Introduction

Botulinum toxin type A has been found to be useful for many applications since its initial introduction, but one of its most popular uses has been for treatment of glabellar rhytides. In 1979, the Food and Drug Administration (FDA) gave limited approval for trials of botulinum toxin A for strabismus. In 1985 it was used for blepharospasm. Two years later, in 1987, Dr Jean Carruthers made an observation that patients who received botulinum toxin treatment for blepharospasm also had improvement of dynamic glabellar rhytides. The first published reports of the use of botulinum toxin for the treatment of facial lines were those by Carruthers & Carruthers and by Borodic in the early 1990s. However, it wasn’t until 2002 that botulinum toxin type A was granted its first approval for cosmetic use specifically for the treatment of glabellar rhytides.

The use of botulinum toxin type A over the last two decades for treatment of glabellar rhytides has revolutionized the field of cosmetic dermatology and plastic surgery. Several multicenter, double-blind, randomized, placebo-controlled studies have proven its efficacy (e.g. that by Carruthers et al in 2003). It is the first quick, less invasive and effective, non-surgical technique for both brow lift and rhytid treatment. The same group demonstrated in 2010 that botulinum toxin type A injection to the glabella has been shown to improve both dynamic glabellar rhytides and those in repose. Subsequent uses of botulinum toxin type A for cosmetic improvement of forehead, perioral area, chin, crow’s feet, and other rhytides have been successful, but its use in the glabella is the first and still the most widely used.

In this chapter, we will discuss the anatomy, injection technique, dosing, special considerations, and potential adverse events of botulinum toxin injection of the glabella.

Anatomy

The glabellar complex consists of the two corrugator supercilii muscles and the procerus muscle that collectively serve upon contraction to pull the brow medially and downward (Fig. 12.1). The corrugator supercilii are two sets of horizontally oriented muscle fibers that lie beneath the medial eyebrow to about the mid-pupillary line. In some patients, the corrugators extend beyond the mid-pupillary line (these muscles can be visualized at maximum contraction when ‘frowning’). The procerus is a vertically oriented muscle that lies in between the eyebrows. The frontalis muscle of the forehead is vertically oriented and the medial belly interpolates with the glabellar complex, and its lateral portion interpolates with the lateral orbicularis oculi. Its main function is to elevate the brow. The orbicularis oculi is a thin circular muscle around the eyes that lies on top of the lateral portion of the corrugator supercilli. The lateral portion of the orbicularis oculi under the tail of the brow is a powerful brow depressor upon contraction. The levator palpebrae muscle lies beneath the orbicularis oculi, underneath the bony orbital rim, and its function is eyelid opening. Rhytides are typically perpendicular to the orientation of muscle fibers, thus contraction of the glabellar muscles typically produces vertically oriented lines between the brows.

Figure 12.1 Muscles of the face.

Courtesy Dr Jean Carruthers, reproduced with permission.

Injection technique (see Video ‘Botulinum Toxin Glabella’)

The proper preparation, storage, and handling of botulinum toxin is discussed in Chapters 9 and 11. Insulin syringes or 1 mL syringes with 30–32 gauge needles are typically used for injection.

In the glabella, there are typically five injection sites: one at each medial corrugator, one at each lateral corrugator (1 cm above orbital rim at the mid-pupillary line), and a single injection into the procerus (Fig. 12.2). For some patients with particularly long or stronger corrugator muscles, an additional injection site may be given midway between the medial and lateral corrugator injection sites (a total of seven injections).

Figure 12.2 Five injection sites for botulinum toxin into the glabella: one at each medial corrugator, one at each lateral corrugator (1 cm above the orbital rim at the mid-pupillary line), and a single injection into the procerus.

Even without the lateral brow injection, injection of 20–40 units of botulinum toxin type A into the glabellar muscles alone leads to eyebrow elevation. This is due to relaxation of the depressor actions of the corrugator procerus muscles, as well as inactivation of the medial muscles of the frontalis, with resultant increased muscle tone of the lateral and superior muscles of the frontalis. Studies by Huilgol et al and by Huang and co-workers found that the eyebrow elevation usually ranges from 1 to 3 mm (mean elevation 1 mm).

