13 Neurotoxins in Cosmetic Facial Surgery
When this chapter was written, only Botox Cosmetic (Allergan Inc., Irvine, CA) was available in the United States as an FDA-approved neurotoxin for the treatment of hyperfunctional lines of the face. Dysport, now known globally as Dysport (Medicis Pharmaceutical Corp., Scottsdale, AZ) was approved in April 2009. In this chapter, however, all references to “units” apply to Botox unless otherwise indicated. It is important for injectors to realize that the potency and measuring schema of various neurotoxins may vary and must be differentiated prior to usage.
If there is one single treatment that has revolutionized cosmetic facial surgery over the past century, it would have to be botulinum toxin type A. Although not the only neurotoxin complex available, Botox was the first botulinum toxin approved by the U.S. Food and Drug Administration (FDA) in the United States and will always be the granddaddy of neurotoxins. Surgeons, patients, and the media are in constant search of a procedure that produces significant effects with insignificant recovery, but it rarely happens. Most products, surgeries, or devices that promise results without recovery time are problematic, and expectations exceed outcomes. Not so with Botox. It is the most common cosmetic treatment in the world and for good reason. This drug is easy to administer, has no downtime, and produces long-lasting cosmetic effects.
The history of cosmetic botulinum is interesting. Botulism, or sausage poisoning as it was originally termed, was first seriously studied following an outbreak in Wildbad, Germany, in 1793. The outbreak involved 13 people, 6 of whom died, and was associated with consumption of a locally produced blood sausage. Following this outbreak, the number of reported cases of sausage poisoning rapidly increased, prompting a study of the disease by local health officer, Justinius Kerner (1829). He described 230 cases, most of which were attributed to the consumption of sausage. The illness became known as botulism after “botulus,” the Latin word for sausage.
Many years later, Van Ermengem (1897) investigated an outbreak of botulism involving 34 individuals who had consumed raw, salted ham served at a gathering of amateur musicians in Ellezelles, Belgium. In the investigation of this outbreak, Van Ermengem established that botulism was an intoxication, not an infection, and that the toxin was produced by a spore-forming obligate anaerobic bacterium, Clostridium botulinum. He also found that toxin was rapidly inactivated by heating and was only toxic to certain animal species.
A later outbreak in Darmstadt, Germany, associated with canned white beans established that there was a second type of botulism. The originally identified strain was type A, and the Van Ermengem strain was probably type B (Landmann 1904).
As the Clostridium bacterium was studied and the toxin isolated, it was largely controlled by the U.S. government and considered for chemical warfare but reportedly could not be aerosolized. The government allowed academic investigation in the late 1940s. Dr. Allen Scott (Figure 13-1, A) had the biggest part in the medical progression of the drug, and around the early 1980s the drug, called Oculinum at the time, was used in studies as a treatment for strabismus and blepharospasm. Dr. Jean Carruthers is an oculoplastic surgeon in Vancouver, BC, and was part of the research using botulinum toxin A for the treatment of blepharospasm. She noticed that the drug was successful in treating the muscular disorder, but some patients were returning without lateral canthal wrinkles on the treated side and were inquiring about using it to “make the wrinkles go away” on the nontreated side. Dr. Jean shared this experience with her husband, Dr. Alastair Carruthers, an accomplished dermatologist who was intrigued with this finding (see Figure 13-1, B). One day, Dr. Alastair electively injected one of his employees in the glabellar region with the botulinum toxin, and the first cosmetic treatment of Botox was born.1
FIGURE 13-1 A, Dr. Alan Scott is shown at the Smith-Kettlewell Eye Research Institute in San Francisco in 1982. B, From left to right are Dr. Alastair Carruthers, April Niamtu, Dr. Jean Carruthers, and Dr. Joe Niamtu.
