Dermatologic Use of Botulinum Toxin 

Updated: Feb 07, 2019
Author: Zoltan Trizna, MD, PhD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Botulinum toxin is the product of Clostridium botulinum. C botulinum bacteria and their spores are ubiquitous. The bacteria are found in soil and marine sediments; the spores can be detected on fruits and vegetables and in seafood. The growing bacteria produce the neurotoxin botulinum toxin, which is often referred to as the most poisonous substance known to mankind. The neurotoxin inhibits the release of acetylcholine and results in the flaccid paralysis of the affected muscles.

Seven serologically distinct types of botulinum toxin exist: A, B, C1, D, E, F, and G. Botulinum toxin type A (BOTOX®; Allergan) was the first commercially available type in the United States.

The different types of botulinum toxin have different molecular sizes, degrees of activation, and mechanisms of action. Various commercial preparations have different characteristics regarding their clinical performance. Significant research is underway to study the molecular causes of these differences.

The available types of botulinum toxin type A are named onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and prabotulinumtoxinA. Botulinum toxin type B is named RimabotulinumtoxinB. OnabotulinumtoxinA is marketed as BOTOX®/BOTOX® Cosmetic, abobotulinumtoxinA as Dysport®, incobotulinumtoxinA as Xeomin®, prabotulinumtoxinA as Jeuveau®, and rimabotulinumtoxinB is marketed as Myobloc®.

This article focuses on the dermatologic applications of botulinum toxin in general. The reader should note that the dermatologic use of botulinum toxin requires an in-depth knowledge of the anatomy and function of the areas treated (eg, in the case of the face, facial muscles, and their relations with the orbit). From the cosmetic point of view, an understanding of the complex functions of the muscles to be injected is especially important.

Botulinum toxin has beneficial effects only on wrinkles caused by muscular contractions. Botulinum toxin is not an appropriate treatment for wrinkles caused by solar exposure or other degenerative processes of the dermal tissues. This article provides only an overview of the technique and of several clinically relevant issues and does not replace hands-on training and experience.

For patient education resources, see the patient education article BOTOX® Injections.

Several Medscape articles address botulinum toxin–related procedures, as follows:

  • Dystonia Treatment using Botulinum Toxin

  • Botulinum Toxin in Pain Management

  • Botulinum Toxin

  • BOTOX® Injections to Improve Facial Aesthetics

  • BOTOX® Injections in Plastic Surgery

History of the Procedure

During the treatment of blepharospasmus with botulinum A exotoxin, the cosmetic appearance of the glabellar frown lines improve. Thus, the cosmetic effects of botulinum toxin were discovered.

Problem

Botulinum toxin is used in dermatology for the treatment of facial wrinkles caused by muscular contractions. These wrinkles are commonly referred to as crow's feet, frown lines, and bunny lines.

Facial expression is influenced by muscular actions of the face. Both voluntary and involuntary contractions of the muscles play a significant role in expressing various emotions, such as fear, anxiety, and anger. However, the exaggeration of the facial lines can be cosmetically unacceptable or socially undesirable.

Hyperhidrosis, caused by increased local cholinergic activity affecting sweat production, can also be socially unacceptable and may interfere with many daily activities (eg, in the case of palmar hyperhidrosis, with the handling of finer instruments or driving).

Epidemiology

Facial wrinkling affects almost 100% of the population. However, its perception varies widely across cultures, age and sex groups, as well as occupations and social positions.

Etiology

Two underlying mechanisms cause wrinkles: muscular contractions and solar damage. Botulinum toxin is appropriate only for the treatment of wrinkles caused by muscular action.

Pathophysiology

The neurotoxin inhibits the release of acetylcholine and results in the flaccid paralysis of the affected muscles.

Presentation

Generally, 3 clinical situations of botulism are distinguished: food-borne botulism, wound botulism, and infant botulism. The common mechanism in these disorders is the paralysis of various muscles caused by the botulinum toxin. The paralysis can ultimately lead to the death of the patient. However, one's poison is another's medicine, because botulinum toxin is useful in the treatment of certain diseases.

