Ứng Dụng Thẩm Mỹ Và Lâm Sàng (Cosmetic and Clinical Applications)


Botulinum Toxins
randomized, double-blind, split-face study.
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Semchyshyn N, Kilmer S. Does laser
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Carruthers J, Carruthers A, Zelichowska A.
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Zimbler M, Holds J, Kokoska M, et al.
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18 Combination Therapy of Botulinum Toxin with other Nonsurgical Procedures
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
Peri-Procedure Botulinum Toxin for Skin Cancer Patients and Scars
Timothy Corcoran Flynn, MD,1,2 Molly C. Powers, MD,3 and David M. Ozog, MD (FAAD, FACMS)4
1Clinical Professor of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, USA
2Medical Director, Cary Skin Center, Cary, USA
3Dermatology Senior Resident, Department of Dermatology, Henry Ford Hospital, Detroit, USA
4Chair, Department of Dermatology; C.S. Livingood Chair in Dermatology; Director of Cosmetic Dermatology, Henry Ford Hospital, Detroit, MI, USA
Introduction
There have been several reports of botulinum
toxins being used to improve outcomes of
facial reconstruction [1–6]. Making use of
the principles of tissue immobilization as
an aid to wound healing, botulinum toxin
is employed to reduce the action of facial
mimetic muscles. By reducing the movement
of these muscles of facial expression, the
overlying skin affected by the musculature
has reduced movement, ultimately leading to
lessened intensity of tensile forces on a heal-
ing wound. Additionally, the use of botulinum
toxin in the treatment of pathogenic scars,
such as hypertrophic scars and keloids, con-
tinues to be evaluated. Additional work sug-
gests that there may be a direct effect of
botulinum toxin on the fibroblasts and their
cytokine expression involved in wound heal-
ing [7–9]. This chapter will explore how
botulinum toxin can be used for reconstruc-
tion in traumatic wounds and skin cancer
patients as well as a potential treatment for
hypertrophic scars and keloids.
Botulinum Toxin for Facial
Reconstruction
Patients are often disappointed in the appear-
ance of their scars. Not only does pathological
scar formation lead to functional limitations,
but it also causes significant anxiety due
to the cosmetic concerns of patients. It
is well reported that patients are often
troubled about the appearance of the recon-
structed surgery site, just as much as they are
about the removal of the cutaneous cancer.
Appearance-related concerns may lead to
increased self-consciousness and social anxi-
ety, which may ultimately result in psycholog-
ical and social dysfunction [10]. Minimizing
the appearance of scars including those for
skin cancers excisions, repairs, and traumatic
scars remains a top priority among surgeons.
Wound healing is very complex, involving
multiple intertwining processes including
inflammation, proliferation, and remodeling.
Any disruption in this complex process
may result in pathological wound healing.
Increased wound tension, for example, has
Botulinum Toxins: Cosmetic and Clinical Applications, First Edition. Edited by Joel L. Cohen and David M. Ozog.
© 2017 John Wiley & Sons Ltd. Published 2017 by John Wiley & Sons Ltd.
Companion Website:

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Botulinum Toxins
been shown to prolong the inflammatory
phase of wound healing [11]. Repetitive
microtrauma leads to increased deposition
of glycosaminoglycans and collagen within
the wound [5, 12]. Given these principles of
wound healing, surgeons have been adopting
wound closure techniques to minimize ten-
sion and ultimately microtrauma with under-
mining, flap reconstructions, deep plicating
sutures, etc. [13]. Exploiting the temporary
paralytic effects of botulinum toxin continues
to be evaluated in surgical and traumatic
wound healing to reduce wound tension
(and such microtrauma) to these healing
wounds.
There have been several reported stud-
ies indicating the effects of botulinum toxin
reducing the appearance of scars in the
immediate surgical repair period. Most stud-
ies have demonstrated superior cosmesis
as compared with placebo. The generally
accepted mechanism of action is currently
the reduction in wound tension attained by
chemical denervation of surrounding mus-
cles; however, some research has suggested
direct effects on promoted wound healing
through TGF-β1, collagen synthesis, CTGF,
and other cytokines that will be addressed in
the chapter.
There are several clinical reports on the
benefits of botulinum toxins in wound heal-
ing. An early report by Choi, et al. in
1997 reported on the benefits of onabo-
tulinumtoxin injected into blepharoplasty
patients at risk for wound complications after
eyelid reconstruction. Risk factors included
prior radiation exposure, burns, scarring
from previous surgeries, muscles spasms, etc.
The dynamic musculature following eyelid
reconstruction may lead to higher rates
of dehiscence, scarring, and eventual eye-
lid malposition. Wound immobilization with
onabotulinumtoxin in the eleven patients
reports lead to promoted wound healing
believed to be secondary to full wound immo-
bilization that was achieved with chemical
denervation as compared with partial wound
immobilization by mechanical measures [14].
However, this was an uncontrolled study.
In 2000, Gassner et al. performed a
double-blind, placebo-controlled trial with
the use of botulinum toxin type A on lat-
eral forehead sutured wounds in primates
[2]. The molecule was used to immobilize
tissue surrounding these wounds and was
able to demonstrate improved cosmesis of
facial scars, as determined by three blinded
observers using the visual analogue scale
(VAS). Final evaluation was conducted 12
weeks after treatment with toxin. Although
these results could not be generalized to
humans, proof of concept was obtained.
Further work by Gassner et al. was reported
on chemoimmobilization for improving facial
scars [5]. Of patients with either fore-
head lacerations or forehead excisions (non-
melanoma skin cancers and other tumors),
31 completed all phases of the study. The
patients were randomized to receive toxin
or placebo into the musculature adjacent to
the wound within 24 hours after closure.
A blinded assessment of standardized pho-
tographs was undertaken by two experienced
facial plastic surgeons at six months. The
overall median visual analogue scale (VAS)
score for the botulinum toxin treated group
was 8.9 compared to 7.2 for the placebo
group (p = .003) indicating improved cosme-
sis and enhanced wound healing. Doses of
onobotulinumtoxinA used in these forehead
wounds were 15 U for wounds up to 2 cm
long, 30 U for wounds 2–4 cm long and 45 U
for wounds > 4 cm.
Wilson in 2006 discussed the use of
botulinum toxin type A to prevent widen-
ing of facial scars [4]. Given that immobi-
lization is a basic therapeutic principle in
wound healing, this study sought to achieve
immobilization through chemical denerva-
tion ultimately leading to reduced tension on
wounds lying with unfavorable orientation to
the lines of Langer. The paper reported on 30
patients with revision surgery for unsightly
and previously widened scars on the face
and 10 patients who were undergoing exci-
sional surgery of facial lesions. All wounds
were perpendicular to the lines of Langer.
OnobotulinumtoxinA was used to induce a

19 Peri-Procedure Botulinum Toxin for Skin Cancer Patients and Scars

temporary paralysis of the muscles during
surgery. A dose of 1.5 U per linear cm was
used. The average repair length was 9.8 cm.
Using objective and subjective scales, 90% of
patients had an improved outcome; however,
there was no placebo arm for this study and
scales were not validated.
Flynn in 2009 published a study using
intraoperative botulinum toxin type A or
B in patients following Mohs micrographic
surgery for treatment of skin cancer [1]. Eigh-
teen subjects were treated. They were consid-
ered for intraoperative treatment with either
onobotulinumtoxinA or rimabotulinumtox-
inB if the Mohs surgery defect was affected
by skin movements of the underlying muscles
of facial expression. These 18 patients had
their defects repaired with either primary
complex closures or adjacent tissue transfers.
Immediately following the repair the patients
were injected with either onobotulinumtox-
inA or rimabotulinumtoxinB. Injections were
placed within a 1–2 cm radius around the
suture lines, to affect muscles directly pulling
on the repair. If the movement of a facial
muscle or muscle groups were found to affect
the closure they were temporarily chemoden-
ervated. For example, if a repair on the scalp
was stretched with the actions of the frontalis
muscle, the entire frontalis muscle was tem-
porarily chemodenervated, as shown in the
case in Figure 19.1. The doses of botulinum
toxin were appropriate for those muscles
with the goal being complete immobilization
of the muscle unit. Figure 19.2 shows a case
of a repair involving the base of the nose.
The entire glabella complex was treated
intraoperatively.
Nine patients received onobotulinumtox-
inA and nine patients received rimabo-
tulinumtoxinB. There was no difference in
outcomes for patients treated with either
toxin and no significant complications were
noted with the botulinum toxins. The only
complication noted was that one patient who
received onobotulinumtoxinA had an epider-
mal slough in one area of the adjacent tis-
sue transfer. Patients were seen in follow up
at three months, and it was noted that no
patient had retained a significant effect of the
botulinum toxins at that time. Cosmetic out-
comes were excellent in most patients.
A previous paper by Flynn et al. has
demonstrated that rimabotulinumtoxinB has
a faster onset of action and an increased area
of effect compared to onobotulinumtoxinA
when dosed at a 100 : 1 ratio [15]. The faster
onset of action of rimabotulinumtoxinB has
been noted in clinical use, as well as the
laboratory study [16]. Therefore, the faster
onset of action of the type B toxin may
be desirable in skin cancer reconstruction
patients when the toxin is infiltrated at the
time of the repair. It has also been noted that
the duration of effect of the type B toxin is less
than that of the type A toxins [17]. This may
be desirable because the return of function
may be achieved faster without longer-
lasting residual effects; however, there is no
clinical evidence to date that supports this
hypothesis.
To investigate if botulinum toxin had a
primary effect on wound healing in normal
skin a separate study was designed. Healthy
adult human volunteers were injected with
18 U of onobotulinumtoxinA on one side of
their buttocks and saline on the other as a
control. Three weeks later subjects under-
went ablative laser resurfacing of the epi-
dermis and upper dermis using an erbium-
YAG laser with a wavelength of 2940 nm and
a fluence of 6 J/cm2. Wounds created areas
of tiny, pinpoint bleeding and the sites were
photographed daily for 6 days and every 3
days thereafter to 41 days. The botulinum
toxin placed intradermally had no effect on
wound healing, as the results for the onobo-
tulinumtoxinA treated sites were identical to
the results of the saline treated controls.
In 2009, Gassner et al. [5] reported two
interesting cases of chemoimmobilization of
lower facial wounds using onabotulinumtox-
inA [6]. The first case involved a 26-year-
old woman who sustained a crush injury
to the lower lip from a motor vehicle. The
irregular defect involved the vermillion bor-
der and complete transection of the orbic-
ularis oris muscle was observed. They used


Botulinum Toxins
Figure .A 42-year-old male underwent Mohs surgery for a squamous cell carcinoma. The wound edges
could be approximated with the surgeon’s hands, but with frontalis contraction there was significant traction
laterally widening the wound. The wound was repaired and his frontalis was treated immediately
post-operatively with 3000 U of rimabotulinumtoxinB. Effect of the toxin is shown at 48 hours after the
injection. Complete effect of the type B toxin is still present at 2 weeks following the repair.
a technique of dissolving 7.5 U of onobo-
tulinumtoxinA per ml of 1% lidocaine con-
taining 100,000 U epinephrine. The total dose
given, using this technique was 40 U. Follow-
up showed a flaccid paralysis of the injected
portion of the lower lip, closely resembling
the degree of paralysis shown from injection
of the lidocaine. This dose of toxin resulted
in their patient having a short-term, 1-month
duration reduced oral sphincter function

19 Peri-Procedure Botulinum Toxin for Skin Cancer Patients and Scars

Figure .A 33-year-old male underwent Mohs surgery for a basal cell carcinoma on the root of the nose. His
postoperative defect is shown and a rhombic transposition flap used for the repair. 24 U of onobotulinumtoxinA
was placed intraoperatively into the entire glabellar complex (procerus, depressor supracilli, and corrugator
supercilli muscles). The result at 4-month follow-up is shown.
with occasional spillage of liquids and mild
dysarthria. The final surgical result was out-
standing [5].
Their second case involved a scar revi-
sion on the left cheek, which resulted from
incision and drainage of a recurrent facial
abscess. In this case 30 U of onabotulinum-
toxinA were injected into the buccinator and
zygomatic facial muscles. The patient expe-
rienced a clinically significant paralysis with-
out any dynamic tension or distortion of the
wound clinically. At 10 weeks after surgery
the muscle function had returned and an
excellent result was seen. The authors have
commented that to eliminate the tension
on the healing tissue, paralysis of the mus-
cle groups adjacent and subadjacent to the
wound should be as complete as possible.
These patients, who were concerned about
the eventual appearance of their scars, were
very accepting of the explained temporary
functional deficits. This study differed from
the study completed by Flynn in that greatly
increased doses of botulinum toxin were used
to affect a complete paralysis; however, these
results may have been possible with lower
doses of toxin. If this technique is used, the
patient should be advised to expect a possible
significant functional impairment of a large
area around the reconstruction [5].
In 2013, Ziade et al. [18] conducted
a blinded, randomized, placebo-controlled
study of facial trauma patients who presented
to the emergency room. Onabotulinum toxin
or placebo was injected into the muscle
groups, which were deemed to cause tension
on the sutured wound at the time of clo-
sure. The mean dose of toxin injected was