After significant investigation and trials, the drug was approved by the FDA in 1989 for the treatment of strabismus and blepharospasm and used off label for cosmetic treatments. In 1991, Speywood, now Ipsen Ltd. (Maidenhead, Burkshire, UK) had their preparation of botulinum toxin A approved as Dysport outside the United States. The year 2000 saw FDA approval of Botox for cervical dystonia, and in the same year botulinum toxin B (Elan, Inc. now Solstice Neurosciences, Dublin, Ireland) was approved and marketed in the United States as Myobloc. In 2002, Allergan achieved FDA approval of Botox for glabellar rhytids and in 2004 received FDA approval for the treatment of axillary hyperhidrosis. Myobloc’s popularity was short lived. With the exception of treating patients who were resistant to botulinum toxin A, it did not emerge as significant competition for Allergan’s Botox. A new botulinum toxin A preparation called Xeomin was developed by Merz (Merz Pharma, Frankfurt, Germany) and is unique as it claims to be free of complexing proteins. It was approved for use in Canada in 2009 and at the time of this writing is in the FDA pipeline.
Botulism is not an infectious disease but rather a type of food poisoning caused by eating food in which C. botulinum has grown and produced toxin. Botulinum toxin has been called “the most poisonous of all poisons”2 and molecule for molecule is the most lethal substance known to man. The U.S. supply of botulinum toxin A (BTA) that lasted for 2 decades was synthesized in a 150-mg batch by Schantz in 1979.3 This batch of crystalline BTA was dubbed batch 11-79. BTA is one of the eight known toxic serotypes produced by Clostridium botulinum that have been purified (A, B, C1, C2, D, E, F, and G). Seven of the eight serologically distinct toxins can produce neuromuscular blockade, although type A is the most potent. This purified serotype of BTA is available in the United States as Botox (Allergan Inc., Irvine, CA) and Dysport (Medicis Inc., Scottsdale, AZ) and is supplied in a hemagglutinin complex in the form of a freeze-dried powder ready for dilution with preserved normal saline.
Due to the extreme potency of this exotoxin, the 100-mg Botox vial content is barely visible as a light coat of precipitate adherent to the floor of the glass vial. The FDA requires specifications of 100 plus or minus 30 units per vial. Allergan indicates specifications closer to 100 plus or minus 10 units per vial. These variations may affect the clinical action, onset, and duration of the treated areas and must be kept in mind: 20 units of Botox are equipotent to 60 units of Dysport, Dysport and these differences must be kept in mind when interpreting the literature.4 Having said this, each different type of Botulinum toxin A is different and technically no official conversion rate exists. In my clinical experience and opinion I equate 20 units of Botox to 60 units of Dysport and hence a 3:1 ratio. It is commonly said that there is a 2.5 : 1 ratio of units between Dysport and Botox, but in my personal experience a more accurate conversion is 1 Botox unit is equal to 3 Dysport units. The LD50 for BTA in mice is 1 unit and is expressed as the amount of toxin injected intraperitoneally that kills 50% of a group of Swiss-Webster female mice weighing 18 to 20 grams.5 The LD50 for humans has been calculated at 2500 to 3000 units for a 70-kg person for a lethal dose of 40 U/kg.6 Since the usual therapeutic dose for the treatment of hyperfunctional muscle lines is 25 to 50 Botox units, a 100× margin of safety exists. The packaged exotoxin is stored in a conventional refrigerator and once reconstituted is stored in the same manner. BTA is ordinarily incapable of crossing the blood-brain barrier and generally exhibits no systemic effects.7 BTA is a neurotoxin and exhibits it effects on the neuromuscular junction by inhibiting the release of acetylcholine (ACh) , which causes weakness or flaccid paralysis (Figure 13-2).
FIGURE 13-2 In the normal situation, acetylcholine (ACh) mediates nerve transmission at the neuromuscular junction by releasing vesicles of ACh across the neuronal membrane into the synaptic cleft and synaptic junction, which bind to specific receptor sites on the muscle and produce contraction.
(Copyright Allergan Inc., Irvine, CA.)
