Botulinum Toxin Injections to Improve Facial Aesthetics 

Updated: Jun 25, 2019
Author: Pramit S Malhotra, MD, MS; Chief Editor: Arlen D Meyers, MD, MBA 

Overview

History

Botulinum toxin is best known to clinicians as a deadly poison produced by the Clostridium botulinum bacterium. Only within the past several decades have clinical applications for this toxin surfaced. Originally, applicability was found for botulinum toxin in the treatment of strabismus; however, this single indication has now grown into many. Currently, the Food and Drug Administration (FDA) has approved botulinum toxin A for several indications, including blepharospasm, strabismus, cervical dystonia, chronic migraines, axillary hyperhidrosis, upper limb spasticity, urinary incontinence, and the aesthetic improvement of glabellar rhytides. The list of indications continues to grow, including off-label use of this product.

OnabotulinumtoxinA (BOTOX®, BOTOX® Cosmetic) is approved in the United States for the following:

  • BOTOX® - Cervical dystonia, severe primary axillary hyperhidrosis, strabismus, blepharospasm, neurogenic detrusor overactivity, chronic migraine, upper limb spasticity
  • BOTOX® Cosmetic - Moderate to severe glabellar lines, moderate to severe lateral canthal lines (crow's feet)

AbobotulinumtoxinA (Dysport®) is approved in the United States for the following in adults:

  • Upper and lower limb spasticity
  • Cervical dystonia
  • Moderate to severe glabellar lines

It is also indicated for lower limb spasticity in children aged 2 years or older.

IncobotulinumtoxinA (Xeomin®) is approved in the United States for the following:

  • Upper limb spasticity
  • Cervical dystonia
  • Blepharospasm
  • Moderate to severe glabellar lines
  • Chronic sialorrhea

PrabotulinumtoxinA (Jeuveau®) is approved in the United States for moderate to severe glabellar lines.[1]

RimabotulinumtoxinB (Myobloc®) is approved in the United States for cervical dystonia.

See an example illustrated below.

Frontalis muscle injections. Frontalis muscle injections.

Common clinical uses

Currently, botulinum toxin is most commonly used in the management of hyperfunctional lines. Previously, hyperfunctional lines were the source of much consternation for those affected by them. These lines often caused patients to be misinterpreted as angry, anxious, fearful, or fatigued. In the past, facial plastic surgeons only had surgical options in their armamentarium. These procedures often provided minimal improvement and exposed patients to the risks associated with surgery. Injections of botulinum toxin A provide an opportunity to manage these hyperfunctional lines with minimal morbidity. The 3 most common sites for injection are the glabella, periorbital crow's feet, and forehead areas.

For patient education resources, see the Procedures Center, as well as BOTOX® Injections.

 

Pathophysiology

Etiology of hyperfunctional lines

Hyperfunctional lines result from the contraction of the underlying facial musculature. The forehead is a complex of the frontalis muscle with insertions onto fibers of the procerus, corrugator, depressor supercilii, and orbicularis muscles. The frontalis muscle, responsible for the surprised appearance when acting unopposed, mediates elevation of the brow and is primarily responsible for horizontal wrinkles. Soft tissue laxity of the forehead and periorbital area causes brow ptosis and reflex contraction of the frontalis muscle to restore brow position, exacerbating forehead rhytides. Treatment of these rhytides with botulinum toxin can increase brow ptosis.

The frontalis muscle can also be responsible for the appearance of scowling. However, the main agent responsible for the appearance of scowling is the corrugator muscle. The normal function of the corrugator is as a brow adductor, bringing the eyebrow medial and inferior. Chronic contraction of the corrugator results in deep vertical hyperfunctional lines between the eyes, sometimes referred to as a glabellar crease. The depressor supercilii muscle pulls the medial brow inferior and medially. The last muscle in this group is the procerus muscle, which overlies the nasal root. Contraction of the procerus results in a snout-nose appearance and a horizontal rhytid at the nasal root.

The anatomy of hyperfunctional lines in the orbit is intricate. Contraction of the orbicularis oculi muscle is primarily responsible for the clinically observed periorbital crow's feet. The orbicularis oculi muscle is bordered superolaterally by fibers of the frontalis muscle and medially by the levator palpebrae muscle. Injection of this area requires special cognizance of adjacent peri-orbital veins to avoid bruising.

