Phẫu Thuật Tạo Hình Grabb & Smith’s (Bản Cập Nhật – Kevin C. Chung)

Bioscience of Injectable Fillers
The number of available injectable filler products, each with its own risk/benefit profile, continues to
rapidly expand. Injectable fillers can be broadly grouped into biologic fillers (including autologous
tissues) and synthetic fillers (Table 46.1).
TABLE 46.1
Soft Tissue Fillers and Their Categorization, Duration of Effect, Need for Allergy Skin Testing, and Recommended Depth of
Injection
Biologic Fillers
Trade Name
Skin Test
Duration
Depth of Injection
Autologous
Years
Subdermal or subcutaneous
Fat
Dermis
Fascia
Nonautologous
Collagen
3–6 months
Mid to deep dermis
Bovine
Zyderm 1
X
Zyderm 2
X
Zyplast
X
Porcine
Evolence
Fibrel
Human
Cosmoderm 1
Cosmoderm 2
Cosmoplast
Hyaluronic acid (HA)
6–12 months
Mid to deep dermis
Restylane
Perlane
Juvederm
Prevelle Silk
Puragen
Captique
Hylaform
Belotero Balance
Elevess
Acellular dermal matrix (ADM)
Years
Subdermal or subcutaneous
Alloderm
Cymetra
Synthetic
Poly-l-lactic acid (PLLA)
Sculptra
24 months
Subdermal or subcutaneous
Calcium hydroxylapatite (CaHA)
Radiesse
18 months
Subdermal or subcutaneous
Polymethylmethacrylate (PMMA)
Artefill/Bellafill
X
Permanent
Subdermal or subcutaneous
Silicone
Permanent
Not FDA approved for soft-tissue augmentation
Polytetrafluoroethylene (PTFE)
Gore-Tex
Permanent
Subdermal or subcutaneous
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Biologic Fillers
Autologous Biologic Fillers
Autologous tissues continue to be used for soft-tissue augmentation of the face and other locations of the
body. Tissues currently employed for soft-tissue volume augmentation include fat, dermis, and fascia.
Despite being the first soft-tissue filler described, autologous fat remains a popular option for volume
augmentation today. In the face, autologous fat is used to fill deep wrinkles, minimize soft-tissue
depressions and skin folds, and improve regions of fat atrophy. In addition, this technique may be
employed for augmentation of lip volume. Fat injection is advantageous because there is no risk of an
allergic reaction or rejection of foreign material. Moreover, the injected fat tends to be longer lasting than
foreign materials used for soft-tissue augmentation. A complete description of autologous fat grafting is
beyond the scope of this chapter. Please see Chapter 48 Fat Grafting in Plastic Surgery for a more in-depth
discussion of this technique.
Dermis and fascia are alternative autologous tissues used for soft-tissue augmentation. Both dermal and
fascial grafts have incorporation rates equivalent to that of autologous fat and provide similar duration of
improvement. 20,21 Because of advancement in lipofilling techniques as well as improvements in
nonautologous filler products, autologous dermal and fascial grafting have been employed less
frequently because they require excision of tissue for graft preparation. 22
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Nonautologous Biologic Fillers
Collagen
The bovine collagen filler Zyderm (Inamed Corp., Santa Barbara, Calif.) was the first nonautologous filler
to be approved by the U.S. Food and Drug Administration (FDA). Because of its high immunologic
reactivity, bovine collagen requires double skin testing consisting of injecting 0.1 mL of the product into
the antecubital area and, 30 days later, injecting a separate body area with the product. A positive skin
test is a local wheal-and-flare reaction within 48 to 72 hours. In general, less than 5% of patients will
manifest a positive test. Furthermore, a negative skin test indicates less than 0.5% risk of allergic reaction
to the bovine collagen product. Both human collagen products, Cosmoderm (Inamed) and Cosmoplast
(Inamed), and porcine collagen products, called Evolence (Colbar LifeScience Ltd., Herzliya, Isreal) and
Fibrel (Mentor Worldwide, LC, Santa Barbara, Calif.), have a low risk of allergic reaction and do not
require skin testing prior to treatment.
Collagen injection has been demonstrated to improve nasolabial folds for a period of 3 to 6 months with a
75% loss of filler correction by 6 months after injection. Collagen injection for the improvement of
wrinkles and nasolabial folds has been compared with other injectable fillers (most commonly HA) in
randomized clinical trials. HA is equal to or superior to collagen in correcting nasolabial folds for longer
periods of time. 23 Furthermore, HAs do not require allergy testing prior to injection. Because of the
above, the manufacture of collagen-based fillers has largely been discontinued.
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Hyaluronic Acid
Hyaluronic acids (HAs) are glycosaminoglycans which are natural components of connective tissue in
living organisms. HAs are chemically identical in all species; therefore, no allergy skin testing is required
prior to their use. A key feature of HA proteins is their hypdrophilic properties which act to maintain
moisture within the dermis, therefore accounting for their capability of filling/lifting soft-tissue deficits.
Regarding their production, HAs may be animal-based or non–animal-based. Animal-based HA fillers,
which are no longer marketed in the United States, are derived from rooster combs whereas non–animal-
based HAs are derived from bacterial fermentation of Streptococcus equi.
HAs have specific, modifiable characteristics that account for their biophysical properties. HA cross-
linking, viscosity, and elastic modulus (G’) account for the physiologic behavior of the filler. A greater
degree of cross-linking correlates clinically with longer duration of effect of the filler. Use of other
chemical compounds such as epoxides, which stabilize cross-links, or the incorporation of varying
degrees of cross-linking in a single product, may contribute to prolong filler efficacy. 24 Viscosity refers to
the ability of the gel to resist shear forces and the elastic modulus refers to the ability of the gel to resist
deformation. Factors affecting viscosity include size and molecular weight of the HA particles. The G’
level is determined by bond strength which, in turn, dictates the degree that bonds between particles
stretch with applied forces. Clinically, variations in G’ manifest as differential ability to lift tissue where
higher G’ translates into greater tissue lift but firmer feel. Higher viscosity is associated with decreased
spread of the filler within tissues but also with decreased ease of injection.
The first HA filler to receive FDA approval for the correction of facial wrinkles was Restylane (Q-Med
Esthetics, Uppsala, Sweden) in 2003. Since that time, HAs, particularly Restylane (Q-Med Esthetics) and
Juvederm (Allergan, Inc., Irvine, Calif.), have been the most studied of the injectable fillers, and treatment
regions included most commonly the nasolabial folds but also the lips, glabellar lines, the upper
extremity (arm and hand), cheeks, and the chin. In general, randomized clinical trials demonstrated that
HAs are equivalent or superior to human, bovine, and porcine collagen in correcting nasolabial folds as
well as volume deficits at other sites including the dorsal hands. 25 In a prospective study from Canada,
HAs were demonstrated to be a safe method to correct age-related lip complaints for over a 6-month
period in some cases 26 (Figure 46.2). In other uncontrolled clinical trials, HAs have been safely utilized
for cosmetic improvement of the chin and cheeks lasting up to 6 to 12 months. 27
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FIGURE 46.2 A 40-year-old woman with lip volume loss treated with hyaluronic acid filler (Juvederm Volbella). Note the
significant improvement in upper lip plumpness and rotation of the upper lip in a cephalad direction producing an aesthetic
improvement in lip appearance.
