There are seven botulinum toxin subtypes (A through G) derived from varying strains of the bacterium Clostridium botulinum (C. botulinum). Of the seven toxin serotypes, only A and B are commercially available for clinical use. Popularity of these toxins in clinical practice has increased dramatically in the past 40 years since their first use for strabismus in children in the 1980s. In 2002, botulinum toxin first gained Food and Drug Administration (FDA) approval for use in glabellar rhytids and has since become one of the most commonly used aesthetic facial nonsurgical interventions since. Type A was initially FDA approved for treatment of glabellar frown lines in patients 65 years or younger and this approval has since expanded to include other indications such as hyperhidrosis, blepharoptosis, and cervical dystonia, as well as other aesthetic indications. Type B is FDA approved only for the treatment of cervical dystonia, so other uses are off label.1,2
2. Lorenc ZP, Kenkel JM, Fagien S, et al. Consensus panel’s assessment and recommendations on the use of 3 botulinum toxin type A products in facial aesthetics. Aesthet Surg J 2013; 33(1, Suppl):35S–40S There are currently three preparations of botulinum toxin A with on and off label indications for facial aesthetics. These preparations are Botox, Xeomin, and Dysport. • Botox is OnabotulinumtoxinA, manufactured by Allergan, Santa Barbara, CA. • Dysport is AbobotulinumtoxinA, manufactured by Medicis Aesthetics, Scottsdale, AZ. • Xeomin is IncobotulinumtoxinA, manufactured by Merz Pharmaceuticals, Greensboro, NC All three have FDA approval for the treatment of glabellar lines/rhytids. In addition, Botox has approval for treatment of crow’s feet (lateral canthal lines and forehead rhytids). Use of these preparations for other facial areas is therefore technically off label, although each manufacturer gives advice on their use and worldwide each preparation is widely used at all anatomical sites including the forehead, periorbital area, perioral area, neck, and nose.1,2
Neuromodulators and injectable fillers are frequently used together as part of the facial rejuvenation process, as they are complimentary to one another, with neuromodulators addressing dynamic rhytids and fillers treating static ones. When using fillers and neuromodulators in the same location, it is possible to perform the injections in two separate settings with the neuromodulator in the first session to correct the dynamic deformities, and the filler in the second session to correct the residual static ones. Of course, many patients will prefer a single clinic visit and will prefer to combine neuromodulators and fillers in one sitting, for both economic and logistic reasons. In this case, it is preferable to inject the filler first followed by the neuromodulator. This allows fine-tuning massage of the injected filler by the injector but avoids massage to an area, which has just received toxin, as this could potentially displace the toxin to unwanted areas. This highlights the need to be flexible with injections and place them in order according to a specific circumstance. Many clinicians like to mark the proposed sites/ areas of injection, but care then must be taken to avoid injection through them in case this results in tattooing.1
Dysport (Medicis Aesthetics, Scottsdale, AZ) is the trade name for AbobotulinumtoxinA. and is a popular choice of neuromodulator in aesthetic practice. It received FDA approval in 2009 for the treatment of glabellar rhytids and cervical dystonia. Prior to this, it had been used for nearly two decades outside of the United States for aesthetic facial rejuvenation purposes. It is available in 300- and 500-unit vials and is typically diluted to a final concentration of 10 to 50 unit/0.1 mL. Units of botulinum toxin A are not directly interchangeable between the three brands. Similar results can be achieved with different preparations using normalized clinical dosing. Consensus recommendations suggest that a 1:1 dosing ratio can be used when switching between Botox and Xeomin, but that a 2:1 or 2.5:1 dosing ratio should be followed when switching to Dysport from either Botox or Xeomin. Indeed, separate dosing and