The storage or synthesis of ACh is not affected by BTA; its action affects the vesicle-bound ACh.8 BTA paralyzes all striated muscle exposed to this neurotoxin. The normal presynaptic membrane contains membranous vesicles poised to release their neurotransmitter cargo of ACh at the motor end plate (see Figure 13-2). This process requires a calcium influx and specialized proteins such as SNAP 25 and syntaxin, which make up a “snare complex” that drives the vesicles to the nerve membrane. Normally the vesicles allow passage of ACh through the nerve membrane into the synaptic cleft and through the synaptic junction to bind with specific receptors on the striated muscle, hence causing muscle contraction. When a neurotoxin is injected, the toxin contacts the motor end plate, binds to the neuron (Figure 13-3, A), becomes internalized in vesicles, and moves throughout the neuron (see Figure 13-3, B). The light chain of the toxin (which contains the zinc-dependent protease) produces proteolytic cleavage of the snare complex proteins and prevents the release of ACh at the vesicle membrane, resulting in neuromuscular blockade (Figure 13-4). The binding of the molecule to the motor end plate is permanent; it takes 24 to 48 hours for the therapeutic condition of weakness or paralysis to ensue due to this chemical denervation. The reason for the delay is the time required for the storage vesicles of ACh within the presynaptic motor end plate to be depleted. Although the binding of the ACh is permanent, the paralytic effect only persists for 2 to 6 months. The reason for this temporary action is the formation of new axonal sprouts, thus reestablishing the neurotransmitter pathway (Figure 13-5). This process of neoneurogenesis allows complete recovery of the transmission pathway and resultant muscle function.9
(Copyright Allergan Inc., Irvine, CA.)
FIGURE 13-4 The light chain of the toxin cleaves the snare complex proteins, which prevents the acetylcholine (ACh) vesicles fusing with the neuronal membrane. Since no ACh can reach the muscle receptors, neuromuscular blockade results.
(Copyright Allergan Inc., Irvine, CA.)
FIGURE 13-5 Binding of the toxin and prevention of the release of acetylcholine is permanent, but muscle function returns after months as the result of the formation of new axonal sprouts, thus reestablishing the neurotransmitter pathway.
(Copyright Allergan Inc., Irvine, CA.)
Resistance to BTA is rare and has been reported with repeated large doses of the exotoxin.10 Resistance from prolonged usage with strabismus treatments appears to increase with the use of more than 300 units within a 30-day period.11 Botulinum toxin serotypes B and F are similarly potent to type A and are being studied for use on patients who have developed immunity to toxin type A.12 Contraindications for BTA include known hypersensitivity to any component of the preparation (including human albumin), systemic neuromuscular diseases, or the use of aminoglycoside or spectinomycin antibiotics which are known to effect neuromuscular transmission and potentiate the effects of BTA.6 Scott13 reported a study of nine pregnant females, one of whom had a premature delivery thought to be unrelated to the treatment. Neurotoxins are never used on pregnant or lactating patients.
Dysport, Dysport, has been used outside the United States for 15 years. It is approved in 73 countries for various therapeutic indications and in 23 countries for the treatment of glabellar or hyperkinetic facial lines.14 Numerous studies have been published in the literature regarding this preparation. One early open-label U.S. study researched a cohort of 1200 patients receiving as many as 5 treatments of Dysport over a 13-month period. The results were strikingly similar to Botox in that the average onset time for effect was 3 days, and the mean duration was 90 days.14 The adverse events associated with this study of over 4000 treatments were not grossly different from Botox studies.14 One difference that must be kept in mind is that the units of delivery of Botox Cosmetic and Dysport are not equipotent. Practitioners must differentiate between the dosages of these different drugs when treating patients.
I have written numerous articles on the clinical usage of Botox for cosmetic facial treatment, and although my treatment has changed in terms of dilution, my basic injection patterns have remained consistent.15–21 Even though Botox injections are the most popular cosmetic treatment in the world, many patients still do not understand the differences between Botox (or Dysport) and injectable fillers. Realizing this, the surgeon and staff must educate patients on what the drug and treatment will do and won’t do. Like all cosmetic procedures, the consent process is paramount for successful treatment and patient relations. It must be made clear in writing that neurotoxin treatments vary in effect and duration from patient to patient, and that some patients will not respond to treatment. The novice injector will soon find out that some patients will complain that their “Botox did not work” because they can still move their forehead, or the drug did not last long enough, or they had unwanted paralysis. The patient may expect free touchup, retreatment, or a refund because their expectations were not met. For all these reasons, the patient must be made aware of the common effects, unwanted effects, expected duration or lack thereof, complications, patient and surgeon responsibilities, and any financial data that may be relevant. Although many doctors charge by the area, I prefer to charge by the unit. This makes treatment and retreatment simple and understandable for the patient. They are charged for what they receive, and touchups, when required, are simple math. In addition, some patients require more drug than others because they have larger muscles or higher hairlines.
