Botox

Botox is a potent neurotoxin produced by the bacteria Clostridium botulinum, consisting of one heavy chain and one light chain. Its molecular weight is 150 kd. It is used in Dermatology to eliminate dynamic wrinkles and to treat excess sweating (hyperhidrosis). It is injected precisely into the site of unwanted muscular or eccrine sweat gland activity. Two serotypes of eight known are commercially available: Botox A and Botox B. It is available under the following trade names: BOTOX (Serotype A), Dysport (Serotype A), and MYOBLOC (Serotype B).

What are the relative potencies of the different formulations of Botox?

Formulation	Relative potency
BOTOX	1
Dysport	0.33-0.50
MYOBLOC	0.01-0.02

How does Botox work?

Botox produces localized chemodenervation and flaccid paralysis. It takes 1-2 days for onset of paralysis and 1 week for full effect (occasionally an effect may be observed within hours). It is effective for 3-6 months or longer, and there is cumulative benefit to repeat injections. However, effects reverse over time.

The neurotoxin binds to presynaptic acetylcholine receptors on motor neurons at the neuromuscular junction (NMJ), where it is taken up by receptor-mediated endocytosis, which is enhanced by nerve stimulation. It translocates to the cytoplasm, where it acts as an endoprotease, cleaving polypeptides (components of SNARE fusion complex) essential for neurotransmitter release. Serotypes A, C, and E cleave SNAP-25; Sertoypes B, D, F, G cleave synaptobrevin II (also known as VAMP); Serotype C also cleaves syntaxin I. All of these proteins are involved in docking, fusion and release of vesicles containing ACH from the nerve terminal.

What are the dermatologic uses of Botox?

The primary uses of Botox are diminishment of facial wrinkles; diminishment of platysmal bands; and treatment of hyperhidrosis.

How is Botox handled?

BOTOX (100 U) and Dysport are freeze-dried and shipped on dry ice. The product should be kept frozen at -5° C until use (up to 9 months). When preparing for use, the product is gently warmed to room temperature and reconstituted with sterile unpreserved 0.9% saline, with minimal agitation. Some suggest that using preserved saline result in decreased pain on injection. Unused reconstituted Botox should be refrigerated (2-8° C) and used within 4 hours (per manufacturer). In practice, some say that it can be used for 2 days, 2 weeks, and even a month after reconstitution. MYOBLOC does not require reconstitution. It is stable for >30 months (refrigerated) and 9 months at room temperature.

How is BOTOX reconstituted?

Common dilutions are as follows:

Saline (ml)	U/0.1 ml
1	10
2	5
2.5	4
5	2
8	1.25

How is BOTOX used?

BOTOX is injected using a small gauge (e.g. 0.3 ml, 30 G, 6 mm, BD Ultrafine II) needle and 0.3-1.0 ml syringe directly into the muscle of facial expression responsible for the wrinkle. Some propose subcutaneous or intradermal placement, especially for the crows foot region in order to minimize bruising. Elevating the injection site can help with intramuscular placement. Veins or arteries must be avoided. Caution must be exercised with patients on NSAIDS or anticoagulants.

The patient can be upright or supine, depending on the site to be injected and preference of the physician. The position of patient slightly below the physician with chin down is a comfortable one. Some practitioners use topical anesthesia or ice to reduce the pain of injection. If the site is marked, one must be sure to avoid tattooing; the mark should be placed slightly above or below to avoid contamination. The patient should be instructed to contract and relax the muscle just prior to injection, but the injection should be placed with the muscle at rest. EMG guidance is sometimes used for precise placement.

Mild to moderate pressure can be applied to stop bleeding. Pressure also helps to spread the Botox. Excessive pressure in the glabellar and supraorbital area should be avoided, as this may result in spread to periocular muscles, and ptosis. Patients should be instructed to avoid manipulation or pressure on injection sites for several hours.

Is BOTOX antigenic?