Since Restylane’s FDA approval, other HA fillers have received similar approval in the United States and
these include Perlane (Inamed), Juvederm Ultra and Ultra Plus (Allergan), Juvederm Volbella, Puragen
and Prevelle Silk (Mentor Worldwide, LC, Santa Barbara, Calif.), Captique and Hylaform (Genzyme
Biosurgery), and Belotero Balance (Merz Aesthetics). HA fillers containing local anesthetics, such as
Restylane Silk, Juvederm XC and Ultra Plus XC, Juvederm Voluma XC, Juvederm Volbella XC, Juvederm
Vollure XC, and Elevess (Anika Therapeutics), are available and patients report less procedural pain
when these formulations are utilized. 28
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Acellular Dermal Matrix
Subdermally implanted acellular dermal matrix (ADM) material has been described for soft-tissue
volume augmentation. Sclafani et al. compared Alloderm (Lifecell) disks or micronized Alloderm to the
bovine collagen product, Zyplast, in the postauricular region of adult patients. Alloderm’s duration of
persistence in this anatomic region was longer than that of bovine collagen and showed promise as an
alternative filler not requiring skin testing. 29,30 An injectable acellular dermal graft (Cymetra; Lifecell
Corp., Branchburg, N.J.) has been developed and demonstrated to be effective in improving upper lip
volume and lower lip projection without local or systemic complications. 31
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Synthetic Fillers
Synthetic fillers are composed of biodegradable materials that stimulate endogenous tissue growth.
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Poly-l-Lactic Acid
Derived from cornstarch, PLLA is a biodegradeable, nontoxic, and inactive material that has been utilized
in the production of indwelling stents, suture material, and meshes. Sculptra (Galderma Laboratories,
L.P., Fort Worth, Texas) was the first FDA-approved PLLA filler. In 2004, it was approved for the
correction of facial lipoatrophy associated with treatment of human immunodeficiency virus (HIV). In
contradistinction to HA fillers, PLLA is a hydrophobic compound and requires reconstitution with
bacteriostatic water for a minimum of 3 hours prior to injection. In the body, PLLA is metabolized to
carbon dioxide, glucose, and water for several months after injection, which accounts for the
characteristic delayed achievement of the desired effect with use of this filler type. Once achieved, the
filler effect has a duration of approximately 18 to 24 months which is due to fibroblast stimulation and
deposition of type 1 collagen into the areas of PLLA microspheres.
PLLA correction of facial lipoatrophy in patients suffering the sequelae of antiretroviral agents has been
demonstrated in randomized controlled clinical trials. 32 Regarding its use in non–HIV patients for
cosmetic improvement of soft-tissue volume deficits of the face (cheeks, chin, perioral, and periorbital
region), PLLA has improved cosmetic complaints for a duration of up to 24 months. Of note, use of the
filler in the perioral and periorbital regions may be associated with an increase risk of skin papules or
subcutaneous nodules; therefore, caution should be used or treatment avoided in these areas. 33
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Calcium Hydroxylapatite
Calcium hydroxylapatite (CaHA) is another highly biocompatible material naturally occurring in the
human body as the mineral component of bone. Radiesse (Bioform Medical, Inc., San Mateo, Calif.)
received FDA approval in 2006 for the correction of antiretroviral medication–associated facial
lipoatrophy as well as for the cosmetic correction of facial wrinkles and folds. Because of CaHA’s
suspension in a cellulose gel, this product is highly viscous and deep injection is recommended.
CaHA as a cosmetic filler has been compared to collagen and HAs in randomized clinical trials. CaHA
was noted to have significantly better nasolabial fold improvement at 8 months postinjection when
compared to several HA fillers and to collagen products. 34,35 In other clinical trials, CaHA has been safely
employed for malar soft-tissue augmentation with injection into the subdermal and subcutaneous planes.
36
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Polymethylmethacrylate
Polymethylmethacrylate (PMMA) is a permanent material that has been used in healthcare since its
introduction in 1928. Applications have included bone surgery and cement, dental rejuvenation, and
cardiac devices. Bellafill (Suneva Medical, San Diego, Calif.) is the FDA-approved version of this product,
and it is approved for the correction of moderate to severe facial scars in patients over 21 years of age. Of
note, this product contains bovine collagen; therefore, patients must undergo skin testing prior to its use.
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Silicone
Injectable silicone is produced from silica and has many manufacturers and different manufactured
viscosities. The use of this permanent product as an injectable filler for cosmetic purposes is considered
off-label. Injectable silicone has been described for soft-tissue augmentation, but its use has been fraught
with inconsistencies in terms of outcomes, the development of granulomas, product infection, and
extrusion.
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Gore-Tex
Polytetrafluoroethylene (PTFE), or Gore-Tex (W. L. Gore Associates, Flagstaff, Ariz.), is a permanent
material that has been described for soft-tissue augmentation. Compared with silicone, this material
allows higher levels of tissue ingrowth. Similar to silicone, it is prone to outcome inconsistencies,
granuloma formation, infection, and extrusion.
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Adverse Events and Their Management
Injectable fillers rarely have side effects such that most complications are procedural rather that product-
related.
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Superficial Filler Placement
Most injectable fillers are recommended to be placed into the deep dermis or deeper planes. Filler
material in planes superficial to the deep dermis appear differently based upon the type of filler used.
HAs placed too superficially produce small lumps or visible bumps. These irregularities frequently
appear quickly and may exhibit a bluish coloration that is called the Tyndall effect. This effect, named
after the physicist John Tyndall, results from differing wavelengths of light scattering because of the filler
particles in a very fine suspension underneath the superficial layers of skin. HAs placed excessively
superficial can be managed immediately with a massage to distribute the filler more evenly in the soft-
tissue region being treated. If this is inadequate, hyaluronidase may be administered. Hyaluronidase is an
enzyme that metabolizes HA and this enzyme is commonly an animal-based preparation. Hyaluronidase
is diluted, commonly with local anesthetic, prior to injection. Practitioners using hyaluronidase must be
aware that, depending upon the preparation of hyaluronidase used, patients may have a reaction to the
medication if it is animal-based and this likely results from a sensitivity to animal protein or thimerisol
contained in the preparation. If hyaluronidase fails to correct the lumps or bumps resulting from HAs
placed too superficially, incision and drainage with the use of an 18-gauge needle or no. 11 blade scalpel
may be completed to express the product from the dermis.
CaHA placed superficial to the deep dermis appears as white nodules in the skin. As described above,
incision and drainage may be required to correct the skin nodules created. Because of the biochemical
properties of CaHA, the material when placed too superficially or in highly mobile regions (lips) tends to
migrate and subsequently coalesce into nodules. Massage and incision/drainage have been described to
treat this problem.
Available preparations of PMMA contain bovine collagen and superficial placement of this product is
associated with pruritis, redness, and hypertrophic scarring. 37 Topical steroid use and intralesional
corticosteroid administration may be employed to ameliorate these problems.
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Hypersensitivity Reactions
Hypersensitivity to nonautologous filler material may range from mild skin irritation to anaphylaxis.
These reactions can occur despite appropriate skin testing and meticulous filler selection individualized
to the patient. HAs, despite their structure being identical in all species, have been associated with
angioedema reactions when injected into the lips. Common manifestations of hypersensitivity reaction to
injectable fillers include erythema, induration, burning, and subcutaneous lumps. The reactions may be
managed with intralesional corticosteroids, oral antihistamines, or systemic steroids depending on the
severity of symptomatology.
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Nodule Formation (Acute Versus Delayed)
Nodule formation may be considered acute or delayed. Acute nodule formation is commonly a result of
filler material placement superficial to the deep dermis (see earlier section Superficial Filler Placement).
Delayed nodule formation may be attributed to a granulomatous reaction and occur several weeks after
filler injection. 38 These nodules may present as painful, red, and inflamed bumps. The differential
diagnosis for these findings includes allergic reaction, foreign body reaction, sterile abscess, or acute
infection. Recently, biofilm-producing bacteria have been implicated in the development of delayed-
presentation nodules after the use of dermal fillers leading to consideration of antibiotic use after a filler
procedure. 39 Specific to the type of filler used, interventions to prevent and manage delayed nodules
have been developed. Despite increasing reconstitution times and placement of this filler in deeper tissue
planes, PLLA nodule risk remains. If PLLA nodules persist or present in a delayed fashion, management
options include intralesional steroids alone or in combination with imiquimod or 5-fluorouracil. If PLLA
nodules persist despite these interventions, surgical excision may be the only option to arrive at
satisfactory result. Similar to PLLA, CaHA nodules can be managed with surgical excision. For HA-
associated delayed nodules, hyaluronidase injection, empiric antibiotics, and incision and drainage are
management options.
