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

23 Primary Focal Palm, Sole, Craniofacial, and Compensatory Hyperhidrosis

irritation, erythema, dryness, and pruritus
are frequent.
Systemic anticholinergic drugs such as
glycopyrrolate, atropine, or oxbutynin pro-
vide a generalized acetylcholine blockade
[15, 18–20]. Dry eyes, dry mouth, and uri-
nary retention may be encountered at the
doses required to achieve symptom relief.
Additionally, generalized sweat reduction can
increase the risk of hyperthermia.
Iontophoresis is an electrical device most
suited to treat palmar-plantar HH. It uses
direct current connected to trays of tap water
and treatment can be performed at home.
The mechanism of action is unknown but
may reduce gland secretion, or physically
block sweat ducts via ions carried into the
ducts. For increased efficacy, anticholinergic
agents (crushed glycopyrrolate) can be added
to the tap water [21]. Side effects are relatively
minimal but cost and time-commitment limit
its use for many patients [22].
Local surgical excision, liposuction, curet-
tage, and microwave ablation techniques can
be used to remove and destroy eccrine units
[23]. Though technology is improving, effi-
cacy is technique dependent and is usually
limited to the axillae.
Endoscopic thoracic sympathectomy (ETS)
can offer long-term improvement for axillary
and palmar symptoms but is not universally
accepted. During the procedure, the sympa-
thetic chain is interrupted by destruction or
clipping at the appropriate level [24,25]. The
most significant potential adverse effect of
ETS surgery is the development of compen-
satory HH [26]. The incidence varies, but
it affects approximately 60–70% of patients.
Severity is unpredictable, having the potential
to affect large portions of body surface area
[24,27,28].
Botulinum Toxin Therapy
OnabotulinumtoxinA, abobotulinumtoxinA
and incobotulinumtoxinA are derived from
botulinum toxin type A (BoNTA). Onabo-
tulinumtoxinA
and
abobotulinumtoxinA
have been the most extensively studied in
HH. Botulinum toxin type B has been studied
and found to be effective. Despite its efficacy,
the side effect profile is quite different from
BoNTA [29, 30]. Given the effectiveness
and safety profile of onabotulinumtoxinA,
it has emerged as the clinically preferred
treatment.
As with other treatment modalities, prior
to treating excessive sweating with BoNTs,
one must objectively identify the area of
excessive sweating using a colorimetric test
such as a starch-iodine test (Figure 23.2 and
Figure 23.3). For optimal BoNT interaction
at the neuron–eccrine interface (typically
at the junction of the dermis and subcu-
taneous fat), it should be delivered as a
deep intradermal injection. Injections are
generally placed 1–2 cm apart. Avoid inject-
ing deeper structures to prevent unwanted
denervation.
Different philosophies exist for choosing a
toxin dilution volume. The prevailing senti-
ment is that high dilution volume (lower con-
centration) will diffuse and treat more area.
One location where high volume is appro-
priate is inguinal HH. However, treating the
forehead requires precision to avoid adverse
effects and higher concentration is preferred
[31].
Compensatory hyperhidrosis is a common
side effect of ETS. The phenomenon is con-
sidered rare in BoNT injection therapy. Occa-
sionally patients report the perception of
increased sweating in untreated anatomic
locations after therapy. Literature supporting
and refuting this phenomenon can be found
[32,33].
Axillary Hyperhidrosis
No area has been as extensively studied as the
axillae. Numerous studies show the benefit
and safety of BoNTA, including large, multi-
center, randomized, placebo-controlled trials
in Europe and the United States. Techniques
are reviewed in Chapter 22.


Botulinum Toxins
Palmar Hyperhidrosis
BoNT injections are useful in the treatment
of palmar HH. Multiple small studies have
demonstrated the ability of BoNT to estab-
lish clinical improvement in symptoms [13,
34, 35]. Several challenges exist when treat-
ing hands such as choosing optimal doses,
control of pain during injection, and the
side effects which include muscle weakness
[13,36–40].
The optimum dose of BoNTA to control
palmar HH is unknown and the issue is com-
plicated by large variations in hand size (Fig-
ure 23.4). AbobotulinumtoxinA doses have
ranged from 120–500 U per hand [34, 41,
42]. Published studies report onabotulinum-
toxinA doses of 50–200 U per hand [35,
43]. OnabotulinumtoxinA is most commonly
used. Some authors have suggested a defined
dose per unit area, with Swartling’s group
using 0.8 U/cm2. Naumann’s group used 2 U
every 1.5 cm on the palm but three injections
per fingertip and two injections into each
of the middle and proximal phalanx using
1–2 U per injection [35, 44]. The Cana-
dian advisory committee recommends 1.5–
2 U/cm2 with a mean dose of 100 U onabo-
tulinumtoxinA per palm [9]. It is unclear
whether larger doses add to the duration of
Figure .Variation in hand size needs to be taken
into consideration when dosing botulinum toxin for
treatment of palmar hyperhidrosis.
symptom relief or increase the risk of devel-
oping muscle weakness. When Wollina used
200 U of onabotulinumtoxinA per hand in 10
patients, his relapse time varied from 3–22
months [43]. Saadia studied 24 patients: 11
received 50 U onabotulinumtoxinA per hand
and 13 received 100 U/hand. Despite more
hand and finger weakness, higher patient
satisfaction was reported in the high-dose
group. There was no difference in duration of
efficacy [35]. Until larger studies are available,
75–100 U onabotulinumtoxinA per hand is a
good starting point. Adjustments should be
made for the size of the hand and efficacy of
past treatment doses [16].
Another challenge with palmar BoNT
therapy is an apparent shorter duration of
efficacy compared to axillary injections [36].
Responses range from 3 to 12 months [45].
Aghaei found that anhidrosis lasted up to
5 months for patients treated with 500 U
abobotulinumtoxinA
per
hand;
however,
hypohidrosis lasted an average of 10 months
[42]. The reason for this shorter duration
is unknown but may be related to a smaller
diffusion radius in the thicker palm skin and
compartmentalized areas of the phalanges
[45]. Another possibility is a higher number
of cholinergic nerve endings or a faster
recovery rate in nerves of the hands.
Injection of the hand is painful due to the
high density of nerve receptors and large
number of injections required. Using a visual
analogue scale (1–100), the pain during injec-
tion of the palm has been rated an aver-
age 68.1 ± 31.8 compared to 29.9 ± 24.5
for axillary treatment [46]. Several methods
of pain control have been tried (Table 23.6).
Topical anesthetic containing lidocaine and
cold packs is often inadequate. More intense
cold exposure is more effective; for example,
dichlorotetrafluoroethane, submersion of the
hand in an ice bath, and direct exposure of an
ice cube [47, 48]. Kreyden describes a tech-
nique of iontophoresis with 2% lidocaine for
30 minutes, followed by a light spray of liquid
nitrogen just prior to injecting BoNTA [49].
The use of a needleless pressure unit to inject
BoNTA was found to be less painful than

23 Primary Focal Palm, Sole, Craniofacial, and Compensatory Hyperhidrosis

Table .Anesthesia techniques used for palmar
injections.
Class
Specific
Topical
Nerve blocks
Cryoanalgesia
Dichlorotetrafluoroethane
Liquid nitrogen spray
Ice cubes, ice pack, or ice
bath
Cold packs
Machine-assisted cold air
Vibration
Intravenous regional
anesthesia (Bier’s
Block)
Conscious sedation
or general anesthesia
standard needle injections, but was much less
effective. As a result, needleless injection of
BoNTA cannot be recommended [50]. Beno-
hanian has described the use of a needle-
less pressure unit to inject lidocaine into the
palms and soles before conventional injec-
tions of BoNTA [51]. The Med-JetMBX II
(MIT Canada) [52] is approved by Health
Canada and the European Union. Once
anesthetic wheals appear, BoNT can be
administered with a standard needle.
Nerve blocks are effective [40, 44, 53, 54]
The palm is innervated by the median, ulnar
and radial nerves. All three can be anes-
thetized at the level of the wrist (Figure 23.5).
Risks include nerve injury and vascular punc-
ture. Furthermore, temporary hand weakness
limits the patient’s activities for several hours.
This effect does not permit the treatment of
both hands in one session. A 30G 0.5 inch
needle should be used to minimize any nerve
trauma. Approximately 2 mL of 1–2% lido-
caine is injected around each of the nerves.
If the patient feels any unusual tingling or
sensation during the injection, the needle
should be withdrawn slightly. Twenty min-
utes or more may be necessary for the full
effect to develop. Intravenous regional anes-
thesia (IVRA), also known as a Bier’s block is
effective [55,56] but requires additional time,
equipment, and cardiovascular monitoring.
Vibratory anesthesia is gaining popularity
[57]. Theoretically, the nervous system is
unable to perceive fully two different sensory
inputs simultaneously. Handheld vibrators
can be applied to the volar and dorsal sur-
face of the hand near the site of injection
(Figure 23.6). This requires an assistant and
Radial nerve distribution
Median nerve distribution
Ulnar nerve distribution
Ulnar N. injection site
Median N. injection site
Radial N. injection site
Figure .The palm is innervated by the ulnar, median, and radial nerves. Nerve blocks may be performed at
the level of the wrist.


Botulinum Toxins
Figure .Use of a two-vibrator technique for pain
control.
creates movement of the patient’s hand,
making injections more challenging. Despite
being easier to maneuver, the use of one
vibrator on the volar aspect is not as effective
as the use of two (personal experience).
Neither technique results in a pain-free
injection, but rather diminished perceived
pain. A study by Scherer found that the
pain threshold is significantly higher during
vibration compared to pre- or postvibration,
and vibration applied distal to the site of pain
was superior to proximal [58].
The author most commonly uses ice with
pressure for palmar injections. An ice cube
is applied firmly to the planned injection site
for 7–10 seconds (Figure 23.7). If the patient
requires additional pain control, a combina-
tion of ice and vibration is used. Ice is applied
for 7–10 seconds and then the vibrator is
Figure .Ice and pressure should be applied for
7–10 seconds.
Figure .Typical injection pattern for palmar
hyperhidrosis.
applied immediately adjacent to the site for
no more than 1–2 seconds prior to the injec-
tion. The injection is delivered during vibra-
tion. This technique requires an assistant and
time coordinated movement. A 30G 0.5-inch
needle with a leur lock syringe or insulin
type syringe is especially helpful for the thick
skin and higher pressure needed to inject the
palm. Injections should be placed every 1–
1.5 cm but the digits will usually need two
to three injection sites per phalangeal unit
(Figure 23.8).
Bruising is common but temporary with
palmar injections. Subepidermal injections
may increase the incidence of hematoma [37].
Injections of BoNTA should be in the dermal
layer, to limit the chance that the drug will
come into contact with the deeper muscle tis-
sue. Weakness can result, with the incidence
varying in published series from 0 to 77%
[13,35–37,59]. The most commonly affected
area is in the thenar eminence. Strength can
be measured in the thumb-index finger pinch,
whereas gross and grip strength are usually
unaffected [35, 38]. There is one report of
atrophy of the intrinsic musculature of the
hands with “debilitating” weakness associated
with BoNTA injections. This effect occurred
after the fifth session using 500 U abobo-
tulinumtoxinA per palm every 9 months [60].
Recent case reports have noted transient dex-
terity limitations while text messaging [61].
Patients should be adequately counseled on
the risks of weakness, which is usually mild
and transient.
Zaiac found the average depth of the
eccrine glands in ten consecutive palmar

23 Primary Focal Palm, Sole, Craniofacial, and Compensatory Hyperhidrosis

biopsies to be 2.6 mm. In an attempt to
control the depth of needle insertion and
prevent muscle weakness, he advocates the
use of the ADG® needle, a device designed
for collagen injection [62]. By adjusting the
needle to a length of 2.6 mm and using
a total of 60–70 U onabotulinmtoxinA per
palm, he had no weakness in a series of ten
patients. Likewise, cut needle caps can func-
tion as an adapter to shorten 7 mm 30G nee-
dles to measure 2.5–3.0 mm [40, 63]. Other
physicians find these techniques insufficient
as ADG® needles can be difficult to obtain
and adaptors obstruct the physician’s view
of the needle. One group has advocated the
use of a sterile clamp to make a right-angle
bend in the needle 2.6 mm from the tip.
The 2.6 mm length can be inserted with
full visualization and depth control. They
report, but do not quantify reduced com-
plications and improved patient satisfaction
[64].
Children with palmar hyperhidrosis can be
treated with BoNTs but pain control remains
the biggest challenge. Less is known about the
dosing, duration, and adverse events associ-
ated with pediatric use. Coutinho dos Santos
published a series of nine children aged 6.5–
15 years with palmar HH successfully treated
with onabotulinumtoxinA. Nerve block anes-
thesia and doses of 75–150 U per palm were
used [65].
Plantar Hyperhidrosis
Little has been published on BoNT therapy
for plantar HH. Like the palms, there is no
consensus on the optimal dose, the duration
is variable and the injections are painful. Nau-
mann used 42 and 48 U of onabotulinum-
toxinA to treat two soles by injecting 3 U
onabotulinumtoxinA (0.15 ml) into each 2
× 2 cm squares [66]. Blaheta’s and Cam-
panati’s groups report success using 100 U
onabotulinumtoxinA per sole (100 U/5 ml
saline) [60]. All patients had an improvement
in symptoms and a “significant decrease of
Minor’s test” for 12 weeks without significant
side effects [67].
Minor’s Starch-Iodine test delineates the
hyperhidrotic area, which can extend up
the sides and onto the dorsum of the foot.
BoNTA should be evenly distributed every
1–2 cm using small gauge needles and inject-
ing into the deep dermis. Injections of the
plantar surface can be technically more chal-
lenging due to the thickness of the stratum
corneum, especially if calloused. The physi-
cian has to adjust for the variation in depth to
accurately place BoNTA.
As for palmar injections, pain control must
be addressed. IVRA can provide sufficient
anesthesia for the sole. In a small series of
eight patients, lVRA was found to be more
effective than nerve blocks [68]. Nerve blocks
used are generally performed at the level of
the ankle. For sole anesthesia, the tibial and
sural nerves are blocked. If the dorsum of the
foot must be injected, the superficial peroneal
nerve can be included [63].
Vadoud-Seyedi reported on using the
Dermojet
to
inject
BoNTA
for
plantar
HH. Ten patients were treated with 50 U
BoNTA/5 ml saline per foot; 15–20 points
were injected per foot and no analgesia was
used. The injections were tolerated well
by all patients, although one developed a
localized hematoma. The duration of benefit
lasted 3–6 months; however, 20% of patients
reported the treatment had no effect [69].
At this time, the author’s preferred method
of pain control is ice combined with vibration
as described earlier (Figure 23.9). Doses of
100–200 U onabotulinumtoxinA per foot are
Figure .When using a combination of ice and
vibration, ice is applied for 7–10 seconds and
vibration is applied in the treatment area
immediately before injection.


