck. Primal Pictures Ltd, Software version 1.10
Chang CS, Bergeron L, Yu CC, et al 2011 Mandible changes
evaluated by computed tomography following Botulinum Toxin
A injections in square-faced patients. Aesthetic Plastic Surgery
35:452–455. Epub 2010 Nov 20
Habib, H, Hatta T, Udagawa J, et al 2005 Fetal jaw movement
affects condylar cartilage development. Journal of Dental
Research 84:474–479
Iglesias-Linares A, Yáñez-Vico RM, et al 2011 Common standards
in facial esthetics: craniofacial analysis of most attractive black
and white subjects according to People magazine during previous
10 years. Journal of Oral and Maxillofacial Surgery 69(6):e216–
24. Epub 2011 Apr 5
Jankovic J, Orman J 1987 Botulinum A toxin for cranial-cervical
dystonia: a double-blind, placebo-controlled study. Neurology
37:616–623
Kim NH, Chung JH, Park RH, et al 2005 The use of botulinum
toxin type A in aesthetic mandibular contouring. Plastic and
Reconstructive Surgery 115:919–930
Kwon JS, Kim ST, Jeon YM, et al 2009 Effect of botulinum toxin
type A injection into human masseter muscle on stimulated
parotid saliva flow rate. International Journal of Oral and
Maxillofacial Surgery 38:316–320. Epub 2009 Feb 23
Lagueny A, Deliac MM, Julien J, et al 1989 Jaw closing spasm – a
form of focal dystonia? An electrophysiological study. Journal of
Neurology, Neurosurgery, and Psychiatry 52:652–655
Lavigne GJ, Montplaisir JY 1994 Restless legs syndrome and sleep
bruxism: prevalence and association among Canadians. Sleep
17:739–743
Liew S 2011 Presentation, Hong Kong, December 9

types I–III). This is largely due to the photoprotective
effect of increased epidermal melanin, which has been
demonstrated in several studies. Most notably, the mean
protective factor from ultraviolet (UV) B in black skin
was found to be 13.4 versus 3.4 for white skin in a cadav­
eric skin study by Kaidbey and colleagues. Furthermore,
in a more recent study by Yamaguchi and co-workers,
UV-induced apoptosis was found to be greater in the
epidermis of black skin compared with white skin, sug­
gesting that photodamaged cells may be removed more
efficiently in darker phototypes.
In a comparative study by Nouveau-Richard et al of
Chinese and French women, the onset of facial wrinkles
was found to be approximately 10 years later in Chinese
versus French women. Other studies in African-Americans
have reported similar findings of later onset of facial rhyt­
ides or fine lines; Grimes found a much lower percentage
of women of color perceived having wrinkles than did
their Caucasian counterparts. In general, signs of facial
aging in darker skin occur 10–20 years later than in Cau­
casians, and is more often evident in the deeper muscular
layers in the face.
Loss of volume in the mid-face and prominent tear
troughs have also been reported to be more striking fea­
tures of aging in African-Americans. Perioral rhytides are
uncommon in darker skin types and therefore the upper
face is the primary site of facial rhytides in patients with
skin of color. Photoaging differences in Hispanics / Latinos
are less well characterized, but vary considerably, given the
broad range of Fitzpatrick skin types (I–VI) found in this
population.
Safety and efficacy of botulinum toxins in
darker skin types
The safety and efficacy of botulinum neurotoxin type A
in the treatment of glabellar lines has been well studied
in numerous populations (Table 21.1). Published data per­
taining to the safety and efficacy of botulinum toxin in
non-white patient populations are reviewed herein.
A multicenter, double-blind, placebo controlled study
of onabotulinumtoxinA (onabot-A) (Botox Cosmetic®,
Allergan, Inc., Irvine, CA) by Carruthers and colleagues
in 2002 investigated safety and efficacy in the treatment
of glabellar lines in 409 patients. No appreciable differ­
ences were observed between various skin phototypes.
21 
Darker skin types
Pearl E. Grimes, Andrew F. Alexis
Introduction
Demographic trends coupled with the increased availabil­
ity of minimally invasive treatment options have led to an
increasingly diverse patient population in the aesthetic
arena. According to the American Society for Aesthetic
Plastic Surgery, 19% of the 10 million cosmetic proce­
dures performed in the United States (US) in 2010, were
performed on racial / ethnic minorities (8% Hispanic,
6% African-American, 4% Asian descent, 1% other non-
Caucasian race / ethnicity). This proportion is expected to
increase over the next decade as non-white racial and
ethnic groups form a rapidly growing segment of the US
population. Similar trends are likely to be seen globally.
As such, understanding racial or ethnic variations in safety,
efficacy, and approaches to treatment is of increasing
importance to the aesthetic physician.
Racial / ethnic differences in photoaging
Facial rhytides are a common concern across the racial
and ethnic spectrum. However, variations in severity, age
of onset, and cultural impact can be seen in different
populations. In general, as the studies by Hexsel & Bru­
netto and Rossi & Alexis reported, individuals with richly
pigmented skin (i.e. Fitzpatrick skin types IV–VI) dem­
onstrate signs of photoaging, including rhytides, at a later
age than do individuals with fair skin (Fitzpatrick skin
Summary and Key Features
•
Botulinum toxin is a safe and effective procedure
in darker skin types
•
In general, efficacy and safety profiles are similar
to lighter skin types
•
With appropriate use, side effects are uncommon
•
Injection techniques are similar to lighter skin types
•
Commonly treated areas are glabellar and
horizontal forehead lines

143
21 
Darker skin types
and transient and did not differ between the dosing
groups. They included mild tingling, slight headaches, and
dullness of the forehead.
In a Phase III study by Kane and colleagues of abobotu­
linumtoxinA (abobot-A) (Dysport®, Medicis Aesthetics,
Phoenix Arizona) for the correction of moderate to severe
glabellar lines, no significant racial / ethnic differences in
overall safety were observed using total doses of 50, 60,
or 70 units for women and 60, 70, or 80 units for men in
a single treatment. However, abobot-A-treated African-
American patients had a slightly higher rate of ocular
African-Americans
Grimes & Shabazz conducted a Phase IV study of onabot-A
in the treatment of glabellar lines in 31 African-American
women with Fitzpatrick skin types V and VI. The authors
assessed the safety and efficacy at doses of 20 and 30 units
(U) of onabot-A. No statistically significant differences in
efficacy or safety were observed between the two doses
(Figs 21.1, 21.2). A maximal response was observed on day
30, with 92.4% and 100% response rates (i.e. a score of
‘none’ or ‘mild’ on the facial wrinkle scale) in the 20 U
and 30 U groups respectively. Adverse events were mild
Figure 21.1  Glabellar rhytides at maximum frown in patient injected
with 30 U botulinum toxin type A at: (A) baseline, (B) day 30, (C)
day 60, (D) day 90, (E) day 120. Reproduced with permission from
Grimes PE, Shabazz D A four-month randomized, double-blind
evaluation of the efficacy of botulinum toxin type A for the treatment
of glabellar lines in women with skin types V and VI. Dermatol Surg.
Mar 2009; 35(3):429–436.
A
B
C
D
E

144
Botulinum toxin
Table 21.1  Published studies of botulinum toxin in darker skin types
Study
Design
Cohort
Treatment
(serotype brand,
dose)
Site
Follow-up
Outcome measures (1:
primary 2: secondary)
Grimes &
Shabazz
Randomized
double-
blind; single
site
31 African-
American
women,
Fitzpatrick skin
types V and VI,
ages 18–65
onabot-A: 20 U,
30 U
Glabellar
rhytides
4 months
1: Investigator’s
assessment on a facial
wrinkle scale at
maximum frown and
repose
2. Patient’s assessment
of rhytid severity at
maximum frown and
repose, patient
satisfaction, and
incidence of adverse
events
Harii &
Kawashima
Randomized,
double-
blind,
placebo-
controlled;
multicenter
142 Japanese
subjects, 90%
female, ages
20–64
onabot-A: 10 U,
20 U
Glabellar
rhytides
5 months
1. Physician-rated line
severity at maximal
contraction 4 weeks
after treatment
2. Physician / subject
ratings and estimates
of the effect’s duration
Kawashima &
Harii
Randomized,
open-
labeled;
multicenter
363 Japanese
subjects,
BoNT-A naive,
95% female,
ages 20–64
years
onabot-A: 10 U,
20 U
Glabellar
rhytides
16 months
1. Physician-rated line
severity at maximal
contraction (used for
the analysis of the
duration of efficacy
and responder rates)
assessed at all
post-treatment visits
for each treatment
cycle
2. Physician-rated line
severity at rest and the
subject-rated line
improvement
Kane et al
Phase III,
double-
blind,
placebo-
controlled;
multicenter
816 subjects,
80.6% BoNT-A
naive, 88.1%
female, 32%
non-Caucasian,
mean age = 49
years
abobot-A:
Female: 50, 60,
70 U
Male: 60, 70, 80 U
Glabellar
rhytides
5 months
1. Live assessment by
a blinded evaluator
and patient self-
assessment at
maximum frown using
the Glabellar Line
Severity Score
Farahvash &
Arad
Retrospective
non-
blinded;
single site
108 Iranian
subjects, 88%
female, ages
20–79 years
abobot-A:
76–90 U
Lateral canthal,
frontal,
glabellar
rhytides
7 months
1. Investigator’s
assessment of
dynamic (animation)
lines on a wrinkle
improvement scale

145
21 
Darker skin types
Efficacy (objective
assessment at
peak response)
Adverse events
Conclusions
Efficacy or safety
differences in
race / ethnicity
Efficacy
Safety
Day 30
20 U: 92.4%
30 U: 100%
20 U: 13.3%,
30 U: 12.5%
1. Mild tingling
2. Headache
3. Dull forehead sensation
Efficacious, safe, and well tolerated at
doses of 20 and 30 U in African-
American women with skin types V
and VI, with no statistical significant
difference between dosage.
None
None
Week 4
10 U: 86.4%
20 U: 88.6%
Adverse events:
10 U: 67.4%,
20U: 75.0%,
Placebo: 59.2%
1. Blepharoptosis
2. Heavy eyelids
Adverse drug reactions:
10 U: 32.6%, 20U: 27.3%,
Placebo: 22.4%
Doses of BoNT-A of 10 and 20 U are
effective and safe for treating
glabellar lines in Japanese subjects.
20 U dosagee provides greater efficacy
and longer duration of effect.
None
None
Week 4
10 U: 92.2-97.6%
20 U: 91.5-98.7%
Adverse events:
10 U: 86.7%; 20 U: 83.1%
Adverse drug reactions:
10 U: 30.6%; 20
U: 32.2%
1. Abnormal sensations in eye
2. Headache
3. Blepharoptosis
4. Pruritus (injection site)
5. Discomfort (injection site)
6. Pain (injection site)
Repeated treatments of glabellar lines
with 10 or 20 U of BoNT-A provided
long-term safety and efficacy in
Japanese subjects.
20 U dose provided longer duration,
greater subject satisfaction, and
greater subject-rated improvement.
Repeated treatments with BoNT-A
did not affect the duration and
effectiveness, provided an
unchanged safety profile, and was
well tolerated.
None
None
30 days
Caucasian: 84%
African-American:
89%
Other race: 85%
Treatment-emergent adverse
events and relatedness to
study treatment:
Probable: 6%
Possible: 3%
1. Eye disorders: eyelid ptosis,
blurred vision, asthenopia,
eyelid edema,
blepharospasm, dry eye,
eyelid disorder
2. Administration-site
conditions: erythema,
bruising, hemorrhage,
pain / discomfort, irritation,
edema
3. Nervous disorder:
headache, migraine,
dizziness, facial paresism
hypoesthesia, parasthesia,
tension headache
A single treatment with BoNT-A, with
the dose based on gender and
muscle mass is well tolerated,
efficacious, and long lasting in the
treatment of moderate to severe
glabellar lines.
Response rates were higher in
African-Americans than in
Caucasians.
Although African-Americans had an
incidence of total treatment-emergent
adverse events similar to other ethnic
groups, BoNT-A-treated African-
Americans had a slightly higher
incidence of ocular adverse events in
the treated group and a lower
incidence of injection-site reactions.
Yes
Yes
<1 month
97.2%
76–90 U:
1. Mild swelling: 13.9%
2. Ecchymosis: 9.2%
3. Eyelid ptosis: 15%
Safe and effective, providing good to
excellent cosmetic results lasting at
least 4 months in the majority of the
Iranian patients.
None
None
Table 21.1  Published studies of botulinum toxin in darker skin types (Continued)
Study
Grimes &
Shabazz
Harii &
Kawashima
Kawashima &
Harii
Kane et al
Farahvash &
Arad

146
Study
Design
Cohort
Treatment
(serotype brand,
dose)
Site
Follow-up
Outcome measures (1:
primary 2: secondary)
Ahn et al
Retrospective,
non-
blinded;
single site
32 Korean
subjects,
86.8% female,
ages 26–56
years
onabotulinumtoxinA:
5–10 U
lateral canthal,
frontal, nasal
dorsum,
glabellar
rhytides
12 mo
1. patient satisfaction
Lew et al
Randomized,
non-
blinded,
non-
placebo
controlled;
single site
20 Korean
subjects, 80%
female,24–60
years
abobotulinumtoxinA:
20 U/0.1 cm3
onabotulinumtoxinA:
5 U/0.1 cm3
lateral canthal,
frontal, nasal
dorsum,
nasolabial
fold,
glabellar
rhytides
12 mo
1. investigator’s
assessment of
changes in degree of
facial wrinkles on a
graded scale and a
graded wrinkle spread
test
Chang et al
Randomized,
double-
blind,
placebo-
controlled,
split face
study;
single site
9 BoNTA-naive
Taiwanese
subjects,
88.9% female,
ages 35–55
years
onabotulinumtoxinA:
20–25 U
bilateral
temporal
areas,
bilateral
cheeks from
infraorbital
to jaw line
4 mo
1. the effect of face-lift,
skin tightness and
wrinkles soothing
on a graded scale
evaluated subjectively
by patients; the
bilateral facial wrinkles
and face-lifting effect
of subjects evaluated
objectively by a
dermatologist
2. evaluation of histologic
changes of biopsy
samples
Kadunc et al
Randomized,
double-
blind,
placebo-
controlled,
intra-patient
study;
single site
12 women,
Fitzpatrick skin
types II–IV ages
47–69
onabotulinumtoxinA:
1.5 U
unilateral
vermillion
border
36 mo
1. investigator’s
assessment of
comparing pre- and
post-treatment
photographs on a
facial wrinkle scale at
maximum contraction
Wu et al
Prospective,
double-
blind,
randomized,
placebo-
controlled,
parallel-
group
comparative
study
222 Chinese
subjects,
83.5% female,
mean age
42.3 years
onabotulinumtoxinA:
20 U
glabellar
rhytides
4 mo
1. investigator’s rating of
glabellar line severity at
maximum frown on
day 30 using a facial
wrinkle scale
2. subjects’ global
assessment of change
in the appearance of
glabellar lines graded
on a 9-point scale
Table 21.1  Published studies of botulinum toxin in darker skin types (Continued)

147
Efficacy (objective
assessment at
peak response)
Adverse events
Conclusions
Efficacy or safety
differences in
race / ethnicity
Efficacy
Safety
4–5 mo
unsatisfied: 6.25%
slightly improved:
15.6%
slight line retained:
78.1%
5–10 U:
1. Altered facial appearance:
9.36%
2. Mild local swelling: 6.25%
3. Ecchymosis at injection site:
9.36%
BoNTA seems to be an effective
method of eliminating wrinkle lines
on the upper third of the face in
Korean patients.
None of the patients experienced
complete removal of wrinkle lines.
None
None
3–5 mo
onabotulinumtoxinA:
72.7%
abobotulinumtoxinA:
64.3%
onabotulinumtoxinA: 35.7%
abobotulinumtoxinA: 100%
1. Lagophthalmos
2. Tingling
3. Temporary lid edema
Either preparation of BoNTA seems to
be a safe, simple and effective
nonsurgical method of eliminating
periorbital wrinkles in Korean patients.
Mean corrective effect was better
in onabotulinumtoxinA than
abobotulinumtoxinA although not
statistically significant.
Complications occurred in all
abobotulinumtoxinA patients and in
35.7% of onabotulinumtoxinA
patients and differences were
statistically significant
None
None
Week 4
66.7%
20–25 U:
1. Periorbital muscle
Weakness: 11.1%
2. Mild/moderate stinging
3. Tolerable pain at injection
site: 100%
Face-lifting effects of intradermal
BoNTA injection in this study was not
conclusive.
The technique demonstrated in this
study, however, showed moderate
but significant wrinkles soothing
effect on the lower face for 8 weeks.
The use of BoNTA among this Asian
cohort demonstrated moderate
efficacy, tolerability and no severe
adverse events.
None
None
6 mo
83.3%
1.5 U:
1. Edema: 100%
2. Erythema: 66.6%
3. Post-inflammatory
hyperpigmentation: 33.3%
4. Localized hypochromia:
8.3%
5. Mild herpes simplex virus
eruption: 8.3%
6. Interference with eating/
drinking: 33.3%
Pretreatment with BoNTA improves
short- and long-term results of
perioral chemabrasion in the
treatment of severe vertical upper
perioral rhytides.
Transient post-inflammatory
hyperpigmentation (PIH) was notably
observed in 16.6% Fitzpatrick type III
and 100% type IV patients. PIH was
reported to be transient and
amenable to bleaching creams.
None
Yes
(however,
not
related to
botulinum
toxin
injection)

30 days
BoNTA: 94.1%
Placebo: 3.5%
Adverse events
BoNTA: 32.3% Placebo:
19.3%
1. Headache BoNTA: 8.8%,
Placebo: 1.7%
2. Abnormal eye sensation
BoNTA: 5.3%
3. Ptosis BoNTA: 0.6%
4. Nasopharyngitis
BoNTA:7.1%
The efficacy results showed highly
statistically significant differences
between the study drug and placebo
groups at all time points, with 94.1%
of subjects in the BoNTA group
responding at maximum frown as
rated at day 30 by investigators.
This response exceeded the results
reported for U.S. studies of 83.7%1
and 76.7%9 and is comparable with
the Japanese response rate of
88.6%.
OnabotulinumtoxinA administered
intramuscularly at a total dose of 20
U in the corrugator and procerus
muscles is an effective treatment for
reducing the severity of glabellar
lines for up to 120 days in Chinese
people with moderate and severe
glabellar lines who are younger than
65. Treatment is safe and well
tolerated.
None
None
Table 21.1  Published studies of botulinum toxin in darker skin types (Continued)
Study
Ahn et al
Lew et al
Chang et al
Kadunc et al
Wu et al

148
Botulinum toxin
adverse events (6% for African-Americans versus 4% for
other ethnicities) and a lower rate of injection-site reac­
tions (3% versus 5% for other ethnicities). With respect
to efficacy, the response rates and duration of action of
abobot-A were found to be slightly higher in African-
American subjects. Specifically, the median duration of
action by blinded investigator evaluation was 117 days and
109 days for African-Americans and the overall popula­
tion, respectively.
The reproducibility and potential etiology of these
observed differences in African-Americans warrant further
study.
Figure 21.2  Glabellar rhytides at maximum frown in patient injected
with 20 U botulinum toxin type A at: (A) baseline, (B) day 30, (C)
day 60, (D) day 90, (E) day 120. Reproduced with permission from
Grimes PE, Shabazz D Mar 2009 A four-month randomized,
double-blind evaluation of the efficacy of botulinum toxin type A for
the treatment of glabellar lines in women with skin types V and VI.
Dermatol Surg 35(3):429-436.
A
B
C
D
E
Pearl 1 
Appropriate magnification of injection sites is important to
avoid vessels in darker skin types.
Pearl 2 
Some patients are fearful of the procedure so consider
avoiding multiple injections of anatomical sites during the first
procedure. Allow the patient time to acclimatize to botulinum
toxin injections.