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Skin Necrosis and Vision Loss
Vascular structure being compressed due to filler material or vessel occlusion due to intravascular
injection of filler material may occur. Although rare, this may result in skin necrosis along the distribution
of the compromised vasculature. The glabellar region is considered a high-risk area due to the small
caliber of the supratrochlear vessels. Anatomic communication between the terminal branches of the
angular artery and terminal branches of the ophthalmic artery (supratrochlear and supraorbital arteries)
has been implicated in the occurrence of blindness after intraarterial injection of filler material in the
dorsal nasal region and glabella. 40 Techniques and interventions to reduce the risk of skin injury or
necrosis include aspiration prior to injection of the filler material, serial puncture technique use,
antegrade or retrograde linear threading technique use, skin tenting prior to injection to allow accurate
placement of filler superficial to arterial structures, and manual occlusion of larger vessels in the
treatment zone prior to injection. If a vascular problem is identified, immediate action to augment blood
flow is necessary to preserve tissue. These interventions include application of warm gauze, tapping the
area to produce vasodilation, and use of nitroglycerin paste to the affected region. If a HA filler was
utilized and the working diagnosis is external compression of the vessel or intraarterial injection,
hyaluronidase injection in the previous injection site and along the affected vessels course is the mainstay
of treatment. Treatment adjuncts may involve intraarterial hyaluronidase, hyperbaric oxygen therapy,
and ancillary vasodilating agents such as prostaglandin E1. 41
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Scarring
Fortunately, scarring after filler procedures is rare. Multiple studies employing a variety of filler material,
including longer-acting products, have not demonstrated increased risk of hypertrophic scarring or
keloid formation, even when employed in Fitzpatrick skin types IV to VI. 42
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Future of Soft-Tissue Augmentation
Multidisciplinary efforts to identify and develop the ideal soft-tissue augmentation material and
technique of its application will continue. Because it is unrealistic to expect that one product will be
applicable to all patients with an indication for filler use, the perfect filler material must continue to be
individualized to the patient based upon the location of the volume deficit, potential for hypersensitivity
reactions or complications, and desired duration of the filler’s effect.
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Questions
1. Which of the following characteristics of hyaluronic acid dermal fillers may be modified to
produce prolonged results?
a. Cross-linking
b. Particle size
c. Viscosity
d. Gel hardness (G´)
2. Accidental injection of hyaluronic acid filler into which of the following areas is most likely to
cause blindness by retrograde occlusion of the central retinal artery?
a. Cheek
b. Lip commissure
c. Nasal dorsum
d. Philtral column
e. Nasolabial fold
3. A 55-year-old woman receives an injection of 0.5 mL of hyaluronic acid filler into the nasolabial
folds bilaterally. She returns to the office 30 minutes later because of moderate pain and mottled skin
discoloration of the nasal tip and right side of her nose. Which of the following is the most
appropriate next step in management?
a. CT angiogram of the face
b. Prostaglandin E1 injection
c. Lidocaine injection
d. Massage
e. Hyaluronidase injection
4. A 40-year-old woman desires longer-lasting correction of her nasolabial folds. She has had
excellent results previously with hyaluronic acid fillers. Calcium hydroxyapatite is injected and on
follow-up examination 1 week later, the patient is unhappy with white nodules along the treated
nasolabial folds. Which of the following is the least effective treatment option to address the white
nodules?
a. Direct excision of the filler
b. Injection of a corticosteroid
c. Massage of the folds
d. Needle disruption and unroofing of the lumps
5. A 45-year-old woman comes to the office for consultation regarding correction of her deep
nasolabial folds. Soft-tissue fillers are considered. Which of the following filler products is most
likely to result in a hypersensitivity reaction?
a. Polymethylmethacrylate (Belafill)
b. Calcium hydroxylapatite (Radiesse)
c. Human collagen (CosmoPlast)
d. Hyaluronic acid (Restylane)
e. Porcine collagen (Evolence)
1. Answer: a. All hyaluronic acids (HAs) are hydrophilic polymers and in the United States, they are
all produced from bacteria. HAs may be differentiated by their degree of cross-linking, viscosity, and
gel hardness (elastic modulus or G’). Cross-linking produces a gel-like product, and the degree of
cross-linking is directly proportional to the products duration. Viscosity is affected by particle size
and molecular weight. It is important when evaluating dermal fillers and relates more to ease of
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injection and depth of injection rather than persistence of the product. Larger particles must be
injected deeper into the dermis or subcutaneously to avoid visibility. The elastic modulus level is
determined by bond strength which, in turn, dictates the degree that bonds between particles can
stretch with applied forces. Clinically, variations in G’ manifest as differential ability to lift tissue
where higher G’ translates into greater tissue lift.
2. Answer: c. The glabellar region and the nasal dorsum are areas considered to be high-risk for
resultant blindness after filler injection. Anatomic communication between the terminal branches of
the angular artery and terminal branches of the ophthalmic artery (dorsal nasal artery,
supratrochlear and supraorbital arteries) has been implicated in this process. During nasal dorsum
augmentation, accidental injection of filler into the dorsal nasal artery under pressure can push the
filler retrograde into the ophthalmic artery. The filler then can flow distally occluding the retinal
artery and causing vision changes or blindness. Intravascular injection of fillers into the angular
artery of the nasolabial fold can also cause blindness, although this would more commonly result in
skin mottling and necrosis of the nasal tip skin. The cheek area, overlying the malar bone, is a safe
place for injectable filler administration, as there are few deep vessels in this region.
3. Answer: e. This patient presents with signs and symptoms consistent with right-sided nasal
vascular embarrassment due to hyaluronic acid (HA) filler injection. Because there are visible
ischemic changes of the nasal tip and lateral nose, emergency treatment to restore circulation is
required. Massage of the HA filler is usually inadequate for management of skin ischemia and
pending necrosis. The mainstay of treatment for intraarterial injection of HA products is local
injection of hyaluronidase into the site of injection and the local area of skin mottling. Other
treatments used as adjuncts to hyaluronidase administration include massaging the area in order to
promote distribution of hyaluronidase, warm compresses, and application of topical nitroglycerin
paste. Intraarterial hyaluronidase, hyperbaric oxygen therapy, and other vasodilating agents such as
prostaglandin E1 have been described as ancillary treatments in conjunction with hyaluronidase use.
Imaging of the affected area with computed tomography angiography, magnetic resonance
angiogram (MRA), or Doppler ultrasound would delay treatment and are not indicated.
4. Answer: b. Calcium hydroxyapatite (CaHA) is a highly biocompatible material naturally occurring
in the human body as the mineral component of bone. It received FDA approval in 2006 for the
correction of antiretroviral medication–associated facial lipoatrophy as well as for the cosmetic
correction of facial wrinkles and folds. Because CaHA is suspended in a cellulose gel, this product is
highly viscous and deep injection is recommended. In addition to injection below the dermis, safe
injection of this material includes prevention of overcorrection, prevention of clumping of filler due
to bolus injections, and use of postinjection massage. The patient described has an acute nodule
formation after CaHA injection. If acute nodules form (which usually occur in areas of thin soft-
tissue coverage such as the eyelids, lips, and nasolabial region), there are multiple described effective
treatments, which include direct excision, observation to allow for the product to resorb, and needle
disruption and unroofing. Intralesional corticosteroids are not effective in the management of acute
nodule formation after CaHA injection.
5. Answer: a. Hypersensitivity reactions with soft-tissue fillers are relatively uncommon. Local
reactions can occur with any of the fillers, but most reactions likely stem from local irritation
associated with the technique of injection or quantity injected versus a true allergic reaction. In the
case of Bellafill, because the preparation of polymethylmethacrylate (PMMA) contains bovine
collagen, risk of allergic reaction is present; so skin testing is required prior to its use. The other fillers
listed have much lower incidences of reactions. Thus, they do not require skin tests prior to injection.