Botulinum Toxins
typically required. Bruising and pain with
injection are the most common side effects.
In the published literature, one patient
reported weakness of plantar flexor muscles
in both feet following BoNTA injections,
with resolution in 10 days [70].
Facial Hyperhidrosis
Primary facial HH has several patterns with
involvement of the forehead, scalp perimeter,
entire scalp, cheeks, nose, upper lip, chin, or a
combination of the areas (Figure 23.10). The
most common pattern affects the forehead
with or without the scalp. All forms of facial
HH tend to respond to BoNTA, with the
duration of gustatory response being excep-
tionally long.
There is a paucity of literature published on
BoNTA therapy for craniofacial hyperhidro-
sis. Kinkelin’s group injected a mean of 86 U
onabotulinumtoxinA (3 U per injection site)
Figure .Facial starch-iodine test demonstrating
excessive sweating of the forehead and to lesser
extent the upper lip.
over the forehead at equidistant locations (1–
1.5 .5) in 10 men with frontal hyperhidrosis
[71]. Intracutaneous injections were placed
≥1 cm superior to the eyebrow to prevent
eyelid ptosis. Five of ten patients had par-
tial disability in frowning, but was limited to
≤8 weeks. No ptosis was noted and satisfac-
tion was good or excellent in 90% of subjects.
Effects were maintained ≥5 months in 90% of
patients. Similarly, Tan and Solish report that
symptoms return on average 4.5 months after
treatment of the forehead [46].
Boger treated 12 men suffering from bilat-
eral craniofacial hyperhidrosis with abobo-
tulinumtoxinA 0.1 ng per injection [72]. Half
of the forehead was treated using a total of
2.5–4 ng injected equidistantly with a total of
25–40 injections. Decreased sweating lasted
≥3 months (up to 27 months). Side effects
were limited to temporary weakness of the
frontalis (100%), and brow asymmetry lasting
1–12 months (17%).
It is the observation of the author that
patients
typically
present
with
forehead
sweating that may be combined with scalp
sweating in a diffuse pattern or an ophiasis
pattern.
OnabotulinumtoxinA
injections
are performed with 2–3 U every 1–2 cm
avoiding the inferior 1–2 cm of the forehead
to reduce the risk of brow ptosis [73]. The
forehead can be treated more inferiorly if
the response is not sufficient and the patient
is willing to accept temporary brow ptosis.
Typical doses of onabotulinumtoxinA used
by the author are 50–100 U to treat the
forehead and frontal hairline, 200 U to treat
the forehead and the perimeter of the scalp,
and 300 U when treating the forehead and
entire scalp [73].
Gustatory Sweating (Frey’s
Syndrome)
Gustatory sweating is a relatively common
complication after surgery or injury in the
region of the parotid gland. It may result from
misdirection of autonomic nerve fibers after
surgery and is frequently observed in diseases

23 Primary Focal Palm, Sole, Craniofacial, and Compensatory Hyperhidrosis

Table .Selected studies on BoNTA treatment of gustatory sweating.
Author
Year
Design
n
Dose (mean)
Duration
(months)
Naumann et al. [101]
1997
Open
45
21 mu OnabotulinumtoxinA
6
Bjerkhoel and Trobbe [102]
1997
Open
15
37 mu OnabotulinumtoxinA
13
Laskawi et al. [103]
1998
Open
19
31 mu OnabotulinumtoxinA
11–27
Laccourreye et al. [104]
1999
Open
33
86 mu AbobotulinumtoxinA
12–36
of the parotid gland and diabetes. Sweating
occurs on the cheek in response to salivation
or anticipation of food.
BoNTA is a highly effective treatment
option for gustatory sweating as shown by
several uncontrolled studies (Table 23.7) [74–
78]. In a large open study of 45 patients, there
was a significant reduction of local facial
sweating after injection of onabotulinumtox-
inA using a mean dose of 21 U (range 5–72 U)
and no recurrence of sweating was observed
during the follow-up period of six months. A
marked long-lasting benefit of 11–36 months
was also observed in three other open studies
[76–78]. The reason for BoNTA’s long-lasting
effect on gustatory sweating is unknown.
It is important to perform a starch-iodine
test before injection to visualize the affected
area. After the iodine and starch have been
applied, it is helpful for the patient to chew
candy or food to stimulate facial sweating.
Injections with 2–3 U onabotulinumtoxinA
or 8 U abobotulinumtoxinA are given intra-
dermally at sites 2–2.5.5 apart and evenly
distributed over the affected area. Specific
side effects include pain on injection, local
hematomas,
and
transient
local
muscle
weakness with facial asymmetry. Care must
be taken to avoid affecting the zygomatic
muscles.
Other Sweating Disorders
Inguinal sweating affects 2–10% of indi-
viduals with HH [8]. It usually develops
in adolescence and can be associated with
HH in other body sites. Intradermal injec-
tions of BoNTA can control symptoms for
≥6 months. As with other body sites, a
starch-iodine test is valuable in identifying
the areas producing sweat, but often is tech-
nically challenging. Treatment is with 2–3 U
onabotulinumtoxinA injected every 1–2 cm
within the affected field; typical doses range
60–100 U per side [79].
Compensatory sweating is the most com-
mon complication of endoscopic transtho-
racic sympathectomy (ETS), ranging from
44 to 91% [80]. Often affecting large areas,
treatment is particularly difficult but suc-
cess has been reported using BoNTA. Belin
and Polo reported good results treating the
upper abdomen with onabotulinumtoxinA.
Unfortunately this patient’s total area affected
was too large to be treated in one sitting
(involved his nipple line to knees) [26]. Huh
used 300 U abobotulinumtoxinA to treat the
chest and abdomen after identifying the area
with an starch-iodine test [80]. Each 100 U
of onabotulinumtoxinA was diluted in 10 ml
saline and 0.1 ml/cm2 was injected. Effi-
cacy gradually diminished, but was main-
tained for 8 months. Kim and colleagues
reported 17 patients treated with 100–500 U
of onabotulinumtoxinA, administering 2 U
every 1.5 cm. The injections were well-
tolerated, but they noted incomplete resolu-
tion due to insufficient dosing, and limited
duration of only 4 months [81].
Chromhidrosis is a rare disorder charac-
terized by the excretion of colored or pig-
mented sweat. It is most commonly confined
to the face or axilla. Matarasso used 15 U
onabotulinumtoxinA to treat the affected
area of each cheek which measured 3 cm in
diameter. Within 48 hours, the patient had


Botulinum Toxins
a marked reduction in the amount of dis-
charged black sweat [82].
Ross Syndrome
First described by the neurologist Alexan-
der T. Ross in 1958, it is characterized by
the triad of unilateral tonic pupils, gen-
eralized areflexia (Holmes-Adie syndrome),
and progressive segmental anhidrosis with
a compensatory band of excessive perspi-
ration. Patients usually do not perceive the
anhidrosis. Instead, the compensatory seg-
mental hyperhidrosis is bothersome [83]. The
pathogenesis of Ross syndrome is unknown.
There is no histologic evidence of nerve fiber
destruction. Therefore, Ross postulated a
defect in acetylcholine cholinesterase activity,
rather than the degeneration of sweat glands.
Although there is no therapy for the progres-
sive segmental anhidrosis, the compensatory
hyperhidrosis can be improved with systemic
antimuscarinic drugs or BoNTA injections to
the affected areas.
Localized Unilateral Hyperhidrosis
Localized unilateral hyperhidrosis (LUH) is
idiopathic and rare. It is a confined area of
hyperhidrosis of less than 10 × 10 cm, mainly
found on the forehead or forearm. Not only
is LUH unusual in localization, but also has
no trigger and occurs while patients sleep.
The etiology may be due to a misdirected
reconnection of the sympathetic nerves after
injury, similar to the Frey syndrome [1].
Excellent results are achieved following injec-
tion the affected area with 30 U of onabo-
tulinumtoxinA.
Use of Botulinum Toxin Type B for
Hyperhidrosis
Botulinum toxin type B (BoNTB) use has
been limited to treatment of cervical dys-
tonia, but there are reports of its use
for HH. Injection of BoNTB can induce
focal anhidrosis in a dose-dependent fashion.
Birklein reported durations up to 6 months
using 125 U [84].
Despite its efficacy, the use of BoNTB is
limited by the occurrence of systemic adverse
events [85]. A patient treated with 2500 U
BoNTB to each palm for HH developed
bilateral blurred vision, indigestion, dry sore
throat, and dysphagia [86]. Another palmar
HH study of 20 subjects used 5000 U BoNTB
per palm [87]. Adverse events were common:
dry mouth or throat (90%), indigestion
(60%), excessively dry hands (60%), muscle
weakness (60%), and decreased grip strength
(50%).
Lower dosing may be the key to reducing
the high incidence of side effects [88]. How-
ever, the incidence of systemic side effects
using BoNTB and the high safety profile using
BoNTA to treat focal hyperhidrosis, to date,
BoNTA remains the neurotoxin of choice.
Future Directions
The use of botulinum toxins has revolution-
ized the treatment of HH and other secre-
tory disorders. Compared with other treat-
ments, it is unmatched in its efficacy, ease
of administration, and patient satisfaction.
Development of quick, safe, and effective
pain control is needed for the treatment of
more tender areas. New delivery devices are
being researched to provide the most com-
fortable and efficient therapy. Kavanagh and
colleagues have successfully used a small
iontophoresis machine to deliver BoNTA
to two patients, sparing them the injec-
tions [89]. Glogau demonstrated that onabo-
tulinumtoxinA can be successfully delivered
into the axillary skin when combined with
a proprietary transport peptide molecule
[90]. Research is ongoing for different BoNT
serotypes. For the present, BoNT therapy is a
valuable, well-tolerated therapy and can pro-
vide meaningful improvement in the quality
of life of patients with HH and other secre-
tory disorders.

23 Primary Focal Palm, Sole, Craniofacial, and Compensatory Hyperhidrosis

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23 Primary Focal Palm, Sole, Craniofacial, and Compensatory Hyperhidrosis
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23 Primary Focal Palm, Sole, Craniofacial, and Compensatory Hyperhidrosis

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33(1 Spec No.):S76–S80.