Botulinum Toxins
20 U (range 15–40 U); 24 patients completed
the study and 1 year follow-up. Their 1-year
photographs were evaluated by six separate
physicians. The median overall visual analog
score (VAS) score was 8.25 in the toxin group
and 6.38 in the control group, p < 0.001.
The strengths of this study include length of
time for follow-up (1 year), blinded nature,
placebo control, and the 1.87 improvement in
VAS score (an improvement of 1.5 is consid-
ered clinically relevant). One patient did have
an asymmetrical smile after injections into
zygomaticus minor and levator labii superi-
oris alaeque nasi on day 7 follow-up [18].
The only split-scar, double-blind, random-
ized controlled trial to assess the safety and
efficacy of botulinum toxin A (BTA) in oper-
ational scars was completed by Kim et al.
in 2015. Fifteen patients who underwent
open thyroidectomy by a single surgeon were
included in the study. The right and left sides
of the scar were randomized to receive treat-
ment with BTA or 0.9% normal saline within
10 days of thyroidectomy, injected by a single
dermatologist who was also blinded. Patient
follow up was at 2 weeks, 1 month, 3 months,
and 6 months postoperatively. The mean scar
length was 8 cm, and mean 32.2 U of BTA
were used. The modified Stony Brook Scar
Evaluation Scale revealed a baseline score of
the BTA-treated side of 4.07 before treat-
ment and 6.70 six months after treatment
and while the control group scores were 4.07
before treatment and 4.17 six months after
treatment (p = 0.000). Clinical photographs
demonstrated excellent results. The superior
cosmetic outcomes are attributed to BTA’s
ability to reduce tension on the wound and
through its direct inhibitory effects on fibrob-
lasts and TGF-β1 expression [19].
Botulinum toxin has been used to improve
results in wounded skin in other clinical
scenarios. Treatment with onobotulinumtox-
inA before and after laser resurfacing has
been shown to diminish wrinkles and prevent
reestablishment of facial lines [20, 21]. Yam-
aguchi found it helpful in periorbital laser
resurfacing [22]. OnobotulinumtoxinA has
been used with 35% TCA and dermasanding
to improve wrinkles in the lip [23]. These
studies continue to demonstrate the bene-
ficial effects of perioperative/periprocedural
BTA use.
Botulinum Toxin in Keloidal and
Hypertrophic Scars
Hypertrophic scars can be a significant prob-
lem due to pain, itching, and limitation
of range of movement. Routine treatments
include intralesional corticosteroids, laser
and excisional therapy, radiation therapy, and
compression treatment among many oth-
ers. There are several interesting reports of
the use of botulinum toxin for the treat-
ment of pathologic scars such as hypertrophic
and keloid scars. The primary effects of
botulinum toxin have been reported by sev-
eral authors. The hypothesis that botulinum
toxin is effective in the treatment of keloidal
and hypertrophic scars is supported by in
vitro biochemical processes that will be dis-
cussed further throughout the chapter. The
studies below discuss this clinical efficacy of
the use of botulinum toxin.
In a prospective 2009 study to evaluate the
effects of onobotulinumtoxinA in the treat-
ment of keloids, Zhibo et al. injected intrale-
sional toxin into 12 keloids [24]. The total
dose used in the keloid sessions was 70–
140 U. The treatment was given at 3-month
intervals for a maximum of 9 months. Out-
comes were assessed at 1 year and were
judged as excellent in three patients, good in
five patients, and fair in four patients. Impor-
tantly, none of the patients showed signs of
enlargements or recurrence of the keloids.
Treatments of mature hypertrophic scars of
greater than 2 years’ duration were reported
in 2009 by Xiao et al., who injected 19 patients
using the type A toxin from China (Lanzou
Biologic Company, Lanzou City, People’s
Republic of China) [8]. Intralesional injec-
tions of this botulinum type A (BTA) toxin
were placed into the hypertrophic scars at a
dose of 2.5 U/cm3 of hypertrophic scars at 1-
month intervals for 3 months. Doses ranged

19 Peri-Procedure Botulinum Toxin for Skin Cancer Patients and Scars

from 2 to 87 U/scar owing to the large differ-
ence in scar sizes. The follow-up conducted
at 6 months showed improvement of the
scars with a high therapeutic satisfaction. The
authors noted that redness and itching had
improved after the injections and the scars
became softer. Patients and plastic surgeons
were asked to rate the overall improvements
in the hypertrophic scars. Possible grades
were: no improvement, poor improvement
(0–25% improvement), fair improvement
(26–50% improvement), good improvement
(51–75% improvement) or excellent improve-
ment (76–100% improvement). Patients felt
the treated hypertrophic scars reached the
level of “good” in twelve cases and “excellent”
in seven cases. Plastic surgeons evaluated the
results rating fifteen cases deemed “good”
and four “excellent.” Limitations of this study
included the lack of a control group and a
relatively short follow-up duration [8].
In contrast, Gauglitz et al. in 2012 reported
on
four
patients
with
steroid-resistant
keloidal scars injected with BTA (70–120 U)
every 2 months for up to 6 months. Height
and volume measurements were obtained
clinically and with a 3D optical profiling sys-
tem. Additionally, the expression of collagen
(COL)1A1,
COL1A2,
COL3A1,
TGF-β1,
TGF-β2, TGF-β3, fibronectin, laminin-β2,
and α-SMA was obtained with real-time
PCR. It was discovered that there was no
difference between pre- and posttreatment
appearance of keloids as well as expression
of ECM, collagen synthesis or TGF-β. This
study was limited by a very small sample size
and a short treatment duration [25].
Robinson reported in 2013 on twelve
patients with keloidal scars with BTA for a
mean duration of 11 months (range 2–43
months). Nine patients had keloids on the
central chest/sternum, and the remaining had
scars on the neck, thigh, and cheek. Eight
of these patients were alternating intrader-
mal steroids with BTA therapy. The patients
had between 20 and 100 U of BTA injected
at any one time based on scar size and loca-
tion. In nine patients, complete flattening of
the keloidal scar in an average of 11 months
was noted using the Vancouver Scar Scale.
Two patients developed recurrences adja-
cent to previously treated areas. One patient
was concomitantly receiving intralesional
steroids with BTA, and the other received
intense pulse light therapy. This study was not
randomized or controlled. While improve-
ment of the scars was noted, delineating the
role of BTA in their improvement is diffi-
cult because many patients were undergoing
treatment with additional modalities [26].
Postexcisional treatment of keloids with
intralesional BTA and 5-fluorouracil (5-FU)
has been reported to have success. In 2013,
Wilson et al. treated 80 patients with keloidal
scars with 0.4 mL of 50 mg/mL of 5-FU every
centimeter in addition to 0.4 mL of 50 IU/mL
of BTA every centimeter for a maximum
dose of <140 IU on the ninth day follow-
ing excision of the keloids. Patients were fol-
lowed for 17–24 months and recurrence rates
were less than 3.75%. This is significantly
less than previously reported studies assess-
ing other therapeutic modalities, including
but not limited to excision alone, pressure
garments, intralesional steroids, radiation,
brachytherapy, silicone sheeting, laser ther-
apies, and cryotherapy. Although the study
demonstrated marked reduced recurrence
rates, the study was not controlled or ran-
domized [27].
There are many reports suggesting the clin-
ical efficacy of botulinum in the treatment
of pathogenic scars. Further research has
been conducted to help explain the beneficial
results that are reflected clinically. For exam-
ple, Xiao et al. have further researched the
effect of the Lanzhou botulinum toxin type
A on fibroblasts derived from hypertrophic
scars [9]. They explored the effect of the toxin
on transforming growth factor beta 1 (TGF-
β1) in these fibroblasts. TGF-β1 is known to
be the most potent growth factor involved
in wound healing and is a key regulator in
the pathogenesis of hypertrophic scars. After
isolating the fibroblasts, the cells from the
hypertrophic scar were treated with the type
A toxin. The growth of the fibroblasts treated
with toxin was slower than those without


Botulinum Toxins
type A toxin treatment (p < 0.01). TGF-β1
was decreased in cells treated with botulinum
toxin type A.
This work is similar to that of Lee et al.
in 2009, who used botulinum toxin type A
to relax adjacent muscles in the backs of
rats [28]. Surgical wounds were created in
the animals and left to heal by secondary
intention.
The
botulinum
toxin
treated
wounds showed larger diameters, but his-
tology
revealed
decreased
inflammation,
fibrosis, number of fibroblasts, and TGF-β1
expression. The larger diameter of toxin-
treated wounds was hypothesized to be sec-
ondary to decreased tension and fibroblast
activity on wound edges.
Further work by Xiao’s group involved
connective tissue growth factor (CTGF) [7].
In hypertrophic scar formation, CTGF is an
important factor that regulates cell growth
and adhesion, as well as excessive deposition
of collagen. It is mediated by TGF-β1 levels,
which were previously shown to decrease
after treatment with BTA. Their laboratory
used the fibroblasts obtained from eight
patients with hypertrophic scars. The cells
were treated with BTA and untreated cells
were the control. Again, the proliferation
of fibroblasts treated with toxin was slower
than those with no toxin treatment. The cells
treated with BTA had a dose response to the
toxin with increasing exposure to BTA reduc-
ing the expression of a CTGF protein. They
plan to study the effects of toxins on keloid-
derived fibroblasts.
Haubner et al. evaluated the effects of
BTA on dermal fibroblasts and microvas-
cular endothelial cells. After incubating the
cells with varying concentrations of BTA,
the expressions of fibroblast growth factor
(FGF), interleukin-6 (IL-6), vascular endothe-
lial growth factor (VEGF), and macrophage
colony-stimulating factor (M-CSF) were not
significantly different. Additionally, these
normal cell lines did not show a difference in
cellular proliferation [29]. The findings are
interesting as this study used commercial
cell lines for fibroblasts and endothelial cell,
whilst the work of Xiao used fibroblasts from
patient hypertrophic scars. This finding may
suggest the selective effect of BTA on abnor-
mal fibroblasts from hypertrophic scars.
Many studies evaluating the use of BTA in
pathological scar treatment are very limited
and not controlled or randomized. Addition-
ally, these studies often demonstrate clinical
improvement with the adjuvant therapy
of intralesional BTA, but do not compare
this
treatment
to
other
well-recognized
treatments for hypertrophic and keloidal
scars such as intralesional steroids, pressure
garments, excisions, silicone sheeting, and
radiation among other treatments. The effect
of BTA on cytokine expression remains a
topic of research and may continue to prove
concept of treatment for these pathologic
scars.
Conclusion
There are multiple reports by several inves-
tigations showing improved wound heal-
ing with intraoperative or pretreatment with
botulinum toxins. Improved results have
been shown in humans and across species.
The use of intralesional botulinum toxin type
A in mature hypertrophic scars and keloids
has also shown improvement. The toxin is
thought to work in these cases by affecting
TGF-β1 and CTGF and ultimately collagen
deposition. Additional studies are ongoing to
delineate the mechanisms of action, dosing,
and timing of injections.
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Flynn TC. Use of intraoperative botulinum
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Gassner HG, Sherris DA, Otley CC.
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toxin A improves cosmetic outcome in

19 Peri-Procedure Botulinum Toxin for Skin Cancer Patients and Scars

primates. Plast Reconstr Surg
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Wilson AM. Use of botulinum toxin type A
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Gassner HG, Sherris DA, Friedman O.
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Xiao Z, Zhang F, Cui Z. Treatment of
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Martel H, Walker DC, Reed RK, Bert JL.
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Zheng Z, Yenari MA. Post-ischemic
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Choi JC, Lucarelli MJ, Shore JW. Use of
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Carruthers A, Carruthers J, Flynn TC,
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Lee BJ, Jeong JH, Wang SG, Lee JC, Goh
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Arch Facial Plast Surg 2012;14(2):122–126.



