Chemodenervation (Botulinum Toxin Type A [BoNT-A])

What are the different branded formulations of botulinum toxin type A (BoNT-A) currently available?

There are currently three available formulations of BoNT-A in the United States: Botox (onabotulinumtoxinA; Allergan Inc; Irvine, CA), Dysport (abobotulinumtoxinA; Galderma; Fort Worth, TX), and Xeomin (incobotulinumtoxinA; Merz Pharma; Germany). Two others are currently in the process of FDA approval in the United States, PurTox (Mentor Corp; Santa Barbara, CA) and Evosyal (Alphaeon; Irvine, CA).

From what organism is BoNT-A made?

BoNT-A is the purified neurotoxin type A complex produced by fermentation of the bacterium Clostridium botulinum type A, Hall strain.

What is the mechanism of action of BoNT-A?

It inhibits acetylcholine release at the neuromuscular junction and may inhibit neuropeptide neurotransmitter release. This blocks nerve stimulation of muscular activity and causes muscular paralysis. When applied to the mimetic muscles of the face in the proper dose, rhytids soften or disappear.

How long does BoNT-A take to act and how long does it last?

It induces partial chemical denervation resulting in reduced muscular activity. This is usually clinically evident within 24 to 72 hours depending on the type of BoNT-A used. The maximal clinical effect may take up to 14 days. The muscle may sustain atrophy, axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop. Reinnervation of the muscle may occur, thus slowly reversing muscle denervation. On average the clinical effect on facial rhytids lasts 3 to 4 months. When used for hyperhydrosis, the effect is much longer, on the order of 8 to 10 months.

What does a “unit” refer to when discussing the dose of BoNT-A?

One unit corresponds to the calculated median intraperitoneal lethal dose (LD50) in mice.

What is the significance of final concentration when reconstituting BoNT-A?

BoNT-A comes in a powder form within a vacuum-sealed glass vial. It is typically reconstituted with preservative free sterile 0.9% saline prior to use. Depending on the volume of saline used differing concentrations can be developed. Using Botox as an example, a final concentration of 5.0 to 2.0 U per 0.1 mL is typically used. The more concentrated the toxin, the more potency per unit volume and thus per injection site can be achieved; however, this requires more precision in injection technique and a more dense tissue effect. With a more dilute injectate more volume needs to be injected, a slightly softer result can be achieved, but there is higher risk of diffusion away from the intended site of delivery.

What is the recommended means by which to store BoNT-A after it has been reconstituted?

Prescribing information states that BoNT-A should be used within 4 hours of reconstitution. However, published data suggest that potency can be maintained for up to 6 weeks with storage at 4°C. Anecdotal reports state potency with even longer storage.

How many BoNT-A treatments were reported in 2014?

In the United States there were 3.5 million neurotoxin procedures (including Botox, Dysport, and Xeomin) for aesthetic purposes according to multispecialty data collected by the American Society for Aesthetic Plastic Surgery (ASAPS statistics 2014). Neurotoxin injections have been the number one nonsurgical aesthetic procedure performed since 2000.

In addition to aesthetic purposes, for what other diagnoses has BoNT-A demonstrated treatment efficacy?

Besides aesthetic applications, BoNT-A has a wide range of on- and off-label applications including treatment of hyperhydrosis, cervical dystonia, muscular spasm associated with cerebral palsy, blepharospasm, spasmodic dysphonia, overactive bladder, oromandibular dystonia, writer’s cramp, migraine headache, tennis elbow, Dupuytren contracture, chronic low back pain, poststroke spasticity, achalasia, and anal fissure.

How is a patient assessed in preparation for treatment with BoNT-A?

A full facial analysis is performed including the location and depth of facial rhytids. Asymmetries are identified before injection and noted to the patient. Particular attention is given to brow position and function, as well as eyelid position and function. It is highly recommended to document with photos before treatment. The extent of sun damage and actinic change is also noted.

Describe the depressor muscles of the brow.

The depressors of the brow are the corrugator supercilii muscles (transverse and oblique heads), the procerus muscles, and the orbital portion of the orbicularis oculi and its associated depressor supercilii muscle medially. All these muscles act on the glabellar complex.

Describe the elevator muscles of the brow.

The elevator of the brow is the frontalis muscle. It has no true bony insertions but blends with the depressors of the brow. It also has dense dermal insertions responsible for transverse forehead rhytids.

Describe the constrictor muscles of the eyelids.

The constrictor muscles of the eyelids are a complex array of concentrically oriented muscles with origins medial to the medial canthus and insertion lateral to the lateral canthus. Collectively, these muscles are referred to as the orbicularis oculi muscles. Further, differentiation is made based on location relative to the underlying lid structures; oriented in a concentric manner from outside to inside they are the:

1. orbital orbicularis

2. preseptal orbicularis

3. pretarsal orbicularis

Further divisions (based on function) can be made, principally the innercanthal orbicularis and the extracanthal orbicularis. Understanding this anatomic and functional differentiation is critical when considering injections of BoNT-A in this area (for further description of the constrictor muscle function, see chapter on eyelid surgery).

Describe the elevator muscles of the upper eyelid.