Abstract
Over the past decade, facial cosmetic procedures have become more commonplace in dentistry and oral and maxillofacial surgery. An increasing number of patients seek minimal invasive procedures. One of the most requested procedures is treatment with botulinum toxin type A (BoNTA). Treatment of dynamic rhytids and lines with BoNTA is effective and produces high rates of improvement with rapid onset and long duration of action (longer than 4 months for some patients) compared with placebo. This paper considers the history and pharmacology of this neurotoxin, and focusses on the literature concerning the treatment of different facial areas with BoNTA. It also presents clinical guidelines on the treatment of glabellar lines, the frontalis muscle, peri-orbital lines, gummy smile and masseter muscle hypertrophy. Knowledge about the mechanisms of action and the ability to use BoNTA as an adjunctive treatment are mandatory for those working in the field of cosmetic facial surgery.
Invasive and non-invasive facial cosmetic procedures are becoming commonplace in oral and maxillofacial surgery. Apart from invasive surgical procedures, many patients choose rejuvenation with injectables such as botulinum toxin type A (BoNTA). In the USA, from 2000 to 2008, minimally invasive cosmetic treatment with BoNTA increased by 537% to 5 million treatments a year, while surgical cosmetic procedures such as blepharoplasty and facelift decreased by 16–32% to 220,000 and 113,000 procedures, respectively . With aging, changes become apparent through the face. Following loss of volume and elasticity in the facial skin, tissues follow gravity in a downward movement. This leads to the formation of wrinkles and fine lines around the eyes and mouth. This is due to hyperdynamic contraction of the underlying muscles in these areas. When a muscle contracts, the overlying skin folds perpendicular to the direction of the muscle . This creates a dynamic wrinkle that can be treated with BoNTA. When age advances, the jaw line begins to sag and more static wrinkles form due to underlying fat displacement and long term skin folding. Factors that are responsible for facial aging include soft tissue maturation, muscular facial activity, smoking habits and solar changes . Botulinum toxin has shown impressive results in softening dynamic wrinkles and can be used as a treatment of first choice or as a ‘test drive’ for a more permanent surgical procedure. There is little scientific data about the effects of BoNTA in the cosmetic field regarding dose-ranging, effectiveness, follow up and patient selection . A recent review found 11 randomized controlled clinical trials on the use of BoNTA in facial aesthetics . Apart from the mechanisms of action of BoNTA, contraindications and restrictions, this article will focus on the most frequent cosmetic indications in the upper facial area (glabella, frontal area and peri-orbital lines) and on gummy smile treatment and masseter hypertrophy. When treating patients with BoNTA, the facial expression can be softened and rejuvenated in dynamic, and to a lesser extent, in static dimensions.
Historical perspective
Food-borne botulism has been around as long as man has tried to preserve and store food. There is little documentation from before the late 18th century, when romantic poet and medical officer Justinus Kerner described a case of lethal food poisoning. He described symptoms of mydriasis, diplopia, gastrointestinal complaints and progressive muscle paralysis after consumption of meat and blood sausage. This is also the derivation of the name botulism ( botulus is sausage in Latin) . It was not until 1897 that the Belgian microbiologist Emile van Ermengem isolated the bacillus Botulinum while investigating an outbreak of botulism. The pathogen was later renamed as a neurotoxin-producing Gram-positive bacterium Clostridium botulinum . Research into the potential use of the botulinum toxin as a biological weapon was intensified during both world wars. After World War II, botulinum toxin was used in local injections to reduce the activity of hyperactive muscles. The American ophthalmologist, Scott, successfully used BoNTA in blepharospasm and strabismus . This led to the first approval by the US Food and Drug Administration (FDA) as ‘Oculinum’ in 1989. The Allergan (Irvine, USA) company received FDA approval to change the therapeutic name from Oculinum to Botox®. In the same period, Ipsen (Slough, UK) developed and received approval for production of Dysport® for the European market .
History of the cosmetic use of BoNTA
In 1990, the dermatologist, J ean C arruthers , and ophthalmologist, A lastair C arruthers , published their first report on the cosmetic use of BoNTA. They discovered this new indication by serendipity while treating patients for blepharospasm, and saw cosmetic side-effects as dynamic rhytids subsequently disappeared. This was the start of their substantial research on the cosmetic use of BoNTA, which led to several publications . Several other authors recognized the potential of BoNTA for the treatment of hyperkinetic lines on the face, which lead to widespread acceptance of the technique after 1995 . Since 2009, BoNTA has been formally registered in several European countries for cosmetic use in the glabella region; use in all other regions remains an off-label use of this product.