149
21 
Darker skin types
chemabrasion with 35% trichloroacetic acid and manual
dermabrasion 7 days’ post-injection. Transient postinflam­
matory hyperpigmentation occurred in 33% (4/12) of
subjects and this was observed in subjects with higher
Fitzpatrick skin types – Type III (n = 2) and Type IV (n =
2). Significantly less wrinkling (on the Facial Wrinkle
Severity scale) was seen from day 90 to year 3 in the
onabot -A-treated sides than in placebo.
Ethnic specific applications of
botulinum toxin
As with any cosmetic procedure, taking into consideration
a patient’s individual aesthetic ideals (which may, in turn,
be influenced by culture and ethnicity) is paramount.
Making broad generalizations about specific approaches
that should be employed for a given racial / ethnic group
can be problematic as can imposing Occidental aesthetic
ideals on all patients regardless of their ethnicity. Notwith­
standing these caveats, certain aesthetic goals can be
observed more frequently in specific racial / ethnic groups
and contribute to variations in the specific uses of botuli­
num toxin in patients of different backgrounds.
In East Asian populations the desire to have a wider
and rounder appearance of the eye is common. Botulinum
toxin is a popular non-invasive option for widening the
palpepral aperture in that population. As reported by
Flynn et al, treating the lower eyelid with 2 U of onabot-A
(into the orbicularis oculi in the mid-pupillary line 3 mm
below the ciliary margin) combined with 12 U in the
crow’s feet, can produce an approximately 3 mm widen­
ing of the palpebral aperture at full smile and is a useful
approach in addressing this concern in East Asians.
The lower third of the face is frequently wider in East
Asians compared with Caucasian due to a larger mandibu­
lar width and / or hypertrophy of the masseter muscle.
However, many East Asian women consider a more
oval facial contour more aesthetically pleasing and seek
cosmetic treatments to reduce the appearance of a square-
shaped face. Reducing masseter hypertrophy using botu­
linum toxin is a popular procedure to achieve this goal,
especially among Korean women. A study by Kim et al of
121 female patients in Korea treated with 100–140 U of
abobot-A to the masseter muscle bilaterally demonstrated
a decrease in masseter thickness by ultrasonography,
which correlated with the number of treatment sessions.
Contouring of the calves using botulinum toxin is a
popular procedure in Korean women. An ovoid shaped
calf is commonly described as ‘radish-like leg’ in Korean
and is frequent cosmetic concern in that population.
Studies by Kim et al and Lee et al have demonstrated
safety and efficacy of botulinum toxin for the treatment
of enlarged gastrocnemius muscles in Koreans.
Conclusion
Given extensive published data demonstrating similar
safety and efficacy in darker skin populations as seen in
Asians
A multicenter, randomized, double-blind, placebo-
controlled study by Harii & Kawashima of 142 Japanese
subjects compared the safety and efficacy of 10 U versus
20 U onabot-A in the treatment of glabellar lines. Response
rates in each active treatment group (10 U and 20 U)
differed significantly from placebo (86.4% and 88.6%,
respectively, versus 0% in the placebo group), but not
from each other. The incidence of adverse events did not
differ significantly between groups. An open-label, ran­
domized, 64-week study by the same group involved 363
Japanese subjects and evaluated the safety and efficacy of
repeated (up to five) treatments of 10 U and 20 U of
onabot-A. The 20 U dose resulted in a significantly longer
duration of effect than 10 U (17.1 ± 6.58 weeks and 14.8
± 5.38 weeks respectively) and greater subject satisfaction
without any significant differences in treatment-related
adverse events.
An open-label study of 38 Korean patients by Ahn and
co-workers evaluated the efficacy and safety of onabot-A
in this population. Injections of 5–10 U were injected into
the lateral canthal area, glabellar region, forehead, and / or
nasal dorsum (depending on the individual patient’s
wrinkle status) and the number of treatment sessions per
subject ranged from 1 to 4. Approximately 69% of the
patients had a duration of response of 13 weeks or more.
Unexpected or ethnic-specific adverse events were not
observed. In another Korean study by Lew et al, subjects
were randomized to receive onabot-A (n = 14) or abobot-A
(n = 6) and monitored 6–12 months post-treatment. Sites
of injection included the lateral canthi, glabella, forehead,
nasal dorsum, and nasolabial fold area. Both botulinum
toxins demonstrated a comparable degree and duration of
effect and were well tolerated.
A small randomized, double-blind, placebo-controlled,
split face study by Chang and colleagues involving nine
Taiwanese subjects evaluated the ‘face-lifting’ and wrinkle-
reducing effect of onabot-A injected into the middle
and lower face. No significant face-lifting effects were
observed, but moderate wrinkle reduction was observed
without unexpected or ethnic-specific treatment related
adverse events.
Brazilians
The adjunctive use of onabot-A for the treatment of peri­
oral vertical wrinkles in Brazilian subjects (Fitzpatrick skin
types II–IV) was investigated in a randomized, double-
blind, intrapatient controlled study by Kadunc et al (n =
12). Subjects with moderate to severe vertical rhytides
of the upper lip were randomized to receive onabot-A
or saline (control) at the vermilion border followed by
Pearl 3 
Very small doses of onabotulinumtoxinA (4 units), may
improve crow’s feet in African-American women.

150
Botulinum toxin
Caucasians, individual variations in muscle anatomy are
more important than skin type or racial / ethnic back­
ground in the context of treating patients with botulinum
toxin for facial aesthetic concerns. As a general rule, tailor­
ing each treatment to a given patient’s individual anatomy
and aesthetic goals (rather than relying on broad general­
izations about racial or ethnic facial features) is the best
strategy to employ when injecting neurotoxins. However,
some ethnic specific variations in common aesthetic con­
cerns exist, and these, in turn, contribute to unique appli­
cations for botulinum toxins in certain populations.
Understanding these nuances in aesthetic ideals and the
specific techniques to address them is increasingly impor­
tant given the growing diversity of the patient population
seeking cosmetic treatments with botulinum toxins.
Further reading
Ahn J, Horn C, Blitzer A 2004 Botulinum toxin for masseter
reduction in Asian patients. Archives of Facial Plastic Surgery
6(3):188–191
Ahn KY, Park MY, Park DH, et al 2000 Botulinum toxin A for the
treatment of facial hyperkinetic wrinkle lines in Koreans. Plastic
and Reconstructive Surgery 105(2):778–784
Carruthers JD, Glogau RG, Blitzer A 2008 Advances in facial
rejuvenation: botulinum toxin type a, hyaluronic acid dermal
fillers, and combination therapies – consensus recommendations.
Plastic and Reconstructive Surgery 121(5 suppl):S5–S30; quiz
S31–S36
Carruthers JA, Lowe NJ, Menter MA, et al 2002 A multicenter,
double-blind, randomized, placebo-controlled study of the
efficacy and safety of botulinum toxin type A in the treatment
of glabellar lines. Journal of the American Academy of
Dermatology 46(6):840–849
Chang SP, Tsai HH, Chen WY, et al 2008 The wrinkles soothing
effect on the middle and lower face by intradermal injection of
botulinum toxin type A. International Journal of Dermatology
47(12):1287–1294
Davis EC, Callender VD 2011 Aesthetic dermatology for aging
ethnic skin. Dermatologic Surgery 37(7):901–917
Flynn TC 2003 Periocular botulinum toxin. Clinical Dermatology
21(6):498–504
Flynn TC, Carruthers JA 2001 Botulinum-A toxin treatment of the
lower eyelid improves infraorbital rhytides and widens the eye.
Dermatologic Surgery 27(8):703–708
Grimes P 2003 Skin of color. Diseases and cosmetic issues of major
concern. Cosmetic Dermatology 16:1–4
Grimes PE (ed) 2004 Aesthetics and Cosmetic Surgery for Darker
Skin Types, 1st edn. Lippincott Williams & Wilkins, Philadelphia
Grimes PE, Shabazz D 2009 A four-month randomized, double-
blind evaluation of the efficacy of botulinum toxin type A for
the treatment of glabellar lines in women with skin types V and
VI. Dermatologic Surgery 35(3):429–436
Han KH, Joo YH, Moon SE, et al 2006 Botulinum toxin A
treatment for contouring of the lower leg. Journal of
Dermatologic Treatment 17(4):250–254
Harii K, Kawashima M 2008 A double-blind, randomized,
placebo-controlled, two-dose comparative study of botulinum
toxin type A for treating glabellar lines in Japanese subjects.
Aesthetic Plastic Surgery 32(5):724–730
Harris MO 2004 The aging face in patients of color: minimally
invasive surgical facial rejuvenation – a targeted approach.
Dermatologic Therapy 17(2):206–211
Hexsel DM, Hexsel CL, Brunetto LT 2008 Botulinum toxin. In:
Grimes PE (ed) Aesthetics and Cosmetic Surgery for Darker
Skin Types, 1st edn. Lippincott Williams & Wilkins,
Philadelphia, p 214–215
Kadunc BV, Trindade DEAAR, Vanti AA et al 2007 Botulinum
toxin A adjunctive use in manual chemabrasion: controlled
long-term study for treatment of upper perioral vertical
wrinkles. Dermatologic Surgery 33(9):1066–1072; discussion
1072
Kaidbey KH, Agin PP, Sayre RM, et al 1979 Photoprotection by
melanin – a comparison of black and Caucasian skin. Journal of
the American Academy of Dermatology 1(3):249–260
Kane MA, Brandt F, Rohrich RJ, et al 2009 Evaluation of
variable-dose treatment with a new U.S. botulinum toxin type
A (Dysport) for correction of moderate to severe glabellar lines:
results from a phase III, randomized, double-blind, placebo-
controlled study. Plastic and Reconstructive Surgery
124(5):1619–1629
Kawashima M, Harii K 2009 An open-label, randomized, 64-week
study repeating 10- and 20-U doses of botulinum toxin type A
for treatment of glabellar lines in Japanese subjects.
International Journal of Dermatology 48(7):768–776
Kim NH, Park RH, Park JB 2010 Botulinum toxin type A for the
treatment of hypertrophy of the masseter muscle. Plastic and
Reconstructive Surgery 125(6):1693–1705
Lee HJ, Lee DW, Park YH, et al 2004 Botulinum toxin a for
aesthetic contouring of enlarged medial gastrocnemius muscle.
Dermatologic Surgery 30(6):867–871; discussion 871
Lew H, Yun YS, Lee SY, et al 2002 Effect of botulinum toxin
A on facial wrinkle lines in Koreans. Ophthalmologica
216(1):50–54
McKnight A, Momoh AO, Bullocks JM 2009 Variations of
structural components: specific intercultural differences in facial
morphology, skin type, and structures. Seminars in Plastic
Surgery 23(3):163–167
Nouveau-Richard S, Yang Z, Mac-Mary S, et al 2005 Skin ageing: a
comparison between Chinese and European populations. A pilot
study. Journal of Dermatologic Science 40(3):187–193
Rossi A, Alexis A 2011 Cosmetic procedures in skin of color.
Giornale Italiano di Dermatologia e Venereologia
146(4):265–272
(website):
Yamaguchi Y, Beer JZ, Hearing VJ 2008 Melanin mediated
apoptosis of epidermal cells damaged by ultraviolet radiation:
factors influencing the incidence of skin cancer. Archives of
Dermatological Research 300(suppl 1):S43–S50

Introduction
Although botulinum toxin (BoNT) effectively targets
hyperfunctional rhytides, deeper folds and wrinkles –
along with changes in skin texture, pigmentation, and
other signs of photodamage – require additional rejuvena­
tion modalities to obtain optimal results. The very nature
of chemodenervation has propelled its use in adjunctive
settings, where reduced muscular activity promotes
healing and remodeling of the skin. Used in combination
with soft tissue augmentation, laser resurfacing, light-
based therapies, or surgery, BoNT has been shown to
prolong and enhance aesthetic results. Moreover, a greater
understanding of volume depletion in the face has led to
a shift in the approach to rejuvenation. Over time, loss of
fat and bony changes in the face cause the skin to sag and
reposition into folds and hollows. A multi-faceted approach
and all-encompassing three-dimensional treatment plan
target not only muscular movement via BoNT but also
volumizing and contouring with soft tissue augmentation
to create an aesthetically pleasing outcome.
22 
Combination treatment
Alastair Carruthers, Jean Carruthers
Summary and Key Features
•
Aging in the face is not simply defined by the
appearance of wrinkles
•
Treatments targeting superficial rhytides do not
address the underlying loss of volume or changes
in skin texture or pigmentation
•
A three-dimensional approach to facial
augmentation must consider the interaction and
influence of adjacent areas
•
Multiple modalities may be required for optimal
outcomes
•
Current approaches to rejuvenation combine
augmentation and contouring with movement
control
•
Augmentation of entire regions may eliminate the
need for additional procedures
•
Lasers and light-based therapies improve
pigmentation and texture of the skin
•
The popularity of surgical procedures has declined
with the availability of less-invasive options
•
BoNT enhances the outcome of soft tissue
augmentation, resurfacing, and surgical procedures
•
Concomitant BoNT extends the duration of the
filling agent and improves cosmetic appearance
•
Used in combination with resurfacing, BoNT
promotes better healing of newly remodeled skin
•
Chemodenervation targets dynamic rhytides and
immobilizes musculature underlying or surrounding
a wound or surgical incision
•
Immobilization of musculature promotes healing
and prevents dehiscence, particularly for wounds
or scars that lie in an area of great mobility
•
Reduced muscular activity during the healing
process leads to superior cosmesis
Pearl 2 
Neurotoxin and filler together give refined and elegant and
more complete aesthetic results, especially in older subjects.
Pearl 1 
Neurotoxin alone and filler alone give very good results,
especially in younger subjects.
Soft tissue augmentation
In the last few years, clinicians have gained a greater
appreciation for the three-dimensional approach to facial
rejuvenation. Treating the surface of the skin – the lines
and wrinkles that emerge over time – does not address the
volume loss that characterizes the aging process. Volume
loss in the glabella and forehead may combine with brow
and eyelid ptosis and reduced lateral brow projection (Fig.
22.1). Repetitive movements of facial expression, loss of
bone, and thinning of the skin due to photodamage all
exacerbate this age-related fat depletion. Loss of support

152
Botulinum toxin
from underlying bony structures and tissue causes skin to
sag and reposition over the changing contours of the face.
Current approaches to facial rejuvenation combine aug­
mentation and contouring with movement control, using
BoNT in combination with HA fillers to achieve results
that are longer lasting and more satisfying in resting glabel­
lar rhytides, brow-height adjustment, horizontal forehead
lines, nasojugal folds, sculpting the zygomatic and perioral
regions, and to improve the appearance of the neck (Table
22.1). Pre-treatment with BoNT serves to reduce the
dynamic component of the target rhytide, which may
allow more accurate estimation of the volume of filler
needed and preventing overcorrection. Moreover, che­
modenervation may increase the longevity of the implant
by reducing microextrusion caused by repetitive muscular
motion.
A number of studies have shown superior efficacy and
patient satisfaction associated with combination therapy
compared to fillers alone, particularly in individuals with
deep resting rhytides. In 2003, Carruthers and colleagues
compared the efficacy of BoNT alone or in combination
with hyaluronic acid (HA) in 16 patients with moderate-
to-severe resting glabellar rhytides via retrospective analy­
sis. Response to the filling agent plus chemodenervation
was compared clinically and photographically to the
response to BoNT alone. In 94% of patients receiving
combination therapy, severity of rhytides decreased from
moderate or severe to mild. By contrast, patients receiving
BoNT alone experienced only moderate success. To further
examine the relationship between chemodenervation and
filling agents, Carruthers and Carruthers conducted a ran­
domized trial of 38 patients with moderate-to-severe gla­
bellar rhytides receiving HA alone or in combination with
Figure 22.1  The aging face is characterized by loss of volume, bony
changes, thinning skin, and rhytides and folds.
Table 22.1  BoNT and soft tissue augmentation
Filling agents
Indications for combination therapy
Outcomes
Hyaluronic acid
– Deep resting glabellar rhytides
– Horizontal forehead rhytides and brow lift
– Nasojugal folds / hypertrophic orbicularis
– Melomental folds / mouth frown
– Facial contouring
– Neck
– Reduced dynamic component of rhytide
– More accurate estimation of filler volume
(preventing overcorrection)
– Increased longevity of implant
– Superior aesthetic result
–  Restylane®
–  Perlane®®
–  Juvéderm®
–  Voluma
–  Prevelle Silk®
Calcium hydroxylapatite
–  Radiesse®
Collagen
–  Evolence®
Poly-L-lactic acid
–  Sculptra®