I am a Diamond level injector, which means that I personally use over 700 vials of Botox per year and I am one of the largest solo injectors in the United States. As a consultant for Allergan and Medicis, I have trained hundreds of doctors from virtually every specialty in the cosmetic use of BTA. Use of Botox and Dysport is very simple and predictable. I personally inject every patient myself and cherish this opportunity as well-spent doctor/patient relations. There have been many Botox patients who turned into eyelid or facelift patients. Although many surgeons employ physician extenders to inject patients, I think they are missing great marketing and patient-relation opportunities.
The most commonly treated areas in my practice are the glabella, the lateral canthal regions, and the frontalis in that order. Most patients present for multiple treatment areas, and most patients are regular users and average 90-day retreatments. The “rule of 3” is explained to all patients. The drug will take effect by 3 days, will maximize by 3 weeks, and will last about 3 months. Obviously this is variable from patient to patient.
The main depressors of the brow are the paired procerus, corrugator supercilii, and medial orbicularis muscles (Figure 13-6). The sole elevator of the brow is the paired frontalis muscle, and the lateral orbicularis muscles are the main contributors to “crow’s feet” wrinkles. This musculature works in conjunction to perform the very complex orchestra of facial expression (Figure 13-7).
FIGURE 13-6 The main muscles of facial expression commonly treated with injectable neurotoxin. The paired muscles include the procerus (1), the corrugator supercilii (2), the medial orbicularis (3), and the sole elevator of the forehead, the frontalis (4).
Some mimetic muscles have bony origins with dermal insertions and commonly interdigitate and in some areas (glabella, modiolus) are interfaced with numerous muscles. These muscles, through continual flexing of the skin, produce rhytids perpendicular to the muscular action. With years of muscular movement, the frown lines, horizontal forehead wrinkles, and lateral canthal (crow’s feet) wrinkles become deeper and more noticeable. Theoretically if there is no muscle movement, rhytids do not form, as evidenced in patients with stroke or nerve injury. Taking this into account, the younger a patient begins to receive neurotoxin treatment, the less chance they have of forming wrinkles. For those patients with existing wrinkles, regularly paralyzing the muscles has a preventive effect.
Botox is shipped as a small, thin precipitate on the surface of the vial (Figure 13-8) and is commonly reconstituted with 1 to 5 mL of preserved saline. This is operator dependent and based on the surgeon’s preference. I personally use a 2.5-mL dilution (Figure 13-9). This makes the math easy. There are 100 units of Botox in a vial. I use an 18-gauge needle to inject 2.5 mL of preserved saline into the vial and mix the solution by gently shaking the bottle. The top of the vial is then removed with a bottle opener, and the solution is drawn up in 1-mL Luer-Lok syringes (Figure 13-10). This is done with an 18-gauge needle and never with the fragile needles that will be used for injection. Five syringes are filled to 0.5 mL, which equals 20 units or 4 units per 0.1 mL. This means that each syringe contains 20 units of toxin, and the five syringes total 100 units. Since 20 units are used to treat the average area, this dilution and associated math is simple for staff, doctor, and patients. It is also important to purge the syringes so that the initial injection does not include air instead of neurotoxin.
I have experimented with dilutions from 1 to 10 mL, and regardless of dilution have never noticed a difference in effect, onset, or duration in patients. The problem with larger dilutions is that they leave large injection wheals that are unsightly. The problem with the 1-mL dilution is that it is much easier to waste the toxin; misplaced drops are more concentrated and therefore expensive. The 2.5-mL dilution has proven most convenient. It is not the dilution that makes a difference, but rather the number of units being delivered.
