Abstract
When properly administered to appropriately selected individuals, botulinum toxin type A (BoNT-A) can have a rejuvenating effect on nearly the entire face and neck. Carefully observing the functional anatomy of each patient is the key to determining how much BoNT-A to administer and where to place each injection. In some facial areas, fine control can be achieved by only partially affecting muscles, causing the neighboring musculature to compensate for the ensuing weakness.
Keywords
botulinum toxin, BoNT-A, Clostridium botulinum , glabellar lines
Introduction
There are many components to the process of facial aging. Thinning of the dermis, elastosis, loss of facial volume, genetic factors, gravity, skeletal changes, sun damage, and smoking all play a part in this process. So does facial animation. Certain rhytids are primarily caused by facial movement. Others are caused by other factors as well as a component of animation. Therefore, as long as a wrinkle or unattractive shape is as least partially caused by muscular action, it can be treated with botulinum toxin A (BoNT-A); however, how well a specific unaesthetic area responds to treatment with BoNT-A depends on how much of the unattractive area is caused by factors other than animation. For example, a glabellar rhytid that is almost completely caused by the actions of the corrugators and procerus muscles in a relatively young patient can be totally eradicated with BoNT-A. In contrast, vertical lip rhytids in an elderly woman with thin skin, sun damage, a history of smoking, and loss of lip volume may only be partially improved by careful injection of the orbicularis oris muscle, which contributes to the accordion-like scrunching of the overlying lip skin.
BoNT-A treatment is currently the most frequently performed cosmetic procedure in the US, and its importance in aesthetic plastic surgery simply cannot be overstated. In 2008, nearly 3.6 million BoNT-A procedures were performed in the US. That is more than all liposuction, breast augmentation, rhinoplasty, facelift, and blepharoplasty procedures combined .
Although the subject of this chapter is focused on the manipulation of facial animation, the ability of the overlying skin to resist these underlying forces that would deform it is also of paramount importance when discussing rhytids.
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The most important elements for facial rejuvenation with BoNT-A are functional anatomy, functional anatomy, and functional anatomy!
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To minimize the risk of a frozen, unnatural appearance, use the minimally effective dose of BoNT-A.
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Brow elevation depends on the relative weakness of the brow elevators versus brow depressors.
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The dose of BoNT-A used should be based on the estimated mass of the muscle being injected, not the depth of the rhytid.
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Avoiding the use of aspirin and non-steroidal anti-inflammatory medications will decrease the occurrence and severity of ecchymosis.
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The lower frontalis muscle has the greatest effect on brow elevation.
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Threading the injection through the lips gives a more natural result than the near universal point technique.
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Cooling the skin before injection minimizes discomfort.
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As a general rule, injecting depressors more strongly than elevators will tend to give a more gentle lift to the area involved.
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Over-injecting the mentalis can result in a “witch’s chin” deformity and oral incompetence.
Basic Science
Pharmacology and Pharmacokinetics
Clostridium botulinum is a Gram-positive, anaerobic bacterium that is known to produce seven serologically distinct types of toxin, designated A through G, of which type A is the most potent. Botulinum toxin types A and B are used medically and are available in the US. The type A toxin is a fully sequenced, 1296 amino acid polypeptide protein consisting of a 100-kDa heavy chain joined by a disulfide bond to a 50-kDa light chain.
In the normally functioning neuromuscular junction, the propagation of an action potential at the presynaptic neuron terminal opens voltage-dependent calcium channels. The influx of extracellular calcium ions causes vesicles containing acetylcholine to dock and fuse to the presynaptic neuron’s cell membrane through the action of a 25-kDa soluble N -ethylmaleimide-sensitive factor attachment protein (SNAP-25). The released acetylcholine crosses the synaptic cleft, where it binds with nicotinic receptors at the motor endplate, opens sodium–potassium ion channels, depolarizes the motor endplate, and initiates the sequence of events that leads to contraction of the muscle fiber.