Topical Botulinum Toxin
Richard G. Glogau, MD1 and Eileen Axibal, MD2
1Clinical Professor of Dermatology, University of California San Francisco, USA
2Department of Dermatology, University of Colorado, Aurora, USA
Introduction
Ten years after initial publication by the Car-
ruthers of the use of botulinum toxin type A
(BoNTA) for the treatment of glabellar lines
[1], the Food and Drug Administration (FDA)
approved the drug in 2002 for “temporary
improvement in the appearance of moderate
to severe glabellar lines associated with
corrugator and/or procerus muscle activity
in adult patients 65 or younger” [2]. This was
the first elective cosmetic indication for a
commercially available botulinum toxin in
the United States market. Prior to this time,
FDA approved therapeutic uses included the
treatment of strabismus, blepharospasm, and
cervical dystonia. In 2013, the FDA expanded
its approval for BoNTA to include a new
use for the temporary improvement in the
appearance of moderate to severe lateral
canthal lines, known as “crow’s feet,” in adults
[3]. Widespread off-label use of the drug for
cosmetic purposes has targeted other facial
muscles including the frontalis muscle for
horizontal lines, depressor anguli oris for
the downturned corners of the mouth, and
orbicularis oris for lip rhytides.
BoNTA is currently available in three
commercial forms in the United States:
Allergan’s Botox® Cosmetic (onabotulinum-
toxinA) [4], Ipsen & Galderma’s Dysport®
(abobotulinumtoxinA)
[5],
and
Merz’
Xeomin® (incobotulinumtoxinA) [6]. Two
other forms are manufactured in Korea and
China and these are marketed under the
names Meditoxin®/Neuronox® and Hengli®/
Prosigne®, respectively. All of these forms of
BoNTA are prepared in dilute form for injec-
tion and, as such, they all share the potential
problems of pain, erythema, bruising, ten-
derness, and potential risk of infection
from needle penetration [7–9]. Because
of the disadvantage of requiring injection
as the route of administration, alterna-
tive methods of drug delivery have been
developed that can address some of these
concerns.
Current Transepidermal Delivery
Mechanisms
Current
transepidermal
approaches
in
drug
delivery
systems
can
only
deliver
small molecules. Some examples of smaller
molecules that can be delivered through
the
skin
topically
include
progesterone,
certain antibiotics, and nicotine. These are
readily delivered in topical preparations,
creams, ointments, adhesive patches, etc.
These vehicles, however, are very inefficient
in delivering biologically active proteins
and other macromolecules across the skin
barrier. The stratum corneum and upper
layers of the epidermis are lipid-rich barriers
to entry for most of the larger molecules;
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
Nicotine
Progesterone
Antibiotics
Antibodies
Toxin
Growth Hormone
Insulin
Small Molecules
Macromolecules/Proteins
Figure .Small molecules can penetrate skin directly (left), while larger molecules have traditionally required
direct injection to penetrate the skin (right). Reproduced with permission of Revance Therapeutics.
the exclusion of assaults on the inner host
by biologically active macromolecules is,
after all, the skin’s primary function. For this
reason, the flux of most proteins across the
skin barrier is essentially zero.
Attempts
to
increase
penetration
by
manipulation of drug structure have been
rudimentary to date. For example, conjuga-
tion of a drug to a carrier can compromise
drug activity. Permeation enhancers may dis-
rupt protein linkages and tertiary structures
vital to biological activity of the protein. At
present, delivery of most macromolecules
across the skin barrier requires direct injec-
tion; for example, insulin, antibodies, toxins,
growth hormone (Figure 24.1).
The stratum corneum and upper layers of
the epidermis are essentially a multilayered
arrangement of the mature and differentiated
horny cells of the epidermis that are interwo-
ven in a lipid matrix with a lamellar struc-
ture (Figure 24.2). This lipid matrix provides
a potential route for the passage of molecules
into the skin by a process called “lipid raft-
ing.” This process is energy independent
and involves the passive movement of the
molecules along the pathways of the lipid
matrix, in the spaces between the horny cells
of the stratum corneum (Figure 24.3). This
process is highly time dependent, concen-
tration dependent, and obviously becomes
much less efficient as the size of the molecule
Horny Cells
Lipid Matrix
Lamellar Structured
Lipid Matrix
Figure .The epidermis consists of cells interspersed in a lipid matrix (left) which demonstrates a lamellar
structure on further examination (right). Reproduced with permission of Revance Therapeutics.

24 Topical Botulinum Toxin

Stratum
Comeum
Epidermis
Figure .The lipid matrix provides a route
between skin cells which permits passive,
non-energy dependent, “lipid rafting”of molecules
through the skin, a very slow and concentration
dependent process. Reproduced with permission of
Revance Therapeutics.
in question increases. Highly ionic and/or
aqueous entities are also less likely to pene-
trate the lipid matrix.
There are several ongoing investigational
studies that aim to determine if various excip-
ients may be able to promote the passive
diffusion of topical botulinum toxin without
barrier disruption, as well as if barrier disrup-
tion techniques may be effective in promoting
pure toxin delivery.
Investigational Transepidermal
Delivery Systems
Botulinum toxin type A topical formula-
tions that are currently under investigation
include RT-001 (Revance Therapeutics, Inc.,
Newark, CA) and ANT-1207 (Allergan Plc.,
Parsippany-Troy Hills, NJ – acquired from
Anterios, Inc. in 2016). RT-001 topical gel
contains an albumin-free 150-kDa BoNTA
and a novel cell-penetrating peptide (CPP)
that enables transcutaneous delivery of the
BoNTA. ANT-1207 utilizes a proprietary
NDSTM
(Nanodermal
Society)
platform
delivery technology focused on the local,
targeted delivery of macromolecules across
the skin; the specifics of the NDSTM platform
are not yet elucidated but the manufacturers
describe long-term stability of BoNTA in
their preparation which does not require
reconstitution of a lyophilized toxin at the
time of use. RT-001 and ANT-1207 are
currently under phase III and phase IIb
investigation, respectively, for the treatment
of moderate to severe lateral canthal lines
(LCLs). This novel approach to BoNTA
administration may eliminate the local pain
and ecchymoses associated with injections
in the lateral canthus and orbicularis oculi
regions.
The development of the Revance propri-
etary peptide that is the transport molecule
joined to the cargo molecule, in this case
botulinum toxin A, was a serendipitous dis-
covery that grew out of study of one of the
human immunodeficiency virus (HIV) genes
called “TAT”, for “trans-activator of tran-
scription.” TAT was originally characterized
in 1988 by two research teams: Frankel &
Pabo [10] and Green & Loewenstein [11].
TAT causes accelerated production of the
HIV double-stranded RNA by binding to cel-
lular factors, controlling their phosphoryla-
tion, resulting in increased transcription of all
the HIV genes. TAT has, within it, a protein
transduction domain (PTD) that is capable
of penetrating cell membranes and it func-
tionally responsible for the propagation of the
virus genomes.
The novelty of the Revance peptide is
that it represents a reverse sequence of basic
residues of the TAT gene. The backbone pep-
tide consists of approximately 35 L-amino
acids in a reverse sequence of TAT. Despite
the reversal of the sequence, the protein
transduction domains continue to function
in the same way. The peptide backbone is
bound through noncovalent (electrostatic)
bonds, with the positive charge of the peptide
attracted to the relatively negatively charged
150 kDa botulinum toxin (Figure 24.5 (a)–(c))
[12]. The toxin is surrounded by peptides
with the PTDs directed outward where they
are free to attach to the cell surfaces. The
cells then absorb the peptide-covered toxin
into the cytoplasm of the cell where it crosses
to the cell membrane on the other side and
passes out and into the next cell. This is an


Botulinum Toxins
Power
Supply
Indifferent
Electrode
Active
Electrode
= Active ingredient
= Indifferent Ion
Applied
Formulation
Figure .Iontophoresis uses an electric current to drive molecules below the active electrode into the skin, a
process that is dependent on current and concentration. The method has been used for hyperhidrosis but is
cumbersome at best. Reproduced with permission of Revance Therapeutics.
Protein Transduction
Domains (PTDs)
(a)
Backbone Core
(lysine residues positively charged
under physiologic conditions)
Non-covalent (electrostatic) Bonds
(b)
(c)
Figure .The TAT gene has a protein transduction domain (PTD) which binds noncovalently to the relatively
negatively charged botulinum toxin. The toxin becomes surrounded by the peptides with the PTDs binding to
cell surfaces and permitting active energy transport of the toxin into the cell, then out the cell and into the next
cell. Reproduced with permission of Revance Therapeutics.

24 Topical Botulinum Toxin

Figure .Now instead of depending on passive movement through the intracellular spaces, the
peptide-covered toxin is actively transported through cells into the neighboring cell, repeating the process
until the toxin exits the epidermis on the dermal side. Reproduced with permission of Revance Therapeutics.
active energy transport system and is not
specific to botulinum toxin. It is a variant
of induced macropinocytosis where the cell
takes a “drink” of the surrounding media and
conveys it out the other side without harming
the cell or the cell membranes (Figure 24.6).
The peptide can be joined to other types of
molecules and may provide an alternative
delivery system for other molecules and
indications.
Once the complex has traversed the cell,
it moves through the next cell, and the next,
until it exits the epidermis on the dermal side.
At this point the toxin is released from the
carrier peptide and is free to exert its usual
action on the SNAP-25 protein, producing
the cholinergic blockade that is characteris-
tic of BoNTA. This action appears identical
to the action of the injected toxin in every way
except, of course, that the total dose deliv-
ered varies depending on the concentration
of the toxin, concentration of the peptide, and
length of time it is in contact with the skin.
Investigational Studies
The digital abduction score as reported by
Aoki uses the startle reflex of the mouse
to demonstrate the amount of botulinum-
induced muscle weakness in the hind limb
that, in turn, inhibits the splay or spread of
the mouse’s toes when lifted by the tail.13
In a normal startle reflex, the toes on the
mouse’s foot spread far apart in a rapid
reflex. If the hind limb is injected with
botulinum toxin, the movement is inhibited.
In 2011, Waugh and associates demonstrated
that limbs treated with a topical peptide–
botulinum complex resulted in statistically
significant reflex inhibition compared with
the application of toxin alone, highlighting
the role of cell-penetrating peptides in tran-
scutaneous drug delivery (Figure 24.7) [12].
They also demonstrated that application of
a topical peptide–botulinum complex pro-
duced a nearly complete reflex inhibition
that was comparable to the effect seen with
injected toxin. The first study to directly com-
pare the application of topical toxin, with-
out a carrier, to local intramuscular injection
in human subjects for the treatment of LCLs
was published by Mahmoud and associates in
2016 [14]. Topical application of 50 units of
Dysport® to one side of the face and injection
of 50 units of Dysport® to the contralateral
side was given to 10 individuals. When evalu-
ated in a dynamic state at 1 week and 1 month,
the topical side showed no statistically signif-
icant difference in facial rhytides and the dif-
ference between the two treatment types was
statistically significant showing improved
LCLs on the injected side. This confirmed the
assumption upon which several prior stud-
ies have relied: topical application of BoNTA
solution on the surface of the skin is ineffec-
tive and, for a topical application to be effec-
tive, the molecule should either be formu-
lated in a way to penetrate the skin or the
stratum corneum barrier should bypassed.


Botulinum Toxins
3.3
(+ –0.3)
0.3
(+ –0.3)
Inhibition of Foot Mobility
Foot Mobility Scores
Control: BoNT-A alone
Control: BoNT-A
Test: BoNT-A +
Excipient Peptide
BoNT-A + Excipient Peptide
Uninhibited Mobility
Inhibited Mobility
DAS – Standardized Mobility at
Identical Times
p = 0.0351
Figure .The combination of toxin plus peptide shows classic inhibition of muscular action of the mouse’s
hind foot, with inhibition significantly greater than that of topical botulinum toxin without the peptide.
Reproduced with permission of Revance Therapeutics.
Several techniques have been developed
to alter the stratum corneum barrier func-
tion, including the use of active energy
sources
(iontophoresis,
electroporation,
sonophoresis,
and
magnetophorsis)
and
stratum corneum abruption (microneedling,
microdermabrasion, fractional CO2 laser,
tape-stripping, and suction) to facilitate
transepidermal
drug
delivery
[15].
Two
of these techniques, ionotophoresis and
fractional CO2 laser, have been studied in
association with topical BoNTA. Iontophore-
sis utilizes direct current of low amplitude
to enhance drug transfer into the skin, but
lacks targeting and delivery specificity and
is very time dependent. With this technique,
an active electrode is placed on the drug
formulation that is to be driven into the skin
by the electrons streaming from the active
electrode. The ionic charge imparted to
the target molecule allows the molecule to be
driven into the skin as the indifferent ions are
pulled from the skin by the indifferent elec-
trode to complete the circuit (Figure 24.4).
Iontophoresis has been reported to be suc-
cessful with botulinum toxin [16, 17]. The
disadvantages are that the technique is very
time and concentration dependent, requires
that the patient can tolerate the sensation of
the direct current, and is less effective with
delivery of lipophilic molecules. In 2015,
Mahmoud, Burnett, and Ozog demonstrated
that the combination of CO2 laser with con-
centrated topically applied BoNTA resulted
in a statistically significant improvement in
LCLs compared to CO2 laser alone [18]. This
result is plausibly the result of the fractional
ablative laser removing the stratum corneum
by creating microscopic columns in the
epidermis and dermis, allowing the large
molecules of BoNTA to reach the lower
dermis and ultimately their target in the
orbicularis oculi muscle. In 2016, these
authors demonstrated that topical BoNTA
without laser was ineffective for improving
LCL. This is the only published clinical study
on the inability of the large BoNTA molecule
to cross an intact cutaneous surface. Another
2016 study by Zhu and colleagues demon-
strated that topical application of BoNTA
applied after fractional CO2 laser could
enhance the facial rejuvenation effect [19].
The first proof-of-concept study using
a peptide–botulinum complex in humans

24 Topical Botulinum Toxin

Left
L-RAC-RGG-022
L-RAC-RGG-022
R-RAC-RGG-022
R-RAC-RGG-022
Minor Test: Patient L-RAC-RGG-022
Baseline
4 Weeks
Right
Topical BoNT-A
Vehicle
Figure .Toxin plus peptide topically demonstrated a qualitative inhibition of sweating as demonstrated by
the Minor starch iodide test of axillary sweating compared to baseline. Source: Glogau 2007 [20]. Reproduced
with permission of John Wiley & Sons.
with idiopathic axillary hyperhidrosis was
reported by Glogau in 2007 in a randomized,
blinded, vehicle-controlled study [20]. Appli-
cation of the topical peptide–botulinum
complex showed significant inhibition of
sweating measured by the Minor starch-
iodine test at 4 weeks after the initial appli-
cation (Figure 24.8). Limitations of this pilot
study included the aqueous vehicle, which
was very unwieldy and difficult to keep in
full skin contact for the required 30 minutes;
day-to-day variability in sweating in both
placebo and active patients, which made con-
sistency in data capture difficult; and a rec-
ognized effect of the sweating inhibition pro-
duced by the topical toxin on one axillary
vault producing a parallel drop in sweating
on the non-treated side likely due to inhibi-
tion from higher cortical function. These fac-
tors limited the interpretation of magnitude
of effect when comparing patient to patient.
Nevertheless, demonstration of the qualita-
tive activity of the peptide–toxin moiety was
firmly established.
Phase I studies examining sensitization and
safety in 41 subjects in a single center with
four repeat doses on the forearm showed
minimal side effects [21]. This was followed
by several phase II studies for treatment of
LCLs with topical BoNTA, the first presented
by Glogau in 2008 at the American Society
for Dermatologic Surgery Annual meeting
[22]. Enrolled subjects were aged 30–55
years with moderate to severe lateral canthal
lines at maximal smile and no treatment in
the head or neck with botulinum toxin in the
preceding 9 months. There were 30 subjects
in each of two participating centers that
were randomly assigned to a range of doses
in five cohorts. Three of five cohorts (con-
centrations of 11, 22, and 25 ng/mL) were
considered treatment successes at 4 weeks