CosmoPlast is derived from a single human fibroblast cell culture and is treated with glutaraldehyde
to decrease its immunogenicity. Evolence is a porcine-derived collagen. It is much less immunogenic
than bovine collagen. During its preparation, it is treated to remove allergenic telopeptides.
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Restylane is a hyaluronic acid–based product. Because it is not derived from animals, it is also
associated with a lower risk of allergic reactions than the bovine collagen–containing product.
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References
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describing the harvest of several small fat grafts from the arms to fill a facial soft-tissue depression in a 20-year-old man. This is the first injectable
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acid gel dermal fillers. Dermatol Surg. 2008;34(suppl 1):S105-S109.
Alam, M, Gladstone, H, Kramer, EM, et al. ASDS guidelines of care: injectable fillers. Dermatol Surg. 2008;34(suppl 1):S115-S148.
Kempf, KK, Seyfer, AE. Facial defect augmentation with a dermal-fat graft. Oral Surg Oral Med Oral Pathol. 1985;59(4):340-343.
Erol, OO. Facial autologous soft-tissue contouring by adjunction of tissue cocktail injection (micrograft and minigraft mixture of dermis,
fascia, and fat). Plast Reconstr Surg. 2000;106(6):1375-1387.
Bassetto, F, Turra, G, Salmaso, R, et al. Autologous injectable dermis: a clinical and histological study. Plast Reconstr Surg. 2013;131(4):589e-
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Baumann, LS, Shamban, AT, Lupo, MP, et al. Comparison of smooth-gel hyaluronic acid dermal fillers with cross-linked bovine collagen: a
multicenter, double-masked, randomized, within-subject study. Dermatol Surg. 2007;33(suppl 2):S128-S135.Multicenter, blinded, and
randomized trial comparing hyaluronic acid (HA) to bovine collagen for nasolabial fold correction in 439 patients. This study demonstrated that HAs
offer longer-lasting correction of the nasolabial folds when compared to collagen and the majority of test subjects preferred HAs to bovine collagen.
Wang, F, Garza, LA, Kang, S, et al. In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler
injections in photodamaged human skin. Arch Dermatol. 2007;143(2):155-163.
Man, J, Rao, J, Goldman, M. A double-blind, comparative study of nonanimal-stabilized hyaluronic acid versus human collagen for tissue
augmentation of the dorsal hands. Dermatol Surg. 2008;34(8):1026-1031.
Carruthers, J, Klein, AW, Carruthers, A, et al. Safety and efficacy of nonanimal stabilized hyaluronic acid for improvement of mouth corners.
Dermatol Surg. 2005;31(3):276-280.
DeLorenzi, C, Weinberg, M, Solish, N, Swift, A. The long-term efficacy and safety of a subcutaneously injected large-particle stabilized
hyaluronic acid-based gel of nonanimal origin in esthetic facial contouring. Dermatol Surg. 2009;35(suppl 1):313-321.
Weinkle, SH, Bank, DE, Boyd, CM, et al. A multi-center, double-blind, randomized controlled study of the safety and effectiveness of
Juvederm injectable gel with and without lidocaine. J Cosmet Dermatol. 2009;8(3):205-210.
Sclafani, AP, Romo, T III, Jacono, AA, et al. Evaluation of acellular dermal graft in sheet (AlloDerm) and injectable (micronized AlloDerm)
forms for soft tissue augmentation: clinical observations and histological analysis. Arch Facial Plast Surg. 2000;2(2):130-136.
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Sclafani, AP, Romo, T III, Jacono, AA, et al. Evaluation of acellular dermal graft (AlloDerm) sheet for soft tissue augmentation: a 1-year
follow-up of clinical observations and histological findings. Arch Facial Plast Surg. 2001;3(2):101-103.
Sclafani, AP, Romo, T III, Jacono, AA. Rejuvenation of the aging lip with an injectable acellular dermal graft (Cymetra). Arch Facial Plast Surg.
2002;4(4):252-257.
El-Beyrouty, C, Huang, V, Darnold, CJ, Clay, PG. Poly-L-lactic acid for facial lipoatrophy in HIV. Ann Pharmacother. 2006;40(9):1602-1606.
Lowe, NJ, Maxwell, CA, Lowe, P, et al. Injectable poly-l-lactic acid: 3 years of aesthetic experience. Dermatol Surg. 2009;35(suppl 1):344-349.
Moers-Carpi, M, Vogt, S, Santos, BM, et al. A multicenter, randomized trial comparing calcium hydroxylapatite to two hyaluronic acids for
treatment of nasolabial folds. Dermatol Surg. 2007;33(suppl 2):S144-S151.
Smith, S, Busso, M, McClaren, M, Bass, LS. A randomized, bilateral, prospective comparison of calcium hydroxylapatite microspheres versus
human-based collagen for the correction of nasolabial folds. Dermatol Surg. 2007;33(suppl 2):S112-S121.
Beer, K, Yohn, M, Cohen, JL. Evaluation of injectable CaHA for the treatment of mid-face volume loss. J Drugs Dermatol. 2008;7(4):359-366.
Lemperle, G, Romano, JJ, Busso, M. Soft tissue augmentation with artecoll: 10-year history, indications, techniques, and complications.
Dermatol Surg. 2003;29(6):573-587.
Lemperle, G, Gauthier-Hazan, N, Wolters, M, Eisemann-Klein, M, Zimmermann, U, Duffy, DM. Foreign body granulomas after all injectable
dermal fillers: part 1. Possible causes. Plast Reconstr Surg. 2009;123(6):1842-1863.
Beer, K, Avelar, R. Relationship between delayed reactions to dermal fillers and biofilms: facts and considerations. Dermatol Surg.
2014;40(11):1175-1179.
Tansatit, T, Moon, HJ, Apinuntrum, P, Phetudom, T. Verification of embolic channel causing blindness following filler injection. Aesthet Plast
Surg. 2015;39(1):154-161.
DeLorenzi, C. Complications of injectable fillers, part 2: vascular complications. Aesthet Surg J. 2014;34(4):584-600.
Marmur, ES, Taylor, SC, Grimes, PE, et al. Six-month safety results of calcium hydroxylapatite for treatment of nasolabial folds in Fitzpatrick
skin types IV to VI. Dermatol Surg. 2009;35(suppl 2):1641-1645.
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C H A P T E R 4 7
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Botulinum Toxin
Scott T. Hollenbeck and David A. Brown
The nerve conduction is brought by the toxin into a condition in which its influence on the chemical
process of life is interrupted. The capacity of nerve conduction is interrupted by the toxin in the same way
as in an electrical conductor by rust.
Justinus Kerner, New Observations on the Lethal Poisoning Occurring so Frequently in Wurttemberg through the Consumption of
Smoked Sausages (1822).
Key Points
Botulinum toxin is derived from the Clostridium botulinum bacterium and functions to inhibit
acetylcholine release from the neuromuscular junction by targeting SNAP/SNARE receptors.
Three commercial preparations of botulinum toxin A are currently available in the United States:
Botox (onabotulinumtoxinA), Dysport (abobotulinumtoxin), and Xeomin (incobotulinumtoxinA).
FDA-approved aesthetic indications for botulinum toxin use are glabellar lines and lateral canthal
lines (crow’s feet); off-label uses include forehead lines, lateral nasal lines, perioral rhytids,
marionette lines, and platysmal bands.
Recommended dosing for treatment of glabellar lines with Botox is 4 units intramuscularly into each
of five sites in the corrugator and procerus muscles, for a total of 20 units.
Aminoglycosides, penicillamine, quinine, and calcium channels may potentiate the effects of
botulinum toxin; whereas choloroquine and hydroxychloroquine may reduce the effects.
Absolute contraindications include known hypersensitivity reactions to any ingredient in the
formulation, including lactose (Dysport) and albumin (all preparations), as well as preexisting
infections at the injection sites.