Achieving a Natural Look
D´oris Hexsel, MD,1 Camile L. Hexsel, MD (FAAD, FACMS),2 and Carolina Siega, BSc3
1Dermatologist and Dermatologic Surgeon, Brazilian Center for Studies in Dermatology, Porto Alegre, Brazil
2Dermatologist and Dermatologic Surgeon, Madison Medical Affiliates, Mohs Surgery, Glendale and Waukesha, USA
3Biologist, Brazilian Center for Studies in Dermatology, Porto Alegre, Brazil
Introduction
The goal of botulinum toxin use is mainly to
achieve a natural look and enhance beauty,
while maintaining facial expressions and
avoiding distortions. Combined procedures,
proper techniques and doses of BoNTA have
been discussed in the past decade, aiming to
provide better cosmetic outcomes and more
harmonious appearance.
The concept of natural beauty varies
according to the culture and fashion, and its
assessment is essentially subjective, varying
among individuals from the same social
groups. There is no scientific definition of
what “natural” looks like [1]. But, the debate
on this matter takes place very often on the
aesthetic field, since patients typically want
to avoid a “procedure-like” face. Dayan has
recently discussed the issue and suggests
that the three-dimensional and movement
aspects of the face should be regarded when
aiming to preserve the natural look of the face
[1]. The frozen look might not be perceptible
while facial muscles are not contracted, but
may give an artificial look while talking or
expressing feelings and emotions.
Botulinum Toxin Formulations
The most widely known botulinum toxin A
(BoNTA) formulations are onabotulinumtox-
inA (ONA; Botox/Vistabel®, Allergan, Inc.,
Irvine, USA), abobotulinumtoxinA (ABO;
Dysport/Azzalure®, Ipsen Ltd, Maidenhead,
UK),
and
incobotulinumtoxinA
(INCO)
(Xeomin®, Merz Pharmaceuticals, Frankfurt,
Germany). They are also the most used com-
mercial preparations of BoNTA. Following
a huge series of well-referenced published
papers, for both pathological and cosmetic
indications, clinical conversion tables have
been drawn up between the drugs: 1 unit of
ONA and INCO is approximately equivalent
to 2.5 units of ABO [2–4].
However, other toxins are currently avail-
able in markets outside the United States, as
displayed in Table 20.1.
Storage and Reconstitution
To obtain effective and long-lasting results,
certain precautions regarding the storage and
reconstitution of BoNTA must be taken.
Botulinum Toxins: Cosmetic and Clinical Applications, First Edition. Edited by Joel L. Cohen and David M. Ozog.
© 2017 John Wiley & Sons Ltd. Published 2017 by John Wiley & Sons Ltd.
Companion Website:


Botulinum Toxins
Table .Other toxins available on the market.
BoNT
Type
Manufacturer
Prosigne®
A
Lanzhou Institute of Biological Products, Lanzhou, China
Neuronox®
A
Medy-Tox Inc., South Korea
PurTox®
A
Mentor Corporation, Santa Barbara, USA
Neurobloc®/Myobloc®
B
Ellan Pharmaceuticals, Ireland
We recommended that reconstitution with
preservative containing 0.9% saline solution
(bacteriostatic saline) be carried out imme-
diately prior to use. Benzyl alcohol, which
is used as the preservative, has an immedi-
ate anesthetic effect, which makes injections
more comfortable. Dilutions from 1 to 5 mL
are currently being used for cosmetic pur-
poses, according to the physician’s choice or
to attend the patients’ needs.
Recently, a consensus on the storage and
reuse of previously reconstituted neuromod-
ulators has been published [5]. The authors
stated that a vial of toxin appropriately recon-
stituted can be safely and effectively used to
treat a single or multiple patients, even if
refrigerated or refrozen for at least 4 weeks
before injection, assuming appropriate stor-
age and handling [5].
Patient Assessment, Preparation,
Education, and Recommendations
A detailed knowledge and understanding of
facial anatomy and a safe and effective indi-
vidual therapeutic approach are the keys for
successful results. These must meet doctors
and patients’ expectations, with safety, har-
mony, balance, and naturalness. An empathic
and respectful attitude towards patients will
make them feel comfortable in revealing
their wishes, expectations, fears, and con-
cepts regarding the procedure. The use of
minimal effective dosing diluted in minimal
volumes is recommended. This is specifically
important in the lower face and seems to
reduce the risks of complications of undesir-
able effects in adjacent muscles.
For the best natural results, patients must
have realistic expectations and wishes. As an
example, the look is not natural if patient
want their muscles as paralyzed as possible.
Patients with unrealistic expectations should
be carefully managed or even avoided [6].
Physicians must also be aware of body dys-
morphic disorder, whose prevalence in der-
matology medical offices varies from 5 to 15%
[7]. The goals of the BoNTA treatment and
the expected cosmetic results must be dis-
cussed with patients. Botulinum toxins alone
improve dynamic wrinkles, mainly superfi-
cial ones, offering better results in the upper
face. Patients must be aware that some static
and/or deep wrinkles may remain after the
treatment. In this case, BoNTA may be com-
bined with other procedures.
For some patients, it is important to keep
a few wrinkles and/or avoid the treatment of
some facial muscles, to obtain a natural look.
It is also important to avoid side effects. These
can be either cosmetic, such as asymmetries
or excessive elevation of the tail of the brow,
or medical, such as eyelid ptosis. Although
side effects of BoNTA injections are usually
transitory, when they happen the patient will
look unnatural.
Patients with previous blepharoplasty and
face lifts should be carefully evaluated, as
well as those with brow tattoos. The tat-
toos are usually asymmetric, and this can
become more evident after BoNTA injec-
tions. The patient must also be informed
that BoNTA effects usually appear from 24
to 72 hours after the injections, reaching a
maximum level at around 2 weeks [8]. The
expected duration of the effects is limited and
the treatment must be repeated at intervals of

20 Achieving a Natural Look

4–6 months to maintain the results. For nat-
ural results, it is preferable to inject BoNTA
every 4 months at lower effective doses than
to overdoses every 6 months or at any inter-
val. The use of effective doses avoids short-
lasting effects.
Besides excellent injection technique and
the choice of correct doses, additional rec-
ommendations are still considered impor-
tant by many physicians to prevent undesir-
able BoNTA action in the adjacent muscles:
patients should remain in the vertical posi-
tion, avoid manipulation of the injected area,
and avoid intense physical exercise for at least
4 hours after injections [9,10].
Touch-ups can be carried out after 15–
30 days to optimize the results by treating
residual unwanted lines and correcting minor
side effects, such as discrete asymmetries that
can occur despite the use of a proper tech-
nique. Nevertheless, avoid performing fre-
quent or repeated touch ups.
Injection Points, Doses and
Techniques
For a natural look, symmetry is very impor-
tant. Botulinum toxin injections should be
symmetric regarding location and dosage,
except for patients presenting previous asym-
metries, when injection sites and doses
should be customized.
In the following paragraphs, a series of rec-
ommendations for natural results are given,
considering the main indications of BoNTA
treatments.
Upper Face
Microinjections of BoNTA
The complete paralysis of the frontalis mus-
cle gives an unnatural appearance, known as
frozen look, and can sometimes lead to brow
ptosis, which is not desired. To prevent the
frozen look, as well as brow ptosis, low doses
should be used to treat this area. On the other
hand, the treatment of the corrugators and
procerus muscle usually requires a full dose
established by consensus due to the strength
of these muscles.
Despite the treatment of specific facial
muscles, a new technique that uses micro-
doses of BoNTA is also being used to target
a natural look. It differs from the traditional
technique
regarding
dilution,
doses
per
site, and number and depth of the injections.
Larger volumes of saline are used, as reported
by Steinsapir, who used 3 ml to dilute a 100 U-
vial of ONA [11]. Doses of 0.33–0.66 U
ONA/injection point and 2 U ABO/injection
point have been reported [11, 12]. Several
intradermal or subdermal points are injected
in the face and/or neck [13]. Recent publica-
tions support that this technique promotes
aesthetic improvement to the upper face –
without the unnatural forehead paralysis
associated with conventional doses – and
resulting in high patient satisfaction [11, 12].
The latest consensus for ONA suggests that
the microdroplet technique is beneficial for
some indications [14].
Glabellar Lines
Treat the glabellar lines in safe and very
effective ways Glabellar lines may be inter-
preted as portraying negative feelings, such
as sadness, anger, and frustration [15]. More-
over, glabellar muscles are strong depressors,
being also responsible for lowering the upper
eyelid, giving patients an aged appearance
of this region. Injections of BoNTA in the
glabella may result in central, medial, and lat-
eral brow elevation [16]. Two-fingered palpa-
tion of these muscles can be used to minimize
the occurrence of side effects, especially eye-
lid ptosis (Figure 20.1) [9]. The usual recom-
mended doses for the treatment of an average
size glabella are 20 U of ONA/INCO [17] and
the consensus of ABO recommends 50 U for
this area [18]. The latest consensus for ONA
indicate that the typical total dose range for
glabellar lines is 12–40 U [14]. As a larger
muscle mass requires a higher dose to achieve
a similar effect, doses are usually adjusted
accordingly [19]. Besides gender differences
in muscle mass, large patient-to-patient


Botulinum Toxins
Figure .Technique of injection in the glabellar
region.
variation
in
mass
and
other
muscular
features are observed [19].
Use combined approach to treat deep
glabellar lines The improvement of deep
glabellar lines may require combined pro-
cedures, such as Subcision® and/or fillers
[9]. Fillers in the glabellar region should
be carefully injected, due to the risk of
vascular injuries with severe repercussions.
Subcision® is a useful and safe technique that
acts synergistically to BoNTA in the glabellar
region [20].
Select the technique according to the
patient’s
needs,
avoiding
side
effects,
including cosmetic side effects Injections
in the glabella can change the brow shape and
position. It is important to prevent a feminine
look for men, with arched eyebrows. The
male and female features differences have
been described by de Maio [21], and are very
Figure .Periorbital area before BoNTA treatment.
important when natural results are wanted.
Eyebrows in a straight line look better and
more natural and appropriate for men. The
excessive elevation of the brow tail is another
undesirable cosmetic side effect of glabellar
injections of BoNTA.
Eyelid ptosis is the most feared compli-
cation related to BoNTA injections on the
glabellar area. In this area, it is important
to avoid injections of high doses and/or
larger volumes of BoNTA, direct injection at
the levator palpebrae superioris muscle and
excessive manipulation of the injected sites
after the application to prevent this side effect
[22].
Follow-up and touch patients up, if
needed Patients can be followed up 15–
30 days after treatment with BoNTA. Exces-
sive brow elevation, asymmetry or undesir-
able brow shape can be easily treated with a
few units of BoNTA in the right sites, giving
a more pleasant, natural look.
Periorbital Wrinkles
Tell patients about the expected results
The treatment of periorbital wrinkles is effec-
tive in reducing hyperkinetic wrinkles, but it
is not suitable for treating the static wrinkles
caused by photoaging, skin redundancies or
sleeping habits (Figure 20.2 and Figure 20.3)
[18].
Use proper technique and doses The
BoNTA is injected lateral and superficially
Figure .Same patient as shown in Figure 20.2
after BoNTA injections; no improvements in the skin
redundancies in the lower eyelid were observed.

20 Achieving a Natural Look

Figure .Injection points for the periocular area.
[18]. The first point is marked at the center
of the maximum contraction area, usually
located at the lateral canthus, at a minimum
distance of 1 cm from the lateral orbital
margin. Two or three additional points may
be injected, 1–1.5 cm above and below the
first marked, in a line that follows the orbital
curvature (Figure 20.4). The recommended
doses range from 4–15 U/side of ONA/INCO
[14] or to 15–30 U/side of ABO distributed in
two to five points on each side, according to
the patients’ needs [18].
Special attention to the crow’s feet wrin-
kles located below the lateral cantus Injec-
tion points below an imaginary line between
zygomatic arch and malar eminency (Fig-
ure 20.5) can reach the zygomatic muscles,
resulting in an unnatural look. It is impor-
tant to avoid the region of zygomaticus major
Figure .Safe injection sites should be above a
line between the zygomatic arch and malar
eminency. This is of particular importance for
patients who underwent one or more face lifts.
muscle as it may also provoke the drooping at
the corners of the mouth [17,18].
Lower eyelid lines are also suitable for
BoNTA injections Hypertrophy of the orbic-
ularis occuli muscles, patients wishing to
increase ocular aperture, and those present-
ing fine wrinkles in the lower eyelid can be
treated with intradermal injections of 0.5 to
2 U of ONA/INCO or 2 to 5 U of ABO at
the mid-pupillary line, about 2 mm below the
lower eyelid border [14,23]. Ideal patients are
those who present a good snap test.
Bad candidates for BoNTA lower lid
treatment Botulinum toxin injections must
be avoided in patients presenting skin redun-
dancies and laxity, eye bulging, static wrinkles
or severe phodamage.
Combination regimes are also suitable
for periorbital lines Since BoNTA relaxes
muscles and treats hyperkinetic wrinkles
effectively [18], wrinkles caused by other fac-
tors can be adjunctively treated with specific
HA fillers (Figure 20.6 and Figure 20.7) [24],
lasers [25], energy-based devices [26,27], and
chemical peels [28].
Horizontal Forehead Lines
Be conservative in treating the frontalis
muscles Frontalis muscles are thin muscles
that respond to small doses of BoNTA. The
consensus papers recommend 10–30 U for
ONA/INCO [17] and 20–60 U for ABO [18].
The latest consensus for ONA refer that the
typical total dose for horizontal forehead lines
is 8–25 U [14]. Low doses are recommended
for a more natural look. For the treatment of
horizontal forehead lines, four to eight points
below the hairline are recommended (Fig-
ure 20.8) [14,18].
Avoid frozen look or mask-like appear-
ance Low doses, limited number of injection
points, and partial treatment of frontalis mus-
cle may be the best option for some patients.
Treatment of the upper part of the frontalis
muscle (Figure 20.8) gives a more natural look
and maintains the patient’s expressiveness.
Give
patients
an
appropriate
brow
shape The injections can be marked in a
slightly curved V-shape in women and a


Botulinum Toxins
Figure .Periorbital area before BoNTA treatment
combined with fillers.
Figure .Injection points for the treatment of
horizontal forehead lines.
straight line in men [18]. The injections
must be applied 1–2 cm above the orbit, and
superficially placed, to prevent brow ptosis,
causing an appearance of tiredness [29]. To
promote a natural look, excessive eyebrow
elevation should be avoided, if possible, even
Figure .Patient before forehead treatment with
BoNTA.
Figure .Same patient as shown in Figure 20.6
after combined treatment.
when requested by patients (Figure 20.9 and
Figure 20.10).
Treat asymmetries Special techniques are
required for patients with asymmetries. This
is discussed in detail in Chapter 16 Correc-
tion of Facial Asymmetry.
Mid and Lower Face
Use low doses for lower face indications
Low doses are recommended to achieve the
best desired effects and to prevent side effects
in the lower face. If needed, touch up patients
with additional doses after one month.
Attention to multiple treatments points
It is important to avoid multiple treatment
points in the lower face due to the risk of sum
of effects and consequent side effects.
Figure .Same patient as shown in Figure 20.9
with brow lift effect after forehead treatment with
BoNTA.