Pharmacology

The Clostridium botulinum bacterium produces 7 distinct toxins, lettered A through G. All 7 toxins are antigenically distinct; however, toxin A is most familiar to clinicians for aesthetic uses. Botulinum toxins cause paralysis by inhibiting acetylcholine release at the neuromuscular junction. This is accomplished in 3 steps. First, the toxin binds the nerve. Second, the toxin is internalized into the nerve. Third, the toxin is cleaved by internal proteolytic enzymes, and the degradation byproducts interfere with the normal process of vesicle fusion to the plasma membrane. This results in the inhibition of the exocytosis of acetylcholine.

The toxin requires 24-72 hours to take effect, reflecting the time necessary to disrupt the synaptosomal process. In very rare circumstances, some individuals may require as many as 7 days for the full effect to be observed. The dose of the toxin is measured as 1 standard unit, which is equal to the amount necessary to kill 50% of Swiss-Webster mice injected with that dose.

The effect of botulinum toxin lasts 8-12 weeks. Typically, at the 10-week mark, patients begin to note a gradual disappearance of the injection effect.

 

Indications

Current approved and off-label indications for botulinum toxin injections include the following:

  • Achalasia
  • Blepharospasm
  • Cervical dystonia
  • Forehead lines
  • Frey syndrome
  • Glabellar lines
  • Hemifacial spasm
  • Hyperfunctional lines
  • Hyperhidrosis
  • Lateral lines
  • Limb spasticity
  • Post–Bell palsy synkinesis [2]
  • Sialorrhea
  • Strabismus
  • Urinary incontinence
 

Contraindications and Cautions

Contraindications to botulinum toxin injections include the following:

  • History of reaction to toxin or albumin

  • Infection at the injection site

Cautions include the following:

  • Cosmetic use for patient’s younger than 18 years
  • Patients receiving concomitant aminoglycosides, muscle relaxants, or other agents, such as curare-like drugs, that intefere with neuromuscular transmission
  • Pregnancy or lactation (avoid)
  • Spread of toxin effects have been reported; can lead to swallowing and breathing difficulties, including death
  • Adverse events involving the cardiovascular system have been reported, including some fatalities
  • The clinical effects of treatment may be exacerbated by a concomitant neuromuscular disorder
  • In patients with compromised respiratory function or dysphagia, botulinum toxin must be used cautiously
 

Treatment

Patient selection

Several prospective studies by Blitzer et al and Pribitkin et al have examined the effectiveness of botulinum injections for hyperfunctional lines.[3, 4] From these studies, certain characteristics of successfully treated patients have been identified. The ideal patients have thin skin, fine wrinkles, lines that are exacerbated by muscle contraction, and hyperfunctional lines that can be spread out with their fingers. Blitzer et al describe a "glabellar spread test" in which the physician is able to spread out the hyperfunctional glabellar lines to project the maximum benefit that a paralytic injection could achieve.

Candidates that have received minimal improvement from botulinum injections include those that failed the spread test, those with previous surgery near treated areas, those with thick skin or deep dermal scarring, and those with actinic skin changes. Facial lines resulting from the loss of dermal elasticity associated with aging are unlikely to respond to botulinum toxin injections. These areas are more appropriately treated with injectable fillers, which efface the static rhytides.

Treatment

Before the procedure is undertaken, a thorough history (including prior facial surgical procedures) and medication review are undertaken. Attention is focused on looking for those patients with contraindications as previously discussed. Preprocedure photographs can be taken but are not routinely performed. A close-up photograph that isolates the area of interest should be taken, as well as a full-face photograph. Photographs are taken at rest and during muscle contraction.

Physical examination concentrates on the identification of prior facial surgical sites, the assessment of the thickness of the skin, and the quality of the skin. Ahn et al note that thicker skinned patients often require higher doses.[5] In addition, the accentuation of hyperfunctional lines with muscle contraction is noted as well as the ability to smooth out these lines with the spread test. Patients with larger muscles, such as men, may require higher doses. Follow-up photographs can be taken 3-4 weeks postinjection.

Unopened vials of onabotulinumtoxinA (BOTOX®) should be stored in a refrigerator at 2-8°C (36-46ºF). The package insert of BOTOX® and BOTOX® Cosmetic recommends dilution with sterile, preservative-free 0.9% sodium chloride. Once reconstituted, keep BOTOX® and BOTOX® Cosmetic refrigerated at 2-8°C.The toxin generally is mixed with 2.5 mL of 0.9% nonpreserved sterile saline solution, creating a concentration of 40 U/mL.

Carruthers et al, in an outstanding consensus panel article, noted that panel members agreed that preserved saline could also be used.[6] An insulin syringe with a 30-gauge needle works nicely for injection. The insulin syringe does not waste any of the solutions in the hub of the syringe. Some clinicians are moving to 32-gauge needles, which demonstrate better patient tolerance.

