The use of chemical denervation products in aesthetic practise helps patients lessen the visible appearance of skin ageing.
Progressive anatomic ageing is a dynamic biological process caused by ongoing malar bone resorption, decreased tissue elasticity, and subcutaneous supporting tissue degradation. This process is also affected by gravity’s synergic effect (Donath et al. 2007), reflecting the degree and severity of facial ageing (Mendelson et al. 2007).
Our goals for providing facial aesthetic treatments should be to create and maintain a more harmonious, balanced and rejuvenated appearance. The number of non-surgical facial aesthetic procedures has been increasing significantly during recent years. These procedures are performed to rejuvenate the facial features by the restoration of the lost facial volume, enhancement of normal facial features, and facial asymmetry correction. Immediate aesthetic result and minimal downtime are some of the advantages of these procedures (Bosniak et al. 2006). Hyperactivity of the facial expression muscles may result in deep frown lines, forehead lines and crow’s feet. When a small amount of purified botulinum toxin is injected into the facial expression muscle responsible for wrinkling, it causes muscle weakness or paresis, giving the face a more relaxed and pleasant appearance. Some wrinkles become smoother or may disappear. This effect appears in 2-4 days and usually lasts for about 4 months (Dayan & Maas 2007).
In this essay, the structure, development, and mechanism of botulinum toxin’s physiological action in the process of chemical denervation will be addressed. The medical and aesthetic indications and contraindications for administering chemical denervation products, their alternative products, potential drug interactions, adverse effects, risks and complications will also be discussed.
Botulinum toxin (BTX) is derived from Clostridium Botulinum, a complex (900-KD) that contains a neurotoxin and associated proteins. The active ingredient, a neurotoxin, blocks the release of acetylcholine (Ach), the substance responsible for transmitting electrical impulses that elicit muscle contraction. The toxin was first identified as an agent, which caused a form of food poisoning (botulism) in the 1800s. In 1895 Prof. E.P Van Ermengem identified the bacteria toxin purified in the crystalline form later on (1946). In the 1950s, V. Brooks discovered the therapeutic effect of BTX-A as a medical product for the treatment of conditions involving hyperactive muscles. During the period of 1960-the 70s, Allan B Scott tested the efficacy of the drug in the treatment of strabismus in monkeys and then utilized it in human volunteers once the drug was FDA approved. After acquiring the BTX-A FDA-patent achieved by Dr Scott, Allergan applied for and was granted the right to re-name the modified form of the drug designed for other therapeutic applications. Each strain of Clostridium Botulinum bacteria produces different protein serotypes with general structural and functional similarities but different biological effects affecting their clinical use. Evidence from clinical trials (Aoki & Guyer 2001) reveals that type-A toxin is the most potent and long-acting of all endotoxin serotypes (A, B, C, D1, E, F and G).
BTX-A neurotoxin acts by inhibiting the neurotransmitter substance acetylcholine (Ach) release at the neuromuscular junction. Once the heavy chain of the BTX-A is initially bound to a specific receptor located on the external membrane of the pre-synaptic neuron at the neuromuscular junction, the BTX-A molecule is internalized via receptor-mediated endocytosis and forms a toxin-receptor vesicle. The light chain of BTX-A is then released into the cytoplasm inside the nerve terminal. It blocks the fusion of neurotransmitter vesicle with nerve membrane by cleaving SNAP-25 and preventing the consequent formation of SNARE complex (SNAP – 25-Syntaxin – VAMP). While the synthesis and storage of the Ach are not affected, this inhibits the exocytosis of the cholinergic vesicle and stimulation of muscle contraction through chemodenervation. Consequently, the endplate region grows and expands with the emergence of collateral axonal sprouts, which may release Ach into the new neuromuscular junction. Eventually, sprouts retract and regress while the original junction resumes its activity. Therefore, to maintain the therapeutic effect, repeated injections of the BTX-A is required.
BOTOX (Allergan) is a BTX-A, licensed and prescribed in the UK for the following conditions: excessive sweating (axillary hyperhidrosis); uncontrolled blinking (Blepharospasm); spasm of the facial muscles (Hemi-facial spasm); involuntary contraction of neck muscles (cervical dystonia/ spasmodic torticollis); focal spasticity in paediatric cerebral palsy patients; and upper limb spasticity in post-stroke patients.