injection guidelines are available for Dysport.1,2 This highlights that there can be subtle nuances between different injectable products and should be a reminder to be flexible in one’s practice if an alternative product is being used compared with what is one’s standard usual. Following injection, the spread of toxin occurs immediately and will be influenced by injection volume and injection technique. Diffusion from the injection site occurs over days and follows a concentration gradient (toxin- dose dependent). The onset of effect following C. botulinum injection is fairly uniform for each of the available preparations and begins within 1–3 days. Patients normally notice results by the end of the first week. Reassessing the patient at 14 days can be useful for neurotoxin injections, especially as this allows touch-ups to be undertaken at that time. The typical interval for treatment is 3–6 months across the three different brands of toxin, so changing from one brand to another should not make a difference to the frequency of injections required by a patient.1,2
Xeomin is also known as incobotulinumtoxinA and is manufactured by Merz Pharmaceuticals. It is one of the three key preparations of C. botulinum toxin. It has FDA approval for use in glabellar rhytids, cervical dystonia, and blepharoptosis. It has two key advantages over other preparations: 1. It does not require refrigeration before use. 2. It has a low immunogenicity. The other preparations (Botox and Dysport) both require refrigeration, which can present a logistical problem in terms of storage and access to toxins in clinic. The reason why Xeomin has the lowest immunogenicity of all preparations is that the amount of complexing proteins is very low and these are believed to be implicated in immune reactions to the injected product. Botulinum toxin A is expressed as a 150-KDa core toxin within a larger 900-KDa protein complex. The immune system may recognize any component of this complex and trigger an immune reaction. The amount of neurotoxin and complexing protein injected defines the foreign protein load. High or repeat protein loads may trigger toxin A antibody production and secondary nonresponse. Current commercial preparations seek to minimize delivered protein load by eliminating complexing proteins. Xeomin has effectively eliminated complexing proteins during preparation, which may suggest the lowest immunogenicity of the available preparations. Xeomin does have 5% risk of headache following treatment of glabellar lines, although this is slightly lower than a quoted 9% risk for patients having Dysport for example. All of the preparations require reconstitution, as they are stored as powders and all require prescription for use.1–5
Each of the botulinum toxins requires reconstitution before use. This is normally performed with preservative- free 0.9% sodium chloride and once done the product should be clear, colorless, and free from particulate matter. Either preserved or nonpreserved saline may be used, although Botox, Dysport, and Xeomin instructions all describe the use of nonpreserved saline. There is evidence that use of preserved saline helps reduce the pain for patients during injections. In one study, both prospective and retrospective approaches were undertaken. In the prospective study, preserved saline was used on one side of the face, while nonpreserved was used on the other. Patients consistently reported less pain on the side treated with preserved saline. In the retrospective study, patients who previously had undergone treatment with nonpreserved saline were treated with preserved saline and described reduced pain with the latter.1 There is no difference to the action of the product, the immunogenicity, or bruising risk due to different saline types. Bruising can be minimized by taking some sensible steps including stopping anticoagulant medication 10–14 days beforehand and taking care to identify and avoid injecting through or past blood vessels. When this does occur, swift application of pressure to the area can help minimize the bruising effects. The cost of using preserved saline may be higher than that of nonpreserved saline, so this would not reduce the business overhead.
