Continuing Education Activity

Botulinum toxin injection is the most commonly performed cosmetic procedure in the world. While it has many areas of application, it is frequently used to manage and treat rhytids in the aging upper face. This activity reviews the indications, contraindications, techniques, complications, and other key elements of botulinum toxin treatment and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Outline the treatment considerations for patients with an aging upper face due to rhytids.
• Identify the physical exam findings associated with an aging upper face due to rhytids.
• Summarize the common complications of treating an aging upper face due to rhytids.
• Review the psychosocial considerations for a patient with an aging upper face due to rhytids.

Introduction

Botulinum toxin injection is commonly performed to chemically denervate certain muscles of facial expression for the purposes of facial rejuvenation and anti-aging. Facial rhytids, or "wrinkles," result from repeated contracture of the muscle underlying the facial skin, which over time causes atrophy of the overlying dermis and pleating of the skin.[1][2] Selective chemodenervation of facial muscles allows for targeted treatment of dynamic rhytids, particularly in the upper face, and also allows for manipulation of eyebrow position and correction of asymmetries. Muscular targets of botulinum toxin in the upper face include the orbicularis oculi, procerus, corrugator supercilii, and frontalis muscles. 

Botulinum toxin prevents acetylcholine release at the presynaptic nerve terminal, blocking neurotransmission. Effects usually take up to 2 days to appear, with maximal effect in 1 week to 1 month and last up to 3 to 4 months.[3] Repeated injections of botulinum toxin may cause muscular atrophy in the injected regions, thereby extending the duration of effects. In addition, a retrospective study of 945 patients receiving at least 3 consecutive treatments showed no loss of effect with repeated treatments. After five treatment cycles, patients and providers both rated satisfaction outcomes higher than after the first cycle.[2]

Botulinum toxin is created by fermentation of the bacteria Clostridium botulinum.[4] Botulinum toxin has 7 serotypes from A-G; however, types A and B are practically used for cosmetic applications. Serotype A exists in three formulations to include onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA. Serotype B exists in one formulation, rimabotulinumtoxinB.[5]

RimabotulinumtoxinB is notable for having the most rapid time to onset; however, it also has the greatest area of diffusion and shortest duration of effect. Its acidic pH (5.5-6.5) also increases the discomfort of an injection.[6] Serotype A botulinum toxins, conversely, have a longer onset to action and longer duration of effect. AbobotulinumtoxinA has a greater spread effect than onabotulinumtoxinA and incobotulinumtoxinA, and therefore dose ratios vary. In cosmetic practice, a typical dose ratio is 2.5 to 1 to 1 (abobotulinumtoxinA: onabotulinumtoxinA: incobotulinumtoxinA).[6]

Anatomy and Physiology

The clinician must have a thorough understanding of the anatomy and mechanical function of the muscles of facial expression. Orientation, origin/insertion, and depth of facial muscles are important factors that must be considered and integrated into one's technique to achieve the desired outcome. Muscles of facial expression are unique from other muscles in the human body, owing to their numerous connections to the overlying cutaneous tissue (rather than having solely bony attachments) via the superficial musculoaponeurotic system, or "SMAS."[1] The intricate relationship between facial musculature and the overlying skin is vital for facial expression as a means of communication. These connections, along with the directional orientation of muscle fibers, contribute to facial rhytids during contraction. Rhytids and resting skin tension lines will typically be oriented perpendicularly to the underlying muscle fibers. In general, treating rhytids involves the injection of the muscle running perpendicular to the wrinkling. In addition, facial muscles with different functions and orientations often overlap, making the depth of injection an important consideration.[7] Injection too superficial or too deep can lead to inadvertent injection of the wrong muscle, potentially causing an opposite effect from the desired outcome.

