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

Question 1

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

Answer 1

There are currently two available formulations of BoNT-A in the United States: Botox (onabotulinumtoxinA; Allergan Inc, Irvine, CA) and Dysport (abobotulinumtoxinA; Medicis Aesthetics Inc, Scottsdale, AZ). Two others are currently in the process of FDA approval in the USA, Xeomin (Merz Pharma) and PurTox (Mentor Corp, Santa Barbara, CA).

Question 2

From what organism is BoNT-A made?

Answer 2

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

Question 3

What is the mechanism of action of BoNT-A?

Answer 3

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.

Question 4

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

Answer 4

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.

Question 5

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

Answer 5

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

Question 6

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

Answer 6

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.

Question 7

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

Answer 7

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.

Question 8

How many BoNT-A treatments were reported in 2008?

Answer 8

In the United States there were 2.5 million patients treated (including Botox and Dysport) for aesthetic purposes according to multispecialty data collected by the American Society for Aesthetic Plastic Surgery (ASAPS statistics 2009).

Question 9

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

Answer 9

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, oromandibular dystonia, writer’s cramp, migraine headache, tennis elbow, Dupuytren contracture, chronic low back pain, poststroke spasticity, achalasia, and anal fissure.

Question 10

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

Answer 10

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. The extent of sun damage and actinic change is also noted.

Question 11

Describe the depressor muscles of the brow.

Answer 11

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.

Question 12

Describe the elevator muscles of the brow.

Answer 12

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

Question 13

Describe the constrictor muscles of the eyelids.

Answer 13

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).

Question 14

Describe the elevator muscles of the upper eyelid.

Answer 14

The two primary muscles responsible for upper eyelid elevation are the levator palpebrae muscle (parasympathetic innervation) and Mueller’s muscle (sympathetic innervation); both insert onto the tarsal plate. A secondary effect on upper lid position is due to the frontalis muscle and brow position. Brow elevation will secondarily raise the eyelid. This is often evident as brow strain and chronic horizontal forehead rhytids in patients with dermatochalasis or upper lid ptosis.

Question 15

What is the cause of ptosis after injection of BoNT-A, how long does it last, and how is it treated?

Answer 15

There are two potential etiologies of upper lid ptosis following BoNT-A injection. One is paralysis of brow elevation in the presence of brow strain compensating for preexisting lid ptosis. Second is migration of toxin to the lid retractors as a direct effect. This occurs if toxin is injected to close to the lid retractors, in the periosteum of the brow (facilitating migration), or toxin is massaged down to the eyelid after injection.
This effect can last up to a month and is managed with alpha-adrenergic agonist ophthalmic drops (eg, phenylephrine ophthalmic drops).

Question 16

What are the two most common undesirable mimetic effects of BoNT-A injections of the glabella and forehead?

Answer 16

1. The “Mephisto” eyebrow or the totally depressed eyebrow. The “Mephisto” or “Spock” brow is the result of medial brow depression and paralysis with preserved lateral brow function. This results in a severely angular appearance to the brow with medial depression and a severe upward lateral sweep. This is treated by a small dose administration to the lateral frontalis muscle responsible for preserved lateral brow elevation, resulting in lateral brow paralysis and resolution of the severe upward lateral sweep. This is avoided by uniform treatment of the forehead and/or conservative treatment of the glabella.
2. Total brow depression is the result of excess toxin administration to the frontalis muscle in the presence of chronic frontalis stain in patients with dermatochalasis or upper eyelid ptosis. This is avoided by proper pretreatment assessment and conservative treatment of the forehead at least 2 cm above the level of the brow.

Question 17

What are bunny lines? Which muscle is responsible for them?

Answer 17

Bunny lines are small obliquely oriented mimetic rhytids of the lateral nasal dorsum. These can be induced by asking the patient to simulate a deep sniff or sneer. The levator labii superioris alaeque nasi and nasalis muscles are responsible for theses lines. A low-dose–low-volume treatment of high concentration with BoNT-A is recommended here to minimize spread into local musculature, especially the medial head of the orbicularis oculi muscle.

Question 18

What application does BoNT-A have in the chin?

Answer 18

An active mentalis muscle with thin skin coverage can result in a “peau d’orange” appearance. Small amounts of BoNT-A into the body of the mentalis muscle (low and close to center) can smooth this appearance. Care is taken to avoid unintentional injection into the depressor anguli oris (DAO).

Question 19

What is the cause of vertical perioral rhytids?

Answer 19

Aging, smoking, and action of the orbicularis oris muscle.

Question 20

What problems can be caused by overtreatment of the perioral area?

Answer 20

Difficulty in pursing the lips, sucking through a straw, speech impairment, difficulty eating, difficulty brushing teeth, and diminished proprioception. Excess injection of the DAO and associated lip depressors can cause oral incompetence, drooling, and asymmetrical smile.