153
22 
Combination treatment
understanding of the three-dimensional nature of aging,
particularly loss of volume from and bone remodeling in
the malar and zygomatic regions, brow, and infraorbital
hollow. Moreover, clinicians take a more holistic approach,
considering not only the treatment of targeted rhytides
and folds, but also their interaction with adjacent regions
and the influence of augmentation on the appearance of
the face as a whole. Volumizing the glabella and medial
forehead, for example, can lift the brow, soften forehead
lines, elevate the root of the nose, and lessen horizontal
procerus rhytides (Fig. 22.4). The authors (JC and AC)
use fillers increasingly to layer in a smooth, thin sheet of
filler throughout entire regions (i.e. the forehead, upper
lip, sides of the chin and anterior cheeks), lessening the
need for other modalities.
Figure 22.2  Response to combination of HA with BoNT:
(A) pre-treatment, and (B) post-treatment.
A
B
BoNT; the latter group showed a better response both at
rest and on maximum frown (Fig. 22.2). The addition of
BoNT also extended the duration of the filling agent, from
18 weeks for HA alone, to 32 weeks for combination
therapy. Patel and colleagues found improved clinical
effects of longer duration and greater patient satisfaction
in 65 subjects who received BoNT and collagen for the
treatment of glabellar rhytides compared to patients who
received either modality alone. In 2010, Carruthers and
colleagues demonstrated similar results in a multicenter,
randomized trial of 90 women treated with BoNT, HA, or
in combination for rejuvenation of the perioral area and
lower face. Combination therapy was superior to either
modality used alone (Fig. 22.3).
Although initially considered treatment for only deeper
folds and rhytides, combination treatment with toxins and
fillers is considered the standard regimen for facial reju­
venation in many cosmetic offices, with a greater emphasis
on augmentation. This shift comes, in part, from a greater
Pearl 6 
In lower face and neck, the combination is also effective, with
the relaxation of the platysma improving the cervicomental
angle and the filler along the mandibular margin elevating the
skin of the neck and smoothing the contour of the jawline.
Pearl 5 
In both upper and lower face, the filler lasts much longer
when the subject also receives neurotoxin to relax the
musculature.
Pearl 4 
In the lower face, neurotoxin added to filler gives a smoother
jawline and elevation of the mouth corners and support for
the vertical perioral rhytides (‘lipstick lines’).
Pearl 3 
In the upper face, filler added to neurotoxin gives a softer and
more natural result, especially with filler reflation of the entire
forehead and temples.
Lasers and light-based therapies
Lasers – including broadband light and radiofrequency
devices – have become an indispensable part of the cos­
metic surgeon’s armamentarium in combating photoaging
(Table 22.2). Concomitant use of BoNT and these devices
leads to optimal improvement of dynamic rhytides, supe­
rior and longer-lasting outcomes, better healing of newly
remodeled skin, and a more permanent eradication of
wrinkles.
Ablative lasers
Ablative laser resurfacing with either carbon dioxide
(CO2) or erbium : yttrium aluminum garnet (Er : YAG)

154
Botulinum toxin
Figure 22.3  Perioral rejuvenation with BoNT alone (A, D), Juvéderm (B, E), or in combination (C,F). (A–C): Baseline; (D–F): after 24 weeks.
A
B
C
D
E
F
Table 22.2  Lasers and light-based therapies with adjuvant BoNT
Lasers / light-based therapies
Indications for combination therapy
Outcomes
Ablative
– Lower eyelid
– Lateral canthus
– Perioral region
– Reduced appearance of rhytides
– Healing of newly remodeled skin
– Superior and longer-lasting outcomes
– Prevention of underlying musculature from
molding into new folds or rhytides
– Carbon dioxide
– Erbium : yttrium aluminum garnet
Non-ablative
– Intense pulsed light
– Thermage

155
22 
Combination treatment
Figure 22.4  (A, B) Soft tissue augmentation of the glabella and
medial forehead enhances aesthetic appearance of the brow without
other modalities.
A
B
lasers has shown dramatic facial rejuvenation. Without
concurrent BoNT, dynamic rhytides commonly recur or
may even appear more pronounced after resurfacing in
the lower eyelid, lateral canthus, and perioral regions
within 6–12 months because of continued animation.
Not only does pre-treatment with BoNT allow for undis­
turbed healing and remodeling and better aesthetic results,
but regular postoperative injections (every 6–12 months),
in addition to an ongoing appropriate skin care program
(sunscreen, alpha-hydroxy acid, tretinoin) can prolong
the effects of resurfacing and provide a better long-
term result. In a prospective, clinical study, Carruthers &
Carruthers first reported better aesthetic result when
combining BoNT and resurfacing to the periocular area,
later corroborated by West & Alster, who showed enhanced
and more prolonged correction of forehead, glabellar, and
lateral canthal rhytides over a 9-month period when com­
bining CO2 laser therapy with BoNT. Additional studies
by Worcester and Zimbler and colleagues confirmed that
chemodenervation prior to laser resurfacing for the treat­
ment of hyperdynamic facial rhytides yielded superior
results compared to resurfacing alone, particularly in areas
of greater mobility.
Combination therapy may be used in a number of
therapeutic areas. Injections in the perioral region must
be approached with caution to avoid interference with the
function of the lips and mouth. When softening vertical
perioral rhytides and marionette lines, concomitant use of
BoNT weakens an overactive depressor anguli oris muscle
contributing to the depressive pull on the lip corners and
formation of deep creases. BoNT administered to the
orbicularis oris can diminish vertical lines caused by the
lip sphincter. Chemodenervation may also be applied prior
to the use of full-face resurfacing to enhance the softening
of the forehead and periocular rhytides and nasolabial
folds by injections into the frontalis, glabella, orbicularis
oculi, and sometimes the zygomaticus complex.
Non-ablative light sources
Photodynamic therapy, such as intense pulsed light (IPL),
and non-ablative radiofrequency energy (Thermage) are
popular, non-invasive technologies used to reverse photo­
aging with less recovery time or risk associated with abla­
tive laser resurfacing.
IPL – a non-ablative broadband light source – is one of
the most successful treatment options for the treatment
of photodamaged skin, reducing both lentigines and vas­
cular lesions, such as telangiectasias, port-wine stains, and
poikiloderma. Studies have shown that IPL improves skin
texture, pore size, and fine wrinkles, though the jury is
out on the treatment of all rhytides with IPL alone. Com­
bination therapy with BoNT, however, increases the
overall aesthetic benefit, with an improvement in texture
and telangiectasis, along with a decrease in the appearance
of rhytides.
Carruthers & Carruthers compared IPL alone or in
combination with BoNT for the treatment of the peri­
orbital area. Patients who received both modalities expe­
rienced a 15% improvement in overall aesthetic benefit
at the 6-month evaluation (Fig. 22.5). Remarkably, the
overall improvement in wrinkling, texture, and blemishes
in the combined treatment group exceeded those of
the IPL-only group more than 6 months after BoNT, far
longer than the expected duration of its direct effect. The
noted improvements in telangiectasias underscore the
ability of BoNT to regulate blood vessel constriction and
treat persistent facial flushing. Although the complete
mechanism of action is not fully understood, this enhance­
ment may be partially due to the denervating effect of
BoNT, which prevents the active muscular disturbance
of newly deposited dermal collagen. Similarly, Khoury
and colleagues evaluated small wrinkles and fine lines,
erythema, hyperpigmentation, pore size, skin texture, and
overall appearance for 8 weeks in a randomized, split-face
study in which patients were treated with BoNT or saline
plus IPL. Adjunctive BoNT achieved a greater degree

156
Botulinum toxin
post-treatment injections aid in stabilizing musculature
while procedures heal (reducing repetitive muscular
actions and thus the rate of dehiscence), improving out­
comes and longevity of the procedure and circumventing
complications, particularly for brow lift, blepharoplasty,
and facelift.
Endoscopic brow lift
Endoscopic brow lift has gained wide recognition as a
novel technique to correct brow ptosis in a minimally
invasive manner with fewer complications than the classic
coronal brow lift method. However, unpredictable results
and postsurgical complications – alopecia, hairline changes,
brow asymmetry, paresthesia, frontal branch nerve paraly­
sis, and scalp dysesthesia – have led to a decline in popu­
larity, particularly with the discovery of the less-invasive
chemical brow lift produced by BoNT that approaches
endoscopic lift in magnitude.
Chemical brow lift through BoNT was discovered ser­
endipitously from treatment of glabellar frown lines, when
it became apparent that treatment resulted in central and
medial brow elevation as well due to partial inactivation
of improvement in small wrinkles and fine lines and
erythema.
A monopolar radiofrequency (RF) device that delivers
a controlled thermal injury to the deep dermis, the Ther­
mage CPT system (Solta Medical, Hayward, California)
was introduced in 2002 and became a popular option to
impart mild tightening of the skin, particularly in the
brow, periorbital region, and mid- and lower face. Research
suggested that Thermage was a safe and effective treat­
ment for rejuvenation that compared favorably to other
non-ablative devices with modest improvements in facial
rhytides. However, Thermage is not without risks: poor
patient selection can result in disappointing outcomes and
satisfaction, and results are often unpredictable. Although
no controlled studies are available, BoNT can be used in
combination with Thermage to immobilize musculature,
prolonging duration of effect and enhancing elevation
when used as part of non-surgical browlift procedures. As
in the case of non-ablative lasers, BoNT serves to inhibit
the underlying muscles from molding the newly formed
collagen into additional wrinkles.
Aesthetic surgery
As a result of the increasing demand for non-invasive,
injection-based facial rejuvenation, the number of surgi­
cal procedures in cosmetic dermatology has declined.
However, some patients – such as those with excessive
lower eyelid fat, for example – cannot be treated ade­
quately with BoNT, fillers, or resurfacing alone and require
surgical intervention. In many surgical approaches in the
head and neck, underlying muscular action can reverse the
intended surgical outcome, and therefore results may be
short-lived. Chemodenervation is a strong partner and key
adjunct to many aesthetic surgeries (Table 22.3). Pre- and
Figure 22.5  The synergy of IPL and BoNT:
greater improvement in overall aesthetic
appearance 6 months after combination
therapy (Botox® plus intense pulsed light).
Data from Carruthers J. Carruthers A 2004
The effect of full-face broad band light
treatments alone and in combination
with bilateral crow’s feet BTX-A
chemodenervation. Dermatologic Surgery
vol 30, issue 3, March:355–366
A little
better
Better
1.77
n=15
1.27
n=15
A lot
better
1
1.5
2
2.5
3
Week 3
Week 6
Week 9
Week 12
Week 18
Week 26
2.07
n=15
1.58
n=15
2.35
n=15
1.80
n=15
2.34
n=14
2.09
n=14
2.33
n=13
1.98
n=13
2.13
n=13
1.80
n=14
IPL
Botox & IPL
Table 22.3  BoNT before surgery
Surgical procedures
Outcomes
Brow lift
Blepharoplasty
Lateral canthal suspension
Facelift
Neck procedures
– Stabilization of musculature
during healing
– Reduced rate of dehiscence
– Fewer post-surgical
complications
– Improved aesthetic outcome
and longevity

157
22 
Combination treatment
recurrent bands with BoNT can avoid further surgery and
improve aesthetic appearance; injection of the platysma
before and after the procedures may enhance the longev­
ity of the outcome. In addition, post-facelift synkinesis –
in which the buccal branch of the VII nerve has been
peripherally damaged and activates the levator labii supe­
rioris or zygomaticus when the patient blinks – can be
alleviated by small doses (1–2 U) of BoNT into the
affected muscle. Similarly, injury to the marginal man­
dibular nerve controlling the depressors of the lower lip
is a complication of neck liposuction that often accompa­
nies facelifts and repairs to the platysma. It is usually
short-lived and BoNT administered to the contralateral
side may re-establish symmetry while the nerve damage
recovers.
Wound healing and scars
Injection of BoNT prior to surgical procedures or into the
muscles underlying or surrounding a sutured wound has
shown to improve cosmesis and aid in the healing process
(Table 22.4). Because the major factor influencing the final
appearance of a scar is the tension exerted on the edges
of the wound in the healing stage, wound immobilization
is a basic therapeutic principle in plastic surgery. Surgi­
cal techniques for immobilization can only reduce – not
eliminate – such tension. As a result, continuous muscle
activity surrounding a wound leads to a prolonged inflam­
matory response and hypertrophic and hyperpigmented
scars. Pre-treatment of the underlying muscles in surgical
procedures allows surgeons to use finer sutures and achieve
better cosmesis. Animal and human studies have shown
that immobilization with BoNT in the muscles surround­
ing or underlying a sutured wound can improve the cos­
metic appearance of cutaneous scars by eliminating tension
produced by muscular forces surrounding the scar in the
face and elsewhere. Gassner and colleagues first demon­
strated a statistically significant improvement in the
appearance of forehead lacerations immobilized by BoNT
compared to control wounds in primates in 2000; a sub­
sequent randomized, placebo-controlled study of 31
human subjects presenting with traumatic forehead lac­
erations or undergoing elective excisions of forehead
masses showed that patients who received BoNT in the
and increased resting tone of the frontalis. Although injec­
tions of BoNT alone can effectively treat mild brow ptosis,
moderate-to-severe ptosis requires endoscopic brow
lifting to restore the brow to its normal position. Brow
lifts may have unpredictable outcome depending on the
postsurgical healing. Stabilization of the brow musculature
is essential since periosteal refixation requires approxi­
mately 6–12 weeks. During this healing period, BoNT
provides the perfect tool to chemically maintain the brows
in elevated positions to prevent a quick descent. Pre-
treatment of the brow depressors 2 weeks prior to opera­
tive lifting can not only promote periosteal fixation to the
desired position (with less resistance to surgical brow
repositioning) but also may prevent uneven regrowth of
the muscles, a possible complication of surgical excision
of the depressor fibers. In the postoperative setting, injec­
tions of BoNT can extend the life of the elevations
provided by endoscopic brow lifts, which are often com­
promised within 6 months, and can be used to correct any
resultant eyebrow asymmetry.
Blepharoplasty
Many patients requiring upper lid blepharoplasty have one
brow slightly lower than the other. In order to prevent
complications, pre-treatment with BoNT in the manner
of a chemical brow lift creates brows of equal height and
allows the surgeon to more accurately estimate the amount
of skin to be resected and hold the incision line within the
confines of the orbital margin, leading to a superior aes­
thetic surgical result.
For lower eyelid blepharoplasty, BoNT enhances wound
healing (see below) and is often used as reinforcement
during lateral canthal suspension procedures, such as the
lateral tarsal strip or lateral retinacular suspension, to
prevent dehiscence and protect the security of the recon­
struction. The results of the surgery are often compro­
mised by the repetitive muscular actions that distort the
outcome. Lateral tarsal strip procedures often end in
dehiscence of the temporal repair; pre-treatment with
5 U BoNT into the lateral fibers of the orbicularis will
minimize the pull on the medial side of the surgical inci­
sion through repeated muscular contraction, treating the
lateral canthal rhytides at the same time. Eyelid malposi­
tion sometimes results from prior surgical procedures; the
clinician can use BoNT in the postoperative setting to
correct any remaining or resultant asymmetries.
Facelift
Facelift, necklift, and platysma repair surgeries involve the
imbrication of the superficial musculoaponeurotic system
and the plication of the platysma muscle, leading to even­
tual platysmal banding and a noted contrast between the
rejuvenated face and the untreated neck. Moreover, in
necklift and platysma repair surgeries, the activity of the
platysma pulls the skin downward and can reverse the
effect of the procedures over time. Treatment of these
Table 22.4  Adjunctive BoNT to promote wound healing
and improve the appearance of scars
Indications for adjuvant
therapy
Outcomes
Anywhere; particularly
useful in areas of greater
mobility, such as the
periorbital or perioral
regions
– Immobilization of wound
– Use of finer sutures
– Eliminated muscular activity
– Decreased tension on
wound edges
– Improved aesthetic outcome
and longevity