Botulinum toxin of the upper face, in addition to addressing rhytids, can also be used to manipulate the position of the eyebrow. The ideal locations of the male and female brow have been described, with the male brow resting at the orbital rim and the female brow lying several millimeters above the orbital rim. The female brow should start above the orbital rim directly superior to the nasal ala and reach its highest position at the lateral canthus or lateral limbus. It should terminate at an area that can be approximated by drawing an oblique line from the nasal ala and intersecting the lateral canthus and also lie at the same level as the medial brow. In males, the brow should generally remain at the height of the supraorbital rim, with the highest point being at the mid-pupillary line. These relationships can be manipulated or accentuated by manipulating the local musculature with botulinum toxin.[8]

The muscles of facial expression are innervated by terminal branches of the facial nerve. The paired orbicularis oculi (OO) are oriented in a circular manner in the periorbital region bilaterally. They are supplied by the supraorbital, supratrochlear, infraorbital, and angular arteries. The OO function in eye closure and are one of the principal depressors of the eyebrow, along with the depressor supercilii and procerus muscles. The orbicularis oculi's brow depressor function is opposed by the brow elevation of the frontalis muscle. The muscle originates from the underlying frontal, maxillary, and lacrimal bones and the medial palpebral ligament. It inserts on the lateral palpebral raphe and the superior and inferior tarsi medially and the undersurface of the overlying skin.[7] Contraction of the OO creates lateral canthal lines known as "crow's feet," in an orientation similar to the spokes on a bicycle wheel, radiating outward from the circular orbicularis.[9] The OO is the principal depressor of the lateral eyebrow and may be targeted to perform a lateral brow lift [10]. Desired outcomes typically include softening/eliminating "crow's feet," creating a larger eye appearance, and elevation of the lateral brow position in females. 

The corrugator supercilii (CS) function to bring the eyebrows toward the midline and inferior.[3] Blood supply to the CS is via the supratrochlear and supraorbital arteries. The CS muscles are unique in that they lie deep to the frontalis medially and superficial to the frontalis muscle laterally. Contraction of this muscle causes vertical forehead wrinkling between the eyebrows, sometimes referred to as "11's".[11] They originate medially from the supraorbital rim and insert laterally on the undersurface of the forehead skin. The bulk of the CS muscle belly lies in a plane drawn through the mid eyebrow region.[12] This muscle is thickest 19 mm from the nasion, between two vertical lines drawn superiorly from the medial canthus and the mid pupillary region. At its thickest, this muscle averages 2-3 mm.[13] The corrugator lies in proximity to the levator palpebrae superiors (LPS), which is innervated by the oculomotor nerve and functions to elevate the eyelid. The LPS is a flat muscle originating from the sphenoid bone in orbit and inserting on the skin and tarsal plate of the upper eyelid.[7]

The procerus is situated between the eyebrows in the glabellar area and functions to pull the eyebrows down towards the nose. Its blood supply is via the supratrochlear artery. The procerus originates near the junction of the nasal bony-cartilaginous junction and inserts on the skin between the eyebrows. It is located approximately 1-4 mm below the skin surface.[12] Injection here aims to reduce horizontal rhytids along the bridge of the nose and the glabellar area. In this region, the frontalis is located just deep into the procerus. 

The frontalis is a thin muscle located in the anterior forehead region. It is supplied by the supratrochlear and supraorbital arteries. It is continuous with the galea aponeurotica layer of the scalp superiorly and interdigitates with the CS, procerus, and OO at the level of the eyebrow. The frontalis is implicated in horizontal forehead rhytids perpendicular to the direction of its contraction, and it functions to raise the eyebrow position.[12] It may form a continuous band across the forehead or be V-shaped with a relative absence of muscle bulk in the midline.[14] The frontalis opposes the eyebrow lowering function of the OO, CS, and procerus muscles.[7] The resting tone, cumulative vector force, and direction of these muscles all contribute to the patient's resting eyebrow position. 