Botulinum Toxins
Baseline
(a)
(b)
Baseline
Subject 014
Case 1L: Topically Delivered BoNT-A
4 Weeks Post Single Treatment
4 Weeks Post Rx
Single Topical Application of BoNT-A
Figure .Single application of toxin plus peptide demonstrated qualitative inhibition of muscular
movement in the lateral canthal lines evaluated at smile and rest.
with no significant irritation or safety issues
reported and a 1- or 2-point change in
grade from the pretreatment assessment of
the canthal lines (Figure 24.9). Patients in
this study were evaluated at smile (primary
endpoint) and at rest (secondary endpoint).
Significant results from this study showed, in
addition to the expected effects of increasing
dose of toxin with peptide on the primary
and secondary endpoints (Figure 24.10), that
measurement of the canthal lines at rest was
a more stable measurement endpoint with
higher reliability and that all observed study
side effects were nonsignificant and equally
distributed
between
active
and
placebo
groups (Figure 24.11). Of the subjects, 18%
had mild to moderate treatment-related
adverse events (AEs), with the most common
AEs being application site erythema, burning
sensation, and eye dryness. Notably, as effi-
cacy increases were observed with escalating
doses of RT001, there was no accompanying
dose-dependent increase in AEs.
Brandt and associates reported another
phase II double-blinded, placebo-controlled,
repeat dosing study in 2010. Subjects under-
went topical treatment at baseline and
repeated again at 4 weeks. The primary

24 Topical Botulinum Toxin

0
Dose 1
Dose 2
Dose 3
20
40
Percent of Subjects
60
80
% 1-Point Improvement at Smile
4 Weeks Post Treatment
• Dose response seen with fixed peptide
and escalating toxin
Overall Efficacy Results
0
Dose 1
Dose 2
Dose 3
10
5
20
15
Percent of Subjects
25
30
% 2-Point Improvement at Rest
4 Weeks Post Treatment
Figure .The toxin-peptide complex demonstrated an increasing effect with increasing doses, in some
cases comparable to that seen with injected toxin.
endpoint
was
improvement
in
baseline
LCL severity using the Investigator’s Global
Assessment of Lateral Canthal Lines (IGA-
LCL) assesment [23, 24]. At 8 weeks, 50%
of LCLs treated with RT001 showed a 2-
point or greater improvement in baseline
IGA-LCL severity compared to 0% of the
placebo-treated subjects, and 94.7% of LCLs
treated with RT001 showed a 1-point or
more
improvement
compared
to
14.7%
of placebo-treated LCLs. There were no
treatment-related adverse events. Clinical
responses seen in this study were comparable
to those seen in injectable BoNTA studies
At Rest
Baseline
4 Weeks Post Treatment
Subject 008–010; Dose 3
Figure .Measurement of canthal lines at rest was a more stable measurement endpoint with higher
reliability.


Botulinum Toxins
(a)
(b)
(c)
Figure .Representative subject photographs showing shorter and shallower LCLs. (a) Screening,
(b) 4 weeks post first application of RT001, and (c) 8 weeks post first application of RT001 (4 weeks post second
application of RT001). Source: Brandt 2010 [24]. Reproduced with permission of John Wiley & Sons.
[7, 25] as well as earlier phase 2 studies
(Figure 24.12).
In 2012, Glogau and associates published
results of another phase II, randomized,
double-blinded, placebo-controlled study to
evaluate the efficacy and safety of topical
RT001 BoNTA for LCLs [26]. Of 90 patients
who were enrolled, 45 underwent single treat-
ment of RT001 to the lateral canthal area
and 45 underwent placebo. The primary end-
point was a rigorous composite of 2-point or
greater improvement on both the IGA-LCL
and patient severity assessment (PSA) scales.
At 4 weeks, 44.4% of subjects treated with
RT001 achieved improvement as defined by
the primary endpoint compared to 0% for the
placebo group, and 88.9% of patients achieved
clinically relevant improvement by investiga-
tor assessment alone. There were no clinically
meaningful or significant differences in safety
assessments between treatment and placebo
group.
Future Directions
Given the success of topical botulinum toxin
delivery demonstrated with iontophoresis
and fractional CO2 laser, further studies
exploring active energy systems and tempo-
rary stratum corneum disruption to facili-
tate topical botulinum – and other drug –
delivery to target areas should be considered.
The ability to pair topical BoNTA applica-
tion with elective cosmetic procedures such
as laser treatments, microdermabrasion, and
microneedling may be a desirable adjunct
for patients wishing to avoid the adverse
effects of BoNTA injection. These techniques
are unlikely to supplant traditional injections
given the additional cost and time, but may
fill niche indications.
Now that previous trials have established
stable outcome measures, established dose
ranges, reproducible patient satisfaction, and
optimized toxin/peptide gel formulations,
further trials of transcutaneous delivery via
botulinum–peptide complexes were com-
pleted. REALISE 1, a phase III clinical trial
investigating the safety and efficacy study of
the Revance topical RT001 gel in subjects
with LCLs, were completed in 2016 but failed
to achieve statistical significance on the pri-
mary endpoints. Revance has since moved
their focus of clinical development to the
use of the toxin-peptide complex in injected
form. Early evidence suggests a longer dura-
tion of action than seen with other toxins.
Allergan is also planning to pursue phase IIb
studies evaluating the use of ANT-1207 to
treat LCLs.
Transcutaneous topical botulinum toxin
delivery may offer opportunities to treat
anatomic sites that are difficult to man-
age with injection and patients who pre-
fer to avoid injectables. There may also be
useful roles for topical botulinum thera-
pies as adjunctive or extender therapies for
the injectable techniques currently in use.
Clearly, molecules besides neurotoxin may be

24 Topical Botulinum Toxin

joined to the carrier peptide to deliver pay-
loads to the dermis. Potential areas of ther-
apy may include melasma, hyperpigmenta-
tion, acne, hirsutism, and vitiligo. The utility
of topical botulinum toxin will likely extend
the novelty of this peptide carrier drug deliv-
ery system to other areas, both in dermatol-
ogy and general medicine.
References
Carruthers JD, Carruthers JA. Treatment of
glabellar frown lines with C. botulinum-A
exotoxin. J Dermatol Surg Oncol 1992;
18(1):17–21.
FDA. BOTOX Cosmetic Approval Letter.
2002.
drugsatfda_docs/appletter/2002/
botuall041202L.htm.
FDA. FDA approves Botox Cosmetic to
improve the appearance of crow’s feet lines.
September 2013;
Events/Newsroom/PressAnnouncements/
ucm367662.htm. Accessed 4 February
2017.
BOTOX® Cosmetic (onabotulinumtoxinA)
for injection, for intramuscular use.
Prescribing information. Irvine, CA:
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DYSPORT® for injection
(abobotulinumtoxinA). Prescribing
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XEOMIN® (incobotulinumtoxinA) for
injection, for intramuscular use.
Prescribing information. Germany: Merz
Pharmaceuticals GmbH, 2014.
Lowe NJ, Lask G, Yamauchi P, Moore D.
Bilateral, double-blind, randomized
comparison of 3 doses of botulinum toxin
type A and placebo in patients with crow’s
feet. J Am Acad Dermatol 2002;47(6):
834–840.
Lowe NJ, Ascher B, Heckmann M, et al.
Double-blind, randomized,
placebo-controlled, dose-response study of
the safety and efficacy of botulinum toxin
type A in subjects with crow’s feet.
Dermatol Surg 2005;31(3):257–262.
Cot´e TR, Mohan AK, Polder JA, et al.
Botulinum toxin type A injections: adverse
events reported to the US Food and Drug
Administration in therapeutic and
cosmetic cases. J Am Acad Dermatol
2005;53(3):407–415.
Frankel AD, Pabo CO. Cellular uptake of
the tat protein from human
immunodeficiency virus. Cell 1988;55(6):
1189–1193.
Green M, Loewenstein PM. Autonomous
functional domains of chemically
synthesized human immunodeficiency
virus tat trans-activator protein. Cell
1988;55(6):1179–1188.
Waugh JM, Lee J, Dake MD, Browne D.
Nonclinical and clinical experiences with
CPP-based self-assembling peptide systems
in topical drug development. Methods Mol
Biol 2011;683:553–572.
Aoki KR. A comparison of the safety
margins of botulinum neurotoxin serotypes
A, B, and F in mice. Toxicon 2001;39(12):
1815–1820.
Mahmoud BH, Ozog D, Burnett C, Cohen
JL. Prospective randomized split-face
comparative study between topical
botulinum toxin a surface application and
local injection for crow’s feet. Dermatol
Surg 2016;42(4):554–556.
Parhi R, Suresh P, Patnaik S. Physical means
of stratum corneum barrier manipulation
to enhance transdermal drug delivery. Curr
Drug Deliv 2015;12(2):122–138.
Kavanagh GM, Oh C, Shams K. BOTOX
delivery by iontophoresis. Br J Dermatol
2004;151(5):1093–1095.
Solomon P. Delivery of Botox by
iontophoresis. Br J Dermatol 2005;153(5):
1075; author reply 1076.
Mahmoud BH, Burnett C, Ozog D.
Prospective randomized controlled study to


Botulinum Toxins
determine the effect of topical application
of botulinum toxin A for crow’s feet after
treatment with ablative fractional CO2
laser. Dermatol Surg 2015;41(Suppl 1):
S75–S81.
Zhu J, Ji X, Li M, et al. The efficacy and
safety of fractional CO2 laser combined
with topical type A botulinum toxin for
facial rejuvenation: A randomized
controlled split-face study. Biomed Res Int
2016;2016:3853754.
Glogau RG. Topically applied botulinum
toxin type A for the treatment of primary
axillary hyperhidrosis: results of a
randomized, blinded, vehicle-controlled
study. Dermatol Surg 2007;33(1 Spec No.):
S76–S80.
Jones T, Scott J, Tranowski D, T. J. Safety
and tolerability of topical botulinum toxin
type A in healthy adults. Poster
presentation at the 69th Annual Meeting
of the Society for Investigative
Dermatology, Montreal, Canada, May
2009.
Glogau R. Topical delivery systems and
botulinum toxins. Poster presentation at
the American Society for Dermatologic
Surgery Annual Meeting, Orlando, Florida,
November 2008.
Kane MA, Blitzer A, Brandt FS, et al.
Development and validation of a new
clinically-meaningful rating scale for
measuring lateral canthal line severity.
Aesthet Surg J 2012;32(3):275–285.
Brandt F, O’Connell C, Cazzaniga A,
Waugh JM. Efficacy and safety evaluation
of a novel botulinum toxin topical gel for
the treatment of moderate to severe lateral
canthal lines. Dermatol Surg 2010;
36(Suppl 4):2111–2118.
Ascher B, Rzany BJ, Grover R. Efficacy and
safety of botulinum toxin type A in the
treatment of lateral crow’s feet:
double-blind, placebo-controlled,
dose-ranging study. Dermatol Surg
2009;35(10):1478–1486.
Glogau R, Blitzer A, Brandt F, Kane M,
Monheit GD, Waugh JM. Results of a
randomized, double-blind, placebo-
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topical gel for the treatment of
moderate-to-severe lateral canthal lines.
J Drugs Dermatol 2012;11(1):38–45.