158
Botulinum toxin
scars with intralesional BoNT and document not only an
improved appearance of the hypertrophic scar, but also
significantly lower incidences of erythema, itching, and
pliability than before injections.
Conclusion
Greater knowledge and understanding of the aging process
and the underlying changes to volume and bone have
caused a shift to a three-dimensional approach to facial
rejuvenation. The appearance of the face as a whole – and
the influence of adjacent anatomical areas – must be con­
sidered for optimal improvement. Often, patients who
present for surgical procedures or invasive ablative resur­
facing can obtain similar results through non-invasive
injections requiring little downtime with fewer complica­
tions. BoNT is enormously effective in addressing hyper­
dynamic musculature contributing to the appearance of
superficial wrinkles. Deeper rhytides and folds are a result
of both volume loss in the glabella, forehead, cheeks, and
lower face, and changes to the bony landmarks. Augmen­
tation restores underlying support and returns the face to
a more youthful yet natural countenance. When used as
an adjunct, BoNT lengthens the duration of filling agents
and complements the effects of other modalities, such as
resurfacing and surgery. Immobilization of the underlying
musculature prevents the emergence of new wrinkles and
serves an important role in the process of wound healing,
decreasing the tension on the edges of a wound or surgical
scar, leading to a superior cosmetic outcome and a greater
level of patient satisfaction.
Further reading
Alster TS 1997 Laser resurfacing of rhytides. In: Alster TS (ed)
Manual of cutaneous laser techniques. Lippincott-Raven
Publishers, Philadelphia, p 104–122
Balikian RV, Zimbler MS 2007 Primary and adjunctive uses
of botulinum toxin type A in the periorbital region.
Otolaryngologic Clinics of North America 40:291–303
Carruthers A, Carruthers J 2001 Botulinum toxin type A: history
and current cosmetic use in the upper face. Seminars in
Cutaneous Medicine and Surgery 20:71–84
Carruthers A, Carruthers J, Cohen J 2003 A prospective,
double-blind, randomized, parallel-group, dose-ranging study
of botulinum toxin type a in female subjects with horizontal
forehead rhytides. Dermatologic Surgery 29:461–467
Carruthers A, Carruthers J, Monheit GD, et al 2010 Multicenter,
randomized, parallel-group study of the safety and effectiveness
of onabotulinumtoxinA and hyaluronic acid dermal fillers
(24-mg/mL smooth, cohesive gel) alone and in combination
for lower facial rejuvenation. Dermatologic Surgery 36(suppl 4):
2121–2134
Carruthers J, Carruthers A 1998 Combining botulinum toxin
injection and laser for facial rhytides. In: Coleman WP,
Lawrence N (eds) Skin resurfacing. Williams & Wilkins,
Baltimore, MD, p 235–243
Carruthers J, Carruthers A 1998 The adjunctive usage of botulinum
toxin. Dermatologic Surgery 24:1244–1247
Carruthers J, Carruthers A 2003 A prospective, randomized,
parallel group study analyzing the effect of BTX-A(Botox) and
nonanimal sourced hyaluronic acid (NASHA, Restylane) in
musculature adjacent to the wound within 24 hours expe­
rienced enhanced healing and cosmesis (Fig. 22.6). Choi
and colleagues showed that postoperative treatment with
BoNT prevented complications in a series of 11 patients
at high risk of impaired wound healing after complex
eyelid reconstruction, and Flynn found that intraoperative
BoNT aided wound healing in patients undergoing surgical
reconstruction after Mohs micrographic surgery for the
treatment of skin cancer.
Chemodenervation is particularly helpful for the treat­
ment of established scars caused by acne, trauma, or
surgery that lie in a highly mobile area, such as the fore­
head and glabella or around the mouth (marionette lines,
lips, and chin), which may be exaggerated by movement.
Over a period of time, recurrent muscular activity is weak­
ened by atrophic scarring, forcing the skin into unnatural
folds and accentuating the appearance of the scar. BoNT
in combination with filling agents targets muscular activity
and augments the deeper lines and folds, improving the
overall appearance of the skin. Wilson induced temporary
paralysis of the muscles with intraoperative injections of
BoNT in 40 patients undergoing revision surgery for
unsightly facial scars; BoNT minimized the tension of the
wound edges and led to improved aesthetic outcomes in
90% of patients. Xia and colleagues treated hypertrophic
Figure 22.6  Traumatic scar to the right forehead: (A) 2 weeks after
suturing and (B) 18 months after dermabrasion and BoNT-A
maintenance.
A
B

159
22 
Combination treatment
Hedelund L, Due E, Bjerring P, et al 2006 Skin rejuvenation using
intense pulsed light: a randomized controlled split-face trial
with blinded response evaluation. Archives of Dermatology
142:985–990
Huilgol SC, Carruthers A, Carruthers JD 1999 Raising eyebrows
with botulinum toxin. Dermatologic Surgery 25:373–375
Khoury JG, Saluja R, Goldman MP 2008 The effect of botulinum
toxin type A on full-face intense pulsed light treatment: a
randomized, double-blind, split-face study. Dermatologic
Surgery 34:1062–1069
Patel MP, Talmor M, Nolan WB 2004 Botox and collagen for
glabellar furrows: advantages of combination therapy. Annals of
Plastic Surgery 52:442–447
Sherris DA, Gassner HG 2002 Botulinum toxin to minimize facial
scarring. Facial Plastic Surgery 18:35–39
Weiss RA, Weiss MA, Beasley KL 2002 Rejuvenation of photoaged
skin: 5 years results with intense pulsed light of the face, neck,
and chest. Dermatologic Surgery 28:1115–1119
Weiss RA, Weiss MA, Munavalli G, et al 2006 Monopolar
radiofrequency facial tightening: a retrospective analysis of
efficacy and safety in over 600 treatments. Journal of Drugs in
Dermatology 5:707–712
West TB, Alster TS 1999 Effect of botulinum toxin type A on
movement-associated rhytides following CO2 laser resurfacing.
Dermatologic Surgery 25:259–261
Wilson AM 2006 Use of botulinum toxin type A to prevent
widening of facial scars. Plastic and Reconstructive Surgery
117:1758–1766
Worcester S 2000 Use of Botox before and after laser facial
resurfacing. Skin Allergy News. Online. Available: http://

Xia Z, Zhang F, Cui Z 2009 Treatment of hypertrophic scars with
intralesional botulinum toxin type A injections: a preliminary
result. Aesthetic Plastic Surgery 33:409–412
Yuraitis M, Jacob CI 2004 Botulinum toxin for the treatment of
facial flushing. Dermatologic Surgery 30:102–104
Zimbler MS, Holds JB, Kokoska MS, et al 2001 Effect of
botulinum toxin pretreatment on laser resurfacing results: a
prospective, randomized, blinded trial. Archives of Facial Plastic
Surgery 3:165–169
Zimbler MS, Nassif PS 2003 Adjunctive applications of botulinum
toxin in facial aesthetic surgery. Plastic Surgery Clinics of North
America 11:477–482
Zimbler MS, Holds JB, Kokoska MS 2001 Effect of botulinum
toxin pretreatment on laser resurfacing results: a prospective,
randomized, blinded trial. Archives of Facial Plastic Surgery
165:165–169
combination compared with NASHA (Restylane) alone in severe
glabellar rhytides in adult female subjects: treatment of severe
glabellar rhytides with a hyaluronic acid derivative compared
with the derivative and BTX-A. Dermatologic Surgery
29:802–809
Carruthers J, Carruthers A 2004 The effect of full-face broadband
light treatments alone and in combination with bilateral crow’s
feet botulinum toxin type A chemodenervation. Dermatologic
Surgery 30:355–366
Carruthers J, Carruthers A, Maberley, D 2003 Deep resting
glabellar rhytides respond to BTX-A and Hylan B. Dermatologic
Surgery 29:539–544
Carruthers J, Carruthers A, Tezel A, et al 2010 Volumizing with a
20-mg/mL smooth, highly cohesive viscous hyaluronic acid filler
and its role in facial rejuvenation therapy. Dermatologic Surgery
36:1–7
Carruthers J, Carruthers A, Zelichowska A 2000 The power of
combined therapies: Botox and ablative facial laser resurfacing.
American Journal of Cosmetic Surgery 17:129–131
Choi JC, Lucarelli MJ, Shore JW 1997 Use of botulinum toxin in
patients with high risk of wound complications following eyelid
reconstruction. Ophthalmologic and Plastic Reconstructive
Surgery 13:259
Coleman KR, Carruthers J 2006 Combination therapy with
BOTOX and fillers: the new rejuvenation paradigm.
Dermatologic Therapy 19:177–188
Fagien S, Brandt FS 2001 Primary and adjunctive use of botulinum
toxin type A (Botox) in facial aesthetic surgery: beyond the
glabella. Clinics in Plastic Surgery 28:127–148
Flynn TC 2009 Use of intraoperative botulinum toxin in facial
reconstruction. Dermatologic Surgery 35:182–188
Frankel AS, Kamer FM 1998 Chemical browlift. Archives of
Otolaryngology – Head and Neck Surgery 124:321–323
Gassner HG, Brissett AE, Otley CC, et al 2006 Botulinum toxin
to improve facial wound healing: A prospective, blinded,
placebo-controlled study. Mayo Clinic Proceedings
81:1023–1028
Gassner HG, Sherris DA 2003 Chemoimmobilization: improving
predictability in the treatment of facial scars. Plastic and
Reconstructive Surgery 112:1464–1466
Gassner HG, Sherris DA, Friedman O 2009 Botulinum toxin-
induced immobilization of lower facial wounds. Archives of
Facial Plastic Surgery 11:140–142
Gassner HG, Sherris DA, Otley CC 2000 Treatment of facial
wounds with botulinum toxin A improves cosmetic outcome in
primates. Plastic and Reconstructive Surgery 105:1948–1953
Goodman GJ 2010 The use of botulinum toxin as primary or
adjunctive treatment for post-acne and traumatic scarring.
Journal of Cutaneous and Aesthetic Surgery 3:90–92

Introduction
Botulinum toxin is a safe, well-established, and effective
treatment for focal axillary hyperhidrosis. This chapter
will present the principles and common techniques for its
practical application in this clinical setting.
Sweating
Sweating is the normal physiological response to increased
body temperature. It is an important mechanism for
releasing heat produced by endogenous and exogenous
sources. Sweating is controlled by the sympathetic nervous
system. The sympathetic nervous system predominantly
utilizes the neurotransmitter norepinephrine to activate
adrenergic receptors on peripheral tissues. Sweating is one
exception. Muscarinic receptors on clear cells of eccrine
glands are activated by acetylcholine from post-ganglionic
neurons, stimulating sweat release.
Eccrine glands are unequally distributed in the skin.
High concentrations occur in areas including the palms,
soles, and forehead. Located at the junction of the dermis
and subcutaneous fat, their function is to secrete a hypo­
tonic solution for thermoregulation by evaporation.
Hyperhidrosis
Hyperhidrosis describes excess sweating beyond that nec­
essary for physiological thermoregulation and homeosta­
sis. The amount of sweat necessary to be considered
‘excessive’ is not well defined and varies between individu­
als. The eccrine glands in patients with primary hyperhi­
drosis do not demonstrate any histopathologic changes or
glandular hyperplasia.
Hyperhidrosis may be classified as generalized or focal.
Generalized hyperhidrosis typically occurs as the result
of an underlying cause (secondary origin). Focal or local­
ized hyperhidrosis may have a secondary origin; for
example, lesions or tumors of the central or peripheral
nervous system. However, more commonly, focal hyper­
hidrosis is idiopathic (primary origin) and referred to
simply as ‘hyperhidrosis’ (HH). Diagnostic criteria for
primary hyperhidrosis have been suggested by a consen­
sus panel (Box 23.1). Evaluation and testing should be
tailored by the history and review of systems. This
chapter will focus on primary focal axillary hyperhidrosis,
23 
Focal axillary hyperhidrosis
Dee Anna Glaser, Adam R. Mattox
Summary and Key Features
•
Sweating is controlled by the sympathetic nervous
system; however, eccrine glands are activated by
acetylcholine
•
Eccrine glands in patients with primary
hyperhidrosis do not demonstrate any
histopathologic changes or glandular hyperplasia
•
Hyperhidrosis prevalence is reported to be 2.8%,
though it may be underestimated owing to
undiagnosed cases
•
The hyperhidrosis disease severity scale (HDSS) is
a validated scale that is used in selecting patients
appropriate for therapy and assessing
effectiveness of treatment
•
The starch iodine test is a simple, colormetric test
to detect the presence of active sweat glands and
identify the surface area involved. In the event of a
negative or equivocal result, the hair-bearing skin
is a good estimate of the area necessary to treat
•
The axillary procedure is well tolerated; no
anesthesia is required as pain is minimal
•
OnabotulinumtoxinA is FDA approved for treatment
of axillary hyperhidrosis. When injected at the
depth of the deep dermis and subcutaneous
tissue, the chemodenervation is localized,
reversible, and long lasting
•
Currently the US standard dose listed in the
package insert for onabotulinumtoxinA is 50 units
per axilla
•
An average of 10–15 injections (0.1–0.2 mL each)
should be delivered to each axilla
•
If symptoms persist after treatment, repeat the
starch iodine test to detect any area that may have
been missed. A small area of active sweating is
easily touched up with 1–2 injections
•
If treatment response is overall inadequate or short
lived (e.g. 1–2 months), simply increase the dose
of onabotulinumtoxinA to 100 units per axilla
•
Retreatment with onabotulinumtoxinA will average
every 6–7 months, but can vary depending on the
patient’s response

161
23 
Focal axillary hyperhidrosis
henceforth identified simply as axillary hyperhidrosis
(AHH).
Epidemiology
The prevalence of HH was reported by Strutton et al
to be 2.8%, though it may be underestimated due to
undiagnosed cases. The prevalence is similar for men
and women, although interestingly, Lear and colleagues
reported that women are more likely to seek evaluation
and treatment. Trigger factors include emotional stress,
higher environmental temperatures, and stimulants such
as caffeine. However, episodes of excessive sweating can
occur without any known trigger. The body areas most
often affected are the axilla, palms, soles, craniofacial,
inframammary and groin (Table 23.1).
Quality of life
Hyperhidrosis has a negative impact on physical, psycho­
logical, and occupational aspects of a patient’s daily living.
Hamm and colleagues found that the greatest impact of
HH is the significant reduction in the quality of life and
alteration of daily function. Patients report a lack of
Table 23.1  Hyperhidrosis site prevalence in a patient
population reported with respect to each site*
Anatomical site
Prevalence (%)
Axilla
73
Palms
45.9
Soles
41.1
Face / scalp
22.8
Groin
9.3
Other sites (eg. Inframammary,
Buttocks, etc.)
9.6
*Data from Lear W, Kessler E, Solish N, et al 2007 An
epidemiological study of hyperhidrosis. Dermatologic Surgery
33:S69–S75.
Table 23.2  Hyperhidrosis disease severity scale
question: Which best describes the impact of sweating
on your daily activity?
Score
Answer
1
My (underarm) sweating is never noticeable and
never interferes with my daily activity.
2
My (underarm) sweating is tolerable but sometimes
interferes with my daily activity.
3
My (underarm) sweating is barely tolerable and
frequently interferes with my daily activity.
4
My (underarm) sweating is intolerable and always
interferes with my daily activity.
*Hornberger J, Grimes K, Naumann M, et al 2004 Recognition,
diagnosis, and treatment of primary focal hyperhidrosis. Journal
of the American Academy of Dermatology 51:274–286.
Box 23.1 
Criteria to diagnose primary focal hyperhidrosis*
n
Focal, visible excessive sweating of at least 6
months’ duration, and
n
No apparent secondary cause, and
n
At least two of the following characteristics:
–
Bilateral and relatively symmetric
–
Age of onset <25 years
–
Positive family history
–
Cessation of focal sweating during sleep
–
Frequency of episodes at least once a week
–
Impairs daily activities
confidence and depressed mood. They refrain from
meeting new people and avoiding intimate activity. Excess
sweat may force patients to change clothes several times
before the end of the day.
The hyperhidrosis disease severity scale (HDSS) is a
validated scale that is used in selecting patients appropri­
ate for therapy and assessing effectiveness of treatment.
The HDSS is based on one question the patient can
answer in the office: ‘Which best describes the impact of
sweating on your daily activity?’ The answer is rated with
a single value 1–4, with 3–4 corresponding to uncontrolled
severe HH (Table 23.2). It is frequently used in clinical
practice to assess the need for therapy and response to it.
Clinical assessment of hyperhidrosis
The starch iodine test is a simple way to detect the presence
of sweat and identify the surface area involved, however it
is not quantitative. The test is effective on both shaved and
non-shaved skin. To perform, the skin to be tested is com­
pletely dried using a towel. An iodine solution (commonly
Betadine®) is painted over the field and allowed to dry (Fig.
23.1). After the solution is thoroughly dry, a starch powder
such as plain cooking corn starch is sprinkled on the surface.
Various tools may be used to accomplish the distribution
of starch such as loose gauze, cosmetic brushes or a fine-
opening shaker (Fig. 23.2). Accurate colormetric results are
achieved when the amount of powder is minimized. Mois­
ture from sweat dissolves the iodine and starch followed
by a chemical reaction producing a purple to black color.
True positive reactions have a speckled appearance as mois­
ture is released from duct openings (Fig. 23.3). For iodine-
sensitive patients, Alizarin or Ponceau red dye and starch
can be used instead. Regardless of which is used, a colori­
metric outline of the sweating area is achieved.
Pearl 1 
The starch iodine test is a simple, colorimetric test to
identify the surface area involved. If results are negative or
equivocal, the hair-bearing skin is a good estimate of the
area necessary to treat.

162
Botulinum toxin
treated with botulinum toxin. These include aminogly­
cosides, penicillamine, quinine, and calcium channel
blockers.
Botulinum toxin A has been used for several decades
to treat AHH. In 2004, onabotulinumtoxinA was FDA
approved for treatment of AHH. It is a purified neuro­
toxin produced by clostridium botulinum. The toxin pre­
vents the release of acetylcholine from the nerve axon at
the neuroglandular junction producing a state of denerva­
tion. Since sweating is mediated by acetylcholine, the use
of botulinum toxin (BoNT) to treat AHH is a logical
choice. When injected intradermally, the chemodenerva­
tion is localized, reversible, and yet long lasting.
OnabotulinumtoxinA, abobotulinumtoxinA, and inco­
botulinumtoxinA are derived from Botulinum toxin type A
(BoNT-A). OnabotulinumtoxinA and abobotulinumtoxinA
False positives occur if the skin has not been thoroughly
dried of sweat or if iodine solution is not thoroughly dry
prior to starch application. This appears as streaks or
smears of dark pigment (Fig. 23.4). False negatives may
occur if starch is applied too heavily (Box 23.2).
Botulinum toxin therapy
Contraindications to botulinum toxin A include prior
allergic reaction, injection into areas of infection or inflam­
mation, pregnancy (category C), or breastfeeding. Relative
contraindications include diseases of the neuromuscular
junction (e.g. myasthenia gravis, Eaton-Lambert) cau­
tiously because underlying generalized weakness can be
exacerbated. Some medications decrease neuromuscular
transmission and would be prudent to avoid in patients
Figure 23.1  Iodine is applied to a clean dry
surface.
Figure 23.2  Cornstarch is applied sparingly
after iodine has dried.

163
23 
Focal axillary hyperhidrosis
have been most extensively studied for HH. Botulinum
toxin type B can be effective, but Dressler et al and Frasson
et al reported that the side effect profile is quite different
from BoNT-A. Given its effectiveness and safety profile,
onabotulinumtoxinA has emerged as the clinically pre­
ferred treatment. As dosing is different among the BoNT-A
products, these agents cannot be used interchangeably.
The foremost principle for using BoNTs to treat exces­
sive sweating is, as discussed, to treat any underlying etiol­
ogy first. The area of involvement should be objectively
identified using a colorimetric test such as a starch iodine
test. Sweat glands are typically located at the junction of
the dermis and subcutaneous fat. For optimal BoNT inter­
action at the neuron–eccrine interface, it should be placed
as a deep intradermal injection. Injections are generally
placed 1–2 cm apart to allow to diffusion into the entire
Figure 23.3  True positive starch iodine
results.
Figure 23.4  If residual sweat or moist
iodine is not dried before starch is applied,
darkened smearing is the result and should
be considered as artifact.
Box 23.2 
Key features of a successful starch iodine test
1. Rule out iodine allergy.
2. Sweat must be thoroughly dried from skin.
3. Iodine in castor oil or a Betadine® swab is used to
apply a layer of iodine to a wide area of skin.
4. Iodine must dry before applying starch powder.
5. Standard cooking corn starch gives superb results
compared with other starch products.
6. Sprinkle starch powder, rubbing may create smear
artifacts.
7. Minimizing the amount of starch powder gives most
accurate results.
8. In the event of a negative or equivocal result, the
hair-bearing skin is a good estimate of the area
necessary to treat.