Following the administration of botulinum toxin, the heavy chain binds to the axon terminal, which enables the toxin to enter the neuron via endocytosis. In the cytoplasm, the proteolytic light chain degrades SNAP-25, thereby preventing fusion of the acetylcholine-containing vesicle with the cell membrane, preventing release of acetylcholine. Within a few days, the affected nerve is incapable of releasing acetylcholine, resulting in flaccid paralysis of the muscle fiber it innervates. Type-B botulinum toxin also causes flaccid paralysis but does so by inhibiting synaptobrevin, a vesicle-associated membrane protein similar to SNAP-25. Unless specified, the remainder of this chapter concerns botulinum toxin type A.
Recovery begins to occur after several weeks, although the mechanism for this is not completely understood. Initially, small neuritic processes grow out of the affected neurons and establish new functional synapses, which are capable of acetylcholine release; however, these neuritic networks shrink and disappear as the original neurons regain function. The initial clinical response to botulinum toxin is usually readily apparent for 3–4 months, although 6–7 months are often required for the effects to completely disappear. BoNT-A begins to display an increased duration of action in most patients when they undergo treatment on a regular basis. When used cosmetically, the duration of action of BoNT-B is significantly less than that of type A, with an effective initial response of 2–3 months.
Commercial Sources of BoNT-A
Several botulinum toxin products are currently available in the US:
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Botox (onabotulinumtoxinA) for injection (Allergan Inc., Irvine, CA) is supplied in vials containing 100 U of vacuum-dried Clostridium botulinum type A neurotoxin complex, 0.5 mg of albumin human, and 0.9 mg of sodium chloride without a preservative.
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Botox Cosmetic (onabotulinumtoxinA) for injection (Allergan Inc., Irvine, CA) is provided in vials containing 50 U of vacuum-dried Clostridium botulinum type A neurotoxin complex, 0.25 mg of albumin human, and 0.45 mg of sodium chloride without a preservative; or 100 U of vacuum-dried Clostridium botulinum type A neurotoxin complex, 0.5 mg of albumin human, and 0.9 mg of sodium chloride without a preservative.
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Dysport for injection (abobotulinumtoxinA) (Tercica Inc., Brisbane, CA; and Medicis Aesthetics Inc., Scottsdale, AZ) is supplied in vials containing 500 or 300 U of lyophilized abobotulinumtoxinA, 125 µg human serum albumin and 2.5 mg lactose.
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Xeomin for injection (incobotulinumtoxinA) (Merz North America, Raleigh, NC) in 50- and 100-unit vials.
Commercial Source of BoNT-B
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Myobloc (rimabotulinumtoxinB) injection (Solstice Neurosciences Inc., South San Francisco, CA) is provided in 3.5-mL vials containing 5000 U of botulinum toxin type B per mL in 0.05% human serum albumin, 0.01 M sodium succinate, and 0.1 M sodium chloride.
The BoNT-A in Dysport and Botox are produced by fermentation of the bacterium Clostridium botulinum type A (Hall Strain), while BoNT-B in Myobloc is produced by fermentation of the bacterium Clostridium botulinum type B (Bean strain). It is important to note that the potency of each product is specific to the preparation and assay method utilized, and is not interchangeable with other preparations of botulinum toxin products .
While this list is comprehensive at the time of writing, there are other toxins in clinical trials, which we will have in our armamentarium. Whether these are injectable or topically applied (RT001, Revance Therapeutics, Newark, CA), the strategy for these products remains the same; to identify the offending muscular segments and relax them to a certain extent. Dosing regimens with these products will always be in a state of flux. Good judgment, a critical eye, and an understanding of functional anatomy will never go out of style. Thus, this chapter is adaptable for neurotoxins not yet in use. New BoNT-A formulations will have different complexing proteins, different excipients, different complex sizes, different pharmacokinetics, and definitely different dosing regimens. The key to evaluating these products will be dissociation. The basic function of the lone 1296 amino acid chain is the same.
Cosmetic Indications
Botox Cosmetic is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients. It is also indicated for the temporary improvement in the appearance of moderate to severe lateral canthal lines associated with orbicularis oculi activity in adult patients.
Dysport is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adult patients <65 years of age.
Xeomin is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients.
Although the approved use of BoNT-A formulations for cosmetic use is limited to glabellar rhytids and lateral canthal lines, it is extensively used off label, and the author has used it to treat every muscle in the face since 1991.