Exciting New Uses of Botulinum Toxin Type A:
Dermatology/Dermatologic Surgery and Beyond
Donna Bilu Martin, MD (FAAD)1,2 and Stephen Mandy, MD (FAAD)2,3
1Dermatologist, Premier Dermatology, Aventura, USA
2Volunteer Professor of Dermatology and Cutaneous Surgery, Miller School of Medicine University of Miami, Miami, USA
3Premier Dermatology, South Beach Dermatology, Miami Beach, USA
Introduction
Botulinum toxin type A (BoNTA) is currently
approved by the Food and Drug Administra-
tion (FDA) in the United States for the treat-
ment of glabellar rhytides, strabismus, pri-
mary axillary hyperhidrosis, blepharospasm,
hemifacial spasm, cervical dystonia in adults,
and, most recently, chronic migraine, over-
active bladder, upper/lower limb spasticity,
and crow’s feet [1–5]. Small studies and
case reports in the literature have demon-
strated positive results using BoNTA for the
treatment of challenging painful and pru-
ritic conditions, dyshidrotic eczema, inverse
psoriasis, Hailey–Hailey and Darier’s disease,
facial flushing, ischemic digits, parotid duct
injury, and more. (Table 25.1). The treat-
ments described in this chapter are all off-
label (not approved by the FDA). While
many show promise for new approaches
for often difficult to treat disorders, large,
well-designed, controlled clinical studies are
needed to establish safety and efficacy.
Pain
Pain is an unfortunate and often difficult
to manage symptom in many conditions.
BoNTA may reduce both nociceptive and
neurogenic pain. The activation and sensiti-
zation of A- and C-nociceptors by neuropep-
tides released in tissue damage, infections,
inflammation, and other stressors results in
nociceptive pain [6]. BoNTA is theorized
to block the local release of these neu-
ropeptides, such as glutamate [7], substance
P [8, 9], vasopressin [10], and calcitonin
gene-related peptides (CGRPs) [7, 11] (Fig-
ure 25.1). BoNTA also appears to increase
the heat pain threshold, likely by affecting
transient receptor potential vanilloid recep-
tor 1 (TRPV1-receptors) located on sensory
nerve endings [10]. Capsaicin is a ligand for
the VR1 receptor [12]. TRPV1-receptors are
expressed on the plasma membrane via solu-
ble N-ethylmaleimide-sensitive factor attach-
ment protein receptor (SNARE) proteins,
the complex that BoNTA cleaves [2, 10].
TRPV1 expression has also been shown to
be increased in keratinocytes in patients with
prurigo nodularis [13], and is likely involved
in the sensation of both pain and pruritus.
Low pH levels, as seen in contracting muscles
and ischemic muscle pain, can also activate
VR1 receptors [12].
BoNTA may also alleviate neurogenic
pain. In a recent study, BoNTA injected in
the foreheads of healthy males was found to
target C-fibers [10]. Patients demonstrated
reduced capsaicin-induced trigeminal pain,
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 .Conditions reported to improve with botulinum toxin type A.
Dynamic rhytides
Hailey-hailey disease
Dyshidrotic eczema
Blepharospasm
Darier’s disease
Inverse psoriasis
Strabismus
Epidermolysis bullosa simplex,
Weber-Cockayne type
Severe knee pain
Hemifacial spasm
Persistent facial flushing
Tennis elbow
Cervical dystonia
Migraine headache
Breast reconstruction
Post herpetic neuralgia
Back pain
Notalgia paresthetica
Multiple cutaneous piloleiomyomas
Wound healing
Granulosis rubra nasi
Primary axillary hyperhidrosis
Anal sphincter spasm
Eccrine hidrocystomas
Frey’s syndrome
Compensatory hyperhidrosis
Raynaud’s syndrome
Parotid duct injury (post surgery)
Drooling
Depression
Benign prostatic hyperplasia
Penile retraction
Lichen simplex chronicus
Pachydermoperiostosis
pachydermia rhytides
Hypertrophic scars
Arthritic joint pain
sensitization,
and
inflammation.
Post-
herpetic neuralgia (PHN) is a complication
that can occur following herpes zoster and
may cause chronic pain (Figure 25.2). Three
patients suffering from PHN for 2.5 months
were injected with 100 U onabotulinumtox-
inA (Botox®, Allergan, Inc., Irvine, CA). A
dilution of 4 ml per 100 U was used [14].
The patients reported pain relief within
72 hours. The mean visual analogue scale
(VAS) score decreased from a baseline of
8.3 to 2 in week 2, although by week 12 it
had increased to 4. A larger randomized,
double-blinded,
placebo-controlled
study
was then conducted with 30 patients. Of all
patients in active treatment, 13 (87%) from
the experimental arm achieved at least a
50% reduction in VAS pain score, compared
with none of the placebo patients. Pain relief
occurred as early as 1 week after BoNTA
(BTX-A) administration, and it was main-
tained until the week 16 of the study. The
therapeutic effect on pain was consistent with
improvement on the secondary outcome of
sleep disturbance by week 1, which was
sustained throughout a 12-week period [15].
The inhibition of neuropeptides such as sub-
stance P and CGRP may reduce neurogenic
Botulinum
Toxin Type A
Glutamate
Substance P
Vasopressin
CGRP
Ach
VIP
Figure .Neuropeptides likely
blocked by botulinum toxin type A.
CGRP: Calcitonin Gene Related
Peptide; Ach: Acetylcholine; VIP:
Vasoactive Intestinal Peptide.

25 Exciting New Uses of Botulinum Toxin Type A: Dermatology/Dermatologic Surgery and Beyond

Figure .Herpes zoster, photo courtesy of Drs.
Jason Emer and Gary Goldenberg.
inflammation and pain [16, 17]. Multiple
painful cutaneous piloleimyomas in a patient
were injected with 200 U of Botox®, resulting
in a decrease in pain lasting for 3 months
[18] (Figure 25.2).
Patients with painful disorders in areas
of medicine outside of dermatology have
been treated with BoNTA. Recent studies
Figure .Piloleimyoma, photo courtesy of Dr.
Michael Paltiel.
have shown promise for the treatment of
arthritic joint pain. Synovial blood vessels and
subsynovial nerve fibers are positive for sub-
stance P and CGRP [19]. In a study of
42 patients with moderate to severe knee
pain, patients were randomized to receive
100 U of BoNTA plus lidocaine or placebo
(saline) injections [19]. A statistically signif-
icant reduction in severe knee pain (48% at
1 month) was seen in the group treated with
BoNTA.
Chronic lateral epicondylitis, or tennis
elbow, is another painful condition. In a ran-
domized, controlled study, 24 patients with
the condition received an injection of BoNTA
(60 U reconstituted in 1 ml normal saline) and
24 patients received a placebo saline injection
at a point one-third the length of the forearm
from the tip of the lateral epicondyle over-
lying the posterior interosseous nerve [20].
There was a statistically significant decrease
in pain at rest in the group treated with
BoNTA, but not during gripping. Adverse
events included a decline in grip strength.
BoNTA has been used as a treatment
for migraine headaches, low back pain, and
headaches of musculoskeletal origin asso-
ciated with strain and discomfort along
the back, neck, and shoulders [2, 21]. The
FDA has approved Botox® for the treat-
ment of chronic migraines in adults (defined
as headache for more than 14 days in
a month) [5]. Multiple injections around
the head and neck can be administered
every 12 weeks to prevent future headache
symptoms. In an open-label study, 18 patients
with a history of imploding, exploding,
and ocular type migraines received Botox®
diluted with 5 ml of preserved 0.9% saline in
the glabella, forehead, and periorbital areas
for cosmetic purposes [22]. The mean dose
injected was 45.7 T per treatment. Three
months after the initial treatment, patients
were interviewed to evaluate the response
of their migraine symptoms. Of the patients,
13 with imploding or ocular headaches
and 3 with exploding headaches reported
a decrease in migraine frequency. Of note,
10 patients also received injections in sites


Botulinum Toxins
of muscle tenderness (temporalis, occipitalis,
cervical paraspinal, and trapezius muscles),
although the authors stated that these addi-
tional injections did not seem to determine
response. Vasoactive intestinal peptide (VIP)
and substance P released from parasympa-
thetic neurons may play a role in vasodilation
and pain in migraine [21]. The exact mecha-
nism of action of BoNTA is unclear, but it may
act on the aforementioned neuropeptides, as
well as CRGP [23].
Women who have undergone mastectomy
for breast cancer may elect reconstruction
with breast implants. The procedure often
involves subpectoral tissue expansion, which
can be very painful due to spasm and con-
traction of the pectoralis muscle [24]. Of
patients undergoing mastectomy with tissue
expander placement, 22 received infiltration
of Botox® (100 U, diluted with 40–60 ml of
normal saline) into the pectoralis major, ser-
ratus anterior, and rectus abdominis inser-
tion [25]; 26 patients had standard mastec-
tomy with tissue expander placement and no
BoNTA. The group treated with BoNTA had
significantly less pain and less narcotic use
during their initial and final expansions. The
authors observed a noted improvement fol-
lowing 1 day of BoNTA injection, due to an
onset of action of 6–36 hours [25].
Pruritus
Many of the aforementioned neuropep-
tides released in pain also play a role in
pruritus. Histamine activates C-fibers in the
skin and causes the release of neuropep-
tides (substance P, VIP, neuropeptide Y,
acetylcholine,
bradykinin,
serotonin,
and
prostaglandin E) that results in the further
release of histamine from mast cells [26].
Substance P sensitizes mast cells, increases
blood vessel permeability, and induces the
synthesis of bradykinin and prostaglandins
[12,27]. In a double-blind, placebo-controlled
study in 14 male patients, 5 U of BoNTA
(dilution of 2.5 ml unpreserved saline per
100 U/vial) was injected into the forearm,
with the same volume of sterile saline injected
into the contralateral forearm as a control
[28]. Histamine prick tests were performed
at the treatment sites before treatment with
BoNTA, on days 1, 3, and 7 after treatment.
BoNTA
reduced
histamine-induced
itch
and vasomotor responses for 1 week after
application. Such findings may have future
applications and benefits for many pruritic
and recalcitrant diseases seen in dermatol-
ogy, such as lichen simplex chronicus (LSC)
(Figure 25.4). In a small open pilot study, four
patients with LSC were injected with 20–80 U
(20 U per 2 × 2 cm2) of abobotulinumtoxinA
(Dysport®; Ipsen Ltd, Slough, United King-
dom) in the affected area [29]. All patients
reported alleviation of itching after 1 week
according to a VAS, with three patients free
of symptoms at 12 weeks. After 4 weeks, five
of six lesions had cleared. The inhibition of
acetylcholine release by BoNTA may play a
role in the alleviation of itch in LSC.
In addition to itch in inflamed skin, BoNTA
may improve noninflammatory pruritus. In
a small study, four patients with notalgia
paresthetica, one with meralgia paresthet-
ica, and one with neuropathic itch on the
foot were injected with 18–100 U of BoNTA
(dilution of 3 ml unpreserved saline per
100 U/vial) for a mean dose of 1 U/cm2 [30].
All but one patient had previously failed top-
ical capsaicin treatment. Five of six patients
had some improvement of pruritus 1-week
posttreatment, but had a mean improve-
ment of only 28% at the 6-week evaluation
Figure .Lichen simplex chronicus (LSC), photo
courtesy of Dr. Tor Shwayder.

25 Exciting New Uses of Botulinum Toxin Type A: Dermatology/Dermatologic Surgery and Beyond

(comparable to placebo). The one patient
who had full improvement with BoNTA had
not tried capsaicin previously. The authors
postulated that as both capsaicin and BoNTA
act through TRPV1, patients that fail cap-
saicin treatment may not respond to BoNTA
for relief of pruritus.
A case report describes a 55-year-old
woman with intractable pruritus on the right
side of her forehead for 6 years [31]. She failed
to respond to various treatments, includ-
ing neurontin and novocaine injections. The
uninflamed pruritic area was in close prox-
imity to a surgical scar resulting from frontal
sinus surgery 14 years earlier. The pru-
ritic area was injected with 15 U of Botox®
and – to maintain symmetry – 15 U were
injected into the nonpruritic side. The patient
reported a significant improvement in pruri-
tus that lasted for 2 months.
Role of Hyperhidrosis in
Dermatologic Conditions
BoNTA is approved to treat primary axil-
lary hyperhidrosis. Hyperhidrosis has been
shown to exacerbate several dermatologic
conditions. There are several case reports and
small studies in the literature reporting the
benefit of BoNTA in the treatment of such
disorders.
Dyshidrotic Eczema
Patients with dyshidrotic eczema present
with recurrent or chronic pruritic, vesicular
eruptions on the hands and feet. (Figure 25.5).
Repeated exposure to moisture, heat, and
occlusion may worsen the condition. Corti-
costeroids, immunosuppressive medications,
and ultraviolet light are all possible treatment
modalities. Hyperhidrosis often aggravates
the condition. A small study of 10 patients
with dyshidrotic eczema was conducted in
which Botox® was injected intradermally
to one palm and fingers with the untreated
side as a control [32]. A dilution of 1.0 ml of
unpreserved saline per 100 U of Botox® was
Figure .Dyshidrotic eczema.
prepared (10 w/0.1 ml); 2 U were injected
intradermally every 15 mm, with a mean
dose of 162 U injected. An improvement in
their hand dermatitis within 5–6 weeks was
experienced by 7 of 10 patients, including
a decrease in pruritus, occurrence of vesi-
cles, infiltration, erythema, and decrease
in disease activity scores. Transient muscle
weakness in the treated hand is a possible
side effect.
In a study of eight patients with dyshidrotic
eczema, patients were treated with either
topical corticosteroids alone or corticos-
teroids plus 100 U of Botox® per palm
[33]. The dilution of the toxin was not
specified. Six of eight patients had signif-
icant improvement in hyperhidrosis, fewer
episodes of eczema, and decreased pruri-
tus in the hand treated with Botox®. In
both studies, improvement was likely due to
anhidrosis induced by the toxin through inhi-
bition of acetylcholine release and the action
on smooth muscle associated with sweat
glands. Improvement in pruritus and pain
were also likely due to inhibition of substance
P. Botulinum toxin type A may be a use-
ful addition to the current treatment options
available for dyshidrotic eczema.
Inverse Psoriasis
Inverse psoriasis presents as erythematous,
well-demarcated plaques in intertriginous
areas (Figure 25.6). Botulinum toxin has been
hypothesized to reduce local sweating in


Botulinum Toxins
Figure .Inverse psoriasis, photo courtesy of Dr.
Tor Shwayder.
the affected sites, thereby limiting irritation
and possible infection, and well as having
anti-inflammatory effects [34]. In a recent
study, 15 patients received Botox® injections
to the affected areas [35]; 87% of patients
had improvement 12 weeks posttreatment. In
addition to the reduction in sweat, improve-
ment may have resulted from the block-
age of the release of neuropeptides such as
prostaglandins and nitric oxide that influence
pain and itch [35,36].
Granulosis Rubra Nasi
Children and young adults are more likely
to have granulosis rubra nasi, a disorder of
the eccrine glands of the nose and cheeks.
Hyperhidrosis can occur first, followed by
erythematous papules, pustules, and telang-
iectasias. The condition is difficult to treat.
A 16-year-old male patient with granulosis
rubra nasi was treated with 10 intradermal
injections of 0.1 ml of Botox® to each side of
his nose [37]. The dilution of the toxin was
not specified. His overall condition improved
for 6 months, with hyperhidrosis recurring at
1 year.
Hailey–Hailey, Darier’s Disease, Epidermolysis
Bullosa Simplex
Hyperhidrosis is a known aggravating factor
in autosomal dominant conditions such as
Benign Familial Pemphigus (Hailey–Hailey
disease), keratosis follicularis (Darier’s Dis-
ease), and epidermolysis bullosa simplex
(EBS)-Weber-Cockayne (WC) type [38–40].
A patient with Hailey–Hailey disease had
Botox® 100 U (diluted with 5 ml of 0.9%
sodium chloride) injected in the bilateral
submammary
areas.
Her
hyperhidrosis
resolved within 3 days and lesions cleared
within 2 weeks (Figure 25.7). No relapse was
observed after 12 months [41]. A patient
with Darier’s disease was treated with 40 U
of Botox® into each inguinal fold and 20 U
into the anal fold [39] (Figure 25.8). She
Figure .Hailey-Hailey, photo courtesy of Dr.
Henry Lim.