164
Botulinum toxin
symptom free after 9 months. Moreover, 58% remained
symptom free for a full 12 months.
Currently the US standard dose listed in the package
insert for onabotulinumtoxinA is 50 units per axilla. This
achieves excellent results, high patient satisfaction, and
helps to keep cost down. If the response is not adequate
or of short duration, it is the authors’ practice to repeat
the starch iodine test to assess the possibility of inade­
quately treated area. Then if indicated, touch up areas or
simply increase the dose of onabotulinumtoxinA to 100
units per axilla. There is no such dosing consensus on
other brands of BoNT-A products.
To concentrate the BoNT-A into the affected area and
optimize treatment, the area of involvement should be
identified by a starch iodine test (as previously reviewed).
Injection points may be marked with a pen to ensure
adequate treatment (Fig. 23.5). The axilla does not need
to be shaved prior to performing a starch iodine test or
before injecting BoNT-A. The BoNT-A is injected into
the deep dermis at the dermal subcutaneous level. Each
injection is placed 1–2 cm apart. Thin axillary skin allows
for visualization of a wheal at each site (Fig. 23.6). An
average of 10–15 injections per axilla are required, but will
depend on the size of the axilla and hyperhidrodic area.
In the event that a starch iodine test cannot be performed
prior to treatment or the test is equivocal, the physician
should treat the hair-bearing areas using the same tech­
nique (Box 23.3).
area. It is important to avoid injecting deeper structures
to prevent unwanted denervation. This basic technique
used to treat axillae can be applied to most areas of the
body with minor variations.
Different philosophies exist for choosing a dilution
volume. The prevailing sentiment seems to be that a high
volume (lower concentration) will diffuse to treat more
area. Locations where high volume would be appropriate
are axillae, scalp, inframammary, and inguinal skin. In an
area such as the forehead, a large diffusion field increases
the risk of developing brow ptosis, thus a lower volume
(higher concentration) may be employed.
Reisfeld and colleagues reported that compensatory
hyperhidrosis is a common side effect of endoscopic
thoracic sympathectomy (ETS). This phenomenon is con­
sidered rare in BoNT injection therapy. Occasionally
patients report the perception of increased sweating in
untreated anatomical locations after having the primary
site treated. The authors have never seen clinically signifi­
cant compensatory HH after onabotulinumtoxinA treat­
ment. However, some patients will notice the sweat more
from other body areas after their primary location has
been treated and is dry.
Axillary hyperhidrosis
No area of the body has been studied as extensively as the
axillae. Numerous studies show the benefit of BoNT-A,
including
large,
multicenter,
randomized,
placebo-
controlled trials in Europe and the United States. One
study by Naumann & Lowe reported on 320 patients with
AHH who received 50 units of Botox® (onabotulinum­
toxinA) per axilla or placebo. At 4 weeks, 94% of the
onabotulinumtoxinA group had responded compared with
36% of the placebo group. Response was determined by
≥50% reduction in sweat production from baseline. By 16
weeks, the response rates were 82% and 21%, respec­
tively. The mean duration between onabotulinumtoxinA
treatments was approximately 7 months.
Similar results were published in a large Phase III
double-blind trial in North America by Lowe and
co-workers. Subjects with AHH (HDSS of 3 or 4) were
randomized to receive placebo, 50 units, or 75 units ona­
botulinumtoxinA into each axilla. A successful response
occurred in 75% of patients in both treatment groups com­
pared with 25% in the placebo group (defined as ≥2 point
reduction in HDSS). No significant differences were noted
between the two doses of onabotulinumtoxinA and the
durability of therapy was approximately 7 months for both.
Although studies have consistently shown that 50 units
onabotulinumtoxinA per axilla provides safe and durable
results, there is some debate whether higher doses of
onabotulinumtoxinA can provide prolonged efficacy.
When Wollina used 200 units of onabotulinumtoxinA per
hand in 10 patients, his relapse time varied from 3 to 22
months. In one small open label study by Heckmann and
colleagues, 250 units of abobotulinumtoxinA in each axilla
resulted in prolonged benefit; 83% of which remained
Pearl 2 
Reconstituted onabotulinumtoxinA is drawn into 1 mL Luer
lock syringes and a 30-gauge needle is attached.
Pearl 3 
The standard dose of onabotulinumtoxinA is 50 units per
axilla delivered by 10–15 wheal-forming injections.
Should symptoms fail to improve within 2 weeks, the
patient should return to the office for a repeat starch
iodine test to identify any persistently ‘active’ eccrine
glands (Fig. 23.7). The skin should be injected with 3–5
units of BoNT-A for each centimeter surface area
identified.
Pearl 4 
If treatment response is not adequate or of short duration,
it is worthwhile to repeat the starch iodine test to assess
inadequately treated areas. If indicated, touch-up areas or
simply increase the dose of onabotulinumtoxinA to 100 units
per axilla.
Pain is minimal and the axillary procedure is well
tolerated. Despite the package insert describing the use
of unpreserved saline to reconstitute BoNT-A, many
physicians (e.g. Alam and colleagues, Sarifakioglu &

165
23 
Focal axillary hyperhidrosis
Retreatment with onabotulinumtoxinA will average
every 6–7 months, but can vary depending on the patient’s
response. In order to extend the interval between injec­
tions, Lowe and colleagues advocate patient use of a
topical antiperspirant twice a week when sweating starts
to return.
Use of botulinum toxin type B for
hyperhldrosis
Botulinum toxin type B (BoNT-B) use has been primarily
limited to treatment of cervical dystonia, but there are
reports of its use for treating HH. Birklein and co-workers
Sarifakioglu) have found the use of preserved saline
reduces pain without altering efficacy. Side effects noted
in studies include pain, hematoma, bruising, headache,
muscle soreness, increased facial sweating, perceived com­
pensatory sweating, and axillary pruritus.
Figure 23.6  Depth of injection is at the
dermal–subcutaneous junction. In the axilla,
a small wheal can be visualized.
Figure 23.5  Injection points are marked
1.5–2 cm apart in a staggered arrangement
for efficient coverage after medication
diffusion.
Pearl 5 
Despite the package insert describing the use of unpreserved
saline to reconstitute botulinum toxin type A, many physicians
have found the use of preserved saline reduces pain without
altering efficacy.

166
Botulinum toxin
Techniques for non-axillary hyperhidrosis
Aside from axillary hyperhidrosis, onabotulinumtoxinA
may be used to treat a wide variety of sweating disorders.
However, it should be noted that its use to treat these
conditions is off-label. The principles for treating other
areas of the body generally parallel the techniques
described above for axillae, but with minor variations.
The optimum dose of BoNT-A to control palmar HH
is unknown and the issue is complicated by large varia­
tions in hand size. Published data by Saadia et al and
Wollina et al report doses as low as 50 units per hand
and as high as 200 units onabotulinumtoxinA per hand.
Naumann’s group used 2 units every 1.5 cm on the palm
but 3 injections per fingertip and 2 injections into each
of the middle and proximal phalanx using 1–2 units per
injection. The authors inject 2.5 units of onabotulinum­
toxinA in the pattern described above. Additionally, pain
is much more a factor in palmar treatment procedures.
Various methods may be used during injection to attain
acceptable pain control. Some of which include cold anes­
thesia, vibratory sensory interference, topical anesthesia,
and nerve blocks.
There is a paucity of literature published on BoNT-A
therapy for craniofacial hyperhidrosis. It is the observation
of the authors that patients typically present with fore­
head sweating that may be combined with scalp sweating
in a diffuse pattern or in an ophiasis pattern. Onabotu­
linumtoxinA reconstituted at 50 units/mL (twice the con­
centration used in axillae) may be used in an effort to limit
the diffusion into the frontalis muscle and reduce the risk
of brow ptosis. Injections are performed with 2–3 units
every 1–2 cm avoiding the inferior 1–2 cm of the forehead
to again reduce the risk of brow ptosis. Typical doses of
onabotulinumtoxinA used by the authors are 50–100 units
to treat the forehead and frontal hairline, 200 units to
Figure 23.7  If treatment is incomplete, a
repeat starch iodine test can help identify
small areas of active sweat production that
may have been missed.
Box 23.3 
Key features of Botox® treatment of axillae
1. Rule out contraindications of botulinum toxin
therapy.
2. Identify involved surface area using starch iodine test
or other colormetric test.
3. Axillary pain is minimal; anesthesia is predominantly
unnecessary.
4. Reconstitute 100 units (one standard vial) of
onabotulinumtoxinA with 4 mL of sterile saline.
5. Fifty units of onabotulinumtoxinA (2 mL) are injected
per axilla.
6. Depending on the size of the axilla, an average of 15
injection points per axilla are used.
7. Injections are delivered at deep dermal to superficial
subcutaneous depth.
found that injection of BoNT-B can induce focal anhidrosis
in a dose-dependent fashion. Dressler reported that 100
units onabotulinumtoxinA, 2000 units BoNT-B, and 4000
units BoNT-B were equally effective in blocking axillary
sweating when studying 19 HH patients. The duration of
relief was similar (16 weeks) in all groups. In general, the
onset of action occurs earlier with BoNT-B.
Despite its ability to induce anhidrosis, Schlereth and
colleagues found that the use of BoNT-B is limited by the
occurrence of systemic adverse events. Additionally, there
was greater discomfort with the BoNT-B compared with
onabotulinumtoxinA. In a study by Nelson and co-workers,
patients treated with 5000 units BoNT-B in each axilla
achieved excellent reduction in sweating, but the inci­
dence of side effects was high and included dry mouth,
headache, and sensory motor symptoms of the hand. Due
to the incidence of systemic side effects using BoNT-B
and the high safety profile using BoNT-A to treat focal
hyperhidrosis, to date BoNT-A is the neurotoxin of choice.

167
23 
Focal axillary hyperhidrosis
Frasson E, Brigo F, Acler M, et al 2011 Botulinum toxin type A vs
type B for axillary hyperhidrosis in a case series of patients
observed for 6 months. Archives of Dermatology 147:122–123
Glaser D, Kowalski J, Eadie N, et al 2004 Hyperhidrosis disease
severity scale (HDSS): Validity and reliability results from three
studies. Poster presented at the 62nd Annual Meeting of the
American Academy of Dermatology, 6–10 February, Washington
DC, p 198
Glaser DA, Hebert AA, Pariser DM, et al 2007 Facial
hyperhidrosis: best practice recommendations and special
considerations. Cutis 79:29–32
Glogau RG 2007 Topically applied botulinum toxin type A for
the treatment of primary axillary hyperhidrosis: results of a
randomized, blinded, vehicle-controlled study. Dermatologic
Surgery 33:S76–S80
Goldsmith L 1999 Biology of ecrine and apocrine sweat glands. In:
Freedberg IM, Fitzpatrick TB (eds) Fitzpatrick’s dermatology in
general medicine, 5th edn. McGraw-Hill, Health Professions
Division, New York, p 157–164
Hamm H, Naumann MK, Kowalski JW, et al 2006 Primary focal
hyperhidrosis: disease characteristics and functional impairment.
Dermatology 212:343–353
Heckmann M, Breit S, Ceballos-Baumann A, et al 1999 Side-
controlled intradermal injection of botulinum toxin A in
recalcitrant axillary hyperhidrosis. Journal of the American
Academy of Dermatology 41:987–990
Hornberger J, Grimes K, Naumann M, et al 2004 Recognition,
diagnosis, and treatment of primary focal hyperhidrosis. Journal
of the American Academy of Dermatology 51:274–286
Huh CH, Han KH, Seo KI, et al 2002 Botulinum toxin treatment
for a compensatory hyperhidrosis subsequent to an upper
thoracic sympathectomy. Journal of Dermatological Treatment
13:91–93
Hund M, Rickert S, Kinkelin I, et al 2004 Does wrist nerve block
influence the result of botulinum toxin A treatment in palmar
hyperhidrosis? Journal of the American Academy of
Dermatology 50:61–62
Kavanagh GM, Oh C, Shams K 2004 BOTOX delivery by
iontophoresis. British Journal of Dermatology 151:1093–1095
Lear W, Kessler E, Solish N, et al 2007 An epidemiological study of
hyperhidrosis. Dermatologic Surgery 33:S69–S75
Lowe N, Campanati A, Bodokh I, et al 2004 The place of
botulinum toxin type A in the treatment of focal hyperhidrosis.
British Journal of Dermatology 151:1115–1122
Lowe NJ, Glaser DA, Eadie N, et al 2007 Botulinum toxin type A
in the treatment of primary axillary hyperhidrosis: a 52-week
multicenter double-blind, randomized, placebo-controlled study
of efficacy and safety. Journal of the American Academy of
Dermatology 56:604–611
Naumann M, Lowe NJ 2001 Botulinum toxin type A in treatment
of bilateral primary axillary hyperhidrosis: randomised, parallel
group, double blind, placebo controlled trial. British Medical
Journal 323:596–599
Nelson L, Bachoo P, Holmes J 2005 Botulinum toxin type B: a new
therapy for axillary hyperhidrosis. British Journal of Plastic
Surgery 58:228–232
Reisfeld R, Nguyen R, Pnini A 2000 Endoscopic thoracic
sympathectomy for treatment of essential hyperhidrosis
syndrome: experience with 650 patients. Surgical Laparoscopy,
Endoscopy and Percutaneous Techniques 10:5–10
Saadia D, Voustianiouk A, Wang AK, et al 2001 Botulinum toxin
type A in primary palmar hyperhidrosis: randomized, single-
blind, two-dose study. Neurology 57:2095–2099
Sarifakioglu N, Sarifakioglu E 2005 Evaluating effects of
preservative-containing saline solution on pain perception during
botulinum toxin type-a injections at different locations: a
prospective, single-blinded, randomized controlled trial.
Aesthetic Plastic Surgery 29:113–115
treat the forehead and the perimeter of the scalp, and 300
units when treating the forehead and entire scalp.
OnabotulinumtoxinA is the treatment of choice for
gustatory sweating and Frey syndrome. The starch iodine
test is performed on the patient’s face in the fashion previ­
ously described. For accurate results, it is helpful to have
the patient eat or chew a food that typically induces
sweating. OnabotulinumtoxinA is injected using 2.5 units
every 1.5–2 cm to cover the area indicated by the starch
iodine test. As when treating craniofacial hyperhidrosis,
OnabotulinumtoxinA reconstituted at 50 units/mL may
be used in an effort to limit the diffusion area and risk of
facial asymmetry.
Reisfeld et al reported that compensatory sweating is
the most common complication of endoscopic transtho­
racic sympathectomy (ETS). Treatment is particularly dif­
ficult, but reports have noted success using BoNT-A. Huh
and colleagues used 300 units abobotulinumtoxinA to
treat the chest and abdomen after identifying the area
with a starch iodine test. Each 100 units of onabotulinum­
toxinA were diluted in 10 mL saline and injected 0.1 mL
into each square centimeter.
Future directions
The use of botulinum toxins has revolutionized the treat­
ment of AHH and other secretory disorders. Compared
with other treatments, it is unmatched in its efficacy, ease
of administration, and patient satisfaction. New delivery
devices are being researched to provide the most comfort­
able and efficient therapy. Kavanagh and colleagues have
successfully used a small iontophoresis machine to deliver
BoNT-A to two patients with severe palmar hyperhidrosis,
sparing them injections. Glogau demonstrated that ona­
botulinumtoxinA can be successfully delivered into the
axillary skin when combined with a proprietary transport
peptide molecule. For the present, BoNT therapy is a
valuable, well-tolerated therapy and can provide meaning­
ful improvement in the quality of life of patients with
AHH and other secretory disorders.
Further reading
Alam M, Dover JS, Arndt KA 2002 Pain associated with injection
of botulinum A exotoxin reconstituted using isotonic sodium
chloride with and without preservative: a double-blind,
randomized controlled trial. Archives of Dermatology
138:510–514
Kowalski J, Ravelo A, Glaser D, et al 2004 Quality-of-life effect of
botulinum toxin type A on patients with primary axillary
hyperhidrosis: Results from a North American Clinical Study
Population. Poster 196. American Academy of Dermatology
62nd Annual Meeting.
Birklein F, Eisenbarth G, Erbguth F, et al 2003 Botulinum toxin
type B blocks sudomotor function effectively: a 6 month follow
up. Journal of Investigative Dermatology 121:1312–1316
Cheshire WP, Freeman R 2003 Disorders of sweating. Seminars in
Neurology 23:399–406
Dressler D, Adib Saberi F, Benecke R 2002 Botulinum toxin type B
for treatment of axillar hyperhidrosis. Journal of Neurology
249:1729–1732