The extent and location of the frown lines should be documented with the patient's face in both a resting position and in an exaggerated expression (eg, frowning, smiling). For comparison, the patient's facial expressions should be photographed before treatment and at the follow-up examination.

Documenting the patient's concerns about the social implications is important. The desired and realistic results and the patient's understanding of these results should also be documented.

Hyperhidrosis should be evaluated on a subjective basis. Note the extent to which it interferes with the patient's daily activities and work. List all over-the-counter and prescribed medications that the patient has used to treat this condition. The starch-iodine test is one method for the visual evaluation of the extent and quantity of sweating. Sweating can be quantitatively measured by applying bibulous paper to the area of concern and then weighing the paper after a period of time (see Diagnostic Procedures).

Indications

The US Food and Drug Administration (FDA) has approved the use of several botulinum toxins for the purposes described below (other regulatory agencies may have additional approved uses).

BOTOX® (onabotulinumtoxinA) is indicated for (1) cervical dystonia in adults to decrease the severity of abnormal head position and neck pain associated with cervical dystonia; (2) severe primary axillary hyperhidrosis that is inadequately managed with topical agents; (3) detrussor muscle hyperactivity; (4) overactive bladder; (5) chronic migraine headache, (6) and strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients aged 12 years and older.

BOTOX® Cosmetic (onabotulinumtoxinA) is indicated for temporary improvement in the appearance of moderate-to-severe glabellar lines associated with corrugator and/or procerus muscle activity in adults (65 y or younger). It is also indicated for temporary improvement in the appearance of moderate-to-severe lateral canthal lines associated with orbicularis oculi activity in adults. It is also indicated for the temporary improvement in the appearance of moderate-to-severe forehead lines associated with frontalis muscle activity in adults.

Dysport® (abobotulinumtoxinA) is indicated for the treatment of adults with cervical dystonia, lower limb spasticity, and spasticity. The cosmetic indication is for the temporary improvement in the appearance of moderate-to-severe glabellar lines associated with procerus and corrugator muscle activity in adults younger than 65 years.

Jeuveau® (prabotulinumtoxinA) is indicated for temporary improvement in the appearance of moderate-to-severe glabellar lines associated with corrugator and/or procerus muscle activity in adults.[1]

Xeomin® (incobotulinumtoxinA) is indicated for the treatment of (1) adults with cervical dystonia to decrease the severity of abnormal head position and neck pain in both botulinum toxin–naive and previously treated patients and (2) adults with blepharospasm who were previously treated with onabotulinumtoxinA. The cosmetic indication is for the temporary improvement in appearance of moderate-to-severe glabellar lines associated with corrugator and/or procerus muscle activity in adults.

Myobloc® (rimabotulinumtoxinB) is indicated for the treatment of patients with cervical dystonia to reduce the severity of abnormal head position and pain associated with cervical dystonia.[2]

Common uses of botulinum toxin A include the treatment of wrinkles caused by contraction of the muscles of the face, which includes glabellar frown lines,[3, 4] transverse forehead lines, lateral canthal wrinkles (ie, crow's feet),[5] and medial and lateral brow lifts.

For an experienced physician, other indications may include treatment of the following: wrinkles on the upper lip, nasal scrunching and flaring, marionette lines, necklines and platysmal bands,[6] mental creases, and dimpling of the chin. These applications can lead to complications that interfere with physiologic functions; therefore, some authors consider them risky. A further indication is the management of localized axillary or palmar hyperhidrosis that is nonresponsive to topical or systemic treatment.[7, 8, 9]

Botulinum toxin is also used to treat other conditions. Multiple off-label uses, including the treatment of palmar and plantar hyperhidrosis, focal dystonias, spasticity, hemifacial spasm, tics, tremors, tension headaches, and migraines, are reported.[10] These treatment options are considered experimental.[11]

Relevant Anatomy

The most important anatomic units and their related effects include the following.