The depressor supercilii (DS) is superficially located, originating from the OO and inserting on the subcutaneous portion of the eyebrow. Its individual presence is debated and is also argued to be a component of the orbicularis oculi. Its function is to depress the medial eyebrow. Injection should be performed superficially and within the eyebrow to avoid accidental injection into the frontalis muscle superiorly and deep to this area.[7]

Indications

Cosmetic botulinum toxin injections may be performed to reduce dynamic facial rhytids/wrinkles, correct facial asymmetry, and accentuate or correct gender-specific anatomic relationships. However, they are not effective in treating static rhytids or deep rhytids caused by photoaging. Botulinum toxin injections are also FDA-approved for non-cosmetic applications, such as treating migraines, blepharospasm, urinary incontinence, upper limb spasticity, cervical dystonia, severe axillary hyperhidrosis, and strabismus. 

Facial asymmetry can occur when patients have a unilateral facial nerve injury (traumatic or iatrogenic), facial dystonia, or Bell's palsy. In cases of hemiparesis, botulinum toxin injection on the contralateral side can help improve symmetry. For example, injury to the frontal branch of the facial nerve can cause unequal eyebrow position and unequal wrinkling with contralateral brow elevation. Contralateral injection to the frontalis muscle is effective in reducing such asymmetry.[15] Furthermore, when there is the development of synkinesis or hyperkinesis ipsilateral to a facial nerve injury, the aberrantly reinnervated or hyperkinetic muscles can be injected to reduce unwanted facial spasms, tightness, and asymmetry.[3]

Contraindications

The main contraindications to botulinum toxin injection are neuromuscular disorders (amyotrophic lateral sclerosis, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis), allergies to botulinum toxin constituents, active infection at injection sites, body dysmorphic disorder, pregnancy, and breastfeeding can potentiate neuromuscular blockade. Therefore injection on patients taking these should be performed with caution.[4][16]

The FDA, given the paucity of patient data, classifies botulinum toxin as a category C drug. There have been reports of women who were unaware they were pregnant and had received botulinum toxin injections without adverse fetal effects. Since botulinum toxin is not expected to enter the systemic circulation after administration, it should not cross the placental barrier, creating controversy over pregnancy as a contraindication. Until additional evidence supports its safety during pregnancy, botulinum toxin should not be offered to pregnant women or breastfeeding mothers.[4]

Equipment

• Botulinum toxin
• 1 mL syringes with 20 gauge needles (for drawing up) and 30 gauge 0.5-inch needles (for injecting). Alternatively, insulin syringes with attached 31 gauge needles can be used.
• 0.9% sodium chloride (preferably bacteriostatic/preserved)
• Alcohol pads
• Gauze
• Ice packs
• Topical anesthetic (optional)
• Marker/pencil (optional)

Preparation

Botulinum toxin is stored in powder form and must be refrigerated (except for incobotulinumtoxinA), with most manufacturers recommending temperatures between 2 to 8 degrees Celsius for up to 36 months before reconstitution.[3] IncobotulinumtoxinA is stable for 3 years at room temperature.[17]

Most manufacturers recommend preservative-free saline for reconstitution and use within 24 hours if refrigerated. However, a recent expert consensus statement based on randomized controlled trials has stated that reconstitution with bacteriostatic/preserved saline may reduce discomfort with injections. A reconstituted vial may be refrigerated or refrozen for at least 4 weeks without significant risk of contamination or decreased effectiveness.[18] Of note, rimabotulinumtoxinB does not require reconstitution.[6]

To reconstitute the lyophilized form of the toxin in physiologic saline, the provider must plan out the desired concentration in units/mL.[3] Some typical dilution protocols for onabotulinumtoxinA include the following:

• 2.5 mL of 0.9% normal saline to a vial of 100 units, creating a dilutional concentration of 4 units of toxin in every 0.1 mL of the reconstituted mixture.
• 2 mL of 0.9% normal saline to a vial of 100 units, creating a dilutional concentration of 5 units of toxin in every 0.1 mL of the reconstituted mixture.
• 1 mL of 0.9% normal saline to vials of 100 units, creating a dilutional concentration of 10 units of toxin in every 0.1 mL of the reconstituted mixture.

A suggested dilution range for abobotulinumtoxinA is 0.6 to 2.5 mL of saline in 300 units of toxin.[5] If more significant dilutions are sought, the provider must be aware that there is an increased risk of spreading the toxin to unwanted areas. This can lead to adverse effects such as eyelid ptosis and suboptimal results.

