Overview of Botulinum Toxins for Aesthetic Uses

Botulinum toxin type A (BTA) can be used for facial aesthetics. The 3 currently available BTA types include onabotulinumtoxinA (Botox; Botox Cosmetic, Allergan, Irvine, CA), abobotulinumtoxinA (Dysport; Ipsen, Ltd, Berkshire, UK), and incobotulinumtoxinA (Xeomin; Merz Pharmaceuticals, Frankfurt, Germany). The mechanism of action and clinical uses for treatment of dynamic lines of the forehead, brow, glabella, lateral orbit, nose, and lips are presented, as well as treatment of masseter hypertrophy, platysmal bands, and improvements of the perioral region. Specific BTA injection sites and suggested doses are presented.

Key points

  • Botulinum type A injections are an integral part of facial aesthetics.

  • OnabotulinumtoxinA (Botox Cosmetic), abobotulinumtoxinA (Dysport), and incobotulinumtoxinA (Xeomin) can all be used with similar results and effectiveness.

  • Individual patient assessment, injection site selection, dosing, and follow-up is critical for optimal results.

Introduction

The clinical use of botulinum toxin to selectively depress skeletal muscle activity in treating facial spasmodic disorders began in the 1970s. Its aesthetic uses were discovered incidentally but have dramatically changed the landscape of facial rejuvenation. Since US Food and Drug Administration (FDA) approval in 1992, injection of botulinum toxin has become the most popular cosmetic procedure in the United States, with more than 6.6 million injections of botulinum toxin type A (BTA) in 2014 alone. Furthermore, there are increasing off-label uses to treat a variety of ophthalmologic, urologic, gastrointestinal, hypersecretory, and pain disorders because of its versatility and favorable safety profile. Here, the current uses of BTA for aesthetic rejuvenation of the face are reviewed.

History

The first clinical uses of BTA were reported in the early 1970s to selectively weaken the extraocular muscles as a treatment for strabismus. The success of BTA as a selective depressor of skeletal muscle activity led to similar applications in treating blepharospasm and hemifacial spasm. In 1989, the FDA approved the use of onabotulinum toxin A (Botox) for the treatment of facial spasmodic disorders. In that same year, Clark and Berris reported the use of Botox as a treatment for facial asymmetry resulting from iatrogenic facial nerve damage during rhytidectomy. This use is widely considered the first aesthetic use of botulinum neurotoxin.

In 1987, ophthalmologist Jean Carruthers, discovered the effect of botulinum toxin on facial rhytides when a patient she treated for blepharospasm requested to have her forehead injected because of the improvement she observed in her periorbital region. Fortuitously, her husband, dermatologist Alastair Carruthers, had several patients asking him for ways to improve facial rhytides. The following day, Jean injected the glabellar frown lines of her receptionist—a willing participant—and the aesthetic use of BTA was born. These preliminary successes led to further experimentation culminating in a report that set the stage for the development of Botox Cosmetic and several other products marketed specifically for aesthetic indications.

Over the last 42 years, the clinical indications for BTA have increased, with various FDA-approved and off-label uses in urology, gastroenterology, ophthalmology, neurology, and several other fields. This article focuses on the aesthetic uses of injectable BTA and reviews the most common treatment sites for improvement of facial rhytides. Currently, BTA is approved for the treatment of glabellar frown lines and crow’s feet; all other facial aesthetic uses remain off-label.

Introduction

The clinical use of botulinum toxin to selectively depress skeletal muscle activity in treating facial spasmodic disorders began in the 1970s. Its aesthetic uses were discovered incidentally but have dramatically changed the landscape of facial rejuvenation. Since US Food and Drug Administration (FDA) approval in 1992, injection of botulinum toxin has become the most popular cosmetic procedure in the United States, with more than 6.6 million injections of botulinum toxin type A (BTA) in 2014 alone. Furthermore, there are increasing off-label uses to treat a variety of ophthalmologic, urologic, gastrointestinal, hypersecretory, and pain disorders because of its versatility and favorable safety profile. Here, the current uses of BTA for aesthetic rejuvenation of the face are reviewed.