20 Achieving a Natural Look

Figure .Presence of bunny lines before
treatment with BoNTA in the upper third of the face.
Nasal Wrinkles
When present, always treat nasal (“bunny
lines”) wrinkles After the treatment of
crow’s feet and glabella, the nasalis mus-
cles are usually more recruited when smiling.
This is the reason why nasal wrinkles worsen
after BoNTA injections in these indications,
known as “bunny lines” or “Botox sign”. To
prevent and treat these wrinkles, it is impor-
tant to also treat the nasalis muscles (Fig-
ure 20.11).
Inject BoNTA at the right sites Low doses
of BoNTA must be applied in the high lat-
eral nasal wall, below the angular vein [30] to
avoid effects of the toxins in the levator labii
superioris muscle.
Use the recommended doses The consen-
sus papers recommend 2–4 U/point of ONA/
INCO and 5–10 U/point of ABO [14, 23] for
the treatment of nasal or bunny lines. These
doses are not sufficient for some patients,
who continue to recruit the nasal muscle.
Considering that the size of the field of mus-
cular effects (also known as “diffusion” halos)
is dose dependent [2], it is preferable to avoid
higher doses and touch up patients giving an
additional dose 15–30 days later as this can
avoid side effects.
Gingival Smile
Identify the type of gummy smile The smile
is influenced by the proper proportion and
arrangement of teeth, gums, and lips. The
exposure of more than 3 mm of gum during
smiling is known as gingival or gummy smile.
Based on the area of excessive gum displayed
and the identification of the muscles involved,
four different types of gingival smile (GS)
were identified: anterior (the most frequent),
posterior, mixed, and asymmetrical [31].
Treat the excessive gum exposure in the
right sites and keeping mouth movements
The use of BoNTA represents a simple, fast,
and effective method for the aesthetic cor-
rection of GS [31, 32]. Botulinum toxin type
A should be applied at two points on each
side of the levator labii superioris alaeque nasi
muscle in the nasolabial fold [30] to prevent
the excessive anterior exposure of the gums
while smiling, thus preserving the remain-
ing mouth movements. For a more natu-
ral look, posterior gummy smile can also be
treated. To reduce posterior gingival expo-
sure BoNTA should be injected in two points
at the malar region, one in the nasolabial fold,
at the point of greatest lateral contraction
during the smile, and the other point 2 cm lat-
eral to the first point, at the level of the tra-
gus [31]. The usual doses of BoNTA to treat
gummy smile are 0.5–2 U of ONA/INCO per
point [18] and 2.5–5 U per side of ABO [31].
Higher doses should be avoided due to the
risk of a cosmetic side effect known as “joker’s
smile”. Natural asymmetries should also be
treated for a more harmonious and natu-
ral look.
Perioral Wrinkles
Low doses promote significant less side
effects The perioral area has an important
role in the aesthetic appearance of the face
as well as in its function. Proper skills to
inject low doses are extremely important to
treat this indication and avoid the occurrence
of side effects such as asymmetry, muscle
dysfunction or temporary incapacity. Injec-
tions of BoNTA are applied at the superfi-
cial dermis, at the vermilion border or up
to 5 mm from the border [9]. Select two
or three sites in the perioral area and use
the lowest effective dose to avoid complica-
tions such as muscle incompetence. The con-
sensus recommended total doses are 1–5 U
for ONA/INCO and from 4 to 12 for ABO,


Botulinum Toxins
distributed in four points on the upper lip and
two on the lower lip [14,23]. Cohen et al. sug-
gest the use of 7.5 U of ONA to obtain signifi-
cant reductions in perioral lines and high lev-
els of subject satisfaction up to 16 weeks [33].
Combine procedures BoNTA is con-
sidered an adjuvant treatment for perioral
wrinkles. For better and more natural results,
the treatment of the perioral area is best
managed by combining procedures, such as
BoNTA, energy based treatments and fillers
[23,34].
Marionette Lines
For safe and effective treatment, combine
procedures Marionette lines give a sad and
dissatisfied expression to the face and are
primarily treated with fillers [23]. However,
BoNTA can also be useful to treat marionette
lines.
Use safe doses at DAO Botulinum toxin
type A may be applied bilaterally into the
depressis angulis oris (DAO). A total of 2–
4 U of ONA/INCO per side and 5–10 U of
ABO per side is recommended [14, 23]. Loss
of control of movement of the mouth corners
should be avoided by using lower doses and
keeping injections toward the lateral aspect
of the muscle, away from the depressor labii
inferioris.
Consider to treat the mentalis first. The
mentalis muscle acts as an agonist of DAO
(Figure 20.12). Injection of BoNTA at the
mentalis imply in less recruitment of DAO.
Figure .The mentalis muscle is an agonist and
supports the contraction of the DAO muscle.
Dimpled Chin
Use BoNTA to improve more than wrin-
kles for better, natural results The treat-
ment of the dimpled or “cellulitic” aspect of
the chin can be optimized by the associa-
tion of BoNTA injections with fillers, since
the contraction of the mentalis muscle, and
loss of collagen and subcutaneous fat in this
region contributes significantly to this condi-
tion [22]. Subcision® can also be combined
with good results. The technique and doses
vary. Whereas the consensus for ONA sug-
gests one to four points of injection [14], the
consensus for ABO suggests two points of
injection [23]. The typical total dose of 4–
10 U of ONA [14] or 10–20 U of ABO is sug-
gested and should be applied at the most
distal point of the mentalis muscle at the
prominence of the chin [23]. There can also
be gender differences in total dose, with
another study recommending 2–8 U of ONA
for men and 2–6 U of ONA for women; it
improves wrinkles and DAO movements as
described earlier.
Face Lifting
The use of BoNTA can improve facial appear-
ance by also promoting discrete a face lifting
effect. It is important to notice that BoNTA
cannot replace the surgical lift with similar
cosmetic results.
Identify correctly if there is indication
for BoNTA face lift Some of the platysma
muscle fibers are located in the mandibular
region, promoting the lowering of this area.
To assess if the patient will respond positively
to the treatment, the physician should ask
the patient to pull down the platysma muscle.
The disappearance of the mandibular border
may indicate the potential success of the pro-
cedure [35].
Obtaining the lift effect For a lift effect
and to improve the definition of the mandibu-
lar border or angle, BoNTA should be applied
in two to four points along the lateral man-
dibular border [9]. The doses are divided into
1–2 U of ONA/INCO or 2–5 U of ABO per
point [9].

20 Achieving a Natural Look

Combine procedures Some procedures
can be combined to improve the lifting
effects, such as radiofrequency, infrared light,
microfocused ultrasound, and fillers.
Neck and Chest
Treating neck and chest simultaneously
to the face can provide a more harmo-
nious
and
natural
rejuvenation
Neck
usually presents more signs of aging than
the face. Neck wrinkles are more frequently
related to photoaging and skin laxity than
platysmal bands, but BoNTA can be used
in cases of visible contractions of this
muscle [9].
Touch ups are usually needed in this
area. Residual platysmal bands can be treated
with additional doses of BoNTA.
Combined treatments can also be used
to improve the appearance of these regions
In general, wrinkles of the anterior midch-
est are caused by the position adopted during
sleep (called “sleep wrinkles”) and photodam-
age, but in some patients, they result from
the action of the medial fibers of the pec-
toralis major muscle and the tail portion of
the platysma muscle Therefore, BoNTA can
be very effective in this case and more effec-
tive results can be obtained by combined pro-
cedures, such as lasers and peelings [23].
To be effective for chest wrinkles, the
pectoralis major muscle must be involved
The involvement of the pectoralis major mus-
cle can be investigated by palpation of these
muscles, while asking the patients to cross
their arms [9]. If these muscles are involved in
these wrinkles, BoNTA can be considered for
the treatment, alone or in combination with
other procedures.
Use proper, effective doses The recom-
mended doses for the neck range from 6 to
12 U of ONA/INCO per band and maximum
total of 60 U [14], and a total of 50–100 U
of ABO [23]. The total number of injection
points depends on the number and length of
platysmal bands. The injections should start
with the first point at the jaw line, and go
down every 2 cm to at least the middle of the
band [23]. The total maximum dose should
not be exceeded as dysphagia, dysphonia, and
neck weakness can appear; they are related to
very high doses [23].
The recommended total doses for the chest
range from 30 to 100 U of ONA/INCO and
75–120 U of ABO, and should be given in
a “V” shape over the wrinkles, divided into
three to six points on each side [9,23].
Conclusion
The current goals of all cosmetic proce-
dures are to achieve a natural look and
improve beauty, avoiding distortions and
keeping facial expressions. To reach these
goals, each patient must be treated with
a safe and effective individual therapeutic
doses and approach, meeting doctors and
patients’ expectations, with harmony, bal-
ance, and naturalness.
The doses of botulinum toxins should be
adjusted depending on the indications, mass,
and anatomical location of the muscles being
treated and on the wishes of the patient. The
use of minimally effective dosing and vol-
ume are highly recommended in some areas
to avoid unwanted side effects, since a larger
field of effect or strong results can result
in a frozen, unnatural appearance. Consider-
ing each patient’s characteristics, needs, and
expectations, as well as knowing the proper
techniques, is essential to obtain optimal,
safer, natural results.
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

Special Considerations in Darker Skin
Cher´e Lucas Anthony, MD1,2 and Marta I. Rendon, MD (FAAD, FACP)1,3
1Medical Director, Rendon Center for Dermatology and Aesthetic Medicine, Boca Raton, USA
2Voluntary Faculty, Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, Miami, USA
3Voluntary Associate Clinical Professor, University of Miami, Dermatology Department, Miami, USA
Introduction
As people embrace ethnic diversity, the ideal
of beauty is changing. This shift has influ-
enced the cosmetic approach for darker skin
types. Successful outcomes hinge on under-
standing key differences in skin properties
and facial shape and utilizing this knowledge
in tailored regimens.
In 2015, 25% of all cosmetic proce-
dures were performed on racial and ethnic
minorities [1]. The rapidly growing ethnic
population underscores the necessity for
healthcare professionals to become familiar
with the unique skin properties and aes-
thetic concerns in people of color. Dynamic
rhytids often predominate in aging, making
botulinum toxin an integral component of
care for this expanding cosmetic popula-
tion. We advocate for early intervention in
patients with pigmented skin, since they have
fewer treatment options to combat aging.
In this chapter, we will discuss the unique
characteristics of darker skin and special
considerations
in
a
treatment
program
utilizing botulinum toxin A.
Unique Qualities in Skin of Color
and Facial Structure
While properties of skin and facial struc-
ture are more similar than different across
ethnic backgrounds, there is some variabil-
ity. Individuals with pigmented skin comprise
a wide range of ethnic groups. Racial cate-
gories are somewhat arbitrary, and significant
variability is seen within these groups. Latin
Americans, black Caribbeans and African
Americans often have diverse genetic back-
grounds. The Latin American population in
particular encompasses all skin types, which
makes generalization difficult.
Understanding the complexity of this issue
is important to evaluation and treatment. For
the purposes of this chapter, we define darker
skin types as Fitzpatrick III–VI in African
Americans; black Caribbeans, Latinos and
Hispanics; Asians; Pacific Islanders; Indians;
Pakistanis; and persons of Middle Eastern
descent.
Differences in skin of color are relevant
to evaluation and treatment of the cosmetic
patient. Current literature supports variance
in melanin content, ultraviolet light penetra-
tion, dermal thickness, and elastic recovery,
in addition to other properties.
The size and distribution of melanosomes
vary among ethnic groups. It has been well
documented that darker skin types have a
greater number of melanosomes and that
these melanosomes are more evenly dis-
tributed and larger. Szabo and colleagues
[2, 3] were among the first to find that
melanosomes are singly dispersed in black
skin and more aggregated in white skin. As
Botulinum Toxins: Cosmetic and Clinical Applications, First Edition. Edited by Joel L. Cohen and David M. Ozog.
© 2017 John Wiley & Sons Ltd. Published 2017 by John Wiley & Sons Ltd.
Companion Website:


