Aesthetic studies for abobotulinum toxin (Dysport^®) by Rzany et al and Ascher et al followed a similar pattern to those performed for Botox^® by Allergan Inc. a few years earlier (reported by Carruthers et al in 2004). The first European studies for aesthetic usage of abobotulinum toxin (Dysport^®) were performed by Ascher and colleagues in the later 90s, and these were followed by Ascher and Rzany in 2004 and 2006. A ‘dose-finding’ study by Vandenbergh & Lison was first performed on 119 patients using placebo, 25, 50, and 75 s.U in a double-blinded control. The subjects were measured for efficacy as a responder at 1 month and then assessed for safety and duration. A responder rate of over 80% was found for all three groups and at 6 months two-thirds of the treated patients were still responders. There was a favorable safety profile of 7% mild adverse events, with headache the most common. There were no reported cases of blepharoptosis or diplopia. The result suggested 50 units was the optimal dosage for the glabella with 10 units injected into each of five glabellar sites.

This was followed by the US studies beginning in 2003 and extending to the present day. The Inamed, Ipsen, and Medicis studies included Phase II dose-ranging and Phase III single and repeat dosage studies with a total of 2300 patients assessed for efficacy and safety. All studies evaluated efficacy and safety of glabellar frown lines with rating scales at rest and at maximal frown. The US studies used the same injection points as the US onabotA trials and were evaluated at maximal frown as the end points. In Europe, end points for response were determined at rest for efficacy and the lateral corrugator injection points were placed centimeter more medially. The results, though, for efficacy and safety were similar for both studies.

Phase II trials involved a dosage-ranging study including placebo, 20 units, 50 units, and 75 units. There was a 90% responder rate at both 50 s.U and 75 s.U. All doses were well tolerated with only minor side effects including headache, needle pricks, and bruising, but blepharoptosis was observed in only three patients. Of those reported cases, only one demonstrated to the investigator a true clinical ptosis. Ptosis had been reported in other product studies but not in other studies involving abobotA (as reported by Kessler et al).

Neutralizing antibody production has always been of concern with clinical usage of BoNT-A. This has been considered a main cause for ‘non-response’ in patients after injection. In 2003 this was studied by Carruthers and colleagues in patients with cervical dystonia. None of the patients in this study showed any evidence of neutralizing antibodies either at baseline or on follow-up evaluations. From these observations, the 50-unit dosage was recommended as the optimal dose for safety and efficacy. The lower dosage of 50 units was chosen for all of the Phase III trials, as reported by Monheit and colleagues. Later, the large Phase III trials by Lawrence & Moy for abobotA examined the potential for antibody generation in patients from up to 9 injection cycles; none was detected in 1200 patients. At present, the rate of antibody formation in patients treated aesthetically during many years and multiple cycles is estimated to be less than 1 in a million patients, based upon all case reports for all such patients and for all products worldwide since aesthetic treatments began (Pickett, data on file).

In 2004 the initial single-dosage, placebo-controlled, double-blinded, randomized trial by Carruthers and colleagues, of glabellar frown lines for FDA Phase III studies, included over 400 subjects followed for 150 days. The patients were then enrolled in a repeat dosage trial for 23 months including four cycles of repeat dosage when the patient’s frown lines returned to baseline. The patients were evaluated for efficacy (i.e. number of responders at 30 days and duration of response) and safety. In 2009 Ascher and co-workers reported that over 90% responder rate was recorded at 30 days, at a duration of 4 months there were 40% responders, and at 5 months 25% were still full responders. This produced a very similar efficacy case for responders and duration as onabotA.

One factor reported by the subjects was an onset of action within 1–2 days. Subsequent studies by Monheit & Cohen have included a diary that the patient recorded when an onset of effect was first noted. In three of the studies the onset was recorded; 50% of subjects noted an onset within 2 days and 80% noted it within 3 days. Re-injection treatment studies were performed to ensure that repeated exposure to the toxin did not influence efficacy or duration. But later data now available indicate a very fast response for abobotA: within a day for the initial onset as studied in a frontalis model by Nestor & Ablon.

The repeat administration studies involved 768 individuals from Phase III clinical trials who received up to six repeated treatments over 17 months. A patient was re-injected when glabellar wrinkle lines returned to baseline. The patients were followed for efficacy and safety including adverse effects and assessment of serum-neutralizing antibodies to abobotA. Results confirmed continued effectiveness throughout the study with no increase of active events and no patients developing neutralizing antibodies.