I prefer -inch 32-gauge needles (0.26 × 13 mm) and feel their expense is a well-justified price for a less painful injection (Figure 13-11) (Airtite Inc., 1-800-231-7762). It is notable that the more expensive syringes of clear, smooth plastic have much smoother plunger activity thanks to the lubricated stopper (1 mL Luer-Lok Tip Reference #309628, BD Inc., Franklin Lakes, NJ). These are much smoother than the cheaper opaque polyethylene syringes with smaller plunger tips, which are more “jerky” and less precise in terms of injection control. This is especially critical when very small units are administered in precise areas such as the lower eyelid.
Allergan provides Botox in single-use vials of either 50 or 100 units and originally recommended that the product be discarded at 4 hours; however, the new package insert allows 24 hours after reconstitution. Studies in the literature have shown that 40-day-old reconstituted Botox produces clinical effects up to 40 days.22 Many practitioners will keep reconstituted toxin in the refrigerator for several days or weeks without apparent loss of potency.
We label every Botox syringe with an appropriate orange label so these syringes are not mistaken for local anesthetic (which has occurred). In addition, a very convenient innovation has been the purchase of small, compact countertop refrigerators. These units are about $100 and not only act as refrigerators but also can be used as heating units for IV fluids and the like. Using these small appliances has made our fast-paced Botox practice much more efficient. The units are aesthetic and occupy a small footprint (Figure 13-12). We use them in our sterilization suite to store our unopened neurotoxin (Figure 13-13) and also keep them in each room where we inject (Figure 13-14). This has saved hours of running around to fetch syringes for use in one of the injection suites and has been a much-appreciated convenience.
The procerus, corrugators, and medial orbicularis collectively produce the common “frown lines” in the central brow region. The two creases seen in this area are frequently referred to as the 11. The common injection pattern of this region involves five injections placed in a manner to decrease contraction of the depressors. The most important pearl when injecting in the periorbital region is to keep all injections 1 cm from the bony orbital rim. Some injectors choose to inject closer to the orbit, but I can testify that in many thousands of injections adhering to the “10 mm away from the orbit” rule, I have never experienced a true eyelid ptosis (Figure 13-15). I have, however, seen it happen to other injectors when neurotoxin is injected too close to the orbital rim. For the novice injector, it is a good idea to mark out the points of injection with a surgical marker and a ruler or caliper prior to injecting.
When considering needle placement, it is important that the offending muscles are not necessarily directly under the wrinkle. Because of variances among patients, the most accurate way to inject is to ask the patient to animate the area to be injected and observe the main area of muscle action. Injecting in the main area of muscle activity is the preferable place for injection. For experienced injectors, the glabellar, frontalis, and lateral canthal region injections are almost standardized. The area of maximum muscle contraction is generally consistent, and by injecting in a common pattern, the average person can be injected without flexing for the injector.
A common question from novice injectors is “At what level is the neurotoxin injected?” Botox or Dysport should be injected intramuscularly, since that is the site of intended drug action. Early accounts instructed injectors to insert the needle to periosteum and then draw back half the way. This is a poor practice for several reasons: the periosteum is innervated, it is painful, and it also will dull the needle quickly. The mimetic muscles are subcutaneous with dermal insertions and are superficial. Depending upon the amount of subcutaneous fat in the region, the muscle mass can be shallower or deeper. A general rule is to insert the -inch needle about one-third of its length for the average patient. In reality, neurotoxins have a great affinity for muscle and even if injected intradermally will generally produce the desired effect. A common mistake of novice injectors (especially those used to giving intramuscular injections on the body) is to hold the syringe between their index finger and thumb similar to holding a pencil. They puncture the skin and then have to regrasp the inserted syringe to find the plunger, which is an awkward maneuver. It is better to inject with the thumb on the plunger and the index and second fingers on the hilt of the syringe.
The main injection sites for glabellar rhytids are a central injection into the procerus, an injection in the region of each corrugator supercilii, and a single injection at the action of the medial orbicularis oculi muscle bilaterally (Figure 13-16). I prefer 20 to 25 units to treat this region; when using 25 units, each treatment site receives 5 units. While many patients manifest the procerus action as a single area, it is not unusual to see some patients scowl and observe two separate procerus ridges. For the single ridge seen when scowling, 5 units can be placed centrally; in the case of two separate ridges, 2.5 units can be placed in each ridge (Figure 13-17).