The area of injection can be covered with topical anesthetic cream or can be anesthetized using ice. The solution then lasts up to 4 hours if refrigerated between injections, according to the manufacturer. Hexsel et al conducted a blinded, multi-institution study and demonstrated that reconstituted botulinum toxin A retained its efficacy for up to 6 weeks when stored at 4°C.[7]

Studies by Blitzer et al and Carruthers et al, and the BOTOX® Consensus Group provide some very reasonable dose suggestions, as follows.[3, 6]

Forehead

A total of 10-30 U should be sufficient for this area. The patient is instructed to contract the areas of concern to demonstrate the approximate location of the hyperfunctional muscle. The injections are divided into 2- to 4-U injections. Most authors recommend that all injections be at least 1 cm above an imaginary line drawn horizontally between the middle portions of the eyebrows to avoid brow ptosis. An imaginary vertical line is drawn passing through the pupil for a reproducible reference point.

The first injection of 3 U is placed 1.5 cm above the superior bony orbital rim on this imaginary line. The second injection of 3.0-3.5 U is injected at a point 1.5 cm superior and 1.5 cm lateral from the first injection. The last injection uses the same dose but is injected 1.5 cm superior and 1.5 medial to the first injection. In effect, this creates a letter V. This set of injections is repeated on the opposite side. The injections are massaged in a direction away from the orbit (see image below).

Frontalis muscle injections. Frontalis muscle injections.

A study by Cohen et al indicated that abobutolinumtoxinA is an effective means of increasing forehead height in individuals with low foreheads (5.5 cm high or less), with the investigators finding a mean elevation from the medial canthus to the frontal hairline (MCFH) of 4.3 mm, and from the midpupil to the frontal hairline (MPFH) of 4.6 mm, in treated patients. The report also found that height gain was greater in patients with a low forehead than in those with a high forehead (over 5.5 cm), with the mean MCFH and MPFH height increases being 5.4 mm and 4.7 mm, respectively, in individuals with a low forehead, and 4.0 mm (for both MCFH and MPFH) in patients with a high forehead. The botulinum toxin was injected into the cranial fibers of the frontalis muscle.[8]

Glabellar region

This region can be divided into 2 areas. The superior-lateral region is the first area, and it is affected by the corrugator supercilii muscle. This muscle is responsible for the vertical furrow between the brows. Each muscle receives an injection of onabotuliniumtoxinA (BOTOX® Cosmetic) 10 U as follows: 5 U is injected into the medial portion of the muscle near its origin, and 5 U is injected in the midportion of the muscle belly (see image below).[9]

Corrugator muscle injections. Corrugator muscle injections.

The central and inferomedial regions comprise the second area, and they are affected by the procerus muscle and depressor supercilii muscle. These muscles are responsible for the horizontal furrow at the root of the nose. A 6-U injection is placed into the middle of the procerus muscle belly, which is slightly off the midline (approximately 7 mm) and at the level of the superior orbital rims. The same injection is repeated on the opposite side. Then 3 U is injected into the depressor supercilii muscle, which is approximately 1 cm above the medial canthal tendon (see image below). Finally, 3 U then is injected on the opposite side. Great care must be taken not to inject the solution too deep, which may place the drug into the orbit, causing an oculomotor paresis. Other botulinum toxins indicated for glabellar lines are dosed as follows:

  • Dysport® (abobotulinumtoxinA) - 50 U total divided in 5 equal intramuscular (IM) injections (ie, 10 U per site)
  • Xeomin® (incobotulinumtoxinA): 20 U total divided in 5 equal IM injections (ie, 4 U per site)
  • Jeuveau® (prabotulinumtoxinA): 20 U total divided in 5 equal IM injections (ie, 4 U per site) [10]

Periorbital crow's feet

A total of 12 U of onabotulinumtoxinA (BOTOX® Cosmetic) are used per side. Injections are divided into 3 U each. Using the patient's right eye as an example, the first injection is approximately 1 cm lateral to the lateral canthus at the outermost portion of the bony orbital rim. This correlates approximately with the 10-o'clock position of the orbicularis oculi muscle (some authors feel that this injection provides a chemical brow lift of several millimeters in the lateral brow region). This is followed by an injection of 3 U at the half-past-9 position. The last 2 injections are placed at the half-past-8 and half-past-7 positions (see image below). Once again, the onabotulinumtoxinA must be placed outside the orbital rim to avoid intraorbital complications.