Using a 20 gauge needle, the desired amount of 0.9% normal saline can be drawn up and inserted into the vacuum-sealed vial. The vial should be gently swirled around, avoiding any shaking movements. Once mixed, the fluid can be drawn up into a 1 mL syringe. Typically, a 30 or 31 gauge 0.5-inch needle is used for injection. When using an insulin syringe with an attached 31 gauge needle, the vial stopper should be removed to avoid blunting the needle tip.

To reduce the chance of post-procedural bruising, patients should avoid supplements and medications known to increase bruising during the days before and after the procedure. These include ginkgo biloba, vitamin E, garlic, alcohol, aspirin, NSAIDs, blood thinners, and SSRIs.[4] Pre- and post-injection application of an ice pack to the injected area has also been shown to decrease bleeding, as well as pain.[19]

Application of pre-injection topical anesthesia is a safe option with a significant reduction in pain scores.[20][4] The use of a vibration device may also help reduce injection pain.[21]

Technique or Treatment

Makeup should ideally be removed and the skin cleansed with an alcohol pad. An option for beginners is to mark injection sites with an erasable marker or pencil; however, injections should be performed just adjacent to the marking to avoid tattooing the skin. There is significant variability in injection technique, and injections should be tailored to the individual patient's needs. Male patients typically have larger and stronger facial muscles and require higher doses.

The glabellar complex is the most commonly injected facial area overall.[2] Injection of the corrugator supercilii begins with the identification of the course of the relatively narrow muscle belly. The provider may ask the patient to move the brows medially and pinch the medial brow to feel for the tensed muscle. In this region, the provider should place the injection deep (supraperiosteal) in order to avoid the more superficially situated frontalis muscle. Laterally, while the patient is contracting the muscle, the insertion can be recognized where there is puckering of the overlying forehead skin. In this region, a superficial injection should be employed to avoid the frontalis.[22] To avoid the diffusion of toxin into the levator palpebrae superioris (LPS) leading to ptosis, the provider should inject the corrugator 1 cm above the superior eyebrow and ask the patient to remain vertical for 2-3 hours post-injection.[3] Extra care must be taken the assure the lateral most of the corrugator injections is performed superficially and slowly to prevent diffusion. Patients who have a history of eyelid ptosis after botulinum toxin injections should be counseled that their particular anatomy might predispose them to the diffusion of toxin into the LPS.[7]

The procerus is also located in the glabellar region. If there is no horizontal rhytid when the patient draws the eyebrows medially, chemical denervation of the procerus may not be required.[8] Injections are performed superficially just below the skin (no greater than 4 mm deep) in the region between the eyebrows.[12] Glabellar complex dosing ranges from 8 to 40 units, dispersed over 3-7 injection points between the CS and procerus.[23] A typical total dose of onabotulinumtoxinA in the glabellar region is 20 units, and the optimum recommended dose of abobotulinumtoxinA in the glabella is 50 units.[2]

The frontalis is injected either intramuscularly or superficially just under the subcutaneous tissues. In general, injection is performed at least 1.5 cm above the superior orbital rim to prevent ptosis.[12] Injections into the mid and upper portions of the frontalis are less likely to cause brow or lid ptosis. The provider may use a finger to pull the forehead skin inferiorly at various heights to predict the effect on the eyebrow at those injection sites. Dosing ranges from 8 to 25 units, dispersed over 4 to 8 injection points.[23] A typical dose of onabotulinumtoxinA in the forehead/frontalis region is 10 to 20 units for women and 20-30 units for men.[13] Another proposed strategy is to inject roughly half of the amount used in treating the glabellar region into the frontalis.[7] If the patient desires an increase in lateral brow height relative to the medial brow, the provider may inject relatively less volume into the lateral than the medial frontalis. Exaggeration of this technique can lead to "Mephisto" or "Spock" deformity, which can be corrected by injecting more toxin laterally.