FIGURE 13-17 A, A single procerus furrow when frowning. B, Double furrows are seen in some patients. I prefer to inject the single furrow with 5 units and use 2.5 units for each furrow in the case of double furrows.
Although 20 units of Botox or 60 units of Dysport are generally sufficient to improve the frown muscles in the average patient, some patients may require double this dose for efficacy. This is very common in men or women with very active depressor muscles. Patients must also understand that lines etched into the dermis are not going to go away but will probably be improved as the resting tension is relaxed. Filler injection may be necessary to improve the dermal lines. Patients must also understand in the preinjection consent process that a given dosage of toxin in a given patient may result in complete paralysis or only a decrease in the amount of muscle movement. If a patient is expecting paralysis without any movement, they must understand that it may require additional amounts of the drug.
Another relatively common phenomenon is when a patient is asked to frown or scowl, and they recruit both the depressors and the central frontalis (Figure 13-18). This is most frequent in the patient who “does not know how to frown.” Hard to believe that when asked to scowl, some patients do not understand the muscles used to convey that emotion and when asked, exhibit this biphasic expression. If they are handed a mirror and asked to repeat the frown or scowl, most often they will use the pure depressors. If they continue to exhibit this multiple-area depressor/frontalis action, it must be explained to them that they will need both regions treated.
So-called “bunny lines” are formed by flexing the upper fibers of the nasalis muscle on the lateral nose (Figure 13-19). These lines can be strictly from the nasalis muscle (Figure 13-20, A) or from a combination of heavy procerus action in conjunction with the nasalis (see Figure 13-20, B). Regardless of causation, this area is easily treated by injecting 2-unit aliquots in the circled areas in the figure, which are of course different from patient to patient. Care is used to inject well above the nasolabial fold to avoid affecting lip function. Some patients may not exhibit nasalis activity until their glabella is treated and then recruit the nasalis muscles when attempting to frown.
The frontalis is a more variable site than the glabella because hairlines and forehead height are so dramatically different from patient to patient (Figure 13-21). A patient with a very low hairline and short forehead may need very little neurotoxin, whereas a patient with a receding hairline or an elongated forehead may need more than the average patient. In fact, a patient with a very short forehead and low hairline may experience frontalis paralysis when the treatment is limited to the glabella.
When treating the frontalis, it is important to remember that this is a paired sheet of muscle that can be very thin (Figure 13-22). The actual horizontal forehead rhytids have little to do with the position of the muscle, especially in the midline where many patients have no frontalis. The horizontal rhytids in the skin are perpendicular to the actual muscle, so the treatment is performed by spreading out the toxin over the active regions of the muscle. The injection should be spread out enough to cover all the active muscle area of the broad, thin sheets of the frontalis. It must be kept in mind that when a neurotoxin is injected, the effect fans out like a bull’s eye from the center of the injection for about 10 mm (Figure 13-23). When injecting the frontalis, there is no need to space the injections closer than this, since the effect will spread. When treating the frontalis, a “field” of muscle area is being treated, much in the same way one injects local anesthetic wheals.
FIGURE 13-23 Each neurotoxin injection can spread out concentrically from 10 to 15 mm. The amount of diffusion may differ from one toxin formulation to another. The key to treating an entire area like the forehead is to space the injections far enough apart to account for the diffusion to cover the entire desired treatment area.
Since the frontalis is a thinner muscle, especially in females, less neurotoxin is required to decrease function. The common dose is 2 to 4 units (Figure 13-24). For patients with very thin skin and muscle, 2 to 3 units per injection may be effective, but for patients with thicker skin and muscle, 4 to 5 units per injection area may be necessary (Figure 13-25).
FIGURE 13-25 A, For a patient with fine rhytids and less active frontalis muscle, 2 to 3 units per injection site is adequate. B, This patient shows thicker skin and heavier muscle action and may require 4 to 5 units per site to prevent movement.
When I began injecting Botox in the mid 1990s, the frontalis was the second most commonly requested treatment area after the glabella. Over the past 5 years, I have seen the frontalis region drop to third, with the lateral canthal region now the second most commonly requested treatment area. I believe the prime reason />