Botulinum Toxins
the skin type changes – or for skin in Asian
or racially mixed people – the melanosome
distribution becomes more complex. It can
also change in sun-exposed skin [4,5].
Melanin content also varies, and this
becomes relevant in aging and in patient
evaluation for cosmetic procedures. Melanin
confers photoprotection by absorbing and
deflecting ultraviolet light. Five times more
ultraviolet A (UVA) and ultraviolet B (UVB)
reaches the upper dermis of white people
than black people. In fact, all wavelengths of
light are filtered equally by melanin [6]. Thus,
darker skin is less susceptible to acute and
chronic actinic damage.
Histologically, the dermis of sun-damaged
skin in white people shows lilac- and blue-
stained elastic fibers, signifying significant
elastosis [7], whereas the skin of black people
demonstrates minimal elastosis and no lilac-
stained elastic fibers. Superior inherent pho-
toprotection secondary to increased melanin
delays the signs of aging until the fifth or sixth
decade in people with darker skin [8].
In Asians, the onset of skin wrinkle is
also delayed. Studies of various Asian ethnic
groups consistently show fewer signs of
aging, when compared with age-matched
non-Asians with light skin [9–11]. While
wrinkling in photoaged Asian skin is less
prominent, hyperpigmentation and solar
elastosis are seen [12]. The frequency and
extent of these changes in the skin of Asians
varies and depends on sun exposure and
proximity to the equator.
While inherent photoprotection and lack
of elastosis are typical in skin of color, the
dermis also exhibits unique properties. In the
skin of black people and Asians the dermis
is thicker and contains more collagen than
in skin of white people [13, 14]. In addi-
tion, elastic recovery time has been found
to be slightly higher in black people than in
white people and Hispanics [15, 16]. These
distinct characteristics account for variations
in the appearance of aging and reinforce the
general notion that skin of color appears
less photodamaged, and signs of aging are
delayed.
Differences also exist in facial structure,
and maintaining these unique characteristics
is important in preserving ethnic appearance.
The shape of the face, particularly the angle
and shape of the eye, are unique.
A review of facial structure among ethnic
groups [17] revealed a great deal of variation,
particularly among Latin Americans and
African Americans, where racial mixture is
common. Nevertheless, some generalizations
have been noted. Asians, Latinos and African
Americans
tend
to
have
rounder
faces
than white people [12, 18, 19]. Additionally,
masseter
muscle
hypertrophy,
primarily
described in Asian populations, can lead
to a more pronounced squareness in jaw
shape.
In some people of Mexican descent, the
length of the columnella is shorter [20, 21].
And fuller, more protuberant lips are seen not
only in African Americans, but also in Asians
[22,23].
The eye and brow vary greatly among eth-
nic populations. The lack of a superior palpe-
bral fold in Asians is often cited in contrast to
other ethnicities; however, more subtle differ-
ences also exist.
Eyebrow shape and placement are similar
in white people, Indians and Asians [24], with
the apex (highest point of the brow) generally
positioned between the lateral limbus and
lateral canthus. The distance from the brow
to the upper lid margin is greater in Asians
[25]. In Indians, the distance from the end
of the brow to the lateral canthus is shorter,
possibly because of an upwardly slanted
eye, or increased palpebral fissure inclina-
tion, a characteristic of Indian and Chinese
populations.
Palpebral fissure inclination is sometimes
referred to as the lateral canthal angle. It was
recently postulated that the lateral commis-
sure may be higher than the medial commis-
sure to a greater degree in African Americans
[26]. Africans and African Americans also
have more prominent orbital proptosis, as
compared with Caucasians. The unique eye
shapes of Asians, Indians, and African Amer-
icans (and many Latin Americans) should be

21 Special Considerations in Darker Skin

considered prior to cosmetic treatment to
preserve normal ethnic appearance.
Cosmetic Implications
Special Considerations when Using Botulinum
Toxin A
The unique skin and facial structure in per-
sons of color cause them to age differently.
These variations impact cosmetic treatment
(see Table 21.1). We will discuss specific con-
siderations in the preservation, restoration,
and enhancement of the ethnic face with
botulinum toxin A.
Upper Face
Increased melanin confers photoprotection,
and thus, dynamic wrinkling predominates
over superficial wrinkling caused by actinic
damage. Therefore, it is not surprising that
aging of the upper face in darker-skinned
individuals is most commonly seen in the
glabella area [27]. Multiple studies have eval-
uated the treatment of glabellar rhytids with
botulinum toxin A in skin of color and have
consistently shown a similarity in dosage
and safety of botulinum toxin A across racial
and ethnic groups [14, 28–30]. On average,
the glabellar region was treated with 20 U of
Botox®
(onabotulinumtoxinA)/Xeomin®
(incobotulinumtoxinA)
and
40–50 U
Dysport®
(abobotulinumtoxinA)
at
five
injection points. Slightly more botulinum
toxin A was used in men than in women.
Interestingly, a secondary finding of one
Dysport® study was increased effectiveness
and longer-lasting results in African Amer-
icans as compared with other patients [31].
The same study showed a slightly higher inci-
dence of ocular adverse events in African
Americans than in other ethnicities (6% ver-
sus 4%), but a lower incidence of injection-
site reactions [31]. Similar findings of longer
efficacy were seen in an analysis of pooled
clinical data. Safety and time of onset was
similar between skin of color and white
patients; however, the response rate after 1
month was greater in skin of color patients
[32].
Botulinum toxin A is placed midline into
the procerus. Injections are performed bilat-
erally into the corrugator supercilii medially
just above the eyebrow along the medial can-
thal line and just inside the lateral corrugator
supercilii. Injection deep and just above
the
periosteum
minimizes
involvement
of the inferior frontalis, minimizing brow
droop and allowing upward pull as the brow
depressors relax.
The first three injections are typically made
with 4–5 U of Botox® and approximately
10 U of Dysport®. The final two injections
into the lateral corrugator supercilii often
require less product, and 2–3 U of Botox®
Table .Characteristics of ethnic groups and how these characteristics impact aging.
Variations in darker skin types
Changes with aging
Facial shape
r Rounder in Asians, African Americans and Latin Americans
r Masseter hypertrophy in Asians
r Loss of volume
r Jowl formation/sagging
r Mental crease
Brows
r Lateral apex
r Shorter distance between end of brow and lateral canthus
(Indians, Chinese)
r Medial apex
r Descending brow
Eyes
r Lack of epicanthal fold, increased distance to brow, palpebral
fissure inclination (Asians)
r Increased lateral canthal angle (African Americans, Indians)
r Descending lateral
canthal angle
Columella
r Shorter columella (some Mexicans)
r Lengthens with age
Lips
r Fuller lips (African Americans, Asians)
r Volume loss


Botulinum Toxins
(a)
(b)
Figure .(a) Baseline. (b) Mild elevation of brow after treatment with BTA, preserving lateral apex.
or Xeomin® and 5 U of Dysport® are typi-
cally used. Because one side of the face is
stronger than the other, we typically have
patients return in 2 weeks for reassessment.
Improvement of forehead rhytids is more
variable. We advocate for earlier treatment
of darker skin to prevent persistent hori-
zontal lines. Different techniques have been
described in earlier chapters. A total of 8–
12 U of Botox® or Xeomin® and 20–30 U of
Dysport® is typically used, depending on the
degree of movement the patient desires, the
proximity of the brow to the upper eyelid,
and the size of the forehead. In a narrow
forehead, injection sites can be placed hori-
zontally. In a fuller forehead, injections can
be made in a V shape, or the products dis-
tributed through a single central injection site
and two vertical sites on each side, with a pos-
sible small aliquot made laterally and higher.
We stress careful evaluation of the face in a
dynamic position and at rest prior to injection
to account for ethnic variations and muscle
strength.
Although the placement of botulinum is a
relatively quick procedure, there is a definite
art to tailoring the treatment. Women tend
to have more shape to the brow, with a
more obvious apex. In some ethnic women,
particularly Asians, the distance from the
brow to the eyelid is greater. It is important
to stay well above the brow – approximately
2 cm – to avoid or minimize brow ptosis.
In our practice, we inject botulinum higher
and more centrally, which allows for some
lateral upward pull, while conserving brow
height.
In addition to improving forehead lines,
botulinum treatment of the forehead can
influence the shape of the brow. In youth,
brow shape peaks laterally, whereas older
people exhibit a more medial brow apex [33].
It is extremely important to evaluate brow
placement and shape in skin of color. We typ-
ically ask patients to raise their forehead to
make the apex of the brow more prominent.
We then draw a diagonal line from the apex of
the brow to the temporal hairline, where the
lateral frontalis pulls superiorlaterally. Injec-
tion sites are kept medial to this line when
treating the forehead. Relaxing the medial
portion of the forehead confers additional lift
to the lateral brow and places the apex to a
more youthful, lateral position (Figure 21.1).
Because the distance from the brow to
the eyelid is greater in Asian and African
American faces, lifting the brow is important
to restore a more natural look. Treating
the glabellar frown lines will lift the brow,
since the procerus and corrugator supercilii
are brow depressors. Chemodenervation of
the orbicularis oculi lateral and outside the
location where the orbital rim curves inferi-
orly usually leads to modest elevation of the
lateral brow [34]. We place 2 U of Botox® or
Xeomin® in this location, being careful not to
breach the orbital rim margin.
Periorbital/Eye Complex
As mentioned earlier, the lateral canthal angle
tends to be greater in young African Amer-
icans as compared with young white peo-
ple. While brow ptosis occurs later in African
Americans, it is postulated that the lateral

21 Special Considerations in Darker Skin

(a)
(b)
Figure .(a) Baseline: downward slanted canthus accentuated in dynamic position with rhytids along the
orbital rim. (b) After: improvement of canthal angle in dynamic position with softening of rhytids and lateral
position of brow apex.
canthal angle descends faster. Thus, aging of
the upper face occurs primarily in the peri-
orbital area. The mean lateral canthal angle
in African Americans measures an average of
2.39◦in youth and 1.05◦after the age of 45
years. The angle is small, but a slight change
in elevation can result in significant aesthetic
improvement. Botulinum toxin can be used
to subtly restore the lateral canthal angle to a
more youthful position (Figure 21.2).
In our practice, approximately 2 U of
Botox® or Xeomin® and 5 U of Dysport® are
injected into the laterosuperior and lateroin-
ferior superficial orbicularis oculi muscle to
relax the downward pull on the lateral canthal
complex. As small a volume as possible is uti-
lized to avoid the diffusion that occurs with
greater volume. We combine this procedure
with shaping and lifting of the lateral brow
as mentioned earlier, to enhance the appear-
ance of an upwardly slanted lateral canthal
complex.
Crow’s Feet
The development of crow’s feet is delayed in
darker skin types, and in some people, may
be minimal. This may be the result of photo-
protection conferred by greater amounts of
melanin and a thicker dermis, as discussed
earlier; however, skin types III and IV, par-
ticularly in individuals who have had signif-
icant sun exposure, may develop crow’s feet.
Typically, 8–15 U of Botox® or Xeomin® and
15–30 U of Dysport® are used per side. Mul-
tiple injection sites in small aliquots with
botulinum toxin A produce a smooth effect
on lateral lines. Anecdotally, Dysport® may
not require as many injection sites as Botox®
or Xeomin®, but this may be more dependent
on the end volume of the reconstituted prod-
uct – more volume can lead to larger areas of
diffusion. The product is injected in two to
four sites placed intradermally lateral to the
orbital rim along the curvature.
While crow’s feet may not be as prominent
in darker skin types, the eyes can appear
smaller and less open with age, despite
minimal superficial wrinkling. Treatment
of the superficial orbicularis oculii not only
softens crow’s feet, but will open the palpe-
bral aperture [35]. Results are particularly
impressive in the Asian eye; however, we


