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Summary

Introduction

Botulinum toxin type A (BTX-A) has been used in humans for 30 years and carries an impressive record of efficacy and safety, particularly when used in small doses for cosmetic enhancement. No longer confined to the treatment of simple rhytides and folds, adept clinicians can now choose from an array of formulations for increasingly sophisticated indications. Modern BTX-A therapy comprises facial sculpting and shaping, alone or in combination with filling agents and resurfacing modalities, and is an important adjunct to surgical procedures.

Content

Clinical Use of Botulinum Toxin Type A

Well over 100 years ago, Clostridium botulinum was identified as a cause of food-borne illness. Over the next 50-odd years, seven immunologically distinct serotypes were identified and one, type A, was purified and isolated in crystalline form for possible application in humans by Edward Schantz in 1947 (1, 2). Decades later, Dr. Alan Scott published his landmark data demonstrating the toxin's efficacy and safety for the treatment of strabismus (3). In 1987, Carruthers and Carruthers noticed a concomitant improvement in glabellar rhytides in patients who received BTX-A injections in the brow for blepharospasm (4), which paved the way for further research with this innovative, noninvasive form of facial rejuvenation (5, 6).

Since those early studies, the United States Food and Drug Administration (FDA) has approved BTX-A for the treatment of strabismus, hemifacial spasm, blepharospasm, cervical dystonia, hyperhidrosis and mild to moderate glabellar rhytides, and it has been approved for various uses by roughly 70 governing bodies worldwide. BTX-A has enjoyed great success in treating a variety of hyperkinetic facial lines, including crow's feet, horizontal forehead lines, melolabial folds and glabellar rhytides, in the upper face, as well as folds and lines in the lower face and neck, with a high level of efficacy and patient satisfaction (7-11).

Formulations

The majority of clinical experience rests with the original formulation of BTX-A, BOTOX^® Cosmetic (Vistabel^®/Vistabex^®; Allergan, Inc., Irvine, California, USA), which has been approved for 20 indications in more than 75 countries (12). Dysport^® is approved in over 65 countries for therapeutic indications (Ipsen Ltd., United Kingdom/Medicis, Scottsdale, Arizona, USA) and received FDA approval for cosmetic applications in June 2009 and is approved in 15 European countries as Azzalure^® (Galderma, France). Dysport^® differs from BOTOX^® in purification procedures (13) and dosing, with a dose ratio of 3: 1 or less (14, 15). Some evidence suggests that Dysport^® is associated with greater diffusion and migration, which could lead to increased side effects or complications (16-18). In an open-label assessment of 1,200 patients receiving up to five treatments in the glabellar area over 13 months, Moy et al. found probable or possible treatment-related adverse events (AEs) in 36% of patients (19). Forty-five patients experienced 55 incidences of ptosis; the rate of ptosis decreased during successive cycles (from 2.4 in cycle 1 to 0.6% in cycle 5). An interim analysis of 768 patients from phase III clinical trials who received up to six treatments of Reloxin^® found that multiple treatments over 17 months were well tolerated, with 74 patients reporting at least one probable or possible treatment-related AE and 10 patients (1%) who experienced ptosis (20).

Two other formulations are in development in the USA for cosmetic indications. PurTox^® (Mentor Corporation, Santa Barbara, California, USA) is an uncomplexed type A neurotoxin in phase III testing for glabellar rhytides, and in various stages of development for therapeutic indications. Xeomin^® (NT-201; Merz Pharmaceuticals, Frankfurt, Germany) is in phase III testing in North America but has already received approval for the treatment of blepharospasm and cervical dystonia in some European countries, Mexico and Argentina, and for glabellar rhytides in Argentina (21). In terms of potency, Xeomin^® appears to exhibit a 1:1 dose ratio when compared with BOTOX^® (21), and therapeutic clinical studies have found similar levels of efficacy and safety (22, 23). Xeomin^® is free of complexing proteins, which some believe may result in purer formulations with greater efficacy and a reduced risk of sensitization and antibody formation (23).