History

The first clinical uses of BTA were reported in the early 1970s to selectively weaken the extraocular muscles as a treatment for strabismus. The success of BTA as a selective depressor of skeletal muscle activity led to similar applications in treating blepharospasm and hemifacial spasm. In 1989, the FDA approved the use of onabotulinum toxin A (Botox) for the treatment of facial spasmodic disorders. In that same year, Clark and Berris reported the use of Botox as a treatment for facial asymmetry resulting from iatrogenic facial nerve damage during rhytidectomy. This use is widely considered the first aesthetic use of botulinum neurotoxin.

In 1987, ophthalmologist Jean Carruthers, discovered the effect of botulinum toxin on facial rhytides when a patient she treated for blepharospasm requested to have her forehead injected because of the improvement she observed in her periorbital region. Fortuitously, her husband, dermatologist Alastair Carruthers, had several patients asking him for ways to improve facial rhytides. The following day, Jean injected the glabellar frown lines of her receptionist—a willing participant—and the aesthetic use of BTA was born. These preliminary successes led to further experimentation culminating in a report that set the stage for the development of Botox Cosmetic and several other products marketed specifically for aesthetic indications.

Over the last 42 years, the clinical indications for BTA have increased, with various FDA-approved and off-label uses in urology, gastroenterology, ophthalmology, neurology, and several other fields. This article focuses on the aesthetic uses of injectable BTA and reviews the most common treatment sites for improvement of facial rhytides. Currently, BTA is approved for the treatment of glabellar frown lines and crow’s feet; all other facial aesthetic uses remain off-label.

Pharmacology

Botulinum neurotoxins are produced by several strains of bacteria from the Clostridium genus, principally Clostridium botulinum. There are 7 known serotypes of botulinum neurotoxin (A–G), of which, types A (BTA) and B (BTB) are commercially produced for clinical use. Botulinum toxin is synthesized as a 150-kDa protein that undergoes posttranslational modification into a 100-kDa heavy chain and a 50-kDa light chain, linked by a disulfide bridge. The heavy chain binds to the presynaptic neurons at the neuromuscular junction and facilitates entry of the light chain into the cell cytoplasm. There, each serotype’s light chain targets a component of the soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, which it cleaves to and thereby inactivates. The components of the SNARE complex are all essential for microvesicle fusion and release of stored neurotransmitter. BTA targets synaptosomal-associated protein, 25 kDa BTB target synaptobrevin, also known as vesicle-associated membrane protein .

By inhibiting the release of stored neurotransmitter at the neuromuscular junction, botulinum neurotoxins cause a flaccid paralysis of target muscles. Paralysis and a near-complete loss of motor end plate potentials occur within a few hours of botulinum neurotoxin injection ; however, the clinical effect may not become evident for up to 1 week after administration. The latency to clinical effect may be caused by spontaneous, non–vesicle-associated release of acetylcholine at the neuromuscular junction. The neuromuscular blockade from botulinum toxin administration is irreversible. Axonal sprouting and the formation of new neuromuscular junctions are responsible for the dissipation of clinical effects over time.

Product composition/available products

Pure botulinum toxin is synthesized as a 150-kDa protein that complexes with varying amounts of nontoxic proteins and hemagglutinin. Each commercially available product has its toxin complexed with a varied quantity of unique proteins. Doses of each product are measured in units, with one unit corresponding to the median lethal intraperitoneal dose (LD 50 ) in mice. However, the method for performing this assay is specific to each manufacturer, which precludes comparison among similar products. Approximate, commonly accepted dosing equivalencies have been determined clinically and are discussed below.

Currently, there are 4 commonly used preparations of botulinum toxin: onabotulinumtoxinA (Botox; Botox Cosmetic, Allergan, Irvine, CA), abobotulinumtoxinA (Dysport; Ipsen, Ltd, Berkshire, UK), incobotulinumtoxinA (Xeomin; Merz Pharmaceuticals, Frankfurt, Germany), and rimabotulinumtoxinB (Myobloc; Solstice Neurosciences, San Francisco, CA). Although the clinical effect of each is similar, they differ in their chemical structure, associated proteins, manufacturing and purification processes, mechanism of action, and clinical efficacy. Because of these differences, there are no established dosing equivalencies between products, although some general clinical guidelines have emerged. Most experienced BTA injectors use the following BTA dose conversions for aesthetic facial uses: 1 unit of onabotulinumtoxinA = 1 unit of incobotulinumtoxinA = 3 units of abobotulinumtoxinA. There is not enough experience to convert BTA doses to rimabotulinumtoxinB doses.