Botulinum Toxins
advise discussing this effect with the patient
prior to injection, since widening may not
be desirable in all ethnic groups. Upon
agreement, we inject about 2 U of Botox® or
5 U of Dysport® to the infraorbital lid where
the lower pretarsal orbicularis widens the
eye. Because periocular skin is thin, creating
a bleb ensures proper intradermal depth of
injection. Appropriate smoothing of crow’s
feet and maintenance of the eyes’ shape can
be achieved by avoiding infraorbital injection.
Lower Face
Lower facial aging in darker skin types mani-
fests as pronounced sagging or laxity. Melo-
mental folds and mouth frown may be the
most significant signs of aging in the lower
face, as little or no superficial wrinkling
will usually develop. Perioral wrinkles appear
later and are rarer.
Downturned mouth corners can be soft-
ened by placing 2–3 U of Botox® or Xeomin®
or 4–6 U of Dysport® into the depressor
anguli oris (DAO). Concurrent treatment of
the mentalis can augment the effect. Inject-
ing small doses of botulinum toxin A to each
lateral mentalis band lessens the potential
of weakening the orbicularis oris. Similarly,
melomental folds are improved by placing a
minimal amount of product into the DAO
1 cm lateral to the oral commissure and at the
angle of the mandible. Flattening of the lower
lip contour can occur if the injection is placed
too high. To find the proper injection point,
we ask the patient to frown, and we follow the
mental crease to the point where it intersects
with the jawline. We then inject lateral to this
point and deep, just above the bone.
Full lips are characteristic of darker skin
types and have been culturally desirable in
this country. Volume loss in the lips does
occur over time, and although lip lines may be
minimal, perioral injections can help restore
fullness to the lips.
If vertical lip rhytids are short, small
aliquots of botulinum toxin A (for example,
1–2 U of Botox® or Xeomin®) are placed in
four locations along the vermillion border.
Dividing the lips into quadrants, the product
is injected one-quarter and three-quarters
laterally in each quadrant and repeated
on the contralateral side. Care should be
taken to avoid the corners of the mouth,
where chemodenervation can cause mouth-
drooping and drooling. If the vertical lines
of the lip are longer, injections can be made
with 1–2 U of Botox® or Xeomin® (Dysport®
requires slightly more), up to a maximum of
4 U for each lip. We dilute 1–2 U of Botox®
or Xeomin® to a volume of 0.1 cm3 and
inject it along the vermillion border on each
side, starting just lateral to the cupid’s bow.
The product is injected into the superficial
orbicularis oris, as opposed to deep place-
ment, to maintain adequate sphincter tone of
the mouth. The technique can be repeated if
desired for the lower lips.
Facial Contouring
Masseter
muscle
hypertrophy
typically
presents between the ages of 20 and 40 years
[36] and can lead to a prominent mandibular
angle that can make the face appear wider.
This is primarily a concern among Asians,
in which it known as square-jaw. Masseter
hypertrophy is commonly considered unde-
sirable, since Asian women prefer an oval
or almond-shaped face [37]. Injections of
botulinum toxin A into the masseter muscle
in the treatment of masseteric hypertrophy
was first reported in 1994 [38], and can be
effective in reshaping and narrowing the
face. Reduction in masseter hypertrophy is
effective and relatively long lasting.
In an early study by Park et al., 25–30 U
of Botox® yielded results out to 10 months,
with
an
average
18–20%
reduction
in
mass demonstrated through ultrasonic and
computed tomography imaging. Another
group reported an average 31% reduction
in masseter hypertrophy in 383 patients
injected with 100–140 U of Dysport® [39].
The duration of efficacy and quantitative
reduction in mass appeared to be dose-
related.
Effective
treatment
doses
were
evaluated using ultrasonic measurements
of the masseter. Improved results were seen
with 20–30 U of Botox®, as compared with

21 Special Considerations in Darker Skin

10 U [40]. In general, suggested doses include
25–30 U of Botox® and 50–70 U of Dysport®
per side [41]. Adequate treatment shows
a dose-dependent effect for 6–9 months.
Side effects may include initial awkwardness
upon smiling, fatigue with vigorous chewing,
speech disturbance, and localized pain at
injection sites. These side effects are tran-
sient and last approximately 1–4 weeks after
injection.
Botulinum
injections
are
distributed
among five to six sites along the mandibular
angle. Multiple injection sites allow for a
more uniform reduction in masseter thick-
ness without compensatory muscle bulging
at other areas along the jawline. The product
is placed from the level of the earlobe to the
lower posterior portion of the masseter at
the angle of the jaw. Injection sites are kept
low on the jawline to prevent damage to the
parotid duct and paralysis of the risorius
and zygomaticus muscles. This textbook also
contains a separate chapter with a compre-
hensive discussion of mandibular contouring
and description of technique.
Other Cosmetic Applications
More recently, recontouring of enlarged gas-
trocnemius muscles has been achieved with
botulinum toxin A [42,43]. The technique has
been mainly described among Asians, and
particularly Korean and Chinese, in whom
slimmer calves are culturally desirable.
Both the appearance of the muscle promi-
nence and actual leg circumference can be
reduced. There are few studies on optimal
dosing; however, as little as 30 U and as much
as 70 U of Botox® and from 150 to 180 U
of Dysport® per side have been used safely,
with results lasting up to 8 months. Injections
are placed into the medial head, since it is
the most prominent muscle of the calf and
is functionally redundant. No functional dis-
abilities have been reported with these doses.
This is also discussed further in a separate
chapter in this textbook.
Conclusion
The unique properties and differences in skin
and facial structure in skin of color affect
aging. Although there are many treatment
options to improve aging, specific variations
are needed when treating ethnic skin. Actinic
damage and superficial wrinkling can be
minimal or absent, and dynamic wrinkling
predominates. Changes in the brow and eye
complex as well as laxity leading to mental
crease and mouth frown are commonly seen.
These changes in darker skinned patients can
be addressed with botulinum toxin A. Early
intervention of these rhytids becomes impor-
tant in skin of color as treatment procedures
such as resurfacing can be problematic. We
advocate for prevention and early treatment,
before rhytids become persistent. Botulinum
toxin A is an effective and integral part of cos-
metic enhancement in darker skin types. The
key to a successful cosmetic outcome in peo-
ple of color is having a clear understanding of
their facial structure, basic histopathological
differences and skin properties, as well
as knowledge about specific ethnic back-
grounds so that diverse and distinct traits are
preserved.
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
Grimes PE, Shabazz D. A four-month
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Lee HJ, Lee DW, Park YH, et al. Botulinum
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250–254.



Axillary Hyperhidrosis
Ada Regina Trindade de Almeida, MD,1 Joel L. Cohen, MD (FAAD, FACMS),2,3,4 and
Chinobu Chisaki, MD1
1Medical Assistant, Dermatology Clinic, Hospital do Servidor P´ublico Municipal de S˜ao Paulo, S˜ao Paulo, Brazil
2Director, AboutSkin Dermatology and DermSurgery, Greenwood Village and Lone Tree, Colorado, USA
3Associate Clinical Professor, University of Colorado Department of Dermatology, Denver, USA
4Assistant Clinical Professor, University of California Irvine Department of Dermatology, Irvine, USA
Introduction
Sweat is the fluid excreted by eccrine glands.
Its production occurs as a normal physio-
logic process and is the most effective way for
humans to regulate their body temperature
[1,2].
Hyperhidrosis is the term used when
sweating occurs in excess, beyond the body’s
thermoregulatory needs. It can be catego-
rized into focal or generalized – depending on
the extent of the affected area – and consid-
ered as secondary to some underlying cause,
or when the etiology is unknown, as primary
or idiopathic.
Focal hyperhidrosis affects localized areas
such as the axillae, palms, soles, face, or
other specific sites. Generalized hyperhidro-
sis usually affects the entire body surface
area and can often be attributed to one
of a variety of causes (including endocrine,
infectious, menopause/physiologic, neuro-
logic, oncologic, or adverse effects of medi-
cations such as antidepressants) [3].
The term “focal hyperhidrosis” usually
refers to the primary or idiopathic form of
hyperhidrosis, and its diagnostic criteria were
described in 2004 [4] as focal, visible, exces-
sive sweating for at least 6 months without
secondary cause, and showing at least two of
the following characteristics:
r Bilateral and relatively symmetric sweating
r Frequency of at least one episode per week
r Impairment of activities of daily living
r Age at onset < 25 years
r Positive family history
r Cessation of sweating during sleep.
A study assessing the prevalence of hyper-
hidrosis in the American population esti-
mates that it may affect 2.8% of the popu-
lation [5]. Of these, 50.8% have the axillary
region affected either alone or in association
with other areas. This disorder affects men
and women equally, with the onset age being
during adolescence, and it is more frequent in
25- to 64-year-old people [5].
Walling, in a retrospective chart review,
found that 93% of patients with hyper-
hidrosis had primary disease, with isolated
axillary distribution occurring in 29% of
cases [6]. In all types of focal hyperhidrosis,
emotional, thermal, and vasodilatory stim-
uli further accentuate the baseline problem.
Hyperhidrosis impairs daily functions, social
interactions, and work activities, and it can
dramatically reduce patients’ quality of life
Botulinum Toxins: Cosmetic and Clinical Applications, First Edition. Edited by Joel L. Cohen and David M. Ozog.
© 2017 John Wiley & Sons Ltd. Published 2017 by John Wiley & Sons Ltd.
Companion Website:


Botulinum Toxins
(QoL) [7–10]. When validated QoL scales are
used to measure the burden of the disease,
the effects of hyperhidrosis are comparable
to severe psoriasis, end-stage renal disease,
rheumatoid arthritis, and multiple sclerosis
[7,11].
Anatomy and Physiology
Sweat glands are distributed throughout the
skin. Distinct anatomic areas have varying
numbers of the three types of sweat glands:
eccrine, apocrine, and apoeccrine.
At birth, 2–4 million eccrine glands are
distributed over almost the entire body sur-
face [12] and are most numerous on the
palms, soles, forehead, axillae, and cheeks. Its
clear cells contain the pump, co-transporter,
and aquaporin channels required for fluid
secretion [13]. In humans, sweat secreted in
response to exercise or thermal stimulation is
produced by these glands in the dermis that
open directly onto the skin surface [14]. They
are innervated by cholinergic postganglionic
sympathetic nerve fibers [15].
Apocrine glands are far less numerous and
open into the infundibular region of the hair
follicle [14]. They are specifically located in
the urogenital regions and the axillae, and
they are stimulated by epinephrine and nore-
pinephrine [16]. They produce a viscid secre-
tion that can become malodorous due to bac-
terial breakdown [17].
According to previous studies, apoeccrine
glands have morphological characteristics
from both eccrine and apocrine types,
develop during puberty, and may correspond
to 10–45% of all axillary glands [12,18]. They
respond to cholinergic stimuli and intensely
to epinephrine and isoproterenol infusion.
[12]; however, recent histologic studies have
failed to show evidence of apoeccrine glands
in the investigated axillary tissue samples
[13, 19]. The existence of these glands
presently remains controversial [19–21].
Hyperhidrosis
is
defined
as
excessive
sweating that is produced by eccrine glands;
however,
histological
studies
comparing
excessive sweating patients with normal
controls have not shown any morphologic
changes or increase in their number or size
[13,21].
The pathophysiology of primary focal
hyperhidrosis
is
not
currently
well-
understood [21]. Findings of several studies
suggest that secretory clear cell of the eccrine
gland has a key role in fluid transport and
is probably the source of excessive sweating
in the axillary type of hyperhidrosis [13, 19].
On the other hand, other studies suggest that
the primary form of hyperhidrosis is possibly
due to abnormal central control of emotional
sweating because it affects the same body
areas as those affected in emotional sweating
(hands, feet, and axillae) [22,23].
Diagnosis and Severity
Documentation
In general, axillary hyperhidrosis diagno-
sis is clinical. It is based on the history,
which should include the onset, duration, fre-
quency, intensity, and distribution, as well
as impact on daily living and family history.
Physical examination and a review of systems
will help rule out a secondary cause or asso-
ciated conditions, such as pregnancy [24].
During
evaluation
of
hyperhidrosis
patients, it is important to determine their
volume of sweat production, the affected
area distribution, and the impact on their
quality of life.
Gravimetric testing measures the volume
of sweat produced over a fixed time under
controlled conditions. The best way to per-
form the test is the following: the affected
area is dried using absorbable tissue; then,
a previously weighted filter paper is applied
and left in place for a certain time. The
weight difference between before and after
the contact quantifies the sweat volume pro-
duced within that time interval. The evalua-
tion period varies among authors [21]. One
group prefers contact with the affected area
for 1 minute [25], whereas other investigators
prefer 5 [26,27], 10 [28] or 15 minutes [29].