25 Exciting New Uses of Botulinum Toxin Type A: Dermatology/Dermatologic Surgery and Beyond

Figure .Darier’s disease, photo courtesy of Dr.
Tor Shwayder.
demonstrated improvement in both hyper-
hidrosis and Darier’s for up to 2 months
posttreatment. The dilution of the toxin was
not specified. A patient with EBS-WC was
treated with 100 U of Botox® to the right sole
of the foot, with saline injected to the left
sole as a control [40] (Figure 25.9). She expe-
rienced a therapeutic benefit 3 weeks after
the treatment that persisted for 3 months.
Frey’s Syndrome and Eccrine Hidrocystomas
Frey’s syndrome, or gustatory sweating,
is caused by inappropriately regenerated
parasympathetic fibers of the auriculotem-
poral branch of the facial nerve, resulting in
Figure .Epidermolysis bullosa simplex, photo
courtesy of Dr. Tor Shwayder.
facial hyperhidrosis [2, 42]. It often results
from parotid surgery, and as a rare com-
plication of diabetes mellitus, where it can
occur bilaterally. Intradermal injection of
botulinum toxin over the parotid gland has
been used to decrease sweat production,
likely due to relaxation of the smooth muscle
surrounding the glands [2,42]. Eccrine hidro-
cystomas are common cystic lesions that
may be solitary or multiple. A patient with
multiple periorbital eccrine hidrocystomas
failed incision and drainage alone but had
flattening of the lesions lasting for 4 months
following
concomitant
Botox®
injection
(2 –3 U per cystic space) [43]. The successful
results suggest that sweat production in
eccrine hidrocystomas may be regulated by
acetylcholine. Another study reported that
BoNTA also reduces axillary odor in healthy
patients [44].
Compensatory Hyperhidrosis
Sympathectomy is a permanent resolution
for patients with palmar hyperhidrosis who
fail conventional therapies; however, most of
these patients often develop truncal com-
pensatory hyperhidrosis, which is difficult
to manage and irreversible. A retrospective
analysis of 17 patients with severe truncal
compensatory hyperhidrosis following sym-
pathectomies was performed. Each patient
received intradermal injections of Botox®,
total dose 100–500 U. The vial of Botox® was
diluted with 5 ml of 1% lidocaine (2 U/0.1 ml).
Of 17 patients, 15 had resolution of hyper-
hidrosis within 5 days. The two remaining
patients had improvement of hyperhidrosis.
Resolution persisted for 2–8 months follow-
ing treatment [45]. The side effects were
minor and included skin irritation.
Persistent Facial Flushing
Facial flushing is a vasomotor condition
commonly seen in Caucasians, causing ery-
thema during exercise, anxiety, temperature
changes, and strong emotion. A recent case
report describes a patient treated with 10 U


Botulinum Toxins
of Botox® (diluted with 5 ml of normal saline)
resulting in a substantial improvement in his
flushing after two weeks [3]. Small amounts
of toxin placed subdermally are crucial to
avoid facial paralysis. Although the mecha-
nism of action of the treatment is currently
unclear, BoNTA may improve the flushing
through a reduction in local inflammatory
mediators such as substance P, TRPV1, and
CGRP [46]. In a larger case series, twenty-
five subjects 35–70 years of age with skin
types I–IV and facial erythema from ery-
thematotelangiectatic rosacea were studied
prospectively. Subjects received 15–45 U of
intradermal injections of abobotulinumtox-
inA to the nasal tip, nasal bridge, and nasal
alae. Blinded observers reported statistically
significant improvement in erythema grade at
1, 2, and 3 months after treatment when com-
pared with baseline. Only 15 patients com-
pleted all visits and were included for data
analysis. Larger, placebo controlled studies
are necessary to confirm these interesting
outcomes [47].
Raynaud’s and Ischemic Digits
Raynaud’s phenomenon is a circulatory dis-
order in which stress and cold exposure
induces reversible intermittent constriction
and ischemia of small digital arteries. Clin-
ically, patients present with pain, fingertip
ulceration, and livido reticularis. In a retro-
spective study of 19 patients with Raynaud’s
phenomenon, 50–100 U of Botox® (diluted
with 20 ml of normal saline) was injected into
the palm around neurovascular bundles at the
level of the metacarpophalangeal joint [48].
Of 19 patients, 16 had resolution of their
pain, with 12 patients pain free for 13–59
months. BoNTA has been shown to block the
cholinergic autonomic innervation of smooth
muscle (in addition to that of sweat glands,
tear ducts, and salivary glands) [49]. Inhibi-
tion of neuromuscular smooth muscle cells
by BoNTA may lead to vasodilation [50]. The
authors postulated that reduction of pain-
related neurotransmitters by BoNTA is likely
play a role in clinical improvement. Three
Figure .Vitiligo, photo courtesy of Dr. Tor
Shwayder.
patients in the study experienced intrinsic
muscle paralysis for 2 months.
Pigmentation Disorders
Vitiligo is an autoimmune disorder in which
focal pigment loss is seen (Figure 25.10).
Melanocytes
express
muscarinic
acetyl-
choline (Ach) receptors on their membranes
[51], and Ach is increased in the depig-
mentation of acute vitiligo [52]. A patient
with periorbital vitiligo received BoNTA
injections to treat rhytides in the glabella
and crow’s feet, and subsequently developed
repigmentation in the vitiliginous area in
the months after treatment [53]. To evaluate
BoNTA as a possible treatment for vitiligo,
10 patients received Botox® injections (100 U
vial diluted with 1 ml unpreserved saline) in
one patch of vitiligo [53]. Another patch of
vitiligo was left untreated as a control. None
of the treated lesions showed evidence of
repigmentation; however, the authors note
that a longer follow-up duration for repig-
mentation or more BoNTA may be needed.
More studies would need to be performed
to prove the utility of BoNTA as an effective
treatment for vitiligo.
Pachydermoperiostosis Pachydermia (PDP)
Patients with PDP, or primary hypertrophic
osteoarthropathy, present with clubbing of

25 Exciting New Uses of Botulinum Toxin Type A: Dermatology/Dermatologic Surgery and Beyond

the digits, periostosis, and pachydermia, or
severe rhytides of the face [54]. The wrinkles
are thought to be a result of thickening of
the dermis, rather than repeated movement.
Often cosmetic facial surgery treatment is
the only option. In a small study, 3 patients
with PDP were injected with BoNTA. A total
of 70–80 U of BoNTA were injected in the
procerus, corrugator muscles, tail of the
eyebrow, and forehead (Neuronox, Medy-
tox Inc, Kak-rl, Ochang-myeon, Cheong-
wongun, Korea). A dilution of 2.0 ml of
preserved sterile saline was used, for a con-
centration of 5 o/0.1 ml. All patients demon-
strated some degree of improvement of
wrinkles that started 1-week posttreatment
with some effect remaining 6 months post-
treatment. The mechanism of action is
unknown.
Wound Healing and Hypertrophic Scars
Botulinum toxin administered 1-week preop-
ereratively may improve wound healing and
reduce scarring in areas such as the forehead,
glabella, or upper lip by reducing tension
and motion. BoNTA may inhibit myofi-
broblasts during primary and secondary
intention healing, limiting contraction [46].
Similarly,
temporary
reduction
of
anal
sphincter spasm with BoNTA allows anal
fissures, or small cuts in anal skin, to heal
[55]. A patient with paralysis secondary to
a traumatic spinal cord injury developed
recurrent muscular spasms and a chronic
gluteal ulcer [56]. Dysport® was injected in
the left gluteus maximus and the muscular
area around the ulcer. The reduction in
spasm and contraction allowed for easier
wound care and facilitated healing of the
ulcer. The authors state that BoNTA also
improves
blood
microcirculation
at
the
ulcer site. (Figure 25.11). In a recent study,
five children less than 6 months old born
with complete cleft lip and palate were
injected with 10 U of BoNTA during sur-
gical repair [57]; 3 U were injected in the
orbicularis oris medially and 2 U in each
lateral portion. The decrease in movement
Figure .Ulceration.
of the muscle decreased tension on the
wound.
Hypertrophic scars can be difficult to treat
and are often painful or pruritic. In a recent
study, 19 patients with one hypertrophic scar
for at least 2 years were treated monthly
with intralesional BoNTA (Lanzou Biochem-
ical Company, Lanzou City, P.R. China) for
3 months [58]. The dilution was adjusted
to 2.5 U/cm3 and did not exceed 100 U per
patient. Six months postinjection, all patients
reported subjective improvement of their
scar. A statistically significant reduction in
erythema, itching sensation, and pliability
was seen. While the exact mechanism of
action is unknown, it may be similar to that
seen in wound healing. BoNTA has been
shown to affect the cell cycle distribution of
fibroblasts seen in hypertrophic scars [59].
Additionally, fibroblasts isolated from hyper-
trophic scar tissue incubated with BoNTA
(Lanzou Biochemical Company, Lanzou City,
P.R. China) demonstrated slower growth than
untreated fibroblasts as well as a decrease in
transforming growth factor β1 (TGF-β1) pro-
tein expression [60].


Botulinum Toxins
Parotid Duct Injury
Infiltrative skin cancers on the cheek may
involve the parotid duct. Mohs micrographic
surgery was utilized to treat a large squa-
mous cell carcinoma on the cheek [61]. A
parotid duct injury resulted in the formation
of a sialocele 5 days after surgery; 23 U of
Botox® (dilution of 50 U/ml) were injected
directly into the parotid gland, with com-
plete resolution of symptoms 2 weeks after
injection that lasted 6 months. Salivary fis-
tulas following parotidectomy may respond
to botulinum toxin injections [62]. Similarly,
sialorrhea (drooling) is seen in many neuro-
logical disorders. The resulting blockage of
acetylcholine from the injection of BoNTA
into the parotid, submaxillary, and salivary
glands decreases the excess secretion of saliva
[63]. Recently, 131 children with moderate to
severe drooling from neurological disorders
were treated with injections of BoNTA to the
submandibular glands [64]. Clinical improve-
ment in drooling was seen in 46.6% of chil-
dren for a median of 22 weeks. Dysphagia and
chewing difficulties are possible side effects of
treatment.
Depression
Depression affects millions of Americans
and is often treated with oral medications
and psychotherapy. Such treatments can be
costly and often have unwanted side effects.
Recent studies have investigated the role
BoNTA plays in emotion/mood. In one study,
20 healthy volunteers with no history of
psychiatric or neurological disease received
Dysport® (200 U/ml) injections in the cor-
rugator supercilli muscles only [65]. Pho-
tos were taken of the volunteers contract-
ing the remaining muscles of the face 1 week
before and after treatment. Forty healthy
volunteers (not injected) were shown the
facial images and asked to rate the emo-
tions on a five-point scale. Photos of faces
treated with BoNTA were rated as express-
ing more happiness and less anger, fear, and
sadness. The authors acknowledge that it
is unknown if the treated patients actually
felt happier as well. However, the passive
facial feedback hypothesis states that facial
expression can affect mood, and therefore,
it has been suggested that botulinum toxin
may decrease negative emotions in those
treated [66, 67]. Similarly, decreasing neg-
ative facial expressions and emotions may
in turn stimulate positive emotional expres-
sions, resulting in smiling and feeling positive
emotions [67].
Exploring this concept further, 10 patients
with moderate to severe depression (accord-
ing to their self-reported Beck Depression
Inventory II test scores; BDI-II and American
Psychiatric Association’s Diagnostic and Sta-
tistical Manual of Mental Disorders, fourth
edition; DSM-IV) and no change to their
medication or psychotherapy treatment dur-
ing the prior 3 months, were injected with
29 U BoNTA into the procerus and corru-
gator supercilli muscles [68]. The patients
were evaluated by a clinical psychologist 2
months posttreatment and given a repeat
BDI-II test. All patients had improvement in
mood, with, according to the authors, nine
patients no longer meeting the clinical cri-
teria for depression by their BDI-II test or
DSM-IV scores. The tenth patient had bipo-
lar disorder. Of note, this was not a con-
trolled, randomized trial, and was not statis-
tically significant, due to the small number of
patients treated. Considering the high costs
of treating depression in the United States,
clinical trials to determine the utility and cost
effectiveness of botulinum toxin in this disor-
der would be warranted [69].
Benign Prostatic Enlargement (BPE)
Benign Prostatic Hyperplasia, resulting in
enlargement of the prostate, is a common
condition seen in older men. In a small study
with no control group, 11 elderly males with
BPE and no evidence of prostate cancer,
received total of 200 U of Botox® (diluted
with 8 ml of saline) under transrectal ultra-
sound guidance to two places in the prostate
[70]. The mean prostate volume progressively