Dosing

Botox^® (onabotulinumtoxinA) (Fig. 12.3)

With standard dilutions of a 100-unit vial of Botox^® (Allergan Inc., Irvine, CA, USA) with 2.5 mL of 0.9% normal saline, a single injection of 0.1 mL yields 4 units. In women, 20–24 units of Botox^® via five injection points are typically injected into the glabellar complex; an additional 3 units may be injected into each lateral eyebrow to achieve brow lift. In our experience, in men, 20–40 or more units may be injected into the glabellar complex depending on the strength of muscle contraction. In a 2005 study by Carruthers and colleagues of 80 men randomized to receive 20, 40, 60, or 80 units of botulinum toxin type A (Botox^® or Vistabel^®, Allergan Inc., Irvine, CA), the 40, 60, and 80 U doses were consistently more effective than the 20-unit dose in reducing glabellar lines (duration, peak response rate, improvement from baseline).

Figure 12.3 (A) Pre-onabotulinumtoxinA injection, relaxed. (B) Pre-onabotulinumtoxinA in maximal glabellar contraction. (C) Pre-onabotulinumtoxinA in maximal frontalis contraction. (D) 1 week after 20 U onabotulinumtoxinA injection to the glabella, relaxed. (E) 1 week after 20 U onabotulinumtoxinA injection to the glabella, in maximal glabellar contraction. (F) 1 week after 20 U onabotulinumtoxinA injection to the glabella, in maximal frontalis contraction.

Onset of response is typically 1–14 days and results last for 3–4 months. In a 2011 study by Beer et al of 45 patients who received a 20 U injection into the glabella, nearly half of patients may experience onset of response by day 1, with 100% by day 14. A meta-analysis by Kane and colleagues of the duration of efficacy pooled results from four global Phase III pivotal trials of onabotulinumtoxinA treatment of glabellar lines and demonstrated that, in 523 subjects of diverse ethnic backgrounds, treatment with a 20 U dose resulted in more than half of the responders sustaining clinical benefit for 4 months. In fact, Dailey and co-workers found that injection of 20 U of onabotulinumtoxinA to the glabellar complex every 4 months for 20 months significantly reduces or progressively eliminates glabellar rhytides for up to 6 months after the last treatment.

Dysport^® (abobotulinumtoxinA) (Figs 12.4 and 12.5)

Dysport^® (Ipsen Biopharm Ltd, Wrexham, England, distributed by Medicis Pharmaceuticals, Scottsdale, AZ, USA) is a clostridium botulinum type A toxin–hemagglutin complex. In a randomized, double-blind, placebo-controlled study of Dysport^® by Monheit et al to determine the optimal dose for treatment of glabellar lines, participants were given 20, 50, or 75 U of Dysport^® or placebo, and followed up on days 7, 30, 60, 90, and 120. Dysport^® treatment resulted in a significant improvement in glabellar lines compared with placebo; the 50 U dose was determined to be optimal. Flynn found that, like Botox^®, glabellar retreatment intervals are every 3–4 months (with a mean of 3.9 months, median 3.3 months). A single comparative study of Botox^® and Dysport^® by Lowe and colleagues demonstrated that the proportion of patients relapsing at week 16 was 23% (95% CI 11.5, 41.6) in the Botox^® group, as compared with 40% (95% CI 25.2, 60.1) in the Dysport^® group.

Figure 12.4 Maximal glabellar contraction: (A) pre-injection and (B) 14 days after 50 U injection of abobotulinumtoxinA in to the glabella, female patient.

Reproduced with permission of Medicis Pharmaceutical Corporation. ©2012 Medicis Pharmaceutical Corporation. All rights reserved.

Figure 12.5 Maximal glabellar contraction: (A) before and (B) 14 days after 50 U injection of abobotulinumtoxinA in to the glabella, male patient.

Reproduced with permission of Medicis Pharmaceutical Corporation. ©2012 Medicis Pharmaceutical Corporation. All rights reserved.