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History of Botulinum Toxin Therapeutic Use
From a deadly food-borne neurotoxin that plagued the premodern era to a cosmetic surgery sensation,
the story of botulinum toxin in human society is as fascinating in its detail as it is ironic in its history.
Botulinum toxin type A is a zinc metalloprotease exotoxin derived from the gram-positive, spore-forming
bacillus Clostridium botulinum; it is the agent responsible for the lethal paralytic condition known as
botulism. The most toxic, known, naturally occurring substance, it is so poisonous that one-millionth of a
gram can kill an adult, and a pint could kill every person on earth. In 2017, over 7 million medical
procedures involving botulinum toxin are performed in the United States annually, with a staggering
growth rate of 819% between 2000 and 2017. As the most frequently performed cosmetic procedure in the
country, this specialty drug occupies a central place in the plastic surgery toolkit. The indications for
botulinum toxin in medicine are ever-expanding, and it is anticipated that many readers of this chapter
will continue to shape the evolution of this drug by contributing to its study across new frontiers in
medicine. As we will elaborate in the following pages, botulinum toxin is a powerful, accessible, and
productive treatment modality for a variety of applications in plastic surgery.
The disease was first described in Europe in 1735, named after the Latin word for sausage, botulus, as it
was originally suspected of being acquired from German sausage. Throughout the 19th century, the
epidemic of sausage poisoningstood as a major source of food poisoning in Europe. 1 Justinus Kerner, a
German physician and romantic poet, was the first to conduct experiments on both animals and himself.
Kerner observed that the toxin acts by interrupting signals in the somatic and autonomic nervous
systems, though spares the central and sensory systems. He uncovered a number of highly relevant
aspects of the toxin, including its lethality in very small dosages and its ability to develop in anaerobic
conditions. 2 In a striking example of forethought, he even postulated the use of the toxin for therapeutic
relevance over 150 years before its first clinical application. 3
Over the next century, the bacterial origins of the toxin were demonstrated, along with strategies to
mitigate growth of Clostridial bacteria in food. Military applications were also explored. According to a
New York Times report in 1982, several nations produced botulism toxins during World War II as a
potential biologic weapon. 4 The agent was even spray-tested over a section of Canadian wilderness,
which reportedly killed all animals within 6 hours, although was never used in war. Today, botulism is
relatively rare, owing to improved techniques of food preparation and storage that limit the growth of
anaerobic organisms. 5
Clinical use of botulinum toxin type A was pioneered by the ophthalmologist Alan Scott, who first tested
the compound in primates 6 and later reported its use in a series of patients with strabismus 7 as an
alternative to surgery. A decade later, Jean Carruthers, also an ophthalmologist, observed the auspicious
ability of the toxin to ameliorate facial wrinkles in patients injected for essential blepharospasm. His
findings were presented at the American Society for Dermatologic Surgery (ASDS) conference the
following year, followed by a landmark publication in the Journal of Dermatology and Surgical Oncology
entitled “Treatment of glabellar frown lines with C. botulinum-A exotoxin.” 8 Although the initial
publication only dealt with glabellar lines, testing was already underway for crow’s feet, nasolabial folds,
mental crease, and nasal flare. Two clinical trials followed that confirmed safety and efficacy of the
method. 9 In 2002, the Food and Drug Administration approved its use for “temporary improvement in
the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle
activity.” Since this time, the indications and familiarity of botulinum neurotoxins (BoNTs) in medicine
have exploded. In plastic surgery, it is a well-established and efficacious treatment modality for facial
rhytids, as well as a promising therapy for functional problems such as migraines, vasospastic disorders,
and hypertrophic scars.
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Structure, Mechanisms of Action, and Pharmacology
Botulinum neurotoxins (BoNTs) are generally produced by the Clostridium genus of bacteria, most
prominently Clostridia botulinum. BoNTs inhibit neurotransmitter release at peripheral cholinergic nerve
terminals which results in the flaccid paralysis characteristic of botulism. Seven major serotypes of BoNT
exist (designated A-G), with over 40 different subtypes identified. 10 The structure of the toxin, which is
highly conserved between serotypes, has evolved to ensure rapid and efficient delivery to within the
cytosol of target cells and execution of its neurotoxic effect.
Transcribed from one of several bont genes, the protein is a 150 kDa single-chain polypeptide that
contains an N-terminal light chain, a C-terminal heavy chain, and a globular L domain that is responsible
for the metalloprotease activity of the protein. The heavy chain (HC) domain, which binds specifically to
unmyelinated areas of motor neurons, consists of an N-terminal portion that mediates translocation into
the cytosol and a C-terminal portion that is essential for binding and endocytosis into the presynaptic
neuron. 11 The L domain is a conserved sequence containing a Zn2+ atom bound to a conserved sequence
motif, which is also shared with tetanus neurotoxin. 5 The unique substrates of the L domain are the three
SNARE proteins: VAMP/synaptobrevin, SNAP-25, and syntaxin. SNARE proteins are involved in fusion
of the synaptic vesicle with the plasma membrane and were the subject of the 2013 Nobel Prize in
Physiology or Medicine awarded to James Rothman, Randy Schekman, and Thomas Südhof.
The mechanism of BoNTs can be grouped into five major steps 5 : (1) binding to skeletal and autonomic
cholinergic nerve terminals that use acetylcholine (ACh), (2) endocytosis inside synaptic vesicles that
require the ATPase proton pump, (3) translocation of the L chain across the vesicle membrane, (4) release
of L chain in the cytosol and activation of the toxin, and (5) cleavage of SNARE proteins. Once the SNARE
protein has been cleaved, it is unable to facilitate fusion of vesicles with the host cell membrane,
preventing ACh release from axon endings. Signal transmission at the neuromuscular junction is
interrupted, and the muscles are unable to respond to neuronal activity. Over time, regeneration of nerve
activity occurs as the toxin loses its activity and the host cell replaces SNARE proteins.
Local movement of injected toxin can be characterized by two distinct phenomena: diffusion and spread.
12 Whereas diffusion refers to the concentration gradient–driven transport of the molecule through the
tissue, spread portrays the initial extent of injection by the practitioner. Diffusion is largely a property of
the initial concentration of toxin, as well as the water content of the tissue and efficiency of receptor
binding and uptake. This process is mostly complete after 24 hours, 13 and no further diffusion to
surrounding tissues should occur. Although there are theoretical differences in diffusivity because of the
larger sizes of onabotulinumtoxinA (900 kDa) and abobotulinumtoxinA (500–900 kDa) versus
incobotulinumtoxinA (150 kDa), 14 no differences in diffusion of the toxins have been observed in vivo. 15
Dilution of the toxin should also impact the extent of diffusion into surrounding tissue, though there is
little evidence supporting this prediction either. 14 Spread is a much more controllable factor in the sense
that distribution of the drug is accomplished by the pathway of the needle and egress into the tissue.
Importantly, BoNT does not appear to cross the blood-brain barrier, but modulatory effects on the central
nervous system can occur. Migration of the toxin, defined as its movement to distant tissues, can occur
either by neuroaxonal transport or hematogenously. Although BoNT primarily acts at the neuromuscular
junction, there is reasonable evidence that BoNTA and BoNTE, injected at therapeutic dosages, undergo
retrograde axonal transport from sites of injection to the spinal cord and motor cortex. 16 Several studies
in stroke patients have observed reduced inhibition of antagonistic muscles after injection into a
particular muscle group, indicating a centrally acting effect of the toxin. 17 An alternative explanation is
that BoNT acts on intrafusal fibers that inhibit afferent nerves in the target muscle as well as Renshaw
cells which also use acetylcholine as a neurotransmitter. This generates an inhibitory effect on alpha
motor neurons, which could produce the same inhibition of antagonistic muscles as a centrally acting
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mechanism of the drug itself. 11
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Commercial Preparations
Currently there are four commercially available BoNT preparations available in Western nations (Table
47.1): Botox® (OnabotulinumtoxinA, Allergen Inc., Irvine CA), Dysport® (AbobotulinumtoxinA, Ipsen
Ltd., Slough, UK), Xeomin® (IncobotulinumtoxinA, Merz Pharmaceuticals, Frankfurt, Germany), and
MyoBloc® or NeuroBloc® (RimabotulinumtoxinB, US World Meds, Louisville, KY). Several other
preparations are available in Asian countries, including Prosigne® (Lanzhou Biological Products, Gansu,
China), Meditoxin® (Medy-tox, Seoul, Korea), and Botulax®(Hugel Inc., Chuncheon, Korea). Although all
formulations of the compound have unique properties and clinical effects, we will focus on the four
common Western formulations in this chapter. The properties of these formulations are outlined in Table
47.1. All formulations except incobotulinumtoxinA (Xeomin) contain complexing proteins. As the
smallest of these formulations, incobotulinumtoxinA contains only the active 150 kDa neurotoxin
responsible for the therapeutic effect and is the most stable of the commercially available preparations (3–
4 year shelf life at room temperature).