Other products in development globally include Chinese BTX-A (CBTX-A; marketed as Prosigne^® in Brazil; Lanzhou Institute of Biological Products, China), which contains bovine gelatin protein and appears to be slightly less effective than BOTOX^® (24). CBTX-A is the only approved BTX-A in China and must not be confused with CNBTX-A (Nanfeng Medical Science and Technology Development Co., Ltd), a product sold on the Internet but neither licensed nor approved in any country. CNBTX-A contains significantly higher levels of botulinum toxin, which may constitute a severe health risk for patients (25).

Advanced Applications

After years of clinical success and consistent safety in the upper face, the use of botulinum toxin has expanded and evolved to include increasingly complicated indications. Indeed, the focus has shifted from the treatment of individual dynamic rhytides to shaping, contouring and sculpting, alone or in combination with other cosmetic procedures, to enhance the aesthetic appearance of the face.

Shaping and sculpting

Over the years, clinicians began to notice that BTX-A has the ability to mould and sculpt the face into more pleasing contours. In the upper face, injections into the glabella result in central, medial and lateral brow elevation (26-28), due to partial inactivation and increased resting tone of the frontalis (28). Similarly, small doses of BTX-A injected into the lower pretarsal orbicularis open the palpebral aperture at rest and at smile in individuals who desire a wider, rounder eye (29, 30). In the lower face, reduction in masseter thickness and bulk by up to 50% following botulinum toxin injections has been well documented in Asian populations (31-34), and more recent research indicates similar benefits in non-Asian patients (35, 36). Liew and Dart investigated the use of botulinum toxin for aesthetic reshaping of the mandibular angle in a Western population compared with an East Asian control group and found that smaller doses of BTX-A were required to achieve aesthetic improvement in the study population compared with doses required for the control group (25-30 U vs. 40 U), and the effects lasted for 9-12 months (35). Moreover, Western patients experienced an additional 6- to 7-month improvement in function attributed to bruxism, which has been previously reported in the literature (37).

Adjuvant botulinum toxin type A

BTX-A is used increasingly in combination with other cosmetic procedures to prolong and enhance aesthetic results. The combination of BTX-A and soft-tissue augmentation is a highly synergistic approach used to achieve more effective, longer lasting results by reducing the dynamic component of the target rhytide, especially when used in the glabella, brow, forehead, nasojugal folds, zygomatic and perioral regions, and in the neck (38-41). While mild to moderate glabellar lines will respond to either BTX-A or fillers, patients who have very deep vertical glabellar grooves may continue to have these lines at rest even after chemodenervation of the underlying muscles.  In these cases, BTX-A will address the muscular cause of the rhytides, while dermal support with tissue augmentation will alleviate the residual dermal grooving. Patel et al. found improved clinical effects of longer duration and greater patient satisfaction in those who received BTX-A and collagen for the treatment of glabellar rhytides compared to patients who received either modality alone (42). Indeed, a number of studies have clearly shown superior efficacy associated with combination therapy compared to fillers alone in patients with deep resting rhytides (40, 43, 44). Older subjects who have deeper static lines who receive combination treatment with BTX-A and dermal fillers achieve a better cosmetic result.  Similarly, the benefits of laser resurfacing can be optimized by pretreatment with BTX-A, leading to superior and longer-lasting aesthetic outcomes (39, 44-46). Without concurrent BTX-A use, dynamic rhytides commonly recur after resurfacing in the lower eyelid, lateral canthus and perioral regions within 6-12 months as a consequence of continued facial movement and expression (47). Similarly, studies of intense pulsed light (IPL), a nonablative broadband light source, show that combination therapy with BTX-A increases the overall aesthetic benefit and improves skin texture and the appearance of telangiectasias (48, 49). Indeed, IPL alone may not always be effective for the treatment of rhytides (50).

Chemodenervation with BTX-A is now a key adjunct to several aesthetic surgery interventions; surgeons now realize that although surgery may remove skin redundancy, they do not address the activity of mimetic muscles, which over time can reverse the correction. BTX-A is used in conjunction with endoscopic brow lifts (either before or after surgery to stabilize the brows), upper and lower eyelid blepharoplasty and facelift. In general, adjunctive BTX-A serves to increase longevity of the procedure and aids in wound healing by reducing repetitive muscular actions that can hasten dehiscence (39, 44). Multiple trials have shown the benefit of BTX-A injections to facilitate wound healing; BTX-A minimizes the repetitive tension on the wound edge and allows for the use of finer sutures, resulting in a cosmetically superior scar (51-53).