Antibodies to BOTOX have been reported with high doses. The manufacturer recommends that less than 200 U/month be used. Neutralizing antibodies are unlikely in dermatologic applications. Also, serotype A and B antibodies are not cross-neutralizing. Non-neutralizing antibodies are common.

What are adverse reactions to Botox?

Ecchymosis and localized swelling.
Headache, usually a mild discomfort or heavy feeling in the mid-forehead. It usually resolves after several days, though severe long-lasting headaches have been reported.
Skin eruptions at the injection site and a diffuse dermatologic eruption have been reported.
Ptosis (droop of eyelids) occurs in less than 2% of glabellar injections; this rate is even lower when performed by experienced physicians. It results from spread of toxin to the levator palpebrae superioris. It is temporary, lasting 2-10 weeks. Ptosis can be reduced with alpha-1 agonist eye drops (e.g. apraclonidine 0.5%, Naphcon A, Vasocon A) that stimulate Mueller’s Muscle (parasympathetic innervation), which raises the upper lid
Asymmetry.
Over- or under-treatment
Deep-seated wrinkles may not be fully eliminated.
Injection into cervical or perioral structures can result in dry mouth, drooling, difficulty with articulation, dysphonia, dysphagia, dyspepsia, neck pain and headache. This is not generally an issue with the small amounts of Botox used and the superficial placement used by dermatologists.
Systemic effects are rate (e.g. allergy, anaphylaxis, fever, flu-like symptoms, cough, and nausea.)

What are contraindications to BOTOX?

A known hypersensitivity to any ingredient in the formulation is a contraindication to Botox use.
Caution should be exercised in patients with neuromuscular disorders (e.g. myasthenia gravis).
Patient with coagulopathies are at increased risk of ecchymosis and other bleeding complications.
The product contains albumin (human blood product).
Patients on aminoglycoside antibiotics should receive lower dosing.
Botox should not be placed in sites of active infection.
The lethal dose is estimated at 2,500-3,000 U.
Botox is pregnancy Category C

Post-injection instructions for BOTOX

Patients should be advised to avoid napping or lying down for several hours and not to manipulate the injected areas. Exercising the injected area for the first 90 minutes can improve uptake of the toxin into muscle. Cosmetics can be applied directly after injection

BOTOX for facial rejuvenation

Botox is useful in eliminating hyperdynamic wrinkles, primarily in the upper face. Lines result from repeated contraction of the muscles perpendicular to the wrinkles; weakening these muscles can smooth these lines. Potentially treatable areas are:

Horizontal lines on forehead (frontalis muscle)

Vertical lines in the glabellar region (between eyebrows, corrugator muscles)

Horizontal creases across bridge of nose (procerus muscle)

“Crows feet” and lateral lines along the lower eyelid (lateral orbicularis)

Perioroal lines (orbicularis oris)

Deep folds or grooves elsewhere that are exacerbated by muscle contraction.

The idea patient is 30-50 years old with hyperdynamic wrinkles; Botox has no effect on wrinkles that result solely from laxity, excess fat, or flaccid muscles. Older patients may require adjunctive treatments to treat loss of skin elasticity.

Facial anatomy

A knowledge of facial anatomy is required to understand the use of Botox.

Facial Anatomy Upper Face

Glabellar wrinkles

Glabellar wrinkles result from the action of the "depressor group" of muscles. The action of these muscles is downward and medial.

Procerus. Straight down

Depressor supercilli. Straight down

Corrugator supercilli. Diagonally oriented. Pulls eyebrows down and in. This muscle contributes most to glabellar wrinkles.

Forehead wrinkles

The frontalis muscle pulls the forehead upward to create horizontal forehead wrinkles. This muscle opposes downward pull of glabellar muscles. Patient’s with “heavy” brows may rely on the frontalis muscle to prevent brow ptosis (droop). This must be tested for by having the patient open and close her eyes and observing for use of the frontalis. If the frontalis contributes to eye opening, then Botox can cause brow droop. Simultaneously treating the glabellar muscles may reduce brow droop in this case.