This article provides treatment guidelines using onabotulinumtoxinA as the reference standard, as most of the available literature focuses on clinical recommendations with this product.

Storage and reconstitution

Myobloc (rimabotulinumtoxinB) is available in reconstituted form, and does not require additional diluent before use. BTA is supplied in powder form and must be reconstituted before use. The manufacturer of each BTA preparation recommends reconstitution exclusively with preservative-free 0.9% sodium chloride solution ; however, many clinicians have switched to sodium chloride solution preserved with benzalkonium alcohol to reduce patient discomfort. Several clinical trials have found equivalent success and reduced patient discomfort, attributed to the more favorable pH balance of the preserved saline.

Once reconstituted, BTA is commonly considered fragile, despite evidence to the contrary. Several studies found that vigorous agitation and storage for up to 6 weeks has no effect on the clinical outcomes of reconstituted BTA. One study even found no change in potency of onabotulinumtoxinA after 6 weeks of continuous agitation.

Duration of effect

The typical duration of botulinum toxin effect is 3 to 4 months, depending on several factors, including dose, concentration, injection technique, patient immune response, and others. In the preapproval studies for each of the commercially available products, the glabellar region was treated and the number of patients maintaining a response was recorded monthly. Three months after treatment, the percentages of patients maintaining a clinical response were approximately 50% for Botox, 40% to 50% for Dysport, and 15% to 25% for Xeomin. The ranges presented for Dysport and Xeomin were owing to differences in clinician versus patient assessment of response. Importantly, the Xeomin study defined a response as at least a 2-point clinical improvement, whereas the Dysport study defined a response as at least a 1-point clinical improvement. Taking this into consideration, Xeomin may not be inferior to Botox or Dysport. Regardless of the product used, fewer than 20% of patients maintained a response beyond 4 months.

It is possible that increased doses at each injection site may prolong the clinical duration and numbers of responders, but maximum doses, after which no clinical benefit is achieved, have not yet been established.

Botulinum toxin injection in the face

The aesthetic uses of injectable botulinum toxins in the face are extensive, and patient satisfaction with treatment has been very high, with significant improvement in patient-reported outcomes. Selective weakening of the muscles of facial expression is found to improve the appearance of the overlying dynamic rhytides caused by muscle activity. Over time, the goals of treatment have shifted from a completely paralyzed, “frozen” look to a softer, more expressive dampening of muscular activity. Weakening the underlying facial musculature can significantly improve dynamic facial rhytides but cannot ameliorate static rhytides and cannot substitute for other skin resurfacing procedures. All patients should be counseled regarding the anticipated effects and the limitations of botulinum toxin injection.

General Injection Guidelines

Patients should discontinue any medications or supplements that interfere with hemostasis 10 to 14 days before the procedure to minimize bruising. Before injecting, ice packs or topical anesthetic can be used to minimize patient discomfort. The smallest gauge needle available should be used for injection, as smaller needles significantly reduce pain and limit bruising.

The concentration of BTA can be varied to limit or increase the diffusion when treating localized or broad areas, respectively. Electromyogram studies have found that injected BTA can spread up to 3 cm from the site of injection. Therefore, care must be taken and concentration considered when attempting highly selective facial muscle weakening.

With regard to dose administration, clinical practice varies widely, and we can only provide a framework from which to approach the patient presenting for botulinum toxin treatment. Clinical consensus recommendations for the use of Botox Cosmetic and Dysport have been published. Owing to its relatively recent market approval, Xeomin does not currently have published recommendations, but dose administration is found to be interchangeable with Botox Cosmetic.

Treatment of the upper face

Compared with the middle and lower thirds, the upper face experiences less volume loss over time, and many of the telltale signs of aging are related to the development of rhytides. As a result, treatment with botulinum toxins in this area generally yields good results.