TABLE 47.1
Properties of Common Botulinum Toxin Preparations 11,18
OnabotulinumtoxinA
AbobotulinumtoxinA
IncobotulinumtoxinA
RimabotulinumtoxinB
Manufacturer
Allergen Inc.
Ipsen Ltd.
Merz Pharmaceuticals
US World Meds
Trade name
BOTOX
Dysport
Xeomin
NeuroBloc/Myobloc
Approved
indications in
plastic surgery
Moderate to severe glabellar
lines, canthal lines, and
forehead lines
Moderate to severe
glabellar lines and
canthal lines
Moderate to severe glabellar
lines and canthal lines,
blepharospasm
None (cervical
dystonia only)
Cleavage target
SNAP-25
SNAP-25
SNAP-25
VAMP
Molecular weight
900 kD
500–900 kD
150 kD
700 kD
Formulation
Vacuum-dried powder
Lyophilized powder
Lyophilized powder
Sterile solution
Shelf life
2–3 y
2 y
3–4 y
2 y
Storage
temperature
2–8°C
2–8°C
Room temperature
2–8°C
Units per vial
50, 100, 200
300, 500
50, 100
2500, 5000, 10,000
Potency
154 U/ng
137 U/ng
227 U/ng
70–130 U/ng
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Clinical Applications
BoNTs were originally described for ophthalmologic conditions and perhaps best known by the public
for aesthetic applications. However, the concept of injectable, longer-term, neuromuscular inhibition has
proven a powerful therapeutic modality and has undergone a vast array of studies in the last 2 decades.
BoNTs have been reported to be safe and effective in the treatment of oromandibular dystonia including
bruxism and tremors including essential tremor, parkinsonian rest tremors, motor tics, overactive
bladder, pain depression, and a number of other movement disorders (see Jankovic 11 for review). The
most commonly used and most extensively tested of the formulations is onabotulinumtoxinA, which will
we refer to by its more commonly known trade name, Botox. Botox has been vetted by more than 60
randomized clinical trials in the last 2 decades and is approved in at least 85 countries for more than 27
indications. 19 In this chapter, we will focus on the plastic surgery applications of all BoNTs, which
include facial rhytids, migraines (as diagnostic and therapeutic tool before migraine surgery), axillary
hyperhidrosis, upper extremity vasospastic disorders, and hypertrophic scars.
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Facial Rhytids
A detailed understanding of facial anatomy is critical to successful application of BoNTs. Muscles of facial
expression are unique in that they attach to a fibrous soft-tissue support system, called the superficial
muscular aponeurotic system, instead of bone. Contraction of facial muscles produces wrinkling of the
overlying skin, which produces many of the rhytids associated with aesthetic dissatisfaction. In addition
to the muscular targets of BoNT injection, the practitioner must have an understanding of surrounding
anatomy to appreciate and anticipate potential off-target effects of injection. The FDA has approved the
use of botulinum toxin for cosmetic treatment of three specific areas and the associated facial muscles,
including:
Glabellar lines associated with corrugator and/or procerus muscle activity
Lateral canthal lines associated with orbicularis oculi activity
Forehead lines associated with frontalis activity
Undoubtedly, a large number of clinicians use botulinum toxin to treat other facial muscles located in the
eyebrow, midface, lower face, and neck.
When considering treatment with botulinum toxin, a discussion with the patient to identify goals and
expectations is warranted. The temporary effect of botulinum toxin (3–4 months) should be emphasized
as well as the risks of the procedure. Next, it is important to assess the patient’s facial anatomy in the
context of their expressed concerns. A consistent approach to examining the patient is helpful. This
should include evaluation in natural repose position as well as during animation. It is helpful to ask the
patient to frown and squint to accentuate facial lines. Eyelid and brow ptosis should be appreciated prior
to injection. Once the examination is complete, a treatment plan can be discussed with the patient. Dosing
calculations and drug reconstruction should occur just prior to injection. A 30 or 33 gauge needle is used
in conjunction with a 1 cc syringe to deliver the drug.
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Glabella
The glabella region was the first area to be treated with botulinum toxin for cosmetic purposes and
remains a common target for therapy (Figure 47.1). Glabellar lines, or frown lines, are formed from a
compound movement of the glabellar complex depressor muscles, which include the corrugator
supercilii, procerus, and depressor supercilii. Contraction of this complex, as well as the orbicularis oculi,
pulls the brow inferiorly and medially, which produces one or more vertical skin lines between the
medial aspects of the eyebrows. Patients seeking treatment of glabellar lines often note that they are
mistaken for being angry, fatigued, or stressed. Jean Carruthers, who initially reported the effects of
botulinum toxin on facial rhytids, published a landmark clinic trial in Plastic and Reconstructive Surgery in
2003, which demonstrated a significant improvement in appearance of glabellar lines with Botox
administration as judged by both blinded physicians and the treated patients. 20 A number of supporting
trials followed, and a 2015 meta-analysis confirmed the safe and effective dosing practice of 20 units for
the glabellar region. 21
FIGURE 47.1 A 32-year-old woman underwent injection of 50 units of Botox, including 15 units to three sites in each of the
glabella and corrugators, 7.5 units to three sites around each orbit, and 20 units to six sites on the forehead. Preinjection (A)
and 8 days postinjection (B) photos are shown. Note the prominent reductions in forehead lines and lateral canthal lines during
facial animation, which are not noticeable in repose.
Surgical approaches to treating glabellar lines exist and may be incorporated with other procedures.
However, chemodenervation of the corrugator and/or procerus with botulinum toxin is effective toward
achieving similar results to open surgical approaches. 22 If using Botox, five injections of 4 units (20 units
total) are typically performed in this area: two injections into each corrugator muscle and one injection
into the procerus muscle. The efficacy of botulinum toxin in treating glabellar lines is very high (60%–
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100%) with the most frequent adverse reaction noted as eyelid ptosis (about 3%). 21,23 To prevent this
complication, avoid injection near the levator palpebrae superioris muscle and make lateral injections at
least 1 cm above the supraorbital ridge. Signs of chemodenervation will begin to occur at 2 to 3 days after
injections, increase in intensity over the first week, and usually persist for 3 to 4 months.
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Lateral Canthal Region (Crow’s Feet)
An appreciation for the extent of the lines associated with the orbicularis oculi muscle should be gained
during the preinjection physical examination. This may include upper, lower, or a fanlike combination of
lines throughout the lateral canthal region. These are best identified while asking a patient to smile.
Lateral canthal lines arise predominantly from forceful contraction of the orbicularis oculi muscles, which
originate from the lateral canthus.
An appreciation for the overlap between the orbicularis oculi muscle and the zygomaticus muscles
should be established to avoid injecting the zygomaticus muscles. If using Botox, 4 units should be
injected into three sites per side (six total injection points) for a total of 24 units. The injection sites for this
area start in the lateral orbicularis oculi muscle, just temporal to the lateral orbital rim. The other areas are
1 cm superior and 1 cm inferior with a 30-degree angle toward the midline. Occasionally, the crow’s feet
lines will be more focused on the lower periorbital region and require a lower placement of injection sites.