168
Botulinum toxin
Wollina U, Karamfilov T 2001 Botulinum toxin A for palmar
hyperhidrosis. Journal of the European Academy of
Dermatology and Venereology 15:555–558
Wollina U, Karamfilov T, Konrad H 2002 High-dose botulinum
toxin type A therapy for axillary hyperhidrosis markedly
prolongs the relapse-free interval. Journal of the American
Academy of Dermatology 46:536–540
Schlereth T, Mouka I, Eisenbarth G, et al 2005 Botulinum toxin A
(Botox) and sweating-dose efficacy and comparison to other
BoNT preparations. Autonomic Neuroscience 117:120–126
Strutton DR, Kowalski JW, Glaser DA, et al 2004 US prevalence
of hyperhidrosis and impact on individuals with axillary
hyperhidrosis: results from a national survey. Journal of the
American Academy of Dermatology 51:241–248

medications such as clonidine and even surgical sympa­
thectomy. In this chapter, we will discuss the role of
botulinum toxin in the treatment of HH of the palms
and soles.
Patient evaluation
Most patients who present with palmar HH have had the
condition since childhood or early adolescence with no
known cause and report ‘sweaty palms’ that cause them
social embarrassment. Solish & Haider reported evidence
suggesting that an autosomal dominant inheritance pattern
with variable expressivity such that a child born to a
parent with palmar HH has a 25% chance of developing
the disorder as well. Patients will go to great lengths to
avoid shaking people’s hands and often keep their hands
in their pockets. The hyperhidrosis can be so severe as to
cause actual physical dripping and maceration and peeling
of the skin itself (Fig. 24.1). Similarly, patients with plantar
hyperhidrosis will report the need to change socks fre­
quently or that they ‘slip’ in their shoes while walking.
Interestingly, a study by Lear and colleagues suggested
that spontaneous regression might occur over time as
there is a low prevalence of the disorder in the elderly
population. It is important for the physician to keep in
mind the severe psychological impact HH has on patients,
many of whom do not seek treatment due to embarrass­
ment and yet decrease their leisure activities and suffer
from depression because of it.
Prior to treatment, it is important to take a careful
clinical history to ensure that the patient suffers from
primary, not secondary, hyperhidrosis. In secondary hyper­
hidrosis, medications or systemic health problems can be
responsible for sweating (Box 24.1) and the condition is
usually generalized. If there is a suspicion of secondary
hyperhidrosis, a complete blood count, fasting glucose
level and thyroid function test are preliminary laboratory
tests to be ordered.
In primary hyperhidrosis, neither the number, density,
nor size of eccrine glands is abnormal; rather there is
overactivity of the postganglionic sympathetic cholinergic
fibers innervating them. For this reason, botulinum toxin
type A can be effective in treatment; the toxin inhibits
presynaptic release of acetylcholine and binds to acetyl­
choline receptors at the postsynaptic membrane thus
disrupting sympathetic input to eccrine glands. Because
24 
Palmo-plantar hyperhidrosis
Kavita Mariwalla, Nowell Solish
Introduction
Hyperhidrosis (HH) is an excessive sweating disorder that
affects 2.8% of the population in the United States alone.
By definition, HH is sweating beyond what is expected
for environmental conditions and thermoregulation. In
practice, it is considered sweating that significantly inter­
feres with daily life. Not only does it cause anxiety and
emotional distress for those who suffer from it, but it can
also be a risk factor for cutaneous infection, eczematous
dermatitis, and muscle cramps. Lear et al reported that
most patients who have HH experience it in areas of high
eccrine density such as the axillae (51%), soles (30%),
palms (24%), and occasionally in the craniofacial area
(10%). Multiple modalities are available for treatment of
primary focal HH, from topical medications such as alu­
minum chloride, to non-surgical approaches such as ion­
tophoresis and botulinum toxin injections, to systemic
Summary and Key Features
•
Palmar and plantar hyperhidrosis cause a
significant impact on the quality of life for people
who suffer from the disorder
•
Botulinum toxin type A can produce hypohidrosis
on the palms and soles for up to 6 months
•
Ice or cooling devices are well-tolerated modes of
anesthesia for the hands; however, regional nerve
blocks are recommended prior to plantar injections
•
Injections should be spaced 1–1.5 cm apart with
2–3 U of botulinum toxin A per injection site on
average
•
Success rates reach 90% for palmar hyperhidrosis
with variable success for plantar hyperhidrosis
despite similar injection techniques
•
Postoperatively, patients may experience some
weakness of thumb–index finger-pinch strength,
which returns after 2–3 weeks; if injections are
placed superficially and spaced properly, however,
most will not

170
Botulinum toxin
palmar hyperhidrosis can present unilaterally in 6% of
cases.
Scoring the impact of hyperhidrosis on the patient’s
quality of life is important as well, not only to gauge treat­
ment success but also to aide in obtaining insurance
approval for treatment. The Hyperhidrosis Disease Sever­
ity Scale (HDSS) is a quick diagnostic tool that the prac­
titioner can administer during the examination and was
found by Solish and colleagues to be a reliable means of
assessment (Table 24.1). HDSS scores should be followed
to guide the choice of treatment and to determine whether
treatment has made an impact (success should be consid­
ered a reduction in HDSS of 1 or more).
General considerations
Treatment of palms and soles for primary focal HH is
considered an off-label use of neurotoxin. In the United
States, botulinum toxin type A (which is FDA approved
for treatment of axillary HH) is commercially available as
Botox® (Allergan, Irvine, CA, USA), Dysport® (Medicis,
Scottsdale, AZ, USA), and Xeomin® (Merz Pharmaceuti­
cals, Greenboro, NC, USA). All are considered pregnancy
category C and it is advisable to avoid injection in actively
nursing women. All patients should be screened for allergy
to botulinum toxin type A components and injections
should not be placed into areas that appear infected or
inflamed. It is important to be aware of the patient’s
current medication list as certain medications can alter the
metabolism of neurotoxin such as aminoglycoside antibac­
terials, cholinesterase inhibitors, and calcium channel
antagonists.
Walling & Swick considered that botulinum toxin injec­
tions for palmar HH should be reserved for patients who
have first failed treatment with topical aluminum chloride
and oral glycopyrrolate at a concentration of 1–2 mg up
to three times a day. These authors then suggested trying
iontophoresis and, if that fails, subsequently using neuro­
toxin injection.
eccrine glands are found in a high concentration in the
axillae, palms, soles, and forehead, these are the areas
where primary focal HH typically presents as excessive
sweating for at least 6 months’ duration. To make a positive
diagnosis of focal primary HH, Hornberger stated that the
patient should also present with at least two of the fol­
lowing criteria: age at onset younger than 25 years, fre­
quency of at least one episode per week, a positive family
history, cessation of sweating upon sleep, impairment of
activities of daily living, and a distribution that is bilateral
and relatively symmetric. Of note, Hamm et al found that
Figure 24.1  Severe palmar hyperhidrosis.
Table 24.1  Hyperhidrosis disease severity scale
Patient response
Score
Clinical
interpretation
My sweating is never noticeable
and never interferes with my daily
activities
1
Mild
My sweating is tolerable but
sometimes interferes with my
daily activities
2
Moderate
My sweating is barely tolerable
and frequently interferes with my
daily activities
3
Severe
My sweating is intolerable and
always interferes with my daily
activities
4
Severe
Box 24.1 
Select causes of secondary hyperhidrosis
n
Febrile illness (e.g. chronic infections)
n
Endocrine or metabolic condition (e.g. thyroid
dysfunction, diabetes mellitus, menopause,
pregnancy)
n
Neurological disorder (e.g. spinal cord injury,
Parkinson disease, stroke)
n
Cardiovascular disorder (e.g. heart failure)
n
Respiratory disorder
n
Medication use (e.g. antidepressants, antiemetics)
n
Substance abuse (e.g. drug withdrawal, alcohol
abuse)
n
Neoplastic disease (e.g. pheochromocytoma,
carcinoid tumors, Hodgkin lymphoma)
n
Anxiety
n
Stress
n
Other (e.g. Frey syndrome, gustatory sweating)

171
24 
Palmo-plantar hyperhidrosis
Figure 24.2  Colorimetric reaction, showing the bluish-purple
discoloration in areas of excess sweating. Starch iodine test showing
significant improvement of palmar hyperhidrosis after injection with
botulinum toxin A.
Figure 24.3  Marking the palm in a grid-like pattern with the
iodine-starch test marking the palm prior to injection with botulinum
toxin A. Injections should be made beside the ink to avoid potential
tattooing.
Pearl 1 
When using ice for pain control on the palms, be careful to
avoid freezing the botulinum toxin solution in the needle when
injecting.
Marking the treatment areas
The Minor’s iodine-starch test can be used to estimate the
areas of involvement that require treatment but should
not be relied upon for precise quantitative measure of
sweating. In brief, the palms or soles are first wiped with
iodine (pre-packaged swabs of povidone-iodine are par­
ticularly useful for this) and allowed to dry. Next, the
painted area is sprinkled with cornstarch powder. A colo­
rimetric reaction ensues, resulting in a bluish-purple dis­
coloration in areas of excess sweating that can then be
marked for injection (Fig. 24.2). To ensure accuracy,
patients should discontinue any topical therapies 5 days
prior to iodine-starch testing. While this test is advocated
for the axillae, we feel it is less helpful for the hands
as the test usually demonstrates a positive reaction over
the entire palm. For most patients, we advocated marking
in a grid-like pattern with the iodine-starch test first
(Fig. 24.3).
Anesthesia
Pain is a common complaint when performing injections
for the palms and soles. For this reason, different tech­
niques to lessen the pain may be employed. Ice cubes held
with gauze (or frozen with gauze on the outside) can be
held on the skin for approximately 10 seconds prior to
injection. This can dramatically decrease the discomfort
associated with the injection. The ice is then moved to
the next location while the injection is taking place. Ice is
preferred over freezer packs, as ice will maintain its tem­
perature. Skin-cooling devices, such as those made by
Zimmer, can also work effectively at decreasing pain prior
to injection.
Another alternative to ice and cooling devices is the use
of nerve blocks. For the palms, median and ulnar nerve
blocks are required. For the median nerve block, locate
the palmaris longus tendon and inject 2 mL of 1% lido­
caine into the radial side at the proximal wrist crease. For
the ulnar nerve block, identify the flexor carpi ulnaris
tendon and inject just radial to it on the proximal wrist
crease at the ulnar styloid process.
Pearl 2 
The best way to accentuate the palmaris longus tendon is to
ask the patient to touch the thumb to the last two digits of
the hand with the wrist slightly flexed in a radial direction. To
find the flexor carpi ulnaris tendon, ask the patient to perform
the same movement but instead flex the wrist toward the
ulnar direction.
For plantar injections, both a sural nerve and a posterior
tibial nerve block are needed. A sural nerve block will
anesthetize the fifth toe and lateral side of the sole. It
requires injection of 3–5 mL of 1% lidocaine between the
lateral malleolus and the Achilles tendon. A posterior
tibial nerve block anesthetizes the heel and middle of the
sole of the foot. For this nerve block, palpate the posterior
tibial artery near the medial malleolus. The nerve is lateral
to the artery. Inject 5 mL of 1% lidocaine in the groove
between the medial malleolus and the Achilles tendon.

172
Botulinum toxin
Injection technique
Proper injection depth for the palms and soles is at the
junction of the dermis and subcutaneous tissue (the loca­
tion of the eccrine glands). The needle should be inserted
at an oblique angle and product placed into the deep
dermis. Superficial injection decreases the probability that
the neurotoxin will diffuse into the intrinsic muscles of
the hands and cause weakness (Fig. 24.4). It is common
to see a small zone of blanching around each injection
point on the palms and soles; the wheal produced during
neurotoxin injection in other parts of the body such as the
axillae and forehead is not seen when performing palmar
and plantar injections. Approximately 50–100 U of Botox
is standard dosing for each palm depending on the size of
the area; 100 U of Botox is reasonable to use per sole
owing to the larger surface area. Though some authors
recommend a range from 100 to 240 U of Botox per hand,
one randomized, single-blind trial by Saadia and colleagues
showed similar efficacy between 50 and 100 U of botuli­
num toxin type A for palmar HH. Of note, the higher
dose was associated with an increased incidence of subjec­
tive hand weakness. For this reason, we recommend start­
ing with 50 U per hand then reassessing the first-time
patient at 1 month. Injections typically need to be repeated
every 6 months.
Wait 15 minutes for regional nerve blocks to take full
effect.
Despite above, some patients continue to experience
pain. In that case, we advise the use of high-intensity
vibration devices (e.g. AcuVibe®) adjacent to each injec­
tion site to overstimulate nerve fibers and lessen the pain.
It should be noted that reactive hyperemia might follow
regional nerve blockade to the wrists, increasing the ten­
dency of the skin to bleed at each injection site.
Dilution and injection
Though many dilution techniques exist, we find that for
palmar and plantar injections, dilution of one vial of Botox®
with 3 mL of bacteriostatic preserved saline results in a
manageable concentration for injection (Table 24.2). With
the 3 mL dilution, each 0.1 mL results in 3.3 U of Botox®.
To prevent unnecessary waste of the toxin, we recommend
removal of the lid and rubber stopper on the bottle vial so
that no product is left behind, and use of hubless syringes.
Since palmar and plantar skin is thick, needles dull
more quickly after serial injection. Therefore, it is best to
draw up the 100 U into six 0.5 mL syringes (B&D Ultra-
Fine II 30-gauge hubless insulin needle syringes, Becton-
Dickinson). Volumes of 0.05–0.1 mL (1.7–3.3 U) of
Botox® should be deposited at each injection point spaced
1–1.5 cm apart because less diffusion occurs on the palms
and soles compared with other body sites.
For severe palmar hyperhidrosis, Dysport® has also
shown efficacy; using a conversion factor of 1 : 4, Sim­
onetta et al demonstrated that Dysport®-treated palms
actually retained anhidrosis for a similar period of time to
those treated with Botox®. Though the decrease in sweat
was more pronounced in the Dysport®-treated palms, this
finding did not reach statistical significance. Local side
effects were more frequent in Dysport® palms than in
those treated with Botox® and manifested as a decrease
in thumb-index pinch for up to 30 days, compared with
up to 21 with Botox®. If using Dysport® for hyperhidrosis,
we recommend dilution with 3 mL of bacteriostatic pre­
served saline, which gives a final dilution of 10 U per
0.1 mL. Unlike Botox® vials, the top and rubber stopper
do not need to be removed from the Dysport® vial as an
insulin syringe can easily penetrate the top without dulling
of the needle.
Table 24.2  Acceptable dilutions for botulinum toxin type
A in the treatment of palmo-plantar hyperhidrosis
Product
Dilution (mL)
Final concentration
Botox®
2.5
4 U / 0.1 mL
Botox®
3
3.3 U / 0.1 mL
Botox®
5
2 U / 0.1 mL
Dysport®
3
10 U / 0.1 mL
Figure 24.4  Superficial injection.
Pearl 3 
It should be noted that, in the palms and soles, neurotoxin
has the tendency to backflow from the injection tract after
injection. To minimize this, we recommend several tips such
as keeping the needle bevel up, angling the needle more
parallel to the skin surface and waiting for 1–2 seconds
following injection to allow time for normalization of pressure,
and making sure there are no air bubbles in the syringe, as
reported by Fujita et al and Hayton et al (Box 24.2).

173
24 
Palmo-plantar hyperhidrosis
weakness of the muscles of the hand and over time may
lead to atrophy. Palmar injections can be complicated by
adverse events related to regional nerve blocks such as
inadvertent vascular puncture, impaired hand dexterity,
and neuropathy from repeated nerve injuries, as reported
by Fujita and colleagues and Hayton et al.
Plantar injections are usually painful and include
adverse side effects of both pain and hematomas at injec­
tion sites. If regional nerve blocks are used, the patient
will have difficulty walking for several hours and it is
recommended that they not attempt to drive for 4–5
hours after the procedure.
Conclusion
Palmar and plantar hyperhidrosis can have severe psycho­
logical impact on those who suffer from the disease. Often
topical medications such as aluminum chloride and oral
medications such as glycopyrrolate are inadequate to treat
the symptoms. In these cases, botulinum toxin type A
injection provides a method for producing anhidrosis.
Though more effective for the palms than for the soles,
the technique for injection is easy to use and reliable. For
both of these sites, the greatest challenge for the physician
is maintaining adequate pain control for the patient. Often
after the first successful treatment, however, patients with
severe disease become quite motivated and are able to
handle the pain with more ease than the physician may
expect.
Further reading
Fujita M, Mann T, Mann O, et al 2001 Surgical pearl: use of nerve
blocks for botulinum toxin treatment of palmar-plantar
hyperhidrosis. Journal of the American Academy of
Dermatology 45:587–589
Glogau RG 2004 Hyperhidrosis and botulinum toxin A:
patient selection and techniques. Clinical Dermatology
22:45–52
Grunfeld A, Murray CA, Solish N 2009 Botulinum toxin for
hyperhidrosis. American Journal of Clinical Dermatology
10:87–102
Hamm H, Naumann M, Kowalski JW, et al 2006 Primary focal
hyperhidrosis: disease characteristics and functional impairment.
Dermatology 212:343–353
Hayton MJ, Stanley JK, Lowe NJ 2003 A review of peripheral
nerve blockade as local anaesthesia in the treatment of palmar
hyperhidrosis. British Journal of Dermatology 149:447–451
Hornberger J, Grimes K, Naumann M, et al 2004 Recognition,
diagnosis, and treatment of primary focal hyperhidrosis. Journal
of the American Academy of Dermatology 51:274–2786
Kaufmann H, Saadia D, Polin C, et al 2003 Primary hyperhidrosis:
evidence for autosomal dominant inheritance. Clinics in
Autonomic Research 13:96–98
Lear W, Kessler E, Solish N, et al 2007 An epidemiological study
of hyperhidrosis. Dermatologic Surgery 33:S69–75
Murray CA, Cohen JL, Solish N 2007 Treatment of focal
hyperhidrosis. Journal of Cutaneous Medicine and Surgery
11:67–77
Naumann MK, Hamm J, Lowe NJ 2002 Effect of botulinum toxin
type A on quality of life measures in patients with excessive
Results and follow-up
Several studies have measured efficacy of botulinum toxin
type A both quantitatively and subjectively in palmar HH
and they report 80–90% improvement with anhidrosis
lasting anywhere from 4 to 12 months (see Grunfeld
et al). Most patients will relate some degree of hand
weakness 24–72 hours after injection that can persist for
up to 2 weeks. Handgrip strength is usually retained
whereas thumb–index finger pinch strength is weakened.
For patients who are in professions that require fine hand
movement and strength, we recommend treating one
hand and then the other at a later visit after discussion
with the patient. After injection, pain and soreness are
common and can last up to 2 days. In addition, mild
numbness, paresthesias, and small hematomas at the injec­
tion sites can occur (though uncommonly and are
transient).
Follow-up is recommended every 5 months in treat­
ment-naïve patients and every 6–7 months in patients
treated on a regular basis. After treatment, it is reasonable
to counsel patients that they will begin to notice a differ­
ence in 7–10 days. Bleeding is common at the time of
injection so it is advisable to ask an assistant to hold pres­
sure with gauze in the areas that have already been treated.
Compared with palmar HH, plantar HH is more dif­
ficult to ameliorate. Treatment efficacy tends to be lower
in the soles than in the hands or axillae and usually higher
doses of botulinum toxin type A are required. Few ran­
domized, controlled trials exist to assess the true efficacy
of neurotoxin injection into the feet. Although we have
observed a decrease in plantar HH after neurotoxin use
to treat palmar HH, recent evidence suggests that no dif­
ference is detected.
Complications
The most common side effect from injection of the
palms is bruising and mild discomfort immediately after
treatment. Persistent superficial injections can lead to
Box 24.2 
Methods to prevent backflow of neurotoxin
during palmo-plantar injections
n
Ensure there are no air bubbles in the syringe; this
decreases inadvertent leakage of toxin when
injecting.
n
Keep the bevel of the needle up.
n
Try to keep the angle of the needle as parallel as
possible to the skin surface.
n
Advance the needle 2 mm prior to injection.
n
Inject slowly.
n
Do not insert the needle into the skin with pressure
on the plunger.
n
Wait 1–2 seconds following injection to allow time for
normalization of pressure.