BoNT-B plays a relatively minor role for cosmetic applications. It has a faster onset of action than BoNT-A, which can be beneficial, but its cosmetic usefulness is limited by greater pain on injection due to its low pH and a shorter duration of action. In isolated instances, it may be considered if a patient fails to respond to BoNT-A. It may also be useful for full-face laser resurfacing and lower-face scar revision, as the shorter duration of action will keep the treated area relatively motionless during the early healing phase while avoiding prolonged, unattractive facial weakness.
The use of BoNT-A and BoNT-B for neurological purposes has become extensive. Its approved use for the treatment of cervical dystonia has grown to include limb spasticity and dystonias, hypersecretory syndromes such as sialorrhea, headache, low back pain, and writer’s cramp.
Warnings and Contraindications
The use of products containing botulinum toxin is contraindicated in the presence of infection at the proposed injection site and in individuals with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation. The use of BoNT-A is contraindicated in patients with disorders of neuromuscular transmission, such as myasthenia gravis or Lambert–Eaton myasthenic syndrome. Dysport contains a small amount of lactose and may contain trace amounts of cow’s milk protein. Dysport should not be use in patients with a known allergy to cow’s milk protein.
BoNT-A products should be used with caution in patients currently taking drugs known to affect neuromuscular transmission such as neuromuscular blockers, lincosamides, aminoglycosides, polymyxins, quinidine, magnesium sulfate, anticholinesterases, or succinylcholine chloride as they may potentiate the effects of BoNT-A. The safety of administering botulinum toxin to pregnant women has not been established, and its use in this population should be avoided.
Adverse Effects
In the United States, due to reports received by the Food and Drug Administration regarding serious systemic adverse reactions including respiratory compromise and death following the use of botulinum toxins types A and B for both approved and unapproved uses, the labeling of all botulinum toxin-containing products are required to containing the following boxed warning:
Postmarketing reports indicate that the effects of all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and adults, and in approved indications, cases of spread of effect have occurred at doses comparable to those used to treat cervical dystonia and at lower doses.
Adverse events reported by the manufacturers of BoNT-A and BoNT-B products include nasopharyngitis, headache, injection site pain, bleeding, bruising, edema, erythema, infection, inflammation, sinusitis, ecchymosis and nausea. Weakness of adjacent muscles may also occur due to spread of toxin resulting in undesired effects. These types of adverse events are described in greater detail below. To minimize bruising, patients should avoid the use of aspirin and non-steroidal anti-inflammatory medications for 2 weeks prior to treatment.
Patients have uncommonly developed neutralizing antibodies for BoNT-A following cosmetic use. These events are more often associated with the use of high doses for neurologic purposes, although this has been reported following cosmetic use resulting in treatment failure.
Dosing
The manufacturer of each BoNT-A product provides recommended dosing for their product, which is limited to the indicated uses. However, the facial musculature of patients is highly variable and precludes the use of standardized dosing for different aesthetic procedures. Gender also presents an obvious difference, as men typically (but not always) have larger muscles requiring higher BoNT-A doses compared to women.
Using Botox for the treatment of glabellar lines as an example, the manufacturer recommends injecting 8 U in each corrugator muscle and 4 U in the procerus muscle for a total dose of 20 U; however, many practitioners inject an average of 25 U per glabella, while some advocate doses as high as 80 U and upper face doses of nearly 100 U. A median dose of 15 U is used by the author with a dose range of 5–22.5 U. Consequently, each clinician must gain familiarity with these products through experience and establish their own optimum BoNT-A dosing techniques.
These principles were demonstrated during a recent clinical study. Patients were stratified by demographics and randomized to receive a single treatment with different doses of BoNT-A (Dysport) or placebo. Based on procerus/corrugator muscle mass, women received doses of 50, 60, or 70 U, while men were treated with 60, 70, or 80 U. Using this variable dosing technique, 85% of BoNT-A-treated patients were rated as treatment responders by a blinded evaluator after 30 days compared with 3% of placebo-treated patients (p < 0.001). Compared with patients in other studies who received 50 U to the glabella (the approved, on-label dose), variably dosed patients tended to have improved efficacy and quicker onset without increased adverse events.