In general, most patients will likely follow a variation of a standard “recipe” for neurotoxin therapy, which tends to most often include treatment of the brow, glabellar region, and crow’s feet. Other patients may request treatment to additional areas such as bunny lines, marionette lines, platysmal bands, or the lips. It is therefore important to adapt treatment plans to be individualized to each patient. Despite this, caution must be taken when asked by a patient to perform treatment solely for transverse forehead rhytids, as this risks brow ptosis. The target muscle for transverse forehead rhytids is the frontalis, which is a brow elevator. Treating this area is ideally combined with glabellar treatments to reduce activity in the corrugator and procerus muscles which are brow depressors. Brow ptosis can occur when the brow depressors in the glabella are left at their normal strength while the frontalis (brow elevator) is weakened. Eyelid ptosis is the most common adverse event of treating the glabellar area rather than treating the forehead and occurs in 3% of patients. To minimize this risk, injections should remain away from the levator palpebrae superioris and lateral corrugator injections should be at least 1 cm above the supraorbital ridge and not less than 1 cm above the central eyebrow. The risk of ectropion is high where the crow’s feet or midface are injected with neurotoxin, especially in the setting of pre-existing lower eyelid laxity. This is therefore not specifically associated with treating a single area alone but injecting in to or beyond an area inappropriately. Providing the patient has a good understanding of what they are after, there is no other reason for not treating a single area only, in terms of achieving patient satisfaction. For the clinician, it may be difficult to accept that only a single area is treated when they feel the best result would be achieved with more, but the key is that the patient’s aims and objectives of treatment are followed and they are satisfied.1–4
Bunny lines refer to wrinkles that appear on the sides of the nose and radiate downward. The target muscles for treating this area are the nasalis and procerus. Two to three injection points are used: one to the dorsal midline of the nose at the level of the medial canthi, and one to each side slightly more caudal. A total of 6 units is usually sufficient when using Botox or Xeomin. To prevent drooping of the upper lip, care should be taken to avoid injecting into levator labii superioris alaeque nasi and levator labii superioris. To prevent botulinum toxin from diffusing into these muscles, vigorous massage should be avoided postinjection.1,2 Procerus is targeted during glabellar treatment along with orbicularis oculi and corrugator supercilii. Orbicularis oris is targeted to decrease the appearance of fine vertical wrinkles of the lips, often in combination with lip filler. Levator labii superioris may be targeted for the “gummy smile” where there is excess show of gums and upper dentition while laughing or smiling. Other muscles implicated in the “gummy smile” include levator labii superioris alaeque nasi which elevates the lip and depressor septi nasi which lowers the nasal tip.1–4
The platysma can be targeted with neurotoxin for reducing lines at the jawline or reducing visible bands on animation within the neck. Where skin elasticity is well maintained, or in patients who are post neck-lifting surgery, treatment of platysmal bands can be effective with standard neurotoxin techniques by direct injection into the palpable and visible bands. However, in those with skin laxity, crepey skin, and jowling, who do not wish to undergo surgery, there is a significant risk of increasing the appearance of skin laxity by taking this approach, which patients will dislike. In this setting, the “microbotox technique” can be used instead. In this technique, microdroplets of 2–4 units of Botox are injected intradermally or just under the skin at 0.8–1.0-cm intervals across the lower face and neck. This produces a smoothing of the skin (atrophy and sweat and sebaceous glands) and weakens the action of the facial muscles where they attach to the skin.1 Care must be taken with any neurotoxin injection in the neck as going too deep or using too high a dose can lead to dysphagia if the strap muscles are incidentally weakened. Rhytids can occur across the jawline because of contraction of platysma and standard injection approaches can be used, although injection here also risks dysphagia if performed too deep or at too higher dosage (Fig. 104.1). Treatment of the dimpled chin involves neurotoxin delivery to the mentalis muscle. It is important to avoid injecting the depressor labii, as weakening this muscle can result in an asymmetric smile as if there is a marginal mandibular nerve branch palsy. In some patients, the depressor septi nasi can draw the nose downward with smiling and they dislike this appearance. This may be corrected during rhinoplasty by division of the depressor muscle at the columella base but can also be done with neurotoxin. A single injection in the philtrum is usually sufficient but must be avoided in patients with a long upper lip, as this may be accentuated. Treatment of marionette lines with neurotoxin requires delivery to the depressor anguli oris muscle. The injection should not be made too near to the corners of the mouth, as diffusion into orbicularis oris can lead to oral incompetence, which patients find particularly distressing. Treatment of masseteric hypertrophy resulting from jaw clenching can be effective with neurotoxin. Care must be taken to inject deep into masseter to avoid causing inadvertent injection into one of the facial mimetic muscles leading to smile asymmetry. These injections do risk causing deep hematomas.1–3