As the data of these initial trials were reviewed it was noted that efficacy and duration of action for men was less than that for women on a 50 s.U dosage for treating the glabella. This observation stimulated a variable-dose study which stratified patients by race / ethnicity, sex and randomized by muscle mass. The muscle mass groups were to receive a single treatment of various doses of abobotA, which was administered as a single dose of 50, 60, or 70 s.U for women and 60, 70, or 80 s.U for men based on glabellar muscle mass. This is based on procerus / corrugator muscle mass – small, medium, or large – and was determined by the observation of an active frown, noted individual muscle bulging, length of the infrabrow space, and brow depression. Efficacy and duration were evaluated during a 5-month period. The results, reported by Rubin et al and Kane et al, indicated that 87% of men and women had full efficacy at 30 days with a mean duration of 109 days for both men and women with no difference in ethnicity or gender. Duration of action was found to be increased with the greater doses for larger muscle mass. Though clinicians have individualized abobotA glabellar treatment as to sex, ethnicity, and muscle mass in clinical practice, this is the first controlled clinical study to verify this common practice.

AbobotA has been used worldwide for aesthetic needs for over 10 years. Both glabella and crow’s feet have been well studied by Ascher with results comparable to onabotA. AbobotA has been used in clinical cosmetic practice worldwide over the last 10 years with similar injection points and techniques as onabotA, but with different dosages. An international consensus conference held in Paris in January 2009 provided general guidelines for effective and safe use of abobotA on the generally useful yet off-label sites for injection, as reported by Ascher and colleagues. These have included the common upper face sites: the glabella, forehead, brow, crows’ feet, and eyelid; and other less common facial sites including: bunny lines, depressor anguli oris, orbicularis oris, mentalis, and platysma. These recommendations gave guidelines to beginning dosage and range for each site (see Table 5.1) as well as injection points and technique.

Table 5.1 Recommended Dysport^® dosages for the upper face

Indications	Total usual dose (Dysport^® / Speywood units)	Dose range (Dysport^® / Speywood units)
Glabella	50	30–70
Forehead	40–50	40–70
Crows’ feet	30 × 2	20–50 × 2
Lateral eyebrow lift	20 × 2	20–40 × 2
Glabella and forehead	90–100	70–140
Glabella and lateral eyebrow lift	90	50–110
Complete upper third face	150	110–240

Treatment of the upper face

The site-specific dosage recommendations for the upper face are shown in Table 5.1.

Glabellar lines

Injection of the glabella is the original and by far most common cosmetic usage of BoNT-A. The standard 5-injection-point approach is appropriate for most patients with two injections in each corrugator and one injection in the procerus as shown in Figure 5.1. The procerus and medial corrugators are injected deeply and directly into the bodies of the muscles, which are easily identified at maximal frown in most patients. The lateral corrugators and orbicularis oculi muscle fibers are injected more superficially as it inserts into the dermis medial to the mid-pupillary line. All injections should be 1.0 cm (approximately one finger-breadth) above the orbital rim to limit the risk of eyelid ptosis from the spread of toxin (at the time of injection) to the levator palpebrae muscle. The measurement should be made from the orbital rim and not from the brow itself as a dropped brow may mislead the physician to inject the toxin below the orbital rim. Injecting too high on the forehead – above 1 cm. at the lateral glabellar site – can also cause ptosis in those individual who recruit eyelid and eyebrow elevation from the frontalis muscle.

Figure 5.1 Injection sites for glabellar line treatment: blue dots = corrugator insertion / orbicularis oculi fibers; yellow dots = corrugator body; green dot = procerus.

The standard total dose of abobotA has been shown to be 50 s.U in women and those with small to medium muscle mass, divided evenly among the five injection points. As always, doses must be adjusted for the strength of individual muscles and the patient’s desired outcome. The author (GM) does use a higher dose of toxin in men and may add two additional injection points at the mid-pupillary line in those with bulky corrugators. The dose range is from 50 s.U to 80 s.U depending on muscle mass.

Forehead lines

For the off-label usage of forehead lines, BoNT-A provides excellent smoothing of forehead rhytides. However, the more severe forms of forehead wrinkles cannot be corrected by BoNT-A denervation alone and may need soft tissue augmentation or surgery.

The goal for the treatment of forehead wrinkles is to soften the undesirable lines without causing brow ptosis or eliminating all expressiveness on the upper face. A conservative approach is preferred, as most patients do not want a ‘frozen face’. The patient is asked to forcefully raise his / her eyebrows and the strength of the frontalis is assessed. Any discrepancy in brow position at baseline and at maximal contraction is noted and brought to the attention of the patient. It is especially important to note brow asymmetry, photograph it and bring it to the patient’s attention prior to treatment.

It is important to evaluate the significance of brow position in relationship to the frontalis, a brow elevator. Very conservative forehead treatment is given to those who use the frontalis to maintain normal brow position.

