Introduction and History

One of the safest, simplest, and most satisfying methods of elective cosmetic reduction of facial rhytides is by the injection of botulinum neurotoxin Type A (BoNT-A, BOTOX® (Allergan, Irvine, CA)). Dysport® (Medicis, Scottsdale, AZ) is another formulaion of BoNT-A which is nearing FDA approval. Doses in this chapter are specific to BOTOX®, and Dysport® doses are approximately 2.5–3 times those for BOTOX®. BoNT-A is currently injected into selected superficial musculo-aponeurotic system (SMAS)-type facial muscles to temporarily reduce associated static and dynamic wrinkles. BoNT-A relaxes muscles by preventing the presynaptic release of the neurotransmitter acetylcholine at the peripheral cholinergic motor neuron endplate ( Fig. 13.1A & B ).

(A) Normal skeletal muscle contraction results when there is presynaptic release of the neurotransmitter acetylcholine (ACh) at the peripheral cholinergic motor neuron endplate or nerve ending. The ACh molecules diffuse across the synapse in order to stimulate skeletal muscle contraction.

(Courtesy of Allergan, Inc.)

(B) ACh is stored in vesicles residing in the motor nerve ending. Docking of ACh-containing vesicles with the nerve membrane is a necessary step prior to release of Ach into the neuromuscular junction. Docking is mediated by a number of molecules including SNAP-25A attached to the nerve membrane (blue strands).

(Courtesy of Allergan, Inc.)

Acetylcholine (Ach) is stored in vesicles residing in the motor nerve ending. Docking is a necessary step prior to release of ACh into the neuromuscular junction. BoNT-A prevents the docking and exocytosis of these acetylcholine vesicles to the nerve endplate. In order for BoNT-A to exert this effect, it must first be absorbed into the nerve ending by a process termed receptor-mediated endocytosis. After BoNT-A is internalized within a cytoplasmic vesicle, the light chain is released into the cytoplasm. The light chain cleaves a protein known as SNAP-25A which must be functional in order for acetylcholine vesicles to dock prior to release into the neuromuscular junction ( Fig. 13.1C–F ).

(C) Following botulinum neurotoxin type A (BoNT-A) injection, molecules of BoNT-A (yellow and gold-colored molecules) diffuse through the tissues and bind to the surface of the nerve ending via specific surface receptors (red and blue structures).

(Courtesy of Allergan, Inc.)

(D) After BoNT-A molecules bind to nerve endings, they are absorbed into the nerve ending through a process termed ‘receptor-mediated endocytosis.’ BoNT-A is then internalized into cytoplasmic vesicles.

(Courtesy of Allergan, Inc.)

(E) and (F) After BoNT-A is internalized within a cytoplasmic vesicle, the light chain of the molecule (yellow) is released into the cytoplasm. The light chain cleaves a protein known as SNAP-25A (blue) which must be functional in order for acetylcholine vesicles to dock prior to release into the neuromuscular junction.

(Courtesy of Allergan, Inc.)

Several distinct immunological BoNT serotypes exist (A, B, C1, D, E, F, G) which vary from approximately 300 to 900kD size. All BoNT serotypes target one or more specific intracellular proteins necessary for synaptic release of neurotransmitter. Proteins targeted by different serotypes include SNAP-25, syntaxin, and vesicle-associated membrane protein (VAMP, also known as synaptobrevin). Over time, the nerve ending may sprout additional axons, which establish new motor endplates ( Fig. 13.1G ). This results in a gradual return of motor function. Clinically, muscle function returns in 3–4 months. Skin testing for allergy to BoNT-A is not necessary, although blocking antibodies may occur in patients who receive high doses repeatedly.

(G) The muscle inactivity produced by a BoNT-A injections is temporary because peripheral nerve ending sprouts eventually develop and re-enervate the skeletal muscle.

(Courtesy of Allergan, Inc.)

Anatomy

The facial mimetic muscles are specialized for several functions including facial signaling and communication. Most of the muscles of facial expression are part of a continuous interconnected layer of muscle and connective tissue known as the SMAS layer ( Fig. 13.2 ). While these muscles are specialized for facial expression, there is also a decline with age in the accuracy with which these muscles convey facial expression. Hence, the age-related development of standing glabellar furrows may create a mistaken expression of disapproval. It is often the goal of BOTOX® injection to reduce the facial ‘miscues’ through selective pharmacologic denervation of the offending muscles. The common target muscles are summarized in Table 13.1 .

Muscles of facial expression.

Clinical Indications and Patient Selection

BoNT-A injection works well and reliably in the crow’s-feet, glabella, and forehead ( Fig 13.3 ). With experience, the eyebrows may be repositioned through treatment of the adjacent orbicularis oculi, procerus, corrugator supercilii, and depressor supercilii. BoNT-A may also be used with caution and experience to reduce the perioral rhytides and to improve the lateral angle of the mouth. However, the risk of perioral treatment resides in the possibility of inducing a neurolytic incompetence of the oral sphincter which may result in temporary drooling, difficulty in pronouncing some sounds (P or B), or inability to whistle, and difficulty playing wind instruments. BoNT-A is not helpful in the treatment of the nasolabial and marionette lines because such treatment results in facial ptosis. Dose is often individualized and may be related to muscle mass such that relatively smaller doses are sometimes used in females and Asians ( Tables 13.2 & 13.3 ). BOTOX® injection is contraindicated in the presence of infection at the injection site or in patients with known hypersensitivity to BOTOX® or any of its components. Caution should be used in treating patients with pre-existing neuromuscular disorders. BoNT-A treatment is contraindicated in women who are pregnant or nursing.

(A) Wrinkles indicated for BOTOX® treatment: green wrinkles respond well; yellow wrinkles should be treated cautiously; red lines should not be treated.

(B) Facial zones and underlying muscle groups. Green areas respond predictably and well. Caution is used in yellow areas because of unwanted effects such as adynamic and ptotic eyebrow. Red areas will produce unwanted effects such as drooping cheek and mouth.

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