For treatment of glabellar lines, Dysport^® is packaged in a 300 U bottle. Manufacturer recommendations for reconstitution are with 2.5 mL or 1.5 mL of 0.9% sodium chloride injection USP (without preservative), to yield a solution of 10 U per 0.08 mL with 2.5 mL, or a solution of 10 U per 0.05 mL with 1.5 mL. The manufacturer also recommends 50 U given intramuscularly in five equal aliquots of 10 U each are recommended to achieve clinical effect.

Two clinical studies (by Trindade et al and Roche et al) have suggested that there may be a greater spread or diffusion (the so-called ‘action halo’) of Dysport^® from the site of injection compared with Botox^®, especially when dosed appropriately for efficacy. However, two other studies by Kranz et al and by Carli et al, in mice and human skin models respectively, suggest that at equal unit doses (i.e. 20 U Botox^® compared with 20 U Dysport^®), there is no difference in diffusion characteristics or spread. Spread is likely to increase as the unit dose increases. As a larger number of units of Dysport^® are required for a similar clinical effect compared with Botox^®, the spread of effect may be larger. The onset of action of Dysport^® may be 1–2 days earlier, but Nestor et al found both products to have similar efficacy.

Xeomin^® (incobotulinumtoxinA) (Fig. 12.6)

Xeomin^® (Merz Pharmaceuticals, Frankfurt, Germany) is a recently approved botulinum toxin type A that is reportedly devoid of the complexing proteins that naturally encapsulate the 150 kDa active portion of the botulinum toxin A molecule. Xeomin^® is available in 50 and 100 U per vial, the same as Botox^®. Studies by Dressler and colleagues have shown that the potency of Xeomin^® and Botox^® is equivalent, and that conversion of doses may be performed in a 1 : 1 ratio; when five unexpired batches of onabotulinumtoxinA (Botox^®) and incobotulinumtoxinA (Xeomin^®) were compared in batch release assay, statistical analyses failed to detect differences in the potency labeling of the two products. Sattler et al demonstrated that Xeomin^® is not inferior to Botox^® in the treatment of glabellar rhytides with a dose of 24 U of either product in 381 patients. Hunt & Clarke performed other potency assays, comparing the potency of a 100 U vial of Xeomin^® with Botox^® by injecting mice intraperitoneally and recording percentage mortality across dilutions; the potency of Xeomin^® recorded was substantially lower than that of Botox^®. This study implied that, at the same dilutions, slightly higher doses of Xeomin^® may be required compared with Botox^® to achieve the same effect. Further studies are warranted.

Figure 12.6 IncobotulinumtoxinA (A) Before: at rest and (B) during contraction. (C) After: at rest and (D) during contraction.

Reproduced with permission of Medicis Pharmaceutical Corporation. ©2012 Medicis Pharmaceutical Corporation. All rights reserved.

A more recent multicenter, randomized, double-blind study by Moers-Carpi and colleagues to evaluate the efficacy of 20 U of onabotulinumtoxinA (Vistabel^®, the European brand of Botox^®) in the treatment of glabellar lines, compared with 30 U of incobotulinumtoxinA (Bocouture, the European version of Xeomin^®), showed that 20 U of onabotulinumtoxinA are as effective as 30 U of incobotulinumtoxinA in reducing severity of glabellar lines 28 days post-injection; it also demonstrated a trend in favor of onabotulinumtoxinA at days 84, 98, and 112. This study reinforces the fact that dosages of onabotulinumtoxinA and incobotulinumtoxinA are not interchangeable.

Myobloc^® (rimabotulinumtoxinB)

Unlike Botox^®, Dysport^®, and Xeomin^®, which are derived from type A strains of botulinum toxin, Myobloc^® (Soltice Neurosciences, South San Francisco, CA) is derived from botulinum toxin type B. This type cleaves synaptobrevin (or VAMP, vesicle-associated membrane complex) rather than SNAP-25 of the SNARE complex to prevent acetylcholine release and thus muscle contraction. Myobloc^® at a dose of 2500 U was shown by Alster & Lupton to be effective in the treatment of glabellar rhytides, particularly in those who showed decreased or negligible clinical effect to botulinum toxin type A. However, the duration of effect was shorter (2–3 months). Myobloc^® is currently FDA approved only for cervical dystonia. (Table 12.1 and Fig. 12.7)

Table 12.1 Optimal dosing for glabellar injection of botulinum toxin in women, by brand, in the United States

Type	Units*
Botox® (Allergan)†	20
Dysport (Ipsen Biopharm)†	50
Xeomin® (Merz Pharmaceuticals)†	20
Myobloc® (Soltice Neurosciences)	2500

^* Doses are based on published studies with standard dilution of the product recommended by the manufacturer.