The author commonly uses a V-shaped configuration for injections in women (Fig. 5.2). While often desirable in females, this should be avoided in male patients. This approach can also produce an excessively arched brow (the mephisto sign or ‘Mr Spock look’). This is prevented with a high lateral forehead injection above the tail of the brow. If an excessive arched brow occurs, it can be corrected with a small dose of additional toxin 1–2 cm superior to the apex of the arched brow.

Figure 5.2 Multiple steps in the mechanism of action of botulinum toxin type A: (1) The 150 kDa core neurotoxin is internalized into the neuron via a process of endocytosis. (2) The endosome is acidified, which facilitates (3) the translocation of the light chain into the neuronal cytosol. (4) Once in the neuronal cytosol the light chain of type A botulinum toxin (yellow) cleaves the membrane-associated SNAP-25 (brown), one component of the SNARE complex. Another neurotoxin serotype, type B, botulinum toxin cleaves a different protein known as synaptobrevin or vesicle-associated membrane protein (VAMP; green).

Unless no significant glabellar lines are present, the author commonly injects the glabella simultaneously whenever treating forehead wrinkles. This generally produces better overall aesthetic results and the concomitant paralysis of the brow depressors reduces the incidence of brow ptosis.

Lateral eyebrow lift

Brow position is influenced by the elevator muscles (forehead) and depressor muscles (glabellar complex and orbicularis). The paresis of muscles of facial expression not only smoothes dynamic wrinkles but can also influence the resting position of various facial elements. This property has been successfully exploited to lift the eyebrow, correcting mild brow ptosis, restoring a youthful brow arch, and giving the eye a more ‘open’ appearance.

The vertical fibers of the lateral orbicularis oculi function to depress the lateral brow. When injected at the tail of the brow the lateral brow will be elevated. For this chemical brow lift, the author typically injects 10 s.U of abobotA intradermally at the lateral tail of the eyebrow 5–7 mm superolateral to the orbital rim (Fig. 5.3A). If performed only for brow lift and not to correct frown lines, an additional 5–10 s.U are injected into each corrugator body. In combination with medial and central frontalis denervation, which tends to lower the medial brow, a pleasingly arched female pattern eyebrow can be shaped (Fig. 5.3B).

Figure 5.3 The chemical brow lift: (A) Injection sites for a chemical brow lift if performed alone are shown (5–10 s.U or 3–5 B.U per injection site). This patient had a male pattern eyebrow without perceptible arching. She received abobotA treatment to the lateral tail of each eyebrow (10 s.U per side) and into the corrugator bodies (total 20 s.U) (blue dots), and to the frontalis (20 s.U). (B) Post-treatment photo at 33 days reveals an elevated and laterally arched feminine brow.

Crow’s feet

Lateral periorbital wrinkling is effectively treated with neurotoxin. Crow’s feet are typically treated with three equal injections of 10–15 s.U evenly spaced along an arc at the external orbital rim (Fig. 5.4A, B). The middle injection is placed in line with the lateral canthus. Injections flanking this point at 8–10 mm are then placed, but their exact positioning depends on the width of the individual’s canthal lines.

Figure 5.4 Crow’s feet injection: the standard 3-point crow’s feet injection is depicted in (A). This patient received 5 B.U at each point and had an excellent response (B).

An additional 2 s.U microinjection can be judiciously placed in the lower lid at the mid-pupillary line 2 mm below the tarsal plate (Fig. 5.5). This will flatten the bulging muscle and create an image of an ‘open eye’. Overaggressive treatment may, though, create an unwanted ectropion.

Figure 5.5 Location of lower palpebral injection: a tiny dose of toxin into the lower eyelid can create a more youthful, ‘open’ eye (2 s.U or 0.5–1 B.U).

Treatment of the lower face

Treatment of the lower face should be performed with more precaution as over-dosage leads to significant dysfunction of the orbicularis oris, creating an asymmetric smile and oral aperture. Dosage recommendations in the lower face are shown in Table 5.2. As with onabotA treatment, the physician must have a thorough understanding of facial musculature. This is especially important in the lower face as injections in or near many perioral muscles can cause facial asymmetry with expression. Because the field of effect may be influenced by volume, one may consider the 1.5 mL reconstitution is recommended to limit abobotA effect to the muscles injected.

Table 5.2 Recommended Dysport^® dosages for the lower face

Indications	Total usual dose (Dysport^® / Speywood units)	Dose range (Dysport^® / Speywood units)
Obicularis oris	2.5 per injection point	10–15 units total
Depressor angularis oris	5–10 units per site	10–20 units
Mentalis	5–10 units per site	10–20 units
Platysma	5–10 units per injection point	20–40 units Maximum total dosage 50/side