Corrugator supercilii muscle - Vertical rhytides

When contracted, the bulk of the corrugator supercilii muscle protrudes at the medial aspect of the eyebrow. The origin of this muscle is relatively consistent at the junction of the nasal and frontal bones close to the supramedial orbital rim. A transverse line drawn coronally through the middle of the eyebrow identifies the horizontal position of the bulk of the muscle. For the best effect and for avoiding the unwanted injection of botulinum toxin through the orbital septum, the needle should be oriented at or slightly above this plane, and the injection should target the thickest portion of the muscle adjacent to the medial aspect of the brow. Do not inject points lateral to the midpupillary line.

Procerus muscle - Horizontal rhytides

The procerus muscle is a narrow muscle located in the midline of the nose; it usually lies 1-4 mm deep to the surface. The muscle is generally longer in women than in men. The optimal injection site is the midline just caudal to the nasal root.

Frontal muscle - Horizontal frown lines

Before injecting the frontal muscle, mark the horizontal lines of the skin. Inject the thickest portions of the muscle at points 1.5-2 cm apart. Laterally, raise the line of the injections away from the brow to maintain some function of expression in the lateral part of the brow. To avoid ptosis, do not inject close to the brow.

Orbicularis oculi muscle - Crow's feet

Mark the lateral canthal line 1 cm lateral to the canthus. Then, the patient should be asked to squint, and the squint lines above and below the lateral canthal line are marked. The injections are symmetrically placed into the muscle on both sides of the face. To avoid problems with eyelid closure, do not inject too close to the eyelids.

Orbicularis oris and mentalis muscles - Excessive lip pursing

The injection site is the point halfway between the vermilion border of the lower lip and the inferior edge of the mentum, approximately 0.5-1 cm medial to the oral commissure. Avoid injecting too close to the lip, and use only small amounts of the toxin.

Platysma - Platysmal bands

The injections are performed under electromyographic control, and the needle should be inserted perpendicular to the muscle fibers.

Axilla

Prior to the injections, an iodine starch test is recommended. The hyperhidrotic areas are delineated by a deep blue-black color. To ensure intradermal placement of the botulinum toxin, each dose should be injected with the needle at a 45° angle to the skin surface. The beveled side should point upwards to minimize leakage. The injection sites should be evenly spaced, taking into consideration that each injection site has a ring of effect of up to approximately 2 cm in diameter. The recommended total dose is 50 U per axilla. Avoid marking the injection sites with ink; if ink is used, do not inject directly through the mark, which may create a permanent tattoo.

Contraindications

Local and systemic contraindications include the following: (1) wrinkles not caused by muscular contractions, (2) neuromuscular disorders, (3) known hypersensitivity to any ingredient in the formulation, (4) pregnancy or breastfeeding, (5) unrealistic patient expectations, (6) possible interference with the patient's work or daily activities due to changed facial expressions (eg, in the case of public performers), and (7) infection at the proposed injection site(s).

 

Workup

Diagnostic Procedures

Electromyography (EMG) is useful in exactly identifying the muscles underlying the wrinkles, especially the smaller muscles. EMG is also a good teaching tool. To perform the procedure, the active EMG electrode is inserted into the muscle and slowly advanced until a signal of maximum intensity is detected. This signal is generated by the contraction of the target muscle. The botulinum toxin is injected into the identified area. EMG is time consuming and adds to the expense of the procedure. Therefore, it is not frequently used in the general dermatologic practice. Several portable devices are available.

The starch-iodine test visually demonstrates the extent of hyperhidrosis and indicates the amount of sweating. This test is performed by exposing the hyperhidrotic area to paper impregnated with iodine or by layering a starch-iodine mixture onto the skin. The paper method may be better on the palms and soles, whereas layering the mixture is easier in the axillae. This test is contraindicated in patients with hypersensitivity to iodine. The presence of sweat results in a blue-black pigment reaction after about 10 minutes. By photocopying the paper or photographing the area, permanent documentation is achieved.