Clinical Safety Profile

Thirty years of clinical experience has firmly established the remarkable safety profile of cosmetic BTX-A. Two phase III, randomized, double-blind, placebo-controlled trials of 405 patients demonstrating similar rates of AEs for both placebo and treatment groups established the safety of cosmetic BTX-A and led to its FDA approval in 2002 (54). Three years later, Coté et al. reviewed AE reports submitted to the FDA for both therapeutic and cosmetic BTX-A (55). Of 1,031 reports, only 36 were classified as "serious", and included headaches, facial paralysis, muscle weakness, dysphagia, flu-like symptoms and allergic reactions. Serious AEs were most commonly associated with higher dose treatment for therapeutic indications. Moreover, 13 of 36 patients had underlying disease that may have contributed to the reported AE. Nonserious AEs included lack of intended cosmetic effect (63%), injection-site reaction (19%), ptosis (11%), muscle weakness (5%) and headache (5%). Similarly, Zagui et al. analyzed eight randomized trials and 13 case reports of cosmetic botulinum toxin up to September 2007 and discovered mostly mild AEs - including headache, local reaction, infection and eyelid ptosis - in 18% of 1,003 patients (56).

Most long-term safety data in the literature pertain to BTX-A administered for therapeutic purposes. An analysis of 235 patients who received BTX-A injections for movement disorders over a 10-year period found mostly minor AEs in 27% of patients (57). Likewise, a review of 36 randomized trials and 1,425 patients who received BTX-A for therapeutic indications revealed no serious AEs (58). Carruthers and Carruthers retrospectively analyzed 50 patients who received 853 upper-face treatment sessions over an average of 5.95 years and found only nine reported AEs, all transient and mild to moderate in severity, of which five were probably or definitely related to treatment (59).

Research suggests that the risk of side effects may diminish over time with multiple treatments. Defazio et al. found that the incidence of AEs fell from 37% during the first year of treatment to 12% in the 10th year in a multicenter study of 65 patients who received regular injections for hemifacial spasm over 10 years (60). In an analysis of 45 women who received continuous BTX-A injections for movement disorders for a mean duration of 15 years, 35.6 and 22.2% of patients reported AEs at first and last visits, respectively (61). Rzany et al. analyzed more than 4,000 treatments in 945 people injected in the upper face and found only mild or moderate side effects, such as bruising and eyelid drooping, and side effects decreased with repeated injections (62).

Injection-related complications

Botulinum toxin works through temporary chemodenervation of the muscle, resulting in localized reduction of muscular activity. Since smaller doses are less likely to cause problems than larger doses, a conservative approach is recommended for most patients. More concentrated doses allow for more accurate placement of BTX-A, less diffusion and greater duration of effect. Side effects are usually mild and transient; although rare, complications can occur but are usually associated with poor injection technique, overenthusiastic doses and/or inappropriate patient selection. Swelling or bruising at the injection site, mild headache and flu-like symptoms are the most common AEs reported (63).

Of the possible complications in the upper face (cocked eyebrow, diplopia, ectropion, asymmetrical smile, decreased strength of eye closure, dry eye and ptosis), brow and eyelid ptosis are the most troubling. Brow ptosis, due to diffusion of BTX-A into the frontalis, can persist for up to 3 months. Upper eyelid ptosis lasting from 2-12 weeks most commonly occurs when BTX-A injections into the glabella diffuse through the orbital septum, affecting the upper eyelid levator muscle. Other complications that have been reported in the upper face include cocked eyebrow, diplopia, ectropion, asymmetrical smile, decreased strength of eye closure and dry eye (64). In the lower face, complications are usually due to overenthusiastic use of large doses, and can include mouth incompetence, asymmetry, drooling, difficulties in speech and the inability to purse the lips (64). Injections too close to the mouth or directly into the mental fold or orbicularis oris are more likely to result in undesirable effects. In the neck, large doses of BTX-A can lead to difficulty swallowing and general weakness.