Chemical denervation of the following muscles has been shown to reduce facial rhytids’ extent and severity, leading to a smoother and more youthful appearance: Frontal m. → horizontal forehead lines, Procerus m.& Corrugators m.: glabellar frown lines, Periorbital m. → crow’s feet, mild brow ptosis & infraorbital lines, Perioral m. & Depressor Anguli Oris m. → lower NLF and marionette lines, Mentalis m. → apple dumpling chin and mental crease, Platysma m. → vertical & horizontal necklines and bands Zygomaticus & risorius m. → mouth frown & folds. Effective use of 25 to 30 U of BTX-A per side of the masseter to reduce hypertrophic Masseter has been reported (Bentsianov et al. 2004).
Type A toxins include Botox, Dysport, Xeomin and Puretox. Type B toxins are known as Neurobloc in the UK and Myobloc in the US. More than 2,000 studies are published in scientific and peer-review journals on the safety and efficacy of Botox supported by Allegan. Botox comes in a 100U vial, while Dysport comes in a 500U vial with different biological preparation and subtle protein changes. According to Allergan, Botox is a crystallisation and acid precipitation process rendering it a more pure product, while Dysport is manufactured by column chromatography. The result from a double-blind, randomised pilot study suggests that Botox-A formulation offer more efficacy than Dysport at a dose ratio of 2.5:1, as well as a longer duration of effectiveness (Lowe et al. 2005).
Differences in diffusion among various BTX-A toxins could affect the incidence of adverse effect (ptosis); therefore, injection patterns and dosing should be adjusted to compensate accordingly (Aoki et al. 2005). Data extracted from both preclinical and clinical research suggest that Dysport/ Reloxin BTX-A formulation is more likely to diffuse from the injection site. Therefore, it should be used with caution around the eyes, upper lip, and depressor Anguli-Oris and in the mentalis muscle (Wenzel et al. 2007).
Type B toxin (Neurobloc) has been shown to have a more rapid onset, a larger diffusion pool, but a shorter duration of effectiveness (app. 6 weeks) than type A. toxin. This can benefit patients who wish to have their wrinkles smoothed or reduced quicker when attending our clinic (Lowe et al. 2002).
In essence, the safe and effective use of BTX-A in treating multiple areas of the upper face has been documented by widespread clinical experience (Carruthers & Carruthers 2007).
Cause-related treatment modalities should: reduce the hyperactivity of the contracting muscles, correct the volume of ptosis, and rejuvenate the photo-aged skin. Flynn (2008) described his observation that patients improve the degree of response with each repeated BTX treatment. Grover (2008) conducted a study including 68 patients who requested a secondary facelift. The results of this study suggest that patient who had been treated consistently with BTX since their first facelift for over 9 years had higher brows (mean +3mm) than patients who did not receive BTX treatment and that only 8% of them needed a brow lift compared to that 54% who had not been treated. These results indicate that long-term use of BTX can slow down the ageing process of upper face regions, e.g. brows. Binder (2006) compared the formation of facial lines in a set of identical female twins and could demonstrate that BTX-A treatments could prevent static rhytids in the forehead and when started at earlier ages, glabella and dynamic rhytids in crow’s feet. In one prospective randomized clinical trial, Caruthers & Caruthers (2003) demonstrated that combination treatment of severe glabellar rhytids using BTX-A one week before administering the hyaluronic acid filler resulted in superior treatment outcomes to that of hyaluronic acid filler alone. The authors showed that combination treatment nearly doubled the median duration of response and the percentage of subjects with aesthetic improvement at week 16, at both rest and maximum attempted muscle contraction. An initial administration of BTX-A has been shown to prolong and enhance the aesthetic improvement achieved by intense pulsed light (IPL) and laser (West & Alter 1999) techniques.