BoNT-A products are not bioequivalent and cannot be used interchangeably because of differences in unit potency and fundamental differences in how these units are measured. A randomized, double-blind study comparing onabotulinumtoxinA and incobotulinumtoxinA was performed at a dose of 24 units per glabella and revealed incobotulinumtoxinA to be non-inferior to onabotulinumtoxinA. I believe it is fair to say that onabotulinumtoxinA and incobotulinumtoxinA have similar dosing regimens while the units of abobotulinumtoxinA are quite different.
The indicated dilution volume for the 100-unit vial of Botox Cosmetic is 2.5 mL and for the 300-unit vial of Dysport is either 2.5 mL or 1.5 mL, both with non-preserved normal saline. In actual practice, a wide range of volumes are used from 1.0 mL to 6.0 mL. Most practitioners use preserved saline (off label) for its weak anesthetic effect (benzyl alcohol is the preservative) and as a preservative if the vial is stored for a few days between uses. A recent poll of a consensus group of experts revealed that nearly all used each vial on more than one patient (also not according to the label). Smaller volumes allow for more concentrated dosing with less pain (based on volume of injection) per dosage point. Larger volumes allow for more injection points per dosage and thus, perhaps, more control. I have used 4.0 mL of non-preserved saline for both onabotulinumtoxinA and incobotulinumtoxinA 100-unit vial since 1991 and 2011 and 3.0 mL of non-preserved saline for Dysport since its introduction.
Patient Selection
Decision-Making Details of Selecting a Patient for BoNT-A
The absolute key to becoming a proficient BoNT-A injector instead of a mere technician is understanding the functional anatomy of the face. Anatomy textbooks show the location of different facial muscles and their origins and insertions. While these texts allow for small and expected anatomic variations, they cannot prepare the clinician for the overwhelming differences in functional anatomy between individuals, or even different sides of the same face. Even though all individuals have the same mimetic muscles, their smile patterns vary depending on which muscles dominate within the group. Even within a single muscle, different portions of that muscle can dominate and severely alter animation ( Fig. 4.1 ).
Therefore, it is essential that the face of each patient be carefully analyzed to determine which portions of which muscles dominate facial activity and cause wrinkles or other unaesthetic shaping of the face. These are the muscle segments that benefit from treatment with BoNT-A. The key is to take the necessary time to analyze the patient’s face and discern these details. This is especially important in the lower face, and plastic surgeons should become highly familiar with these muscles and their possible anatomic variations. Understanding how the lower face moves is the key to using BoNT-A to improve nasolabial folds, perioral rhytids, chin dimpling, marionette lines, and downturned oral commissures. This is not an area for the novice injector, as a few misplaced units of BoNT-A is not tolerated nearly as well as they are in the upper face.
Treatment Technique
Treatment with BoNT-A does not need to be an all-or-nothing phenomenon. A certain amount of toxin will block a certain number of nerve terminals. Thus, fine control over the amount of denervation desired is possible. Despite the common use of the word “paralysis” when discussing the toxin, it is rare that this is actually the desired effect. Rather, a selective weakening of the musculature is performed to achieve a pleasant cosmetic effect.
Glabella
The glabella was the first area to be treated cosmetically with BoNT-A injections. Similar to other areas of the upper face, this use of BoNT-A was based on longstanding surgical procedures. During a bicoronal browlift, it was common to debulk the glabellar musculature to ease glabellar furrowing and reduce downward pull on the brow.
Even in a seemingly straightforward area of the face as the glabella, there is a great deal of variation in functional anatomy. When most people frown, they primarily bring their brows together as well as depress them; however, not everyone does this. Some people primarily frown in a vertical pattern, dramatically depressing their brows. When others frown, they may actually raise their medial brows while moving them medially, resulting in a quizzical look.
The median dose of BoNT-A used by the author for treating the corrugators and procerus muscles is 15–17.5 U of Botox and Xeomin for women and men, respectively, or 50–60 U of Dysport for women and men, respectively (total dose). After observing the normal animation of each patient during the consultation process, the patient is asked to frown and relax, repeatedly, and then scrunch their nose as if smelling something unpleasant and relax, repeatedly. This allows gauging as to which sections of which muscles dominate and which specific areas are to be targeted with BoNT-A ( Fig. 4.2 ).