174
Botulinum toxin
Solish N, Haider A 2005 Focal hyperhidrosis: diagnosis and
management. Cutaneous Medicine Association Journal
172:169–175
Strutton DR, Kowalski JW, Glaser DA, et al 2004 US prevalence
of hyperhidrosis and impact on individuals with axillary
hyperhidrosis: Results from a national survey. Journal of the
American Academy of Dermatology 51:241–248
Walling HW 2009 Primary hyperhidrosis increases the risk of
cutaneous infection: a case-control study of 387 patients.
Journal of the American Academy of Dermatology 61:242–246
Walling HW, Swick BL 2011 Treatment options for hyperhidrosis.
American Journal of Clinical Dermatology 12:285–295
axillary sweating: a randomized controlled trial. British Journal
of Dermatology 147:1218–1226
Simonetta MM, Cauhepe C, Magues JP et al 2003 A double-blind,
randomized, comparative study of Dysport vs. Botox in primary
palmar hyperhidrosis. British Journal of Dermatology
149:1041–1045
Solish N, Benohanian A, Kowalski JW 2005 Canadian dermatology
study group on health-related quality of life in primary axillary
hyperhidrosis. Prospective open-label study of botulinum toxin
type A in patients with axillary hyperhidrosis: effects on
functional impairment and quality of life. Dermatologic Surgery
31:405–413

One of the problems with discussing the clinical use of
botulinum toxin is that the regulatory pathway and the
rigorous scientific investigation of the efficacy and safety
of new indications have consistently lagged behind off-
label clinical use. We were using BoNT-A to treat glabellar
lines more than 10 years before the regulatory studies
began and 15 years before US FDA approval for glabellar
lines. So it is not easy to keep track of the many areas
where BoNT-A is being used and sort out those areas
where its use is a major therapeutic advance. Some years
ago we were in communication with a physician who
was using aerosolized BoNT-A to treat asthma, but have
heard nothing of this indication since. The same is true
for the treatment of allergic rhinitis. By comparison, the
use of BoNT-A to treat detrusor overactivity in individuals
with paraplegia or other neurological problems appeared
as an indication very early in the clinical development of
BoNT-A. Urologists have subsequently gone on to use the
toxin for overactive bladder in females and benign pros­
tatic hypertrophy in males, and both of these indications
should be approved by the FDA in the near future.
This short chapter will be speculative and opinionated.
In addition, it may well be proven wrong! But we are close
to the expanding body of knowledge about BoNT and
hope that we shall be able to suggest at least some of the
important areas of future knowledge and clinical use.
Newer indications
As the understanding of the mechanism of action of BoNT
expands and as the number of clinicians exposed to the
toxin increases, there have been great extensions in the
clinical use of the toxin. For example, the use by physi­
cians of the toxin for cosmetic purposes led to recognition
that some of the treated individuals experienced improve­
ment in headache and migraine. This led to a wider under­
standing of the mechanism of action of BoNT and
subsequently use of the toxin to treat a range of conditions
associated with pain. The recognition that BoNT treat­
ment of hyperhidrosis would shrink sweat glands has led
other physicians to treat other glands, thus improving
benign prostatic hypertrophy and sialorrhea.
The range of conditions involving abnormal muscle
function, pain, and excessive glandular function that is
now being treated is extremely wide and is expected to
expand further. Some of these are relatively specialized.
25 
The future of botulinum toxin
Alastair Carruthers, Jean Carruthers
Introduction
The world of botulinum toxin has changed dramatically in
the 30 years of our involvement. In 1982 the only available
product was called ‘Oculinum’ and was available only
from Alan Scott, MD, at the Smith-Kettlewell Institute
for Visual Sciences in San Francisco. The dramatic concept
of using ‘the most deadly poison’ to treat muscle disorders
had, of course, already been published in Readers’ Digest
and was soon to be published in the National Enquirer and
other popular publications. At that time the indication for
use was the treatment of strabismus although dystonia,
especially blepharospasm, and hemifacial spasm were soon
added to the list. Many other indications have since fol­
lowed especially after the FDA’s first approval in the USA
in 1989.
When discussing the future of this dramatic molecule
it is hard to stay ahead of reality and common usage. We
shall endeavor to tread the fine line between documenting
what has been shown scientifically and wild speculation.
However, the field is expanding so rapidly that this will
be difficult.
Summary and Key Features
•
The clinical use of BoNT-A continues to expand as
physicians dream up new uses for it
•
The use of BoNT-A topically will expand the use
of the neurotoxin as well as helping us to better
understand its effect on the skin and appendages
•
Changes in the molecule may allow for increased
duration of effect and also allow different targeting
of the endoprotease, for example allowing a
greater antinociceptive effect
•
The question of a central effect of BoNT-A is still
unresolved. There is no doubt that the toxin can
move along neurons and can be demonstrated in
the brain in experimental situations. Whether this
will have any relevance to the clinical use of the
toxin remains to be seen
•
The use of glabellar BoNT-A in the treatment of
depression is another exciting area for research

176
Botulinum toxin
(rimabotulinumtoxinB, Myobloc®) was approved for the
treatment of cervical dystonia in the US almost coinciden­
tally with Botox®. BoNT-B has a shorter duration than
BoNT-A. Some preliminary work was done with BoNT-F,
but the duration of effect proved to be much too short.
BoNT-E has a similarly short duration of effect.
Short duration of effect is not necessarily a bad thing.
For example, it is possible to imagine many conditions
such as post-surgery states or post-traumatic conditions,
where short duration of effect would actually be advanta­
geous. It might be necessary to rest an area for 2 weeks
but not beyond that time. An individual will tolerate
having weakness on one side of the face for 2 weeks but
not for 3 months. Some of the post-traumatic indications
appear to respond so rapidly to BoNT-A that a 2-week
duration of effect might be all that is needed. We hope
that this potential area of research will get the attention
it deserves at some time in the near future.
The other direction for duration of effect is to increase
it. This is obviously desirable and many of our patients
would be delighted if the BoNT-A effect could be
increased by 50% or more. There is some preliminary
evidence by Stone and colleagues that this may be possi­
ble. These authors were exploring the action of the
peptide-added BoNT-A molecule that is the active ingre­
dient of the Revance Therapeutics topical preparation.
They injected the gastrocnemius muscle in mice with
various doses of the Revance product (RT002) and Botox®.
When they looked at the tibialis anterior muscle of the
injected mice, there was a significant degree of spread of
effect in the Botox®-injected group but less in the RT002-
injected group. When they attempted to work out the
dose that produced approximately equal degrees of spread
to tibialis anterior the respective doses were 2 U/kg of
Botox® and 5 U/kg of RT002. When the authors went
back to look at the effect on gastrocnemius they observed
an approximate doubling in the duration of effect in the
RT002-injected animals. This is very preliminary evi­
dence, but it does suggest that it might be possible to
lengthen the duration of effect of BoNT-A.
The next part of the story is even more speculative,
probably owing to the commercial pressures involved. The
neurotoxin molecule consists of three parts: the binding
domain, the translocation domain, and the endoprotease.
It has long been speculated that changing one of these
domains to change the target or effect would produce
interesting results. For example, adding the BoNT-A endo­
peptidase to different heavy chains would change the
target of the enzyme but not its intracellular action; it
appears that this concept may be coming into more practi­
cal use. Allergan has announced that it is collaborating
with a company (Syntaxin) that has created engineered
forms of BoNT using the endopeptidase portion of the
toxin in fusion with various targeting moieties which allow
them to selectively target a specific cell type and then
block exocytotic release of desired mediators (e.g. neu­
rotransmitters involved in nociception, excessive growth
hormone secretion for acromegaly, etc.). This would have
The conditions that dermatologists recognize as being
worsened by excessive sweating, such as benign familial
pemphigus, can be improved by BoNT-A injection into
the area. This is important, providing relief for those indi­
viduals but not being as important in sheer numerical
terms as, for example headache and migraine.
Topical versus injectable
We had long presumed that the large size of the BoNT-A
molecule would prevent it from passing through intact
skin. That assumption has been proven incorrect and
the effectiveness of topically applied BoNT-A has now
been established (see Ch. 10). This will have important
implications beyond the current clinical development
both in axillary hyperhidrosis and in lateral orbital wrin­
kles and lines (crow’s feet). We would expect that the
advantage of a needleless approach will encourage many
more individuals to have excessive sweating treated, espe­
cially that of the palms and soles, face, and scalp. Also,
those individuals who have normal levels of sweating but
who choose not to sweat in these areas can be safely and
effectively treated.
There has been discussion about the injection of tiny
doses of BoNT-A in the face with multiple injections
(‘MesoBotox’) and arguments as to whether or not this is
effective. The ability to be able to apply BoNT-A topically
to the face will answer these questions and we shall know
what effect to expect on sebaceous glands, flushing, tel­
angiectasias, rosacea, etc. So far the clinical development
program has experimented with different concentrations
of toxin in order to produce the desired effect. What will
become available to clinicians will be a single concentra­
tion and we shall have to work out how long to apply the
gel in different areas and for different indications. It might
be anticipated that the application time in the cheeks for
flushing / rosacea would be less than in the lateral orbital
area, but we do not know and it will be an exciting new
era in botulinum toxin research when the topical product
becomes available to clinicians.
Changes in the toxin molecule
Changing both the target and the duration of action of
the toxin have long been dreams of clinicians and basic
scientists involved in toxin research. Some of this has
been attainable for many years. For example, when the
effectiveness of BoNT-A was established, resistance to
the toxin also occurred, because clinicians did not
understand the immunogenicity of the molecule and the
original preparations available contained amounts of inef­
fective botulinum toxin, increasing the treated individual’s
exposure to the antigenic epitopes. For Botox® this
changed dramatically in 1997 with the change from origi­
nal Botox® to current Botox® with approximately 20% of
the immunogenic potential. However, the existence of
patients who were clinically resistant to BoNT-A stimu­
lated examination of other serotypes. As a result, BoNT-B

177
25 
The future of botulinum toxin
accumulating evidence helps us to better understand the
mechanism of action of BoNT and not that it is inherently
worrying. This understanding should help us to use the
neurotoxins more safely and to the greater benefit of our
patients.
Depression
Some indications for the clinical use of BoNT-A rapidly
become obvious because of both the safety and efficacy
of the indication. Treatment of the glabella is a good
example. In other indications, such as migraine, it is more
difficult to establish efficacy. The treatment of depression
comes into this latter category. The problem is the pres­
ence of a significant degree of placebo effect. Despite
the considerable amount of research done on the use
of BoNT-A for migraine, there are still clinicians (e.g.
Solomon) who believe this to be a placebo effect.
The effect of glabellar BoNT-A injections on depression
was first reported by dermatologists Finzi & Wasserman
who described improvement in mood in 10 women after
glabella BoNT-A. A further paper by Lewis & Bowler
demonstrated improvement in depression after glabella
B0NT-A but not after other cosmetic procedures. The
problem with this research is the difficulty in truly con­
trolling the placebo effect. It is a fact that individuals who
have had their glabella treated with BoNT-A know whether
they have received active drug or placebo within a few
days. A properly controlled study of the effect of BoNT-A
on depression will be a challenge. It may be that the effect
is a manifestation of the facial feedback hypothesis where
it is postulated by Alam and colleagues that individuals
who cannot frown do not look grumpy so others interact­
ing with them will respond in a more positive manner,
improving the mood of the treated individual.
Conclusion
BoNT-A is without doubt an amazing molecule. Each time
we think we understand its actions and its diverse clinical
effects we are illuminated by yet another action and inter­
action. The molecular modifications will permit even
more specific targets to be treated.
The recent explosion of new neurotoxin research –
both clinical and basic science – heralds another genera­
tion of exciting advances. There has never been a more
carefully researched molecule and the future is bright
indeed. We are still just in neuromodulator kindergarten.
Further reading
Alam M, Barrett KC, Hodapp RM, et al Botulinum toxin and the
facial feedback hypothesis: Can looking better make you feel
happier? Journal of the American Academy of Dermatology
58:1061–1072
Antonucci F, Rossi C, Gianfranceschi L, et al 2008 Long-distance
retrograde effects of botulinum neurotoxin A. Journal of
Neuroscience 28(14):3689–3696
a dramatic effect on the clinical use of molecules derived
from the neurotoxin!
Central effects of the neurotoxin
In 2008, Antonucci and co-workers reported what
appeared to be central effects of BoNT-A resulting from
peripheral injection. Great concern was expressed about
the validity of their results, but they have subsequently
expanded on this original work and presented data to back
it up at the Toxins 2011 meeting in Santa Fe, NM.
An early report by Blood and colleagues, which sug­
gested an intracranial effect of BoNT-A, came from the
Department of Neurology, Massachusetts General Hospi­
tal. These researchers used diffusion tensor imaging to
screen for white matter abnormalities in regions between
the basal ganglia and the thalamus in cervical and hand
dystonia patients. All patients exhibited an abnormal
hemispheric asymmetry in a focal region between the pal­
lidum and the thalamus. This asymmetry was absent 4
weeks after the same patients were treated with intramus­
cular botulinum toxin injections. In other words, a periph­
eral injection of botulinum toxin produced an observable
change inside the brain.
The report from Pisa by Antonucci and co-workers
demonstrated that catalytically active BoNT-A is retro­
gradely transported by central neurons and motoneurons
and is then transcytosed to afferent synapses, in which it
cleaves SNAP-25. SNAP-25 cleavage by BoNT-A was
observed in the contralateral hemisphere after unilateral
BoNT-A delivery to the hippocampus. Appearance of
cleaved SNAP-25 resulted in blockade of hippocampal
activity in the untreated hemisphere. These findings reveal
a novel pathway of BoNT-A trafficking in neurons and
have important implications for the clinical uses of this
neurotoxin.
Subsequent to the Pisa reports other authors have
reported similar findings. Dr Ed Chapman from the
University of Wisconsin reported at Toxins 2011 a new
hypothesis in which BoNT-A (and other serotypes) are
trafficked along neuronal processes away from the initial
site of injection in the periphery to exert many of their
clinical effects by entering neurons in the central nervous
system! Lawrence and colleagues from Dublin and Aller­
gan, using compartmented cultures of rat sympathetic
neurons, demonstrated cleaved SNAP-25 through intra­
neuronal migration of BoNT-A. However, they pointed
out that ‘neither spontaneous nor evoked transmission to
cell bodies were inhibited by retrogradely-migrated
BoNT-A, concurring with the lack of evidence for a central
action when used clinically’.
This and other evidence points to the central effect of
BoNT-A. What is the significance of this? When we look
at new evidence suggesting that BoNT-A gets into the
brain it is easy to be concerned about the effects of such
central transcytosis. However, we prefer to bear in mind
the more than 30 years of clinical, safe use in humans
when thinking on this evidence. We presume that this

178
Botulinum toxin
Lewis MB, Bowler PJ 2009 Botulinum toxin cosmetic therapy
correlates with a more positive mood. Journal of Cosmetic
Dermatology 8:24–26
Solomon S 2011 Botulinum toxin for the treatment of chronic
migraine: the placebo effect. Headache 51:980–984
Stone HF, Zhu Z, Thai T, et al 2011 Characterization of diffusion
and duration of action of a new botulinum toxin type A
formulation. Toxicon 58:159–167
Blood AJ, Tuch DS, Makris N, et al 2006 White matter
abnormalities in dystonia normalize after botulinum toxin
treatment. Neuroreport 17(12):1251–1255
Finzi E, Wasserman E 2006 Treatment of depression with
botulinum toxin A: a case series. Dermatologic Surgery
32:645–650
Lawrence GW, Ovsepian SV, Wanj J, et al 2012 Extra-vesicular
intra-neuronal migration of internalised botulinum toxins
without detectable inhibition of distal neurotransmission.
Biochemical Journal 441:443–452