However, injections should not extend inferior to the maxillary prominence. The overall satisfaction of
treating lateral canthal lines with botulinum toxin at 6 months is about 50%. 23 The most frequent adverse
reactions following injection of botulinum toxin in the lateral canthal region are eyelid edema and
bruising (about 1%). 19,20
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Forehead
The forehead lines can be evaluated by asking the patient to raise and lower their eyebrows. The extent of
the frontalis muscle can be appreciated by visual inspection and palpation with the superior aspect
extending just above the highest forehead crease. Typically, two treatment rows are used to treat the
frontalis muscle. The lower treatment row will be halfway between the superior extent of the frontalis
muscle and the eyebrow. The upper treatment row will typically be halfway between the superior aspect
of the frontalis muscle and the lower treatment row. Forehead lines are typically treated in conjunction
with glabellar lines using 40 units total, to minimize the possibility of brow ptosis. The most frequent
adverse reactions following injection of botulinum toxin for forehead lines are headache (9%), brow ptosis
(2%), and eyelid ptosis (2%). 19,20
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Brow Elevation
The use of botulinum toxin for treating brow ptosis and asymmetry has been somewhat challenging
because there is no standard approach for achieving brow elevation. In general, the two muscles targeted
for generating brow elevation are the frontalis and the orbicularis oculi. When the central and lateral
portions of the frontalis are weakened, there is compensatory contraction of the frontalis muscle directly
over the brow resulting in elevation. Likewise, injections directed toward the superolateral aspect of the
orbicularis muscle can result in a significant increase in brow height without a significant risk of
asymmetry. 24 Although the standard plane of injection is intramuscular, subcutaneous injections may be
equally effective in achieving paralysis. 25
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Nasolabial Fold and Gummy Smile
The levator labii superioris alaeque nasi muscle is attached to the frontal process of the maxilla and
attaches to the skin of the upper lip and lateral nostril. The muscle name translates to lifter of the upper
lip and wing of the nose. The zygomaticus major also contributes the smile and nasolabial fold as it
primarily pulls and elevates the oral commissure. In a classic article published in Plastic and Reconstructive
Surgery, Leonard Rubin described three major smiling patterns (Mona Lisa, Canine, and Gummy) and the
impact that each muscle has on the resulting appearance. 26 Botulinum toxin can be used to modify the
appearance of the gummy smile by direct injection into the levator labii muscle which can be palpated
during smiling along the lateral aspect of the piriform aperture. This can be accomplished typically with
one injection on each side with a modest dose. 27 Excess gingival display (>2 mm) can be addressed with
this approach, and further softening of the nasolabial folds can be achieved with targeting the
zygomaticus muscles.
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Neck
Visible bands in the neck resulting from platysma muscle attenuation can be a source of dissatisfaction
for patients. Patients are evaluated by asking them to clench their necks and show their lower teeth.
Hyperactive platysmal bands in the superficial subdermal space can be visualized and are the target of
treatment. Numerous approaches to treating platysma bands with botulinum toxin have been reported
with varying doses techniques. 28,29 It is well accepted that patients with excess skin laxity in the neck are
not good candidates for this procedure as they have minimal overall improvement. In a recent study,
patients were injected with botulinum toxin along the inferior border of the mandible and with the
platysmal bands using a mean dose of 124.9 units. 30 The authors noted a significant improvement using
this technique; however, some express concern given the high dose needed for effect and the potential
risks of dysphagia and salivary gland dysfunction. Other more conservative approaches include direct
platysmal band injection with 20 units of botulinum toxin. 29 Again, patient selection through proper
physical examination is paramount for success in this approach.
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Noncosmetic Uses
Axillary Hyperhidrosis
Hyperhidrosis is characterized by the excessive sweating without any specific cause and can be socially
stigmatizing for patients. The axilla, palms, and soles are the most common sites for hyperhidrosis. A
variety of topical agents have been used for hyperhidrosis as well as surgical sympathectomy, all with
formidable downsides. In 2001, a multicenter trial utilizing botulinum toxin injections for axillary
hyperhidrosis was performed. 31 In this randomized double-blinded study, participants received 200 units
of botulinum toxin injected into one axilla in comparison to placebo injections into the other. Within
2 weeks, there was a noticeable drop in sweat production from the treatment side. This effect continued
for 24 weeks, and patients were highly likely to recommend this treatment to other patients. Further
validating this technique was a modeled comparison study between endoscopic thoracic sympathectomy
and intradermal botulinum toxin published in 2016. 32 The authors concluded that treatment costs
reached an equivalence at 13 years, yet because of the low risk of botulinum toxin injections, they would
recommend this over surgical sympathectomy. With this approach, the duration of effect is typically
7 months, and high patient satisfaction is typical. 33 Although side effects remain somewhat uncommon in
most studies, a low rate of compensatory sweating in other areas was noted to occur with some
regularity. 34,35
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Chronic Migraines
An emerging treatment for chronic migraines lies in the neurolysis of sensory nerves of the head, which
can be achieved by both surgical (decompression, neurolysis, and ablation) and chemical (BoNT injection)
means. Chronic migraines affect over 3 million people in the US population and are distinguished from
episodic migraine by a distinct frequency, epidemiology, pathophysiology, and response to treatment. 19
The effectiveness of BoNTs was incidentally discovered by William Binder, a facial plastic surgeon, who
was conducting studies with Botox for aesthetic applications and noted a correlation between pericranial
injections and alleviation of migraine symptoms. 36 He published the first open-label clinical trial on Botox
for chronic migraines in 2000. 37
The pathophysiology of chronic migraines is incompletely understood, and the knowledge base
surrounding this issue exceeds the scope of this chapter. The current model of the disease process is
based on abnormal excitability in both central and peripheral neurons, particularly in the trigeminal
neurovascular bundles. 19 It is thought that peripheral sensitization occurs, in which the threshold of
sensory neurons responses to external stimuli is altered because of various maladaptive processes, and
the neurons become hyperexcitable. Botox is thought to interrupt both neurotransmitter and
neuropeptide release from sensory neurons, which interrupts signal transmission to the central nervous
system and mitigates the effects of peripheral sensitization.
Two phase III clinical trials were conducted that led to FDA approval of Botox for chronic migraines. The
Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT 1 38 ) and PREEMPT 2 trials 39
consisted of a multicenter, randomized, double-blind, placebo-controlled clinical trial of Botox for chronic
migraines in both North America and Europe. The pooled analysis of 1384 patients randomized to Botox
or placebo demonstrated that Botox significantly reduced the number of headache days per month
(−8.4 days for Botox and −6.6 days for placebo, P < 0.001, 95% CI −2.52 to −1.13), as well as frequency of
migraine days, moderate or severe headache days, cumulative hours of headaches, and other measures of
migraine severity and frequency. Safety analysis from the trials also revealed no new concerns, with the
percentage of adverse events similar between treatment and control groups.
Botox is currently indicated for the treatment of chronic migraines, defined as at least 15 days per month
with headaches that last 4 hours or longer. The recommended dosage is 155 units administered
intramuscularly, divided between seven sites in the head and neck: corrugators (5 U each side), procerus
(5 U), frontalis (5 U each side), temporalis (5 U each side), occipitalis (15 U each side), cervical paraspinal
muscles (10 U each side), and trapezius (15 U each side).