Transverse Forehead Rhytides

Although considered an off-label use of BTA, treatment of transverse forehead rhytides can provide excellent results and high levels of satisfaction in properly selected patients. Each individual must be assessed to determine the relative degree of static versus dynamic forehead rhytides. Although treatment with botulinum neurotoxin can produce significant smoothing of dynamic transverse rhytides, static rhytides may require dermal fillers or a skin resurfacing procedure for marked improvement. Furthermore, the anatomy of each patient’s forehead region, with particular attention to the relative muscle strength, muscle orientation, brow height, and overall forehead anatomy should be carefully considered in the treatment plan to maximize outcomes and patient satisfaction.

Anatomy

Contraction of the frontalis muscle elevates the brown and results in dynamic transverse forehead rhytides. The frontalis is the principal elevator of the brow, originating in the galea aponeurotica and inserting into the subcutaneous tissues and deep dermis of the skin overlying the superciliary arch. Although commonly depicted as 2 distinct muscle bellies, anatomic variation is common, with many showing significant medial overlapping and structural difference between the medial and lateral aspects.

Treatment recommendations

The goals of treating the forehead are to soften the appearance of dynamic rhytides without giving an unnatural, unexpressive appearance and avoiding iatrogenic brow ptosis. The efficacy and safety of BTA in treating this area of the face have been well documented in the literature.

Treatment of the forehead is highly variable because of the anatomic variability of the frontalis muscle and characteristics of each patient’s animation patterns. Moreover, some patients exhibit several fine transverse rhytides, where others have only 1 or 2 deep transverse creases. Before injection, any brow asymmetry is noted and discussed with the patient, as this may only come to their attention after treatment. Patients are asked to forcefully elevate their brow to assess the strength of frontalis contraction and the location of dynamic rhytides. The frontalis is typically injected in 4 to 6 sites, with care taken to stay at least 1 to 2 cm above the supraorbital rim to avoid brow or eyelid ptosis. The authors prefer to inject each belly of the frontalis in a V-shaped pattern ( Fig. 1 ); however, this varies based on each patient’s muscular anatomy. In women, 10 to 20 units are spread among the predetermined number of injection sites, with lower doses used in toxin-naive patients. As with most treatment areas, men typically require a higher dose (16–24 units) to achieve the same effect because of larger, stronger muscles.

Fig. 1
Typical injection sites in frontalis muscle for forehead lines. May range from 4 to 10 injections points (2 U of Botox or Xeomin or 6 U of Dysport per injection point).

Glabellar Region

Treatment of vertical glabellar rhytides was the first FDA-approved aesthetic use of BTA in 2002 and remains the most frequent indication for its use. BTA has become widely used in this region with many published experiences. Several randomized, placebo-controlled trials showed efficacy of BTA in treating this area. Moreover, treatment of glabellar rhytides with botulinum toxin type A can improve quality of life and may reduce negative moods. A recent multicenter study in Europe found high levels of patient satisfaction and improved perception of self up to 4 months after injection of the glabellar complex with botulinum neurotoxin type A.

Anatomy

The glabellar complex depresses the medial brow and consists of the paired corrugator supercilii muscles and the central procerus muscle. The action of the medial orbicularis is also to depress the brow, but its contribution is weak by comparison. The corrugators originate on the frontal bone medially, where their fibers can interdigitate with those of the medial preorbital orbicularis oculi, and insert into the dermis of the forehead, just above the eyebrow at the midpupillary line. Their primary action is to medialize and depress the medial brow. Hyperactivity contributes to vertical glabellar rhytides.

The procerus muscle is a vertically oriented, midline structure, originating from the soft tissues overlying the nasal bones and inserting into the skin of the lower central forehead, superior to the nasal root. Contraction of this muscle produces transverse horizontal rhytides at the nasal root.

Treatment recommendations

Muscle size, strength, and location can be estimated by asking the patient to frown maximally. Any asymmetry in muscle strength or contraction should be carefully evaluated before injection. The authors typically inject in a 5-point V pattern, with 2 injection sites in each corrugator and 1 in the central procerus ( Fig. 2 ). Injections should be kept a minimum of 1 cm above the orbital rim to avoid diffusion into the levator palpebrae superioris muscle, causing iatrogenic ptosis. The patient is asked to frown to confirm the location of each muscle belly just before injection. In patients with mild muscle activity, 3 injection points may be used instead.