Page numbers followed by ‘f’ indicate figures, ‘t’ indicate tables, and ‘b’ indicate boxes.
for Nefertiti lift, 130
for palmo-plantar hyperhidrosis, 170, 172
reconstitution, 61–62, 72–73
resistance, 64–65, 176
safety, 22, 64
serotypes, 18–19
sterility, 74
storage, 65, 74
structure, 18–19, 19f
unique dosing, 24
vs. other botulinum toxins, 27–28, 36t, 53,
60t
botulinum toxins
changes in the toxin molecule, 176–177
characterization, 6–7
clinical applications, 67
comparison of, 59–66
compositional differences, 61, 62f–63f
diffusion, 27, 64
dosing, 62–63
duration of action, 63–64, 176
efficacy, 63
exploration of clinical potential, 7–8
field of effect, 64
future of, 175–178
history of, 6–12
identification, 6–7
isolation, 6–7
mechanism of action, 61
newer indications, 175–176
nomenclature, 8
reconstitution, 64
resistance, 44, 44b, 64–65
safety, 64
serotypes, 18–19
storage, 65
structure, 18–19
therapeutic uses of, 1–5, 2b
topical versus injectable, 176
types of, 59–61
see also specific products
botulinum toxin type B
focal axillary hyperhidrosis, 165–166
pharmacology of, 43–44, 44t
botulism, 1, 6
Brazilians, 149
breastfeeding, 162
broadband light, 153
brow
ptosis, 14–15
see also eyebrow(s)
brow depressors
eyebrow height/shaping, 86
see also specific muscles
bruising, 67
crow’s feet treatment, 107–108
palmo-plantar hyperhidrosis injection, 173
bruxism, 3, 135, 137
buccinator muscle, 126–128
bunching, lower eyelid, 108
bunny lines, 117–119, 119f
adverse effects, 119
dosage, 118
injection sites, 118
Xeomin treatment for, 40f, 41
bupivacaine, 73
C
calcitonin gene-related peptide (CGRP), 1, 4
calcium hydroxylapatite, 152t
INDEX
A
A-beta fibers, 21
ablative lasers, 153–155, 154t
abobotulinum toxin A see Dysport
accessory proteins see neurotoxin-associated
proteins (NAPs)
acetylcholine
blocking/inhibition, 1, 20, 59
release, 3
acromegaly, 1
action halo, 80
A-delta fibers, 4, 21
adjunctive treatments
for crow’s feet, 106f
for eyelids, 114–115
adverse events, 64
Botox, 83
bunny lines treatment, 119
crow’s feet treatment, 107–109, 107f
glabellar lines injection, 83
levator labii superioris alequae nasii injection,
120
risorius injection, 121
see also complications
afferent nervous system, 4
African-Americans, 143–148, 148f
aging
chin, 124–125, 125f
eyes, 102
face, 14, 151–152, 152f
neck, 129, 132
perioral region, 124–125, 125f
periorbital region, 111
albumin for reconstitution, 73
allergic rhinitis, 175
alpha-adrenergic agonist eye drops, 83,
108–109
alpha-hydroxy acid (AHA), 114
aluminium chloride, 170
analgesia see pain relief
anaphylaxis, 73
anesthesia
lower eyelid injections, 112
palmo-plantar hyperhidrosis, 171–172
perioral and chin regions, 126
angle of beauty, 138, 138f
anhidrosis, 165–166
animal studies
diffusion, 47, 80
dosing, 62
hyperhidrosis, 10
reconstitution, 73–74
Xeomin, 80–82
antibodies
blocking, 64–65
neutralizing, 29, 44
anticoagulants, 103
anti-inflammation, 4
apraclonidine, 83
Arnica montana, 115
Asians, 53–57, 54t, 149
aspirin, 103, 107
asthma, 175
asymmetry
eyebrow height/shaping, 90–91, 91b, 91f
eyelids, 113–114
facial, 90–91, 120
atrophy
disuse muscular, 57, 57f
vermilion, 124, 124t
augmentation, soft tissue see fillers; soft tissue
augmentation
autonomic nervous system, 3
axillary hyperhidrosis, focal see focal axillary
hyperhidrosis
axonal sprouts, 21
Azzalure see Dysport
B
banding, vertical neck, 132–134, 157
Bell’s palsy, 15–16, 120
benign prostatic hypertrophy, 3, 175
benzyl alcohol, 72
bimatoprost, 115
bleeding
crow’s feet treatment, 107
palmo-plantar hyperhidrosis treatment, 173
risk reduction, 67
blepharoplasty, 114, 157
blepharoptosis, 83
blepharospasm, 1–2, 110
Botox treatment for, 8–10, 9t
dilution for, 75
Neuronox treatment for, 52–53
Xeomin treatment for, 37
blinking, excessive, 2
Bocouture see Xeomin
body contouring, 54–55
Botox, 18–25
adverse events, 83
approvals, 24
cervical dystonia, 176
clinical applications, 60, 67
clinical pharmacology, in aesthetics, 22–24
composition, 61–62
for crow’s feet, 103–104, 106
cumulative benefits, 23–24
in darker skin types, 143–144, 143f,
144t–146t, 149
diffusion, 64
dilution, 74t, 75–76
dose-response effects, 22–23
dosing, 62–63, 117, 118t
duration of action, 63–64
efficacy, 22, 22f–23f
for eyebrow height/shaping, 88b
for focal axillary hyperhidrosis, 162–164,
166b
formulation, 19–20
frozen vs. fresh, 74
general description, 60, 60f
for glabellar lines, 78–79, 79f, 82f, 82t
for horizontal forehead lines, 93–96
for hyperhidrosis, 75–76, 166–167
immunogenicity, 21
indications for, 8–11, 9t
for limb muscle dystonia/spasticity, 75
lower face treatment with, 126
manufacturing, 19
mechanism of action, 20–21, 20f
binding, 20
cleavage, 20–21
dissociation of NAPs from the 150 kDa
neurotoxin, 20
internalization, 20
potential actions on the sensory system,
21
recovery of neurotransmitter release, 21
translocation, 20
mid-face treatment with, 117, 118t

180
Index
calves
contouring, 149
muscle reduction, 56f, 57
canthal lines, lateral see crow’s feet
carbon dioxide (CO2) lasers, 153–155
Carruthers, Dr Alastair, 59
Carruthers, Dr Jean, 59
cell-based potency assay, 11
cell-penetrating peptides (CPPs), 68
central effects of the neurotoxin, 177
cerebral palsy
dilution for, 75
equinus foot deformity, juvenile, 9t, 10
spasticity, 52–53
cervical dystonia, 1–3, 176
Botox for, 9t, 10
Myobloc treatment for, 43
Xeomin treatment for, 37
C-fibers, 4
cheeks, sunken, 55
chemodenervation, 123, 153–156, 158
children
cerebral palsy in, 10, 75
strabismus in, 8
chin
aging, 124–125, 125f
dimpling, 124t, 126
musculature, 123
rejuvenation, 125–128
chromatography, 26–27
clinical trials, 14–16, 15f
corrugator supercilii muscles, 14–15
crow’s feet, 16
Dysport, 28–30
eyebrow height/shaping, 85
glabellar lines, 14–16
Neuronox, 52–53
Oculinum, 7–8, 7f
rhytides, 16
tibialis anterior, 75
see also animal studies
Clostridium botulinum, 6, 13, 35–36, 52
collagen fillers, 14, 152t
combination treatment, 151–159
compensatory hyperhidrosis, 164, 167
complications
crow’s feet treatment, 107–109, 107f
depressor angularis oris treatment, 128, 128f
eyebrow height/shaping, 87–88
lower face treatment, 128
masseter muscle treatment, 140
mentalis treatment, 128
Nefertiti lift, 132, 133f
orbicularis oris muscle treatment, 128
palmo-plantar hyperhidrosis treatment, 173
contraindications
eyelids treatment, 112b
focal axillary hyperhidrosis treatment, 162
periorbital lines treatment, 112b
cooling devices, 171
corrugator supercilii muscles
clinical trials, 14–15
eyebrow height/shaping, 85–87
glabellar lines, 77, 78f
cross-reactivity, 44
crow’s feet, 100–109, 111t
adjunctive treatments, 106, 106f
aging eyes, 102
anatomy, 100–101
bruising, 67
case studies, 107, 108f
clinical trials on, 16
complications, 107–109, 107f
contraindications and precautions, 112b
definition, 100
dynamic, 100–101
Dysport treatment for, 29–32, 30t, 32f
general discussion, 100
Myobloc treatment for, 45t–46t
Neuronox treatment for, 53
patient assessment and selection, 111–112
patterns, 101, 102f
preoperative assessment, 102–103, 103f
static, 100–101
topical neurotoxin, 70
treatment, 103–106, 104f–105f
Xeomin treatment for, 38–41, 40f
youthful eyes, 101–102
D
darker skin types, 142–150
African-Americans, 143–148, 143f, 148f
Asians, 149
Brazilians, 149
ethnic specific applications, 149
racial/ethnic differences in photoaging, 142
safety and efficacy in, 142–149
depression, 177
depressor angularis oris, 123–128, 126t
complications of treatment, 128, 128f
Dysport treatment of, 32, 32t
injection, 126–128, 127f
depressor labialis inferior, 132
inadvertent injecting of, 126–128, 128f, 132,
133f
lower face treatment, 32
depressor supercilii, 86, 91
dermal edema, 54
dermatochalasis, 93–94, 94f
detrusor overactivity, 9t, 11, 175
diffusion, 27, 64
animal studies on, 47, 80
Botox, 64
Dysport, 27, 64
Myobloc, 47
topical neurotoxin, 69–70
Xeomin, 36–37, 64
dilution see reconstitution
disuse muscular atrophy, 57, 57f
dosing/dosages, 62–63
animal studies on, 62
Botox, 24, 62–63, 117, 118t
for bunny lines, 118
Dysport, 30t, 62–63, 117, 118t
for glabellar lines, 78–82, 79f–82f, 82t
for mid-face, 117, 118t
for risorius muscle, 118t
for tibialis anterior, 75
Xeomin, 62–63, 117, 118t
for zygomaticus muscles, 118t
dry eyes, postoperative, 102–103
dry mouth, 47, 138
dysphagia, 132
Dysport, 26–34
clinical applications, 60
clinical studies, 28–30
composition, 61–62
for crow’s feet, 103–105
in darker skin types, 143–148, 144t–146t
diffusion, 27, 64
dilution, 28, 74t, 75
dosing, 62–63, 117, 118t
duration of action, 63–64
efficacy, 27, 29
for focal axillary hyperhidrosis, 162–164
frozen vs. fresh, 74
general description, 60, 61f
for glabellar lines, 79–80, 80f, 82f, 82t
for horizontal forehead lines, 93–96
isolation, 26
lower face treatment, 32–33, 32t
masseter muscle, 139
mid-face treatment, 117, 118t
for palmo-plantar hyperhidrosis, 170, 172
purification, 26–27
reconstitution, 72–73
resistance, 65
safety, 27, 64
stability, 27
sterility, 74
storage, 65, 74
upper face treatment
crow’s feet, 31–32, 32f
forehead lines, 30–31, 31f
glabellar lines, 30, 30f
lateral eyebrow lift, 31, 31f
recommended dosages, 30t
vs. other botulinum toxins, 27–28, 36t, 60t
dystonia
cervical see cervical dystonia
facial, 135
feet, 3
focal, of the hand, 3
limb, 75
oromandibular, 3
research for treatment of, 7–8
E
ecchymoses see bruising
eccrine glands, 160
ectropion, 32, 102–104
endoscopic brow lift, 156–157
endoscopic thoracic sympathectomy (ETS),
164, 167
epinephrine, 72–73
equinus foot deformity, juvenile cerebral palsy,
9t, 10
erbium:yttrium aluminium garnet (Er:YAG)
lasers, 106, 153–155
erythema, facial, 45t–46t
esophageal sphincter achalasia, 3
ethnic specific applications, 149
expression, facial muscles of, 100–101, 101f
extensor digitorum brevis, 37
eyebrow height/shaping, 85–92
asymmetry, 90–91, 91b, 91f
attractiveness, 86, 86f
case study, 90
complications, 87–88
general discussion, 85–86
technique, 87–90, 88f–90f
trials, 85
eyebrow(s)
anatomy, 86–87
and attractiveness, 86, 86f
ideal, 86, 86f–87f, 90
lift
endoscopic, 156–157
lateral, 30t, 31, 31f
ptosis, 156–157
after crow’s feet treatment, 108–109
after HFL treatment, 93–94
volume, 90
Xeomin treatment for, 39–41, 40f
eyelid(s), 110–116
adjunctive treatments for, 114–115
aging, 111
asymmetry, 113–114
bimatoprost, 115
contraindications and precautions, 112b
indications, 112–114
laser and light-based therapies, 114–115
lower
aging, 111
anatomy, 110
asymmetry, 113
blepharoplasty, 157
bunching, 108

181

Index
festooning, 115
injections, 112
malposition, 113
snap-test, 102–103, 103f, 112
Xeomin treatment for, 40f, 41
malposition, 113–114
patient assessment and selection, 111–112
ptosis
clinical trials, 14–15, 22
crow’s feet treatment complications,
108–109
eyebrow height/shaping complications,
87
glabellar lines treatment complications,
83
as a side effect, 64
treatment for, 113–114
skin, 100, 111
soft tissue augmentation, 115
surgery for, 114
techniques, 112–114
topical agents for, 114
upper
anatomy, 110
blepharoplasty, 157
ptosis, 114f
eye(s)
aging, 102
anatomy, 110–111, 111f
opening up of, 40f, 41
postoperative dryness, 102–103
widening of the, 112, 113f, 149
youthful, 101–102
F
face
aging, 151–152, 152f
asymmetry, 90–91, 120
contouring, 54–55, 55f–56f, 55t
dynamic musculature, 39, 39f
dystonia, 135
erythema, 45t–46t
Liew’s angle of beauty, 138, 138f
shapes, 86, 87f, 90, 135, 137–138, 138f,
149
synkinesis, 2
Xeomin treatment for, 39–41, 39f–40f
see also lower face; upper face; specific areas
facelift, 157
facial muscles, 77, 78f
dilution for, 75
of expression, 100–101, 101f
facial nerve (VII), 2, 157
FDA approval, 16
feet dystonia, 3
festooning, lower eyelid, 115
fields of effect, 28
fillers, 96, 152t
see also specific fillers
flu-like symptoms, 47
flushing, 155–156, 176
focal axillary hyperhidrosis, 160–168
botulinum toxin therapy, 162–166,
165f–166f, 166b
clinical assessment, 161–162, 162f–163f,
163b
contraindications to treatment, 162
epidemiology, 161
quality of life, 161, 161t
food poisoning, 6, 26
forehead lines
Dysport treatment for, 30–31, 30t, 31f
horizontal see horizontal forehead lines
(HFLs)
Myobloc treatment for, 45t–46t
Xeomin treatment for, 39–41, 40f
formulation, Botox, 19–20
freezing botulinum toxins, 53, 65, 74
Frey syndrome, 1, 3, 167
frontalis muscle, 77, 78f
eyebrow height/shaping, 85–86
horizontal forehead lines see horizontal
forehead lines (HFLs)
G
gastric acid, 26
gastroparesis, 3
glabella, 77–84
anatomy, 77
eyebrow height/shaping, 87, 88f (see also
eyebrow height/shaping)
glabellar lines, 77
adverse events, 83
in African-Americans, 143–148, 143f,
148f
Botox treatment for, 9t, 10, 21–24
clinical trials on, 14–16
dilution for, 75
dosing, 78–82, 79f–82f, 82t
Dysport treatment for, 29–30, 30f, 30t
ethnic variation, 83
injection technique, 77–78, 78f
in men, 82
Myobloc treatment for, 45t–46t
Neuronox treatment for, 53
special considerations, 82–83
Xeomin treatment for, 38–41, 40f
glandular cell modulation, 4
Glogau photoaging scale, 111, 111t
glutamate, 1
glycopyrrolate, 170
grip strength, 173
growth hormone, 1
gummy smile, 40f, 41, 119–120, 120f
gustatory sweating, 3, 167
H
hand, focal dystonia, 3
headaches, 175
glabellar lines injection, 83
as a side effect, 64
tension, 4
hemagluttinin (HA), 19
hemifacial spasm, 2
high-intensity vibration devices, 172
history
of cosmetic botulinum toxin, 13–17
of therapeutic botulinum toxin, 6–12
horizontal forehead lines (HFLs), 93–99, 95f,
97f
injection techniques, 94–96
side effects of treatment, 93–94, 94f
hyaluronic acid fillers
combination treatment, 152–153, 152t,
153f
eyebrow volume, 90, 90f
hyaluronidase, 72
hyperfunctional muscles, 2–3
hyperfunctional rhytides, 67
hyperhidrosis, 1, 3, 160–161
axillary see focal axillary hyperhidrosis
classification, 160–161
compensatory, 164, 167
definition, 160, 169
dilution for, 75–76, 76t
focal see focal axillary hyperhidrosis
generalized, 160–161
Myobloc treatment for, 48, 49t
palmo-plantar see palmo-plantar
hyperhidrosis
primary, 160–161, 161b, 169–170
primary axillary, 9t, 10
secondary, 169, 170b
site prevalence, 161t
techniques for, 166–167
hyperhidrosis disease severity scale (HDSS),
161, 161t, 170, 170t
hyperkinetic rhytides, 44–47, 45t–46t, 50t
hypersecretion, 1
hypertrophic scars, 96
hypertrophy
benign prostatic, 3, 175
masseteric see masseter muscle, hypertrophy
orbicularis oculi muscle, 112, 113f
temporalis, 135–136
hypotrichosis, 115
I
ice, for pain relief, 171
immunogenicity
Botox, 21
Myobloc, 44
Xeomin, 37
incobotulinumtoxinA see Xeomin
infraorbital region, 110–116, 113f
injection techniques see specific procedures
intense pulsed light (IPL), 155–156, 156f
intercanthal distance, 87b
iodine-starch test
focal axillary hyperhidrosis, 161, 162f–163f,
163b
palmo-plantar hyperhidrosis, 171, 171f
iontophoresis, 68, 170
Iopidine, 108–109
J
juvenile cerebral palsy equinus foot deformity,
9t, 10
K
keloids, 96
L
labiomandibular folds, 123
see also marionette lines
labiomental fold, 125–126
lactation, 162
lagophthalmos, 115
larynx, focal dystonia, 3
laser therapy, 153–156, 154t
ablative lasers, 153–155, 154t
eyelids, 114–115
lateral canthal lines see crow’s feet
lateral canthal tendon, 114
lateral eyebrow lift, 30t, 31, 31f
lateral tarsal strip procedures, 157
lethal dose (LD50), 62–63
levator labii superioris alequae nasii, 118–120,
118t, 119f–120f
levator palpebrae, 77
lidocaine, 72–73
Liew’s angle of beauty, 138, 138f
light-based therapies, 114–115, 153–156, 154t,
156f
limb contouring, 149
limb dystonia, 75
liposomes, 68
liposuction
neck, 157
side effects, 14
lips
anatomy, 123
lower, 123
ptosis after crow’s feet treatment, 107f,
108
upper, 123
Xeomin treatment for, 40f, 41
lipstick lines, 124, 124t, 126