Sweating can be quantitatively measured by placing bibulous paper on the affected area. After a period of time, the increase in the weight of the paper is documented. Repeated measurements should be obtained under the same conditions of ambient temperature and elapsed time.

 

Treatment

Surgical Therapy

The selected areas are treated by injecting either 2-4 units of BOTOX® or clinically equivalent amounts of Myobloc or Dysport into the thickest part of the muscle.

The injection can be a single-point injection or a skewered injection. With the latter method, which is used primarily in the platysma, the preferred injection site is identified with EMG. The needle is then inserted parallel to the plane of the muscle, and the injection is performed while the needle is carefully withdrawn.

Orbicularis muscle/periorbital crow's feet injecti Orbicularis muscle/periorbital crow's feet injection.
Frontalis muscle injections. Frontalis muscle injections.
Corrugator muscle injections. Corrugator muscle injections.
Procerus muscle injections. Procerus muscle injections.

Preoperative Details

Preoperative details include the following: identifying contraindications, if any; discussing the realistic expectations with the patient; identifying the areas to be treated; locating the targeted muscles; and preparing a plan of injection.

For later comparison, the patient's face should be photographed before treatment in both the resting position and in an exaggerated expression (eg, frowning, smiling).

Any makeup should be carefully removed, and the planned injection sites should be cleaned with isopropyl alcohol.

Cooling of the injected areas prior to the injections can provide proper anesthesia.[12]

Intraoperative Details

The patient should lie on his or her back, comfortably propped up.

Postoperative Details

To prevent the unwanted diffusion of botulinum toxin into the adjacent muscles, do not massage the injection site, and advise patients to avoid doing so as well. Female patients should not reapply their makeup in the office. All patients should avoid exertion on the day of treatment.

Follow-up

Follow up with the patient in 1-2 weeks, and photograph the patient's face with the same expressions as those in the preoperative pictures.

Re-treat the patient as needed after the effects diminish.

Complications

All unwanted local effects of botulinum toxin are generally transient and gradually wear off. However, some unwanted effects (eg, drooling) can seriously affect the patient's everyday activities. As with any injection, pain, mild bruising, and infection can occur. Diffusion of botulinum toxin can lead to weakness of the muscles adjacent to the injection site. Therefore, advising the patient not to massage the injected areas is important.

Ptosis can occur when injections above the brow are too lateral (past the midpupillary line) or too close to the brow. Some authors use phenylephrine apraclonidine (Iopidine) eye drops to minimize ptosis. Delayed eyelid closure, a decreased blink response, and excessive tearing can occur when injections into the orbicularis oculi muscle in the temporal region are too close to the eyelid. Asymmetry of the face can occur because of differences in injection techniques or doses between the 2 sides of the face. Drooling can occur when injections of the orbicularis oris muscle are too close to the lip.[13]

Systemic complications are possible. Headache has been reported and is usually transient. Hypersensitivity reactions have not been described. Antibody development is described in patients receiving high doses of botulinum toxin (eg, for the treatment of torticollis or dysphonia); as a result, their muscles become resistant to further therapy.[14] One case of necrotizing fasciitis occurred after botulinum toxin was injected into a patient who was immunocompromised.[15]

During the treatment of hyperhidrosis, complications can result from the use of local anesthetics. Muscular paralysis and a temporary loss of manual functions are possible alarming complications.

Overdosing can theoretically occur by accidental injection or oral ingestion. The patient should be supervised medically for up to several weeks for signs or symptoms of paralysis or systemic weakness. If the overdose or inappropriate injection is immediately known, an antitoxin is available. However, this will not reverse the unwanted effects that were present at the time of antitoxin administration.