Injection of the orbicularis oculi should be done superficially, approximately 1 to 2 mm deep, with small wheals of toxin, injected directly under the skin 1 cm lateral to the lateral orbital rim or 1 cm lateral to the lateral canthus.[3][12] The provider can have the patient close their eyes tightly in order to locate the muscle fibers. In addition, this will allow the provider to analyze whether contraction of the orbicularis oculi causes depression of the lateral brow. If so, lateral and superior injection of this muscle may result in elevation of the lateral brow position at rest.[7] Dosing ranges from 4 to 15 units per side, dispersed over 1 to 5 areas of injection.[23]

A “chemical brow lift” may be performed to raise the height of the eyebrow and can be aimed at medial elevation, lateral elevation, or both. If the provider aims to perform a lateral brow lift, 8 to 10 units of toxin can be injected just inferiorly to the lateral eyebrow. Weakening the superolateral OO will cause unopposed elevation of the lateral brow by the frontalis in this region. Chen et al. describe 3 injection sites just inferior to the lateral eyebrow, starting at the superior most point of the brow and working laterally. A medial brow lift may be performed by injection of the CS, depressor supercilii (DS), and procerus via unopposed elevation by the frontalis. Injection of the DS should be performed superficially, at or within the level of the eyebrow. Along with slow injection, these methods will help to prevent accidental injection into the frontalis muscle superiorly.[10]

Complications

Complications of botulinum toxin injections may include mild bruising (11 to 25% of patients), brow or eyelid ptosis (0.59% of patients), local hypesthesia, dry skin, allergic reaction to components, injection site pain, headache, asymmetry, and unwanted cosmetic result.[2][4] In a retrospective study of 945 patients and 4,103 injection cycles with abobotulinumtoxinA, mild bruising was the most common adverse event, occurring in only 1.25% of patients. Adverse events were not experienced in the majority of patients (90.6%) included in the study.[2]

Procedural techniques to reduce bruising include careful avoidance of superficial blood vessels (which can be more easily visualized by removing makeup and having adequate lighting) and application of pressure and ice post-injection. Gentle stretching of the skin can also reveal superficial blood vessels. If a vessel is punctured, prompt digital pressure should be applied to the region.[4] Positioning the patient at 30 degrees with a stable headrest might also limit unnecessary movement during injection that can lead to bruising. Using a small gauge needle may limit bruising; however, no significant difference was found in a study comparing 30 and 32 gauge needles.[24] Post-procedure, patients can also limit bruising by avoiding sleeping face down, bending over to stretch, and exercising vigorously. Patients should ideally remain vertical for up to 3 hours post-injection to prevent diffusion of toxin and bruising.[3]

Given the variation in depth along the course of the corrugator supercilii, injecting too superficially medially can lead to inadvertent injection of the frontalis muscle, causing brow ptosis rather than elevation. In addition, diffusion of toxin into the levator palpebrae superioris can lead to eyelid ptosis. The treatment for refractory ptosis caused in this manner is apraclonidine eye drops. Apraclonidine is an alpha-2 agonist and sympathomimetic that stimulates the contraction of Muller's muscle, causing eyelid elevation.[4] Apraclonidine also causes pupillary dilation.[25] Administration of apraclonidine should be reserved for severe and refractory cases, as apraclonidine can unmask underlying glaucoma.

Inadvertent injection deep to the procerus and into the frontalis muscle can cause skin drooping between the eyebrows. This is best avoided by superficial injection in the glabellar area when targeting the procerus.[8]

Frontalis injection can lead to ptotic eyebrow position in multiple ways, including injecting too inferiorly, injecting too superficially when attempting to address the medial corrugator, neglecting to inject the opposing orbicularis oculi and glabellar muscles, and administering too large a unit volume compared to the opposing musculature. Blepharoptosis can also occur if there is a pre-existing LPS weakness that is unmasked. As mentioned previously, overcorrection of the medial versus the lateral frontalis can lead to "Mephisto" or "Spock" deformity. It may occur if frontalis injections are only performed between the mid-pupillary lines and can be corrected with the careful injection of the lateral frontalis, with care not to overcorrect and cause brow ptosis laterally.[14] 