25 Exciting New Uses of Botulinum Toxin Type A: Dermatology/Dermatologic Surgery and Beyond

decreased until month 6, with a return to
baseline by month 18. BoNTA may induce
prostate gland apoptosis in rats by block-
ing sympathetic innervation and decreasing
adenergic stimulation to the gland [71].
Tinnitus
Tinnitus can result from multiple factors,
such as infection, malignancy, medication,
and repeated exposure to loud noises. In
a patient with tinnitus due to stapedius
myoclonus, gelfoam infused with BoNTA
(25 U/ml, Lanzhou Institute of Biological
Products,
Lanzhou,
China)
was
placed
through a perforation in the left tempanic
membrane close to the stapedius [72]; 2 days
after treatment, the tinnitus resolved, and
did not recur until 4 months posttreatment.
At that time, the same treatment was per-
formed, with resolution of the tinnitus again.
The authors postulated that in patients with
an intact tympanic membrane, the BoNTA
could be administered by microinjection.
The mechanism of action is unclear.
Atrial Fibrillation
Arrhythmias such as atrial fibrillation can
occur after cardiac surgery, and are associ-
ated with patient morbidity [73]. Denervation
may play a role in atrial fibrillation. In a small
study, the right atrium-pulmonary vein and
left atrium-inferior vena cava fat pads in six
dogs were injected with BoNTA (50 U/ml)
[74].
Atrial
fibrillation
was
significantly
reduced, and vagal stimulation effects on
the sinus node were eliminated. Large, con-
trolled, and long-term studies would need to
be performed in humans to evaluate the effi-
cacy and safety of botulinum toxin for short-
term autonomic denervation of the atria.
Penile Retraction and Premature Ejaculation
Contraction of the bulbospongiosus and
ischiocavernosus muscles contributes to the
expulsion of semen during ejaculation [75].
Although no trials have been conducted, it
has been hypothesized that the inhibition of
the contraction of these muscles may play a
role in the treatment of premature ejacula-
tion [76]. A possible side effect could be ane-
jaculation. Currently, there is a vast market
for products and surgical procedures to cor-
rect penile retraction, or the appearance of a
“short/small penis.” Contraction of the dartos
muscle results in retraction of the non-erect
penis. In a recent study, the dartos muscle of
10 male patients with flaccid short penises
(although average length when erect) was
injected with 100 units of BoNTA [77]. Seven
of ten patients had a subjective decrease in
the frequency and amplitude of penis retrac-
tion, with an objective measurement of less
retraction, and no side effects, for 6 months.
Linear Immunoglobulin A Bullous
Dermatosis (LABD)
LABD is an immunobullous disease in which
IgA auto-antibodies react to components of
the hemidesmosome and basement mem-
brane and cause a split in the dermo-
epidermal junction. Clinically, bullae and
blisters form, often in an annular or linear
arrangement, although the eruption can be
polymorphic in adults. It is the most com-
mon bullous disease in children. Recently, a
single case report was published of a 17 year
old female with LABD who developed a flare
of blisters in the axillae bilaterally despite
receiving treatment with dapsone [78]. 50 0
of BoNTA were injected in her left axil-
lae only. Six weeks post treatment, only 1
lesion was seen in the left axillae, whereas
the right axillae continued to develop lesions.
The right axilla was subsequently treated as
well, with a resulting decrease in blisters that
persisted for 6 months, and then recurred.
The authors postulated that the improvement
from BoNTA was likely due to the decrease in
sweating and inflammation in the axilla.
Summary
The uses of botulinum toxin type A have
expanded since its FDA approval in 1989


Botulinum Toxins
to treat blepharospasm and strabismus [46].
Recent discoveries in the use of botulinum
toxin for painful and pruritic conditions have
applications in many fields of medicine. More
applications are likely on the horizon. Cur-
rently, a phase 3 study is underway to investi-
gate the safety and efficacy of Botox® in mild
to moderate acne vulgaris [78]. A phase 1
study is investigating botulinum toxin for the
treatment of seborrheic dermatitis in Parkin-
sonian patients [79]. Although large, con-
trolled studies are needed for the treatments
discussed in this chapter, the future looks
promising.
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

Modulating Affect and Mood with Botulinum Toxin Injections:
Psychosocial Implications of Neuromodulators
James L. Griffith, MD (MSci),1 Kevin C. Smith, MD (FRCPC (DERM)),2 and Murad Alam,
MD (MSCI, MBA)3
1Dermatology Resident, Department of Dermatology, Henry Ford Hospital, Detroit, USA
2Private Practice Dermatologist, Niagara Falls, Ontario, Canada
3Professor and Vice-Chair, Department of Dermatology, Section of Cutaneous and Aesthetic Surgery, Departments of Dermatology, Otolaryngology, and
Surgery, Northwestern University, Chicago, USA
Introduction
“Can there be emotion without facial
expression?”
Paul Ekman [1]
While the answer is yes, this seemingly
simple question highlights the importance
of facial expression in conveying emotion,
and poses a subtler, second question: Does
facial expression influence our emotional
experience?
A growing body of observational, exper-
imental, and radiologic evidence indicates
that muscles of facial expression not only are
influenced by an individual’s emotional state,
but also have an influence on one’s emotional
experience and his/her interpretation of
another’s emotions, experience and inten-
tions. Interestingly, this influence does not
appear to correspond with aesthetic-induced
improvements, which by itself, could impart
a positive emotional state through improved
personal and social feedback. Thus, manip-
ulating muscles of facial expression (MFE)
may alter the neuronal firing at emotional
epicenters
of
the
cortex
affecting
an
individual’s
emotional
context
(affect,
mood, and interpretation of social interac-
tions), and in turn, open up new therapeutic
avenues to normalize dysregulated cerebral
activity in those with psychiatric disease.
To evaluate the accuracy of this assertion,
this chapter will first briefly discuss the dis-
plays of facial emotion and the relevant aes-
thetic targets on the upper face for botulinum
toxin (BoNTA) injection before examining its
recent clinical trials in major depressive dis-
order and the evidence for/against relevant
psychologic theories that postulate a dynamic
two-way relationship between one’s MFE and
emotional context. Lastly, the future direc-
tion of investigations on botulinum’s use in
neuropsychiatric disease and potential prog-
nostic factors for identifying both good and
poor responders to BoNTA therapy will be
discussed.
For the purposes of this discussion, facial
expressions of fear, anger, sadness, disgust,
and contempt will be considered “negative”
emotions, and happiness (laughing, smiling,
and joy) will be considered “positive”; sur-
prise will be considered “neutral.”
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
Indicators of Facial Emotion and
their Aesthetic Targets for
Neuromodulation
There are six, very clear facial indications of
emotion — anger, sadness, fear, surprise, dis-
gust, contempt and happiness (Figure 26.1)
[2]. Often, each expressions requires multi-
ple muscles to be recruited. In so doing, each
facial muscle is involved (to varying degrees)
in a range of facial expressions – positive,
negative, and neutral (Figure 26.2). For exam-
ple, anger is expressed through eight muscles
of facial expression (Figure 26.3). However,
anger is primarily conveyed through corru-
gator muscle activity, which also can express
the neutral and positive emotions of surprise
and happiness (when laughing), respectively.
Still, systematic investigations have demon-
strated a strong association between negative
emotions and activation of the corrugator,
procerus, and frontalis muscles [3–6] while
positive emotions primarily correlate with
orbicularis oculi activity [7,8].
Although the primary aesthetic targets
for BoNTA injection on the upper face
include the glabellar rhytides (corrugator
supercilii and procerus), horizontal forehead
lines (frontalis), and crow’s feet (orbicularis
oculi), it is important to remember that the
effects of treatment cannot be limited to a sin-
gle muscle as:
1. Mechanical approaches, such as holding
a pen between the teeth [9] or lifting the
cheeks with tape [10] to simulate a smile,
will inevitably affect a variety of target and
Figure .The six clear facial indications of emotion — happy, sad, fear, anger, surprise, and disgust.

26 Modulating Affect and Mood with Botulinum Toxin Injections: Psychosocial Implications of Neuromodulators

Figure .Muscles of facial expression and the expressions they participate in. Source: Victoria Contreras.
Reproduced with permission of ARTNATOMYA.
Figure .The muscles of facial expression that play roles in the facial expression of a single emotion: anger.
Source: Alam 2008 [25]. Reproduced with permission of Elsevier.


Botulinum Toxins
nontarget muscles and other structures.
Likewise, surgical ablation of the glabellar
complex or the motor nerves controlling
the glabellar complex will inevitably affect
nontarget tissues to some extent.
2. Relaxation of muscles for facial expres-
sion via BoNTA will always cause some
degree of relaxation in adjacent muscles
due to diffusion of BoNTA from the injec-
tion site to nontarget tissues (e.g., inject-
ing the glabellar complex will also effect
the frontalis muscle and/or various com-
ponents of the orbicularis oculi to a lesser
extent).
3. Attenuation of a muscle’s action by sur-
gical or pharmacologic means inevitably
induces some degree of compensable
recruitment of nearby muscles to con-
tract. For example, relaxation of the
glabellar complex is sometimes associated
with recruitment of the nasalis and levator
labii alaeque nasi, causing the formation
of “bunny lines” on the proximal bridge of
the nose.
Therefore, when making observations and
designing experiments to affect the per-
ception or expression of emotional states
through mechanical, surgical, or neurochem-
ical modulation, it is important to consider
the broad spectrum of primary and sec-
ondary effects such interventions may incur;
these, at least in theory, may affect facial feed-
back and the underlying neural systems.
Botulinum Toxin in Major
Depressive Disorder
Despite the broad range of behavioral, sur-
gical, electrical, and pharmacological treat-
ments, major depressive disorder (MDD) is
a debilitating condition with no universally
effective intervention. In fact, up to one-third
of patients on pharmacologic therapy fail to
achieve remission despite multiple antide-
pressant trials [11]. Therefore, clinicians and
researchers continue to seek new and effec-
tive treatment options for this condition.
BoNTA has recently been investigated
by three similarly designed, randomized,
double-blind, placebo-controlled trials and
their pooled analysis to determine if BoNTA
injection into the glabella has a role in the
treatment of MDD [12–16]. In total, 134
subjects, who were diagnosed with stable,
mild-to-severe MDD by study psychiatrists
or clinical psychologists and had no recent
changes to psychiatric medication(s) for the
past 28 or 60 days (depending upon the
study), were randomized into either placebo
or BoNTA treatment groups. All BoNTA
cohorts received 29 U injected into the pro-
cerus (7 U), medial corrugators (6 U), and lat-
eral corrugators (5 U) if female and 39 U (2 U
more per site) if male; Finzi et al. adminis-
tered 40 U total per male subject [14]. An
equivalent volume of 0.9% NaCl was injected
into the same MFE of those enrolled in the
placebo treatment arm. Response to therapy
was assessed at baseline and 6 weeks after
BoNTA injection using the Beck Depres-
sion Index (BDI) and Clinical Severity Score
of Glabellar Frown Lines (CSS-GFL) for all
studies. Additional depression scoring sys-
tems and total study duration (6, 16, and
24 weeks) varied by trial. Other notable differ-
ences between these trials included whether
moderate-severe baseline frown lines upon
maximum effort and active antidepressant
medication were required for enrollment.
The 24-week trial also included a double-
crossover at 12 weeks with similar out-
comes to those from the first 12 weeks.
All trials attempted to maintain psychologic
evaluator blinding with two of the stud-
ies covering the glabella and forehead with
a cap during psychiatric assessments, and
the third not informing psychiatric eval-
uators on the effects of the study drug.
To assess whether potential unblinding may
have influenced the outcomes between the
two treatment arms (placebo or active treat-
ment), subjects and psychiatric evaluators
guessed which treatment arm the subject
was assigned at the conclusion of two of
these studies. No association was found
between correctly identifying the treatment