Pharmacology
Voluntary muscle contraction is a response to stimulation by action potentials passing along a nerve to the muscle end plate. Once the action potentials reach a synapse at the neuromuscular junction, they stimulate an influx of calcium into the cytoplasm of the nerve ending, and mobilization of acetylcholine towards the synapse occurs. Acetylcholine fuses with the nerve ending membrane and then crosses the synapse to bind with receptors on the muscle fibre, which leads to contraction ( Fig. 1 a ). BoNTA inhibits the discharge of acetylcholine into the synapse by bonding to the nerve at the neuromuscular ending. The toxin is then internalized via receptor-mediated endocytosis, and a toxin-containing vesicle is formed within the nerve ending. These internalized vesicles inhibit the acetylcholine protein (SyNaptosomal Associated Protein-25) that is located on the cell membrane ( Fig. 1 b). This inhibits muscle contraction, which leads to reversible muscle atrophy . The first cessation of muscle function occurs after 2–3 days, and the maximum effect occurs after 2 weeks. Binding of BoNTA to the nerve is irreversible, and recovery of muscle function occurs by proliferation of axonal nerve buds to the target muscle and regeneration of muscle end plates. Clinically relevant reduction of muscle contraction last for 4 months in glabellar lines and can last up to 6 months in the frontalis region, depending on individual variation .
Dosage and administration
Several companies manufacture BoNTA. Vistabel® (also known as Botox®, Allergan, Irvine, USA) and Azzalure® (Ipsen, Slough, UK) have recently been registered for facial cosmetic use in Europe. The dosages mentioned in this article are based on Vistabel®, which is delivered in a 50 IU vial (or a 100 IU vial). The contents of the 50 IU vial are diluted in 1.25 ml 0.9% saline solution to give a solution of 4 IU/0.1 ml. Using this concentration, small amounts of solution can be injected, giving a precise placement of toxin and less diffusion. When using a less potent solution, the amount of injected solution increases, and diffusion into neighbouring muscles can increase. This can cause unwanted side-effects such as blepharoptosis .
Reconstitution of the botulinum toxin takes place by gently injecting the diluent into the vial, avoiding the formation of foam in the complex, which may result in toxin denaturation . Once reconstituted, the drug must be stored at a temperature of 2–8 °C. After reconstitution, the drug should be used within 4–8 h, as recommended by the manufacturer. This recommendation is for sterility and efficacy purposes. Recent studies have shown that toxin efficacy remains the same until 15 days after reconstitution, and bacterial contamination does not take place .
The most commonly used syringes are 1 ml insulin syringes with removable 30 gauge needles. These needles are not traumatic to tissue and minimally painful because of their size. Local anaesthesia is usually not necessary. There is still debate on skin preparation before injection. There is no evidence-based consensus on whether skin should be disinfected with alcohol or chlorhexidine to prevent local infection, or that this should be avoided because of the belief that alcohol can inactivate the BoNTA .
Contraindications
Administration of BoNTA should be avoided during pregnancy and breast feeding and in patients with disorders of the neuromuscular junction (such as myasthania gravis, Lambert-Eaton syndrome) and neurodegenerative diseases such as amyotrophic lateral sclerosis. Simultaneous use of aminoglycoside antibiotics (gentamycin, tobramycin) should be avoided because of their potentiating effect on BoNTA. Other theoretical drug interactions could occur with calcium channel blockers, cyclosporine and cholinesterase inhibitors. Highly frequent administration of BoNTA (more than every 12 weeks) and repeated exposure can lead to formation of neutralizing antibodies against the toxin which lead to disappointing results .
Safety of BoNTA in cosmetic procedures and adverse events
Pharmacological BoNTA has an excellent safety record that is diametrically opposed to the devastating presentation of systemic botulism secondary to food poisoning. The estimated lethal dose of BoNTA for humans falls in the range of 2500–3000 U .
The most common patient complaints about BoNTA are injection site pain and bruising. During clinical trials of BoNTA for glabellar lines and horizontal forehead rhytids, the most frequently reported adverse events were headache, asymmetric appearance, lack of facial animation and blepharoptosis. In patients with pre-existing lower lid laxity, weakening of the orbicularis oculi muscle with BoNTA can cause ectropion .
Indications
As with any other type of treatment, before performing cosmetic procedures with BoNTA, both patient and physician should discuss treatment expectations, to prevent disappointment. Consistent with current treatment approaches that aim to provide a more natural and relaxed look, clinical practice frequently involves treating multiple facial areas rather than a single area. Research has indicated that this is consistent with better patient-reported outcomes . BoNTA reduces the mimetic effects of wrinkles and folds, and should therefore be applied in areas of dynamic motion, such as the glabella, frontal region, and peri-orbital lines. Static wrinkles and very deep folds are less suitable for the use of BoNTA alone, and a combination with other injectables, such as hyaluronic acid is preferred. The safest indications are dynamic wrinkles in the upper third of the face. The existence of rhytids in this area is based on the equilibrium of opposing elevator and depressor muscles, which are outlined in Fig. 2 . More advanced indications are the peri-oral area, which is mostly combined with hyaluronic acids, and the gummy smile. All injection sites and advised injection units are outlined in Table 1 . There are differences in the dosage relating to muscle volume in males and females. In general, males have a larger muscle volume and require more units of BoNTA to achieve the same results as female patients .
| Indication | Number of injection sites | IU per injection site | Total IU injected | Ml solution per injection site |
|---|---|---|---|---|
| Glabella | 5 | 4 | 20 | 0.1 |
| Frontalis | 5–7 | 4 | 20–28 | 0.1 |
| Crow’s feet | 2 × 3 | 4 | 24 | 0.1 |
| Gummy smile | 2 | 4 | 8 | 0.1 |
| Masseter hypertrophy | 2 × 3 | 12 | 72 | 0.3 |
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