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Facial Rejuvenation: Application and Safety of Neurotoxins

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Introduction

Advances in type A neurotoxins for facial rejuvenation was a hot topic at the American Society of Plastic Surgeons (ASPS) 2008 Annual Meeting, held October 31-November 5 in Chicago, Illinois. Neurotoxins have become the cornerstone of facial rejuvenation; currently, several new formulations are in development.

Botulinum toxin, derived from the anaerobic bacterium Clostridium botulinum, has been used for nearly 2 decades to treat a variety of medical conditions. Soon after its introduction as a treatment to selectively weaken muscles in and around the eyes, Carruthers and Tromovich recognized that patients treated for blepharospasm also enjoyed aesthetic improvements in upper facial rhytides.[1] This finding led to US Food and Drug Administration (FDA) approval in 2002 of a botulinum toxin type A (BTA) formulation as a neuromodulator for the treatment of moderate-to-severe glabellar rhytides. Since then, BTA has quickly become an integral component of facial/aesthetic rejuvenation. In fact, by 2005, both the ASPS and the American Academy of Facial Plastic and Reconstructive Surgery reported BTA injection to be the most commonly performed cosmetic procedure -- vs all other surgical and nonsurgical procedures -- by their respective members.

The cosmetic success of BTA has been attributed to its ability to produce a natural look without blunting facial expression of emotions as well as its nominal migration from the site of injection to other tissues, minimizing any affinity to cause unwanted muscle weakening or systemic side effects.

Types of Neurotoxins

Botulinum neurotoxin comprises 7 distinct serotypes (A, B, C1, D, E, F, and G), but only serotypes A and B have demonstrated clinical use.[2] These serotypes have similar molecular structure and mechanism of action, but there are notable differences as well. Different formulations of the same serotype have different properties (eg, distribution and spread patterns and dose-response curves). This variation is due to the bacterial strains from which the formulations are derived as well as to preparation techniques, which can influence clinical activity.[3]

Currently, one formulation of botulinum toxin is approved in the United States for cosmetic purposes: BOTOX® Cosmetic (Allergan; Irvine, California). Numerous other botulinum toxin formulations (BTA and BTB) are available worldwide.[3,4] BTA represents the majority of the formulations. There are far more similarities than differences between the BTA formulations: All have the same mode of action (cleavage of synaptosomal associated protein with a molecular mass of 25 kD, or SNAP-25); all are formulated as powders dissolved in solution for injection; and all are reconstituted in 0.9% NaCl solution.[5] However, the molecular weight of the active substance varies from 150 kD to 900 kD, and the relative dose in units ranges from 1:1 to 1:2-1:4.

Proper injection of botulinum toxin induces temporary relaxation, weakening, or paralysis of the injected muscles, resulting in a reduction (or temporary elimination) in the lines and furrows caused by dynamic muscular activity.[2] In addition to their utility in cosmetic enhancement, BTA injections have been approved for a wide range of therapeutic uses, including blepharospasm, cervical dystonia, hyperhidrosis, and strabismus.

Currently, BTB (Myobloc®; Solstice Neurosciences; Malvern, Pennsylvania) is indicated only for the treatment of patients with cervical dystonia. It appears to have a faster onset (yet shorter duration) of action than BTA and may be associated with greater pain during injection.[4] Numerous unlicensed and counterfeit products currently inundate the marketplace. It is imperative that clinicians use only branded products approved for use in their country and purchased from reputable pharmaceutical sources.[2]

New formulations of type A neurotoxins in development was a hot-topic issue at ASPS 2008.[6] Reloxin® (Medicis; Scottsdale, Arizona), an injectable, shown good early safety data (approximately 2% eyelid ptosis). PurTox® (Mentor; Santa Barbara, California), another injectable, also has shown good efficacy and safety data. A topical formulation was also discussed; it has shown positive data in one study for aesthetic application. These new formulations will provide more options for patients and clinicians.