There are seven subtypes of botulinum toxin (A to G), but only two are commercially available (A and B). All of the subtypes cause chemodenervation by blocking the action of acetylcholine at the neuromuscular junction. Type A works on the SNAP-25 protein, and type B on the synaptobrevin protein. Both of these proteins act at the SNARE complex. Only type A is intended for use in facial aesthetics, while type B is for use in cervical dystonia. FDA approval for botulinum toxin A is limited to glabellar rhytids, crow’s feet lines, forehead rhytids, cervical dystonia, migraine, or blepharoptosis (depending on brand), so other uses are off-label. The units of different botulinum toxin preparations are not uniformly comparable, although they are derived from the effects on laboratory mice. One unit is sufficient to cause death in 50% of a specific strain of mouse with intraperitoneal injection. Botox (onabotulinumtoxinA; Allergan, Santa Barbara, CA) and Xeomin (incobotulinumtoxinA; Merz Pharmaceuticals, Greensboro, NC) units are roughly equivalent. Between 2 and 2.5 Dysport (abobotulinumtoxinA; Medicis Aesthetics, Scottsdale, AZ) units are equivalent to a single Botox unit. The difference in units between products arises from differences in the specifics of the assays used and this has the potential to cause confusion when changing from Botox or Xeomin to Dysport in clinical practice.1,2
Botox is available in 100- and 200-unit vials and is typically diluted with normal saline to provide 4 units per 0.1 mL. Reconstitution should be performed gently to avoid damage to the product. It should be clear following reconstitution. Consensus opinion suggests it may be stored for up to 6 weeks, providing it is stored at 4°C. However, the manufacturers of botulinum toxins recommend that the product is injected within 4 hours of reconstitution. Because the products do not contain an antimicrobial agent, prolonged storage does not have FDA approval. A typical starting dose would be 20 units placed via five to seven injections. The central injection is placed below the superior orbital rim, but the lateral ones must be placed above.1,2
This patient could benefit from chemodenervation of the orbicularis oculi muscle; the options include Xeomin, Dysport, or Botox. Treatment of the crow’s feet area (lateral canthal lines) is commonly performed, often in conjunction with the brow and glabellar regions. A suggested starting dose for crow’s-feet Botox injection is 18–24 units (three injections per side of 4 units each). Since Xeomin units are roughly equivalent, the same dose can be used. The approximate dosing conversion from Botox to Dysport is 2:1 to 2.5:1, so a starting dose would be 36–48 units. The other volumes would be somewhat homeopathic for this patient. When injecting into the crow’s feet or lateral canthal area, three sites are normally injected per side (up to 4 units per injection; Fig. 104.2). The first site should be 1.5–2 cm lateral to the lateral canthus, just lateral to the orbital rim. Additional sites should be medial and superior and/or inferior to this depending on whether the lines are distributed above and below the lateral canthus or isolated below the lateral canthus. Injection should be performed with the needle at one-third of its depth. The patient should keep their eyes closed and the injector should use a finger to protect the upper eyelid. Before injecting this area, a snap test should be performed to the lower lids. If they are lax, there is significant risk for postinjection ectropion, and low injections must be avoided.1–3 Fig. 104.2 Injection sites for lateral canthal lines. (Adapted from Carruthers J, Fagien S, Matarasso SL; Botox Consensus Group. Consensus recommendations on the use of botulinum toxin type a in facial aesthetics. Plast Reconstr Surg 114(Suppl 6):S1–S22, 2004.)
Eyelid ptosis is the most common adverse event following botulinum toxin injection to the glabellar region. It occurs in around 3% of cases. In general, accurate and carefully placed injections can help minimize risk of unwanted muscle weakness. For example, eyelid ptosis risk can be minimized by avoiding injecting near the levator palpebrae superioris and by placing lateral corrugator injections at least 1 cm above the supraorbital ridge. In the central eyebrow area, injections must not be placed less than 1 cm of the supraorbital ridge. The other key risks that must be discussed with patients include pain, bleeding, bruising, swelling, infection, allergic reaction, over- or undercorrection of rhytids, residual static rhytids, headache, eyelid edema, double vision, flulike symptoms, asymmetry, and dissatisfaction with cosmetic result.1–4