During the consultation process, the patient’s concerns and expectations are discussed. Facial features, soft tissue cover, support and volume, the symmetry of facial contours, static respective dynamic rhytids, lips and scars are assessed and evaluated. Effective communication is vital to establish realistic expectations and discuss: the aetiology of patient’s aesthetical concerns; the availability, effect, limitation, advantages and disadvantages of each alternatives product and treatment option; onset and duration of the effectiveness of each treatment; the amount of product required; and finally the cost and the need for maintenance. Before the administration of the BTX, patients are advised that: the initial effects of treatment become visible within 2-3 days; the maximum effect is reached in about 1 to 2 weeks when their facial expression will become more relaxed and natural, and they are not going to be able to use these muscles voluntarily before the effectiveness of treatment is reversed (app. 4-6 months) and when re-treatment is required. The effectiveness of treatment can be evaluated by comparison of pre- resp. Post- clinical parameters recorded, e.g. changes in the distance between the brows and the pupils. Information & post-operative instruction check-list is provided & explained (see Appendix 1). Post-op follow-up visits are scheduled to assess the clinical outcome. A consent form is signed, and the patient is advised to contact the direct line should they have any concern. Clinical photos are then taken from the frontal lateral and oblique aspect of the face to visualise the face from a different profile before and after the facial muscle contractions.
Botulinum toxin injection is generally a safe and effective treatment method. Nevertheless, similar to its reversible treatment effects, certain side effects can occur. Patients are informed about the potential drug interactions, contraindications to therapy, adverse drug reaction (ADR), and possible BTX therapy complications (see Appendix 1). Drug interactions have been reported in cases when BTX is used concomitantly with other medications, e.g. aminoglycoside antibiotics, anaesthetics and muscle relaxants. Since these medications can alter the effects of botulinum toxin, the patient must ensure that his/her doctor is aware of any current medications they are taking.
History of Bells’s palsy, dysmorphophobia, respiratory symptoms, prolonged muscle weakness, pregnancy and lactation, NSAIDs, vitamin E, St John’s wort may be considered with precaution. Some conditions, such as infected injection site, hypersensitivity to BTX/albumin, coagulopathy, generalized disorder, e.g. Myasthenia gravis and Eaton- Lambert syndrome, are contraindicated to the application of BTX. Feeling of nausea, tiredness, pain in the arms and legs, brief visual disturbances, dryness of the eyes, skin rash, itching, allergic reactions, dry mouth, pyrexia, dysphagia and muscle weakness/ atrophy have been associated with administration of BTX. Bruising or swelling at the injection site can be ameliorated with the application of Arnica cream, gentle pressure or an ice pack. Treatment of frown lines utilizing BTX can cause minor temporary droop of one eyelid in approximately 1% of injections. This usually lasts for 2-3 weeks. The natural resolution could be expected, or otherwise, the administration of the infra-brow and full glabellar injection may be advised. A small number of diluents (1ml) is advocated to achieve a more localized effect and avoid unwanted diffusion of the toxin (Carruthers et al. 2004). Injecting in the medial aspect of frontalis fibres with BTX without treating the lateral frontalis fibres could result in cocked eyebrows in some patients. To correct the unwanted excessive eyebrow elevation, injection of 1 to 3 units of BTX-A at about 3cm supra-orbitally into the untreated frontalis fibres may counteract the upward muscle pull (Carruthers & Carruthers 2007).
Conclusion
The literature review suggests the safe and effective use of BTX-A in the treatment of upper facial rhytids. When BTX-A is administered before using dermal fillers, the synergic effect of BTX-A is demonstrated by optimising and prolonging the clinical outcome achieved following treating the facial rhytids. While BTX-A and HA-fillers are integral to combination approaches to facial rejuvenation, BTX-A can also enhance and prolong light and laser techniques’ effectiveness. Therefore, the commencement of facial aesthetic treatment by an initial administration of BTX-A is highly recommended. This is to enable the clinician to reassess the residual static lines or deep folds and facilitate planning for further correction required by combination therapy.
It is vital to consider gender differences, ethnicity, the strength of muscles, skin type and elasticity, wrinkle extent and previous individual response to BTX treatment before determining the BTX-A dosing. The consensus of advances in facial aesthetics recommends the administration of lower effective doses of BTX-A to create a more harmonious and lively face by minimizing adverse effects and retaining some muscle movement and natural facial expression.
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