Measuring Activity

Activity of botulinum toxin is measured in units of LD50 (lethal dose in 50% of a population of mice). Of note is the absence of an international reference standard for botulinum toxin LD50.[2] The majority of research has been performed using the type A toxin, and important differences between different formulations suggest that information about dosing of one product cannot be used interchangeably with the other.[4] Even at doses that produce comparable clinical efficacy (specifically degree of muscle weakening), differences exist between formulations; these can have an impact on duration of effect, tolerability, adverse-event profile, and cost.[2]

Safety of Neurotoxins

BTA has been used safely in a wide range of facial areas, including (but not limited to) the upper face (glabellar complex, horizontal forehead rhytides and crow's feet), mid-face region (lower eyelid, widening of the palpebral aperture, bunny lines, nasal flare, nasolabial folds, perioral rhytides), lower face (mouth frown and melomental fold, chin, deep smile lines, and masseteric hypertrophy), and neck (platysma and horizontal lines).[7] It has no known long-term adverse events, even after nearly 20 years of use.

Nevertheless, adverse effects or events may arise, most often from improper placement of the product, resulting in unintended muscle weakening. Most adverse events are transient, minor, and reversible, often resolving in a short amount of time and without requiring additional interventions.[8] The most common adverse effects include injection-site pain as well as bruising, which can be minimized by having the patient avoid aspirin, nonsteroidal anti-inflammatory drugs, and high-dose vitamin E for 10 days prior to the procedure. Applying direct pressure and a cold compress to the injection site can also minimize ecchymosis.[8] Headache, respiratory infection, and blepharoptosis are the most commonly reported adverse events associated with facial BTA injections.[2]

There have been reports of primary (immediate absence of effect) and secondary (lack of effect with repeated use, often owing to antibody development) resistance to the therapeutic use of botulinum toxin.[2] Although repeated injections can prolong the duration of the aesthetic effect, anecdotal evidence suggests that it may also induce resistance.

Optimizing Patient Outcomes

Appropriate patient selection is one of the most important considerations prior to recommending treatment with botulinum toxin. Treatment effects can persist for up to 3-6 months, depending upon the area being addressed. This is particularly important when neuromodulators are to be injected into the lower vs upper face.[9] Treatment effects in the lip area can persist for up to 10-12 weeks. Consequently, it has been recommended that botulinum toxin should be avoided in the perioral lip line for persons in whom disruption of oral competency could compromise their lives or livelihoods, such as singers and scuba divers.[4] Treatment to the neck (platysmal bands) requires very careful patient selection, although there is some disagreement about who is the ideal candidate. Risks associated with these injections include dysphagia, dysphonia, and neck weakness.

Neurotoxin type A is most commonly injected in the upper face into the procerus muscle and corrugator.[9] Injections well above the midpupillary brow should be avoided. BTA can be injected into the lateral orbicularis oculi to treat crow's feet and to reshape the eyebrow. Modest amounts can be (uniformly) injected into the forehead region.[9] Although botulinum toxin is predominantly used for upper facial rhytides and dynamic line applications, including glabellar lines, crow's feet, and horizontal forehead lines, it may also be used to enhance the lower face and neck regions.[10]

The use of botulinum toxin in the perioral lip line to correct lip rhytides is well tolerated by most patients.[10] However, the lower face is less forgiving than the upper face, necessitating the use of proper technique and dosing. To optimize results, clinicians should have a good understanding of the functional anatomy of the lower face, including knowledge regarding site- and patient-specific dosing. Good injection technique, including precise placement, is mandatory. It is recommended that lower doses be used initially to avoid complications.[10]

Finally, it is imperative that clinicians ensure that prospective patients have realistic expectations regarding the procedure and that patients are counseled in regard to both potential benefits as well as possible adverse effects. Risks associated with injections in the nasolabial fold include changes to facial animation and smile patterns. Consequently, it is particularly important to carefully select patients who are most likely to benefit from these injections; specifically, the procedure is ideal for patients with "canine" smile patterns vs those with "Mona Lisa" smiles.[11] Botulinum toxin can be used to correct a dimpled chin, with effects persisting for 3-6 months, but known risks can include drooling, a drooping mouth, and even oral incompetence.

Conclusions

A patient's aesthetic goals, as well as target area, gender, muscle mass, skin thickness, and individual anatomical variations, should all be considered prior to recommending botulinum toxin injection. Injection technique and placement are of paramount importance.

This activity is supported by an independent educational grant from Medicis.

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