The use of unlicensed botulinum toxin product was documented in a series of 4 iatrogenic botulism cases in 2004. Laboratory tests suggested that by receiving injections of a highly concentrated unlicensed botulinum toxin A preparation, these patients might have received doses 2857 times the estimated human lethal dose by injection.[16]

Outcome and Prognosis

The effects of botulinum toxin injections are not immediately noticeable. The full effect is achieved approximately 3-7 days after treatment, with the peak at around 1 month. The results last for about 4-6 months with a gradual reappearance of the wrinkles.

The results are cumulative; repeated treatments tend to lead to longer-lasting effects. After several injections of botulinum toxin into the same anatomic region, the underlying muscles may become atrophied. This effect usually leads to the permanent resolution of the wrinkles.

For comparison, the patient's face should be photographed before treatment and at follow-up visits.

In the treatment of hyperhidrosis, the use of botulinum toxin results in dramatic improvement, which can be objectively documented by repeating the starch-iodine test. The treatment must be repeated every 4-6 months.

Botulinum toxin treatment of hyperhidrosis in persons with social anxiety disorder has led to improvement of social functioning and a reduction of overall disability.[17]

Recent studies compared onabotulinumtoxinA (Botox) and abobotulinumtoxinA (Dysport) with split-face injections. In a randomized, double-blinded study of 10 U of onabotulinumtoxinA and 30 U of abobotulinumtoxinA for the treatment of lateral orbital rhytids, abobotulinumtoxinA showed a statistically significant advantage compared with onabotulinumtoxinA in the treatment of lateral orbital rhytids at maximal contraction.[18]

Future and Controversies

Future

In addition to the treatment of glabellar lines, the number of FDA-approved indications for the use of botulinum toxin in cosmetic applications may increase.

The treatment of wrinkles with botulinum toxin is becoming more popular, and demand for it is expected to increase. The cosmetic use of botulinum toxin is essentially controlled by market forces because most health insurance does not cover it. Economic trends (especially trends in the amounts of disposable income) and social issues influence the number of people seeking treatment. Also, the limited number of products and suppliers affect the current prices of the treatment.

Controversies

What conditions should be treated with injections of botulinum toxin? Generally, treatment of the glabellar, frontal, and temporal frown lines is considered safe. Several authorities consider other uses around the mouth and on the neck risky.

Which preparation should be used? Each preparation is unique, and the products are not necessarily interchangeable. Different botulinum toxin serotypes significantly differ in their relative potencies and durations of action that affect the clinical outcome. Even different preparations of the same serotype can have marked differences. For instance, 1 U of BOTOX® has a potency that is approximately equal to 4 U of Dysport®. From a clinical point of view, these preparations may be used interchangeably with appropriate dosage adjustments. However, the current data are insufficient to determine whether one product is superior to another.[19]

Both products have advantages and disadvantages. BOTOX® (Allergan) has been widely used in the United States and Canada for more than a decade. Its safety is well established. The drawback is that once the contents of a vial are dissolved, the reconstituted product loses its potency. Therefore, dermatologists tend to schedule the treatments for several patients on the same day so that they can use the entire contents of the vial. This scheduling may be inconvenient for some patients, who may decide not to proceed.

Myobloc (Elan), when reconstituted, has a shelf life of more than 12 months. This feature is advantageous in terms of patient scheduling. However, larger volumes of Myobloc may be needed to obtain effects similar to those of BOTOX®. Antibody formation against this product may occur more often because of its higher protein content.

Studies with botulinum toxin type B (Myobloc, Neurobloc) showed safety and efficacy in the treatment of axillary hyperhidrosis.[20, 21]

Comparative studies of BOTOX®, Dysport, and Myobloc are relatively rare. A 2007 review analyzed these products in patients with cervical dystonia. Differences were noted in the rates of adverse events.[22] Another study found that Dysport had a greater area of diffusion than BOTOX®.[23] A review analyzed data from three botulinum toxin type A products in the treatment of facial rhytides.[24]

Dose conversion

Based on limited data, the most frequently used dose conversion factors between BOTOX® and Dysport® were between 1:2.5 and 1:3.