^† Botox^®, Dysport^®, and Xeomin^® are the only forms of botulinum toxin that are currently FDA-approved for glabellar injection (see Fig. 13.6).

Figure 12.7 The three FDA-approved brands of botulinum toxin A approved for treatment of glabellar rhytides. From left to right: incobotulinumtoxinA (Xeomin^®, Merz Pharmaceuticals), abobotulinumtoxinA (Dysport, Ipsen Biopharm), onabotulinumtoxinA (Botox, Allergan).

Special considerations

Potential adverse events

The most common adverse events from botulinum toxin injection of the glabella are mild, and include temporary pain at the injection sites, edema, bruise, headache, eyebrow ptosis, and upper eyelid ptosis.

In the first multicenter, double-blind, randomized, placebo-controlled trials of the safety of botulinum toxin type A in the treatment of glabellar lines, performed by Carruthers and colleagues in 2002, out of the 264 patients studied (BoNT-A 203, placebo 61), 5.4% (11/203) had mild blepharoptosis in the BoNT-A group, which had resolved by day 120. The group’s second multicenter randomized trial for safety and efficacy, published 1 year later, showed that in 273 patients (BoNT-A 202, placebo 71) the most common adverse event was headache (BoNT-A 11%, placebo 20%). In this study the incidence of blepharoptosis was 1% (2/202) for the botulinum toxin group. The incidence of blepharoptosis decreased with subsequent treatments in a 1-year follow-up study of the two trials where botulinum toxin was administered to glabellar rhytides at day one and then at two subsequent treatments 4 months apart.

A meta-analysis by Brin et al of the safety and tolerability of onabotulinumtoxinA, from global clinical studies in 1678 participants, demonstrated that the only adverse events with significantly greater incidence in the onabotulinumtoxinA group compared with placebo were eyelid sensory disorder (2.5% versus 0.3%, p = 0.004; verbatim phrases ‘tight’, ‘pressured’, ‘heavy’, ‘drooping feeling’, ‘feeling of droopiness’), and eyelid ptosis (1.8% versus 0%, p = 0.02), both present only in glabellar studies. Eyelid sensory disorder was more common in Asian patients. Both adverse events decreased with subsequent treatment cycles. Interestingly, acne, injection site pruritus, oral herpes, rash, lower respiratory tract infection, dental caries, and eye pain were significantly more common in placebo controls than in the onabotulinumtoxinA-treated patients.

Botulinum toxin-induced lid ptosis can manifest within 48 hours or as late as a week after injection, and can last for weeks. Vartanian & Dayan found that it typically resolves within 2–6 weeks.

Apraclonidine 0.5% (Iopidine^®, Alcon Labs, Fort Worth, Texas), naphazoline (Naphcon-A^®, Alcon Labs) and phenylephrine 2.5% (Mydfrin^® 2.5%, Alcon Labs) are alpha-adrenergic agonist ophthalmic eye drops that may be used to correct eyelid ptosis as a result of botulinum toxin injection. The alpha-adrenergic agonist effect stimulates Müller’s muscle to help elevate the ptotic eyelid. Typical dosage is 2 drops, 2–3 times a day, until the ptosis is resolved. GaAs laser was also reported by Majlesi to improve upper eyelid ptosis as a result of botulinum toxin injection.

Conclusion

Botulinum toxin injection of the glabella is a safe and proven treatment for glabellar rhytides and may also provide eyebrow elevation. Patient satisfaction with botulinum toxin type A treatment is consistently high and a review by Fagien & Carruthers of patient-reported outcomes indicated significant improvement, demonstrating that treatment significantly improves patient self-perceptions and reduced perceived age relative to current age by approximately 5 years.