Immunogenicity

Total protein load seems to contribute to the risk of antibody formation, which occurs only rarely with current lots of BTX-A, and usually in conjunction with large doses associated with the therapeutic use of BTX-A (61, 65). Clinicians recommend injecting the lowest possible doses with the longest feasible intervals between treatments to reduce the risk (54). Lee describes an unusual case of a 20-year-old patient with masseteric hypertrophy who developed antibody-induced therapy failure (detected by indirect enzyme-linked immunosorbent and mouse protection assay) after the fourth injection series of 60 U per session (and treatment intervals of 4-5 months) (66).

Allergic reaction

Allergic reaction to BTX-A is rare but can be found in the literature. Reported reactions include serious or nonserious rashes (55, 67) and granulomas (68). Other allergic responses include a localized anaphylactic reaction in one leg (67), a case of anaphylaxis after injection of BTX-A and lidocaine for the treatment of chronic neck and back pain (69), and one patient who experienced severe respiratory failure after leg injections of 300 U BTX-A (70).

Safety: Cosmetic versus therapeutic botulinum toxin type A

On the whole, BTX-A - particularly when used for cosmetic purposes in small doses - is extremely safe, and examination of decades of research reveals no reports of long-term AEs or systemic effects associated with any cosmetic indication for BTX-A. However, doses used for therapeutic applications are much higher: hundreds of units, versus 20-50 U typically used in cosmetic procedures. This difference in dosing, along with general patient health, is critical when assessing the risk of BTX-A-related complications.

A large examination of 1,031 AE reports submitted to the FDA revealed 407 AEs associated with the therapeutic use of BTX-A (median dose, 100 U) (55). The reports included 28 deaths and other serious AEs, such as arrhythmia and myocardial infarction, but could not determine a causal relationship between the fatalities and BTX-A injections, especially since 26 patients who died had underlying cardiovascular diseases with an elevated risk of mortality. By contrast, no deaths or cardiovascular complications were associated with cosmetic doses.

In February 2008, national consumer advocacy group, Public Citizen, petitioned the FDA to warn the public about potential serious side effects associated with BTX-A treatment after reviewing FDA-submitted 658 AEs that included 180 cases of aspiration, dysphagia, and/or pneumonia, and 16 deaths, four of which occurred in young children (71).  None of the deaths were a result of cosmetic BTX-A. The subsequent safety review announced by the FDA (ongoing at publication) involves a small number of AEs and large doses in patients with juvenile cerebral palsy and other lower-limb spasticities (72). In April 2009, the FDA requested safety label changes - featuring black box warnings - and a risk evaluation and mitigation strategy (REMS) for all botulinum toxin products (types A and B) (73). The required REMS include a medication guide for consumers outlining the risks associated with treatment and a communication plan.

Safety: "Fake" or untested botulinum toxin type A

The safety of BTX-A has been established only for FDA-approved formulations. Some reports have circulated about deaths or paralysis occurring after cosmetic injections; all were eventually linked to inauthentic products, some of which continue to be sold at reduced prices worldwide (often via the Internet) (74, 75).  Another report found that BTX-A injected into the whisker muscles of rodents traveled to the brainstem, where trace amounts were discovered 3 days later (76). However, the toxin used in the study was an uncomplexed, veterinary-grade toxin produced in the laboratory and not approved for use in humans, and the doses injected into the rats and mice were up to 150 times higher per kilogram/body weight than doses injected into humans for the treatment of glabellar rhytides.

Conclusion

Nearly 30 years of therapeutic experience with BTX-A in humans have demonstrated a high level of safety and efficacy for a variety of applications. Today, BTX-A is one of the most frequently requested procedures in facial rejuvenation, successful both as a unique primary aesthetic treatment and as a powerful adjunct working synergistically in combination with other cosmetic procedures to enhance and prolong clinical benefits and restore aesthetic harmony. Side effects are mostly mild and transient; more serious complications and AEs are due to poor injection technique or too-large doses in already medically compromised patients. After years of clinical success and consistent safety, BTX-A now represents an extremely valuable part of the clinical armamentarium.

Tables & figures

References

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