Orbicularis oculus. Primary muscle responsible for crow’s foot wrinkles.

Zygomaticus major and minor. These muscles run diagonally upward and contribute to wrinkles to a minor degree. They are activated when one smiles. This group raises the cheeks and causes lower crows foot wrinkles. They also contribute to melolabial fold formation.

Facial Anatomy Lower Face

Orbicularis oris. This is the sphincter around the mouth. It contributes to perioral wrinkles.

Mentalis. Pulls mouth straight down. It can contribute to a deep chin crease.

Depressor anguli oris. Extends from corner of mouth diagonally out to mandible. It depresses the corner of mouth.

Platysma. A thin muscle on the anterior and anterolateral neck and chest. In the face, it extends to the lower mandible and chin. It pulls the neck and upper chest upward, and the mouth downward. It contributes to horizontal and vertical bands in neck.

Glabellar lines and depressed brow

These lines are caused by the corrugator and orbicularis muscles (medial movement of brow) and the procerus and depressor supercilli (inferior movement). There is significant variation in the location and size of “frown” muscles, necessitating individualized treatment. Deep-seated wrinkles that cannot be eliminated by spreading with a fingertip on either side will be decreased but not eliminated with Botox. Adjunctive treatment, such as dermal fillers, may be necessary to treat such lines.

Botox eliminates or reduces dynamic wrinkles in this area, reducing a stern or angry countenance. It can also elevate the medial brow by up to 2 mm, opening up the medial eye. Injection of 2-3U at the lateral eye brow can result in further elevation of lateral brow (this is not usually performed in men.)

Numerous approaches are possible. Injections in the procerus and corrugator supercilli is the goal. Due to greater muscle mass, men usually need more units of Botox than women. The needle should be aimed up and away from the eyes, at least 1 cm above the orbital rim to avoid lid ptosis. This area should not be massage afterward to prevent spread and ptosis. The first injections should be placed directly above the medial canthus on either side. The second injections should be placed 2 cm lateral and slightly superior (at least 1 cm superior to orbital rim in the mid-pupillary line). A second injection can be avoided by re-angling and advancing the needle. Placement in the corrugator muscle can be confirmed by having the patient frown and relax. An additional injection at the intersection of a line drawn between each medial eyebrow and the contralateral medial canthus (i.e. procerus) is desirable. This injection can be massaged horizontally. Many other approaches are possible.

Horizontal forehead lines

Horizontal forehead lines result from contractions of the frontalis (brow elevator). The goal is to soften lines, rather than eliminate them. It is advisable to treat depressors (i.e. glabellar) at the same time. Adverse effects that can result from treatment are lack of expression and brow ptosis; more lateral injections are more likely to lead to ptosis. Treatment of only medial aspects can result in “Botox Eyebrows”—a raised lateral eyebrow.

Four to six evenly distributed injections 2-3 cm above the eyebrows is the usual placement, especially if the glabella is also treated. Extend up to, or just beyond, the mid-pupillary line. An additional 2-3U lateral to the midpupillarly line, at mid-brow, can drop the lateral brow, eliminating “Botox Eyebrows” (which are especially undesirable in men.) Wider foreheads may require more injections, while taller foreheads warrant more of a V-pattern or additional injections in the upper forehead. Pressure is safe on the forehead and helps to distribute the injection.

Crow's feet

For crow's feet, the injection is usually placed superficially; thin skin is prone to ecchymosis. Two to four injection sites are typical, each 1 cm from the orbital rim. The injections should be directly into the wrinkle accentuated by smiling , and 1 cm above and below this site. The goal is to weaken the lateral fibers, not the entire orbicularis occuli.

Other uses of botox

There are numerous other uses of Botox that will not be explored in this article, including: lower eyelid orbicularis hypertrophy, overactive zygomaticus muscles, lip pucker lines, down-turned mouth, pebbly chin, deep mental crease, and nasal scrunch lines.

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