Unintended outcomes of orbicularis oculi injection may occur if the injection is carried out too medially and inferiorly. If this occurs, the zygomaticus major and minor muscles may be inadvertently injected. These muscles are important in smiling function, and therefore injection can lead to an asymmetric smile. An aggressive medial/inferior OO injection may also create the appearance of a "shelf" at the lid/cheek junction, where the cheeks elevate during smiling, but there is no movement of the periorbital skin.[7] Similarly, aggressive lateral/superior OO injection in a male patient may cause undesirable lateral eyebrow elevation. Excessive injection near the canthus or eyelids may cause lagophthalmos or ectropion, strabismus or diplopia, and worsening orbital fat pad pseudogenization.[4] Lastly, injection in the periorbital area may lead to temporary periorbital edema, possibly due to a lack of muscular pump mechanism integral to local lymphatic drainage.[26]

Asymmetry can occur if botulinum toxin is dosed or administered unequally between sides of the face. This is best avoided by careful attention to injection quantity and consistent dilution technique.

Clinical Significance

Treatment of the aging face has become extremely popular in the United States, with a tenfold increase in cosmetic procedures performed from 1997 to 2010. Botulinum toxin has been the most popular aesthetic procedure performed since 1999, with almost 2 million botulinum injections performed by plastic surgeons alone in the U.S. in 2019, more than twice as many as the next most popular procedure, hyaluronic acid dermal filler.[27]

Interestingly, postmarketing safety surveillance data has shown that botulinum toxin injection to the glabellar area is associated with a clinically significant antidepressant effect in cosmetically motivated patients. This effect was observed in patients seeking injection to treat migraines, blepharospasm, hyperhidrosis, neck pain, and solely for cosmetic enhancement. A proposed mechanism is via modulation of the reciprocal, mutually enforceable, interrelation of facial expression (and therefore muscle tension) and mood. Muscle tension is a common symptom in depression and may also act as a positive reinforcing mechanism. This is the basis of treatment of depression with progressive muscle relaxation. It is proposed that botulinum toxin injection to the glabellar region may decrease depression via a similar pathway.[28] Conversely, there are postmarketing safety surveillance data supporting an increase in depression scores with injection into the orbicularis oculi. A proposed mechanism is the inability to perform the Duchenne smile, which is associated with positive emotions.[28]

The practitioner must carefully balance patient expectations, degree of psychosocial distress in light of the specific cosmetic concern, and the possibility of adverse side effects.

Enhancing Healthcare Team Outcomes

All healthcare team members performing botulinum toxin injection should be familiar with its indications, contraindications, techniques, complications, and psychosocial implications. Botulinum toxin injection may be performed by a broad range of specialties and disciplines, including dermatology, plastic surgery, facial plastic surgery, otolaryngology, ophthalmology, neurology, and oral maxillofacial surgery. Practitioners may work with a nurse or medical assistant who reconstitutes the botulinum toxin, but botulinum toxin injection must be performed by a licensed healthcare practitioner, such as a physician, physician assistant, dentist, or registered nurse.

Provider and patient communication and expectation setting are paramount in the management of patients seeking cosmetic procedures. Careful planning, discussion of cosmetic goals, and pre-procedure documentation are vital. The provider may desire pre- and post-procedure photography to accurately document desired and undesired outcomes, pre-existing facial features, as well for teaching trainees. The photography should be standardized and reproducible.[29] 

It may be wise for the provider to work closely with a nurse, physician assistant, medical assistant, or technician trained specifically in medical photography related to facial plastic surgery. This individual may also be responsible for obtaining patient consent to use "before and after" photos for training, patient recruitment, and/or technique publication purposes. In addition, the provider should screen for comorbid psychiatric conditions (such as body dysmorphic disorder) and may require the patient to be screened by a mental health professional before any interventions.[30] [Level 4]