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Upper Extremity Vasospastic Disorders
Patients with Raynaud phenomenon have abnormal vascular function in the hand who may develop
chronic pain and ulceration. Botulinum toxin injections are a promising nonsurgical option for these
difficult-to-manage patients. Prior to injection, patients should undergo vascular imaging studies to rule
out occlusive disease. Neumeister et al. demonstrated improvements in hand pain, hand blood flow, and
healing of chronic ulceration in a retrospective study evaluating the efficacy of botulinum toxin for
patients suffering with Raynaud condition. 40 In this study, 50–100 units of Botox was injected into the
palm directed toward the neurovascular bundles of the digits, and many patients demonstrated long-
term relief of symptoms. Likewise, a study by Fregene et al. demonstrated similar improvements with
pain and blood flow to the hand in patients with Raynaud conditions undergoing 100 unit Botox
injections to the palm. 41 Side effects from this approach can include recurrence of pain and intrinsic
muscle weakness. 40-42
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Hypertrophic Scarring
A fascinating application of BoNT lies in the treatment and prevention of hypertrophic scars. Because
wound tension is known to lead to an exuberant and potentially pathologic fibrotic response, chemical
paralysis of muscles surrounding a wound may reduce tension during the critical healing period.
Although only smaller studies have been performed to date, a 2016 meta-analysis showed statistically
significant differences in both scar width and patient satisfaction with the use of botulinum toxin type A
43 for head and neck scars. Future studies are needed to flesh out the clinical utility and generalizability of
this practice.
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Contraindications and Warnings
The absolute contraindications for BoNTs are only two: hypersensitivity to any BoNT preparation
(including any component of the preparation) and infection at the injection site. However, there are a
number of warnings and precautions issued by the FDA, as well as potential drug interactions of which
the practitioner should be aware. The dosages of BoNTs, even of the same toxin family (e.g.,
OnabotulinumtoxinA and AbobotulinumtoxinA, or Botox and Dysport), are not interchangeable and
cannot be compared. As described earlier, movement of toxin beyond the site of injection is always a
concern, particularly when injecting the toxin around the airway muscles as is performed for spasticity.
Although ongoing controversy exists about the retrograde migration of BoNTs to the central nervous
systems (see above), no adverse events have been reported during dermatologic uses of BoNTs. The
practitioner should be especially careful when treating patients with cardiovascular disease or
neuromuscular disorders (e.g., myasthenia gravis or Lambert-Eaton), who should be monitored after
treatment.
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Adverse Effects
As with any medical intervention, the side effects of treatment must be well understood by the clinicians
prior to application. Distant spread of the effects of botulinum toxin may occur following local infections.
These effects are reported to include generalized muscle weakness, diplopia, eyelid ptosis, dysphagia,
dysphonia, urinary incontinence, and breathing difficulties. Symptoms may occur hours or even weeks
after injection and are most common in children being treated for spasticity. Spread of the toxin effect
during facial dermatologic treatments is unlikely when labeled doses are used. For Botox, this includes
20 units for glabellar lines, 24 units for lateral canthal lines, 40 units for forehead lines, 44 units for
simultaneous lateral canthal and glabellar lines, and 64 units for simultaneous lateral canthal, glabellar,
and forehead lines. Finally, treatment with botulinum toxin is contraindicated when there is an active
infection at the injection site. Hypersensitivity to botulinum injections can occur and may include
anaphylaxis and other forms of immediate allergic reactions.
Botulism-like symptoms have been reported in patients undergoing BoNT injections for dystonia, 44
hyperhidrosis, 45 and blepharospasm. 46 These symptoms included dry eyes and mouth, gastrointestinal
disturbances, dysphagia, hoarseness, and breathing difficulties. Notably, it is suspected that an
underlying condition of myasthenia gravis was not recognized in these patients, 46 and none of the
patients received the drug for aesthetic indications. Dosages of the drugs were also far higher than used
for typical aesthetic indications: 6.25 to 32 U/kg of Botox and 388 to 625 U/kg of MyoBloc. Nonetheless,
practitioners injecting BoNTs for plastic surgery indications must be aware of the potential for serious
adverse events, particularly in patients with preexisting cardiovascular conditions or compromised
respiratory function.
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Acknowledgments
The authors thank Andre Marshall, MD, for his assistance with Figure 47.1.
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Questions
1. A 44-year-old woman presents with unilateral ptosis 1 week after undergoing botulinum toxin
injection for glabellar rhytids. Which of the following is the most likely explanation for this finding?
a. Horner syndrome
b. Corrugator paralysis
c. Levator palpebrae superioris paralysis
d. Orbicularis oculi paralysis
e. Incomplete administration of toxin
2. A 49-year-old woman presents to your clinic with dissatisfaction of fine rhytids radiating outward
from the lateral canthus. Twelve units of Botox are injected intramuscularly in regions of the lateral
orbicularis oculi muscle on each side. The procedure is uncomplicated, although 3 days later the
patient calls to state that she has minor bruising in the area and has no visible improvement in the
rhytids. Which of the following factors is most likely contributing to the lack of effect?
a. Injection of improper anatomic region
b. Inadequate dosage of injected toxin
c. Failure to recognize underlying comorbidity
d. Inadequate time for effect
e. Wrong depth of injection
3. A 25-year-old man reports migraine headaches that persist more than half the day and occur most
days of the month. Symptoms are present diffusely, but predominantly localized to the frontal,
temporal, and occipital regions. Ten units of Botox are injected intramuscularly in both the frontalis
and temporalis muscles. Which of the following factors is most likely to contribute to a weaker effect
of treatment?
a. Frequency of migraines
b. Insufficient injection into the frontalis and temporalis muscles
c. Lack of injection into other pericranial muscles
d. a, b, and c
e. b and c
1. Answer: c. The levator palpebrae superioris muscle is innervated by the superior division of the
ipsilateral oculomotor nerve (cranial nerve III). Its function is to elevate and retract the upper eyelid.
Loss of innervation, which may occur from botulinum toxin administration or trauma, will cause
blepharoptosis. Although this is considered an adverse event in aesthetic botulinum toxin
administration, purposeful levator chemodenervation has been used as a strategy to protect the
cornea after facial nerve paralysis–induced lagophthalmos. Although ptosis may also result from
inadvertent chemodenervation of the superior tarsal muscle (Müller muscle), Horner syndrome is
defined by the classic constellation of ptosis, miosis, and anhidrosis. The latter symptoms are not
present in this patient. Horner syndrome is due to lesions in the ipsilateral sympathetic pathway
responsible for innervating the superior tarsal muscle. Symptoms can arise from the lesion at any
point in the sympathetic nerve pathway including the hypothalamospinal tract, sympathetic trunk of
the thoracic spinal cord, sympathetic chain, internal carotid plexus, or superior cervical ganglion.
Botulinum toxin injected would not be expected to interrupt sympathetic nerve transmission at these
locations. Corrugator paralysis is an anticipated and desirable effect of botulinum toxin injection for
glabellar rhytids. Orbicularis oculi paralysis would result from facial nerve (cranial nerve VII)
paralysis and cause lagophthalmos, an inability to close the eye. Incomplete administration of toxin
would result in persistent rhytids and would not be expected to cause ptosis.
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2. Answer: d. BoNTs typically demonstrate an effect between 3 and 7 days postinjection and persist
for 4 to 6 months. If no visible improvement is seen after 3 days, the best course of action is to
reassure the patient and reassess in another week. The correct anatomic region for lateral canthal
lines (Crow’s feet) is in the lateral orbicularis oculi region, within the muscle, as was done in this
patient. A total of 24 units are recommended for lateral canthal lines (12 on each side). The injection
sites for this area start in the lateral orbicularis oculi muscle, just temporal to the lateral orbital rim.
The next areas are 1 cm superior and 1 cm inferior with a 30-degree angle toward the midline. A
comorbidity that predisposes the patient to poor effect of the toxin is unlikely. Minor bruising is a
common phenomenon after injections and usually resolves without intervention.
3. Answer: c. The recommended administration of Botox for chronic migraines is 155 units divided
between seven sites on the head and neck (see text for specific dosages). The frontalis and temporalis
muscles comprise two of these sites, which should both receive 5 units of toxin on each side, as was
done for this patient. However, the patient’s diffuse symptoms suggest that complete coverage of the
seven sites is appropriate. Chronic migraines are defined as those occurring more frequently than 15
days per month with symptoms lasting at least 4 hours per episode. The patient in this question
qualifies for this diagnosis and should benefit from Botox therapy.
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