Two double-blind, placebo-controlled studies by Baumann et al in which patients received onabotulinumtoxinA for crow’s feet lines found that the lines in most patients responded to treatment, with the response duration for both static and dynamic lines in the two trials being 4 months or more.[11]

Orbicularis muscle/periorbital crow's feet injecti Orbicularis muscle/periorbital crow's feet injections.

Nasolabial

This area has been difficult to inject and offers mixed results. Electromyograph (EMG)–guided injection of 2-3 U to paralyze the levator labii superioris alaeque nasi has demonstrated some success. The authors' center does not use botulinum toxin in this area because of complications of upper lip paresis.

Platysma

Platysmal bands can be treated with the direct injection of botulinum toxin into the concerning band. Once the band is identified, 5 U can be injected at 1-cm to 3-cm intervals along the vertical line created by the platysma. Some authors find these areas more amenable to surgical treatment.

A literature review by Sugrue et al reported that platysma band injections with botulinum toxin are an effective means of neck rejuvenation, with response rate and mean improvement in the Merz platysma score being 93.7% and 2.0 points, respectively, after 14 days, and 86% and 1.2 points, respectively, at 3 months. Treatment included administration of a maximum of 20 IU of incobotulinumtoxinA or 5 IU of abobotulinumtoxinA, per platysma band.[12]

Electromyograph monitoring

Historically, some authors had chosen to perform their injections under the guidance of EMG monitoring. This technique involves using a 27-gauge (1.5 in) polytef-coated EMG needle connected to an EMG recorder by an alligator clip on its shaft. The patient is asked to contract the muscle in question. The injection is placed where the maximal EMG recording can be found within the muscle. This technique ensures that the injection is at the portion of the muscle that is contributing most to the hyperfunctional facial line. As these injections have become routine, many centers have obtained satisfactory results without EMG guidance. Many physicians use a readily available 30-gauge insulin syringe instead.

Reinjection

If a patient feels that little benefit was derived from the original injection, reinjection can be performed 1 week postinjection. However, 2-3 weeks postinjection is probably a more practical time for a return clinic visit. Generally, 2.5-5 U of onabotulinumtoxinA are used for reinjection. Reinjection strategies are still evolving. Once the patient has a satisfactory result, the next visit is at 2-3 months or when the patient requests another treatment.

A randomized, double-blind study by Carruthers et al supported the efficacy of repeated botulinum toxin A treatments in reducing crow’s feet, as measured via the Facial Winkle Scale and patient-reported outcomes. Among patients who received the drug for treatment and then, in a 5-month extension of the original 7-month study, retreatment of crow’s feet alone or of crow’s feet and glabellar lines, the response rates were 56.5% and 63.6%, respectively, compared with just 1.1% for patients who received placebo.[13]

A study by Lee et al indicated that in lower facial contouring via bilateral injections of botulinum toxin A to the masseter muscle, better aesthetic results are achieved if the patient undergoes two injection sessions instead of just one. In the study, which involved 20 patients, individuals in the two-injection group received the doses 4 months apart.[14]

 

Complications

The most feared complication is temporary paralysis of nearby facial musculature. Approximately 1% of patients may experience a temporary upper lid or brow ptosis; the most troublesome complication to the patient is upper lid ptosis. This results from migration of the botulinum toxin to the levator palpebrae superioris muscle. The ptosis usually lasts 2-6 weeks. It can be treated with apraclonidine (Iopidine, Alcon). This is an alpha-adrenergic agent that stimulates the Müller muscle and immediately elevates the upper eyelid. This treatment can usually raise the eyelid 1-3 mm. The treatment of 1-2 drops 3 times per day continues until the ptosis resolves.

Bruising can occur, particularly if a small vein is lacerated or a patient is taking aspirin, vitamin E, or NSAIDs. Ideally, patients should stop taking these products 2 weeks before the procedure. Headaches can occur after botulinum toxin injections; however, in one study by Carruthers et al, this did not exceed the placebo group.[15] This is thought to be due to the trauma of the injection and not something inherent in the toxin. In fact, botulinum toxin injections are extremely safe. To date, no significant long-term hazards of botulinum toxin injections have been identified in excess of placebo groups.

 

Future

Future

The popularity of botulinium toxin is unmatched in cosmetic surgery, and its use and scope increase every year. Patients have shown a high degree of satisfaction with the procedure. Current research focuses on using botulinum toxin as an adjunct to a myriad of surgical and ablative procedures.

Botulinum toxin A now has been used in significant numbers for decades. Its injection has proved to be an extremely safe strategy for selectively inducing muscle paralysis.