Question 21

What causes platysmal bands and can they be treated with BoNT-A?

Answer 21

Platysmal bands are the result of platysma muscle laxity and descent and thin coverage. Mild to moderate banding
can be improved with BoNT-A injections directly into the body of the band.

Question 22

Why do men require a higher dose of BoNT-A?

Answer 22

In general the muscles of men are greater in mass and therefore require higher doses of BoNT-A to achieve a similar
clinical effect as seen in women with a lower dose.

Question 23

What are the most common reported adverse events due to BoNT-A injections?

Answer 23

Bruising, swelling, and temporary skin irritation are common adverse events and mostly related to the use of a
needle for percutaneous injection.

Question 24

How can the undesirable side effects of BoNT-A be minimized?

Answer 24

Proper patient selection and analysis is crucial. Use the smallest needle possible, minimize the number of percutaneous punctures, avoid known vessels, use ice packs after injection, avoid nonsteroidal anti-inflammatory drugs and aspirin prior to injection, and avoid vigorous activity immediately after injection.

Question 25

What is a “Botox party?”

Answer 25

This is a colloquial term applied to a social gathering outside the auspice of a medical office (often a hotel room or personal residence) where multiple people are injected with BoNT-A. Performing injections in settings like this are generally frowned upon for the following reasons: proper informed consent is often not obtained and is invalid if alcohol is involved, the proper medical equipment and supplies are not available should they be needed, some patients may feel pressured to be treated who would not otherwise choose to be, injections in a “party” setting are not thought of as a medical procedure when they should be, proper preparation and handling of the toxin and sterile technique are all put at risk.

Question 26

What is the effect of administering a toxin and a dermal filler at a single treatment session?

Answer 26

There is a synergistic effect of injecting a toxin and filler at the same session. There is a better chance that severe rhytids can often be totally effaced and one can expect that the filler will last longer in the area where the muscle has been weakened by BoNT-A. There is less physical stress on the filler; therefore, it is slower to be broken down.

Question 27

What is the current cosmetic indication for BoNT-A recognized by the FDA?

Answer 27

Currently the FDA recognizes injection of cosmetic BoNT-A for the treatment of glabellar lines.

Question 28

What does “off-label” use of BoNT-A mean?

Answer 28

When the FDA approves a drug for use in the United States it includes a precise description of the exact indication for usage. Botox Cosmetic, for example, is FDA approved 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.” Using Botox for this indication is considered “on-label” use; any use otherwise is considered “off-label” use (eg, crow’s feet or any other area).

Question 29

What is the “black box” warning?

Answer 29

The “black box” warning was instituted by the FDA in 2009 and is a required inclusion on the drug description for all makers of BoNT-A in the United States. It is intended to inform product users about the potential distant spread of toxin and its effect. The black box warning for Dysport is included in its entirety below for reference.

Question 30

Distant spread of toxin effect?

Answer 30

Postmarketing reports indicate that the effects of Dysport and 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 been reported at doses comparable to those used to treat cervical dystonia and at lower doses.

Question 31

What are the common off-label uses of Botox?

Answer 31

Cosmetic uses: forehead horizontal rhytids, lateral orbital wrinkles (crow’s feet), vertical perioral rhytids, dimpled
appearance (peau d’orange) of the chin, and platysmal bands.
Noncosmetic uses: migraine headache, chronic low back pain, poststroke spasticity, traumatic brain injury, cerebral palsy, achalasia, anal fissure, and various dystonias.

Question 32

What are absolute contraindications to the use of Botox?

Answer 32

1. infection at the proposed injection site
2. in individuals with known hypersensitivity to any ingredient in the formulation
3. during pregnancy (High doses in pregnant rabbits resulted in abortion or fetal malformations. While no evidence of adverse effects in human fetuses exists, there is insufficient clinical safety data to support the use of Botox in pregnant, cosmetic patients.)
4. patients with peripheral motor neuropathic disorders (amyotrophic lateral sclerosis or motor neuropathy) or neuromuscular junctional disorders (myasthenia gravis or Lambert–Eaton syndrome) may be at increased risk of serious side effects from typical doses of Botox including severe dysphagia and respiratory compromise

Question 33

What are the relative contraindications to the use of Botox?

Answer 33

1. diseases of neuromuscular transmission
2. coagulopathy (including therapeutic anticoagulation)
3. nursing mothers
   The effect of the toxin may be potentiated with coadministration of aminoglycosides or other agents interfering with neuromuscular transmission (curare-like nondepolarizing blockers, lincosamides, polymyxins, quinidine, magnesium sulfate, anticholinesterases, and succinylcholine chloride).

Question 34

What is the evidence that Botox works as a treatment for migraine headaches?

Answer 34

Double-blinded, placebo-controlled studies have reported reduction in the frequency of migraine headaches, particularly in those patients not taking other medication.