26 Modulating Affect and Mood with Botulinum Toxin Injections: Psychosocial Implications of Neuromodulators

arm and improvement/worsening of depres-
sion scores.
In each study and overall, a statistically
significant reduction in depression scores
was noted at 6 weeks. Approximately one-
third of patients in each study achieved
remission (BDI ≤9, Montgomery–Asberg
Depression Rating Scale ≤10, and 17-item
version of the Hamilton Depression Rat-
ing Scale ≤7). Their pooled response and
remission rates correlated with outcomes of
citalopram from the STAR∗D trial, which
was one of the largest antidepressant trials
[15]. No statistically significant differences
were noted between response and remission
rates of citalopram versus BoNTA. Improved
BDI scores were not associated with visual
changes in glabellar frown lines by pooled
analysis. Additionally, baseline frown lines
poorly predicted baseline depression sever-
ity or subject response to BoNTA treat-
ment. Interestingly, the long-term, 24-week
trial also noted continued improvement in
depression scores even after dissipation of
BoNTA’s paralytic effects. Improved BDI
scores were even reported in an individual
that disliked the cosmetic effect from BoNTA
injection and those without baseline frown
lines. As most subjects were female, extrapo-
lations without firm conclusions can be ascer-
tained for male subjects. Given the results
of these three studies and their pooled anal-
ysis, BoNTA appears to induce a remission
or reduction in depression severity by factors
beyond aesthetic, patient–provider interac-
tion, or placebo effects.
Following these trials, a Phase 2 proof-
of-concept clinical trial assessing Allergan’s
onabotulinum toxin A in adult females with
major depressive disorder was launched. The
trial concluded in 2017 revealing a trend
towards treatment benefit, but failing to
reach its primary endpoint of a statistically
significant improvement in depression scores
at 6 weeks (p = 0.053) compared to placebo.
However, statistically significant outcomes
were achieved at week 3 (p = 0.005) and
week 9 (p = 0.049). The company plans to
proceed with Phase 3 trial development [17].
Proposed Neuropsychiatric
Mechanisms of Botulinum Toxin
Hyperactivity of the left amygdala has been
linked to anxiety, depression, post-traumatic
stress
disorder
and
a
heightened
fear
response. Normalization of this hyperactivity
appears to be one of the potential effects of
BoNTA injected into the glabella. Functional
magnetic resonance imaging (fMRI), which
provides an indirect assessment of neuronal
activity by identifying changes in cerebral
blood, has demonstrated reduced activity
in the left amygdala following glabellar
injection when imitating angry, but not sad
facial expressions, compared to untreated
controls [18]. A similar reduction in activity
of the left amygdala has been shown follow-
ing initiation of antidepressant medications.
Interestingly, improvements in depression
scores have been demonstrated following
BoNTA injection of the glabella (MFE of
negative emotion – frown), while worsening
of depression scores occurred following
injection of the crow’s feet (MFE of positive
emotion – smiling) [19]. However, the exact
mechanism(s) by which BoNTA imparts this
and other neuropsychiatric effects remains
of great debate.
The prevailing proposed mechanisms for
this effect include (a) proprioceptive feed-
back from muscles of facial expression,
(b) societal positive/negative feedback via
mirror neuron activity and (c) aesthetic
preferences, (d) BoNTA migration to the
emotional epicenters of the brain, and (e)
improved feelings about oneself due to aes-
thetic and placebo effects, or the interaction
of a friendly, sympathetic, nonthreatening,
and nonjudgmental professional administer-
ing BoNTA. As previously noted, the findings
from the randomized, double-blind, placebo-
controlled trials reduce the likelihood that
(c, e) visual/aesthetic-based (societal or per-
sonal), placebo, or patient–provider interac-
tion confounders are the primary mechanism
behind BoNTA’s neuropsychiatric effects.
Therefore, this section will focus on the
evidence regarding proprioceptive feedback


Botulinum Toxins
(facial feedback hypothesis), social feedback
(emotional contagion and facial mimicry
from mirror neurons), and BoNTA’s potential
migration to the brain.
Facial Feedback, Emotional
Contagion, and Facial Mimicry
Hypotheses
The discussion of the facial feedback, emo-
tional contagion and facial mimicry hypothe-
ses are relevant in the discussion of BoNTA as
if (a) the “facial feedback” hypothesis, which
suggests facial displays of emotion feeds back
to physiologically influence/determine one’s
emotional experience, (b) “emotional conta-
gion,” which involves the emotional responses
to someone else’s emotional display, and (c)
“facial mimicry,” which involves imitation of
another’s facial response (and in turn, could
lead back to emotion contagion if the facial
feedback hypothesis is correct) do systemat-
ically occur, then botulinum toxin injections
might lead to changes respectively in: (a) the
patient’s own emotional experience and phys-
iological reaction; (b) the emotional experi-
ences of others with whom the patient inter-
acts, and (c) the emotional displays of another
with whom the patient interacts. In short,
botulinum toxin injections might have the
potential to affect a large set of processes in
the patient undergoing the procedure as well
as in those with whom the patient interacts.
Facial Feedback Hypothesis
In simple terms, the facial feedback hypothe-
sis proposes that expressive behavior can alter
one’s emotional state and how he/she inter-
prets the expressions, actions, and intentions
of others [20, 21]. This idea echoes through-
out history with examples documented in
the ancient narrative of the Iliad and even
Elizabethan texts like Shakespeare’s Henry
V where soldiers are instructed to con-
struct formidable expressions in prepara-
tion of their upcoming exertion in battle
[20]. However, this idea reverberates beyond
fictional texts into the scientific literature
through the writings of Charles Darwin [22]
and Gelhorn’s laboratory findings [23] of
a decreased responsiveness in sympathetic
nervous system and hypothalamus following
curare-induced relaxation of animal striated
muscles.
Numerous studies have sought to deter-
mine whether the manipulation of a subject’s
facial displays affect his/her emotional expe-
riences. The best of these have carefully tried
to manipulate facial displays in a manner
that minimizes the participants’ awareness
that they even are producing an emotional
display. Results from these trials generally
support the facial feedback hypothesis. For
example, Strack, Martin, and Stepper found
that having subjects hold a pen between their
teeth (simulating a smile) caused them to
find cartoons funnier [24] (Figure 26.4), and
Larsen, Kasimatis, and Frey noted subjects
Figure .Subjects asked to hold a pen between
their teeth to simulate a grin found a cartoon to be
funnier than did subjects who were not asked to
perform this maneuver. Source: Alam 2008 [25].
Reproduced with permission of Elsevier.

26 Modulating Affect and Mood with Botulinum Toxin Injections: Psychosocial Implications of Neuromodulators

Figure .Subjects who had two golf tees attached to either side of their foreheads and were asked to try to
move these together to simulate a frown concurrently rated unpleasant photographs more negatively than
subjects who viewed the same photographs but did not simultaneously attempt the movement. Source: Alam
2008 [25]. Reproduced with permission of Elsevier.
rated unpleasant photographs more nega-
tively when attempting to move two tees
taped to either side of their forehead together
(simulating a frown) [26] (Figure 26.5).
Expanding upon this body of work, Ekman
and Levenson imbued the study of facial
feedback with laboratory rigor in the 1970s
and 1980s [27–29]; these efforts culminated
in the widely discussed article published
in
Science
that
examined
physiological
responses to facial movements [30]. In this
study, six target emotions – surprise, disgust,
sadness, anger, fear, and happiness – were
evaluated using a “directed facial action
task.” In each case, a coach provided subjects
precise instructions regarding which muscles
to contract to replicate the facial expression
of a target emotion instead of providing a
global command to make a representative
emotional expression (e.g., in lieu of posing
anger, subjects were asked to: “pull your eye-
brows down and together, raise your upper
eyelid and tighten your lower eyelid, narrow
your lips, and press them together.”) These
artificial emotions elicited similar autonomic
responses, measured by electrodermal and
cardiovascular
responses,
as
the
actual
emotions re-experienced from the subject’s
past. Not only did negative expressions differ
from positive expressions on autonomic
parameters, regardless of the method used
to create these expressions, but expressions
of particular emotions differed from another
by autonomic parameters. These findings
provided some of the initial evidence in sup-
port of the hypothesis that facial expressions
are not merely a manifestation of antecedent
internal emotional states, but rather can
induce the internal and biological experience
of emotions.
There has been some criticism of stud-
ies that utilize facial expression coding sys-
tems when investigating the facial feedback
hypothesis. One problematic claim is that


Botulinum Toxins
such studies contain cues that lead partic-
ipants to behave in certain ways. A simi-
lar worry is that instructions regarding facial
expressions are silly or embarrassing, thus
potentially changing emotional responses.
Further, the evidence demonstrating the
validity of the “categorical” model, in which
specific facial expressions are used to elicit
specific emotions, is less than complete [31].
Facial Mimicry and Emotional
Contagion
Facial mimicry and emotional contagion
are two additional concepts that have been
demonstrated empirically. Lanzetta [32] was
instrumental in exploring the extent of the
latter, which can be loosely described as
the process whereby one person’s emotions
are transmitted to another, especially when
the transmission occurs in the absence of sig-
nificant conscious awareness. “Contagion” of
this type has applicability for group cohe-
sion (e.g., smiles can instigate acceptance,
approval, and bonding) and group survival
(e.g., fearful facial displays and vocalizations
can alert other group members to danger)
[33] as normal subjects display enhanced
facial reactions to angry, but not neutral faces,
when fear is induced prior to viewing the
facial expressions [18].
Facial mimicry, on the other hand, entails
the rapid elicitation of spontaneous syn-
chronous facial expressions by others in
response to similar facial expressions in the
index individual. Such mimicry has been doc-
umented in human infants as early as the first
few days of life[34]. In adults, more complex
emotions are subject to transmission in this
manner. These are implicated in emotional
contagion, social perception, and the embod-
ied affect [35].
Both facial mimicry and emotional conta-
gion intimately rely upon the activation of
mirror neurons as demonstrated on fMRI
[36], positron-emission tomography (PET)
[37]), and single-pulse transcranial magnetic
stimulation (TMS)[38] when viewing vari-
ous facial expressions. Mirror neurons, which
were originally discovered in the premo-
tor cortex of monkeys, discharge when an
individual performs a given motor act and
when they observe others perform that same
motor act. The human mirror neuron system
is believed to be involved in understanding
another’s actions and the intentions under-
lying those actions. However, it appears that
mimicry is only one tool for emotional intel-
ligence as a study on Moebius syndrome, a
condition in which patients lack the ability to
make facial expressions, found these patients
could correctly interpret the facial expres-
sions of others equally as well as controls and
normative data within the conditions of the
experiment [39]. Thus, although the ability to
mirror the facial expressions of others helps
one express and interpret another’s feelings,
this skill appears to be a useful, but nonessen-
tial component for interpretation of another’s
emotions.
BoNTA Migration to the Brain
In addition to the indirect effects of neu-
ropsychiatric
modulation
via
the
facial
feedback hypothesis, facial mimicry, and
emotional contagion, BoNTA hypothetically
could produce direct effects on cortical
neurons through central anterograde or
retrograde migration. Although BoNTA has
been demonstrated to lack the ability of ret-
rograde migration and transcytosis of tetanus
toxin [40], Antonucci et al. potentially iden-
tified cleaved SNAP-25 proteins in rat brains
after injecting their whisker muscles with
BoNTA [41]. The conclusions of this study
remain controversial as the antibody chosen
for western blotting or immunohistochem-
istry remains incompletely characterized for
differentiating cleaved and uncleaved SNAP-
25. Additionally, injecting supratherapeutic
quantities (150-fold greater than clinically
used for the entire glabella) limit clinical
extrapolation.
A
separate
investigation,
which utilized radioiodinated neurotoxin,
failed collaborate these findings [42]. Human
correlates have not been studied. Thus, until
more evidence arises supporting BoNTA’s

26 Modulating Affect and Mood with Botulinum Toxin Injections: Psychosocial Implications of Neuromodulators

migratory ability to the central nervous
system, the anterograde/retrograde migra-
tion of BoNTA does not appear to be the
likely underlying mechanism for BoNTA’s
neuropsychiatric effects.
Future Potential Uses of
Neuromodulators in
Neuropsychiatry Beyond
Depression
As with many other aspects of human biology
and neuropsychology, there is a broad spec-
trum of activity in the mirror neuron system
for the human population. While “normal”
people can be found at various points within
this spectrum, a number of disease states
(notably autistic spectrum disorders [43, 44],
Asperger’s syndrome [45], psychopathic per-
sonality disorder [46] and schizophrenia [47])
are characterized by very low levels of mirror
neuron activity and have low or inappropri-
ate rapid facial reactions and facial feedback
in response to emotional stimuli.
High-functioning individuals with autistic
spectrum disorders may be relatively unim-
paired in the cognitive assessment of basic
emotions, in part because they recruit dif-
ferent neural networks and rely on different
strategies to process facial emotions; how-
ever, they still show differences in the auto-
matic processing of facial expressions [48].
Tardiff et al. observed in an experimental
setting that slowing down the presentation
of facial expressions improved the ability of
autistic children to recognize those emotions
[49]. It would be interesting to determine
if modulating the degree and rate of facial
expressions (e.g., in the parents of autistic
children) by treatment with BoNTA would
improve the ability of autistic children to rec-
ognize and correctly interpret those expres-
sions. Conversely, one would have to consider
whether some of these parents have low levels
of mirror neuron activity or facial feedback
activity themselves [50, 51]. Thus, it would
also be of interest to determine whether mod-
ulating facial expression by BoNTA in parents
of autistic children would limit the ability of
such individuals to maintain empathy [52].
At the other end of the mirror neuron and
facial feedback spectrum, individuals, who
display excessive empathy and/or expres-
sion mimicry, may make those around them
become uncomfortable [53]. These individ-
uals with “high self-monitoring” [54] could
feel more natural, and be able to internally
mirror the feelings of others more accurately
when facial feedback and associated mirror
neuron activity is modulated by treatment
of certain muscles of facial expression with
BoNTA. Some experimental evidence indi-
cates that reducing facial mimicry may allow
an individual to more accurately assess the
truth or falsehood of the statements of a con-
versational partner [55]; recent studies have
revealed that excessive emotion impairs cog-
nitive processing and reasoning [56]. There-
fore, modulation by treatment with BoNTA
may help an affected individual feel more “in
control” and better understand others after
this tendency has been attenuated. Similarly,
those seeking BoNTA due to elevated stress,
anxiety or grief may find attenuating negative
facial expressions associated with these situa-
tions helpful in coping with their situation; in
fact, one of the authors has collected over 20
cases where individuals sought BoNTA treat-
ment specifically because they felt treatment
improved their coping with such emotions
in previous experiences. Perhaps, this self-
selected population of individuals are at the
high end of the mirror neuron and facial feed-
back activity spectrum, and being so, derive
particular benefit from moderating these sys-
tems with BoNTA.
Conclusion
Although BoNTA treatment initially may
appear to be an insensitive and shallow
approach to the management of neuropsy-
chiatric conditions, scientific investigations
indicate a potential role for BoNTA in the
treatment of depression and possibly other
conditions. Due to the wide variety of non-
mutually exclusive mechanisms by which