22 Axillary Hyperhidrosis

Figure .Minor starch test showing true sweaty
(deep purple) area and regions of false positive test.
In a study comparing normal controls with
excessive axillary sweating patients, Hund
et al. considered axillary hyperhidrosis when
the gravimetric tests showed values over
100 mg of sweating for 5 minutes for men and
50 mg for women [27]. While this method is
useful in research trials, it is not practical for
routine clinical practice.
The Minor starch-iodine test provides
assessment of sweat production volume and
extent of distribution [1] as well as identi-
fication of posttreatment residual sweating.
Iodine in contact with starch turns the sweat
dark purple making it easily identifiable (Fig-
ure 22.1). The test must be carried out before
any topical or regional anesthesia and it is
easy and cheap to perform [21, 30]. For a
better performance, first dry the test area
by touching it with absorbable paper. Then,
apply a 3–5% iodine solution and allow it to
dry for a little while. In some patients with
constant sweating, the area has to be dried
again with absorbable paper just before the
starch application to prevent false positives.
For patients with a history of sensitivity to
iodine, Ponceau’s red tincture may be used,
which will turn sweat in contact with starch
from red to pink [31]. The distribution and
maximal perspiration sites can be recorded in
photographs for future comparison.
Another important detail to observe is that,
very often, the axillary hyperhidrotic area
does not coincide with the hairy underarm
region. In some cases, it assumes a bizarre
shape and may be located outside the hairy
area, while in others, by contrast, it is con-
fined to smaller regions inside the hairy loca-
tion. For this reason, we consider the Minor’s
test as mandatory to identify the affected area
precisely, so that the toxin injection can be
optimized and an effective treatment can be
ensured. The association of the two previous
methods – gravimetry and Minor test – with
point counting using a transparent square-
lattice grid was proposed by Bahmer et al.
as the Hyperhidrosis Area and Severity Index
(HASI). Each 1 centimeter (cm) represents 1
point. After estimating the sweating area, the
volume of secretion weighted by gravimetry
after 10 minutes is divided by the number of
points in the affected area. The HASI score
is given in mg of sweat by cm2 per minute.
Hyperhidrosis is assumed present with HASI
values above 1 mg/cm2 per minute [28].
The QoL of patients affected by focal
idiopathic hyperhidrosis can be measured
with several tests, such as the Dermatology
Life Quality Index (DLQI), the Hyperhidro-
sis Impact Questionnaire (HHIQ) [9,10], the
Hyperhidrosis Disease Severity Scale (HDSS)
[5], and measures of psychiatric morbidity
[32]. In routine clinical practice, they are not
required.
Treatment of Axillary
Hyperhidrosis
Topical
The treatment of focal hyperhidrosis gener-
ally begins with the use of topical antiper-
spirants that will locally reduce the sweat
production. Today, aluminum chloride (AlCl)
salts are the most common active ingredient.
They reduce sweat by mechanical obstruc-
tion of eccrine sweat ducts [33, 34] and its
long-term use may cause atrophy of the secre-
tory cells [35]. The hexahydrate compound
is more effective; this is seen in prescription
formulations containing 10–35% absolute


Botulinum Toxins
alcohol or salicylic acid gel [36, 37]. It should
be applied every night on dry skin, and
washed off after 6–8 hours. When sweating
is reduced to a tolerable level, the frequency
of application may be reduced accordingly,
commonly decreasing to once every 1–
3 weeks. If irritation occurs, especially with
higher concentrations, the application of
a 1% hydrocortisone cream the following
morning would be useful [4, 37]. Currently,
several companies are developing new vehi-
cles, such as microemulsions and liquid
crystals, to allow higher concentrations of
antiperspirant
with
lower
irritation
and
higher compliance [38].
Other topical agents, such as aldehydes,
have also shown to effectively reduce hyper-
hidrosis; however, they are rarely used due to
irritating, allergic contact dermatitis and/or
yellow-brown skin staining [39].
Topical anticholinergic agents have been
tried as a therapeutic option for hyperhidro-
sis. There were reports of patients success-
fully treated with topical glycopyrrolate for
craniofacial and compensatory hyperhidrosis
[40–42]. Unfortunately, cutaneous absorp-
tion is often insufficient and, when an addi-
tional volume is used to compensate the
problem or to treat large areas, unpleasant
systemic effects emerge [43–45].
Iontophoresis Therapy
Iontophoresis consists of introducing an ion-
ized substance into intact skin through the
application of a direct current [46, 47]. Its
exact mechanism of action is still unclear.
The most generally accepted explanation is
poral plugging, as the effect is reversed by
cellophane tape stripping of the skin over-
lying eccrine sweat gland [46]. Other possi-
ble explanations are rapid temporary inter-
ference with ion pumps and/or innervation
of eccrine sweat glands [48] and a complex
mechanism involving changes in reabsorp-
tion of ductal Na+ [49].
Tap water is most frequently used, but anti-
cholinergic agents are sometimes added to
improve efficacy [46]. Irritation may occur,
causing dry, peeling and cracked skin, which
may be relieved with the use of moisturiz-
ers and/or by reducing the frequency of treat-
ments.
Iontophoresis is considered as a second-
line therapy for palmar or plantar hyper-
hidrosis when topical antiperspirants have
failed, and it is not used for other affected
areas, such as underarms and forehead due to
practical problems [37,50].
Systemic Agents
Oral anticholinergic agents have been used in
the therapy of hyperhidrosis. Glycopyrrolate,
amitriptyline, methantheline bromide, and
oxybutynin have been described, especially
when large or multiple areas are affected.
They can be added to other topical therapies
such as iontophoresis and botulinum toxin
to enhance improvements. They act as com-
petitive inhibitors of acetylcholine at mus-
carinic receptors, which are present through-
out the central and autonomic nervous
system [51]. However, the treatment is lim-
ited by side effects due to secondary blockage
of physiologic cholinergic processes result-
ing in dry mouth, palpitations, blurred vision,
constipation, and urinary retention that will
be worsened depending on the chosen drug
and dosage, the cumulative time of use, and
individual susceptibility [1,37,50].
There are a few isolated case reports with
some level of efficacy (mostly in generalized
hyperhidrosis patients) with several other
systemic drugs, including diazepam, pro-
pranolol, belladonna, indomethacin, cloni-
dine, phentolamine, phenoxybenzamine, dil-
tiazem, and Gabapentin [1].
Local Procedures
Local Excision
Removal of eccrine glands from the axilla can
be achieved by curettage, liposuction, or even
direct skin excision [1, 52]. There are several
different treatment techniques, which differ
in their type and size of incisions, type of can-
nula and curette used, and the aggressiveness

22 Axillary Hyperhidrosis

of the procedure. The experience of the sur-
geon is also an important factor [53].
In a literature review, Wollina et al. counted
1,270 individuals who underwent suction
curettage and 693 patients who underwent
minor skin excisions [52]. Both surgical
methods were considered effective and safe
with only minor, temporary complications
and no reports of compensatory sweating.
Refractory cases are described for all meth-
ods. Bechara et al. [54], when analyzing some
of these cases, found three residual sweating
patterns after local surgery. These are the cir-
cular one, in which surgeons mainly focus the
central axillary area, leaving a circular region
of residual sweat; crescent, which is related
to the interference of a cupped depression
between the pectoralis muscle and the axilla,
making careful curettage difficult; and spot-
like surrounding entry points of previous
surgery that makes it difficult to reach by
curettage regularly performed in a fan-like
fashion.
Minimal skin resection – with or without
the association of subcutaneous sweat gland
curettage – is more effective in permanently
reducing hyperhidrosis than suction curet-
tage [52, 55]. However, they are both associ-
ated with higher rates of infection, bleeding,
delayed healing, prolonged downtime, and
significant scarring [1,37,56].
A
combination
of
surgical
resection
and carbon dioxide laser vaporization was
reported as effective for axillary hyperhidro-
sis with few complications [57, 58]. Because
liposuction is less invasive and results in min-
imal residual scars in axillary hyperhidrosis,
it is considered as the surgical treatment of
choice by many authors [52,59,60].
Emerging Therapies
Devices that deliver heat targeting eccrine
glands or the surrounding tissue may be
able to injure those glands, thereby reduc-
ing sweat production. Various technologies
such as lasers, radiofrequency, and ultra-
sound applied externally or inserted into the
soft tissue, are used for this purpose, with lim-
ited available data so far, in treating hyper-
hidrosis [61].
A device recently approved by FDA – called
MiraDry – uses microwave energy to destroy
eccrine sweat glands. This energy is prefer-
ably absorbed by tissue with a high water con-
tent, such as the sweat glands, leading to rapid
molecular rotation, generation of frictional
heat, and cellular thermolysis [61].
After identification of the affected area by
a starch-iodine test, the axillary vault is mea-
sured with the grid supplied and then injected
with an anesthetic tumescent solution con-
taining saline, lidocaine, and epinephrine. A
hand piece with a single-use bioTip delivers
focused microwave energy on to the dermal-
adipose interface, regardless of the skin thick-
ness [62, 63]. The skin temperature is simul-
taneously cooled and monitored during the
energy cycle to prevent thermal transfer of
heat into the epidermis.
The device was effective in reducing exces-
sive sweating. Based on gravimetric assess-
ments, 90% of patients experienced a 50% or
greater reduction in axillary sweating, with an
average reduction of 81.7%.
At 12 months after treatment, 85.5% of
patients were satisfied with their treatment
outcome [64]. Patients also noticed improve-
ment of axillary odor [65].
Common,
minor
side
effects
include
edema, axillary tenderness/pain for several
days, and numbness and tingling in the upper
arm or axilla for several weeks [66].
Endoscopic Thoracic Sympathectomy
Endoscopic (thoracoscopic or video-assisted)
sympathectomy (ETS or VATS) is the most
invasive of the therapeutic options. This is
recommended for those with moderate-to-
severe hyperhidrosis who have not responded
to any other treatments [67]. The goal of any
sympathectomy for hyperhidrosis is to dis-
connect the eccrine sweat glands from the
sympathetic signals that trigger them to ini-
tiate sweating [68].


Botulinum Toxins
In this surgery, the sympathetic ganglia are
interrupted by excision, ablation, or clipping
[69]. ETS has been most frequently indicated
for focal palmar hyperhidrosis, for which the
success rates have been high [67–69]; how-
ever, there are still questions about its efficacy
in treating axillary hyperhidrosis.
The appropriate level of division of the
sympathetic chain is chosen according to
the location of the primary symptoms. The
recent consensus recommendations by the
Society of Thoracic Surgeons include sympa-
thetic chain interruption above the third rib
for palmar hyperhidrosis, above the fourth
and fifth rib for axillary hyperhidrosis, and
above the third rib for craniofacial hyper-
hidrosis [68].
Milder reflex sweating – also known as
compensatory sweating or compensatory
hyperhidrosis – is the main problem when
performing
sympathectomies
for
focal
hyperhidrosis, with very high incidence
(more than 50%) occurring in most patients,
as reported in most of the studies [67–69].
It affects other anatomical areas, such as the
back, anterior chest, abdomen, buttocks, and
less frequently, legs. Often mild in severity, it
may remain stable or be reduced over time,
although it can also be severe in some indi-
viduals. It typically begins 2–8 weeks after
sympathectomy [1]. Due to the significance
of this side effect, up to one third of patients
treated with ETS are moderately dissatisfied
with their treatment [69].
Other less commonly reported complica-
tions include chest wall paresthesia, Horner’s
syndrome, pneumothorax and hemothorax,
and rarely, cardiac arrest or arrhythmias
[1,67].
In a recent review of ETS publications,
Krasna [70] found that “studies by ETS sur-
geons have claimed satisfaction rates around
85–95% with only 2% regretting the surgery,
generally because of compensatory sweating”.
He concluded, however, that the exact results
of ETS are unpredictable due to anatomic
variations in the sympathetic nerve distribu-
tion and the surgical techniques chosen [70].
Botulinum Toxin
The use of botulinum toxin A (BoNTA) for
axillary hyperhidrosis was first reported by
Bushara et al. in 1996 [71], and since then, this
therapeutic indication has emerged. Many
open-label and controlled studies [25, 72–
82] have supported the safety and efficacy
of intradermal or subcutaneous botulinum
toxin injections for axillary hyperhidrosis.
To date, onabotulinumtoxinA (Botox/
Botox Cosmetic® in the US, Latin America,
Allergan, Inc., Westport, Ireland) [83] is the
only FDA-approved formulation for hyper-
hidrosis. It is also the most studied type for
this indication, followed by abobotulinum-
toxinA (Dysport® in the United States,
Europe and Latin America, Ipsen Biopharm
Ltd., Wrexham, UK [84] and rimabotulinum-
toxinB (Myobloc®/Neurobloc® in the United
States and Neurobloc® in Europe; Solstice
Neurosciences Inc./Eisai Co., Ltd.) [85].
To date, there is only one study of incobo-
tulinumtoxinA
for
axillary
hyperhidrosis
(Xeomin® in North and Latin Americas and
in Europe; Merz Pharma, Frankfurt) [86,87].
After BoNTA injection, the anhidrotic
effect usually begins within 7 to 10 days and
lasts 6 to 10 months, with a mean duration
of 7 to 9 months [1, 2, 25, 76, 80]. For axillary
hyperhidrosis, reported average doses range
from 50–100U of onabotulinumtoxinA or
100–250U of abobotulinumtoxinA, injected
intradermally. [25, 88, 89]. Although two
reports using high doses of onabotulinum-
toxinA (200 units) per axilla described pro-
longed efficacy – for as long as 29 months
[90, 91], other studies comparing different
dosages found little advantages with doses
higher than 50 onabotulinumtoxinA U [76] or
100 abobotulinumtoxinA U per axilla [92].
With
regard
to
rimabotulinumtoxinB,
studies suggested doses varying from 2,500
to 5,000 U/axilla and described quicker onset
of anhidrotic effect – within 3–5 days, lasting
around 9–16 weeks. Higher dosages were
associated with systemic side effects such
as dry mouth, accommodation difficulties,

