Botulinum toxin (BoNT-A)

3 Botulinum toxin (BoNT-A)






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 2.5 million BoNT-A procedures were performed in the US, representing approximately 30% of all nonsurgical cosmetic procedures. That is more than all liposuction, breast augmentation, rhinoplasty, facelift, and blepharoplasty procedures combined.1


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.





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.6


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 end plate, opens sodium-potassium ion channels, depolarizes the motor endplate, and initiates the sequence of events that leads to contraction of the muscle fiber.7


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-25.7 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 source of BoNT-B




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).12 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.13,14


While this list was comprehensive at the time it was written, there are many 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.



Indications


Botox is indicated for the treatment of cervical dystonia in adults to decrease the severity of abnormal head position and neck pain associated with cervical dystonia and also for the treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients ≥12 years of age. Botox is also approved for the treatment of severe primary axillary hyperhidrosis that is inadequately managed with topical agents.8 BoNT-A preparations are effective treatments for hyperhidrosis by decreasing cholinergic stimulation of eccrine glands responsible for sweat production.


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 ≤65 years of age.9


Dysport is indicated for the treatment of adults with cervical dystonia to reduce the severity of abnormal head position and neck pain in both toxin-naive and previously treated patients and also 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.10


Xeomin is indicated for the treatment of adults with cervical dystonia to decrease the severity of abnormal head position and neck pain in both botulinum toxin-naïve and previously treated patients and also for the treatment of adults with blepharospasm who were previously treated with onabotulinumtoxinA (Botox) and temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients.


Myobloc (BoNT-B) is indicated for the treatment of adults with cervical dystonia to reduce the severity of abnormal head position and neck pain associated with cervical dystonia.11


Although the approved use of BoNT-A formulations for cosmetic use is limited to glabellar rhytids in patients under 65, it is extensively used off-label for this purpose 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 dystonia15 has grown to include limb spasticity and dystonias, hypersecretory syndromes such as sialorrhea, headache, low back pain16 and writer’s cramp.17




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,18 the labeling of all botulinum toxin-containing products are required to containing the following boxed warning:




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.811 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 antiinflammatory medications for 2 weeks prior to treatment.


Patients have rarely developed neutralizing antibodies for BoNT-A following cosmetic use. These events are more commonly associated with the use of high doses for neurologic purposes19,20 although this has been reported following cosmetic use resulting in treatment failure.21



Dosing


The manufacturer of each BoNT-A product provides recommended dosing for their product, which is limited to the indicated use of treating glabellar lines. 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, most 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 17.5 U is used by the author with a dose range of 10–27.5 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.22 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. As randomized, double-blind, placebo-controlled clinical trials comparing the aesthetic efficacy of these products have not been performed, numerous studies have attempted to use surrogate endpoints to establish relative potency rations for these products. To date, these attempts have not been successful.12–14,2328 The reason for this is simple: the dose-response curves of onabotulinumtoxinA and abobotulinumtoxinA are not parallel and therefore a single dosing ratio between the two products cannot be established throughout the range of doses used.


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 nonpreserved 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 nonpreserved saline for Botox 100 unit vial since 1991 and 3.0 mL of non-preserved saline for Dysport since its introduction.


Feb 21, 2016 | Posted by in General Surgery | Comments Off on Botulinum toxin (BoNT-A)
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