Fig. 2
Typical injection sites in corrugator muscle for glabellar lines. May range from 3 to 5 injection points (2–5 U of Botox or Xeomin or 6–15 U of Dysport per point).

The deeper location of the brow depressors relative to the brow elevators has led to the belief that deep injection of botulinum toxins can selectively target brow depressors and, thus, result in brow elevation. This technique has been recommended for chemical brow lifting and correction of brow asymmetries but has not been found to be effective because of diffusion of the toxin between muscle layers.

The recommended total treatment dose of Botox Cosmetic in this region is 20 U divided among 5 injection sites; however, clinical practice varies widely in terms of total dose and number of injection sites. As with other areas, male patients have been found to require higher doses of botulinum toxin to effectively treat the glabellar region, presumably because of relative increase in muscle mass. One study found a dose-dependent improvement in results when men were treated with higher doses (20 vs 40 units) of botulinum toxin for treatment of the glabellar region.

Brow Lift

The lateral brow lift is most often performed as a component of treating the rest of the face. When combined with treatment of the glabellar complex and frontalis, an aesthetically pleasing contour of the brow can be achieved. The lateral brow lift can also be used to camouflage an overelevated medial brow, which can occur after chemically weakening the glabellar complex.

Injection in the medial brow depressors can modestly elevate the medial and central brow, but also has an elevating effect on the lateral brow. In fact, glabellar complex treatment alone has also been found to lift the lateral brow by as much or more than the medial brow. It is theorized that diffusion of toxin from the glabellar complex injections weakens the inferomedial frontalis fibers, resulting in increased tone in the lateral frontalis fibers.

Anatomy

As described above, the brow is a complex structure, and its position is determined by the relative balance between the forces of brow elevation and depression. Using BTA to selectively weaken the depressors of the brow is the foundation for the so-called chemical brow lift. At the lateral orbital rim, the vertical fibers of the lateral component of the orbicularis oculi muscle act as depressors of the lateral brow.

Treatment recommendations

Chemically weakening the lateral fibers of the preorbital orbicularis oculi can result in lateral brow elevation by 2 to 4 mm. Typical starting doses are from 2 to 5 U of Botox Cosmetic injected intradermally, just beneath the tail of the lateral brow ( Fig. 3 ). If the lateral brow is inadvertently overelevated, the upward pull of the lateral frontalis can later be weakened with additional botulinum toxin to balance brow elevation and depression forces.

Fig. 3
Typical injection sites in the superior portion of orbicularis oculi muscle for lateral brow elevation (2–4 U of Botox or Xeomin or 6–12 U of Dysport per point).

Lateral Orbital Region (Crow’s Feet)

Among the earliest signs of aging, lateral canthal lines, commonly referred to as crow’s feet , are the result of hyperkinetic orbicularis oculi muscles. BTA to soften the appearance of these rhytides (crow’s feet), has been well documented.

Anatomy

The orbicularis oculi muscle is a sphincter muscle that encircles the orbit and allows forceful closure of the eye. It also contributes minimally to medial and lateral brow depression. Traditionally, this muscle is considered in 3 parts: pretarsal, preseptal, and preorbital. The preorbital division is the most peripherally located and is the target of botulinum toxin treatment. Because of the important function of the orbicularis oculi, it is important to avoid such a profound paresis that eye closure is impaired.

Treatment recommendations

It is important to discuss expectations with patients, as dynamic rhytides are just one element of a multifactorial periorbital aging process and cannot single handedly restore a youthful appearance; however, in properly selected patients, treatment of the lateral canthal region can be very satisfying. Patients with excessive skin damage and static rhytides should be counseled regarding resurfacing procedures in conjunction with neurotoxin treatment.

Crow’s feet are typically treated with 3 equal injections of 2 to 4 U of Botox Cosmetic at each site ( Fig. 4 ). These injections should be placed superficially (intradermal), producing a visible bleb beneath the skin. The middle injection is placed in line with the lateral canthus, and the remaining 2 injections are placed 8 to 10 mm above and below this point. Total starting doses should range between 8 to 16 U and 12 to 16 U of Botox Cosmetic per side in women and men, respectively.

Nov 21, 2017 | Posted by in Dental Materials | Comments Off on Overview of Botulinum Toxins for Aesthetic Uses
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