22 Axillary Hyperhidrosis

and corneal irritation, leading researchers
to recommend 2000 U/axilla as the optimal
effective dose [93–95].
There is no standardized dilution for
botulinum toxin treatment of focal hyper-
hidrosis. Reported dilutions range from 1 to
10 ml of saline [2, 11] for onabotulinumtox-
inA, with most clinicians using between 2–
5 ml. As for abobotulinumtoxinA, dilution
volumes vary from 1.25 to 10 ml, [2, 11, 92,
96] with the use of 2.5–5 ml being the most
frequent. In the study of incobotulinumtox-
inA compared with onabotulinumtoxinA for
hyperhidrosis, the authors considered that
both had similar efficacy; the dilution used
was 10 U/ml for both products [87].
Some substances had been added to the
toxin solution with no harm to the toxin, such
as hyaluronidase, lidocaine, and epinephrine.
Among these substances, the most interest-
ing for axillary treatment is lidocaine, which
showed similar efficacy and reduced pain,
turning the procedure more comfortable
[97–99] when compared to the saline alone.
No downtime is required for the axillary
injection procedure and patients’ quality of
life has shown to dramatically improve after
treatment [7–10, 79]. Although some studies
found no reduction in the duration of symp-
tom relief after repeated BoNTA injections
[9, 26, 77, 89], others noticed increased effi-
cacy after multiple treatments [21,100].
The use of ice or a topical anesthetic cream
can further minimize discomfort. Subcuta-
neous injections may also be less painful than
dermal injections, while maintaining a simi-
lar level of efficacy [101].
No significant side effects were found with
BoNTA injections into underarms. Pruritus
in the treated region [76] and mild local
urticaria lasting for 2 days were described
[89]. Discrete compensatory sweating was
observed in 5% of patients treated with
onabotulinumtoxinA [26] and in 2 of 52 indi-
viduals of another study with abobotulinum-
toxinA [89].
Studies suggest that body odor can be
improved in healthy volunteers with the use
of intradermal injections of onabotulinum-
toxinA into the axillae. The underlying mech-
anisms may include interference with axil-
lary bacterial growth by decrease of moist
environment as well as denervation of apoec-
crine sweat glands [102, 103]. Also, a com-
plete [104] or partial [105] remission of moist
and eroded axillary plaques of Hailey-Hailey
disease have been anecdotally reported.
Botulinum Toxin Injection
After the iodine starch test, when the affected
area is identified and photographed, it has to
be delineated with a marker pen or gentian
violet. Although some authors prefer to inject
directly through the purple-colored residues,
we like to remove them and make the interior
of the highlighted region clear.
The soft, thin axillary skin is easily tres-
passed by 30G needles. In general, pain is
not a big issue in this area; however, to
make the procedure more comfortable, top-
ical anesthetic creams can be applied at this
moment and ice cubes or packs may be help-
ful just before the injections or following the
procedure.
Cheshire
self-injected
1 U
of
onabo-
tulinumtoxinA into his forearm and observed
an anhidrotic halo of 1.5 cm2 [106], while
Braune et al. found that 2.5 U of abobo-
tulinumtoxinA was needed to obtain 1 cm2
of anhidrotic skin [107]. The toxin con-
centration would be higher at the injection
site and the concentration gradient rapidly
decreases with distance from this site [108].
For hyperhidrosis, the goal is to place injec-
tions in such a pattern that creates conflu-
ent overlapping anhidrotic halos in order to
achieve maximum outcome and minimize
the risk of affecting underlying musculature
[109].
Injections are administered by using small,
delicate syringes with sharp short fixed 30G
needles or luer lock syringes with 32G nee-
dles. The former is preferable because no
toxin is lost in the idle space inside a
removable needle (0.3 or 0.5-ml syringes


Botulinum Toxins
[Ultrafine II 30-U or 50-U insulin syringes;
Becton-Dickinson Co, New Jersey, USA]).
To avoid dulling the needles when trespass-
ing the rubber stopper, BoNT vials should
be opened with a bottle opener after saline
reconstitution and syringes should be directly
filled from the opened vial.
Our technique is to distribute intrader-
mal injections across the previously identi-
fied hyperhidrotic regions, spaced 1–1.5 cm
apart. The number of injections and the total
dose should depend on the involved surface
area. According to the surface area involved,
we use approximately 10–20 intradermal
injections in 0.1–0.2 ml aliquots, totaling 50–
100 0 onabotulinumtoxinA for each axilla.
Injections into the axillae may also be per-
formed in the superficial fat without adverse
events or significant reduction in efficacy. In
our practices, the treatment of the axillae
results in successful improvement of hyper-
hidrosis in nearly all patients. The effects last
approximately 6–9 months; however, in some
cases, they may last more than 1 year, as
shown in Figure 22.2, Figure 22.3, Figure 22.4,
Figure 22.5 Figure 22.6 and Figure 22.7.
Transcutaneous Botulinum Toxin
Alternative
methods
of
toxin
delivery
through the skin without the use of needles
or punctures have been recently tried with
promising
results.
However,
botulinum
Figure .Right axilla of a 28-year-old woman
before treatment.
Figure .Left axilla of the same patient as shown
in Figure 22.2 before treatment.
Figure .Right axilla 21 days after injection of 50 U
of onabotulinumtoxinA.
Figure .Left axilla 21 days after injection of 50 U
of onabotulinumtoxinA.

22 Axillary Hyperhidrosis

Figure .Right axilla 15 months after injection of
50 U of onabotulinumtoxinA.
toxin directly injected into the skin is not
absorbed due to its large molecular size
[110]. Some other driving force may be
necessary to allow transcutaneous absorp-
tion [110]. Iontophoresis units to deliver
onabotulinumtoxinA
via
electric
current
were
reported
in
patients
with
palmar
hyperhidrosis [111–113].
A small controlled clinical trial investi-
gated a novel proprietary transport peptide
to deliver botulinum toxin A through the
Figure .Left axilla 15 months after injection of
50 U of onabotulinumtoxinA.
skin. By using 200 U of onabotulinumtoxinA
reconstituted with saline admixed with the
transport peptide, the author found statisti-
cally significant reduction of sweat produc-
tion in 12 cases of axillary hyperhidrosis. The
duration of effect was not reported in that
paper [114].
This innovative method is likely to open
a window of opportunity to treat other
hyperhidrosis-affected areas and may be use-
ful in the future for other indications as well.
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

Primary Focal Palm, Sole, Craniofacial, and Compensatory
Hyperhidrosis
Dee Anna Glaser, MD1 and Adam R. Mattox, DO (MS)2
1Professor and Interim Chairman, Department of Dermatology, Saint Louis University School of Medicine, Saint Louis, USA
2Micrographic Surgery & Dermatologic Oncology Fellow, Department of Dermatology, Saint Louis University School of Medicine, Saint Louis, USA
Botulinum toxin can be safely and effec-
tively used to treat a multitude of cutaneous
secretory problems such as hyperhidrosis,
chromhidrosis, and Frey’s syndrome. The
focus of this chapter is the rationale for and
the practical application of using botulinum
toxins in this clinical setting.
Sweating
Sweating is controlled by the sympathetic
nervous
system
[1].
The
postganglionic
sympathetic nervous system predominantly
utilizes the neurotransmitter norepinephrine
to activate adrenergic receptors on periph-
eral tissues. Sweating is one exception.
Muscarinic receptors on clear cells of eccrine
glands are activated by acetylcholine.
Eccrine glands are unequally distributed
in the skin. High concentrations occur in
the palms, soles, and forehead (Table 23.1).
Eccrine glands are stimulated by heat, exer-
cise, anxiety, and stress [2,3].
Sympathetic innervation also regulates
apocrine
sweat
glands;
however,
they
respond to adrenergic stimuli, from the neu-
rotransmitter epinephrine. The highest con-
centration of apocrine sweat glands occurs
in the nipples, axillae, and perineum. Apro-
crine glands produce a sterile, thick, milky,
odorless fluid containing protein, lipids, fatty
acids, and carbohydrates. An odor is only
produced when the secretions are decom-
posed by bacteria at the skin surface [1,2].
Hyperhidrosis
Hyperhidrosis
describes
excess
sweating
beyond that necessary for thermoregulation.
The amount necessary to be considered
“excessive” is not well defined and varies
between individuals. Problems can occur
within any portion of the system, from the
hypothalamus to the sweat gland or duct [4].
The eccrine glands in patients with primary
focal
hyperhidrosis
do
not
demonstrate
any histopathologic changes or glandular
hyperplasia.
A detailed history, comprehensive review
of symptoms, and thorough physical exam-
ination are the first steps in identifying the
type (bilateral or unilateral, symmetric or
asymmetric, and primary or secondary ori-
gin) and cause of hyperhidrosis. Further
workup is guided by the findings.
Furthermore, hyperhidrosis is classified
as generalized or focal. Generalized hyper-
hidrosis affects the entire body whereas focal
hyperhidrosis occurs in discrete anatomic
sections
[5].
Generalized
hyperhidrosis
Botulinum Toxins: Cosmetic and Clinical Applications, First Edition. Edited by Joel L. Cohen and David M. Ozog.
© 2017 John Wiley & Sons Ltd. Published 2017 by John Wiley & Sons Ltd.
Companion Website:


Botulinum Toxins
Table .Eccrine sweat gland concentration.
Anatomic Area
Quantity/cm
Sole of foot
620
Forehead
360
Palms
300
Axillae
300
Thigh
120
Scrotum
80
Back
65
Lips
None
Nipple
None
Labia majora
None
typically occurs as the result of an under-
lying cause (secondary). Focal or localized
hyperhidrosis may have a secondary origin;
for example, lesions of the peripheral ner-
vous system [6, 7]. More commonly, focal
hyperhidrosis is idiopathic (primary) and
referred to simply as “hyperhidrosis.” It is
characterized by excessive sweating of small
areas, usually the axillae, palms, soles, face,
or groin (Figure 23.1) [8]. The onset is usually
during adolescence to early adulthood but
can begin in early childhood, especially the
palmar-plantar variants [9].
Primary focal hyperhidrosis tends to have
an age of onset before 25 years, and presents
as bilateral, symmetric, and focal sweating.
It does not occur during sleep. In cases of
secondary hyperhidrosis, an extensive dif-
ferential diagnosis exists for the underlying
cause; commonly an endocrine or neurologic
disease (Table 23.2).
This chapter will focus on primary focal
hyperhidrosis henceforth identified simply
as hyperhidrosis (HH). Diagnostic criteria
for primary hyperhidrosis have been sug-
gested by a consensus panel and described
statistically in the literature (Table 23.3)
[10,11].
Quality of Life
The greatest impact of HH is the significant
reduction in the quality of life and alteration
of daily function [12]. Several questionnaire
tools to assess disease severity and quality of
life are described in the literature. The most
common of which is the Hyperhidrosis Dis-
ease Severity Scale (HDSS), which is based
Axillary
Palmar
80
70
60
50
40
30
20
10
0
Plantar
Crainiofacial
Groin
Other
Problematic anatomic area
Percentage of HH patients reporting
Figure .Sites of hyperhidrosis reported to be problematic.

23 Primary Focal Palm, Sole, Craniofacial, and Compensatory Hyperhidrosis

Table .Hyperhidrosis classification.
Focal/localized
Generalized
Primary focal
hyperhidrosis
Fever
Intrathoracic tumors
Infection
Rheumatoid arthritis
Malignancy
Spinal cord disease or
injury
Tumors
Stroke
Thyrotoxicosis
Syringomelia
Pheochromocytoma
Ross syndrome
Diabetes mellitus
Atrioventricular fistula
Diabetes insipidus
Gustatory sweating
Hypoglycemia
Frey’s syndrome
Hypopituitarism
Localized unilateral
hyperhidrosisa
Endocarditis
Cold-induced
hyperhidrosis
Gout
Eccrine nevus
Medications
Social anxiety disorder
Menopause
Granulosis rubra nasi
Anxiety
Drug withdrawal
aAlso referred to as unilateral circumscribed idiopathic
hyperhidrosis.
Table .Criteria to diagnose primary focal
hyperhidrosis.
Focal, visible excessive sweating of at least
6 months’ duration
And
No apparent secondary cause
And
At least two of the following characteristics:
Impairs daily activities
Bilateral and relatively symmetric
Frequency of episodes at least once a week
Age of onset <25 years
Positive family history
Cessation of focal sweating during sleep
Table .Hyperhidrosis Disease Severity Scale (27).
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.
on one question the patient can answer in
the office, “Which best describes the impact
of sweating on your daily activity?” Answer
choices are assigned integer values 1–4 with
3–4 corresponding to severe uncontrolled
HH (Table 23.4).
Measuring Hyperhidrosis
It is essential to objectively assess hyper-
hidrosis before prescribing treatment. The
Minor’s Starch-Iodine test is a simple way
to detect the presence of sweat and local-
ize the area involved. The skin to be tested
is dried thoroughly and an iodine solution is
painted over the field. When the solution is
thoroughly dry, a starch powder is sprinkled
on the surface. A modified starch-iodine test
can use BetadineTM solution, which is avail-
able in most offices (Figure 23.2). Plain cook-
ing corn starch is effective and inexpensive.
Starch is applied with a brush, cotton ball,
sifter or loose gauze (Figure 23.3). Accurate
colorimetric results are achieved when the
amount of powder is minimized. Moisture
from sweat dissolves the iodine and starch
followed by a chemical reaction producing
polyiodide chains which are purple to black.
Gravimetric testing is quantitative and
determines the rate of sweat production. It
is typically reserved for research purposes. It